86 Medicographia

Vol 28, No. 1, 2006

ISSN 0243-3397

I S S U E

E merging T rends in the D iagnosis and T reatment of O steoporosis

J. A. KANIS, UNITED KINGDOM EDITORIAL OSTEOPOROSIS: TAKING ACCOUNT OF RISK FACTORS
AND QUALITY OF LIFE

OSTOPOROSE : PRISE EN COMPTE DES FACTEURS

DE RISQUE ET DE LA QUALIT DE VIE

O. JOHNELL, SWEDEN

RISK FACTORS FOR OSTEOPOROSIS:

AN EPIDEMIOLOGICAL OVERVIEW

C. COOPER, UNITED KINGDOM, AND S. GELBACH, USA

IDENTIFICATION OF PATIENTS IN NEED OF

ANTIOSTEOPOROTIC TREATMENT: WHO TO TREAT TODAY?

13

S. ADAMI, ITALY

WHO WILL MANAGE THE DIAGNOSIS AND

TREATMENT OF OSTEOPOROSIS?

21

R. G. JOSSE AND S. A. JAMAL, CANADA

RISK FACTORS FOR OSTEOPOROSIS: USE OF BONE

MINERAL DENSITY IN GUIDING TREATMENT DECISION

27

E. MCCLOSKEY, UNITED KINGDOM A journal of medical information and international communication from Servier

HEALTH-RELATED QUALITY OF LIFE

IN OSTEOPOROSIS

33

B. JNSSON, SWEDEN

RISK FACTORS AND PHARMACOECONOMIC

CONSEQUENCES

40

Contents continued overleaf...

Vol 28, No. 1, 2006

Medicographia
I S S U E

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...Contents continued from cover page

E merging T rends in the D iagnosis and T reatment of O steoporosis

Medicographia a Servier publication Editor in Chief: Jean-Philippe Seta, MD Editorial Board: Laurence Alliot, PharmD; Christophe Charpentier, MD; William Gaussens, PharmD; Yves Langourieux, PhD; Didier Mochon, PharmD; Antoine Moukheiber, BSc Ph; Pascal Poullali, MA; Frdric Sesini, PharmD Publisher: Laurence Alliot, PharmD Production Manager: Noelle Gunot Medical Publications Editor: David Mason, MD Production Editor: Iain Matheson, MB ChB Editorial Assistant: Judit Siklosi Design & Layout: Myriam Bucquoit and Bernard Crespin Medicographia is published 4 times a year and circulated throughout the world, in Africa, the Americas, Asia, Australasia, and Europe, by Les Laboratoires Servier 22, rue Garnier 92578 Neuilly sur Seine Cedex France, and printed by Imprimerie Kapp Lahure Jombart, rue de lIndustrie Z.I. N1 27025 Evreux Cedex Printed in France Directeur de la Publication: Jean-Philippe Seta, MD

G. JONES, AUSTRALIA / CONTROVERSIAL QUESTION Y. GOKCE-KUTSAL, TUR- IS ULTRASOUND A USEFUL METHOD FOR THE KEY / J. F. CHEN, TAIWAN / DIAGNOSIS OF OSTEOPOROSIS? H. M. ZHU, CHINA / W. PLUSKIEWICZ, POLAND / H. P. DIMAI, AUSTRIA / A. DEZ-PEREZ, SPAIN / J. A. MELO-GOMES, PORTUGAL PROTELOS PROTELOS, THE FIRST DUAL-ACTION BONE AGENT
FOR THE TREATMENT OF POSTMENOPAUSAL OSTEOPOROSIS

45

V. LEBLANC, FRANCE

55

B. CORTET, FRANCE

INTERVIEW DO RISK FACTOR PROFILES FOR OSTEOPOROTIC FRACTURES DIFFER IN WOMEN AND MEN? FOCUS MUSCULOSKELETAL REHABILITATION IN
POSTMENOPAUSAL OSTEOPOROSIS

63

S. BOONEN, BELGIUM
2006 by Les Laboratoires Servier All rights reserved throughout the world and in all languages. No part of this publication may be reproduced, transmitted, or stored in any form or by any means either mechanical or electronic, including photocopying, recording, or through an information storage and retrieval system, without the written permission of the copyright holder. Opinions expressed do not necessarily reflect the views of the publishers, editors, or editorial board. The authors, editors, and publishers cannot be held responsible for errors or for any consequences arising from the use of the information contained in this journal. Address for correspondence: Servier International / Medical Publishing Division 192, avenue Charles de Gaulle, 92578 Neuilly sur Seine Cedex France Tel. + 33 1 55 72 60 00 / Fax 68 88

66

G. BOIVIN AND P. J. MEUNIER, FRANCE

UPDATE DETERMINANTS OF BONE QUALITY

72

C. RGNIER, FRANCE I. SPAAK, FRANCE

A TOUCH OF FRANCE FRENCH MEDICINE IN RUSSIA. A TALE OF PASSION A TOUCH OF FRANCE WHEN RUSSIA SPOKE FRENCH

78 88

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MEDICOGRAPHIA, VOL 28, No. 1, 2006

D I T O R I A L

Osteoporosis: taking account of risk factors and quality of life

by J. A. Kanis, United Kingdom

John A. KANIS, MD WHO Collaborating Center University of Sheffield Medical School, Sheffield UNITED KINGDOM

Address for correspondence: Prof John A. Kanis, MD, WHO Collaborating Center, University of Sheffield Medical School, Beech Hill Road, Sheffield S10 2RX, UK (e-mail: w.j.pontefract@sheffield. ac.uk)

Medicographia. 2006;28:3-8.

HERE IS NOW AN INCREASING ARRAY OF PHARMACOLOGICAL interventions that have been shown to decrease the risk of fractures in patients with osteoporosis. These developments, together with the increasing prevalence and awareness of osteoporosis, pose many challenges in the management of osteoporosis. Not least is the question of whom to treat. In other words, how do we identify patients in whom the risk of fracture is sufficiently high that treatment is warranted, and conversely, patients in whom treatment is best avoided. These difficult issues are addressed in this issue of Medicographia. The clinical significance of osteoporosis resides in the fractures that arise, with their attendant morbidity and mortality. The common osteoporotic fractures include those at the spine, forearm, hip, and proximal humerus, and are a major cause of morbidity, particularly in the Western world. At the age of 50 years, the remaining lifetime risk of an osteoporotic fracture exceeds 50% (see Cooper and Gehlbach; this volume), and fractures particularly at the spine and hip are a very significant cause of morbidity with long-term consequences on quality of life (see McCloskey; this volume). Unfortunately, the disorder crosses many disciplines of medicine with the result that neither the treatment nor prevention of fracture is optimally managed (see Adami; this volume). From an operational point of view, osteoporosis has been defined in terms of low bone mineral density (BMD). Attention has focused, therefore, on the estimation of BMD to determine fracture risk and to direct interventions on this basis. Many population-based studies indicate that the risk of fracture increases by a factor of 1.5 to 3.0 for each standard deviation decrease in BMD (Josse and Jamal; this volume). The ability of BMD to predict fracture is comparable to the use of blood pressure to predict stroke, and significantly better than serum cholesterol to predict myocardial infarction. The highest gradient of risk is found at the hip to predict hip fracture where the gradient of risk is 2.6 (see Josse and Jamal; this volume). Thus, an individual with a T-score of --3 standard deviations (SD) at the hip would have a 2.63 (ie, greater than 15-fold) higher risk than an individual with a T-score of 0 SD. By contrast, the same T-score at the spine would yield a much lower risk estimateapproximately 4-fold increase (1.63). This emphasizes the importance of accuracy or gradient of risk in the categorization of fracture risk. Although bone mass is an important component of the risk of fracture, other abnormalities occur in the skeleton that contribute to fragility. These include the shape of bone, its microarchitecture, the ability to repair microdamage, and the material properties of bone such as the degree of mineralization (see Boivin and Meunier; this volume). In addition, a variety of nonskeletal factors such as the liability to fall and the force of impact contribute to fracture risk. It is evident, therefore, that the measurement of BMD is not a perfect strategy for identifying those who will fracture, since BMD represents but one component of a multifactorial causation. It is for this reason that there has been a great deal of interest in the identification of risk factors for fracture in addition to that provided by BMD.
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There are broadly two ways in which the identification of risk factors can be applied to clinical management. The first is to identify causally related risk factors that might be modified by intervention (see Boonen; Cooper and Gehlbach; this volume). A good example is the prevention of falls, since the majority of forearm and hip fractures arise from a fall. Although effective fall prevention strategies have been established in the elderly, as noted by Boonen in this volume, studies have so far failed to show an advantage of fall prevention programs for fracture risk. Efforts to reduce the impact of falls such as the use of hip protectors have also been met with limited success. Other potential modifiable risk factors include the level of physical activity, attention to nutritional factors, particularly calcium, vitamin D, and protein intake in the elderly, and the avoidance of tobacco and excess amounts of alcohol. Modification of lifestyle in this way assumes that the association between the risk factor and fracture is both causal and reversible by lifestyle advice. Such global policies could have a major impact on the burden of disease, but have not been formally tested. A second use of risk factors is in case-finding to identify individuals at particularly high risk for future fractures (see Johnell; this volume). The risk factors themselves do not necessarily need to be causally related to the fracture nor necessarily reversible, but they should identify a risk that is amenable to intervention. An example is provided by a history of prior fragility fractures, which is a strong risk factor for further fractures. Clinical trials have shown that patients recruited on the basis of a prior vertebral fracture can benefit from a pharmacological intervention. The risk factors used in case-finding vary according to different practice guidelines, but include a family history of fragility fracture, a previous fragility fracture, low body mass index, and the long-term use of corticosteroids (Josse and Jamal, this volume). Patients so identified are referred for BMD measurements and intervention offered if BMD falls below a given threshold. Current guidelines in Europe suggest that intervention should be considered in those individuals subsequently shown to have osteoporosis (ie, a T-score of --2.5 SD or less). In North America, a less stringent threshold (--2.0 SD) is recommended in the absence of significant risk factors and --1.5 SD in the presence of risk factors. Despite these differences, both strategies direct intervention on the basis of BMD. A major problem with this approach is that the majority of fractures will occur in that segment of the population considered to be at low risk. In other words, the sensitivity or detection rate of the test (BMD) is low, even at relatively high specificities. Because of the limitations of BMD tests alone there has been a great deal of interest in the identification of risk factors that might give prognostic information on their own or in conjunction with BMD. Several algorithms have been devised to predict osteoporosis, for example the, osteoporosis self-assessment tool. The algorithm is derived simply from weight and age and can be used to predict the likelihood of a diagnosis of osteoporosis. This algorithm, and others like it, have a high sensitivity (detection rate) for the prediction of osteoporosis, but poor specificity (Josse and Jamal; this volume). The high sensitivity provides opportunities for cost savings by excluding patients who do not need a BMD test. The use of such tests does not, however, help in the more accurate identification of individuals at high risk, since it ultimately depends on the use of BMD. The performance characteristics of assessment algorithms can, however, be improved by the concurrent consideration of risk factors that operate independently of BMD. Perhaps the best example is age. The same T-score with the same technique at any one site has a different significance at different ages. At the threshold for osteoporosis (T-score =--2.5 SD) the probability of hip fracture varies more than 5-fold between the ages of 50 and 80 years. Thus, the consideration of age and BMD together increases the range of risk that can be identified. In addition, there are a large number of other risk factors that provide information on fracture risk independently of both age and BMD. The risk factors that have been best characterized on an international basis include: prior fragility fracture; family history of hip fracture; smoking; chronic use of glucocorticoids; high intakes of alcohol; and rheumatoid arthritis. The integration of the information provided by these risk factors improves the performance of the test. In other words, the gradient of risk is improved, which increases the detection rate without trading off specificity. Thus, more individuals above a threshold risk can be identified. The ability to integrate risk factors with BMD poses some problems in the units of risk to be used. The T-score becomes of little value and, although the use of relative risks is feasible, they can be misleading for patients and physicians alike. The metric best suited is absolute risk or probability of fracture (see Cooper and Gehlbach; this volume). The fracture probability depends on age and life expectancy as well as the current relative risk. Estimates of lifetime risk are of value in considering the burden of osteoporosis in the community, but are less relevant for assess4 MEDICOGRAPHIA, VOL 28, No. 1, 2006
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ing risk of individuals in whom treatment might be envisaged, so that the International Osteoporosis Foundation (IOF) and the World Health Organization (WHO) recommend that risk of fracture should be expressed as the probability over a 10-year interval. The major advantage of using absolute probability is that it standardizes the output from the multiple techniques available for assessing risk. The more accurate identification of fracture probability demands the question as to when is the probability unacceptably high so that intervention should be offered. This is a complex question that depends upon local circumstances including the risk of fracture and death and willingness to pay for treatment. In many countries, treatment of osteoporosis has to compete with other health care priorities, which are usually based on health economic arguments, as outlined by Jnsson, in this volume. Assessments that can be used include the cost per life-year saved, the cost per fracture averted, or the cost per quality of life year gained (quality-adjusted life-year, QALY). The cost per life-year gained is problematic in those disorders that are not fatal, but cause a high degree of morbidity. Assessment of the cost per fracture averted is also problematic because of the multiple outcomes in osteoporosis. Thus, the significance of averting a forearm fracture is quite different from that of preventing a hip fracture. For this reason, the favored approach has been to integrate life-years lost with quality of life. Quality of life is graded on the scale of 0 (death) to 1 (perfect health). The strength of this approach is that it allows comparisons across disease states so that priorities can be made. In the UK, for example, a treatment that costs 30 000/QALY is considered to be cost-effective. Using this criterion, a 10-year hip fracture probability of 10% or more provides a cost-effective threshold for women in Sweden. When account is taken of other fractures, the threshold for hip fracture probability at which interventions become cost-effective decreases, particularly in younger individuals. The contributions in this volume highlight the multifactorial nature of osteoporosis, and our inability to perfectly discriminate who will and who will not fracture. There is a growing appreciation that risk factors other than BMD can contribute independently to fracture risk and that their use with BMD can more optimally direct interventions to those most at need and, as importantly, avoid unnecessary treatment in those at low risk. The formalization of algorithms to predict osteoporosis poses a challenge for the development of future practice guidelines.

Keywords: osteoporosis; quality of life; risk factor; bone mineral density; treatment; guideline

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MEDICOGRAPHIA, VOL 28, No. 1, 2006

I T O R I A L

Ostoporose : prise en compte des facteurs de risque et de la qualit de vie

par J. A. Kanis, Royaume-Uni

ES TRAITEMENTS PHARMACOLOGIQUES CAPABLES DE RDUIRE le risque fracturaire chez les patientes ostoporotiques sont maintenant de plus en plus nombreux. Cette volution, tout comme la prvalence grandissante de lostoporose et la prise de conscience accrue de cette maladie, soulvent de nombreux dfis dans la prise en charge de lostoporose, dont la question du qui traiter nest pas le moindre. Autrement dit, comment pouvonsnous identifier les patientes pour lesquelles le risque de fracture est suffisamment important pour justifier le traitement, et inversement, les patientes pour lesquelles il est prfrable ne pas traiter. Ces questions difficiles sont abordes dans le numro prsent de Medicographia. Cest la survenue de fractures et leurs consquences en termes de morbidit et de mortalit qui font toute la gravit de lostoporose sur le plan clinique. Les fractures ostoporotiques communes comprennent celles du rachis, de lavant-bras, de la hanche et de lhumrus proximal et constituent une des causes principales de morbidit, en particulier dans le monde occidental. lge de 50 ans, le risque de fracture ostoporotique au cours de la vie restante est suprieur 50 % (voir larticle de Cooper et Gehlbach) et les fractures, en particulier du rachis et de la hanche, sont une cause trs significative de morbidit avec des consquences long terme sur la qualit de vie (voir larticle de McCloskey). Malheureusement, cette pathologie se situe au carrefour de nombreuses spcialits mdicales, avec comme consquence que ni le traitement ni la prvention des fractures ne sont pris en charge de faon optimale (voir larticle dAdami). Dun point de vue oprationnel, lostoporose a t dfinie en termes de densit minrale osseuse basse (DMO). Lattention sest donc porte sur lestimation de la DMO pour dterminer le risque de fracture et prescrire un traitement en fonction des valeurs releves. De nombreuses tudes de populations montrent que le risque de fracture est multipli par 1,5 3,0 pour chaque diminution dune dviation standard de la DMO (voir larticle de Josse et Jamal). La fiabilit de la DMO pour prvoir une fracture est comparable celle de la pression artrielle pour prvoir un accident vasculaire crbral et significativement meilleure que celle de la cholestrolmie pour prvoir un infarctus du myocarde. Le gradient de risque le plus lev pour prvoir une fracture soit 2,6 est retrouv la hanche (voir larticle de Josse et Jamal). Ainsi, un individu avec un T-score de --3 dviations standard (DS) la hanche devrait avoir un risque suprieur ou gal 2,6 3 soit 15 fois plus important quun individu avec un T-score de 0 DS. loppos, le mme T-score au niveau du rachis devrait donner une estimation du risque beaucoup plus basse augmentation denviron 4 fois (1,6 3). Ceci renforce limportance de lexactitude ou du gradient de risque dans la classification du risque de fracture. Bien que la masse osseuse soit un lment important du risque fracturaire, il existe dautres anomalies du squelette qui contribuent sa fragilit. Celles-ci comprennent la forme de los, sa microarchitecture, la possibilit de rparer les microlsions et les proprits matrielles de los comme le degr de minralisation (voir larticle de Boivin et Meunier). De plus, plusieurs fac6 MEDICOGRAPHIA, VOL 28, No. 1, 2006
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teurs indpendants de ceux du squelette, tels que la prdisposition la chute et la force du choc, contribuent au risque de fracture. La mesure de la DMO nest donc pas la stratgie idale pour identifier les sujets qui auront une fracture, puisquelle ne reprsente quun seul des aspects dune causalit multifactorielle. Cest pourquoi lidentification des facteurs de risque de fracture autres que ceux fournis par la DMO a suscit un grand intrt. Il y a grossirement deux faons dappliquer lidentification des facteurs de risque la prise en charge clinique. La premire est didentifier les facteurs de risque qui peuvent tre modifis par un traitement (voir larticle de Boonen et celui de Cooper et Gehlbach). La prvention des chutes en est un bon exemple, puisque la majorit des fractures de lavant-bras et de la hanche est due des chutes. Cependant, malgr lefficacit des techniques de prvention des chutes mises en place chez les personnes ges, comme lindique Boonen dans ce numro, les tudes nont jamais russi montrer un bnfice des programmes de prvention de ces chutes dans le risque de fracture. Les efforts pour rduire limpact des chutes, tels que lutilisation de protecteurs de hanche, ont galement rencontr un succs limit. Le niveau dactivit physique, lattention porte aux facteurs nutritionnels, en particulier la prise de calcium, de vitamine D et de protines chez les personnes ges, labstention de tabac et dexcs dalcool sont dautres facteurs de risque potentiellement modifiables. La modification du mode de vie dans ce sens implique que lassociation entre un facteur de risque donn et la fracture est la fois causale et rversible grce aux conseils sur le mode de vie. Une telle politique pourrait avoir un impact majeur sur le fardeau de la maladie, mais na pas t teste officiellement. Lidentification des sujets risque particulirement lev de futures fractures est une seconde faon dutiliser les facteurs de risque (voir larticle de Johnell). En eux-mmes, les facteurs de risque ne ncessitent pas obligatoirement dtre lis la fracture ni dtre obligatoirement rversibles, mais ils devraient identifier un risque qui relve dun traitement. Un antcdent de fracture de fragilit constitue un bon exemple de puissant facteur de risque pour des fractures ultrieures. Les tudes cliniques ont montr que les sujets recruts sur la base de fractures vertbrales antrieures peuvent tirer bnfice dun traitement pharmacologique. Les facteurs de risque utiliss varient selon les diffrents critres dfinis, mais en tout tat de cause doivent inclure les antcdents familiaux de fracture de fragilit, les fractures de fragilit antrieures, un indice de masse corporelle bas, et une corticothrapie prolonge (voir larticle de Josse et Jamal). Les sujets ainsi identifis sont alors orients pour des mesures de DMO et un traitement leur est propos si la DMO est en dessous dun certain seuil. Les recommandations europennes actuelles suggrent quil faut envisager un traitement chez les personnes pour lesquelles une ostoporose a t retrouve (p. ex. T-score de --2,5 DS ou moins). En Amrique du Nord, les seuils recommands sont moins svres, de --2,0 DS en absence de facteurs de risque significatifs et de --1,5 DS en prsence de facteurs de risque. Malgr ces diffrences, cest bien sur la base de la DMO que sont orientes ces deux stratgies de traitement. Le problme majeur de cette approche rside dans le fait que la majorit des fractures survient dans la tranche de la population considre faible risque. Autrement dit, la sensibilit ou le taux de prdiction du risque fracturaire par la DMO est faible, mme pour des niveaux de spcificit relativement levs. tant donn les limites des mesures de la DMO, lidentification des facteurs de risque qui peuvent donner une information pronostique, seule ou en association la DMO, a suscit un intrt marqu. Plusieurs algorithmes ont t conus pour prdire lostoporose, tels le questionnaire dautovaluation de lostoporose. Lalgorithme est simplement driv de la masse corporelle et de lge et peut tre utilis pour calculer la probabilit dun diagnostic dostoporose. Cet outil, et dautres comme lui, ont une haute sensibilit (taux de dtection) pour prdire lostoporose, mais une faible spcificit (voir larticle de Josse et Jamal). Cette sensibilit leve permet des conomies en excluant les sujets qui nont pas besoin de mesure de la DMO. Cependant, lutilisation de tels tests ne permet pas lidentification plus prcise des individus haut risque, puisque quelle dpend en en dfinitive de lutilisation de la DMO. La performance des algorithmes dvaluation peut cependant tre amliore par la prise en compte simultane des facteurs de risque indpendants de la DMO. Le meilleur exemple en est peut-tre lge. Le mme T-score mesur avec le mme appareil et quel que soit le site, prsente une signification diffrente selon lge. la valeur seuil pour lostoporose (T-score = --2,5 DS), la probabilit de fracture de hanche est multiplie par 5 entre 50 et 80 ans. La prise en compte simultane de lge et de la DMO accrot lintervalle de risque qui peut tre identifi. De nombreux autres facteurs de risque fournissent galement des renseignements sur les risques de fracture indpendants de lge et de la DMO. Les facteurs de risque les mieux dfiditorial Kanis

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nis sur des bases internationales sont les suivants : antcdents de fracture de fragilit ; antcdents familiaux de fracture de hanche ; tabagisme ; corticothrapie prolonge ; consommation leve dalcool ; et polyarthrite rhumatode. Lintgration des donnes fournies par ces facteurs de risque amliore la performance du test. Autrement dit, le gradient de risque est amlior, ce qui augmente le taux de dtection sans que cela soit au dtriment de la spcificit. Nous pouvons ainsi identifier un plus grand nombre de personnes situes au-del dun risque seuil. Lintgration des facteurs de risque la DMO pose quelques problmes en ce qui concerne les units de risque utiliser. Le T-score perd alors beaucoup de sa valeur et, bien que lutilisation du risque relatif soit possible, elle peut prter confusion pour les patientes comme pour les mdecins. Le risque absolu ou la probabilit de fracture (voir article de Cooper et Gehlbach) sont les mesures les mieux adaptes. La probabilit de fracture dpend de lge et de lesprance de vie comme du risque relatif du moment. Les estimations de risque sur la vie entire sont valables en ce qui concerne le poids de lostoporose pour la collectivit, mais moins pertinentes pour valuer le risque des individus chez lesquels il faut envisager un traitement. Cest pourquoi lInternational Osteoporosis Foundation (IOF) et lOrganisation Mondiale de la Sant (OMS) recommandent que le risque de fracture soit exprim sous forme de probabilit 10 ans. Largument majeur pour utiliser une probabilit absolue est quelle standardise le donnes issues de multiples moyens pour valuer les risques. Lidentification la plus exacte possible dune probabilit de fracture amne se poser la question suivante : partir de quand cette probabilit atteint-elle un seuil partir duquel on doit proposer un traitement ? Cette question complexe dpend des circonstances locales comme le risque de fracture et de dcs et lacceptation de payer pour un traitement. Dans de nombreux pays, le traitement de lostoporose entre en comptition avec dautres priorits de soins, ce qui fait gnralement intervenir des arguments conomiques de sant (cf. larticle de Jnsson). Les critres dvaluation qui peuvent tre utiliss sont : le cot par anne de vie gagne, le cot par fracture vite, ou le cot par anne de vie ajuste sur la qualit (quality-adjusted life-year, QALY). Le cot par anne de vie gagne est problmatique dans les pathologies qui ne sont pas fatales mais dont le degr de morbidit est lev. Lvaluation du cot par fracture vite est galement problmatique cause des multiples volutions de lostoporose. Ainsi, la prvention dune fracture de lavant-bras na pas la mme signification que la prvention dune fracture de hanche. Cest pourquoi on a privilgi lintgration des annes de vie perdues avec la qualit de vie. La qualit de vie est cote sur une chelle qui va de 0 (dcs) 1 (sant parfaite). La force de cette approche, cest quelle permet des comparaisons entre des tats pathologiques, dgageant ainsi des priorits. Par exemple, en Angleterre un traitement slevant 30 000 par QALY est considr comme rentable. Sur la base de ce critre, le seuil de rentabilit pour les femmes sudoises se situe un niveau de probabilit de 10 % ou plus pour une fracture de hanche 10 ans. Si lon prend en compte dautres fractures, le seuil de probabilit de fracture de hanche partir duquel les traitements deviennent rentables diminue, en particulier chez les sujets plus jeunes. Les auteurs ayant contribu ce numro de Medicographia soulignent la nature multifactorielle de lostoporose, et notre incapacit distinguer parfaitement qui fera ou ne fera pas de fracture. Lopinion se dgage de plus en plus que des facteurs de risque autres que la DMO peuvent contribuer de faon indpendante au risque de fracture et que leur utilisation avec la DMO peut orienter de faon plus optimale les traitements vers les malades qui en ont le plus besoin et, de faon tout aussi importante, viter un traitement non justifi chez les sujets faible risque. La mise au point dalgorithmes de prdiction de lostoporose constitue un dfi pour llaboration de futures recommandations pratiques.

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Olof JOHNELL, MD, PhD Professor, Lund University Department of Clinical Sciences Malm, SWEDEN

Risk factors for osteoporosis: an epidemiological overview

by O. Johnell, Sweden

isk factors for osteoporosis low bone mass have been investigated in several studies.1 The practical usefulness of current case-finding strategies has been to identify men and women with clinical risk factors and, based on these risk factors, select them for bone mineral density (BMD) measurement. If the BMD measurement showed a low value, usually a T-score <2.5, an intervention was indicated. Guidelines for the diagnosis and management of osteoporosis were drawn up by the European Foundation For Osteoporosis.2 Using this approach, clinical risk factors were identified that could provide an indication for the diagnostic use of bone densitometry, such as the presence of strong risk factors: estrogen deficiency, corticosteroid therapy, maternal family history of hip fracture, low body mass index (<19), other disorders associated with osteoporosis, radiographic

revious case-finding strategies for osteoporosis were based on identifying risk factors to justify bone mineral density (BMD) measurement. However, the clinical significance of osteoporosis is due to the fractures that occur. Therefore, identifying risk factors for fractures is important for casefinding strategies. Algorithms for identifying high-risk patients should be based on clinical risk factors, BMD, gender, and age. The risk factors for fractures should be validated in an international setting and in multiple populations, be adjusted for type of fractures, be readily assessable by primary care physicians, and contribute to a risk that is amenable to the therapeutic manipulation intended. Besides age, BMD, and gender, these risk factors are previous fractures, use of oral glucocorticoids, low body mass index, family history of fractures, smoking, high alcohol intake, and secondary osteoporosis. The intervention threshold should be based on absolute risk.
(see French abstract on page 12)

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Keywords: osteoporosis; risk factor; bone mineral density; absolute risk

evidence of osteopenia and/or vertebral deformity, previous fragility fractures (particularly hip, spine, or wrist), loss of height, and thoracic kyphosis. The National Osteoporosis Foundation (NOF) presented their Physicians Guide to Prevention and Treatment of Osteoporosis.3 In the United States, BMD measurement should be offered to all women >65 years of age and for those <65 years of age depending on whether they have a major risk factor such as a personal history of fracture as an adult, a history of fragility fracture in a first-degree relative, low body weight (<127 lbs [58 kg]), current smoking, or use of oral corticoid therapy for more than 3 months. The NOF had additional risk factors in its algorithm. Moreover, based on age, BMD, and risk factors such as previous fractures, the intervention was decided according to the BMD values. Thus, clinical risk factors were used to identify individuals for BMD measurement. However, the clinical significance of osteoporosis is the fracture that occurs because of it. BMD is an important component of the risk of fracture, but other abnormalities that occur in the skeleton contribute to fragility. In addition, a variety of nonskeletal factors such as a liability to fall and the force of impact contribute to fracture risk.4 Assessment of fracture risk should take into account other readily measurable indices of fracture risk that add further information to that provided by BMD. Thus, new algorithms for interventions should be based on clinical risk factors and absolute risk. Following an initial assessment of clinical risk factors, if the absolute risk is high then the individual should be treated; if it is low, no action should be taken. In the case of intermediate absolute risk based on clinical risk factors, a BMD measurement should be made
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Address for correspondence: Professor Olof Johnell, Department of Orthopedics, Malm University Hospital, SE-205 02 Malm, Sweden (e-mail: olof.johnell@med.lu.se)

bone mineral density National Osteoporosis Foundation dual energy x-ray absorptiometry European Foundation For Osteoporosis

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and thereafter the new absolute 10-year risk should be calculated based on both BMD and clinical risk factors. Thus, the intervention threshold is the fracture risk expressed as absolute 10-year risk.5 Identification of risk factors for fracture is important. In the previous guidelines2,3 based on BMD measurement, the majority of fractures will occur in those individuals who will never be assessed. Other disadvantages with only using the BMD T-score as the indication for intervention are that the T-score is only defined for dual energy x-ray absorptiometry (DXA), the absolute risk is different for different ages with exactly the same T-score,4 the T-score is different for different techniques, many high-risk individuals go undetected, and DXA is not universally available. Risk factors for assessment of fracture risk
x Age Age is the most important risk factor. A woman at the age of 50 with a T-score of <2.5 has an absolute 10-year risk of 1.7%, while a woman with exactly the same T-score at the age of 80 has a 10-year risk of 11.5%, a more than 6-fold difference in fracture risk with exactly the same BMD value.6 x Gender Women have a higher incidence of osteoporotic fractures than men.7 The lifetime risk of an osteoporotic fracture at the age of 50 is 53.2% for women and 20.7% for men in the United Kingdom,8 46.4% for women and 22.4% for men in Sweden,9 and 39.7% for women and 13.1% for men in the United States.10 This is only partly dependent on the shorter life expectancy in men. x BMD BMD is one of the most important risk factors for osteoporotic fractures, and the ability of BMD to predict fracture is comparable to the use of blood pressure to predict stroke and substantially better than serum cholesterol to predict myocardial infarction.11 In a meta-analysis, it was shown that the age-adjusted relative increase in risk of fracture is best for hip fracture when BMD is measured at the femoral neck with a risk increase of 2.6 and less for measurement at the distal radius and lumbar spine. In the same meta-analysis, BMD measurement at the lumbar spine was is slightly better at predicting vertebral fractures (relative risk [RR] 2.3) than measurement at the femoral neck and distal radius.11 A recent meta-analysis based on data for individuals in 12 large cohorts in a total follow-up of 168 366 person-years was undertaken in Europe, North America, Australia, and Asia, and thus was an international study. The study quantified the relationship between BMD and fracture risk and examined the effect of age, sex, and time since measurement and initial BMD value, as well as the predictive ability of ultrasound and peripheral measurements in relation to fracture risk.12 In this study, BMD was measured at the femoral neck using DXA and was found to be a strong predictor of hip fracture both

in men and women with no significant sex difference in the predictive ability. The effect was dependent on age with a significantly higher gradient of risk at age 50 years than at age 80 years. For osteoporotic fracture, it was the opposite. The gradient of risk with the BMD measured at the femoral neck was lower for any osteoporotic fracture compared with hip fractures where the relative risk (RR) for each SD decrease was 2.9 (95% confidence interval [CI], 2.0-4.3). For prediction of osteoporotic fractures, the gradient was higher the lower the BMD. Data from ultrasound and peripheral measurements were available only from 3 cohorts. The predictive ability of these techniques was somewhat less than that of DXA at the femoral neck.12 Thus, BMD is a risk factor for fractures of substantial importance and is similar in both sexes. Its validation on an international basis permits its use in case-finding strategies. The variation in predictive value with age and BMD should, however, be taken into account. The reason for the decreasing gradient of risk for hip fractures with age is not known. It is possible that extraskeletal risk factors, such as liability to falls, have an effect on the gradient, but this does not seem likely, since most falls do not cause hip fracture. Another hypothesis is that age adversely affects the structure or material, and thus properties, of the femur not captured by BMD measurement. Additional risk factors Apart from these important risk factors (age, gender, and BMD), there are now several risk factors that have been validated in an international setting, such as previous fracture, use of corticosteroids, a family history of fracture, low body mass index, certain diseases associated with osteoporosis (secondary osteoporosis), smoking, and alcohol. Other potential risk factors are biochemical markers of bone resorption and ultrasound findings. There are, however, several considerations concerning the selection of these risk factors for use in fracture prediction, and different risk factors might have a different relevance at different ages. Different risk factors also have a different relevance for different fracture sites.4 Thus, clinical risk factors to be used in fracture prediction need to be chosen with care and they should be: x Validated in multiple populations x Adjusted for age, sex, and type of fracture x Readily assessable by primary care practitioners x Proven to contribute to a risk that is amenable to the therapeutic manipulation intended x Intuitive rather than contraintuitive to medical care. In the large international cohorts where we have access to individual data, validations have been carried out for risk factors and the following have been found to work in case-finding in an international setting3,4:
x Previous fracture A previous fracture is a well-documented risk factor for future fracture. In the meta-analysis, 11 cohorts worldwide were used for the follow-up of 250000

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person-years.13 A history of previous fracture was associated with a significantly increased risk of any fracture (RR=1.9; 95% CI, 1.8-2.0). The risk ratio outcome was similar for osteoporotic fracture and for hip fracture. There was no significant difference in risk ratio between men and women. It was marginally adjusted downward when BMD was taken into account. Low BMD explained only a minority of the risk for any fracture (8%) and for hip fractures (22%). The risk ratio was stable with age for osteoporotic and any fracture, but in the case of hip fracture outcome the risk ratio decreased significantly with age. Thus, previous fracture can be used for case-finding in an international setting, also when taking into account that the risk is highest in the lower ages. Previous fracture was also the major risk factor in all guidelines presented and is easy to pick up as the information is already available in the health care system and no screening is needed. In another study,14 it was shown that when almost 2000 consecutive patients were followed for 5 years, the risk of having a new fracture was highest immediately following the initial fracture.
x Use of glucocorticoids

reduction in hip fracture risk of 17%. Body mass index also qualifies as an internationally validated risk factor, which is partly dependent on BMD. The significance of body mass index as a risk factor varies according to the level of body mass index.
x Family history of fracture This is a well-established risk factor, based on epidemiological studies and genetic studies. Seven international cohorts were studied to determine the effect of a family history of osteoporotic or hip fractures in first-degree relatives.18 In the meta-analysis, a family history of fracture in first-degree relatives was associated with a significantly increased risk of any fracture, osteoporotic fracture, and hip fracture. The estimate of risk was slightly higher at younger ages, but not significant. No difference was seen between men and women. A family history of hip fracture in parents was associated with a high risk of osteoporotic fractures, and was 1.6 (95% CI, 1.3-2.0) in women and 2.5 (95% CI, 1.5-3.9) for hip fractures but not significant in men. The risk was not significantly changed when BMD was added in the model. Thus, we can conclude that a parental history of hip fractures confers an increased risk of fracture that is mainly independent of BMD, and this can be used on an international basis in casefinding strategies. x Secondary osteoporosis Secondary osteoporosis is also a well-recognized risk factor for osteoporosis.16,19 Several studies have examined this issue and there are various lists of diseases that affect osteoporosis and fractures. x Smoking Smoking is also widely considered to be a risk factor for future fractures. In a meta-analysis of international cohorts, current smoking was associated with a significantly increased risk of any fracture compared with nonsmokers (RR 1.3; 95% CI, 1.21.4).20 For an osteoporotic fracture, the risk was marginally higher (RR 1.3; 95% CI, 1.1-1.3). The highest risk was observed for hip fractures (RR 1.8; 95% CI, 1.5-2.2), but was also somewhat lower after adjustment for BMD (RR 1.6; 95% CI, 1.3-2.2) (the risk ratio was significantly higher in men than in women for all fractures and osteoporotic fractures, but not for hip fractures). Low BMD accounted for only 23% of the smoking-related risk of fractures. Adjustment for body mass index gave a small downward effect on the all-fracture outcome. Thus, smoking is an interesting risk factor in a case-finding strategy, but also has implications for a public health approach. x Alcohol intake Excessive alcohol intake is also a well-recognized risk factor for osteoporosis. The question is whether moderate intake has an adverse effect. However, a higher level of intake appears to be associated with an increased risk of fractures. In the international cohorts, a meta-analysis was undertaken with regard to alcohol intake, and alcohol in the linear model was associated with a 7% increase for each unit of

Several studies have shown that the use of glucocorticoids is associated with increased fracture risk.15 This risk factor is also included in most guidelines, such as the EFFO and NOF guidelines. In a new meta-analysis based on 7 prospective international cohorts worldwide, the simple question previous corticosteroid use?was associated with a significantly increased risk of any fracture, osteoporotic fracture, and hip fracture, including when adjusted for BMD.16 The RR for hip fractures ranged from 4.4 at age 50 to 2.5 at age 85, thus the estimate of RR was higher in younger ages, but was not significant, with no difference between men and women. The risk was only marginally changed when BMD was included in the model and was independent of previous fracture. Again, a risk factor has been identified that can be used in an international setting.
x Low body mass index

Low body mass index has also been well documented in several studies, mainly because of its association with BMD. This parameter was studied in 12 prospective worldwide cohorts. The age-adjusted risk of fractures increased significantly with lower body mass index.17 Overall, the risk ratio per unit of higher BMD was 0.93 for hip fractures (95% CI, 0.91-0.94). The RR per unit change in body mass index was similar in men and women. After adjusting for BMD, the RR was only significant for hip fractures, being 0.98 in women for one unit higher body mass index. The contribution to fracture risk was much more marked at low values of body mass index than at values above the median. Compared with the body mass index of 25 kg/m2, a body mass index of 20 was associated with an almost 2-fold increase in RR for hip fracture; in contrast, a body mass index of 30 when compared with a body mass index of 25 was only associated with a RR of 0.83, a

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alcohol above 1 unit daily.21 The RR when comparing individuals consuming more than 2 units per day versus the rest was 1.7 for hip fracture (95% CI, 1.2-2.4) and after adjustment for BMD the RR was unaffected. Nor did it change by adding the body mass index. It fell slightly to 1.5 (95% CI, 1.12.2) when adjusted for smoking. Thus, high alcohol intake is an important risk factor and can be used in the case-finding strategy and also in a public health approach. There are several other risk factors, but these are ones that have been validated in an international setting and found to be significant in cohorts all over the world. There are several risk factors that also have an implication for public health, such as a tendency to falls22 and physical exercise23 (a topic that is beyond the scope of this article). Risk factors that have now been tested in international settings are biochemical markers of bone turnover and ultrasound measurement. The interactions between risk factors are also important, such as BMD and age. BMD has a higher predictive value at younger ages.12 If an algorithm with all these validated clinical risk factors is deREFERENCES 1. Khan AA, Syed Z. Bone densitometry in premenopausal women: synthesis and review. J Clin Densitom. 2004;7:85-92. 2. Kanis JA, Delmas P, Burckhardt P, Cooper C, Torgerson D. Guidelines for diagnosis and management of osteoporosis. Osteoporos Int.1997;7:390-406. 3. National Osteoporosis Foundation. Physicians guide to prevention and treatment of osteoporosis. http://www.nof.org. Accessed October 30, 2005. 4. Kanis JA, Black D, Cooper C, et al. A new approach to the development of assessment guidelines for osteoporosis. Osteoporos Int. 2002;13:527-536. 5. Kanis JA, Borgstrm F, De Laet C, et al. Assessment of fracture risk. Osteoporos Int. 2005;16:581-589. 6. Kanis JA, Johnell O, Odn A, Dawson A, De Laet C, Jnsson B. Ten year probabilities of osteoporotic fractures according to BMD and diagnostic thresholds. Osteoporos Int. 2001;12:989-995. 7. Johnell O, Kanis J. Epidemiology of osteoporotic fractures. Osteoporos Int. 2005;16(suppl 2):S3-S7. 8. van Staa TP, Dennison EM, Leufkens HG, Cooper C. Epidemiology of fractures in England and Wales. Bone. 2001;29:517-522. 9. Kanis JA, Johnell O, Odn A, et al. Long-term risk of osteoporotic fracture in Malm. Osteoporos Int. 2000;11:669-674. 10. Melton LJ III, Chriscilles EA, Cooper C, Lane AW, Riggs BL. Perspective: how many women have osteoporosis? J Bone Miner Res. 1992;7:1005-1010. 11. Marshall D, Johnell O, Wedel H. Meta-analysis of how well measures of bone mineral density predict occurrence of osteoporotic fractures. BMJ. 1996;312:1254-1259. 12. Johnell O, Kanis JA, Odn A, et al. Predictive value of BMD for hip and other fractures. J Bone Miner Res. 2005;20:1185-1194. 13. Kanis JA, Johnell O, De Laet C, et al. A meta-analysis of previous fracture and subsequent fracture risk. Bone.2004;35:375382. 14. Johnell O, Kanis JA, Odn A, et al. Fracture risk following an osteoporotic fracture. Osteoporos Int. 2004;15:175-179. 15. van Staa TP, Leufkens HG, Abenhaim L, Zhang B, Cooper C. Use of oral corticosteroids and risk of fractures. J Bone Miner Res. 2000;15:993-1000. 16. Kanis JA, Johansson H, Odn A, et al. A meta-analysis of prior corticosteroid use and fracture risk. Osteoporos Int. 2004;19:893896.

signed, they will interact and alter the RR that was found in the univariate analyses; the risks will thus be a little different in the final model with all risk factors together. Such a model has to be created, and once this has been done, treatment can be based on the absolute fracture risk. In this way, we can identify and treat those at highest risk who need treatment the most.5 Conclusion The diagnosis of osteoporosis is based on a BMD measurement using the DEXA technique. The intervention thresholds should be based on absolute fracture risk as well as on several clinical risk factors that contribute to fracture risk in an international setting and should be partly independent of BMD in order to be able to contribute to the fracture risk. BMD is still one of the most important risk factors together with age and gender. Other risk factors that can be clinically used are a history of previous fracture, the use of oral corticosteroids, a family history of fracture, secondary osteoporosis, high alcohol intake, and smoking.
17. De Laet C, Kanis JA, Odn A, et al. Body mass index as a predictor of fracture risk: a meta-analysis. Osteoporos Int. 2005;16: Jun 1 [Epub ahead of print]. 18. Kanis JA, Johansson H, Odn A, et al. A family history of fracture and fracture risk: a meta-analysis. Bone. 2004;35:1029-1037. 19. Seeman E. Invited Review: Pathogenesis of osteoporosis. J Appl Physiol. 2003;95:2142-2151. 20. Kanis JA, Johnell O, Odn A et al. Smoking and fracture risk: a meta-analysis. Osteoporos Int. 2005;16:155-162. 21. Kanis JA, Johansson H, Johnell O, et al. Alcohol intake as a risk factor for fracture. Osteoporos Int. 2004;15:734-742. 22. Pfeifer M, Sinaki M, Geusens P, Boonen S, Preisinger E, Minne WH. Musculoskeletal rehabilitation in osteoporosis: a review. J Bone Miner Res. 2004;19:1208-1214. 23. Lock CA, Lecouturier J, Mason JM, Dickinson HO. Lifestyle interventions to prevent osteoporotic fractures: a systematic review. Osteoporos Int. 2005;16:Jun 1 [Epub ahead of print].

FACTEURS

DE RISQUE DE LOSTOPOROSE UNE REVUE PIDMIOLOGIQUE

es stratgies de recherche de cas taient autrefois bases sur la mise en vidence de facteurs de risque cliniques justifiant de recourir la mesure de la densit minrale osseuse (DMO). Cependant, cest la survenue de fractures qui est lvnement significatif dans lostoporose sur le plan clinique. Cest donc la mise en vidence des facteurs de risque de fractures qui est importante dans les stratgies de recherche de cas. Les algorithmes didentification des patients haut risque doivent tre fonds sur les facteurs de risque cliniques, la DMO, le sexe et lge. Les facteurs de risque pour les fractures, quant eux, doivent tre valids dans un cadre international et sur des populations multiples, tre ajusts selon le type de fracture, tre facilement valuables par les mdecins gnralistes et faire partie dun risque relevant des traitements proposs. Outre lge, la DMO et le sexe, ces facteurs de risque comprennent les antcdents de fractures, la corticothrapie par voie orale, un indice de masse corporelle bas, des antcdents familiaux de fractures, le tabagisme, une consommation dalcool leve et lostoporose secondaire. Enfin, le seuil dintervention thrapeutique doit tre bas sur le risque absolu.

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Cyrus COOPER, Ma, DM, FRCP, FFPH, FMedSci Professor of Rheumatology & Director, MRC Epidemiology Resource Center, University of Southampton, Southampton General Hospital, Southampton, UNITED KINGDOM Stephen GEHLBACH, MD, MPH Professor of Epidemiology, School of Public Health and Health Sciences, University of Massachusetts at Amherst Amherst, USA

Identification of patients in need of antiosteoporotic treatment: who to treat today?

b y C . C o o p e r, U n i t e d K i n g d o m and S. Gehlbach, USA

ncreased likelihood of fracture has often been expressed as relative risk, or risk ratio, defined as the ratio of fracture occurrence among individuals with, versus without, a given risk factor. Thus, an osteoporotic bone mineral density (BMD) carries a risk ratio of 9.6 for hip fracture versus a ratio of 1.7 for cigarette smoking, suggesting that low BMD confers markedly greater risk. However, relative risk alone is inadequate in informing clinical decisions: it does not express actual outcome frequency. Ten-year relative risks of fracture are similar in osteoporotic women aged 50 years and 70 years3.7 and 4.2, respectively, versus their normal counterparts but absolute rates are twice as high in the older group. This difference has important implications for preventive who-to-treat strategy. More informative than relative risk is an approach that estimates the absolute risk of an individual with a given constellation of factors (age, sex, BMD, prior fracture, parental hip fracture, lifetime systemic glucocorticoid use, body mass index, alcohol intake >2 units/day) sustaining a fracture over a relative, but practical, time interval, eg, 10 years. The recent multivariate World Health Organization algorithm was derived from several large epidemiological surveys. The greatest benefit of absolute risk is its transparent role in economic analyses and its ability to dovetail with health economic modeling. Comparison of the impact of alternative interventions on absolute risk can be used to set intervention thresholds for specific agents and target treatments against osteoporotic fracture to those clinical scenarios in which these agents are most cost-effective.
Medicographia. 2006;28:13-20. (see French abstract on page 20)

Fracture impact t the age of 50 years, the remaining lifetime risk of at least one fracture of the hip, vertebral body, or distal forearm, approaches 50% among white women and 20% among white men.1 The most frequent site of fracture is the thoracolumbar spine, with prevalence rates of morphometric vertebral deformities being around 25% among white women in the USA aged 50 years and over.2,3 Around two thirds of these morphometric vertebral deformities are subclinical. Other skeletal sites linked with osteoporosis include the hand, rib, foot, and toe. While fragility fractures of the proximal femur occur less frequently (lifetime risk =18% among women aged 50 years), the mortality and morbidity associated with fractures at this site is considerably greater than that associated with vertebral deformity. Hip fractures invariably require hospitalization; 1 year following fracture, 27% of patients enter a nursing home for the first time, 40% are unable to walk independently, 60% have difficulty with at least one essential activity of daily living (ADL), and 80% are restricted in other activities such as

Keywords: osteoporosis; fracture; bone mineral density; risk factor; epidemiology; prevention; treatment; cost-effectiveness

SELECTED
ADL BMD BMI DXA ERT PTH QUS SOF

ABBREVIATIONS AND ACRONYMS

Address for correspondence: Professor Cyrus Cooper, MRC Epidemiology Resource Center, University of Southampton, Southampton General Hospital, Southampton SO16 6YD, UK (e-mail: cc@mrc.soton.ac.uk)

activity of daily living bone mineral density body mass index dual energy x-ray absorptiometry estrogen-replacement therapy parathyroid hormone quantitative ultrasonography Study of Osteoporotic Fracture

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Men
400 400 Hip fracture Vertebral fracture Forearm fracture

Women

Incidence per 10 000/year

300

300

200

200

Figure 1. Incidence of osteoporotic fractures.

Adapted from reference 1: Harvey NC, Dennison EM, Cooper C. The epidemiology of osteoporotic fractures. Osteoporos Rev. 2005;13:1-6. Copyright 2005, Springer Verlag, USA.

100

100

0
50-54 55-59 60-64 65-69 70-74 75-79 80-84 85+

0
50-54 55-59 60-64 65-69 70-74 75-79 80-84 85+

Age group (y)

Age group (y)

driving and shopping. Mortality rates are increased among subjects with both hip and vertebral fractures; reductions in survival of around 15% are reported during the 5 years following fracture at both of these sites. The excess mortality in the case of vertebral deformities is apparent among patients with clinically diagnosed vertebral fracture, as well as those with asymptomatic, morphometric deformities. Figure 11 shows the age- and sex-specific incidence rates for fractures of the hip, distal forearm, and vertebral body. The economic burden of fragility fractures is considerable. In the USA, the care of these fractures costs around US $20 billion each year. In the UK, this figure totals UK 1.5 billion. The most expensive fracture is hip fracture, and around half of hip fracture costs arise from care required after departure from hospital. In the UK, 20% of all orthopedic beds are occupied by patients with a hip fracture, and 19% of patients require long-term nursing care (Table I).1
Hip Lifetime risk (%) Women Men Cases/year Hospitalization (%) Relative survival 143 3 400 000 100 0.83 Spine 29 14 810 000 2-10 0.82 Wrist 13 2 330 000 5 1.00

eral density (BMD) is a major determinant of bone strength; dual-energy x-ray absorptiometric (DXA) measurements of BMD account for 75% to 90% of the variance in bone strength observed during in vitro and in vivo studies.5 However, bone strength is determined by other aspects of bone structure including size, geometry, microarchitecture, and turnover. Bone density in adult life is a function of the peak bone mass attained during early adulthood and the subsequent rate of bone loss. The two major causes of involutional bone loss are secondary hyperparathyroidism (consequent upon reduced calcium intake and hypovitaminosis D) and reduced physical activity. In addition, estrogen deficiency predisposes to bone loss among women. Other important causes of bone loss include thinness, cigarette smoking, heavy alcohol consumption, and drugs/diseases that secondarily predispose to osteoporosis (most importantly glucocorticoids). The multifactorial etiology of fracture is illustrated in Figure 2. Preventive strategies For regulatory purposes, specific definitions of prevention and treatment are used in the context of osteoporosis. The term prevention is used to denote the prevention of bone loss in postmenopausal women with osteopenia, whereas treatment is defined as a reduction in fracture risk in postmenopausal women with osteoporosis. In clinical practice, this distinction between prevention and treatment is less appropriate, since many agents currently in use act fundamentally in the same manner, ie, by inhibition of bone resorption. Furthermore, with the increasing evidence for a relatively rapid rate of treatment onset and offset for these interventions, there has been a move away from long-term preventive strategies toward the use of shorter-term therapy in high-risk individuals. The latter approach is supported by the demonstration of a significant reduction in vertebral and nonvertebral fracture rate among postmenopausal women with established osteoporosis after only 1 year of treatment with antiresorptive agents. A variety of bone mass measurement techniques are predictive of fracture, including DXA and quan-

Costs: All sites combined ~ 25 billion Euros

Table I. Impact of osteoporosis-related fractures in Europe.

Based on data from reference 1 (Harvey et al, 2005).

Pathophysiology of fracture Fracture incidence depends on two factors: bone strength and trauma. During the first three decades of life, fractures typically arise from high-energy trauma, such as road traffic accidents. Above the age of 65 years, around 90% of fractures result from a fall from standing height or less.4 Reduced bone strength is therefore an important, modifiable, determinant of fracture risk in the elderly. Bone min14 MEDICOGRAPHIA, VOL 28, No. 1, 2006

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titative ultrasound (QUS). Site-specific measurements are more predictive (relative risk (RR) =2.02.8 for 1 standard deviation (SD) reduction in BMD) than assessments at more distant sites (RR=1.52.2 for 1 SD reduction in BMD). The definition of osteoporosis, according to World Health Organization (WHO) guidelines6,7, is a T-score of <- 2.5 for white postmenopausal women. Diagnostic thresholds for other subpopulations such as men and patients using glucocorticoids, are less clear. Since different approaches to bone mineral measurement result in a variable classification of individuals as having osteoporosis, it has recently been proposed that the gold standard for diagnostic purposes be total hip BMD measured by DXA. However, the most rational utility of these measurements is in fracture risk prediction, and measures are already under way in order that bone mineral measurements be expressed as absolute fracture risk related to a relative time interval, for example 10 years. The aim of preventive strategies is to reduce the number of subsequent fractures in someone who has been diagnosed with a low bone mass or who may already have fragility fractures. The first line in such preventive approaches is to correct the underlying cause of osteoporosis (hypogonadism in men, hyperthyroidism, hyperparathyroidism, or glucocorticoid exposure). Lifestyle measures directed at the population The main lifestyle changes that may impact on the occurrence of fracture in patients with osteoporosis are smoking, exercise, and diet. Smoking affects the skeleton in many ways; there is a direct toxic effect on new bone growth. Smoking may also reduce calcium absorption as well as increasing the risk of falling in elderly patients. The smoking-related increase in the risk of hip fracture is age-related, with greater deleterious effects in the postmenopausal age group.8 The effect of smoking cessation on bone mass and fracture rate has been studied in a 5-year Norwegian cohort. Despite adjustment for confounding variables such as body mass index (BMI), physical inactivity, and self-reported poor health, ex-smokers still had an increased risk of hip fracture compared with nonsmokers, but a lower risk than current smokers.9,10 This would suggest that the effect of smoking is partially reversible, but perhaps a portion of the damage to the skeleton is irreversible. However, these findings have not been supported by a study of younger women where there was no effect of smoking status on wrist fracture11 or by the Framingham Study, which found a reduction in the benefit from estrogen replacement therapy (ERT) in smokers, but no independent effect of smoking on BMD.12 The level of physical activity has been shown to be associated with increased bone mass13 and also reduced fracture rate14 in observational studies. Exercise therapy can be used to prevent fracture in those at risk or form part of a rehabilitation program after a fracture. A study of patients with vertebral osteoporosis having twice-weekly exercise

classes showed a significant reduction in back pain and a nonsignificant trend in reduced further vertebral fractures.15 A small study has assessed a simple home exercise program after hip fracture and found an increase in quadriceps strength, walking speed, and subjective measures.16 However, there was no effect on postural stability nor any comment possible on fall prevention. Another study has examined the role of early mobilization following Colles fracture and confirmed previous evidence that there is quicker regain of wrist movement and that this is not at the expense of increased analgesic use nor worsening bony deformity.17

Bone mass

Peak bone mass

x Genetic factors x Intrauterine programming x Childhood nutrition and exercise x Endocrine dysfunction x Thinness x Smoking x Estrogen deficiency x Secondary hyperparathyroidism x Drugs/disease (eg, cortico-

Bone strength

Bone loss

steroids)

Other skeletal factors Fracture

Risk of falling

Size Architecture Geometry Turnover

x Vision x Muscle strength x Gait x Medication x Balance x Cognitive impairment x Domestic hazards

Intrinsic

Trauma

Although most nonvertebral fractures occur following a fall, no study has shown an intervention that has reduced fracture.18 Protecting the hip with hip protectors has been shown to reduce hip fracture.19 However, in view of their cumbersome design, compliance is poor. Both calcium and vitamin D act to reduce parathyroid hormone (PTH) levels and so may preserve bone mass. Some epidemiological studies of calcium intake comparing different populations have shown a protective effect against fracture in men,20 while others have not.21 After the menopause, calcium has been shown to reduce bone loss by reducing bone turnover and increasing bone density.22 Calcium alone in pharmacological doses (1.2 g) has been shown to reduce the risk of further vertebral fracture in patients who have a prevalent vertebral fracture.23 The evidence for hip fracture reduction has only been shown by epidemiological studies (Figure 3, next page).24,25 VitaminD is biologically inert from dietary sources or from the skin. It is metabolized by the liver and then the kidney to the active moiety 1,25(OH)2 vi-

Identification of patients in need of antiosteoporotic treatment Cooper and Gehlbach

Extrinsic

x Outdoor hazards

(eg, loose rugs)

(eg, icy pavements)

Type of fall

Direction of fall Point of impact

Figure 2. Pathophysiology of fracture.

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Lau et al, 1988 Holbrook et al, 1988 Meyer et al, 1996 Johnell et al, 1995 Looker et al, 1993 Cooper et al, 1988 Cummings et al, 1995 Jaglal et al, 1993 Nieves et al, 1992 Tavani et al, 1996 Meyer et al, 1995 Paganini-Hill et al, 1991 Michaelsson et al, 1995 Wickham et al, 1989 Cumming et al, 1994 Krieger et al, 1992
POOLED ODDS RATIO
0.5 0.75 1.0 1.5 2.0 * * Not to scale

interval [CI] 0.510.91) including the hip (OR 0.70; 95% CI 0.510.91).29 Another study has shown that an annual intramuscular injection of 150 000 200 000 units of vitamin D to those over 75 years resulted in a significant reduction in all fractures.30 Although participants in these studies were not diagnosed as osteoporotic before entry, the benefit would seem to be greatest in those at greatest risk.31 Individual risk assessment Several individual characteristics have been linked to fracture risk in case-control and cohort studies. These factors are interrelated to a variable extent, and in many instances the independence of their contribution to fracture risk from BMD, and from each other, may not be clear. Moreover, risks coexist in differing combinations among different patients. These issues constitute a major challenge to the development of preventive strategies, an issue highlighted by current guidelines. A number of investigators have employed multivariable statistical techniques to build scoring systems that assess the influence of each risk factor while controlling or adjusting for the presence of the others. Factors that are found to contribute independently to risk are weighted by importance (as determined in the modeling) and allocated points. Each patient is then evaluated and receives a score, based on accumulated points, that predicts the risk of fracture. Some scoring systems have been designed to predict low BMD (osteoporosis, as defined by the WHO) in the expectation that these scores will assist clinicians in identifying patients who will benefit from bone density referrals to confirm suspected diagnoses.32,33 Other researchers have targeted fractures as the outcome of importance.34,35 In these schemes, BMD becomes one of the predictor variables. The latter approach has the dual virtues of utilizing easily obtained clinical variables, such as age, sex, and weight, and personal history to estimate risk before resorting to the added expense of a bone density determination, as well as predicting the outcome (fracture) of clinical importance. Two large population-based studies, one in Europe and one in North America, provide useful illustrations of how variables can be combined to estimate fracture risk. A cohort of over 5000 women and men aged 55 years and above from a Netherlands community was extensively evaluated from 1990 through 1993, then followed over a 4-year period for the occurrence of hip fracture.35 Ten factor assessed at entry were associated with the outcome. After these were modeled in multivariable equations, the factors seen in Table II 35 emerged as independent contributors to fracture risk. Age, sex, height, use of an aid for walking, and current cigarette smoking are included as are nine categories of bone density. As seen in Table II, the rounded estimates of the coefficients (weights of the factors) when multiplied by 10 become points given to each factor. Points in turn are multiplied by the category value and summed to make a composite score. Within the Dutch population in which the scoring system was devised, subjects scores range from 6 to

Figure 3. Calcium treatment and risk of hip fracture based on findings from epidemiological studies. The odds ratios and 95% confidence intervals are shown for an increase of 300 mg/day of calcium and the risk of hip fracture in postmenopausal women.
Adapted from reference 25 (Cumming et al, 1997).

tamin D. Its main action is to increase the absorption of calcium and to a lesser extent phosphorus from the small bowel. In the calcium-deficient state, it also acts on bone via osteoblasts to increase osteoclast numbers and mobilize calcium from the skeleton. Importantly, active vitamin D inhibits the synthesis and secretion of PTH. In this way vitamin D may act to inhibit PTH-mediated age-related bone loss. The effects of calcitriol on bone mass have been inconsistent, reflecting the different calcium intakes in each of the studies.26,27 Calcitriol, compared with calcium, has been shown to reduce vertebral fracture rates in postmenopausal women with prevalent vertebral deformity,27 but other studies have found no benefit. A side effect of calcitriol therapy includes hypercalcemia, causing nephrocalcinosis and renal failure. One of the main mechanisms of age-related bone loss involves increased resorptive activity of PTH on the bone, secondary to hypovitaminosis D. In ambulatory elderly women resident in nursing homes, the combination of 1.2 g of calcium and 800 IU of vitamin D3 (cholecalciferol) daily was given for 3 years. After 18 months, the treatment group had significant increases of 2.7% in total femur BMD compared with a decline in the placebo group of 4.6%.28 By the end of the 3-year period, there was a significant reduction in fracture rates at nonvertebral sites (odds ratio [OR] 0.70; 95% confidence 16 MEDICOGRAPHIA, VOL 28, No. 1, 2006

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103 with a median value of 43. The scheme performs well in discriminating patients who are at high and low risk of fracture. Those with a score of less than 50, for example, have a chance of only 1 in 1000 of sustaining a hip fracture over a 4-year interval. This risk increases 100-fold for those with scores of 75 or higher; their risk of hip fracture is 10%. Data from the US-based Study of Osteoporotic Fracture (SOF) subjects with hip DEXA measurements available were also used to produce multivariable derived prediction models.34,36 Twenty potential risk factors were included in the modeling. Their results compiled into the FRACTURE Index are shown in Table III.34 Like the Dutch models, age, weight and cigarette smoking appeared as independent risks, as did an indicator of physical condition, in this instance using arms to stand from a chair instead of using a walking aid. Significant additions to the SOF models are the history of maternal hip fracture after the age of 50 years and the personal history of a fracture in adult life. As in the Dutch study, the American group built models that included and excluded BMD determinations. Scores from both FRACTURE Index models showed good discrimination for fracture risk. Subjects with scores in the lowest quintile have a 5-year risk of hip fracture of about 0.5% compared with a 14-fold increased risk of 8.5% for scores in the highest quintile. Good separation for those at high and low risk of vertebral fracture was also demonstrated. As with the Dutch models, adding BMD values to the models derived from clinical variables alone improves performance, although not dramatically. A particular strength of the SOF study is the validation of the instrument in a different population. The scoring system was applied to 6600 women aged 75 years and older from five regions in France who were participants in a hip fracture follow-up study.34 Although this group was on average 10 years older than SOF participants, the models, both with and without BMD, showed good discrimination with 23fold and 6-fold increases in estimated risk respectively between lowest and highest quintiles. Other efforts to combine risk factors have found more than 20 characteristics that predict increased fracture risk in multivariate models.37-40 In addition to those observed by Black et al34 and Burger et al,35 ADLs, cognition, propensity to fall, poor overall health status, history of stroke, seizure disorder, and several different medications have been identified. In four of five of these investigations, simple counts of increasing number of risk factors have been shown to demonstrate increasing risk. In data from the Duke Established Population for Epidemiologic Studies of the Elderly in the USA the presence of 1 of 9 factors carries a fracture risk of 1.8, while 4 factors increase risk to almost 10.37 Findings from the General Practice Research Database in the UK indicate that the presence of 3 or more of 11 medical risk factors (made up of diagnoses and medications) raises the risk of vertebral fracture 8-fold and of hip fracture by a factor of 4.6 when compared with patients with none of the attributes.38 Neither included measurements of BMD.

Predictor Model including bone mineral density Intercept Age (5 years)* Gender (female) Height (5-cm class) Use of a walking aid (yes/no) Current cigarette smoking (yes/no) Bone mineral density (0.05 g/cm2) Model excluding bone mineral density Intercept Age (5 years)* Sex (female) Height (5 cm) Weight (5 kg) Use of a walking aid (yes/no) Current cigarette smoking (yes/no)

Odds ratio (95% confidence interval) 1.8 (1.5-2.3) 2.6 (1.0-6.4) 1.5 (1.1-1.9) 2.7 (1.4-5.2) 2.2 (1.1-4.4) 1.5 (1.3-1.7)

Points

10.2 0.61 0.94 0.39 0.98 0.80 0.39 -9.6 0.70 1.20 0.40 0.17 1.08 0.87

6 9 4 10 8 4

2.0 (1.6-2.5) 3.3 (1.3-8.3) 1.5 (1.1-2.0) 1.2 (1.0-1.4) 2.9 (1.5-5.8) 2.4 (1.2-4.6)

5 7 12 4 2 11 9

* Age classes 0 to 6 are <60-64 etc, to 85 years. Height classes 0 to 5 are <1.60-1.64 etc, to 1.80 m. Bone mineral density classes 0 to 9 are 1.00, 0.95-0.99 etc to <0.60 g/cm2. Weight classes 0 to 9 are 95, 90-94 etc, to <55 kg.

Table II. Risk factors predicting hip fracture in the Rotterdam study.
Based on data from reference 35 (Burger et al, 1999).

Point value 1. What is your current age? Less than 65 65-69 70-74 75-79 80-84 85 or older 2. Have you broken any bones after age 50? Yes No/Dont know 3. Has your mother had a hip fracture after age 50? Yes No/Dont know 4. Do you weigh 125 pounds or less? Yes No/Dont know 5. Are you currently a smoker? Yes No 6. Do you usually need to use your arms to assist yourself in standing up from a chair? Yes No If you have a current bone mineral density (BMD) assessment, then answer next question 7. BMD results: Total Hip T-score T-score --1 T-score between --1 and --2 T-score between --2 and --2.5 T-score <22.5 0 1 2 3 4 5 1 0 1 0 1 0 1 0

1 0

0 2 3 4

Table III. Fracture risk prediction using multiple clinical risk factors and bone density in the Study of Osteoporotic Fractures (SOF).
Based on data from reference 34 (Black et al 2001).

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Models that avoid reliance on BMD appear promising. However, the prospect that preventive treatment decisions might be made without obtaining BMD determinations is mitigated by concern that antiresorptive agents may not be equally effective across a range of BMD. Data from randomized trials of alendronate41 and risedronate42 suggested that the bisphosphonates may have little effect on fracture reduction among subjects with BMD levels above the osteoporotic range. However, recent observations made in randomized controlled trials of selective estrogen receptor modulators, hormone replacement therapy, and strontium ranelate, suggest that fracture risk may be effectively reduced among postmenopausal women with bone density levels in the osteopenic (and even perhaps normal) range. Relative risk, absolute risk, and risk difference Identifying patients at increased likelihood of fracture is commonly expressed in terms of relative risk: the ratio of occurrence of fracture among those with the factor or characteristic over the occurrence in those without the characteristic. Relative risk (also referred to as risk ratio) estimates the potency or strength of an association between a factor and an outcome. A BMD in the osteoporotic range carries a risk ratio of 9.6 for hip fracture compared with a relative risk of 1.7 for cigarette smoking, for example, suggesting that low BMD has the greater impact on producing fracture risk.
50 years old Absolute risk (per 100) Osteoporosis (BMD,* T<- 2.5 SD) Normal (BMD, T = mean) Relative risk Risk difference (per 100) NNT 13.9 3.8 3.7 10.1 9.9 70 years old 29.8 7.1 4.2 22.7 4.4

tion were able to reduce the osteoporotic risk to the normal level, more fractures would be averted in the older women (22.7 per 100 compared with 10.1 per 100). This risk difference can be expressed in the useful notation number needed to treat (NNT) to avoid 1 fracture (the reciprocal of the risk difference). Ten younger women would require treatment to avert 1 fracture compared with 4 in the older age group. Recent thinking has moved away from describing fracture risk in relative terms.43 A more informative approach is to estimate the likelihood that an individual with a given constellation of factors (age, BMD, prior fracture) will sustain a fracture over a particular period of time. This means constructing an estimate of absolute risk and utilizing risk differences as a basis for evaluating intervention strategies. The principal value to employing absolute risk is its transparent role in economic analyses. The cost-effectiveness and cost-utility calculations that are assuming essential roles in both clinical and policy decision-making depend upon the values obtained from comparisons of the risk differences of alternative interventions. The interval over which risk is determined is arbitrary, but 10 years has been proposed as a practical length of time in which to observe maximum benefits of a treatment program.43 Couching estimates in longer frames, such as lifetime risk, presumes extended benefits that are not yet demonstrated and ignores the improvements in treatment approaches that seem likely in coming years. Integrating risk factors The WHO has recently undertaken an initiative that entailed amalgamation of several large epidemiological studies worldwide.44 From these, estimates of the association between a number of risk factors and osteoporotic fracture have been derived, both before and after adjustment for BMD. These include BMI; prior fracture after 50 years; parental history of hip fracture; current smoking; ever use of systemic glucocorticoids; alcohol intake greater than 2 units daily; and secondary osteoporosis. The combined use of these risk factors together with age and BMD have been entered into a multivariate model permitting the prediction of 10-year probability of hip and other fractures. Thus, a woman at the age of 60 years has on average a 10-year probability of hip fracture of 2.4%. In the presence of a prior fragility fracture, this risk is increased approximately 2-fold and a probability increases to 4.8%. Intervention thresholds for various agents to combat osteoporosis can also be derived using health economic modeling. Although the diagnosis of osteoporosis centers on the assessment of BMD at the hip using DEXA, other risk factors can be used to assist in enhancement of fracture prediction. Since these risk factors are partly independent of BMD, their use in conjunction with BMD improves sensitivity of fracture prediction without adverse effects on specificity. In the absence of validated population screening strategies, a case-finding approach can be developed based on the assessment of fracture probability uti-

* BMD: bone mineral density. mean BMD for young adult. NNT: number needed to prevent one fracture (1/risk difference).

Table IV. Ten-year risk of fracture associated with osteoporosis for 50-year-old and 70-year-old women.
Based on data from reference 4 (Kanis et al, 2001).

However, relative risk alone does not provide sufficient information for informed clinical decisions. It fails to convey an important dimension of risk, the absolute value. What is the actual magnitude of risk, the frequency with which the outcome or disease occurs? Table IV ref shows data on the 10-year fracture rates for women who are 50 years old and women aged 70 years by two levels of BMD, osteoporotic and normal. The relative risks for the two groups are similar (3.7 and 4.2, respectively), but the absolute rates of fracture appear quite different. The 10-year risk of fracture is 2-fold higher for older osteoporotic women. This has important implications for any preventive strategy. If an interven18 MEDICOGRAPHIA, VOL 28, No. 1, 2006

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lizing clinical risk factors, and where appropriate additional testing such as BMD. Because there are many techniques for assessing fracture risk, and multiple fracture outcomes, the most suitable measure to determine intervention thresholds appears to the be 10-year probability of fracture. Many treatments can now be given cost-effectively to men
REFERENCES 1. Harvey NC, Dennison EM, Cooper C. The epidemiology of osteoporotic fractures. Osteoporos Rev. 2005;13:1-6. 2. Melton LJ, Lane AW, Cooper C, et al. Prevalence and incidence of vertebral deformities. Osteoporos Int. 1993;3:113-119. 3. Matthis C, Weber U, ONeill TW, Raspe H. Health impact associated with vertebral deformities: results from the European Vertebral Osteoporosis Study (EVOS). Osteoporos Int. 1998;8: 364-372. 4. Parkkari J, Kannus P, Palvanen M, et al. Majority of hip fractures occur as a result of a fall and impact on the greater trochanter of the femur: a prospective controlled hip fracture study with 206 consecutive patients. Calcif Tissue Int.1999;65:183-187. 5. Lauritzen JB. Hip fractures: incidence, risk factors, energy absorption, and prevention. Bone. 1996;18:65S-75S. 6. Meunier PJ. Evidence-based medicine and osteoporosis: a comparison of fracture risk reduction data from osteoporosis randomised clinical trials. Int J Clin Pract. 1999;53:122-129. 7. World Health Organization Study Group. Assessment of Fracture Risk and its Application to Screening for Postmenopausal Osteoporosis. Geneva, Switzerland: WHO; 1994. 8. Law MR, Hackshaw AK. A meta-analysis of cigarette smoking, bone mineral density and risk of hip fracture: recognition of a major effect. BMJ. 1997;315:841-846. 9. Forsen L, Bjartveit K, Bjorndal A, et al. Ex-smokers and risk of hip fracture. Am J Public Health. 1998;88:1481-1483. 10. Cornuz J, Feskanich D, Willett WC, Colditz GA. Smoking, smoking cessation, and risk of hip fracture in women. Am J Med. 1999;106:311-314. 11. Hemenway D, Colditz GA, Willett WC, et al. Fractures and lifestyle: effect of cigarette smoking, alcohol intake, and relative weight on the risk of hip and forearm fractures in middle-aged women. Am J Public Health. 1988;78:1554-1558. 12. Kiel DP, Baron JA, Anderson JJ, et al. Smoking eliminates the protective effect of oral estrogens on the risk for hip fracture among women. Ann Intern Med. 1992;116:716-721. 13. Chow R, Harrison JE, Notarius C. Effect of two randomised exercise programmes on bone mass of healthy postmenopausal women. BMJ (Clin Res Ed). 1987;295:1441-1444. 14. Joakimsen RM, Magnus JH, Fonnebo V. Physical activity and predisposition for hip fractures: a review. Osteoporos Int.1997;7: 503-513. 15. Harrison JE, Chow R, Dornan J, et al. Evaluation of a program for rehabilitation of osteoporotic patients (PRO): 4-year follow-up. The Bone and Mineral Group of the University of Toronto. Osteoporos Int. 1993;3:13-17. 16. Sherrington C, Lord SR. Home exercise to improve strength and walking velocity after hip fracture: a randomized controlled trial. Arch Phys Med Rehabil. 1997;78:208-212. 17. Dias JJ, Wray CC, Jones JM & Gregg PJ. The value of early mobilisation in the treatment of Colles fractures. J Bone Joint Surg (British Volume). 1987;69:463-467. 18. Tinetti ME, Baker DI, McAvay G, et al. A multifactorial intervention to reduce the risk of falling among elderly people living in the community. N Engl J Med. 1994;331:821-827. 19. Lauritzen JB, Petersen MM, Lund B. Effect of external hip protectors on hip fractures. Lancet. 1993;341:11-13. 20. Cooper C, Barker DJ, Wickham C. Physical activity, muscle strength, and calcium intake in fracture of the proximal femur in Britain. BMJ. 1988;297:1443-1446. 21. Smith RW, Frame B. Concurrent axial and appendicular osteoporosis: its relation to calcium consumption. N Engl J Med. 1965;273:72-78. 22. Kanis JA. Calcium nutrition and its implications for osteoporosis. Part II. After menopause. Eur J Clin Nutr.1994;48:833841. 23. Recker RR, Hinders S, Davies KM, et al. Correcting calcium nutritional deficiency prevents spine fractures in elderly women.

and women where hip fracture probability over 10 years ranges from 1% to 10%, depending on age. The widespread use of such algorithms of risk prediction will enhance our ability to target effective treatments against osteoporotic fracture to clinical scenarios in which these agents are most costeffective.
J Bone Min Res. 1996;11:1961-1996. 24. Kanis JA, Johnell O, Gullberg B, et al. Evidence for efficacy of drugs affecting bone metabolism in preventing hip fracture. BMJ. 1992;305:1124-1128. 25. Cumming RG, Nevitt MC. Calcium for the prevention of osteoporotic fractures in post-menopausal women. J Bone Miner Res. 1997;12:1321-1329. 26. Aloia JF, Vaswani A, Yeh JK, et al. Calcitriol in the treatment of postmenopausal osteoporosis. Am J Med. 1988;84:401-408. 27. Falch JA, Odegaard OR, Finnanger AM, Matheson I. Postmenopausal osteoporosis: no effect of three years treatment with 1,25-dihydroxycholecalciferol. Acta Med Scand.1987;221:199-204. 28. Chapuy MC, Arlot ME, Duboeuf F, et al. Vitamin D3 and calcium to prevent hip fractures in the elderly women. N Engl J Med. 1992;327:1637-1642. 29. Chapuy MC, Arlot ME, Delmas PD, Meunier PJ. Effect of calcium and cholecalciferol treatment for three years on hip fractures in elderly women. BMJ. 1994;308:1081-1082. 30. Heikinheimo RJ, Inkovaara JA, Harju EJ, et al. Annual injection of vitamin D and fractures of aged bones. Calcif Tissue Int. 1992;51:105-110. 31. Ranstam J, Kanis JA. Influence of age and body mass on the effects of vitamin D on hip fracture risk. Osteoporos Int.1995;5: 450-454. 32. Cadarette SM, Jaglal SB, Murray TM, McIsaac WJ, Joseph L, Brown JP. Evaluation of decision rules for referring women for bone densitometry by dual-energy x-ray absorptiometry. JAMA. 2001;286:57-63. 33. Geusens P, Hochberg MC, van der Voort DJ, et al. Performance of risk indices for identifying low bone density in postmenopausal women. Mayo Clin Proc. 2002;77:629-637. 34. Black DM, Steinbuch M, Palermo L, et al. An assessment tool for predicting fracture risk in postmenopausal women. Osteoporos Int. 2001;12:519-528. 35. Burger H, de Laet CE, Weel AE, Hofman A, Pols HA. Added value of bone mineral density in hip fracture risk scores. Bone. 1999;25:369-374. 36. Seeley DG, Browner WS, Nevitt MC, et al. Which fractures are associated with low appendicular bone mass in elderly women? The Study of Osteoporotic Fractures Research Group. Ann Intern Med. 1991;115:837-842. 37. Colon-Emeric CS, Pieper CF, Artz MB. Can historical and functional risk factors be used to predict fractures in community-dwelling older adults? Development and validation of a clinical tool. Osteoporos Int. 2002;13:955-961. 38. van Staa TP, Leufkens HG, Cooper C. Utility of medical and drug history in fracture risk prediction among men and women. Bone. 2002;31:508-514. 39. McGrother CW, Donaldson MM, Clayton D, Abrams KR, Clarke M. Evaluation of a hip fracture risk score for assessing elderly women: the Melton Osteoporotic Fracture (MOF) study. Osteoporos Int. 2002;13: 89-96. 40. Walterui LY, Eng C, Covinsky KE. Risk of hip fracture in disabled community-living older adults. J Am Geriatr Soc. 2003;51: 50-55. 41. Cummings SR, Black DM, Thompson DE, et al. Effect of alendronate on risk of fracture in women with low bone density but without vertebral fractures: results from the Fracture Intervention Trial. JAMA. 1998;280:2077-2082. 42. McClung MR, Geusens P, Miller PD, et al. Effect of risedronate on the risk of hip fracture in elderly women. Hip Intervention Program Study Group. N Engl J Med. 2001;344:333-340. 43. Kanis JA, Black D, Cooper C, et al. A new approach to the development of assessment guidelines for osteoporosis. Osteoporosis Int. 2002;13:527-536. 44. Kanis JA, Borgstrom F, De Laet C, et al. Assessment of fracture risk. Osteoporosis Int. 2005;16:581-589.

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DES PATIENTS NCESSITANT UN TRAITEMENT ANTIOSTOPOROTIQUE : QUI TRAITER AUJOURDHUI ?

augmentation de la probabilit de fracture sexprime souvent en risque relatif, en dautres termes en rapport de risque, dfini comme le taux de survenue dune fracture pour des individus avec un facteur de risque donn sur celui sans ce facteur de risque. Ainsi une densit minrale osseuse (DMO) de catgorie ostoporotique est associe un rapport de risque de 9,6 pour une fracture de hanche contre 1,7 pour le tabagisme, ce qui suggre quune DMO basse confre un risque nettement plus important. Cependant, le risque relatif seul ne permet pas de prendre de dcisions cliniques : il nexprime pas le vritable taux de survenue de fracture. Ainsi, le risque relatif de fracture 10 ans est identique chez les femmes ostoporotiques ges de 50 et de 70 ans (tant respectivement de 3,7 et 4,2, en comparaison avec leurs homologues normales) mais les taux absolus sont deux fois plus levs dans le groupe plus g. Cette diffrence a des implications importantes pour la stratgie prventive du qui traiter . Plus instructif que le risque relatif est lestimation du risque absolu pour un individu prsentant un cortge de facteurs (ge, sexe, antcdent de fracture, fracture de hanche parentale, corticothrapie prolonge par voie gnrale, indice de masse corporelle, prise dalcool >2 verres par jour) et qui subit une fracture dans les limites dun intervalle relatif mais rel de 10 ans environ. ce titre, lOrganisation Mondiale de la Sant a rcemment dfini un algorithme multivari partir de plusieurs grandes tudes pidmiologiques. Le risque absolu prsente un avantage trs important : il est transparent dans les analyses conomiques et sadapte parfaitement avec la modlisation conomique de la sant. La comparaison de limpact des diverses interventions thrapeutiques contre les fractures ostoporotiques sur le risque absolu peut tre utilise pour fixer des seuils dintervention pour chaque type de traitement, et ainsi cibler ces traitements sur les scnarios cliniques dans lesquels ils savrent les plus rentables.

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Silvano ADAMI, MD Full Professor of Rheumatology University of Verona, Verona ITALY

Who will manage the diagnosis and treatment of osteoporosis?

by S. Adami, Italy

he diagnostic term osteoporosis refers to a skeletal condition that predisposes to fragility fractures. Osteoporosis may be secondary to a number of conditions and the specialists dealing with the primary disease are also expected to manage the bone complications. This is the case for the large majority of patients with rheumatic or endocrine diseases. In other conditions, the risk of osteoporosis is either ignored or the patients are referred (usually too late) to bone specialists. Primary osteoporosis is traditionally defined as a condition of low bone mass appearing with advancing age especially in postmenopausal women. Even though several specialists may be involved in one way or another, the prevalence of primary osteoporosis is so high that general practitioners (GPs) are inevitably the physicians who will see the largest number of osteoporotic patients. Their level of knowledge of the disease is relatively good, but they tend to grossly underestimate both the prevalence and the clinical consequences of the disease. Inadequate access to densitometric centers further limits the possibility of intervention by GPs, but the implementation of specific screening programs was shown to be a good strategy for increasing both the frequency and efficacy of interventions managed by GPs. Patients who have had fractures are at very high risk of new fractures and an early intervention in these cases is highly warranted. Almost all fragility fractures require the intervention of orthopedic surgeons. Although their level of knowledge is good, orthopedic surgeons are scarcely keen to intervene, also because of their busy surgical practice. In such a context, the most successful strategy that has so far been explored is the appointment a trained nurse in the orthopedic department to ensure that the patient with a fragility fracture receives appropriate osteoporosis management. The ineffective management of osteoporosis by orthopedic surgeons and GPs contributes to osteoporosis being severely underdiagnosed and undertreated.
Medicographia. 2006;28:21-26. (see French abstract on page 26)

steoporosis is, by definition, a systemic skeletal disease characterized by low bone mass and microarchitectural deterioration of bone tissue, resulting in an increase in bone fragility and susceptibility to fracture. Osteoporosis may derive from a number of factors. Traditionally, we refer to primary osteoporosis as a condition of reduced bone mass appearing in postmenopausal women (postmenopausal osteoporosis) and in elderly individuals (senile osteoporosis). Consequently, primary osteoporosis is in a way a normal phase of aging and is considered a disease when the risk of fracture is unacceptably high for the individual life expectancy. It is for this reason, as with cardiovascular diseases, that the intervention strategy is now evaluated in terms of lifetime risk rather than absolute risk.1 The high prevalence of primary osteoporosis places general practitioners (GPs) on the front line. However, several specialists, such as gynecologists, geriatricians, physiatrists, rheumatologists, endocrinologists, and orthopedic surgeons, may be involved. All these physicians are dealing with the management of osteoporosis as part of their practice, but occasionally they may operate as bone specialists, or be a bone specialist in a referral center.
SELECTED
BMD DXA EMEA GP IOF NOF

Keywords: osteoporosis management; osteoporosis awareness; orthopedic surgeon; general practitioner; fracture intervention program

ABBREVIATIONS AND ACRONYMS

Address for correspondence: Professor Silvano Adami, Department of Rheumatology, Ospedale Valeggio, University of Verona, 37067 Valeggio, Verona, Italy (e-mail: silvano.adami@univr.it)

bone mineral density dual energy x-ray absorptiometry European Agency for the Evaluation of Medicinal Products general practitioner International Osteoporosis Foundation National Osteoporosis Foundation

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Osteoporosis may be secondary to a large variety of other conditions. The primary condition identifies the reference specialist whose interests and knowledge may vary considerably. In this review, I will analyze the type of intervention carried out by the individual specialists. The manager of secondary osteoporosis Secondary osteoporosis is defined a condition of reduced bone mass resulting from a large variety of specific and well-defined disorders (Table I).
x Endocrine/metabolic diseases

Hyperparathyroidism Thyrotoxicosis Cushing syndrome Hypogonadism Diabetes mellitus Pregnancy Anorexia nervosa

ed to effectively deal with the bone involvement of osteoporosis secondary to rheumatic and endocrine diseases, respectively, but information on how effectively this is done is lacking. The general impression is that, for example, only a few endocrinologists assess the risk of osteoporosis in their patients starting suppressive doses of T4 , which is associated with severe bone loss, and that not all rheumatologists are aware that rheumatoid arthritis is a major risk factor for osteoporosis. The risk of osteoporotic fracture in patients on chronic treatment with corticosteroids is extremely high. Although remedies for reducing this risk are available, the proportion of patients who receive preventive therapy is still low.2 It is also likely that this proportion is particularly low for specialists, like lung specialists, whose practice is far removed from the problem of osteoporosis, but who are frequent prescribers of corticosteroids. The manager of primary osteoporosis A number of specialists are potentially involved in prevention strategies for osteoporosis. Since peak bone mass is an important contributor to bone mass in the elderly, pediatricians should be aware of the risk factors associated with inadequate acquirement of peak bone mass. Most of the patients seen by geriatricians are at high risk of primary osteoporosis and the disease is considered of direct interest for the endocrinologist and even more so for the rheumatologist. The latter is frequently involved for the differential diagnosis of back pain. However, the three health care providers dealing with the largest number of patients at risk of osteoporosis are gynecologists, orthopedic surgeons, and general practitioners (GPs).
x Gynecologists Gynecologists, by dealing with menopausal symptoms, have been heavily involved in the management of osteoporosis for a long time and osteoporosis has been rated as one of the main factors to consider when recommending hormonal therapy, testifying to a good level of awareness for osteoporosis. Gynecologists are, in principle, involved in the early diagnosis and early treatment of the disease. Both these areas of intervention have been debated and challenged in the most recent guidelines. Because bone loss in women occurs at menopause, a readily diagnosable event, it has been intuitively reasoned that screening should be considered in women at the time of menopause. The most obvious intervention is testing by bone mineral density (BMD) by dual energy x-ray absorptiometry (DXA). There have been several analyses of the potential utility of screening at the time of the menopause.3,4 These analyses acknowledge that the cost of screening is not the dominant factor, since most treatments are relatively expensive. Opinions vary over the use of BMD as a screening tool, but most do not recommend widespread screening at the time of the menopause on the basis of BMD alone. The reasons relate to sensitivity and specificity. It has been esti-

x Inflammatory diseases

Rheumatoid arthritis Ankylosing spondylitis

x Functional

Immobilization/weightlessness Chronic obstructive lung diseases Postgastrectomy Hepatic disease (particularly primary biliary cirrhosis) Alcohol abuse Following organ transplantation
x Hematopoietic

Multiple myeloma Lymphoma/leukemia Mastocytosis

x Congenital

Osteogenesis imperfecta Menkes syndrome Ehlers-Danlos syndrome Homocysteinuria Marfan syndrome Corticosteroids Thyroxine Anticonvulsants (barbiturates, phenytoin) Anticoagulants (heparin, coumarin) Antimetabolites (methotrexate, cyclosporine)

x Drugs

Table I. Etiology of secondary osteoporosis.

In some cases, osteoporosis may be so severe (eg, corticosteroid-induced osteoporosis and rheumatoid arthritis) as to represent a major source of morbidity in addition to the underlying disease. In other cases, osteoporosis may also be severe, but because of the short life expectancy may not be considered a major cause of concern (eg, multiple myeloma). In some conditions, osteoporosis is part of the disease, such that by treating the disease, osteoporosis is also cured (eg, primary hyperparathyroidism). Rheumatologists and endocrinologists are expect22 MEDICOGRAPHIA, VOL 28, No. 1, 2006

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mated that 1000 patients would need to be screened to detect 100 for treatment, and the maximal impact on the community after menopause (% of hip fractures saved) would be approximately 8%.2 Current guidelines consistently recommend5 that all women have a measurement of BMD at the age of 65 years, while earlier screening is justified only in the presence of specific risk factors. In other words, guidelines negate the appropriateness of generalized screening by the time of menopause. Hormone therapy is also an issue in the context of screening at the menopause. Estrogen/hormone therapy is an effective antiresorptive agent for preventing postmenopausal bone loss and, at medium estrogen doses, is equivalent to bisphosphonates in its effect on bone density. Hormone therapy reduces fractures even in women without osteoporosis and may be the most effective antiresorptive agent in preventing fractures.6 For these reasons, for a number of years, hormone therapy has been the most widely accepted intervention for the prevention of postmenopausal osteoporosis. However, hormone therapy must be taken continuously for bone protection, since, after discontinuation, rapid bone loss ensues and fracture rates increase. It was also recognized that only treatment prolonged for at least 10 years by the time of menopause provides optimal benefits in terms of future fracture risk. However, even this effect tends to wane 15 to 25 years later.7,8 The need for long-term treatments in order to achieve clinically meaningful benefits 2 decades later, when the risk of fracture becomes high, contrasts with two recent observations. The duration of hormone therapy in clinical practice is much shorter: it has been estimated that only about 10% of American women continue treatment for more than 1 year.9 In addition, the results of the Womens Health Initiative (WHI) study10 indicate a benefitside effect ratio that is particularly negative the longer the duration and the older the age of the patients! As a consequence of these obvious contradictions, the European Agency for the Evaluation of Medicinal Products (EMEA) decided to modify the label of hormone replacement therapy, deleting the indication of prevention and treatment of osteoporosis. These various considerations have suggested that interventions might be more optimally targeted in later life, perhaps with the use of nonhormonal treatment modalities.11 The risk of osteoporosis might still be considered when deciding on the appropriateness of initiating hormonal therapy at the menopause, but only as an additional reason to the main aim of relieving menopausal symptoms. Gynecologists should become aware of this new philosophy and redesign their approach to osteoporosis prevention. A DXA scan can be recommended at the time of menopause not only in women at risk, but also in women generally concerned about osteoporosis. However, what should be realized is that a normal value at the age of 50 years should not exclude another assessment at 65 years, as recommended in all guidelines. In any case, the role of the gynecologists remains crucial. It should be their responsibility to generate

awareness of osteoporosis in women by the time of the menopause and to carry out an initial assessment of osteoporosis risk.
x General practitioners The World Health Organization (WHO) has defined osteoporosis in terms of bone mass that is more than 2.5 SD below the mean peak bone mass in healthy young adults.3 Based on these criteria, approximately 15% of women aged 50 and over have osteoporosis and for those over the age of 80, the proportion rises to 70%.12 Fifty-one out of 1000 women aged 65 and over or 6 per 1000 men and women of all ages have sustained a hip fracture. The prevalence of vertebral deformities has been estimated in several epidemiological studies, by adopting different diagnostic criteria: the prevalence of vertebral deformities among postmenopausal women ranges from 18% to 25%.13 Based on these epidemiological findings, a GP taking care of 2000 adult subjects is expected to have among his patients approximately 300 persons with osteoporosis and/or with a vertebral or hip fracture. Given these figures, osteoporosis should be regarded as one of the main areas of intervention for GPs and makes them the most obvious health provider for the management of the disease. In a recent survey in 10 000 patients attending a densitometry center for osteoporosis screening, we observed that 16% of all patients were referred by GPs (manuscript in preparation). The overall number is very large, but the relative proportion is rather low. The general impression is that GPs are keener to refer their patients to specialists even for evaluating whether DXA screening is appropriate. A few studies have examined the knowledge of GPs, including their knowledge regarding the diagnosis and treatment of osteoporosis. Many family doctors in the United Kingdom report that they have never seen a case of osteoporosis.14 In specific studies, GPs showed a reasonable level of knowledge about the definition of osteoporosis and its risk factors, but they tended to underestimate the prevalence of the disease.15,16 In data from a large sample of postmenopausal women attending 925 primary care physicians in Australia, 29% of women reported one or more fractures after the menopause.17 However, the great majority (72%) were not on any specific therapy. In my experience, the level of knowledge among GPs is distributed in a patchy manner. In our Health Districts (Azienda Sanitaria Locale 22, Regione Veneto, Italy) our center is the only one providing a bone densitometry service. We have found that only 18% of local GPs directly refer their patients for osteoporosis screening following the regulatory restriction of the Regione Veneto. For patients under the care of other GPs, the referral is made through other specialists (in order of frequency: gynecologists, physiatrists, and orthopedic surgeons) and then inevitably to a much lower extent. In Spain, a survey of 850 GPs revealed a reasonable level of knowledge with a mean correct response rate of 63% in a questionnaire on the most important risk factors.18 Younger practitioners were

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those with the most up-to-date information on the disease. The GPs interviewed also reported that a specific program for osteoporosis was implemented in only 4% of their primary care centers and that bone densitometry was readily available to 27.8% of them. Among GPs in the United Kingdom, a case selection strategy for osteoporosis combined with open access to DXA scans as opposed to no casefinding strategy and no DXA scan access is not associated with an increased prescription rate of bone active agents, but rather with more accurate treatment targeting.19 The implementation of specific programs for osteoporosis management aimed at GPs appears to be cost-effective. The outcomes of such a program set up in Geisenger (Pa, USA)20 are quite striking. The age-adjusted incidence of hip fracture fell significantly and this was associated with substantial reduction in health care costs! The inadequate access to densitometric centers is obviously a factor limiting prevention and treatment of osteoporosis by GPs. However, the implementation of specific screening programs, associated with direct access to DXA evaluation, appears to be effective and even more economically efficient than referral to specialists.21
x Orthopedic surgeons Orthopedic surgeons are the specialists most closely involved with fragility fractures. All peripheral fractures require intervention by the orthopedic surgeon and he/she is usually the first and often only physician seen by the fracture patients. The proportion of patients requiring hospitalization after a symptomatic vertebral fracture varies considerably among different European countries,22 and is of the order of 2% to 10%.23 In the United States, symptomatic vertebral fractures account for 111 999 hospitalizations, a rate of 17.1 per 10 000 women. The annual rate in men was 3.7 per 10 000.24 The hospital unit where patients with symptomatic vertebral fractures are referred has never been specifically investigated, but is likely to be in most cases an orthopedic ward. In the last decade, interest on the part of orthopedic surgeons in recent painful vertebral fractures has increased due to the possibility of successful treatment of symptoms by vertebroplasty.25 In the general strategy for preventing fragility fractures, orthopedic surgeons should play a crucial role, because they are the specialists contacting the patients at highest risk. Patients with low-energy fracture of the wrist, hip, proximal humerus, or ankle have a nearly 4 times greater risk of future fractures than individuals who have never experienced a low-energy fracture.26,27 Despite the fact that orthopedic surgeons see most of the fragility fractures, a number of reports suggest that they do not manage the risk of new fractures. Up to 95% of fracture patients are discharged without adequate determination of the cause of the fracture and several recent reports indicate that the majority of the patients with recent fractures have not been assessed for low BMD.28-33 It has been reported that only 13% of orthopedic surgery departments in Denmark refer their patients with low-energy fracture for DXA

scan34 and only a minority (0%-24%) of the patients underwent a DXA evaluation while in hospital.31,35 Only 2.8% of patients who sustained a fracture of the distal radius were evaluated for the presence of osteoporosis in an American survey.28 According to National Osteoporosis Foundation (NOF) guidelines,5 individuals older than 70 years who have a fragility fracture can be treated for osteoporosis without undergoing a DXA scan. Most of the patients with fragility fractures seen by orthopedic surgeons fall into this category. Yet only 6 of 56 Danish orthopedic surgery departments treat patients with low-energy fractures for osteoporosis.34 It has been reported that both in United States and in the United Kingdom only a small proportion of patients with a hip fracture are discharged with any kind of treatment.33,35,36 This disappointing attitude of orthopedic surgeons to detecting and treating osteoporosis has been recently investigated in a multinational survey supported by the International Osteoporosis Foundation (IOF) and carried out among 3422 orthopedic surgeons in France, Germany, Italy, Spain, the UK, and New Zealand.37 The survey revealed substantial differences between countries in the perception of the osteoporosis problem. German orthopedic surgeons are apparently very keen to order a DXA evaluation in patients with fragility fractures and to prescribe medication, while orthopedic surgeons in the United Kingdom, France, and New Zealand prefer to refer patients to other specialists for both diagnosis and treatment. Overall, more than half of the orthopedic surgeons surveyed said that they received no or insufficient training in osteoporosis. While only approximately 40% of orthopedic surgeons refer patients with a fragility fracture for a bone density test, 60% to 70% admit that the orthopedic surgeon should assume the responsibility for identifying and initiating the assessment of osteoporosis in such patients! The results of the IOF survey37 among European orthopedic surgeons provide a somewhat confusing picture with a self-declared interest for osteoporosis management that contradicts the extremely poor data from patients discharged from orthopedic surgery departments after any type of fracture. However, it should be mentioned that only 1 in 4 European orthopedic surgeons responded to the survey. The surgeons who responded had probably already positively selected themselves! The general impression is that interest in osteoporosis is greater among orthopedic surgeons working predominantly in outpatient clinics rather than in hospitals with a large surgical practice. Indeed, during the IOF survey, German orthopedic surgeons who showed the greatest interest in osteoporosis were largely made up of physicians working in private practice only. It therefore appears that in a busy orthopedic surgery department orthopedic surgeons find it easier to ignore the underlying cause and simply treat the fracture.38 In such a setting, the concept of a fracture liaison nurse has been tried with much success in several countries. The Glasgow center has pioneered this procedure, which consists in delegating a trained nurse of the orthopedic depart-

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ment to ensure that fragility fracture patients receive appropriate osteoporosis evaluation in addition to the fracture management.39 Using this approach, three quarters of patients were considered for BMD testing and 20% of patients were recommended treatment without the need for BMD testing.39 These figures are impressively different from those observed in orthopedic department in all Western countries. Conclusions Two characteristics make osteoporosis a peculiar condition: it is very common and it is of multifactorial origin. For these reasons, a large variety of physicians are involved in its management. The levREFERENCES 1. Kanis JA, Johnell O, Oden A, De Laet C, Jonsson B, Dawson A. Ten-year risk of osteoporotic fracture and the effects of risk factors on screening strategies. Bone. 2002;30:251-258. 2. Ramsey-Goldman R. Missed opportunities in physician management of glucocorticoid-induced osteoporosis? Arthritis Rheum. 2002;46:3115-3120. 3. World Health Organisation. Assessment of fracture risk in screening for osteoporosis. Geneva, Switzerland: WHO Technical Report Series, No 843; 1994. 4. Marshall DA, Sheldon TA, Jonsson E. Recommendations for the application of bone density measurement. Int J Technol Assess Health Care. 1997;13:411-19. 5. National Osteoporosis Foundation (NOF). Physicians Guide to Prevention and Treatment of Osteoporosis.Washington, DC: National Osteoporosis Foundation; 2003. 6. Cauley JA, Robbins J, Chen Z, et al; Womens Health Initiative Investigators. Effects of estrogen plus progestin on risk of fracture and bone mineral density: the Womens Health Initiative randomized trial. JAMA. 2003;290:1729-1738. 7. Cauley JA, Seely DG, Ensud K, Ettinger B, Black D, Cummings SR for the Study of Osteoporotic Fracture Research Group. Estrogen replacement therapy and fracture in older women. Ann Intern Med. 1994;122:9-16. 8. Felson DT, Yuquin Z, Hannan MT, Keil DP, Wilson PWF, Anderson JJ. The effect of postmenopausal estrogen on bone density in elderly women. N Engl J Med. 1993;329:1141-1146. 9. Barrett-Connor E, Gore R, Browner WS; Cummings SR. Prevention of osteoporotic hip fracture: global versus high-risk strategies. Osteoporos Int.1998;8(suppl 1):S2-S7. 10. Rossouw JE, Anderson GL, Prentice RL, et al; Writing Group for the Womens Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Womens Health Initiative randomized controlled trial. JAMA. 2002;288:321-333. 11. Kanis JA. Treatment of osteoporosis in elderly women. Am J Med. 1995;98(suppl 2A):60-66. 12. Schuit SCE, van der Klift M, Weel AEAM, et al. Fracture incidence and association with bone mineral density in elderly men and women: the Rotterdam study. Bone. 2004;34:195-202. 13. Cummings SR, Melton LJ. Epidemiology and outcomes of osteoporotic fractures. Lancet. 2002;359:1761-1767. 14. Edwards L, Fraser M. How do we increase awareness of osteoporosis? Bull Clin Rheumatol. 1997;11:631-644. 15. Werner P, Vered I. Attitudes, knowledge and practice regarding diagnosis of osteoporosis: a survey of Israeli physicians. Aging: Clin Exp Res. 2002;14:52-59. 16. Fleming R, Patrick K. Osteoporosis prevention: pediatricians knowledge, attitudes, and counseling practices. Prev Med.2002; 34:411-421. 17. Eisman J, Clapham S, Kehoe L. Osteoporosis Prevalence and Levels of Treatment in Primary Care: The Australian BoneCare Study. J Bone Miner Res. 2004;19:1969-1975. 18. Perez-Edo L, Ciria Recasens M, Castelo-Branco C, et al. Management of osteoporosis in general practice: a cross-sectional survey of primary care practitioners in Spain. Osteoporos Int. 2004; 15:252-257. 19. Morison LS, Tobias JH. Effect of a case-finding strategy for osteoporosis on bisphosphonate prescribing in primary care. Osteoporos Int. 2005;16:71-77. 20. Newman ED, Ayoub WT, Starkey RH, Diehl JM, Wood GC. Osteoporosis disease management in a rural health care population: hip fracture reduction and reduced costs in postmenopausal wom-

el of knowledge about the disease is inconsistent among specialists and within the same specialty. Generally, the highest level of expertise in osteoporosis is found among rheumatologists and endocrinologists, who make up the largest proportion of bone specialists. Even when the average level of knowledge is acceptable, the intervention is hampered among GPs by the underestimation of the prevalence of the disease and among orthopedic surgeons by their reluctance to intervene. Orthopedic surgeons and GPs are the physicians likely to see the vast majority of osteoporotic patients. The lack of involvement of the former and the underestimation of the prevalence by the latter contributes to making osteoporosis severely underdiagnosed and undertreated.
en after 5 years. Osteoporos Int. 2003;14:146-151. 21. Dhillon V, Creiger J, Hannan J, Hurst N, Nuki G. The effect of a DEXA scanning on a clinical decision making by general practitioners: a randomized, prospective trial of direct access versus referral to a hospital consultant. Osteoporos Int.2003;14:326-333. 22. Johnell O, Gullberg B, Kanis JA. The hospital burden of vertebral fracture in Europe: a study of national register sources. Osteoporos Int.1997;7:138-44. 23. Kanis JA, McCloskey EV. Epidemiology of vertebral osteoporosis. Bone.1992;13:S1-S10. 24. Jacobson SJ, Cooper C, Gottlied MS, et al. Hospitalization with vertebral fracture among aged: A national population-based study, 1986-89. Epidemiology.1992;3:515-518. 25. Hide IG, Gangi A. Percutaneous vertebroplasty: history, technique and current perspectives. Clin Radiol. 2004;59:461-467. 26. Klotzbuecher C, Ross P, Landsman P, Abbott T, Berger M. Patients with prior fractures have an increased risk of future fractures: a summary of the literature and statistical synthesis. J Bone Miner Res. 2000;15:721-739 27. Robinson CM, Royds M, Abraham A, McQueen MM, CourtBrown CM, Christie J. Refractures in patients at least forty-five years old. A prospective analysis of twenty-two thousand and sixty patients. J Bone Joint Surg Am. 2002;84:1528-1533. 28. Freedman KB, Kaplan FS, Bilker WB, Strom BL, Lowe RA. Treatment of osteoporosis: are physicians missing an opportunity? J Bone Joint Surg Am. 2000;82:1063-1070. 29. Bellantonio S, Fortinsky R, Prestwood K. How well are community-living women treated for osteoporosis after hip fracture? J Am Geriatr Soc. 2001;49:1197-1204. 30. Castel H, Bonneh DY, Sherf M, Liel Y. Awareness of osteoporosis and compliance with management guidelines in patients with newly diagnosed low-impact fractures. Osteoporos Int.2001; 12:559-564. 31. Harrington JT, Broy SB, Derosa AM, Licata AA, Shewmon DA. Hip fracture patients are not treated for osteoporosis: a call to action. Arthritis Rheum. 2002;47:651-654. 32. Khan SA, de Geus C, Holroyd B, Russell AS. Osteoporosis follow-up after wrist fractures following minor trauma. Arch Intern Med. 2001;161:1309-1312. 33. Kiebzak GM, Beinart GA, Perser K, Ambrose CG, Siff SJ, Heggeness MH. Undertreatment of osteoporosis in men with hip fracture. Arch Intern Med. 2002;162:22172222. 34. Eiken PA. Osteoporosis: assessment, prevention and treatment in Danish departments of orthopedic surgery [in Danish]. Ugeskr Laeger. 1996;158:5790-5793. 35. Gardner MJ, Flik KR, Mooar P, Lane JM. Improvement in the undertreatment of osteoporosis following hip fracture. J Bone Joint Surg Am. 2002;84:1342-1348. 35. Marshall D, Johnell O, Wedel H. Meta-analysis of how well measures of bone mineral density predict occurrence of osteoporotic fractures. BMJ. 1996;312:1254-1259. 36. Torgerson DJ, Dolan P. Prescribing by general practitioners after an osteoporotic fracture. Ann Rheum Dis.1998;57:378-379. 37. Dreinhofer KO, Anderson M, Feron JM, et al. Multinational survey of osteoporotic fracture management. Osteoporos Int. 2005;16:S44-S53. 38. Stephen AB, Wallace WA. The management of osteoporosis. J Bone Joint Surg Br. 2001;83:316-323. 39. McLellan AR, Gallacher SJ, Fraser M, McQuillian C. The fracture liaison service: success of a program for the evaluation and management of patients with osteoporotic fracture. Osteoporos Int. 2003;14:1028-1034.

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PRENDRA EN CHARGE LE DIAGNOSTIC ET LE TRAITEMENT DE LOSTOPOROSE ?

e terme diagnostique d ostoporose se rfre un tat pathologique du squelette qui prdispose des fractures de fragilit. Lostoporose peut tre secondaire un certain nombre de troubles et les spcialistes qui soccupent de la maladie primitive doivent aussi en traiter les complications osseuses. Cest le cas pour la grande majorit des patientes qui prsentent des maladies rhumatologiques ou endocriniennes. Dans dautres contextes pathologiques, soit le risque dostoporose est ignor, soit les patientes sont adresses (habituellement trop tard) des spcialistes des os . Lostoporose primaire est traditionnellement dfinie comme un tat pathologique o la masse osseuse est basse, apparaissant un ge avanc et en particulier chez les femmes postmnopauses. Mme si plusieurs spcialistes sont impliqus divers titres dans le suivi de ces patientes, la prvalence de lostoporose primaire est telle que les mdecins gnralistes (MG) sont invitablement ceux qui verront le plus grand nombre de patientes ostoporotiques. Ceux-ci connaissent relativement bien la maladie, mais ont tendance beaucoup en sous-estimer la prvalence et les consquences cliniques. Si laccs insuffisant aux centres de densitomtrie limite dautant la possibilit dintervention des MG, la mise en uvre de programmes spcifiques de dpistage semble une bonne stratgie pour augmenter la frquence et lefficacit des traitements pris en charge par les MG. Les patientes ayant des antcdents de fractures ont un risque trs lev de nouvelles fractures et dans ce cas, un traitement prcoce est hautement justifi. Presque toutes les fractures de fragilit ncessitent lintervention des chirurgiens orthopdiques. Cependant, bien que le niveau de connaissance de ces derniers soit bon, ils ne sont gure enthousiastes pour intervenir, surtout cause de leur surcharge de travail. Ainsi, la stratgie qui sest avre la plus fructueuse jusqu maintenant est le recrutement dinfirmires exprimentes dans un service dorthopdie pour veiller ce que les patientes prsentant des fractures de fragilit soient prises en charge correctement pour lostoporose. La prise en charge inefficace de lostoporose par les chirurgiens orthopdistes et les MG contribue faire de cette pathologie une maladie sous-diagnostique et sous-traite.

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Risk factors for osteoporosis: use of bone mineral density in guiding treatment decision
by R. G. Josse and S.A. Jamal, Canada

steoporosis is traditionally defined as a systemic skeletal disease characterized by low bone mass and microarchitectural deterioration of bone tissue with a resultant increase in fragility and risk of fracture.1 Reflecting on this definition, it is clear that bone mineral density (BMD), typically assessed by dual-energy x-ray absorptiometry (DXA) and operationally based on T-scores, is key to defining the condition. Indeed, even if we consider the recently updated definition of osteoporosis:

v v

Robert G. JOSSE, MB, BS, FRCP, FRCPC, FACP Associate Physician-in-Chief, St Michaels Hospital and Professor of Medicine, University of Toronto Toronto, Ontario, CANADA Sophie A. JAMAL, MD, PhD, FRCPC Endocrinologist, St Michaels Hospital and Assistant Professor of Medicine, University of Toronto Toronto, Ontario, CANADA

A skeletal disorder characterized by compromised bone strength predisposing a person to an increased risk of fracture () bone strength reflects the integration of two main features: bone density and bone quality.2

the definition of osteoporosis is still largely based on BMD values. This chapter will review the standard method for assessing BMD, DEXA, the clinical use of BMD testing, and potential pitfalls of using BMD alone to guide treatment decisions. DXA measurements and fracture risk

hile bone mineral density (BMD) assessed by dual-energy x-ray absorptiometry (DXA) is a key component of fracture risk, it has become increasingly clear that other factors such as age, prior fragility fracture, and family history of osteoporosis also influence risk. Indeed, the use of BMD alone as a screening strategy to identify men and women at high risk for fracture has a poor sensitivity; most individuals who fracture have normal BMD. One way to improve the clinical utility of BMD testing is to consider the result together with other clinical risk factors to determine a fracture probability. Clinicians can use these fracture probabilities to guide treatment decisions. In addition, clinicians can apply clinical risk factors to help guide who should have BMD testingthere are some patients in whom the combination of risk factors yields a fracture risk so high or so low that a BMD test will not change treatment decisions. Incorporating clinical risk factors and BMD results is similar to the current approach of combining laboratory data and risk factors to guide treatment decisions in patients with cardiovascular disease. Ultimately, this approach will improve the clinical utility of BMD testing and enhance the care of patients at risk for fracture.
(see French abstract on page 32)

Until recently little distinction was made between definitions of osteoporosis (typically defined by BMD values) and fracture risk. Yet, this distinction is critical, particularly as the goal of treatment is to reduce fracture risk and BMD, while important, is only one component of fracture risk. Indeed, additional risk factors such as age, prior fragility fracture, body mass index, use of corticosteroids, family history of osteoporosis, and current smoking, among others, have been shown in prospective studies to be consistently and strongly associated with fracture risk and are somewhat independent of BMD.3-10 The following section reviews the influence that four of these factors low BMD, age, prior fragility fracSELECTED
BMD DXA LSC SOF

Medicographia. 2006;28:27-32.

ABBREVIATIONS AND ACRONYMS

Keywords: osteoporosis; fracture; risk factor; bone mineral density; dualenergy x-ray absorptiometry; treatment
Address for correspondence: Robert G. Josse, St Michaels Hospital, 61 Queen Street East, 6th Floor, Suite 6122, Toronto, Ontario M5C 2T2, Canada (e-mail: josser@smh.toronto.on.ca)

bone mineral density dual energy x-ray absorptiometry least significant change Study of Osteoporotic Fractures

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ture, and family history of osteoporosis has on fracture risk. Note, that while we will discuss the effect of each separately, patients often have more than one of these risk factors, which may interact to increase fracture risk.

Low BMD by DXA is a risk factor for fracture

x T-scores, Z-scores, and defining osteoporosis DXA measurements correlate well with fracture risk, so although more fractures occur in people with nonosteoporotic BMD scores (Figure 1), the fracture rate is higher the lower the BMD.11,12 Note that there is no fracture threshold or cut point below which fracture risk abruptly increases. Indeed the predictive ability of BMD for hip fracture is similar to the relationship between blood pressure and stroke, and better than the relationship between cholesterol and cardiovascular disease.13 BMD results from DXA are reported using two terms: the T-score and the Z-score. Both of these terms rely on a standard deviation (SD) for the measurement. The SD represents the normal variability in a measurement in a population: the distance between the 5th and 95th percentile of a group covers about 4 SDs. For hip and spine BMD, 1 SD corresponds to about 10% to 15% of the mean value.14 A Z-score is the number of SDs below (minus) or above (plus) the mean value for people of the same age. A T-score is the number of SDs below the mean value of BMD for young (20- to 29-year-old) adults. Osteoporosis is defined as a T-score of -2.5 at any of the lumbar spine, femoral neck, or total hip sites.15 x DXA: which site to use DXA can measure BMD at the spine, hip, forearm, heel, and total body. The diagnosis of osteoporosis varies greatly depending on the measurement site, and the number of sites measured. That said, hip DXA is considered by many to be the gold standard for diagnosing osteoporosis and assessing fracture risk.16-18 Hip DXA is a stronger predictor of hip fracture than BMD at other sites and predicts the risk of all fractures as well as or better than other measurements (Table I).19 Spine BMD measures the lumbar vertebrae, typically L1 to L4. Note that spine BMD can be artifactually increased by degenerative arthritis and aortic calcification, both of which become increasingly common and severe after age 65. As a result, spine BMD may increase after age 65, rather than decrease, which might be seen with BMD measurements at other sites.20 The relationship between BMD and fracture risk is customarily quantified by the relative risk (RR) per standard deviation decrease in BMD. For example, a relative risk to standard deviation ratio (RR/SD) of 1.5 means that a woman with a BMD that is 1 SD below the mean for her age has a 50% higher fracture risk than a woman with a BMD that is average for her age. Among postmenopausal white women, the relationship between hip BMD and hip fracture is about 2.6 RR/SD.17 There are fewer data on the relationship between BMD and fracture risk in men, premenopausal women, and nonwhite populations. However, most experts agree that for men the same threshold as utilized for women is reasonable since for any absolute BMD measurement the aged-adjusted fracture risk is more or less the same.21-24

BMD distribution 60 Fracture rate No. of women with fractures 450 400

Fracture per 1000 person-years

50 40 30 20 10 0

No. of women with fractures

350 300 250 200 150 100 50 <2.0 >1.0 0.5 to 0.0 0.5 to 1.0 1.5 to 2.0 1.5 to 2.0 1.0 to 0.5 0.0 to 0.5 1.0 to 1.5 2.0 to 2.5 3.0 to 3.5 0

BMD T-scores (peripheral)

Figure 1. Population bone mineral density (BMD) distribution, fracture rates, and number of women with fractures.
Adapted from reference 12: Siris ES, Chen YT, Abbott TA, et al. Bone mineral density thresholds for pharmacological intervention to prevent fractures. Arch Intern Med. 2004;164:1108-1112. Copyright 2004, American Medical Association.

Fracture site Wrist Vertebrae Hip

BMD measurement site Forearm Lumbar spine Calcaneus Femoral neck 1.8 1.6 1.6 1.6 2.0 1.3 1.8 n/a 1.8 1.6 1.9 2.6

Table I. Comparison of ability of various bone mass measurements to predict fracture risk. n/a, not available.
Adapted from reference 19: No authors listed. Osteoporosis: review of the evidence for prevention, diagnosis, and treatment, and cost-effective analysis. Status report. Osteoporos Int. 1998(suppl 4):1-88. Copyright 1998, Springer Verlag USA.

Major risk factors Age >65 years Vertebral compression fracture Fragility fracture after age 40 Family history of osteoporotic fracture (especially maternal hip fracture) Systemic glucocorticoid therapy of >3 months duration Malabsorption syndrome Primary hyperparathyroidism Propensity to fall Osteopenia apparent on x-ray film Hypogonadism Early menopause (before age 45)

Minor risk factors Rheumatoid arthritis Past history of clinical hyperthyroidism Chronic anticonvulsant therapy Low dietary calcium intake Smoker Excessive alcohol intake Excessive caffeine intake Weight of <57 kg Weight loss >10% of weight at age 25 Chronic heparin therapy

Table II. Risk Factors for fragility fracture that identify people who should be assessed for osteoporosis.
Adapted from reference 28: Brown JP, Josse RG; Scientific Advisory Council of the Osteoporosis Society of Canada. 2002 clinical practice guidelines for the diagnosis and management of osteoporosis in Canada. CMAJ. 2002;167:S1-S34. By permission of the publisher. Copyright 2002, CMA Media Inc.

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x Risk factors for fracture putting DXA in

Evaluate for treatment

1 major or 2 minor risk factors

Repeat BMD to evaluate response to treatment (at 1-2 years)

Yes

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Osteoporosis

Osteopenia

x Age

The incidence of both vertebral and nonvertebral fractures rises steadily after about age 50 in men and women.33-35 While part of this increased fracture risk is related to bone loss there are also age-related changes, such as alterations in microarchitecture and an increased propensity for falling.36 Such an increase in fracture risk is independent of BMD. As a result, two women with exactly the same BMD, one at age 50 and one at age 80 have very different

* >4-cm historical height loss; >2-cm prospective height loss. Low-to-moderate: 2.5-7.5 mg prednisone/day; moderate-to-high: >7.5 mg prednisone/day. Central DEXA = spine and hip. As defined by the World Health Organization.

Consider repeat BMD testing at 2-3 years to monitor changing risk

Figure 2. Who should be tested for osteoporosis?

Abbreviations: BMD, bone mineral density; DXA, dual-energy x-ray absorptiometry. Adapted from reference 28: Brown JP, Josse RG; Scientific Advisory Council of the Osteoporosis Society of Canada. 2002 clinical practice guidelines for the diagnosis and management of osteoporosis in Canada. CMAJ. 2002;167:S1-S34. By permission of the publisher. Copyright 2002, CMA Media Inc.

Long-term glucocorticoid therapy *

Personnal history of fragility fracture after age 40

Nontraumatic vertebral compression deformities

Clinical risk factor (1 major or 2 minor)

Low BMD by DXA (T-score below --1.5)

Start bisphosphonate therapy

AND Low BMD by DXA (T-score below --1.5)

Repeat BMD by DXA after 1 or 2 years

Risk factors for osteoporosis and use of BMD in guiding treatment Josse and Jamal

Obtain BMD by DXA for follow-up

Consider therapy

Defined in reference 28.

* 7.5 mg prednisone for more than 3 months.

Arbitrary choice of T-score below 1.5; nontraumatic vertebral compression deformities; personal history of fragility fracture after age 40; clinical risk factors.

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Measure BMD by central DXA

context There have been several recently published guidelines concerning the diagnosis and treatment of osteoporosis.25-28 In general, in all of these guidelines, individuals are identified as being at risk for fracture on the basis of clinical risk factors (Table II),28 then referred for BMD testing and subsequently offered intervention if the BMD falls below a given threshold. Guidelines from Europe suggest intervention should be offered to patients who have osteoporosis (T-score of -2.5). In North America, treatment is recommended at T-scores of between --1.5 and --2.0.29 The clinical risk factors noted in all the guidelines are similar and include personal history of fracture, long-term use of glucocorticoids, and age greater than 65 years. Figures 2 and 3 illustrate the recommendations from the recently published Canadian evidence-based guidelines for the assessment and management of osteoporosis.28 A limitation of all these guidelines is the fact that they use BMD as a case-targeting strategy (screening test) and because most fractures occur in patients without an osteoporotic BMD T-score, this test has a poor sensitivity. In addition to guidelines, researchers have developed decision aids designed to help clinicians in selecting patients for BMD testing.27,30,31 These decision aids have used a variety of risk factors, such as age, prior fractures, smoking, and low body weight, to identify patients at high risk for fracture in whom BMD testing would be useful. These tools have a high sensitivity (identifying 95% to 99% of women who have osteoporosis, defined as a T-score of -2.5 at the hip), but a poor specificity (only 10% to 25% of postmenopausal women without osteoporosis would avoid testing).32

fracture risks; the 80-year-old woman will have a several-fold greater risk of hip fracture than the 50-year-old woman.37 The relationship between age and fracture is illustrated in Table III and Figure 4 (next page).

Height loss* kyphosis

Spine radiography

Long-term moderate- to high-dose glucocorticoids

History of low trauma fracture confirmed by radiography

Age

Yes

No

Yes

No

<65 y

65 y

Measure BMD if available

Clinical and risk factor evaluation

Stop Reassess at age 65

Normal

Figure 3. Who should undergo fracture risk assessment and be treated for osteoporosis?
Abbreviations: BMD, bone mineral density; DXA, dual-energy x-ray absorptiometry. Adapted from reference 28: Brown JP, Josse RG; Scientific Advisory Council of the Osteoporosis Society of Canada. 2002 clinical practice guidelines for the diagnosis and management of osteoporosis in Canada. CMAJ. 2002;167:S1-S34. By permission of the publisher. Copyright 2002, CMA Media Inc.

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Age (y) Men 50 55 60 65 70 75 80 85 Women 50 55 60 65 70 75 80 85

Overall average probability 3.3 3.9 4.9 5.9 7.6 10.4 13.1 13.1 6.0 7.8 10.6 14.3 18.9 22.9 26.5 27.0

T-score 1 1.8 1.9 2.5 3.0 3.4 4.1 5.3 5.3 2.4 2.6 3.2 4.0 4.3 4.2 4.6 4.5 0 2.7 3.0 3.6 4.3 5.1 6.3 7.7 7.5 3.8 4.1 5.1 6.3 7.1 7.0 7.7 7.4 -1 4.2 4.6 5.4 6.2 7.4 9.6 11.1 10.4 5.9 6.7 8.2 10.0 11.5 11.8 12.7 12.0 -2 6.3 7.0 7.9 8.8 10.9 14.4 15.8 14.3 9.2 10.7 13.0 15.6 18.3 19.4 20.5 19.1 <-2.5 9.2 10.4 11.6 13.0 16.2 21.5 23.2 21.4 13.9 16.8 20.5 24.9 29.8 32.6 34.5 33.1

with the same BMD, one who had a fractured clavicle at age 55 and one who has no history of fractures. The woman with the history of fracture has about a 1.5- to 2.0-fold greater risk of hip and other types of fractures than does the woman without any fracture history.39,40 The risk of subsequent fractures is influenced by other factors including age, the site of the incident fracture, and the number of prior fractures.10,41-46
x Family history Data from observational studies suggest that a family history of fractures indicates an increased risk for future fractures, and this appears to be type-specific, so that an individual is at increased risk for hip fracture if there is a family history of hip fractures. This effect is independent of hip BMD, and suggests that determinants of fracture risk, besides BMD, presumably must also be inherited.6,39 While most studies have focused on the fractures in female relatives, it is likely that fractures in male relatives also contribute to fracture risk.

Table III. Average 10-year probability (%) of an osteoporotic fracture by sex, age, and BMD expressed as T-score.
Adapted from reference 37: Kanis JA, Johnell O, Oden A, Dawson A, De Laet C, Jonsson B. Ten year probabilities of osteoporotic fractures according to BMD and diagnostic thresholds. Osteoporos Int. 2001;12:989-995. Copyright 2001, Springer Verlag USA.

DXA whom should we test? From this discussion, it is clear that BMD is not the only factor that influences fracture risk and that there are some patients in whom a combination of other risk factors would yield a fracture risk so high that a BMD test may not be required, for example, an 80-year-old female with a prior fragility fracture. Furthermore, while the majority of therapeutic trials report fracture reduction in those with low BMD, there are studies in which patients selected only on the basis of fracture respond to bisphosphonates, which lends support to the concept of possibly limiting BMD testing to those patients in whom fracture risk is not clear. Thus, it is reasonable to first assess fracture risk based on clinical risk factors, which will lead to 3 categories of individuals: (i) patients at very high risk for fracture who should receive treatment regardless of BMD by DXA; (ii) patients at very low risk for fracture (for example, no major or less than 2 minor risk factors listed in Table II), who regardless of BMD, should not need or receive specific treatment; and (iii) patients with moderate risk in whom a BMD test would shift them to either a highrisk or low-risk category. Preliminary data suggest that a smaller number of individuals would require a BMD test if this type of system was used.47 Use of BMD to monitor response to treatment
x How to interpret changes in BMD While initial BMD measurements are used to diagnose osteoporosis, assess fracture risk, and guide treatment decisions, repeat measurements are used to monitor response to treatment. There are several limitations in using BMD for this purpose. First, a response to treatment is not necessarily the same as a gain in BMD. For example, a patient who loses 3% of bone mass at the lumbar spine on treatment may still be showing some response (albeit not a

20

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10-Year fracture probability (%)

70

10

60

50
0 3 2 1 0 1

T-score (SD)

Figure 4. Age and bone mineral density (BMD) are independent risk factors for hip fracture.
Adapted from reference 34: Kanis JA, Johnell O, Oden A, De Laet C, Jonsson B, Dawson A. Ten-year risk of osteoporotic fracture and the effect of risk factors on screening strategies. Bone. 2002;30:251-258. Copyright 2002, Elsevier Science Ltd.

x Prior fragility fracture Clearly, women with low bone mass are more likely to suffer a fragility fracture, and the same low bone mass that increased the likelihood of the first fracture also predisposes them to further fractures. However, even beyond this observation, a history of fracture indicates an increased risk of future fractures regardless of bone mass, which highlights the point that fracture risk is influenced by factors that we cannot yet measure, such as weaker bone strength or an increased predisposition to falls.3,10,13,38 This is well-illustrated using data from the Study of Osteoporotic Fractures (SOF): consider two women

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robust response) because without treatment she could have lost more (5% to 6%). Second, most patients who lose bone mass over the first year of treatment regain much of that bone mass over the next year, even without changing therapy.48 Third, while therapeutic agents result in differing gains in BMD, the reduction in fracture risk with all these agents is similar.49 Fourth, from regression analyses, the gain in BMD with the usual therapeutic agents accounts for only a small part of the observed reduction in fracture (some 5% to 35%). Indeed, a metaanalysis of 12 trials to describe the relationship between improvement in spine BMD and reduction in vertebral fracture risk demonstrates that a 1% improvement in spine BMD was associated with a 0.03 decrease in the relative risk of vertebral fracture. The reductions in risk were greater than predicted from the improvement in BMD; for example, based on improvements in BMD we would expect a reduction in fracture risk of about 20%, but these agents decrease fracture by about 45%.49 Fifth, small changes in BMD are often related to random variations in testing. In order to interpret changes in BMD it is important to keep this in mind and to calculate the least significant change (LSC). The LSC is calculated as 2.8-fold precision error of the test on a specific machine and measurement site. For example, femoral neck BMD in expert centers has a 2% precision error; therefore, changes of less than 5.6% may be due to random variation and would not be of clinical significance.50
x How often should we perform BMD testing?

and the presence of fractures should dictate treatment decisions, not simply changes in BMD. In addition, using BMD to reinforce adherence with therapy has limited value as most problems with adherence occur in the first 3 months of starting treatment, long before BMD is useful enough to assess changes in BMD. Summary BMD assessed by DXA is a powerful tool for identifying patients at risk for osteoporotic fractures, and selective use of densitometry is a valuable technique for identifying and caring for patients with osteoporosis. However, there are some limitations to DXA, the most important of which is that DXA only captures one component of fracture risk. Additional factors that contribute to fracture risk, as described earlier (Table II),28 must be taken into consideration. These risk factors are somewhat independent of BMD and as such can be used together with BMD to improve the clinical utility (sensitivity and specificity) of fracture prediction. It follows from this discussion that the best approach to identify and treat patients at high risk for fracture is the approach suggested by Kanis et al, in which clinicians concentrate on a combination of easily identifiable and/or modifiable risk factors (such as age, prior fracture, body mass index, current smoking, etc) in addition to DXA to provide a 5- to 10-year fracture probability.47 Clinicians can use these fracture probabilities to guide treatment decisions. This approach is similar to the current use of clinical risk factors in combination with laboratory data to predict risk and guide treatment decisions in patients with cardiovascular disease. Incorporation of such fracture prediction data into BMD reports would make them more clinically useful.
thresholds for pharmacological intervention to prevent fractures. Arch Intern Med. 2004;164:1108-1112. 13. Cummings SR, Cosman F, Jamal SA, eds.Osteoporosis. An evidenced-Based Guide to Prevention and Management. Philadelphia: Pa: American College of Physicians; 2002. 14. Grampp S, Genant HK, Mathur A, et al. Comparisons of noninvasive bone mineral measurements in assessing age-related loss, fracture discrimination, and diagnostic classification. J Bone Miner Res.1997;12:1954-1955. 15. Kanis JA, Melton LJ, Christiansen C, Johnston CC, Khaltaev N. The diagnosis of osteoporosis. J Bone Miner Res.1994;9:11371141. 16. Cummings SR, Black DM, Nevitt MC, et al. Bone density at various sites for prediction of hip fractures. The Study of Osteoporotic Fractures Research Group. Lancet.1993;341:962-963. 17. Marshall D, Johnell O, Wedel H. Meta-analysis of how well measures of bone mineral density predict occurrence of osteoporotic fractures. BMJ. 1996;312:1254-1259. 18. Kanis JA, Gluer CC. An update on the diagnosis and assessment of osteoporosis with densitometry. Osteoporos Int. 2000; 11:192-202. 19. No authors listed. Osteoporosis: review of the evidence for prevention, diagnosis, and treatment, and cost-effective analysis. Status report. Osteoporos Int. 1998(suppl 4):1-88. 20. Steiger P, Cummings SR, Black DM, Spencer NE, Genant HK. Age-related decrements in bone mineral density in women over 65. J Bone Miner Res. 1992;7:625-632. 21. Kanis JA, Johnell O, Oden A, De Laet C, Mellstrom D. Diagnosis of osteoporosis and fracture threshold in men. Calcif Tissue Int. 2001;69:218-221. 22. Ross P, Huang C, Davis J, et al. Predicting vertebral deformity

The optimum frequency with which to perform BMD testing is not known. In order to decide the optimum frequency, one must consider that most patients gain BMD over the first year of treatment with therapeutic agents. Also, an increase or decrease in BMD may be due to measurement error
REFERENCES 1. Consensus development conference: diagnosis, prophylaxis, and treatment of osteoporosis. Am J Med.1993;94:646-650. 2. Osteoporosis prevention, diagnosis, and therapy. NIH consensus statements 2000. 2000;17:1-45. 3. Kanis JA, De Laet C, Delmas P, et al. A meta-analysis of previous fracture and fracture risk. Bone. 2004; 35:375-382. 4. Kanis JA, Johansson H, Oden A, et al. A meta-analysis of prior corticosteroid use and fracture risk. J Bone Miner Res. 2004;19: 893-899. 5. Kanis JA, Johnell O, Oden A, et al. Smoking and fracture risk: a meta-analysis. Osteoporos Int. 2005;16:155-162. 6. Kanis JA, Johansson H, Oden A, et al. A family history of fracture and fracture risk: a meta-analysis. Bone. 2004;35:1029-1037. 7. Kanis JA, Johansson H, Johnell O, et al. Alcohol intake as a risk factor for fracture. Osteoporos Int. 2005;16:581-589; Epub ahead of print. 2004, Sept 29. 8. Van Staa TP, Leufkens HGM, Abenhaim L, Zhang B, Cooper C. Use of oral corticosteroids and risk of fractures. J Bone Miner Res. 2001;15:993-1000. 9. Van Staa TP, Leufkens HGM, Cooper C. The epidemiology of corticosteroid-induced osteoporosis: a meta-analysis. Osteoporosis Int. 2002;13:777-787. 10. Klotzbuecher CM, Ross PD, Landsman PB, Abbott TA 3rd, Berger M. Patients with prior fractures have an increased risk of future fractures: a summary of the literature and statistical synthesis. J Bone Miner Res. 2000;15:721-739. 11. Seeley DG, Browner WS, Nevitt MC, Genant HK, Scott JC, Cummings SR. Which fractures are associated with low appendicular bone mass in elderly women? The Study of Osteoporotic Fractures Research Group. Ann Intern Med.1991;115:837-842. 12. Siris ES, Chen YT, Abbott TA, et al. Bone mineral density

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using bone densitometry at various skeletal sites and calcaneous ultrasound. Bone. 1995;16:325-332. 23. de Laet CE, Van Hout BA, Burger H, Weel AE, Hofman A, Pols HAP. Hip fracture prediction in elderly men and women: validation in the Rotterdam study. J Bone Miner Res. 1998;13:15871593. 24. Lunt M, Felsenberg D, Reeve J, Benevolenskaya L, Cannata J, Dequeker J. Bone density variation and its effect on risk of vertebral deformity in men and women studied in thirteen European Centres: the EVOS Study. J Bone Miner Res.1997;12:1883-1894. 25. Kanis JA, Delmas P, Burckhardt P, Cooper C, Torgerson D. Guidelines for diagnosis and management of osteoporosis. Osteoporos Int. 1997;7:390-406. 26. No authors listed. Clinical guidelines for the prevention and treatment of osteoporosis. London, UK: Royal College of Physicians. 1999. 27. Physicians guide to prevention and treatment of osteoporosis. Washington, DC: National Osteoporosis Foundation; 1998. 28. Brown JP, Josse RG; Scientific Advisory Council of the Osteoporosis Society of Canada. 2002 clinical practice guidelines for the diagnosis and management of osteoporosis in Canada. CMAJ. 2002;167:S1-S34. 29. Kanis JA, Torgerson D, Cooper C. Comparison of the European and USA practice guidelines for stoeoporosis. Trends Endocrinol Metab. 2000;11:28-32. 30. Ungar WJ, Josse R, Lee S, et al. The Canadian SCORE questionnaire: optimizing the use of technology for low bone density assessment. Simple Calculated Osteoporosis Risk Estimate. J Clin Densitom. 2000;3:269-280. 31. Cadarette SM, Jaglal SB, Kreiger N, McIsaac WJ, Darlington GA, Tu JV. Development and validation of the osteoporosis risk assessment instrument to facilitate selection of women for bone densitometry. CMAJ. 2000;162:1289-1294. 32. Cummings SR, Bates D, Black DM. Clinical use of bone densitometry: scientific review. JAMA. 2002;288:1889-1897. 33. Melton LJ. Epidemiology of fractures. In: Riggs BL, Melton LJ, eds. Osteoporosis Etiology, Diagnosis, and Management. Philadelphia, Pa: Lippincott-Raven; 1995:225-248. 34. Kanis JA, Johnell O, Oden A, De Laet C, Jonsson B, Dawson A. Ten-year risk of osteoporotic fracture and the effect of risk factors on screening strategies. Bone. 2002;30:251-258. 35. Hui SL, Slemenda CW, Johnston CC. Age and bone mass as predictors of fracture in prospective study. J Clin Invest.1988;81: 1804-1809. 36. Nguyen T, Sambrook SP, Kelly P, Jones G, Freund J, Eisman J. Prediction of osteoporotic fractures by postural instability and bone density. BMJ. 1993;307:1111-1115. 37. Kanis JA, Johnell O, Oden A, Dawson A, De Laet C, Jonsson B. Ten year probabilities of osteoporotic fractures according to BMD and diagnostic thresholds. Osteoporos Int. 2001;12:989-995. 38. Ross PD, Genant HK, Davis JW, Miller PD, Wasnich RD. Predicting vertebral fracture incidence from prevalent fractures and bone density among non black, osteoporotic women. Osteoporos Int.1993;3:120-126. 39. Cummings SR, Nevitt MC, Browner WS, et al. Risk factors for hip fracture in white women. Study of Osteoporotic Fractures Research Group. N Engl J Med. 1995;332:767-773.

40. Melton LJ, Wahner HW, Riggs BL. Bone density measurement. J Bone Miner Res. 1988;3:ix-x. 41. Wasnich RD, Davis JW, Ross PD. Spine fracture risk is predicted by non-spine fractures. Osteoporos Int. 1994;4:1-5. 42. Davis JW, Grove JS, Wasnich RD, Ross PD. Spatial relationships between prevalent and incident spine fractures. Bone. 1999;24:261-264. 43. Ross PD, Davis JW, Epstein RS, Wasnich RD. Pre-existing fractures and bone mass predict vertebral fracture incidence in women. Ann Intern Med. 1991;114:919-923. 44. Tromp AM, Smit JH, Deeg DJH, Bouter LM, Lips P. Predictors for falls and fractures in the longitudinal aging study Amsterdam. J Bone Miner Res. 1998;13:1932-1939. 45. Black DM, Palermo L, Nevitt MC, Genant HK, Christensen L, Cummings SR. Defining incident vertebral deformity: a prospective comparison of several approaches. The Study of Osteoporotic Fractures Research Group. J Bone Miner Res.1999;14:90-101. 46. Fox KM, Cummings SR, Williams E, Stone K. Study of Osteoporotic Fractures. Femoral neck and intertrochanteric fractures have different risk factors, a prospective study. Osteoporos Int. 2000;11:1018-1023. 47. Kanis J, Borgstrom F, De Laet C, et al. Assessment of fracture risk. Osteoporos Int. 2005;16:581-589. 48. Cummings SR, Palermo L, Browner W, et al. Monitoring osteoporosis therapy with bone densitometry: misleading changes and regression to the mean. Fracture Intervention Trial Research Group. JAMA. 2000;8:1318-1321. 49. Cummings SR, Karpf DB, Harris F, et al. Improvement in spine bone density and reduction in risk of vertebral fractures during treatment with antiresorptive drugs. Am J Med. 2002; 112:281-289. 50. Gluer CC. Monitoring skeletal changes by radiological techniques. J Bone Miner Res. 1999;14:1952-1962.

FACTEURS DE RISQUE DE LOSTOPOROSE : UTILISATION DE LA DENSIT MINRALE OSSEUSE POUR GUIDER LA DCISION THRAPEUTIQUE

ien que la densit minrale osseuse (DMO) value par absorptiomtrie bi-nergtique aux rayons X (DXA, dual-energy x-ray absorptiometry) soit un lment cl du risque de fracture, il devient de plus en plus vident que dautres facteurs tels que lge, un antcdent de fracture de fragilit, et des antcdents familiaux dostoporose influent aussi sur ce risque. Lutilisation de la DMO seule comme stratgie de dpistage pour identifier les hommes et les femmes ayant un risque lev de fracture prsente une faible sensibilit, car la plupart des personnes qui prsentent une fracture ont une DMO normale . Lutilit clinique de cet examen peut tre amliore en associant la DMO dautres facteurs de risque clinique pour en dduire une probabilit dune fracture, sur laquelle le clinicien pourra fonder sa dcision thrapeutique. Les facteurs de risque clinique peuvent galement tre utiliss pour dterminer quels patients doivent tre soumis une mesure de la DMO, tout en sachant que chez certains patients lassociation de facteurs de risque implique un risque de fracture tellement lev ou tellement faible que la valeur de la DMO ne changera pas la dcision thrapeutique. Cette association de la DMO et des facteurs de risque clinique suit la mme logique que lassociation dsormais courante des rsultats des dosages biologiques et des facteurs de risque pour guider les dcisions thrapeutiques chez les patients prsentant une pathologie cardiovasculaire. Une telle approche est garante dune meilleure utilit clinique de la DMO et dun meilleur suivi des patients prsentant un risque de fracture.

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Eugene McCLOSKEY, MD Academic Unit of Bone Metabolism Metabolic Bone Center Northern General Hospital Sheffield, UNITED KINGDOM

Health-related quality of life in osteoporosis

by E. McCloskey, United Kingdom

ealth-related quality of life (HR-QOL) has emerged as an important attribute of clinical investigation and patient care. It is a reflection of the way that patients perceive and react to their health status, and incorporates their physical, functional, emotional, and mental well-being. HR-QOL is usually captured by questionnaires that are either generic health-status instruments or disease-specific instruments. Generic HR-QOL instruments (eg, the SF-36 [36-Item Short-Form]) are designed to be applicable across a wide range of populations and diseases. A number of osteoporosis-specific instruments have also been developed over the last 10 to 15 years (eg, OPAQ [Osteoporosis Assessment Questionnaire], QUALEFFO [Quality of Life Questionnaire of the European Foundation for Osteoporosis], QUALIOST [QUAlity of LIfe questionnaire in OSTeoporosis]), but few comparative studies have been undertaken to assess the relative performances of these instruments. The morbidity associated with osteoporosis is almost exclusively related to the occurrence of fragility fractures, and differs between genders and across skeletal sites of fracture. Hip and clinical vertebral fractures appear to cause the greatest and comparable decreases in QOL. Limited data suggest that some osteoporosis therapies can improve HR-QOL by decreasing the incidence of fractures. Continuing use of HR-QOL instruments will lead to a better understanding of the burden of osteoporosis and will allow the development of therapeutic strategies to minimize this burden for patients and society.
(see French abstract on page 39)

he immense impact of osteoporosis and its related fractures on worldwide health resources is widely recognized. Osteoporosis in women is associated with more days in hospital per year than several other major conditions, including myocardial infarction, breast cancer, and chronic obstructive pulmonary disease,1 while hip fractures account for more than 20% of orthopedic bed occupancy in the UK.2 The combined social care and acute costs for treating the current level of osteoporotic fractures in the UK have been estimated at more than 1.7 billion annually.3 The majority of osteoporotic fractures give rise to significant morbidity and, at least in the case of hip and vertebral fractures, are associated with significant mortality, particularly in the elderly.4-8 Of those patients surviving for at least 1 year after a hip fracture, 40% still cannot walk independently, 60% have difficulty with at least one activity of daily living (ADL) and 20% are institutionalized.9,10 Vertebral fractures are associated with acute and chronic back pain, the consequences of kyphosis (loss of height, abdominal protuberance, breathing difficulties, early satiety with reflux and other gastrointestinal symptoms, stress incontinence) and depression.11 While the impact on quality of life appears rather obvious, it is only relatively recently that data have been reported for the impact of fractures on health-related quality of life (HR-QOL) using well-defined and validated tools. This impact is important to document, not just because of the consequences for an individual, but also to allow estimates of the impact for society and the derivation of utility values to inform cost-effectiveness analysis.12,13 The latter can facilitate the development of intervention strategies as well as permitting comparisons of the effects of therapies both within and across diseases within the setting of finite health care resources. This article will give some background to HR-QOL, the impact of osteoporosis, and will describe some of the emerging data about the effects of osteoporosis therapies on HR-QOL. Health-related quality of life Over the past 30 years, quality of life (QOL) has emerged as an important attribute of clinical investigation and patient care, and is now a key component of what has recently come to be known as patient-reported outcomes.14 But what do we mean by health-related quality of life? It is clear that HR-QOL is a reflection of the way that patients perceive and react to their health status, not simply a description of a patients health or functional status.13 It incorporates their physical, functional, emotional, and mental well-being, but does not capture
SELECTED
ADL BMD HR-QOL QALY QOL
ABBREVIATIONS AND ACRONYMS

Medicographia. 2006;28:33-39.

Keywords: osteoporosis; quality of life; fracture; disability; therapy

Address for correspondence: Dr Eugene McCloskey, Academic Unit of Bone Metabolism, Metabolic Bone Center, Sorby Wing, Northern General Hospital, Herries Road, Sheffield S5 7AU, UK (e-mail: e.v.mccloskey@sheffield.ac.uk)

activity of daily living bone mineral density health-related quality of life quality-adjusted life years quality of life

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Generic SF-36: Medical Outcomes Study 36-Item Short Form NHP: Nottingham Health Profile SIP: Sickness Impact Profile QWB: Quality of Well-Being Scale* HUI: Health Utilities Index* EQ-5D: EuroQol Instrument*

Osteoporosis-specific OQLQ and mini OQLQ: Osteoporosis Quality of Life Questionnaire OPAQ: Osteoporosis Assessment Questionnaire QUALEFFO: Quality of Life Questionnaire of the European Foundation for Osteoporosis OPTQoL: Osteoporosis Targeted Quality of Life Questionnaire OFDQ: Osteoporosis Functional Disability Questionnaire QUALIOST: Quality of life Questionnaire in Osteoporosis

*Most widely used systems for the derivation of health state values or utilities. Recently, the SF-6D has been developed to derive utilities from SF-36.

Table I. Quality of life instruments used in studies of osteoporosis.

directly the impact of nonmedical factors, such as family issues, friends, jobs, and other life events, unless these have a direct effect on health. HR-QOL is usually measured through the administration, by the individual or an interviewer, of an instrument (usually a questionnaire), which tries to achieve a balance between being too simple or too sophisticated. Commonly, such instruments are made up of a number of items or questions that are divided between a number of domains or dimensions that refer to specific areas of health. Examples would include physical function (usually encompassing mobility and self-care) or emotional function (encompassing depression, anxiety, and mental well-being). Such instruments can be devised to measure cross-sectional differences in HR-QOL at a point in time (eg, between patients with and without osteoporotic fractures) or longitudinal changes in HR-QOL within patients during a period of time (eg, in clinical trials or recovery post fracture). Regardless of their use, the instruments need to undergo a process of validation to demonstrate that they actually measure what they are supposed to measure and to optimize their signal-to-noise ratio so that they are reliable and/or responsive.13 Broadly speaking, two categories ofquestionnaires have now been developed, namely generic healthstatus instruments and disease-specific instruments (Table I). Generic HR-QOL instruments are designed to be applicable across a wide range of populations and interventions.15 To date, the 36-Item Short-Form (SF-36) health survey has been the most commonly used generic HR-QOL measure, but a recent review of 7 generic instruments reported that none of these performed uniformly better or worse than the others.15 A number of osteoporosis-specific instruments have also been developed over the last 10 to 15 years (Table I) and have recently been the subject of reviews.12,16 Few comparative studies have been undertaken to assess the relative performances of these instruments, the most widely used of which are the Osteoporosis Assessment Questionnaire (OPAQ) and Quality of Life Questionnaire of the European Foundation for Osteoporosis (QUALEFFO). Clearly, the chosen instrument should be the most relevant for the partic-

ular HR-QOL measurement needs within a study. It has also been recommended that in most studies of HR-QOL consideration should be given to using a combination of disease-specific and generic instruments.12,13 The advantage of using generic instruments is that several of these, particularly the Quality of Well-Being (QWB) Scale, Health Utilities Index (HUI), EuroQol (EQ-5D) Instrument, and more recently the SF-36 derived SF-6D, are preference-based measures designed to summarize HRQOL in a single number or utility ranging from 0 (worst imaginable health state) to 1 (best imaginable health state). The mechanisms by which these preference-based measures are derived, including visual analog scales, time trade-off, or standard gamble techniques, are beyond the scope of this review and are described in more detail elsewhere.12,17,18 They are, however, critical to economic evaluations of the cost-effectiveness of therapeutic interventions across the full range of health, including osteoporosis, as they encompass the effect of the intervention on morbidity as well as mortality. A range of indices has been developed to combine quality and quantity of life, the best known of which is quality-adjusted life-years (QALY). These are calculated by aggregating the number of days/years gained from a drug or health care intervention, weighted by a proportion that represents the relative value attached to the health state (ie, length of life iQOL).19 Economic results can be presented as the cost per QALY gained or, more correctly, the incremental cost per QALY gained (ie, taking into account the costs and benefits of any competing intervention) and is increasingly used in informing decisions about the allocation of resources within finite health care budgets.20,21 Recently, attention has been brought to bear, however, on discrepancies between utilities derived by different instruments within the same populations,22,23 suggesting that there may be potential implications for the interpretation and comparability of health outcome studies and economic analyses.23 Fractures and HR-QOL in osteoporosis The morbidity associated with osteoporosis is almost exclusively related to the occurrence of fragility fractures. Low bone mineral density (BMD), a central component of the definition of osteoporosis as a disease,24 does not appear to have direct effects on quality of life once adjustments are made for age or other comorbidities.25 It is clear that the effect on HR-QOL differs between genders and across skeletal sites of fracture. For example, in the Canadian Multicenter Osteoporosis Study, HR-QOL measured by the Health Utilities Index (HUI) was significantly lower in both women and men who had experienced a hip fracture as compared with those without fractures.26 In women, a past history of pelvic fracture had a similar impact as a hip fracture and a history of clinical vertebral deformity was negatively associated with pain, self-care, and emotion. No comment could be made for pelvic or clinical vertebral fractures in men due to a low number of

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events. In women, a lower-body fracture was negatively associated with self-care, pain, and emotion, whereas it was associated with decreased dexterity in men. In both sexes, upper-body and wrist and hand fractures appeared to have a minimal impact on HR-QOL apart from a negative association with manual dexterity in men.26 This is not surprising, perhaps, given that most forearm fractures usually demonstrate good fracture healing with regain of function. QOL data obtained in 40 patients with distal forearm fracture using the EuroQol (EQ-5D) instrument have demonstrated that while there was considerable loss of HR-QOL in the first 3 months, recovery was fast, and the total QOL loss was 0.05 for 1 year, ie, 0.05 QALY.27 In contrast, it is now becoming clear that clinical vertebral fractures also have a severe impact on QOL, similar to or greater than that of hip fractures.28 The impacts of different fractures on health and QOL are reviewed in more detail below.
x Hip fractures

Over 6 years, 120 individuals sustained an incident hip fracture, of whom 18% died within the first 6 months afterwards. Among survivors, there was a sustained decline in all of the physical functions at 6 weeks after the fracture with little improvement by 6 months (Figure 1). Prefracture physical function, mental status, and depression were the factors significantly associated with physical function at 6 months after the fracture.31 Several studies have also undertaken formal QOL assessments in patients with hip fracture.29,32-34 In a prospective case-control study, the revised Osteoporosis Assessment Questionnaire (OPAQ2) and the SF-36 were completed on two separate occasions,

Before fracture 90 80 70 Patients (%) 60 50 40 30 20 10 0 Climb stairs Dress unaided Walk unaided Walk 1/2 mile 6 months after fracture

Virtually all patients with hip fracture are admitted to hospital, have surgery, and undergo relatively lengthy periods of rehabilitation. Cognitive impairment and other disabilities including deafness and poor vision may hamper the collection of robust information on HR-QOL in this population. Nevertheless, there is overwhelming evidence that hip fracture results in significant impairment of functional capacity that may be irretrievable in the long term, even in those returning to the community. For example, in a cross-sectional study of 92 cases of hip fracture recruited 6 to 12 months after the fracture, and age-matched controls, the fracture group was slower on the Timed Up & Go assessment (19 vs 10.5 seconds), had more difficulties with balance, was less active, and was more dependent than the control group for activities of daily living. Furthermore, the fracture cases had significantly lower values across all eight domains of the SF-36 questionnaire.29 In a further case-control study undertaken an average of 7 years after a trochanteric hip fracture, only half of the surviving fracture cases were residing in their own homes or service apartments compared with over 90% of the controls.30 Only 35% of the patients compared with 79% of the controls were able to move about independently and the patients were significantly worse at ADLs, required more home help, and had fewer social contacts and outdoor hobbies than the controls. The potential drawback of such studies is that the crosssectional nature may not detect or completely account for a lower functional status or QOL that existed prior to the fracture. Prospective data on the impact of hip fracture are available from a study in which functional status was assessed before and after the fracture event as part of a longitudinal study of health and aging (Figure 1).31 In this prospective cohort study of over 2800 men and women aged 65 years and older living in the community, self-reported performance of dressing, transferring, walking across a room, climbing stairs, and walking one-half mile were obtained before the fracture occurred and 6 weeks and 6 months post-fracture.

Figure 1. Impact of hip fracture on independence and mobility.

Adapted from reference 31: Marottoli RA, Berkman LF, Leo-Summers L, Cooney LM Jr. Predictors of mortality and institutionalization after hip fracture: the New Haven EPESE cohort. Established Populations for Epidemiologic Studies of the Elderly. Am J Public Health. 1994;84:1807-1812. Copyright 1994, American Public Health Association.

within 1 week of fracture and 12 to 15 weeks after fracture; the controls completed both questionnaires on two occasions 12 weeks apart. The scores on both instruments were stable in the control subjects, but the scores across all domains were lower at baseline in the hip-fracture group and deteriorated further over the next 3 months after the fracture (Figure 2, next page).32 In a further study, 90 patients with recent femoral neck fractures completed the EQ-5D instrument at 1 week, 4 months and a mean of 17 months post-fracture.33 Patients with severe cognitive dysfunction, not living independently or unable to walk unhindered prefracture, were excluded from the study. The EQ-5D scores decreased from 0.78 before the fracture (based on recall) to 0.59 at 4 months and 0.51 at 17 months after surgery. Similar values for hip fracture have been reported by Tosteson and colleagues.35 The decrease was significantly larger among patients with displaced fractures at baseline, partly but not completely related to healing complications.35 Interestingly, the rated prefracture EQ-5D scores showed good correspondence with the scores of an age-matched reference population. This contrasts with prospective data using the EQ-5D before and after hip fracture in a population of community-dwelling elderly women recruited into a clinical trial that may offer a more valid estimate of the loss in health status associated with a hip fracture.36 The mean scores at 6 and 12 months after hip fracture were 0.49 and 0.48, MEDICOGRAPHIA, VOL 28, No. 1, 2006 35

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Baseline A. Fracture patients Physical function Role physical Bodily pain General health Vitality Social function Role emotional Mental health 0 B. Control subjects 25 50 75
* *

3 months post hip fracture OPAQ2 Physical Activity-social Symptoms General health Body image Social support Psychological Tension 100 0 25 50 75 100
* * *

SF-36
*

Figure 2. Mean absolute SF-36 and OPAQ2 scores at baseline and 3 months after hip fracture, reported by fracture patients (A) and controls (B). *P<0.05 between baseline and the assessment at 3 months.
Adapted from reference 32: Randell AG, Nguyen TV, Bhalerao N, Silverman SL, Sambrook PN, Eisman JA. Deterioration in quality of life following hip fracture: a prospective study. Osteoporos Int. 2000;11:460-466. Copyright 2000, Springer Verlag, USA.

Physical function Role physical Bodily pain General health Vitality Social function Role emotional Mental health 0 25 50 Score 75 100
*

Physical Activity-social Symptoms General health Body image Social support Psychological Tension 0 25 50 Score 75 100

respectively, but prior to the fracture patients had a significantly lower health state value compared with the average for their age (0.60 vs 0.73).36
x Vertebral fractures Several studies have now reported the impact of vertebral fractures on symptoms, functional status, and/or QOL. In one of the earliest studies of back pain and vertebral fractures in Japanese-American and white postmenopausal women, back pain was associated with recent vertebral fractures (detected within the previous 4 years).37 Back pain increased progressively with the number and severity of fractured vertebrae: a history of a single recent fracture was associated with a 2.8-fold increase in the odds of back pain, two recent fractures with a 7.8-fold increase, and three recent fractures with a 21.7-fold increase. The same research group reported that in a prospective study, vertebral fractures occurring after the initial radiograph were strong predictors of back pain and disability at the end of follow-up.38 In this longitudinal analysis, new fractures were associated (odds ratio [OR]=6.4; 95% confidence interval [CI]=2.6, 15.6) with increases in back pain frequency (relative to prefracture levels). Hall and colleagues reported a study in which the number, position, and severity of vertebral fractures on lateral spine radiographs were recorded in 100 female clinic patients with vertebral fractures.39 QOL was measured using the SF-36 and a utility score derived. The fracture subjects had a mean of 3 vertebral fractures and the mean time since last fracture was approximately 5 years. A total of 100 agematched controls without vertebral fractures were recruited. Both cases and controls were judged to be free of radiological evidence of degenerative disc or spine disease. The SF-36 physical function scores

were significantly lower in the women with fracture (3611 vs 489, P<0.001) as were the mental health component (5011 vs 548, P<0.05) and the utility scores (0.640.08 vs 0.720.07, P<0.001). In contrast to other studies, they observed no correlation between QOL and either the number of vertebral fractures or the time since last vertebral fracture. The impact of the first vertebral fracture on HR-QOL has been demonstrated in many of the validation studies for the disease-specific instruments. For example, the performance of the QUALEFFO was studied in 159 patients aged 55 to 80 years with clinical osteoporosis compared with age- and sexmatched controls without chronic back pain or vertebral fractures.40 The median scores of QUALEFFO were significantly higher in patients with vertebral fractures than in controls in all five domains (P<0.001), consistent with decreased QOL in patients with osteoporosis. Across patients and controls, the QUALEFFO showed a significant trend for increasing scores with increasing numbers of fractures, but the significance was largely determined by the step from no fracture to 1 fracture.40 Larger studies have, however, shown a dose response between the number of fractures and HR-QOL. In a subgroup of women enrolled to the phase 3 vertebral fracture study of raloxifene (the Multiple Outcomes of Raloxifene Evaluation [MORE] study), 449 women with vertebral fractures were compared with 302 women with low BMD, but no evidence of vertebral fracture.41 The instruments used included the QUALEFFO, the Nottingham Health Profile (NHP), and the EQ-5D. The women with vertebral fractures were slightly, but significantly, older (mean 69 vs 66 years, P<0.001) and had a higher prevalence of reported nonvertebral fractures (25% vs 36%; P=0.002). The QUALEFFO scores were higher, indi-

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cating worse HR-QOL in the fracture group (3617 vs 2614, P<0.001), and increased progressively with increasing numbers of vertebral fractures, especially lumbar fractures (P<0.001).41 Very similar results were reported from another subgroup analysis within the MORE study using the OPAQ.42 At baseline, women with a prevalent vertebral fracture had significantly lower OPAQ scores on physical function, emotional status, clinical symptoms, and overall HR-QOL compared with women without a prevalent fracture (all P<0.01) and HR-QOL scores were lower with each additional fracture (Figure 3). The more marked impact of vertebral fractures in the lumbar region was again noted. It has also been suggested that the severity of vertebral fractures, as judged by the loss of vertebral height, may also contribute to impaired HR-QOL independently of the number of fractures.43 Patients with the most severe vertebral fractures (Grade 3) as classified by the semiquantitative method of Genant (or the SQ

disability at the end of follow-up, and resulted in greater back pain and disability than for prevalent fractures.38 These observations suggest that studies of incident vertebral fractures are required to better characterize the effects on HR-QOL. During the MORE study, 1058 women at non-European sites had follow-up radiographs and OPAQ assessments, and 157 (14.8%) developed at least 1 incident vertebral fracture during the 3-year study period.42 Of these, 151 (96.2%) had at least 1 prevalent vertebral fracture at baseline. The incident vertebral fractures significantly decreased OPAQ scores on physical function, emotional status, clinical symptoms, and overall HR-QOL (all P<0.001) to a similar or greater degree than prevalent fractures.42 Interestingly, in a further analysis of a subset of 361 women with prevalent vertebral fractures from the MORE study, 67 patients sustained an incident fracture in a vertebra that was not fractured at baseline (incident vertebral fractures).46 Twenty of these

95 90 85 Mean OPAQ score 80 75 70 65 60 55 50 0 1 2 3 4 Physical function

0 Fracture (n=371) 1 Fractures (n=559) 2 Fractures (n=250) 3 Fractures (n=102) 4 Fractures (n=113)

Figure 3. Number of prevalent vertebral fractures and progressive decreases in health-related quality of life (HR-QOL; assessed by the Osteoporosis Assessment Questionnaire [OPAQ]). All P<0.001 for linear trend for each dimension/ overall HR-QOL. For subjects with 0 to 1 fracture, P<0.05 for physical function and emotional status.
Adapted from reference 42: Silverman SL, Minshall ME, Shen W, Harper KD, Xie S. The relationship of health-related quality of life to prevalent and incident vertebral fractures in postmenopausal women with osteoporosis: results from the Multiple Outcomes of Raloxifene Evaluation Study. Arthritis Rheum. 2001;44:2611-2619. Copyright 2001, John Wiley & Sons.

0 1 2 3 4 Emotional status

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method) had a significantly lower overall HR-QOL score with significantly lower physical function, symptoms, and emotional status dimension scores than nonfractured patients at entry to a trial of teriparatide.43 Several studies have suggested an interaction between the time since a vertebral fracture and the degree of pain or impairment of function and QOL. For example, in a prospective cross-sectional casecontrol study, 51 women with osteoporosis with at least one vertebral fracture were divided into two subgroups, according to the delay since the last vertebral fracture had occurred (ie, more or less than 3 months).44 NHP scores for physical mobility and energy were significantly poorer (P<0.05) in women with osteoporosis with a recently diagnosed vertebral fracture, compared with other women with osteoporosis.44 In a further study, 50 patients with vertebral fractures were split into two groups based on the time since fracture being less than or greater than 2 years.45 Patients with the more recent fractures had greater pain, social extroversion, and poorer well-being, but there was no difference in limitations in everyday life.45 In one of the earliest studies, new fractures that occurred after the initial radiograph were strong predictors of back pain and

were accompanied by signs and symptoms necessitating immediate doctors attention (clinical vertebral fractures) and 47 vertebral fractures were only diagnosed on radiographs (subclinical vertebral fractures). Incident vertebral fractures (clinical and subclinical) were associated with an increase in back pain (mean score change 6.4; 95% CI 2.1-10.7), deterioration of physical function (mean score change 2.4; 95% CI 0.1-4.8), and worse general health perception (mean score change 3.8; 95% CI 0.1-7.5). The score changes for patients with subclinical vertebral fractures were intermediate between those with clinical vertebral fractures or no incident vertebral fracture, demonstrating that even subclinical incident vertebral fractures can have an adverse impact on HR-QOL.46 Osteoporosis therapies and HR-QOL Given the impact of incident vertebral and/or hip fractures on HR-QOL, it might be expected that a therapy that reduces the incidence of such fractures would result in a relatively better quality of life. A recent review of utility values for osteoporotic fractures to be used in economic analyses has highlighted the remarkably few studies of the impact MEDICOGRAPHIA, VOL 28, No. 1, 2006 37

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of osteoporotic fractures.36 The authors have recommended the administration of a preference-based generic health status measure to a large prospective population cohort with long-term follow-up to improve the reference case values. Until recently, few studies have shown a direct effect on QOL in patients with osteoporosis, so that this has to be inferred.42,43,46 For example, in a study of teriparatide, therapy was associated with an 86% reduction in new or worsened severe (grade 3 SQ) vertebral fractures, but, as conceded by the authors, this does not directly demonstrate a benefit of teriparatide on HR-QOL.43 Such observations probably relate to inadequate statistical power in the majority of studies, which are usually designed to show a reduction in vertebral fracture risk, but not HR-QOL. In the Fracture Intervention Trial (FIT) of alendronate, investigators examined the impact of new vertebral fractures on the number of days of limited activity and bed rest caused by back pain.47 Both indices were significantly increased in the period after a new clinical vertebral fracture, as compared with the period before a clinical vertebral fracture and the increase was similar in women receiving alendronate or placebo. Severe back pain, as indicated by 7 or more limited-activity days and 7 or more bed-rest days, increased sharply immediately after a clinical vertebral fracture so that by 3 months after a new fracture, about 30% of women had experienced 7 or more bed-rest days and about 80% had 7 or more limited-activity days. Women in the alendronate-treated group had 63% fewer bed-rest days and 16% fewer days of limited activity because of back pain compared with those in the placebo group. The effect was even more pronounced for the cumulative incidence of 7 or more days of bed rest: 4.2% of women receiving alendronate reported this more severe degree of functional limitation, compared with 8.7% of women receiving placebo.47 More recently, results have been presented for the effect of strontium ranelate on QOL in women with established vertebral osteoporosis.48 In the socalled SOTI trial (Spinal Osteoporosis Therapeutic Intervention), QOL was assessed using a generic questionnaire, the SF-36, and a disease-specific questionnaire developed for use in the study, the Quality-of-Life Questionnaire in Osteoporosis (QUALIOST).49 The QUALIOST questionnaire was specifically designed to assess the impact of verteREFERENCES 1. Lippuner K, Golder M, Greiner R. Epidemiology and direct medical costs of osteoporotic fractures in men and women in Switzerland. Osteoporos Int. 2005;16(suppl 2):S8-S17. 2. Hoffenberg R, James OFW, Brocklehurst JC, et al. Fracture of neck of femur: prevention and management. J R Coll Phys (Lond). 1989;23:8-12. 3. Torgerson DJ, Iglesias CP, Reid DM. The economics of fracture prevention. In: Barlow DH, Francis RM, Miles A, eds. The Effective Management of Osteoporosis. London, UK: Aesculapius Medical Press; 2001. 4. Jalava T, Sarna S, Pylkkanen L, et al. Association between vertebral fracture and increased mortality in osteoporotic patients. J Bone Miner Res. 2003;18:1254-1260. 5. Johnell O, Kanis JA. An estimate of the worldwide prevalence, mortality and disability associated with hip fracture. Osteoporos Int. 2004;15:897-902. 6. Kanis JA, Oden A, Johnell O, De Laet C, Jonsson B. Excess mortality after hospitalisation for vertebral fracture. Osteoporos Int.

bral fractures in established postmenopausal osteoporosis on patients HR-QOL. It was developed as a specific module of the generic SF-36 questionnaire and therefore avoids the redundancy of items that often exists when both a generic and a specific questionnaire are used.12 It comprises 23 items, 10 of them addressing physical dimensions regarding pain, limitations, and difficulties while the 13 others correspond to the emotional dimension, characterized by negative feelings. Of 1649 patients included in the multicenter study for 3 years, 1240 patients (75%) participated in the HR-QOL evaluation, with both instruments being completed at baseline and 6-monthly thereafter. Regardless of treatment group, the QUALIOST global score showed a significant impact of incident vertebral fractures on HR-QOL. Strontium ranelate was associated with a significant 41% reduction in the risk of experiencing a first new vertebral fracture over the 3 years of the study. Moreover, the QUALIOST global score showed a small, but significantly lower impairment of HR-QOL in the SR group (P=0.016) as compared with the placebo group. Similar effects were drawn from results of the psychological or the physical scores of the QUALIOST (P=0.019 and 0.032, respectively) demonstrating for the first time improvements in HR-QOL by an osteoporosis therapy, mediated at least in part by the prevention of vertebral fractures. These positive effects of strontium ranelate on QOL have been enshrined in the European Summary of Product Characteristics, and this agent is the only antiosteoporotic treatment thus qualified.50 Summary The impact of osteoporosis and its treatment on QOL has become a major interest in recent years. While the number of studies addressing HR-QOL has recently increased, further information is required, particularly with regard to fractures at sites other than the spine and hip. The accuracy of utility estimates of these fracture types needs to be further enhanced and supported as they play a key role in cost effectiveness analyses and policy decisionmaking. A better understanding of the burden of osteoporosis will allow the development of current and novel therapeutic strategies to minimize this burden for patients and society.
2004;15:108-112. 7. Kanis JA, Oden A, Johnell O, De Laet C, Jonsson B, Oglesby AK. The components of excess mortality after hip fracture. Bone.2003; 32:468-473. 8. Empana JP, Dargent-Molina P, Breart G. Effect of hip fracture on mortality in elderly women: the EPIDOS prospective study. J Am Geriatr Soc. 2004;52:685-690. 9. Cooper C. The crippling consequences of fractures and their impact on quality of life. Am J Med.1997;103:12S-17S; discussion 17S-19S. 10. Norton R, Butler M, Robinson E, Lee-Joe T, Campbell AJ. Declines in physical functioning attributable to hip fracture among older people: a follow-up study of case-control participants. Disabil Rehabil. 2000;22:345-351. 11. Silverman SL. The clinical consequences of vertebral compression fracture. Bone. 1992;13(suppl 2):S27-S31. 12. Tosteson AN, Hammond CS. Quality-of-life assessment in osteoporosis: health-status and preference-based measures. Phar-

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macoeconomics. 2002;20:289-303. 13. Guyatt GH, Feeny DH, Patrick DL. Measuring health-related quality of life. Ann Intern Med.1993;118:622-629. 14. Willke RJ, Burke LB, Erickson P. Measuring treatment impact: a review of patient-reported outcomes and other efficacy endpoints in approved product labels. Control Clin Trials. 2004; 25:535-552. 15. Coons SJ, Rao S, Keininger DL, Hays RD. A comparative review of generic quality-of-life instruments. Pharmacoeconomics. 2000;17:13-35. 16. Lips P, van Schoor NM. Quality of life in patients with osteoporosis. Osteoporos Int. 2005; 16:447-455. 17. Torrance GW. Measurement of health state utilities for economic appraisal. J Health Econ. 1986;5:1-30. 18. Torrance GW. Utility approach to measuring health-related quality of life. J Chronic Dis. 1987;40:593-603. 19. Hughes D, Lara AM, Mujica-Mota R. Approaches to pharmacoeconomic analysis. In: Walley T, Haycox A, Boland A, eds. Pharmacoeconomics. Edinburgh, New York: Churchill Livingstone; 2004:101-126. 20. NICE 2005 A guide to NICE. National Institute for Health and Clinical Excellence. http://www.nice.org.uk/page.aspx?o= guidetonice. Accessed 29 September 2005. 21. NICE Framework Document. National Institute for Health and Clinical Excellence. http://www.nice.org.uk/pdf/appendixB_ framework.pdf. 22. Hatoum HT, Brazier JE, Akhras KS. Comparison of the HUI3 with the SF-36 preference based SF-6D in a clinical trial setting. Value Health. 2004;7:602-609. 23. Hawthorne G, Richardson J, Day NA. A comparison of the Assessment of Quality of Life (AQoL) with four other generic utility instruments. Ann Med. 2001;33:358-370. 24. Osteoporosis Prevention, Diagnosis, and Therapy. NIH Consens Statement Online. 2000;17:1-36. 25. Martin AR, Sornay-Rendu E, Chandler JM, Duboeuf F, Girman CJ, Delmas PD. The impact of osteoporosis on quality-of-life: the OFELY cohort. Bone. 2002;31:32-36. 26. Adachi JD, Loannidis G, Berger C, et al. The influence of osteoporotic fractures on health-related quality of life in community-dwelling men and women across Canada. Osteoporos Int. 2001;12:903-908. 27. Dolan P, Torgerson D, Kakarlapudi TK. Health-related quality of life of Colles fracture patients. Osteoporos Int.1999;9:196-199. 28. Zethraeus N, Borgstrm F, Johnell O, Kanis J, nnby K, Jnsson B. Costs and quality of life associated with osteoporosis related fractures. SSE/EFI Working Paper Series in Economics and Finance. October 2002; No 512. 29. Hall SE, Williams JA, Senior JA, Goldswain PR, Criddle RA. Hip fracture outcomes: quality of life and functional status in older adults living in the community. Aust N Z J Med.2000;30:327-332. 30. Willig R, Keinanen-Kiukaaniemi S, Jalovaara P. Mortality and quality of life after trochanteric hip fracture. Public Health. 2001;115:323-327. 31. Marottoli RA, Berkman LF, Leo-Summers L, Cooney LM Jr. Predictors of mortality and institutionalization after hip fracture: the New Haven EPESE cohort. Established Populations for Epidemiologic Studies of the Elderly. Am J Public Health.1994; 84:1807-1812. 32. Randell AG, Nguyen TV, Bhalerao N, Silverman SL, Sambrook PN, Eisman JA. Deterioration in quality of life following hip fracture: a prospective study. Osteoporos Int. 2000;11:460-466. 33. Tidermark J, Zethraeus N, Svensson O, Tornkvist H, Ponzer S. Femoral neck fractures in the elderly: functional outcome and quality of life according to EuroQol. Qual Life Res. 2002;11:473-481. 34. Tidermark J, Zethraeus N, Svensson O, Tornkvist H, Ponzer S. Quality of life related to fracture displacement among elderly patients with femoral neck fractures treated with internal fixation. J Orthop Trauma. 2002;16:34-38. 35. Tosteson AN, Gabriel SE, Grove MR, Moncur MM, Kneeland TS, Melton LJ 3rd. Impact of hip and vertebral fractures on quality-adjusted life years. Osteoporos Int. 2001;12:1042-1049. 36. Brazier JE, Green C, Kanis JA. A systematic review of health state utility values for osteoporosis-related conditions. Osteoporos Int. 2002;13:768-776. 37. Huang C, Ross PD, Wasnich RD Vertebral fractures and other predictors of back pain among older women. J Bone Miner Res. 1996;11:1026-1032. 38. Ross PD, Davis JW, Epstein RS, Wasnich RD. Pain and disability associated with new vertebral fractures and other spinal conditions. J Clin Epidemiol. 1994;47:231-239. 39. Hall SE, Criddle RA, Comito TL, Prince RL. A case-control study of quality of life and functional impairment in women with long-standing vertebral osteoporotic fracture. Osteoporos Int. 1999;9:508-515.

40. Lips P, Cooper C, Agnusdei D, et al. Quality of life in patients with vertebral fractures: validation of the Quality of Life Questionnaire of the European Foundation for Osteoporosis (QUALEFFO). Working Party for Quality of Life of the European Foundation for Osteoporosis. Osteoporos Int. 1999;10:150-160. 41. Oleksik A, Lips P, Dawson A, et al. Health-related quality of life in postmenopausal women with low BMD with or without prevalent vertebral fractures. J Bone Miner Res. 2000;15:1384-1392. 42. Silverman SL, Minshall ME, Shen W, Harper KD, Xie S. The relationship of health-related quality of life to prevalent and incident vertebral fractures in postmenopausal women with osteoporosis: results from the Multiple Outcomes of Raloxifene Evaluation Study. Arthritis Rheum. 2001;44:2611-2619. 43. Crans GG, Silverman SL, Genant HK, Glass EV, Krege JH. Association of severe vertebral fractures with reduced quality of life: reduction in the incidence of severe vertebral fractures by teriparatide. Arthritis Rheum. 2004;50:4028-4034. 44. Cortet B, Houvenagel E, Puisieux F, Roches E, Garnier P, Delcambre B. Spinal curvatures and quality of life in women with vertebral fractures secondary to osteoporosis. Spine. 1999;24: 1921-1925. 45. Begerow B, Pfeifer M, Pospeschill M, et al. Time since vertebral fracture: an important variable concerning quality of life in patients with postmenopausal osteoporosis. Osteoporos Int.1999; 10:26-33. 46. Oleksik AM, Ewing S, Shen W, van Schoor NM, Lips P. Impact of incident vertebral fractures on health related quality of life (HRQOL) in postmenopausal women with prevalent vertebral fractures. Osteoporos Int. 2005;16:861-870. 47. Nevitt MC, Thompson DE, Black DM, et al. Effect of alendronate on limited-activity days and bed-disability days caused by back pain in postmenopausal women with existing vertebral fractures. Fracture Intervention Trial Research Group. Arch Intern Med. 2000;160:77-85. 48. Marquis P, De la Loge C, Diaz-Curiel M, et al. Beneficial effects of strontium ranelate on the quality of life in patients with vertebral osteoporosis (SOTI study). Osteoporos Int.2005;16(suppl 3): S54(P223). 49. Marquis P, Cialdella P, De la Loge C. Development and validation of a specific quality of life module in post-menopausal women with osteoporosis: the QUALIOST. Qual Life Res.2001;10: 555-566. 50. European Medicines Agency (EMEA). Summary of Product Characteristics Protelos. http://www.emea.eu.int/humandocs/ Humans/EPAR /protelos/protelos.htm. Accessed November 3, 2005.

QUALIT

DE VIE LIE LA SANT DANS LOSTOPOROSE

a qualit de vie lie la sant (QVLS) sest impose comme un paramtre important de la recherche clinique et du soin des patients. Elle reflte la faon dont les patients peroivent et ragissent leur tat de sant, et intgre leur bien-tre physique, fonctionnel, motionnel et mental. La QVLS est habituellement value grce des questionnaires dont il existe deux types, gnriques ou spcifiques. Cest ainsi quoutre les instruments de QVLS gnriques (par exemple la SF-36 [36-Item Short-Form]), destins un large ventail de populations et de maladies, un certain nombre dinstruments dvaluation spcifiques de lostoporose ont t dvelopps ces 10 15 dernires annes (par exemple, le Questionnaire dvaluation de lostoporose [OPAQ, Osteoporosis Assessment Questionnaire], le Questionnaire de Qualit de Vie de la Fondation Europenne pour lOstoporose [QUALEFFO, Quality of Life Questionnaire of the European Foundation for Osteoporosis], le Questionnaire de Qualit de Vie dans lOstoporose [QUALIOST, QUAlity of LIfe questionnaire in OSTeoporosis]). Toutefois, peu dtudes comparatives ont t entreprises pour valuer les rsultats respectifs de ces instruments. La morbidit associe lostoporose est presque exclusivement lie la survenue de fractures de fragilit, et diffre selon le sexe et les sites de fracture du squelette. Les fractures vertbrales et les fractures de hanche expression clinique semblent induire de faon comparable les baisses les plus importantes de la QVLS. Des donnes encore limites suggrent que certains traitements anti-ostoporotiques peuvent amliorer la QVLS en diminuant lincidence des fractures. La gnralisation de lutilisation des instruments de QVLS devrait permettre une meilleure comprhension du fardeau reprsent par lostoporose ainsi que le dveloppement de stratgies thrapeutiques destines allger ce fardeau pour les patients et la socit.

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Bengt JNSSON, PhD Professor, Stockholm School of Economics, Stockholm SWEDEN

Risk factors and pharmacoeconomic consequences

by B. Jnsson, Sweden

he prevention and treatment of osteoporosis involves costs for case finding, treatment, and follow-up. Drug costs are only one part of the intervention costs. But the risk of fractures and the side effects of treatment positive as well as negative also have cost consequences, which have to be considered when assessing the cost-effectiveness of different measures to reduce the risk of fractures. Since the beginning of the 1990s, cost-effectiveness modeling in osteoporosis has been based on fracture reduction data from clinical trials. The advantage of this approach, compared with earlier models based on changes in bone mineral density, is that the measured effectiveness variable in the trial is directly related to the final objective of the intervention, a reduction in fractures. Since fractures are associated with mortality, reductions in quality of life, and costs, a reduction in fracture rates can be translated into cost savings and quality-adjusted life years gained. The method and data used for modeling cost-effectiveness of the treatment of osteoporosis are described. Results using this type of model for determining cost-effectiveness are presented. Cost-effectiveness is sensitive to the cost of the intervention, the relative risk reduction, and the absolute risk of a fracture if not treated. Such models can also be used for assessing intervention thresholds. With the base case (US $500 per year; 35% efficacy), treatment in women was cost-effective with a 10-year hip fracture probability that ranged from 1.2% at the age of 50 years to 7.4% at the age of 80 years. Similar results were observed in men except that the threshold for cost-effectiveness was higher at younger ages than in women (2.0% versus 1.2%, respectively, at the age of 50 years). Intervention thresholds were sensitive to the assumed effectiveness and intervention cost. The exclusion of osteoporotic fractures other than hip fracture significantly increased the cost-effectiveness ratio because of the substantial morbidity from these other fractures, particularly at younger ages.
(see French abstract on page 44)

he aim of the prevention and treatment of osteoporosis is to reduce the risk of fractures. The risk of an osteoporotic fracture varies with a number of factors, one of the most important being age.1,2 The assessment of risk is thus the key to the cost-effectiveness of interventions. Since most interventions involve the same costs, regardless of the risk level of the patient, and the relative risk reduction is also similar, treating patients at high risk will yield more benefits, and thus be more cost-effective. Targeting high-risk populations has thus been one strategy in identifying efficient ways of using scarce resources for reducing the burden of osteoporosis.3 Finding the right population for intervention, through different strategies for screening and case finding, can also be seen as an economic problem. The more resources that are spent on finding a patient for treatment, the more costs will be added, which has to be balanced by the benefits of intervention. This is particularly important if compliance with treatment is low, and benefits thus accordingly reduced. If the patient stays on therapy for a long time, the initial costs of case finding will be relatively less important. Defining cost-effectiveness and intervention criteria is thus a complicated undertaking, involving epidemiological, clinical, and economic factors. A thorough analysis requires these data to be combined in a logical, consistent, and transparent way. The following section describes the principles for such models, and the data required. A description of available data for such models, and the results from simulations based on Swedish data, will follow. Cost-effectiveness models There is a long history of modeling cost-effectiveness in osteoporosis.4,5 Until the mid 1990s, most models were aimed at evaluating the costs and benefits of hormone replacement therapy. The models thus included a number of extraskeletal effects, mainly coronary heart disease and cancer. The results were thus strongly influenced by the assumption made about these positive and negative side effects of treatment. Later models, aimed at studying the effects of bone-specific interventions, such as bisphosphonates, are simpler to compare and interpret, since the results only depend on the reduction in fractures. However, the result differs with respect to which fractures are included in the model, the risk factors considered, and the data used for the study. The need for a reference model is thus recognized.6 Jnsson et al7 introduced a computer model including hip, wrist, vertebral, and other fractures (Figure 1). The model was the first osteoporosis model of the Markov type, based on absolute risks of fracture and relative risk reduction from intervention, with outcome defined as quality-adjusted life years (QALYs). This makes it possible to aggregate the benefits in terms of survival and quality of life from a reduction in several different fractures. The health states that are included are: healthy, hip fracture first year, hip fracture second and follow-

Medicographia. 2006;28:40-44.

Keywords: osteoporosis; risk; cost; cost-effectiveness

Address for correspondence: Professor Bengt Jnsson, Stockholm School of Economics, Klarabergsgaten 33, Box 6501, SE 113 83, Stockholm, Sweden (e-mail: Bengt.Jonsson@hhs.se)

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Figure 1. Model structure for evaluating the cost-effectiveness of fracture prevention. Adapted from reference 7.

culation method. Instead of using the Markov cohort technique, individual state transition-based calculations have been used.16 However, the calculation method used for the model evaluation should not impact the results if the models are populated with the same data. Data An economic evaluation should ideally be based on cost and health data as reflected in the routine care of patients. To obtain such data, a naturalistic study design can be used where patients are randomized to different treatment alternatives in a real-world setting (eg, a phase 4 study). Data for cost-effectiveness studies can also be obtained from randomized controlled trials (RCTs) where the main purpose is to investigate whether the treatment is safe and has an effect. The advantage of using a controlled trial as the basis for the economic evaluation is that the results from the clinical study are of high internal validity showing whether a new therapy has an effect or not. The drawback is that the clinical study may not reflect the cost and health effects for patients in routine care when the drug is on the market. Placebo-controlled studies pose a special problem, since a placebo is not an alternative used in clinical practice. Compliance and costs observed in a placebo-controlled clinical trial may not thus reflect the real world. However, since the only evidence-based effectiveness data that we have come from such trials, it is standard practice to perform at least one set of economic evaluations linked closely to the trial data. But such studies cannot assess the long-term costs and outcome in terms of survival and quality of life in patients with and without fracture. The short-term clinical trial data must be complemented with data from registries of different types. MEDICOGRAPHIA, VOL 28, No. 1, 2006 41

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ing years, vertebral fracture first year, forearm fracture first year, and other fracture first year, and death. A defined population is subject to risks of having a fracture over its lifetime. The model can follow the population (set at 1000 initially) and keep track of the patient distribution each year. Intervention decreases the risk of fracture, which means that the population will be distributed differently among health states each year. Linked to each health state is a cost and quality-of-life weighting. By summating costs and health effects for all patients for all years, the total costs and health effects are obtained for the natural course (without treatment). The intervention affects the transition probabilities and implies a different allocation of individuals each year. The cycle length is 1 year and all patients are followed through the model from the age of treatment initiation until they are 100 years old or dead. There is always the probability of remaining in the same state or dying. All the patients begin in the well health state. Each year, a patient has the probability of having a fracture, remaining healthy, or dying. If a patient dies, she will move to the dead health state and remain there for the rest of the simulation (arrows to the dead health state were excluded to simplify the figure). If the patient incurs a fracture she will move, depending on fracture type, to the hip fracture, spine fracture, wrist fracture, or other osteoporotic fracture health state. After 1 year in one of these states, the patient can have a new fracture, move to the posthip fracture state, or die. Wrist fracture, spine fracture, and other osteoporotic fracture were assumed to have an impact on costs and morbidity only in the first year after fracture, therefore after 1 year in these health states patients move, if not fractured once more, back to the well health state. From the posthip fracture state, it is only possible to stay in the posthip fracture state, have another hip fracture, or die. Consequently, patients who have had a hip fracture cannot experience any future wrist, vertebral, or other osteoporotic fractures. The probability of having a vertebral or a wrist fracture after a hip fracture is low, and the consequences on mortality and quality of life after having experienced multiple, different fractures has been poorly investigated. Also, the costs and quality of life reductions from multiple fractures can be included in the state posthip fracture. The slight underestimation of the number of fractures in the model will not significantly effect the cost-effectiveness estimates. An application of the model is found in Jnsson et al3 where the cost-effectiveness of the treatment of a 62-year-old woman is investigated. A 5-year treatment duration was assumed and a risk reduction of 50% during treatment. The annual intervention cost was assumed to be SEK 6000. The resulting cost per QALY gained was estimated as SEK 107 000, which was similar to the cost-effectiveness ratio of treating the same women for mild hypertension. The model introduced by Jnsson et al7 dates back to 1993 and since then the model has gone through several developments.8-10 The main change that has

been implemented is a health state for vertebral fracture the second and following years after the fracture event, which is in line with data that indicate that vertebral fractures are associated with both cost and quality of life reductions that last longer than the first year.11-13 There are different versions of fracture models in the literature.14-16 All these models are similar in their structure, but can differ somewhat in the cal-

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Most studies are thus based on models that integrate clinical, epidemiological, and cost data. Models are very flexible, but their validity and reliability depend on the quality of the data used. Hip fracture risk data are available for many countries, or can be calculated.17 For other fractures, data on risk are scarce and, for most countries, nonexistent.

Cost in added life years (SEK) Parameters Base case Starting age 65-year treatment initiation 75-year treatment initiation Effect envelope Offset time = 0 years Offset time = 10 years Discount rate Health effects = 0 Costs and effects = 5 Costs and effects = 0 Relative risk of fracture Hip RR=3 Hip RR=4 Intervention 10-year treatment duration Risk reduction fracture = 50% Intervention costs = 3000 Intervention costs = 7000 Quality of life during intervention +1% +0.5% -1% -0.5% Quality of life after fracture +10% -10% included 520 000 850 000 330 000 810 000 350 000 400 000 610 000 410 000 330 000 230 000 520 000 320 000 250 000 800 000 250 000 340 000 Dominated 1 140 000 800 000 400 000 excluded 420 000 790 000 200 000 720 000 240 000 320 000 510 000 300 000 240 000 140 000 410 000 220 000 150 000 700 000 200 000 280 000 Dominated 920 000 650 000 320 000

ciated with osteoporosis-related fractures (the KOFOR study). The KOFOR study prospectively follows fracture patients for 18 months after the fracture event and collects information about all relevant resource use for the estimation of fracture-related costs in a societal perspective.18 For some fractures, increased mortality is a reality that can be calculated if the relevant epidemiological data are available.19-22 However, it is important that the modeled excess mortality after fracture is adjusted for comorbidity. Results In the model presented in Zethraeus et al,23 the costeffectiveness of a bone-specific treatment is compared with no treatment. The base case assesses the cost-effectiveness of the treatment of a 70-year-old woman with a twofold increase in the risk of hip, spine, and wrist fracture. A 5-year treatment duration is assumed to reduce the risk of fracture by 35%. After the cessation of the therapy, the risk gradually adjusts to the normal risk 5 years later. An annual treatment cost of SEK 5000 is assumed, and costs and health effects are discounted at a 3% discount rate. Two scenarios are shown, one where costs in added life years are included and one where they are excluded. In a sensitivity analysis, the costeffectiveness is calculated changing some of the base case assumptions. The results presented in Table I show the costeffectiveness ratios in the base case and for different assumptions about the parameters in the model. If quality of life is assumed to improve slightly during treatment, the cost-effectiveness ratios decrease. On the other hand, if a small negative side effect is assumed, the no intervention alternative dominates the treatment alternative. The results are also sensitive to changes in relative risk of fracture and set time after cessation of therapy. Higher risk and longer set time reduce the cost-effectiveness ratios and thus improve cost-effectiveness. The costeffectiveness results are not very sensitive to the inclusion of costs in added life years, since the effect on mortality is small. Models can be designed to take into account differential effects on different fractures. Data on fracture reduction rates from clinical trials can be used for translating the results for that specific population and specific end-point into cost-effectiveness ratios. This has been done for alendronate in the Fracture Intervention Trial (FIT) and for the risedronate clinical trials.8-10 Data from clinical trials have limitations, however, since the trial is usually powered only for a specific population, end point (fracture), and time of follow-up. It would be an advantage to have a model that took into account the effect on all osteoporotic fractures, particularly if it could be shown that the relative risk reduction from intervention is similar over fracture types. Since very few countries have a detailed risk function for all possible, or even the major, osteoporotic fractures, but many countries have data on hip fractures, the concept of hip fracture equivalents has been used for assess-

Table I. Cost-effectiveness ratios for a 5-year bone specific treatment based on the model presented by Zethraeus et al.5,23 The base case indication is a 70-year-old woman with a twofold increase in fracture risk. The base case assumes a risk reduction of 35% during therapy and a 5-year offset time. The annual intervention cost is assumed to be SEK 5000. All ratios are given in Swedish crowns (SEK).
Adapted from reference 5: Zethraeus N, Ben Sedrine W, Caulin F, et al. Models for assessing the cost-effectiveness of the treatment and prevention of osteoporosis. Osteoporos Int. 2002;13:841-857. Copyright 2002, International Osteoporosis Foundation and National Osteoporosis Foundation.

Intervention costs and the cost of patient management can be fairly easily calculated. However, costs related to different types of fractures need to be collected through registries or observational studies. Registries are the easiest, but limited to the information previously collected. Registries capture hospitalization data very well, but less well ambulatory care and costs in the community. To have data on quality of life, informal care, and absence from work, there is generally a need for specific studies. An example of such a study is the Swedish-based study estimating the costs and quality of life asso42 MEDICOGRAPHIA, VOL 28, No. 1, 2006

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Age (years) 50 55 60 65 70 75 80 85 90

Hip fracture probability Hip fracture probability (% at 10 years) (% at 10 years)* Men 1.98 2.36 2.96 3.72 4.74 5.42 6.46 6.31 6.16 Women 1.17 1.80 2.73 3.98 5.11 6.08 7.40 7.23 6.62 Men 0.41 0.68 1.17 2.02 3.22 4.46 6.23 7.25 8.03 Women 0.55 1.16 2.35 4.54 7.67 12.24 18.38 21.90 22.00

Proportion of population identified (%) Age (years) 50 55 60 65 70 75 80 85 90 Gradient of risk = 2.6/SD Men 1.4 3.4 6.8 12.5 18.0 24.4 30.2 37.5 43.0 Women 9.7 16.9 26.0 37.0 49.6 62.9 72.6 80.7 84.3 Gradient of risk =4.0/SD Men 3.1 5.2 8.2 12.4 16.0 20.0 23.5 28.0 31.4 Women 10.4 15.3 21.0 27.7 35.5 44.6 52.0 59.2 62.9

* Average probability in the general population for age and sex.

Table II. Threshold 10-year hip fracture probability at which intervention became cost-effective.
Adapted from reference 25: Kanis JA, Johnell O, Oden A, De Laet C, Oglesby A, Jnsson B. Intervention thresholds for osteoporosis. Bone. 2002;31:26-31. Copyright 2002, Elsevier Inc.

Table III. The percentage of men and women at the ages shown who would be identified as having a risk that exceeds the intervention threshold according to the gradient of fracture risk/SD of the assessment algorithm specified.
Adapted from reference 25: Kanis JA, Johnell O, Oden A, De Laet C, Oglesby A, Jnsson B. Intervention thresholds for osteoporosis. Bone. 2002;31:26-31. Copyright 2002, Elsevier Inc.

ing intervention thresholds. When defining such thresholds, it is important that all positive effects of the intervention be taken into account, not just the effect on hip fracture. Table II shows the threshold for intervention defined as absolute 10-year risk of hip fracture.24,25 The threshold is lower for younger ages, since they lose more from an event, but also since the relative importance of fractures other than hip fracture increases with reduced age. Table III shows the percentage of the population treated at different ages using two different assumptions on the gradient of fracture risk. Discussion Economic evaluations have gained increasing importance for the design of cost-effective strategies for prevention and treatment. Such studies take into account both costs of the interventions, the effect on the risk of fracture, and the consequences of fractures. One important positive impact of such studies is that they have put the focus on the significant, and often underestimated, burden of osteoporotic fractures. Hip fracture has major consequences in terms of costs, mortality, and quality of
REFERENCES 1. Kanis JA, Johnell O, Oden A, De Laet C, Jonsson B, Dawson A. Ten-year risk of osteoporotic fracture and the effect of risk factors on screening strategies. Bone. 2002.30:251-258. 2. Kanis JA, Johnell O, Oden A, et al. Long-term risk of osteoporotic fracture in Malm. Osteoporos Int. 2000;11:669-674. 3. Jonsson B. Targeting high-risk populations. Osteoporos Int. 1998;8(suppl 1):S13-S16. 4. Johannesson M, Jonsson B. Economic evaluation of osteoporosis prevention. Health Policy. 1993;24:103-124. 5. Zethraeus N, Ben Sedrine W, Caulin F, et al. Models for assessing the cost-effectiveness of the treatment and prevention of osteoporosis. Osteoporos Int. 2002;13:841-857. 6. Kanis JA, Jonsson B. Economic evaluation of interventions for osteoporosis. Osteoporos Int. 2002;13:765-767. 7. Jnsson B, Hedbrandt J, Johnell O. A computer simulation model to analyse the cost-effectiveness of fracture prevention of osteoporosis. EFI research paper no. 6525. Stockholm, Sweden: Stockholm School of Economics; 1993.

life reduction, but other osteoporosis-related fractures contribute significantly to the burden, particularly at younger ages.24 Models are useful tools for assessing the relation between risk, risk reduction, and cost-effectiveness of intervention. Clinical trials provide evidence of how different interventions can be used for reducing the risk of fractures, and to some extent their consequences in terms of costs and quality of life reductions. But there is also a need for additional epidemiological and economic data to feed into the models in order to provide a correct estimate of the cost-effectiveness of such interventions in different populations and in different countries. Such studies are also important for the access of patients to treatment, as is seen by the use of such studies for making decisions about reimbursement and funding for treatment. See, for example, the study of a range of osteoporosis drugs by the National Institute for Clinical Excellence (NICE).26 Thus, there is a responsibility to make sure that such studies are undertaken with the best scientific methods and based on the most relevant data. With the introduction of additional new alternatives for treatment and intervention, such studies will be even more important.
8. Borgstrom F, Johnell O, Jnsson B, Zethraeus N, Sen SS. Cost effectiveness of alendronate for the treatment of male osteoporosis in Sweden. Bone. 2004;34:1064-1071. 9. Kanis JA, Borgstrom F, Johnell O, Jnsson B. Cost-effectiveness of risedronate for the treatment of osteoporosis and prevention of fractures in postmenopausal women. Osteoporos Int. 2004;15: 862-871. 10. Johnell O, Jnsson B, Jnsson L, Black D. Cost effectiveness of alendronate (fosamax) for the treatment of osteoporosis and prevention of fractures. Pharmacoeconomics. 2003;21:305-314. 11. De Laet CE, van Hout BA, Burger H, Weel AE, Hofman A, Pols HA. Incremental cost of medical care after hip fracture and first vertebral fracture: the Rotterdam study. Osteoporos Int. 1999; 10:66-72. 12. Oleksik A, Lips P, Dawson A, et al. Health-related quality of life in postmenopausal women with low BMD with or without prevalent vertebral fractures. J Bone Miner Res. 2000;15:13841392.

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13. Zethraeus N, Borgstrm F, Johnell O, Kanis J, nnby K, Jnsson B. Costs and Quality of Life Associated with Osteoporosis Related Fractures Results from a Swedish Survey. Working Paper Series in Economics and Finance, 512. Stockholm, Sweden: Stockholm School of Economics; 2002. 14. Schousboe JT, Nyman JA, Kane RL, Ensrud KE. Cost-effectiveness of alendronate therapy for osteopenic postmenopausal women. Ann Intern Med. 2005;142:734-741. 15. Iglesias CP, Torgerson DJ, Bearne A, Bose U. The cost utility of bisphosphonate treatment in established osteoporosis. Q J Med. 2002;95:305-311. 16. Stevenson MD, Oakley J, Chilcott JB. Gaussian process modeling in conjunction with individual patient simulation modeling: a case study describing the calculation of cost-effectiveness ratios for the treatment of established osteoporosis. Med Decis Making. 2004;24:89-100. 17. Kanis JA, Johnell O, Oden A, Jnsson B, De Laet C, Dawson A. Risk of hip fracture according to the World Health Organization criteria for osteopenia and osteoporosis. Bone. 2000;27:585-590. 18. Borgstrm F, Zethraens N, Johnell O, et al. Cost and quality of life related to osteoporotic fractures in Sweden. Accepted for publication, 2005. 19. Melton LJ 3rd. Excess mortality following vertebral fracture.

J Am Geriatr Soc. 2000;48:338-339. 20. Kanis J et al. Excess mortality after vertebral fracture. Sheffield, UK: WHO Collaborating Centre for Metabolic Bone Diseases; 2002. 21. Cauley JA, Thomson De, Ensrud KC, Scott JC, Black D. Risk of mortality following clinical fractures. Osteoporos Int. 2000;11: 556-561. 22. Johnell O, Kanis JA, Oden A. Mortality after osteoporotic fractures. Osteoporos Int. 2004;15:38-42. 23. Zethraeus N. A computer model to analyse the cost-effectiveness of hormone replacement therapy: a revised version. SSE/EFI Working Paper Series in Economics and Finance, 368. Stockholm, Sweden: Stockholm School of Economics; 2000:57. 24. Kanis JA, Oden A, Johnell O, Jnsson B, de Laet C, Dawson A. The burden of osteoporotic fractures: a method for setting intervention thresholds. Osteoporos Int. 2001;12:417-427. 25. Kanis JA, Johnell O, Oden A, De Laet C, Oglesby A, Jnsson B. Intervention thresholds for osteoporosis. Bone. 2002;31:26-31. 26. Stevenson M, Lloyd-Jones M, De Nigris E, Brewer N, Davis S, Oakley J. A systematic review and economic evaluation of alendronate, etidronate, risedronate, raloxifene and teriparatide for the prevention and treatment of postmenopausal osteoporosis. Health Technol Assess. 2005;9:1-160.

FACTEURS DE RISQUE ET CONSQUENCES PHARMACOCONOMIQUES

a prvention et le traitement de lostoporose comportent des cots lis aux recherches de cas, aux traitements et au suivi. Les mdicaments ne reprsentent quune partie des cots de la prise en charge thrapeutique. Mais le risque de fractures et les effets secondaires du traitement, aussi bien positifs que ngatifs, ont aussi des consquences financires qui doivent tre prises en compte dans lvaluation du rapport cot/efficacit des diffrentes mesures visant rduire le risque de fractures. Depuis le dbut des annes 90, la modlisation du rapport cot/efficacit dans lostoporose a t base sur les donnes de rduction du nombre de fractures, issues des tudes cliniques. Lavantage de cette approche, compare aux modles prcdents bass sur des modifications de densit minrale osseuse, est que la variable efficacit mesure dans ltude est directement lie lobjectif final du traitement, cest-dire la rduction du nombre de fractures. Les fractures tant associes la mortalit, la diminution de la qualit de vie et aux cots, une rduction des taux de fractures peut se traduire en conomies et en annes de vie gagnes ajustes sur la qualit. La mthode et les donnes utilises pour cette modlisation sont dcrites et les rsultats obtenus sont prsents. Le rapport cot/efficacit dpend du cot du traitement, de la rduction du risque relatif et du risque absolu de fracture en labsence de traitement. De tels modles peuvent tre aussi utiliss pour valuer les seuils dintervention. Dans le cas de base (500 $ par an; 35% defficacit), le traitement chez les femmes tait rentable avec une probabilit de fracture de hanche 10 ans allant de 1,2% lge de 50 ans 7,4% lge de 80 ans. Des rsultats similaires ont t observs chez les hommes lexception des ges plus jeunes pour lesquels le seuil de rentabilit est plus lev que celui des femmes (2% versus 1,2% respectivement lge de 50 ans). Les seuils dintervention taient sensibles lefficacit prsume et au cot du traitement. Le rapport cot/efficacit tait significativement amlior par lexclusion des fractures ostoporotiques autres que les fractures de hanche en raison de la morbidit importante lie ces autres fractures, en particulier aux ges plus jeunes.

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Graeme JONES, MD, FRACP Professor and Head Musculoskeletal Unit Menzies Research Unit Private Bag 23, Hobart Tasmania 7000 AUSTRALIA (e-mail: g.jones@utas.edu.au)

ractures are a very common and increasing public health problem. Fracture risk is determined by both bone strength and risk of falls. All measures of bone strength can never be perfect measures of fracture risk as they cannot take the risk of falls into account. It is only when markers of bone strength and risk of falls are combined that highly sensitive and specific fracture prediction models can be developed (as in the Dubbo study for both elderly men and women). There are numerous methods of noninvasively assessing bone strength in humans. These include plain x-ray, computed tomography, dual photon absorptiometry, dual energy x-ray absorptiometry (DXA), and ultrasound. The current gold standard is DXA, although current evidence for all of these measures indicates that they have similar ability to predict fractures. The relationship between each measure and fracture risk is exponential, with fracture risk roughly doubling for each standard deviation (or 10%) decrease in that measure. Thus, there is no cutpoint above which fractures do not occur and similarly there is no lower level below which fractures are guaranteed. The World Health Organization (WHO) derived cutoffs for osteoporosis (T<--2.5) and osteopenia (T --1.0 to --2.5) from comparison with a young reference range. These are based on DXA scans only and have obvious limitations as the majority of fractures occur above the osteoporosis cutpoint. Nevertheless, many of the trials that have been performed in osteoporosis in recent years have used these WHO cutoffs and have yielded much information on who to treat, both with and without fracture. Despite DXA being widely used for monitoring osteoporosis therapy, there is only a modest relationship between change in bone mass in the individual and reduction in fracture risk. The reasons for this are poorly understood and may include the effect of measurement error (so called regression dilution bias) or that change in DXA does not adequately reflect underlying bone quality. So why not use ultrasound? This is a totally noninvasive scan mode that can accurately and reproducibly measure bone status (even in inexperienced hands and diverse locations) without any radiation exposure. It is portable and

generally the machines are considerably cheaper than DXA, making it more likely to have widespread uptake (even in the absence of health system rebates in most countries). Ultrasound can measure multiple sites (heel, radius, tibia, and phalanges), although different machines are needed for different sites. Ultrasound measures are predictive of bone breaking strength ex vivo and there are a number of studies confirming that ultrasound measures are significant predictors of fracture in younger and older populations of males and females. As the site measured is generally peripheral, the fracture prediction is not quite as good as DXA at the hip for hip fractures or DXA at the spine for spine fractures, but is better than hip DXA and total fracture risk. Many studies have shown a modest correlation between DXA and ultrasound, which has led to dismissal of ultrasound as an alternative. However, this is erroneous as both look at different components of bone and it is fracture risk that matters. Indeed, ultrasound adds to DXA for fracture prediction. Thus, a patient with both low ultrasound and low DXA is at higher fracture risk than someone who is low in one measure. Ultrasound also has potential as a screening tool in locations where DXA is not available. Furthermore, ultrasound is responsive to antiresorptive treatment, but it is uncertain whether this responsiveness leads to a reduction in fracture risk, as the trials have not been of sufficient size. Therefore, ultrasound is a reasonable measure of fracture risk, but can the WHO criteria be applied? Unfortunately, the answer is no. Most authors are suggesting that ultrasound cutoffs be more liberal, in the range of --1 to --1.5 (especially for lower-limb measures). Certainly, someone below this range, aged over 65 with a low DXA score, is also at high fracture risk. However, a fracture intervention trial measuring both ultrasound and DXA at baseline is required to accurately answer the question regarding cutoffs for intervention for ultrasound alone and combinations of ultrasound and DXA, which will benefit most from treatment. Such data are now necessary to move the ultrasound debate forward, particularly given the limitations of DXA.

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t is well known that bone strength and fracture risk depend not only on bone mass, but on bone microarchitecture and quality of bone tissue as well. In spite of the importance of these parameters, it is not always possible to measure them in daily clinical practice. Measurement of bone mineral density (BMD) by dual-energy x-ray densitometry (DXA) is the validated method for assessing bone mass, and is widely available in most of the clinical centers in the world. Nevertheless, it is very difficult to apply this procedure in community-based studies because of its lack of portability and costs. Furthermore, DXA measures areal density and the procedure exposes subjects to low, but significant doses of ionizing radiation.1 Clinical assessment of bone in public health setting has been facilitated by the availability of quantitative ultrasound (QUS) instruments designed to measure bone quality quickly and relatively inexpensively. Because of its being portable and involving less radiation, QUS was thought to be an ideal tool to screen for osteoporosis at the community level and has been proposed for measuring bone density in large populations.1,2 The World Health Organization (WHO) approach to the definition of osteoporosis means that QUS results cannot currently be diagnostic of osteoporosis, and DXA is likely to remain central to diagnosis and follow-up. However, in recent years, ultrasound measures have been shown to be highly correlated to BMD measures by DXA throughout life, and QUS measures have thus been used in research undertaken in collegeaged adults, to identify postmenopausal women who are at risk for osteoporotic fractures, to exclude osteoporosis, and for follow-up studies.3-7 In primary health care, selective screening by QUS could be used to screen for low BMD in patients with fragility fracture or stress fracture.8,9 Since patients with diseases causing secondary osteoporosis may be prone to osteopenia, a low-cost preventive medicine screening strategy, with a convenient detection method and minimal biohazard, such as that offered by ultrasound, is needed.10 In patients in whom central DXA BMD assessment is not possible (for geographic, financial, cognitive, or mobility reasons), peripheral QUS, despite its limitations, likewise provides valuable additional information, on top of clinical data, thereby facilitating the diagnosis of osteoporosis.11 The correlation between QUS and DXA has long been debated by many researchers, and no strong consensus has yet emerged. Diagnostic performance of QUS calcaneus measurement was evaluated in a case-finding study for osteoporosis in Thai postmenopausal women, using DXA as a gold standard. The results showed that BMD measurement for predicting osteoporosis using QUS had very low sensitivity.12 Considerable diagnostic disagreement existed between quan-

titative sonography and DXA of the forearm, as was true for most quantitative techniques in the assessment of skeletal status.13 QUS was also found to not correlate well with DXA in a highrisk population of transplant recipients.14 In contrast, another study showed that QUS identified severe bone abnormalities in children with celiac disease (CD), and the authors suggest that in this small cohort of children with CD, QUS provided more information relevant to the disease status than DXA.15 In a study comparing the ability of QUS and DXA measurements to discriminate between rheumatoid arthritis patients with or without vertebral deformities, BMD discriminated significantly between patients with and without vertebral deformities, and the results were similar to those obtained in controls.16 Risk factors usually associated in other studies with DXA-BMD in elderly women were found to be associated with calcaneal bone stiffness, as measured by QUS in postmenopausal women.6 In some studies, there is poor correlation between the results obtained from the two methods This could be due to the fact that while DXA is only affected by bone mineral content, QUS is affected by other variables, namely elasticity and bone microarchitecture.17 Most clinical ultrasound devices use calcaneus measurements to determine broadband ultrasound attenuation (BUA) and speed of sound (SOS). Studies showed that, although a normal BUA did not exclude an osteoporotic BMD result at hip or lumbar spine, a low BUA appeared to be a highly specific predictor of low BMD at these sites. Hakulinen et al performed a study to find the most sensitive frequency range for the QUS analyses. Normalized BUA, SOS, broadband ultrasound backscatter (BUB), and integrated reflection coefficient (IRC) were determined for each sample and the results of the study suggested that frequencies up to 5 MHz can be useful in QUS analyses for the prediction of bone mechanical properties and density.18 To demonstrate in vitro the feasibility of QUS imaging at the upper part of the femur, and to investigate the relationships between BUA and BMD, Padilla et al carried out research that yielded results consistent with previous findings at the calcaneus, and demonstrated the feasibility of QUS measurements at the femur in vitro with reasonable reproductibility.19 Significant efforts have been devoted to the development of a noninvasive, easy, and relatively inexpensive method for the assessment of bone quality with a portable device. A large number of studies published in the last decade have convincingly shown that both BUA and SOS measurements at the calcaneum can identify individuals at risk for osteoporotic fracture as reliably as BMD. Because of its low cost, QUS has become the preferred tool for large-scale screening.6,20

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REFERENCES 1. Hien VTT, Khan NC, Lam NT, et al. Determining the prevalence of osteoporosis and related factors using quantitative ultrasound in Vietnamese adult women. Am J Epidemiol. 2005;161:824-830. 2. Inanc-Ersoz F, Gokce Kutsal Y, Oncel S, Eryavuz M, Peker O, Ok S. A multicenter, case control study of risk factors for low tibial speed of sound among residents of urban areas in Turkey. Rheumatol Int. 2002;22:20-26. 3. Wetter AC, Economos CD. Relationship between quantitative ultrasound, anthropometry and sports participation in college aged adults. Osteoporos Int. 2004;15:799-806. 4. Saadi HF, Reed RL, Carter AO, Al-Suhaili AR. Correlation of quantitative ultrasound parameters of the calcaneus with bone density of the spine and hip in women with prevalent hypovitaminosis D. J Clin Densitom. 2004;7:313-318. 5. Gudmundsdottir SL, Indridason OS, Franzson L, Sigurdsson G. Age related decline in bone mass measured by dual energy x-ray absorptiometry and quantitative ultrasound in a population based sample of both sexes: identification of useful ultrasound thresholds for osteoporosis screening. J Clin Densitom. 2005;8:80-86. 6. Adami S, Giannini S, Giorgino R, et al. Effect of age, weight and lifestyle factors on calcaneal quantitative ultrasound in premenopausal women: The ESOPO study. Calcif Tissue Int. 2004;74:317-321. 7. Hans D, Schott AM, Duboeuf F, Durosier C, Meunier PJ. Does follow-up duration influence the ultrasound and DXA prediction of hip fracture? The EPIDOS study. Bone. 2004;35: 357-363. 8. Blivik J, Karlsson MK, Mller M. Screening for low bone mineral density with quantitative ultrasound within the primary health care system. Scand J Prim Health Care. 2004;22:78-82. 9. Lappe J, Davies K, Recker R, Heaney R. Quantitative ultrasound: use in screening for susceptibility to stress fractures in female army recruits. J Bone Mineral Res. 2005;20:571-578. 10. Zadik Z, Sinai T, Zung A, Reifen R. Longitudinal monitoring of bone measured by quantitative multisite ultrasound in patients with Crohns disease. J Clin Gastroenterol. 2005; 39:120-123. 11. Juby AG. The use of calcaneal ultrasound evaluation of

bone mineral density in cognitively impaired seniors. J Am Med Dir Assoc. 2004:377-381. 12. Panichkul S, Sripramote M, Sriussawaamorn N. Diagnostic performance of quantitative ultrasound calcaneus measurement in case finding for osteoporosis in Thai postmenopausal women. J Obstet Gynaecol Res. 2004;30:418-426. 13. Krestan CR, Grampp S, Henk C, Peloschek P, Imhof H. Limited diagnostic agreement of quantitative sonography of the radius and phalanges with dual energy x-ray absorptiometry of the spine, femur and radius for diagnosis of osteoporosis. AJR Am J Roentgenol. 2004;183:639-644. 14. Mack-Shipman L, OGrady DM, Erickson JM, et al. Heel ultrasonography is not a good screening tool for bone loss after kidney and pancreas transplantation. Clin Transplant. 2004; 18:613-618. 15. Hartman C, Hino B, Lerner A, et al. Bone quantitative ultrasound and bone mineral density in children with Celiac disease. J Pediatr Gastroenterol Nutr. 2004;39:504-510. 16. Orstavik RE, Haugeberg G, Uhkig T, et al. Quantitative ultrasound and bone mineral density: discriminatory ability in patients with rheumatoid arthritis and controls with and without vertebral deformities. Ann Rheum Dis. 2004;63:945-951. 17. Camozzi V, Carraro V, Zangari M, Fallo F, Mantero F, Luisetto G. Use of quantitative ultrasound of the hand phalanges in the diagnosis of two different osteoporotic syndromes: Cushings syndrome and postmenopausal osteoporosis. J Clin Invest. 2004;27:510-515. 18. Hakulinen MA, Day JS, Tyras J, et al. Prediction of density and mechanical properties of human trabecular bone in vitro by using ultrasound transmission and backscattering measurements at 0.2-6.7 MHz frequency range. Phys Med Biol. 2005;50:1629-1642. 19. Padilla F, Akrout L, Kolta S, Latremouille C, Roux C, Laugier P. In vitro ultrasound measurement at the human femur. Calcif Tissue Int. 2004;75:421-430. 20. Boonen S, Nijs J, Borghs H, Peeters H, Vanderschueren D, Luyten F. Identifying postmenopausal women by calcaneal ultrasound, metacarpal digital x-ray radiogrammetry and phalangeal radiographic absorptiometry: a comperative study. Osteoporosis Int. 2005;16:93-100.

J. F. Chen, Taiwan

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Jung Fu CHEN, MD Division of Metabolism Chang Gung Memorial Hospital at Kaohsiung Taiwan TAIWAN

n 2001, the National Institutes of Health (NIH) redefined osteoporosis as a skeletal disorder characterized by compromised bone strength, as determined through bone density and bone quality, in spite of the fact that dualenergy x-ray absorptiometry (DXA)the only currently available method for measuring bone mineral density (BMD)can only reveal 70% of associated fracture risk and that it is limited by its relatively high cost, exposure to a certain degree of ionizing radiation, and the fact that it can only be carried out in hospital setting.1 In 1984, diagnosis of osteoporosis and fracture prediction were aided by the development by Langton et al 2 of quantitative ultrasound (QUS). Subsequently, speed of sound (SOS) and/or broadband ultrasound attenuation (BUA) were defined, and mathematically combined into a stiffness index or quantitative ultrasound index (QUI).3 Several QUS devices have been approved by the FDA. Although the most common site of measurement is at the calcaneus, measurements can also be carried out at the radius, fingers, and tibia. The physics of ultrasound suggested it would be able

to provide information beyond the mere calculation of bone mass density (ultrasound tissue characterization), and numerous authors have contributed to defining the clinical applications of QUS, of which three have major implications 4: x QUS can be used to diagnose patients with osteoporosis and associated fracture. In the French PIDmiologie de lOStoporose (EPIDOS) study,5 QUS has shown equivalent ability to hip DXA for the in diagnosing osteoporosis and hip fracture. x QUS can independently predict the risk of osteoporosis-related fractures. In two large-scale prospective studies, (Study of Osteoporotic Fractures [SOF] 6 and EPIDOS 5), ultrasound parameters (SOS and BUA) predicted the risk of hip fracture as well or better than did measurements of BMD at the femoral neck, using DXA. x Serial QUS testing for monitoring. Longitudinal data 7 found a decline in QUS measurements over time of a similar magnitude to DXA, suggesting QUS testing may be used for serial monitoring of osteoporotic individuals or those at high risk. Antiosteoporotic treatment studies (hormone MEDICOGRAPHIA, VOL 28, No. 1, 2006 47

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therapy, nasal calcitonin, alendronate, etc) have consistently shown that serial QUS measurements successfully monitored the extent of pharmacological response, though parathyroid hormone (PTH) and strontium data are still lacking.8-10 Although the majority of countries across the world currently have no reimbursement schemes
REFERENCES 1. NIH Consensus Development Panel on Osteoporosis Prevention, Diagnosis, and Therapy. JAMA. 2001;285:785-795. 2. Langton CM, Palmer SB, Porter RW. The measurement of broadband ultrasound attenuation in cancellous bone. Eng Med. 1984;13:89-91. 3. Bonnick SL. Bone Densitometry in Clinical Practice. Totowa, NJ: Humana Press; 2004;13:301-343. 4. Gler CC, Wu CY, Jergas M, Goldstein SA, Genant HK. Three quantitative ultrasound parameters reflect bone structure. Calcif Tissue Int. 1994;55:46-52. 5. Hans D, Dargent-Molina P, Schott AM, et al. Ultrasonographic heel measurements to predict hip fracture in elderly women: the EPIDOS prospectively study. Lancet. 1996;348: 511-514. 6. Bauer DC, Gler CC, Cauley JA, et al; Study of Osteoporotic Fractures Research Group. Broadband ultrasound attention predicts fractures strongly and independently of densitometry

for QUS, there is a great expectation that QUS will in future play an important and cost-effective role in the screening, diagnosis, and monitoring of osteoporosis and its treatment, especially in the developing world and when applied to community surveys, but many challenges still remain to be met.
in older women: a prospective study. Arch Intern Med. 1997; 157:629-634. 7. Van Daele P, Burger H, De LC, et al. Longitudinal changes in ultrasound parameters of the calcaneus. Osteoporos Int. 1997;7:207-212. 8. de Aloysio D, Rovati LC, Cadossi R, et al. Bone effects of transdermal hormone replacement therapy in postmenopausal women as evaluated by means of ultrasound: an open oneyear prospective study. Maturitas. 1997:27:61-68. 9. Gonnelli S, Cepollaro C, Pondrelli C, Martini S, Rossi S, Gennari C. Ultrasound parameters in osteoporotic patients treated with salmon calcitonin: a longitudinal study. Osteoporos Int. 1996;6:303-307. 10. Giorgino R, Mancuso S. Oral alendronate and calcaneus ultrasound densitometry: a three-year prospective study. The Second International Conference on Osteoporosis. Osteoporos Int. 1997;7(suppl 2):15.

H. M. Zhu, China

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Hanmin ZHU, MD Osteoporosis Center Division of Geriatrics, Hua Dong (East China) Hospital Fu Dang University Teaching Hospital, 221 Yen-An Road West, 200040 Shanghai CHINA (e-mail: ZhuHanmin@yeah.net)

ver the past decade, several quantitative ultrasound (QUS) devices have been developed for the assessment of bone status.1,2 Although QUS measurements do reflect bone mass,3 some reports suggest that QUS also assesses elements of bone quality, including trabecular thickness, separation, orientation, and connectivity.4,5 Many studies have shown that low QUS predicts increased risk of hip and other nonspinal fractures in older women.6,7 The main advantages of these systems consist in the use of nonionizing radiation, their portability, user-friendliness, and low cost. QUS is an attractive choice for population-based screening programs and a promising tool in diagnosing osteoporosis and monitoring treatment response. However, while the practice of QUS appears to have undisputable value, there are still some questions that remain to be discussed. QUS in evaluation of mechanical strength of bone Currently, there are two definitions of osteoporosis that emphasize the role of decreased bone strength. One is from the World Health Organization (WHO), which characterizes the disease by low bone mass and microarchitectural deterioration of bone tissue, leading to enhanced bone fragility and a consequent increase in fracture risk.8 The other definition is from the National Institute of Health (NIH) describing osteoporosis as a skeletal disorder characterized by compromised bone strength predisposing a person to an increased risk of fracture. Bone strength results

from the combination of bone density and bone quality.9 Osteoporosis treatment aims to improve bone strength and increase the threshold of loading failure of bone. Mechanical testing has been considered as a gold standard investigation, and rate of fracture as a good clinical marker to indicate bone strength. Clinical studies have shown that QUS measurements are reproducible and useful to quantity fracture risk.7,10 Between 2003 and 2005, we performed a survey of the relationship between nonviolent (low-trauma) fracture (at any site) and G. E. Achilles QUS parameters in 15 772 citizens aged 20 to 85 years (unpublished data). The result showed that prevalence of fracture was 9.9% (1371 cases) with a strongly significant difference among three groups: T-Score --1, --2, and -- 3 SD of speed of sound (SOS) and broadband ultrasound attenuation (BUA) parameters on the calcaneus, suggesting that QUS may be used to assess fracture risk. The predictive power of fracture risk by QUS is generally lower than with dual-energy x-ray absorptiometry (DXA) because osteoporotic fractures occur mainly at vertebral, proximal femur, and distal radius sites, which are characterized by the presence of more abundant trabecular bone. QUS has not been used at these sites so far. Some experimental studies have shown that QUS parameters provide no significant improvement over DXA alone. Measurement of bone mass by DXA or pQCT (peripheral quantitative computed tomography) appears to be sufficient as a surrogate of mechanical strength and fracture risk of the distal radius.11

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QUS in women with low axial BMD The most common osteoporotic fracture regions are located at the spine and femur, which contain more cancellous bone than other sites. Imbalance of bone turnover is a major pathophysiological mechanism, which results in bone loss and microarchitectural deterioration of bone tissue in osteoporosis. The ratio of metabolic area to cortical and cancellous bone is about 2/8. Measurement of bone mass at the spine and femur is a key parameter in diagnosing osteoporosis and monitoring its treatment. The degree of mineralization is a determinant of bone strength As we know, the strength of bone depends on bone matrix volume, bone microarchitecture, and also on the degree of mineralization of bone. Clinical experience shows that, in osteoporotic patients treated with alendronate, fracture risk decreased and bone mineral density (BMD) increased, with a parallel increase in the mineralization of bone due to prolonged secondary mineralization, but without modifications of bone matrix volume or bone microarchitecture. Bone strength will also increase when mineralization of bone is modified in a physiologic range, without there having to be a change of bone matrix volume or bone microarchitecture.12 BMD assessed by DXA explains up to 70% to 75% of the variance in bone strength.13 Can the widespread availability of QUS scanners predict measurements of axial BMD? Recent studies have shown that SOS at the proximal phalanx of the third finger (SOSP) is a better measurement than SOS at radius (SOSR) in discriminating diseased subjects from healthy womREFERENCES 1. Blake GM, Wahner HW, Fogelman I. The Evaluation of Osteoporosis. Dual Energy absorptiometry and ultrasound in clinical practice. London, UK: Martin Dunitz; 1999:127-146. 2. Njeh C, Hans D Fuerst T, Gler CC, et al: Quantitative ultrasound assessment of osteoporosis and bone status. London, UK: Martin Dunitz London; 1999:107-162. 3. Gler CC. Quantitative ultrasound techniques for the assessment of osteoporosis: expert agreement on current status. The International Quantitative ultrasound Consensus Group. J Bone Miner Res. 1997;12:1280-1288. 4. McCarthy RN, Jeffcott LB, McCartney RN. Ultrasound speed in equine cortical bone: effects of orientation, density, porosity and temperature. J Biomech. 1990;70:691-696. 5. Bouxsein ML, Radloff SE. Quantitative ultrasound of the calcaneus reflects the mechanical properties of calcaneal trabecular bone. J Bone Miner Res. 1997;12:839-846. 6. Buauer DC, Gler CC, Cauley JA, et al: Broadband ultrasound attenuation predicts fractures strongly and independently of densitometry in older women: a prospective study. The Osteoporotic Fractures Research Group. Arch Intern Med. 1997;157:629-634. 7. Hans D, Dargent-Molina P, Schott AM, et al. Ultrasonographic heel measurements to predict hip fracture in elderly women: the EPIDOS prospective study. Lancet. 1996;348: 511-514. 8. Report of a WHO Scientific Group. Prevention and Management of osteoporosis, WHO Technical Report Series 921. Geneva, Switzerland: World Health Organization; 2003. 9. NIH consensus Development Panel on Osteoporosis Prevention, Diagnosis, and therapy. JAMA. 2001;285:785-795. 10. Damilakis J, Perisinakis K, Vagios E, et al. Effect of region

en.14,15 But using SOSR as a preselection tool, the percentage of women with or without osteoporosis that could have avoided DXA examinations of the axial skeleton was only 1%. QUS measurements at the phalanges and radius appear to have less value for the detection of healthy women and those with low axial BMD.16 Another problem is the different sensitivity to bone loss change revealed by different methods. Annual rates of bone loss measured by QUS were significantly lower than with spine DXA, so that QUS was not considered to be suitable for monitoring bone change in the context of response to aging, intervention, and treatment.17 QUS devices from different manufacturers vary significantly, making the clinical use of QUS even more complex than that of DXA. The World Health Organization bases the diagnostic criteria for osteoporosis (and low bone mass) on BMD measurement at spine and femur. However, the T-score defined as the threshold value for osteoporosis cannot be used interchangeably between sites and across technologies. Although several threshold QUS devices are used routinely in clinical practice around the world, no criteria for diagnostic decision-making have yet been established. Despite the widespread acceptance of the T-score, the WHO threshold is not suitable for use in multisite QUS measurements.18 For these reasons, although the QUS method is an inexpensive and relatively portable noninvasive technique, its utilization in clinical practice is still limited. Its main current advantage resides in its use in screening programs.
of interest location on ultrasound measurements of the calcaneus. Calcif Tissue Int. 1998;63:300-305. 11. Hudelmaier M, Kuhn V, Lochmller EM, et al: Can geometry-based parameters from pOST and material parameters from quantitative ultrasound (QUS) improve the prediction of radial bone strength over that by bone mass (DXA)? Osteoporos Int. 2004;15:375-381. 12. Follet H, Bovin G, Rumelhart C, et al. The degree of mineralization is a determinant of bone strength: a study on human calcanei. Bone. 2004;34:783-789. 13. Hans D, Hartl F, Krieg MA. Device-specific weighted T-score for two quantitative ultrasounds: operational propositions for the management of osteoporosis for 65 years and older women in Switzerland. Osteoporos Int. 2003;14:251-258. 14. Has D, Ish-Shaloms S, Wu CY, et al. Discrimination between hip fractures and age matched controls using a commercialized multisite quantitative ultrasound device. Bone. 23: S638. 15. Knapp KM, Blake GM, Fogelman I, et al. Multisite quantitative ultrasound: Colles fracture discrimination in postmenopausal women. Osteoporos Int. 2002;13:474-479. 16. Damliasis J, Papadokostakis G, Perisinakis K, et al: Can radial bone mineral density and quantitative ultrasound measurements reduce the number of women who need axial density skeletal assessment? Osteoporos Int. 2003;14:688-693. 17. Ito M, Nishida A, Kono J, et al. Which bone densitometry and which skeletal site are clinically useful for monitoring bone mass? Osteoporos Int. 2003;14:959-964. 18. Knapp KM, Blake GM, Spector TD, et al. Can the WHO definition of osteoporosis be applied to multi-site axial transmission quantitative ultrasound? Osteoporos Int. 2004; 15:367-374.

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W. Pluskiewicz, Poland

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Wojciech PLUSKIEWICZ, MD Professor, Head of Metabolic Bone Diseases Unit Department and Clinic of Internal Diseases Diabetology, and Nephrology Silesian School of Medicine Katowice, POLAND (e-mail: osteolesna@poczta.onet.pl)

ensitometry is the most commonly used method in clinical practice to assess skeletal status in osteoporosis. Dual-energy x-ray absorptiometry (DXA) has become the gold standard of densitometry. It provides quantitative data on the content of hydroxyapatite calcium in bones, but provides no information on qualitative features. Yet, is well known that the biomechanical competence of the skeleton is dependent both on bone mineral density (BMD) measured by DXA and qualitative features of bone, like elasticity or microarchitecture. The role of bone quality is currently widely recognized and there is an urgent need to develop new methods able to assess it. Other methods may give additional data on bone tissue, like quantitative ultrasound (QUS). QUS has several important advantages: the ability to assess some qualitative features of bone tissue, the lack of ionizing radiation, relatively low costs, and the small size of equipment. QUS also has some disadvantages, such as the difficulty in obtaining precise measurement of bone tissue features, and the fact that it can only be applied to peripheral skeletal sites. The calcaneus is the most popular measurement site as it is an easily accessible weight-bearing bone that consists almost exclusively of metabolically active trabecular tissue. Osteoporosis is a common disease causing fractures in several skeletal sites, including spine and hip. Currently, bone densitometry serves as a method for diagnosis of the disease, but it is important to point out that the most important problem is the assessment of fracture risk. Fracture risk may be established in cross-sectional (fracture discrimination) and prospective studies (fracture prediction). QUS was used in several retrospective studies (subjects with fractures versus subjects without fractures), and showed that patients with past, low-energy fractures (due to minimal trauma caused by a fall from standing height or less) had significantly lower QUS values.1-8 The odds ratios (OR), calculated as increasing risk per 1 standard deviation (SD) decrease in measured QUS parameters, usually ranged from to 1.5 do 4.0. Longitudinal studies provide the most important data on the clinical utility of QUS in osteoporosis, and show that calcaneal QUS measurements are able to predict future
REFERENCES 1. Bauer DC, Gler CC, Genant HK, et al. Quantitative ultrasound and vertebral fracture in postmenopausal women. J Bone Miner Res. 1995;10:353-358. 2. Schott AM, Weill-Engerer S, Hans D, et al. Ultrasound discriminates patients with hip fracture equally well as dual energy x-ray densitometry and independently of bone mineral density. J Bone Miner Res. 1995;10:243-249. 3. Pluskiewicz W, Drozdzowska B. Ultrasonic measurement of the calcaneus in Polish normal and osteoporotic women and men. Bone. 1999;24:611-617. 4. Benitez CL, Schneider DL, Barrett-Connor E, Sartoris DJ. Hand ultrasound for osteoporosis screening in postmenopausal women. Osteoporos Int. 2000;11:203-210. 5. Wuster C, Albanese C, de Aloysio D, et al. Phalangeal osteo-

osteoporotic fractures.9-13 The only other skeletal site used, besides the calcaneus, in fracture prediction has been the phalanges.14 Studies comparing the value of DXA and QUS measurements have found that fracture discrimination or prediction is comparable with QUS and DXA.10,11,13,15 The clinical utility of QUS was also evaluated using receiving operating characteristic (ROC) analysis, to determine how this method discriminates between subjects with and without fractures. ROC analysis plots a sensitivity versus specificity curve and quantifies the accuracy of QUS by estimating the area under the ROC curve (AUC). A perfect tool, which would correctly classify individuals into a disease or no disease state 100% of the time, would have an AUC estimate of 1.0. With QUS, AUC values ranged from 0.62 13 to 0.96.5 The majority of studies using QUS measurements have been performed in female populations, and only a few studies have looked at the method's ability to detect skeletal changes in males as well. Some studies found adequate fracture discrimination in males, with OR values ranging from 1.05 to 3.4.16,17 The sensitivity and specificity of ultrasound measurements in males was also established, with AUC values ranging from 0.66 to 0.81.16,17 Prospective fracture studies are not available. Despite these promising results, longitudinal observation of bone changes is hampered by relatively poor precision, and methods with improved precision are eagerly awaited. To conclude, QUS has proven utility in fracture risk assessment in osteoporotic female and male populations and is therefore helpful in guiding management. There is a wide consensus that diagnosis of osteoporosis should be based on DXA measurement, but, from the clinical point of view, it is vital to be able to measure the enhanced fracture risk resulting from osteoporosis, which is assessed by QUS. In my opinion, the term diagnosis of osteoporosis should be replaced by fracture risk assessment, as from the clinical point of view the consequences of the disease are mainly due to fractures. Thus, the answer to the title question is YES: QUS is currently useful as a screening method for fracture risk assessment. Future progress in methodology and further studies will doubtless result in much improvement in the diagnosis of osteoporosis.
sonogrammetry study: age-related changes, diagnostic sensitivity, and discrimination power. J Bone Miner Res. 2000;15: 1603-1614. 6. Drozdzowska B,. Pluskiewicz W. Quantitative ultrasound at the calcaneus in premenopausal women and their postmenopausal mothers. Bone. 2001;29:79-83. 7. Drozdzowska B, Pluskiewicz W. The ability of quantitative ultrasound at the calcaneus to identify postmenopausal women with different types of non-traumatic fractures. Ultrasound Med Biol. 2002;28:1491-1497. 8. Drozdzowska B, Pluskiewicz W. The usefulness of quantitative ultrasound at the hand phalanges in the detection of different types of non-traumatic fractures. Ultrasound Med Biol. 2003;29:1545-1550.

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9. Porter RW, Miller CG, Grainger D, Palmer SB. Prediction of hip fracture in elderly women: a prospective study. BMJ. 1990;29:638-641. 10. Hans D, Dargent-Molina P, Schott AM, et al. Ultrasonographic heel measurements to predict hip fracture in elderly women: the EPIDOS prospective study. Lancet. 1996;348: 511-514. 11. Bauer DC, Gluer CC, Cauley JA, et al. Broadband ultrasound attenuation predicts fractures strongly and independently of densitometry in older women: a prospective study. Study of Osteoporotic Fractures Research Group. Arch Int Med. 1997;157:629-634. 12. Pluijm SMF, Graafmans WC, Bouter LM, et al. Ultrasound measurements for the prediction of osteoporotic fractures in elderly people. Osteoporos Int. 1999;9:550-556. 13. Huopio J, Kroger H, Honkanen R, Jurvelin J, Saarikoski S, Alhava E. Calcaneal ultrasound predicts early postmenopausal

fractures as well as axial BMD. A prospective study of 422 women. Osteoporos Int. 2004;15:190-195. 14. Mele R, Masci G, Ventura V, et al. Three-year longitudinal study with quantitative ultrasound at the hand phalanx in a female population. Osteoporos Int. 1997;7:550-557. 15. Langton CM, Langton DK. Comparison of bone mineral density and quantitative ultrasound of the calcaneus: sitematched correlation and discrimination of axial BMD status. Br J Radiol. 2000;73:31-35. 16. Pluskiewicz W, Drozdzowska B. Ultrasound measurements at the calcaneus in men: differences between healthy and fractured persons and the influence of age and anthropometric features on ultrasound parameters. Osteoporos Int. 1999;10: 47-51. 17. Mullemann D, Legroux-Gerot I, Duquesnoy B, et al. Quantitative ultrasound of bone in male osteoporosis. Osteoporos Int. 2002;13:388-393.

H. P. Dimai, Austria

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Hans P. DIMAI, MD Professor of Medicine and Endocrinology, Medical University of Graz Department of Internal Medicine, Division of Endocrinology and Nuclear Medicine, Auenbruggerplatz 15, A-8036 Graz AUSTRIA (e-mail: hans.dimai@meduni-graz.at)

steoporosis is currently defined as a skeletal disorder characterized by compromised bone strength predisposing to an increased risk of fracture 1 Bone strength itself is determined by both bone density and bone quality. Because no clinical tool is currently available to measure specified determinants of bone quality, individuals with increased fracture risk are primarily identified by measurement of bone mineral density. The current gold standard method for measurement of bone mineral density (BMD) is dual-energy x-ray absorptiometry (DXA). BMD is defined as the measured bone mineral content in grams divided by the measured two-dimensional projected area of the bone being measured. Accordingly, BMD is always expressed as g/cm2. In clinical practice, however, the results of a DXA measurement are given as T-scores, which are calculated by comparing the patients BMD with the mean value for young normal individuals. This standardized procedure is based on the fact that in 1994, a World Health Organization (WHO) working group on osteoporosis proposed diagnostic categories based on such T-scores. Accordingly, a T-score of --1.0 and above is considered normal; a T-score between --1.0 and --2.5 is considered as osteopenia (low bone mass), and a T-score of --2.5 and below is considered as osteoporosis.2 Furthermore, according to the recently published Position Guidelines of the International Society for Clinical Densitometry (ISCD), for diagnosis in postmenopausal women, the lowest T-score of posterior-anterior (PA) spine, femoral neck, total hip, trochanter, or the 33% radius, if measured, should be selected.3 As an alternative to DXA, which is a radiation-based bone densitometry technique, quantitative ultrasound (QUS) for the noninvasive assessment of fracture risk is attracting increasing attention. Compared with DXA, QUS is relatively inexpensive, simple to use, portable, and radiation-free. QUS would thus appear to have greater potential

for widespread application than DXA. Ultrasound is a mechanical wave that can be measured both in transmission and in reflection. Measurement outcomes are typically expressed as SOS (speed of sound = the velocity of the wave traveling through skin and bone), and as BUA (broadband ultrasound attenuation = rate at which the energy is attenuated with increasing frequency). While BUA is considered to be related more to bone structure, SOS appears to be more strongly related to material properties.4 Thus, QUS parameters reflect not only BMD, but also other bone properties, some of which may be related to bone quality. It is therefore not surprising that QUS measurement, particularly at the heel, has been demonstrated in several cross-sectional and prospective studies to discriminate prevalent, or predict incident, osteoporotic fractures at the hip, wrist, or spine at least as well as DXA (eg, references 5, 6, 7, and 8). In addition, QUS parameters have been shown to better predict women with low bone mass than do clinical risk factors.9 However, in view of the fact that diagnosis of osteopenia or osteoporosis should be based on WHO T-score criteria, QUS results often are also routinely expressed in terms of T-scores. Unfortunately, this practice can potentially lead to misdiagnosis, as it has been clearly demonstrated that T-scores in a given population significantly differ between DXA and QUS.10 In other words, QUS parameters have been found to correlate only moderately with BMD measurements by DXA, and identification of individuals with osteopenia or osteoporosis would greatly disagree between QUS and DXA if WHO T-score criteria were equally applied to QUS and DXA. For example, using a T-score of --2.5, roughly 15% of white women aged 60 years would be expected to be osteoporotic based on DXA of the spine, whereas only 3% of the same population would be diagnosed as osteoporotic based on measurement at the heel by QUS.10 These differences have been shown MEDICOGRAPHIA, VOL 28, No. 1, 2006 51

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to be primarily due to discordances in age-related BMD loss.10 Although numerous efforts have been undertaken, hitherto no algorithm has been developed to overcome these inconsistencies. Thus, at present, QUS appears to suffice to identify individuals at risk of fracture at different skeletal sites if results are carefully interpreted
REFERENCES 1. NIH Consensus Development Panel on Osteoporosis Prevention, Diagnosis, and Therapy. Osteoporosis prevention, diagnosis, and therapy. JAMA. 2001;285:785-795. 2. Kanis JA, Melton LJ III, Christiansen C, Johnston CC, Khaltaev N. The diagnosis of osteoporosis. J Bone Miner Res. 1994;9:1137-1141. 3. Leib ES, Lewiecki EM, Binkley N, Hamdy RC; International Society for Clinical Densitometry. Official positions of the International Society for Clinical Densitometry. J Clin Densitom. 2004;7:1-6. 4. Glueer CC, Vahlensieck M, Faulkner KG, Engelke K, Black D, Genant HK. Site-matched calcaneal measurements of broadband ultrasound attenuation and single x-ray absorptiometry: do they measure different skeletal properties? J Bone Miner Res. 1992;7:1071-1079. 5. Bauer DC, Gluer CC, Cauley JA, Vogt TM, Ensrud KE, Genant HK, Black DM. Broadband ultrasound attenuation predicts fractures strongly and independently of densitometry in older women. A prospective study. Study of Osteoporotic Fractures Research Group. Arch Intern Med. 1997;157:629-634.

by an experienced clinician. Diagnosis of osteopenia or osteoporosis in terms of WHO criteria, however, cannot be achieved using QUS parameters. To assign an individual to one of the WHO diagnostic categories, measurement of BMD by DXA continues to remain the gold standard.
6. Hans D, Dargent-Molina P, Schott AM, Sebert JL, Cormier C, Kotzki PO, Delmas PD, Pouilles JM, Breart G, Meunier PJ. Ultrasonographic heel measurements to predict hip fracture in elderly women: the EPIDOS prospective study. Lancet. 1996;348:511-514. 7. Thompson PW, Taylor J, Oliver R, Fisher A. Quantitative ultrasound (QUS) of the heel predicts wrist and osteoporosisrelated fractures in women age 45-75 years. J Clin Densitom. 1998;1:219-225. 8. Gluer CC, Eastell R, Reid DM, Felsenberg D, Roux C, Barkmann R, Timm W, Blenk T, Armbrecht G, Stewart A, Clowes J, Thomasius FE, Kolta S. Association of five quantitative ultrasound devices and bone densitometry with osteoporotic vertebral fractures in a population-based sample: the OPUS Study. J Bone Miner Res. 2004;19:782-793. 9. Stewart A, Reid DM. Quantitative ultrasound or clinical risk factors which identifies women at risk of osteoporosis? Br J Radiol. 2000;73:165-171. 10. Faulkner KG, von Stetten E, Miller P. Discordance in patient classification using T-scores. J Clin Densitom. 1999;2:343-350.

A. Dez-Perez, Spain

U
Adolfo DEZ-PEREZ, MD, PhD Professor of Medicine Autonomous University of Barcelona Department of Internal Medicine Hospital del Mar Passeig Maritim 25-29 08002 Barcelona SPAIN (e-mail: adiez@imas.imim.es)

ltrasounds are the basis for the noninvasive investigation of bone tissue. Measurements can be obtained in several anatomical regions, mainly the phalanges, tibia, and heel. The main advantages of quantitative ultrasound (QUS) devices are their portability, lack of ionizing radiation, and relative low cost when compared with conventional dual-energy x-ray (DXA) densitometers. However, in clinical practice, the precision and reproducibility of QUS are limited by its coefficient of variability, even though it has demonstrated good ability to predict bone stiffness and failure load.1,2 The World Health Organization (WHO) definition of osteoporosis is based on bone mineral density measured by DXA. However, in clinical practice, DXA equipment availability is limited, which poses a problem. Therefore, in recent years, considerable attention has been given to the diagnostic capability of ultrasound for the diagnosis of osteoporosis. A technique able to diagnose osteoporosis should be efficient in differentiating patients with the disease from normal individuals. Ultrasounds have been found to be effective in detecting osteoporotic fracture vs nonfracture. Results from a number of cross-sectional studies have demonstrated that QUS values are lower in women with fracture than in controls.3-8 Moreover, in prospective studies, the predictive ability of QUS for fractures is comparable to that of DXA.9-13 In the ECOSAP study of 5200 postmenopausal women,

of whom 1042 (20.1%) had prevalent fracture, QUS parameters showed a significant odds ratio for every standard deviation (SD) decrease, ranging from 1.47 to 1.55.14 In this same study, we demonstrated that the area under the ROC curve was as high as 0.656. All these values were comparable to those obtained in similar studies with DXA. Another question is how well QUS results correlate with DXA results, measured in the same patient. Since DXA values taken in different regions show only modest correlation, the same can be expected for QUS vs DXA. In a subgroup of 267 women from the ECOSAP cohort, both hip DXA and heel QUS measurements were obtained.15 The overall correlation was 0.47 (0.37-0.56) (r, 95% CI). For a QUS T-score of --1.5, the sensitivity and specificity of the diagnosis of osteoporosis were 64% and 58%, respectively, when compared with DXA-based World Health Organization (WHO) criteria. The kappa index of agreement between the two techniques was over 0.2. These results enable a diagnostic threshold to be established when QUS is the only available technique to assess a patient with possible osteoporosis. A QUS T-score below --1.5 roughly compares with the classic --2.5 T-score measured by DXA. Extreme values exclude or support the diagnosis of osteoporosis in more than 20% of cases, even in the absence of a DXA measurement. From all these data we can draw some conclusions. First, the ability of QUS to predict

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fractures is good and similar to the prediction made by DXA. In this respect, the technique acceptably stratifies individual risk in a population of postmenopausal women, thereby selecting candidates for intervention. Second, for a T-score of --1.5 measured by QUS, the quantitative values are comparable to the values measured by DXA that provide the widely accepted diagnostic T-score threshold value of --2.5. However, the agreement between both measurements is only modest, though statistically significant.
REFERENCES 1. Gler CC. Quantitative ultrasound techniques for the assessment of osteoporosis: expert agreement on current status. J Bone Miner Res. 1997;12:1280-1288. 2. Bouxsein ML, Radloff SE. Quantitative ultrasound of the calcaneus reflects the mechanical properties of calcaneal Trabecular bone. J Bone Miner Res. 1997;12:839-846. 3. Karlsson MK, Duan Y, Ahlborg H, et al. Age, gender, and fragility fractures are associated with differences in quantitative ultrasound independent of bone mineral density. Bone. 2001;28:118-122. 4. Frost ML, Blake GM, Fogelman I. Quantitative ultrasound and bone mineral density are equally strongly associated with risk factors for osteoporosis. J Bone Miner Res. 2001;16: 406-416. 5. Frost ML, Blake GM, Fogelman I. Does the combination of quantitative ultrasound and dual-energy X-ray absorptiometry improve fracture discrimination? Osteoporos Int. 2001;12: 471-477. 6. Hartl F, Tyndall A, Kraenzlin M, et al. Discriminatory ability of quantitative ultrasound parameters and bone mineral density in a population-based sample of postmenopausal women with vertebral fractures: results of the Basel Osteoporosis Study. J Bone Miner Res. 2002;17:321-330. 7. Frost ML, Blake GM, Fogelman I. A comparison of fracture discrimination using calcaneal quantitative ultrasound and dual x-ray absorptiometry in women with a history of fracture at sites other than the spine and hip. Calcif Tissue Int. 2002; 71:207-211. 8. Lpez-Rodrguez F, Mezquita-Raya P, de Dios Luna J, Escobar-Jimnez F, Muoz-Torres M. Performance of quantita-

So what is the overall answer to the controversial question posed? In settings in which access to DXA devices is difficult, ultrasounds permit a reliable diagnosis of osteoporosis and of the increased risk of fracture. Even when DXA is accessible, a QUS-based screening policy can be beneficial to better select candidates for DXA. Future developments of the QUS technique should improve its intrinsic variability and make it a suitable method to monitor the evolution of osteoporosis.
tive ultrasound in the discrimination of prevalent osteoporotic fractures in a bone metabolic unit. Bone. 2003;32:571-578. 9. Lee SH, Dargent-Molina P, Brart G. Risk factors for fractures of the proximal humerus: results from the EPIDOS prospective study. J Bone Miner Res. 2002;17:817-825. 10. Bauer DC. Clinical applications of quantitative ultrasound. In: Njeh CF, Hans D, Fuerst T, Glur CC, Genant HK, eds. Quantitative Ultrasound: Assessment of Osteoporosis and Bone Status. London, UK: Martin Dunitz Ltd; 1999:284-297. 11. Miller PD, Siris ES, Barrett-Connor E, et al. Prediction of fracture risk in postmenopausal white women with peripheral bone densitometry: evidence from the National Osteoporosis Risk Assessment. J Bone Miner Res. 2002;17:2222-2230. 12. Pluijm SMF, Graafmans WC, Bouter LM, Lips P. Ultrasound measurements for the prediction of osteoporotic fractures in elderlypeople. Osteoporos Int. 1999;9:550-556. 13. Thompson PW, Taylor J, Oliver R, Fisher A. Quantitative ultrasound (QUS) of the heel predicts wrist and osteoporosisrelated fractures in women age 45-75 years. J Clin Densitom. 1998;1:219-225. 14. Hernndez JL, Marin F, Gonzlez-Macas J, et al. Discriminative capacity of calcaneal quantitative ultrasound and of osteoporosis and fracture risk factors in postmenopausal women with osteoporotic fractures. Calcif Tissue Int. 2004; 74:357-365. 15. Diez-Prez A, Marn F, Vila J, et al. Evaluation of calcaneal quantitative ultrasound in a primary care setting as a screening tool for osteoporosis in postmenopausal women. J Clin Densitom. 2003;6:237-245.

J. A. Melo-Gomes, Portugal

Jos A. MELO-GOMES, MD Senior Consultant Rheumatologist Instituto Portugus de Reumatologia Lisbon PORTUGAL (e-mail: melo.gomes@mail.telepac.pt)

or more than a decade, quantitative ultrasound (QUS) has been considered as having a good potential for the diagnosis of osteoporosis due to its lack of ionizing radiation, low cost, fast and simple operation procedures, and lightness of the hardware, allowing easy transportation from one place to another.1 In the early days of the technique, some authors even predicted that QUS would, in the near future, supersede dual-energy x-ray absorptiometry (DXA). However, so far, this hasnt happened, and the main reasons are: x We still dont know what exactly is measured by QUS devices; x Whatever is measured, it does not correlate well with bone mass or the response to treatment with the most efficacious drugs available for the treatment of osteoporosis; x Diversity is the main feature of QUS technology, either in the sites chosen for evaluation (gen-

erally nonfracture sites, like the heel, shin, patella, and phalanges) or in the modes of data acquisition and analysis; x Different QUS devices give different values for the same patient.2 The only good correlation of ultrasound determinations is with fracture, independently of the measured bone mass of the patient,3,4 and even this correlation only holds for population groups, being poor on an individual basis. However, anything that would in some way correlate with the aging process would also be a good method of assessing the risk of fracture on a population basis. The most obvious parameter is the age of the patient. Since age is a main determinant of the risk of fracture, we would also have a good correlation with fracture rates, on a population basis, but not on an individual basisand this is much cheaper. Could this, to some extent, be the case with QUS? In some studies,5,6 QUS has shown a MEDICOGRAPHIA, VOL 28, No. 1, 2006 53

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good discriminatory ability in the diagnosis of osteoporosis, similar to that of DXA in the identification of risk for vertebral osteoporotic fracture. However, others7 have shown that QUS is not substantially more cost-effective than DXA alone for the diagnosis of postmenopausal osteoporosis. The fact that all drugs now available to treat osteoporosis act by changing bone turnover and/or increasing bone mass makes these two parameters the best surrogate markers for the decrease of osteoporotic fracture risk, leaving thus QUS with an, yet, uncertain role in the diagnosis and evaluation of osteoporosis. Due to
REFERENCES 1. Faulkner KG. Update on bone density measurement. Rheum Dis Clin N Am. 2001;27:81-99. 2. Falgarone G, Porcher R, Duch A, et al. Discrimination of osteoporotic patients with quantitative ultrasound using imaging and non-imaging device. Joint Bone Spine. 2004;71: 419-423. 3. Bauer D, Gluer C, Cauley J, et al. Bone ultrasound predicts fractures strongly and independently of densitometry in older women. A prospective study. Arch Intern Med. 1997;157: 629-634. 4. Marshall D, Johnell O, Wedel H. Meta-analysis of how well measures of bone mineral density predict the occurrence of osteoporotic fractures. BMJ. 1995;312:1254-1259. 5. Pinheiro MM, Castro CHM, Frisoli Jr A, Szenfeld VL. Discriminatory ability of quantitative ultrasound measurements is similar to dual-energy x-ray absorptiometry in a Brazilian

the lack of ionizing radiation, QUS may also become a good method to study osteoporosis in children with chronic rheumatic diseases 8 or other forms of osteoporosis, provided that the doubts laid out above are resolved. In conclusion, I would say that the compact and nonradiation technology of QUS make it an appropriate choice for population-based screening programs and could be used on an individual basis only if DXA is not available locally. However, provided that DXA is available, I wouldnt feel comfortable using QUS alone to make a decision on whether or not treat an individual patient.
women population with osteoporotic fracture. Calcif Tissue Int. 2003;73:555-564. 6. Gluer CC, Eastell R, Raid DM, et al. Association of five quantitative ultrasound devices and bone densitometry with osteoporotic vertebral fractures in a population-based sample: the OPUS study. J Bone Miner Res. 2004;19:782-793. 7. Marin F, Lpez-Bastida J, Diez-Prez A, et al. Bone mineral density referral for dual-energy x-ray absorptiometry using quantitative ultrasound as a pre-screening tool in postmenopausal women from the general population: a cost-effectiveness analysis. Calcif Tissue Int. 2004;74: 277-283. 8. Hartman C, Shamir R, Eshash-Adiv O, et al. Assessment of osteoporosis by quantitative ultrasound versus dual energy x-ray absorptiometry in children with chronic rheumatic diseases. J Rheumatol. 2004;31:981-985.

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PROTELOS, THE FIRST DUAL-ACTION

BONE AGENT FOR THE TREATMENT OF POSTMENOPAUSAL OSTEOPOROSIS
b y V. L e b l a n c , F r a n c e

steoporosis is characterized by a decrease in bone mass and a deterioration in skeletal microarchitecture, leading to increased fragility and susceptibility to fracture. Bone loss is a major determinant of skeletal weakness in osteoporosis and the single most important risk factor is the menopause.1 After the menopause sets in, there is an increase in bone turnover in which the marked increase in bone resorption is partly balanced by the increase in bone formation, thus leading to bone loss. The prevalence of osteoporosis peaks in middle-aged to elderly postmenopausal women, even though it is observed in all age groups and populations. Osteoporotic fractures, in particular verte-

Vronique LEBLANC, MD International Scientific Project Leader Neuilly-sur-Seine FRANCE

bral and hip fractures, are associated with important morbidity and often permanent loss of quality of life, and high mortality.1 Postmenopausal osteoporosis requires effective treatment, and because osteoporosis is a chronic disease, persisting into old age, patients are often on multiple therapies, so that antiosteoporotic treatment needs to be as free as possible of any untoward drug interactions, and have excellent tolerability and safety. Most agents available today are limited by the fact that they have a mode of action that is either antiresorptive or bone-forming. Due to the coupling of bone formation and bone resorption, antiresorptive agents are associated with a con-

rotelos (strontium ranelate) is a new first-line therapy for the treatment of postmenopausal osteoporosis, with demonstrated efficacy in reducing the risk of the osteoporotic fractures and good tolerability. Postmenopausal osteoporosis is a dramatically increasing, widespread, and urgent clinical problem. One out of two women will experience an osteoporosis-related fracture in their lifetime, with major associated morbidity and mortality, which increases with age. Fragility fractures most commonly involve the vertebrae, hips, and wrists. Although vertebral fractures are the most frequent, hip fractures are associated with the highest morbidity and mortality. Osteoporosis results from an imbalance between bone resorption and formation. Most currently available therapies are either exclusively antiresorptive or exclusively bone-forming. Protelos, discovered and developed by Servier, is the first antiosteoporotic agent with a dual mode of action, resulting in a simultaneous increase in bone formation and decrease in bone resorption. This dual action rebalances bone turnover in favor of the formation of new, thus strong, bone. Two international, randomized, doubleblind phase 3 placebo-controlled clinical trials have been conducted to establish the efficacy and safety of Protelos (strontium ranelate 2 g/day orally) in the treatment of postmenopausal osteoporosis, SOTI (Spinal Osteoporosis Therapeutic Intervention) and TROPOS (TReatment Of Peripheral OSteoporosis). These trials confirmed the effectiveness of Protelos whatever the severity of the disease (with or without previous vertebral fractures), whatever the site (vertebra, hip), and whatever the age (including patients aged 80 and above). Protelos resulted in a significant 49% reduction in relative risk of new vertebral fractures as early

as by the first year of treatment, with sustained efficacy over 3 years, and in a significant 41% reduction in relative risk in patients with prevalent vertebral fractures. In osteoporotic patients without prevalent vertebral fractures, Protelos decreased fracture risk by 48% over 3 years of treatment. New clinical vertebral fractures (ie, those associated with back pain and/or loss of body height of at least 1 cm) were reduced by 52% as early as by the 1st year of treatment. Protelos resulted in a significant 16% reduction in relative risk of nonvertebral fractures, with a 19% decrease in risk of major osteoporotic nonvertebral fractures, and a 36% decrease in risk of hip fractures in osteoporotic patients aged 74 years or more, ie, the population mainly suffering from hip fractures. Protelos significantly increased bone mineral density (BMD). After 3 years, mean BMD difference between groups was 14.4% at the lumbar spine and 8.3% at the femoral neck. Protelos not only provides fracture risk reduction, but also improves patient quality of life, with studies showing good tolerability, including in elderly patients. These findings confirm the indication of Protelos 2 g/day orally (one sachet at bedtime), in the first-line treatment of postmenopausal osteoporosis in women, to reduce the risk of vertebral and hip fractures.
Medicographia. 2006;28:55-62. (see French abstract on page 62)

Keywords: osteoporosis; fracture; bone mineral density; Protelos (strontium ranelate); mode of action; antifracture efficacy; quality of life
Address for correspondence: Vronique Leblanc, MD, Servier International, 192 avenue Charles de Gaulle, 92578 Neuilly-sur-Seine Cedex, France (e-mail: veronique.leblanc@fr.netgrs.com)

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Protelos: a unique dual mode of action

SELECTED
BMD FIRST
ABBREVIATIONS AND ACRONYMS

bone mineral density Fracture International Run-in Strontium ranelate Trial QUALIOST QUAlity of LIfe questionnaire in OSTeoporosis SERM selective estrogen receptor modulator SF-36 36-Item Short-Form Survey SOTI Spinal Osteoporosis Therapeutic Intervention TROPOS TReatment Of Peripheral OSteoporosis

The majority of treatments available today are antiresorptive (bisphosphonates, selective estrogen receptor modulators [SERMs], and calcitonins). They decrease or inhibit bone resorption. As a consequence of the coupling between bone formation

BONE FORMATION
+
Pre-OB

BONE RESORPTION
Pre-OC

PROTELOS

Replication Differentiation
PROTELOS

comitant decrease in bone formation, while boneforming agents are associated with an increase in bone resorption. Ideally, an optimal drug treatment for osteoporosis should be able to both increase bone formation and decrease bone resorption: Protelos fulfills this requirement. Protelos: a new antiosteoporotic agent Protelos, or strontium ranelate (5-[bis(carboxymethyl)amino]-2-carboxy-4-cyano-3-thiophenacetic acid distrontium salt), discovered and developed by Servier, is a new antiosteoporotic treatment with an innovative mode of action on bone turnover. It is the first antiosteoporotic agent able to simultaneously increase bone formation and decrease bone resorption,2 thereby rebalancing bone turnover in favor of the formation of new and strong bone, resulting in an increase in bone mass. Protelos is composed of an organic moiety (ranelic acid) and two atoms of stable (nonradioactive) strontium. Ranelic acid was chosen among 26 strontium salts for its pharmacokinetic characteristics (eg, bioavailability), physicochemical characteristics (eg, solubility, stability, etc), high ratio between strontium and organic moiety (two atoms of strontium linked to the molecule), good tolerability (especially excellent gastric tolerance), and safety (Figure 1).

OB

OB

OB OC

Bone-forming activity
PROTELOS

Bone matrix

Boneresorbing activity

Figure 2. The dual mode of action of Protelos: simultaneous increase in the replication of preosteoblasts (Pre-OB) resulting in an increase in osteoblasts (OB), and decrease in the differentiation of preosteoclasts (Pre-OC) into osteoclasts (OC), and a decrease in the bone-resorbing activity of osteoclasts.
Modified from reference 2: Marie PJ, Ammann P, Boivin G, Rey C. Mechanisms of action and therapeutic potential of strontium in bone. Calcif Tissue Int. 2001;69:121-129. Copyright 2001, Springer-Verlag New York Inc.

--OOC

CN COO--

Sr ++
--OOC

N COO--

Sr ++

Figure 1. Molecular structure of Protelos (strontium ranelate).

Protelos was granted a European marketing authorization by the European Agency for the Evaluation of Medicinal Products (EMEA) with the following indication: Treatment of postmenopausal osteoporosis to reduce the risk of vertebral and hip fractures. Only alendronate and risedronate had previously been given this indication. Recently registered products in Europe like teriparatide and ibandronate have not obtained a hip fracture indication.3 Protelos is now registered and launched in European Union (EU) countries as well as several non-EU countries, with many more to follow shortly. 56 MEDICOGRAPHIA, VOL 28, No. 1, 2006

and bone resorption, they also decrease bone formation, so that the net result is a global decrease in bone turnover. In contrast, parathyroid hormone and its analogs increase bone formation, while also increasing bone resorption. Protelos has a unique dual mode of action, and is the first and only treatment to dissociate the processes of bone resorption and bone formation, thereby rebalancing bone turnover in favor of formation and achieving early and sustained antifracture efficacy (Figure 2).2,4-10 The molecular basis for this dual mode of action is still under investigation. Current knowledge suggests that Protelos influences the cellular mechanisms regulating bone cell differentiation and activity. Protelos enhances preosteoblastic cell replication, leading to an increase in bone-forming activity by osteoblasts,4-7 and this is accompanied by a decrease in the differentiation of preosteoclasts, thus a decrease in the resorbing activity of osteoclasts.7-10 The dual mode of action of Protelos was tested in vitro and confirmed in the intact animal and in animal models of osteoporosis. Its unique mode of action was clinically confirmed by the resulting changes in bone metabolism markers. In postmenopausal patients with osteoporosis, findings from the Spinal Osteoporosis Therapeutic Intervention (SOTI) trial showed that serum bone-specific alkaline phosphatase (bALP) levels (a marker of bone formation) were significantly higher (+8.1%, P<0.001 at the

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3rd month of treatment), and that serum type I collagen C-telopeptide crosslinks (sCTX) levels (a marker of bone resorption) were significantly lower (-12.2%, P<0.001 at the 3rd month of treatment) in patients receiving Protelos than in the placebo group. These changes were sustained throughout the 3 years of treatment (Figure 3).11

Absolute change from baseline between groupsa *** b-ALP ng/mL

0.8

***

1.2

Bone formation
**

*
0.4

*
*P <0.05 **P<0.01 ***P<0.001

s-CTX pmol/L

a = Estimate change of difference PROTELOS minus placebo, covariance analysis, baseline-adjusted

200

***
400

**

*** ***
0 3 6 12

Bone resorption
36

600

Protelos proved similarly effective in immobilization-induced osteoporosis in rats.14 Evidence from these studies thus confirmed that Protelos consistently decreases bone resorption, while having a stimulatory effect on bone formation, thereby rebalancing bone turnover in favor of bone formation and improving bone strength. Experiments in monkeys show that strontium is dose-dependently incorporated into the mineral substance of cortical and trabecular bone. The greatest proportion of strontium is adsorbed on the surface of the hydroxyapatite crystals, and only a very small proportion is incorporated into the crystal. Less than 1 out of 10 calcium ions present per crystal unit are substituted by strontium ions at high doses. Strontium is rapidly cleared from bone after cessation of treatment with Protelos. Bone strontium content decreases by up to 50% within 10 weeks after stopping treatment. Protelos preserves the characteristics of bone crystal structure and of the mineralization process.15,16 Based on the results of a phase 2 study, 2 g/day orally was found to be the adequate effective dosage for osteoporosis treatment, ensuring the best combination of clinical benefits (eg, significant increase in bone mineral density) and tolerability.17 Clinical efficacy of Protelos on vertebral and nonvertebral/hip fracture risk A large-scale phase 3 development program was carried out in women with postmenopausal osteoporosis to assess the antifracture efficacy of Protelos.18 This program consisted of an initial run-in trial called FIRST (Fracture International Run-in Strontium ranelate Trial) followed by two multicenter, randomized, double-blind, placebo-controlled clinical trials: the Spinal Osteoporosis Therapeutic Intervention (SOTI) trial, to study the effect of Protelos on vertebral fracture risk, and the TReatment Of Peripheral OSteoporosis (TROPOS) trial, which did the same on nonvertebral fracture risk. FIRST, which included more than 9000 patients, was intended to start normalizing the patients calcium/ vitamin D status. Of these patients, 6740 could subsequently be included in SOTI or TROPOS. Both trials were planned for a duration of 5 years and the main statistical analysis was carried out after 3 years of treatment. Analyses were performed on the intention-to-treat (ITT) population (Table I, next page).19 Clinical efficacy of Protelos on vertebral fracture risk In osteoporotic patients with prevalent vertebral fracture, Protelos resulted in early and sustained antifracture efficacy. In SOTI, Protelos, 2 g/day orally, significantly reduced the risk of experiencing a new vertebral fracture by 49% (relative risk [RR], 0.51; 95% confidence interval [CI], 0.36-0.74; P<0.001) as early as by the first year of treatment, and by 41% (RR, 0.59; 95% CI, 0.48-0.73; P<0.001) over 3 years, compared with placebo, based on a semiquantitative visual assessment of vertebral fractures. From these data it can be calculated that treatMEDICOGRAPHIA, VOL 28, No. 1, 2006 57

Time (mo)

24

Figure 3. Between-group differences over time in biochemical markers of bone metabolism with Protelos. bALP, serum bone-specific alkaline phosphatase (marker of bone formation); sCTX, serum type I collagen C-telopeptide crosslinks (marker of bone resorption).
Modified from reference 11: Meunier PJ, Roux C, Seeman E, et al. The effects of strontium ranelate on the risk of vertebral fracture in women with postmenopausal osteoporosis. N Engl J Med. 2004;350:459468. Copyright 2004, Massachusetts Medical Society.

Preclinical evidence of efficacy of Protelos: increase in bone strength with preserved mineralization There is extensive in vitro and in vivo evidence of a significant decrease in bone resorption and increase in bone formation with Protelos. Thus, Protelos shares the characteristic profile of antiresorptive agents in exhibiting a direct and/or matrix-mediated decrease in osteoclast activity9 and differentiation.8 In addition, Protelos stimulates bone formation by increasing preosteoblast cell replication, leading to an increase in bone-forming activity.4 The effect of Protelos has also been extensively studied in various models of estrogen deficiency, a condition that results in significant bone loss and high bone turnover. After 8 weeks, Protelos significantly increased femoral bone mineral content and bone volume in ovariectomized rats,6 and partially inhibited trabecular bone loss. Histological indices of bone resorption were reduced compared with those in untreated models. Protelos significantly increased cortical area without any change in cortical porosity. Periosteal perimeter was also significantly increased, while endocortical bone perimeter remained unchanged,12 resulting in an increase in cortical thickness. No variation in osteoid thickness or in osteoid volume was observed, indicating that the mineralization process was preserved.13

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SOTI Age (y) Time since menopause (y) BMD T-score (lumbar spine)

Protelos (2 g per day) (n=719) 69.47.2 22.18.8 -3.51.3 Protelos (2 g per day) (n=2479) -3.130.59 -2.700.94 -2.831.63

Placebo (n=723) 69.27.3 21.68.7 -3.61.2 Placebo (n=2453) -3.130.60 -2.700.96 -2.841.62

TROPOS Age (y) Time since menopause (y) BMD T-score (lumbar spine)

Table I. Baseline characteristics of the SOTI (Spinal Osteoporosis Therapeutic Intervention) and TROPOS (TReatment Of Peripheral OSteoporosis) trials (meanSD): the Protelos and placebo populations are comparable. BMD, bone mineral density. (Based on data from reference 19.)

ing 9 patients for 3 years would prevent 1 patient from having a vertebral fracture (Figure 4).11 Clinical vertebral fracture is defined by back pain and/or body height loss of at least 1 cm over 3 years. In SOTI, the number of patients experiencing a new clinical vertebral fracture was significantly reduced by 52% (RR, 0.48; 95% CI, 0.29-0.80; P=0.003) over the first year and by 38% (RR, 0.62; 95% CI, 0.470.83; P<0.001) after 3 years of treatment with Protelos (Figure 5).11 Vertebral fracture risk reduction was a secondary end point in TROPOS. The risk reduction of new vertebral fracture in the Protelos-treated group, compared with placebo, was 45% (RR, 55; 95% CI, 0.39-0.77; P<0.001) over the first year of treatment and 39% (RR, 0.61; 95% CI, 0.51-0.73; P<0.001) over 3 years.18 In addition, the efficacy of Protelos in preventing vertebral fractures was assessed separately in patients without prevalent fracture. Protelos, 2 g/day orally, significantly reduced the risk of experiencing a first vertebral fracture by 45% (RR, 0.55; 95% CI, 0.42-0.72; P<0.001) compared with placebo over 3 years.18 These data are consistent with the findings of SOTI, confirming the effectiveness of Protelos in decreasing the risk of vertebral fractures in postmenopausal women whether or not they had a prevalent vertebral fracture. This result was confirmed in a pooled analysis of the SOTI and TROPOS studies, which showed that Protelos reduced vertebral fracture risk in patients without prevalent vertebral fracture by 48% (RR, 0.52; 95% CI, 0.40-0.67; P<0.001).20 Thus, Protelos is effective in reducing the vertebral fracture risk whatever the severity of the disease, including women with severe osteoporosis (T score <--2.5 SD with at least one prevalent vertebral fracture). Protelos achieves an early and sustained reduction in vertebral fracture risk in women with postmenopausal osteoporosis, whatever the severity of the disease. Clinical efficacy of Protelos on nonvertebral/hip fracture risk Efficacy on nonvertebral fractures was evaluated in TROPOS, in which the primary end point was global nonvertebral fracture risk reduction. As required 58 MEDICOGRAPHIA, VOL 28, No. 1, 2006

by the European Committee for Medicinal Products for Human Use (CHMP), subsequent to the start of the approved protocol of TROPOS, nonvertebral fractures (hip and other major nonvertebral fractures) were documented separately. Moreover, a posthoc subgroup of particular medical interest was analyzed to complete the TROPOS efficacy data.21 TROPOS included 5091 osteoporotic postmenopausal women aged 74 years and over or 70 years with one additional osteoporotic fracture risk factor (eg, personal history of osteoporotic fracture after the menopause, or residence in a retirement home, or maternal history of osteoporotic fracture. Analysis of the findings in postmenopausal osteoporotic patients over 3 years of treatment showed that Protelos significantly reduced the total risk of nonvertebral fracture by 16% vs placebo (RR, 0.84; 95% CI, 0.702-0.995; P=0.04) and decreased the risk of major nonvertebral osteoporotic fractures (hip, wrist, pelvis and sacrum, ribs-sternum, clavi-

New vertebral fractures

35 30 25 Patients (%) 20 15 10 5 0 0-1 year 0-3 years
RR=0.51 95% CI [0.36; 0.74]

Protelos 2 g/day Placebo

*P <0.001

N=1442

41%
*

NNT=9

49%
*
RR=0.59 95% CI [0.48; 0.73]

Figure 4. Reduction in new vertebral fractures over 1 and 3 years with Protelos 2 g/day in the Spinal Osteoporosis Therapeutic Intervention (SOTI) trial (Grading of H. K. Genant).
Modified from reference 11: Meunier PJ, Roux C, Seeman E, et al. The effects of strontium ranelate on the risk of vertebral fracture in women with postmenopausal osteoporosis. N Engl J Med. 2004;350:459-468. Copyright 2004, Massachusetts Medical Society.

New clinical vertebral fractures

20 Protelos 2 g/day Placebo
*P=0.003 **P <0.001

N=1442

15 Patients (%)

38%
**

10

RR=0.48 95% CI [0.29; 0.80]

52%
*

RR=0.62 95% CI [0.47; 0.83]

0 0-1 year 0-3 years

Figure 5. Reduction in new clinical vertebral fractures over 1 and 3 years with Protelos 2 g/day in the Spinal Osteoporosis Therapeutic Intervention (SOTI) trial. (Based on data from reference 11.)

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Patients (%)

cle, and humerus) by 19% (RR, 0.81; 95% CI, 0.660.98; P=0.031). In osteoporotic patients aged 74 years Protelos significantly reduced the risk of hip fracture by 36% (RR, 0.64; 95% CI, 0.412-0.997; P=0.05) (Figure 6).18 Thus, based on the above phase 3 study results, Protelos can be summed up as a powerful antiosteoporotic agent providing protection against both vertebral and hip fractures. Clinical efficacy of Protelos in elderly patients A preplanned pooled analysis of 1488 elderly SOTI and TROPOS patients was carried out in order to assess the antifracture efficacy of Protelos in patients aged 80 years and above, a population in whom the risk of osteoporotic fracture is particularly high.22 Results of the analysis showed that Protelos significantly reduced the relative risk of experiencing new vertebral fractures by 32% (RR, 0.68; 95% CI, 0.50-0.92; P=0.013) over 3 years. A similar significant decrease, by 31% (RR, 0.69; 95% CI, 0.52-0.92; P=0.011), was seen in nonvertebral fracture risk reduction. Thus, Protelos is the only treatment able to achieve proven effective and safe reduction in risk of vertebral and nonvertebral fractures in osteoporotic women aged 80 years and over (Figure 7).22 Clinical efficacy of Protelos in patients with osteopenia Another pooled analysis of SOTI and TROPOS patients was carried out in 176 patients with baseline lumbar spine and/or femoral neck bone mineral density (BMD) in the osteopenic range (at least one site T-score between 1 and 2.5 SD, and both Tscores >2.5 SD), and no prevalent fracture. In these patients, Protelos significantly reduced the risk of a first vertebral fracture by 72% (RR, 0.28; 95% CI, 0.07-0.99; P=0.045) over 3 years.23 Overall, Protelos is effective in reducing osteoporotic vertebral and hip fracture risk, regardless of the severity of the patients disease and whether or not they have had previous vertebral fractures, and whether they are osteopenic or osteoporotic. Protelos improves quality of life

Hip fractures

36%
*

4 Protelos 2 g/day Placebo

*P<0.05 N=1977

0 0 1 2 3

Time (y)

Figure 6. Reduction in hip fracture risk with Protelos 2 g/day in the TReatment Of Peripheral OSteoporosis (TROPOS) trial. (Based on data from reference 19.)

Elderly: vertebral and peripheral fractures

30 25 10 8 Protelos 2 g/day Placebo

Patients (%)

Patients (%)

20 15 10 5 0

RR: 32%
*

0-3 years

Figure 7. Effectiveness of Protelos 2 g/day in reducing the risk of vertebral and nonvertebral fractures in patients aged 80 years and above. (Based on data from reference 22.)

Back pain

RR: 31%
*

6 4 2 0

*P =0.013

*P =0.011

N=895 RR=0.68; 95% CI [0.50; 0.92]

N=1488 RR=0.69; 95% CI [0.52; 0.92]

0-3 years

global score on quality of life.25 By using QUALIOST in the SOTI study, the effect of Protelos on quality of life, assessed after 3 years of treatment, showed a significant benefit (P=0.016 for the total score; P=0.019 and 0.032 for emotional and physical scores, respectively, in favor of Protelos). In SOTI, Protelos increased the number of patients free of back pain by 29% (P=0.006 after 3 years), with a significant effect from the first year of treatment.26 Protelos was also shown to decrease the number of patients experiencing a body height loss of at least 1 cm, by 20% (P=0.003) (Figure 8).11,26

Height loss
Patients with height loss 1 cm (%) 40

It is well known that osteoporosis is associated with a reduction in health-related quality of life in relation with the frequent back pain and loss of height associated with vertebral fractures.24 These disorders can seriously affect patients quality of life. Protelos not only reduces the fracture risk, but also directly improves patients quality of life. The effect of Protelos on quality of life was assessed using two questionnaires during the phase 3 program, the 36-Item Short-Form Health Survey (SF-36) and the QUAlity of LIfe questionnaire in OSTeoporosis (QUALIOST). As opposed to SF-36, which is a generic questionnaire, QUALIOST is a specific questionnaire for vertebral osteoporosis containing 23 items assessing various aspects of patients physical and emotional well-being and which gives an overall

20 Patients without back pain (%)

15 10

29%
*

20%
**

30

20
**P =0.003

*P =0.03

5 0

10

N=1088

0-1 year Protelos 2 g/day

0 Placebo

0-3 years

Figure 8. Increase in number of patients free of back pain at 1 year (left) and decrease in risk of height loss at 3 years (right) with Protelos 2 g/day in the Spinal Osteoporosis Therapeutic Intervention (SOTI) trial. (Based on data from reference 11).

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BMD, a good tool to monitor patients progress and compliance In SOTI, Protelos progressively increased lumbar spine BMD by 12.7% vs baseline after 3 years of treatment (P<0.001). This represents a difference of 14.4% (P<0.001) between the active treatment and placebo at 3 years. The increase in lumbar spine BMD was linear and significant from the 6th month

16 Mean change (%) 12 8 4 0 -4 0 6 *

Lumbar spine BMD (SOTI)

* * *

* At M36

E (SE)=14.4 (0.58) 95% CI [13.27; 15.53]

+14.4%

12

18 Months

24

30

36 Protelos 2 g/day Placebo

telos did not differ from that with placebo and the percentage of withdrawals following adverse events was the same as in the placebo group. The most common adverse events were nausea (6.6% vs 4.3%), diarrhea (6.5% vs 4.6%), headache (3.0% vs 2.4%), dermatitis (2.1% vs 1.6%), and eczema (1.5% vs 1.2%). These were usually mild and transient. The safety and tolerability of Protelos were thus studied in a large population of elderly and very elderly (80 years of age and over) women and was considered as very good. No dosage adjustment is needed in the elderly, or in the very elderly, or in patients with moderate or mild renal dysfunction. Analysis of bone biopsies, obtained from postmenopausal osteoporotic patients during the clinical development program, confirmed that Protelos is safe at the bone tissue level: patients having taken Protelos for up to 5 years had normal lamellar bone with no mineralization defects or delay and no sign of osteomalacia.11,27 Practical recommendations Protelos is easy to use: it is administered once daily orally, as one 2-g sachet diluted in water, to be taken at bedtime. As Protelos is very well tolerated at the upper gastrointestinal level, patients are not subjected to complicated dosage instructions (as is the case with the bisphosphonates): there is no need to remain in upright position for any length of time following administration of Protelos). Due to the chronic nature of osteoporosis, Protelos is intended for long-term use. Conclusion Clinical development findings indicate that Protelos is an effective first-line treatment for postmenopausal women with osteoporosis. Protelos provides early and sustained vertebral and hip antifracture efficacy and is effective regardless of the severity of the patients disease and of their age. This efficacy results from Protelos unique dual action on

16 Mean change (%) 12 8 4 0 -4 0 6 *

Femoral neck BMD (TROPOS)

*P <0.001

* At M36

E (SE)=8.3 (0.41) 95% CI [7.60; 9.10]

+8.3%

12

18 Months

24

30

36

Figure 9. Increase in lumbar (top) and femoral neck bone mineral density (below) with Protelos 2 g/day in the Spinal Osteoporosis Therapeutic Intervention (SOTI) trial.
Modified from reference 11: Meunier PJ, Roux C, Seeman E, et al. The effects of strontium ranelate on the risk of vertebral fracture in women with postmenopausal osteoporosis. N Engl J Med. 2004;350:459-468. Copyright 2004, Massachusetts Medical Society.

of treatment and sustained thereafter (P<0.001).11 In TROPOS, femoral neck and total hip BMD increased by 5.7% and 7.1%, respectively, at 3 years in the Protelos group compared with baseline. Compared with placebo, the differences were 8.3% (95% CI, 7.7-8.7; P<0.001) and 9.8% (95% CI, 9.3-10.4; P<0.001), respectively.18 Treatment with Protelos induced a sustained increase in BMD. Importantly, this increase did not wane over a period of 3 years, which is a strong asset in long-term therapy. This increase in BMD provides a good tool to monitor the improvement in the course of the disease and compliance with treatment, and helps motivate patients to continue their treatment (Figure 9).11 Tolerability and safety The phase 3 studies showed that Protelos was well tolerated, especially at upper gastrointestinal level.11,18 There was no difference between Protelos and placebo groups concerning esophagitis, gastritis, and gastric ulcers. The safety of Protelos was assessed based on the pooled data from the SOTI and TROPOS trials involving a total of 6669 patients. Overall, the incidence of adverse events with Pro60 MEDICOGRAPHIA, VOL 28, No. 1, 2006

Vertebral fractures
Favors PROTELOS
After 1 year

Peripheral - Hip fractures

RR
Clinical VF Vertebral F Over 3 years

VF=vertebral fracture

Figure 10. Summary of the antifracture efficacy of Protelos on vertebral and peripheral/hip fractures. (Based on data from reference 11.)

52% 49%

Favors PROTELOS

RR

Over 3 years

48% 41% 32%

Vertebral F, without prevalent VF Vertebral F, with prevalent VF Vertebral F, 80 years

36% 31%

Hip fractures Peripheral fractures 80 years 0.5 1 1.5

0.5

1.5

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bone metabolism, which rebalances bone turnover in favor of formation and creates new strong bone. The efficacy of Protelos on vertebral and hip fracture prevention and the sustained increase in BMD were demonstrated over the 3 years covered by the analyses of the phase 3 studies. Protelos has also been shown to improve patients quality of life and osteoporosis-related symptoms, and is very well tolerated. All of these key properties of Protelos have been enshrined in the Summary of Product Characteristics accepted across the European Union, and have also been registered in many other countries. Protelos is now available for the treatment of all postmenopausal women with osteoporosis to reduce the risk of vertebral and hip fractures (Figure 10).11,18,20,22,23 The findings discussed in this article confirm Protelos (strontium ranelate) as an effective and safe treatment for vertebral and hip osteoporosis, characterized by a unique dual bone-forming and antiresorptive mode of action. The dissociation of bone
REFERENCES 1. Woolf A, Pfleger B. Burden of major musculoskeletal conditions. Bull WHO. 2003;81:646-656. 2. Marie PJ, Ammann P, Boivin G, Rey C. Mechanisms of action and therapeutic potential of strontium in bone. Calcif Tissue Int. 2001;69:121-129. 3. SPC Protelos. European Medicines Agency. www.emea.eu.int. Accessed 25 Oct 2005. 4. Canalis E, Hott M, Deloffre P, et al. The divalent strontium salt S12911 enhances bone cell replication and bone formation in vitro. Bone. 1996;18:517-523. 5. Delannoy P, Bazot D, Marie PJ. Long-term treatment with strontium ranelate increases vertebral bone mass without deleterious effect in mice. Metabolism. 2002;51:906-911. 6. Arlot ME, Braillon P, Roux JP, Deloffre P, Tsouderos Y, Meunier PJ. A new agent containing strontium (S12911) has a protective effect on bone loss in ovariectomized rats. Bone. 1992;13:A1. Abstract 4. 7. Marie PJ, Hott M, Modrowski D, et al. An uncoupling agent containing strontium prevents bone loss by depressing bone resorption and maintaining bone formation in estrogen-deficient rats. J Bone Miner Res. 1993;8:607-615. 8. Wattel A, Hurtel-Lemarie AS, Godin C, et al. Strontium ranelate decreases in vitro osteoclastic differentiation and bone resorption. Osteoporos Int. 2005;16: S53-S54. Abstract P222. 9. Baron R, Tsouderos Y. In vitro effects of S12911-2 on osteoclast function and bone marrow macrophage differentiation. Eur J Pharmacol. 2002;450:11-17. 10. Takahashi N, Sasaki T, Tsouderos Y, Suda T. S12911-2 inhibits osteoclastic bone resorption in vitro. J Bone Miner Res. 2003;18:1082-1087. 11. Meunier PJ, Roux C, Seeman E, et al. The effects of strontium ranelate on the risk of vertebral fracture

resorption from bone formation, with a positive bone balance, results in creation of strong, new bone, thereby ensuring sustained antifracture efficacy. These assets, together with its good tolerability, make Protelos a major new weapon in the treatment of osteoporosis.
ESSENTIALS PROTELOS

OF

x Protelos is a new antiosteoporotic treatment

with a unique dual mode of action, increasing bone formation and decreasing bone resorption
x Protelos is effective in the treatment of post-

menopausal osteoporosis whatever the severity of the disease (with or without previous fractures), whatever the site (vertebrae, hip), whatever the age (including patients 80 years of age and above)
x Protelos has very good tolerability x Protelos is administered orally, as a 2-g sachet,

once daily, at bedtime

in women with postmenopausal osteoporosis. N Engl J Med. 2004;350:459-468. 12. Ammann P, Shen V, Robin B, et al. Strontium ranelate improves bone resistance by increasing bone mass and improving architecture in intact female rats. J Bone Miner Res. 2004;19:2012-2020. 13. Buehler J, Chappuis P, Saffar JL, et al. Strontium ranelate inhibits bone resorption while maintaining bone formation in alveolar bone in monkeys (Macaca fascicularis) Bone. 2001;29:176-179. 14. Hott M, Deloffre P, Tsouderos Y, et al. S12911-2 reduces bone loss induced by short-term immobilization in rats. Bone. 2003;33:115-123. 15. Farlay D, Boivin G, Panczer G, et al. Long-term strontium ranelate administration in monkeys preserves characteristics of bone mineral crystals and degree of mineralization of bone. J Bone Miner Res. 2005;20:1569-1578. 16. LeGeros R, Lin S, LeGeros J, et al. Strontium ranelate treatment preserves bone crystal characteristics and bone mineral reactivity. Osteoporos Int. 2004;15(suppl 1):S116-S117. Abstract P420MO. 17. Meunier PJ, Slosman DO, Delmas PD, et al. Strontium ranelate: dose-dependent effects in established postmenopausal vertebral osteoporosis: a 2-year randomized placebo-controlled trial. J Clin Endocrinol Metab. 2002;87:2060-2066. 18. Reginster JY, Seeman E, De Vernejoul MC, et al. Strontium ranelate reduces the risk of nonvertebral fractures in postmenopausal women with osteoporosis: treatment of peripheral osteoporosis (TROPOS) study. J Clin Endocrinol Metab. 2005;90:2816-2822. 19. Meunier PJ, Reginster JY. Design and methodology of the phase 3 trials for the clinical development of strontium ranelate in the treatment of women with

postmenopausal osteoporosis. Osteoporos Int. 2003; 14(suppl 3):S66-S76. 20. Reginster JY, Rizzoli R, Balogh A, et al. Strontium ranelate reduces the risk of vertebral fractures in osteoporotic postmenopausal women without prevalent vertebral fracture. Osteoporos Int. 2005;16:S53. Abstract P220. 21. Wasnich RD. Epidemiology of osteoporosis. In Favus MJ, ed. Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism. Philadelphia, Pa: Lippincott Williams & Wilkins; 1999:257-259. 22. Seeman E, Vellas B, Meunier PJ, et al. Vertebral and nonvertebral antifracture efficacy of strontium ranelate in very elderly women with osteoporosis. Osteoporos Int. 2005;16:S6. Abstract OC21. 23. Sawicki A, Reginster JY, Roux C, et al. Strontium ranelate reduces the risk of vertebral fractures in postmenopausal women with osteopenia. Calc Tissue Int. 2004;74(suppl 1):S84. Abstract P153. 24. Hallberg I, Rosenqvist AM, Kartous L, et al. Health related quality of life after osteoporotic fractures. Osteoporos Int. 2004;15:834-841. 25. Marquis P, Cialdella P, De la Loge C, et al. Development and validation of a specific quality of life module in post-menopausal women with osteoporosis: The QUALIOST. Qual Life Res. 2001;10:555-566. 26. Marquis P, De La Loge C, Diaz-Curiel M, et al. Beneficial effects of strontium ranelate on the quality of life in patients with vertebral osteoporosis. Osteoporos Int. 2005;16:S54. Abstract P223. 27. Arlot, ME, Delmas P, Burt-Pichat B, et al. Effects of strontium ranelate on bone remodeling and bone safety assessed by histomorphometry in patients with postmenopausal osteoporosis. J Bone Miner Res.2005; 20(suppl 1)S22. Abstract 1084.

(see French abstract on next page)

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PROTELOS :

PREMIER TRAITEMENT DE LOSTOPOROSE POSTMNOPAUSIQUE AVEC UN MODE DACTION DOUBLE

rotelos (ranelate de strontium) est un nouveau traitement de premire ligne pour le traitement de lostoporose postmnopausique, dont lefficacit dans la rduction du risque fracturaire ostoporotique et la bonne tolrance ont t dmontres. Lostoporose postmnopausique reprsente un problme clinique important, en forte croissance et urgent. Une femme sur deux, au cours de sa vie, aura une fracture ostoporotique, et ces fractures sont source dune morbi-mortalit majeure. Les sites les plus concerns par les fractures de fragilit sont les vertbres, les hanches et les poignets. Alors que les fractures vertbrales sont les plus frquentes, ce sont les fractures de hanche qui sont associes aux taux de morbidit et de mortalit les plus levs. Lostoporose rsulte dun dsquilibre entre la rsorption et la formation de los. La plupart des traitements actuellement disponibles sont soit antirsorptifs, soit ostoformateurs. Protelos, dcouvert et dvelopp par Servier, est le premier agent antiostoporotique prsentant un mode daction double : il augmente simultanment la formation osseuse et diminue la rsorption osseuse. Cette double action permet de rquilibrer le mtabolisme osseux en faveur de la formation osseuse, avec production dun os nouveau rsistant. Deux tudes cliniques internationales de phase III, randomises, en double aveugle, contrles contre placebo ont t menes pour dmontrer lefficacit et la tolrance de Protelos (ranlate de strontium la dose de 2 g/jour par voie orale) : SOTI (Spinal Osteoporosis Therapeutic Intervention) et TROPOS (TReatment Of Peripheral OSteoporosis) dans le traitement de lostoporose postmnopausique. Ces tudes ont dmontr lefficacit de Protelos quelle que soit la svrit de la maladie (quil

y ait ou non des antcdents de fractures vertbrales), quel que soit le site (vertbre ou hanche) et quel que soit lge (y compris chez les patientes ges de 80 ans et plus). Protelos rduit de faon significative le risque relatif de nouvelles fractures (49 %) ds la premire anne de traitement, avec une efficacit qui persiste sur 3 ans, et diminue de faon significative le risque relatif, de 41 %, chez les patientes ayant une fracture vertbrale prvalente. Chez les patientes ostoporotiques sans fracture vertbrale prvalente, Protelos a diminu le risque de fracture de 48 % sur 3 ans de traitement. Les nouvelles fractures vertbrales cliniques (fractures vertbrales associes des douleurs dorsales et/ou une perte de taille dau moins 1 cm) taient rduites de 52 % ds la premire anne de traitement. Protelos a entran une rduction significative du risque relatif de fractures non vertbrales (16 %), des fractures de hanche (36 %) chez les patientes ostoporotiques de 74 ans ou plus, cest--dire la population risque pour ce type de fractures. Protelos augmente de faon significative la densit minrale osseuse (DMO). Aprs 3 ans, la diffrence intergroupes de la DMO moyenne tait de 14,4 % au niveau du rachis lombaire et de 8,3 % au niveau du col fmoral. Protelos na pas seulement permis une rduction du risque fracturaire, mais galement damliorer la qualit de vie des patientes. Dans ces tudes, Protelos a t bien tolr mme chez les personnes ges. Ces donnes confirment lintrt de Protelos, raison de 2 g/jour par voie orale (un sachet au coucher) dans le traitement de premire ligne de lostoporose postmnopausique chez les femmes pour rduire le risque de fractures vertbrales et de hanche.

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DO RISK FACTOR PROFILES

FOR OSTEOPOROTIC FRACTURES DIFFER IN WOMEN AND MEN?
Interview with B. Cortet, France

Bernard CORTET MD, PhD Rheumatology Department, Hpital Roger Salengro CHU Lille Lille, FRANCE

Could you comment on the prevalence of osteoporosis in men in comparison with women? steoporosis is overwhelmingly a disease of women. The epidemiologic data show a 40% prevalence of osteoporotic fracture in women over 50, which is three times the figure in men of the same age (13%). As in women, the main sites of fracture in men are the wrist, spine and, at a later stage, hip. Their specificities in men are as follows: Wrist. Fracture of the wrist is alone in being relatively less common in men (sex ratio: one man to four women). In addition, unlike in women, the incidence does not increase with age. Wrist fracture can produce a number of complications, in particular reflex sympathetic dystrophy (30% of cases), as in women, with

no sex difference in this regard. What matters is that despite its relative rarity, wrist fracture in man should prompt an osteoporosis workup as it is predictive of other potentially more serious osteoporotic fractures. It increases the risk of vertebral fracture 10-fold, as opposed to 5-fold in women, and the risk of hip fracture 2- to 3-fold, as opposed to only 40% to 50% in women. Spine. Earlier studies showed that vertebral fracture prevalence in men was half that in women, at least in the under80s. The most recent data, however, point to a similar prevalence of vertebral deformities. In the European Vertebral Osteoporosis Study (EVOS), the prevalence of vertebral fractures in men under 65 was 18.7% versus 14.3% in women. A North American study reached similar conclusions, with a 29% prevalence of vertebral deformities in men over 50 versus 11% in women; sex differences in prevalence only ceased over the age of 80 (40% in men and 45% in women). Although these more recent studies are interesting, they need to be interpreted with caution. Not all deformities were fractures. In addition, one explanation

may be that a many men had vertebral fractures when young that had nothing to do with osteoporosis, but were traumatic in origin (eg, an industrial or sports injury). Proximal femur. The sex ratio is similar to that for fractures as a whole, ie, two to three times less frequent in men. There are many reasons, in particular the longer lifespan of women. The most important and consistently observed difference is that hip fracture mortality is two to three times higher in men (10% to 14% versus 5% in women at 1 month), again for many reasons, not all fully elucidated, but in part related to the higher rates of smoking and alcoholism. Recent data also suggest a higher prevalence of postoperative infection in men. Could you explain the reasons why such differences in prevalence are observed between genders? he reasons are multiple. Peak bone mass, by which we mean the maximum bone mass achieved at the end of growth, is much higher in men. This in itself is enough to account for

lthough overwhelmingly a disease of women, osteoporosis is still a significant problem in men, with a 13% prevalence of osteoporotic fracture in those over 50, affecting the same sites, namely wrist, spine, and hip. In men, wrist fracture should always prompt an osteoporosis workup as it increases the risks of vertebral fracture 10-fold (versus 5-fold in women) and of hip fracture 2- to 3-fold (versus only 40% to 50% in women). Hip fracture in men carries double to triple the mortality in women, partly because of higher rates of smoking and alcoholism. Otherwise, the main sex differences are based on peak bone mass and bone thickness, both of which are higher in men and directly related to mechanical resistance. These two factors, combined with the absence of a true male equivalent of the menopause, account for the comparative rarity of osteoporosis in men. For these reasons, it is particularly important in men to exclude secondary osteoporosis, which can account for 6 in 10 cases. Metastasis and

multiple myeloma are the key primary suspects, but exogenous glucocorticoids are much more frequently involved, especially in men, notably due to chronic obstructive airways disease, which is far more frequent than in women. Densitometry is as useful in screening men as it is in women. The same T-score threshold of -2.5 should probably apply, provided the reference population consists of young men, not young women, since this would lower the prevalence of densitometric osteoporosis to an unrealistic figure of only 3%.
Medicographia. 2006;28:63-65. (see French abstract on page 65)

Keywords: osteoporosis; secondary osteoporosis; sex difference; epidemiology; fracture risk; densitometry; glucocorticoid
Address for correspondence: Prof Bernard Cortet, Service de Rhumatologie, Hpital Roger Salengro, CHU Lille, 59037 Lille Cedex, France (e-mail: bcortet@chru-lille.fr)

Risk factor profiles for osteoporotic fractures in women and men Cortet

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osteoporosis being so much rarer in men, given the close correlation between bone mass, whether trabecular bone volume or bone mineral density (BMD), and mechanical resistance. However, this point requires qualification in so far as most studies have determined peak bone mass using dual-energy x-ray absorptiometry (DXA), a technique that has been extensively validated (including in men), and that measures areanot volumebone density. The few data derived using volume density measures acquired by quantitative computed tomography (qCT) show that peak bone mass is largely similar in men and women. A second important reason for the sex difference in osteoporosis prevalence lies in the thickness of the bones studied. Bones are thicker in men, which is one reason why area bone density is higher than in women. In addition, it is a basic biomechanical fact that bone thickness is directly related to mechanical resistance. A third reason is the absencedespite what is sometimes said of a true male equivalent to the menopause, with its major impact on bone. Bone loss in men over 50 is relatively linear, in parallel with the decline in circulating levels of androgens, in particular testosterone. In fact, however, what little bone activity testosterone may have seems to be mediated by estrogen. Could you briefly comment on the pathophysiology of osteoporosis in men in comparison with women? steoporosis in men is a mixed bag, much more so than in women. The main culprit in women is the menopause. In the absence of a genuine male equivalent, we have to look elsewhere. The main message to get across is the importance in men of excluding secondary osteoporosis. Previously one should exclude malignancy, such as metastasis or multiple myeloma, as well as other causes of low bone mass not related to osteoporosis, such as osteomalacia and primary hyperparathyroidism. Otherwise, the main cause of osteoporosis in men is hypercortisolism, due to the noxious effects of exogenous steroids on bone rather than to the comparatively rare cases of Cushing disease. It is not that glucocorticoids are especially toxic in men, but rather that they are more often prescribed in men, especially for chronic obstructive airways disease, which is much more frequent than in women. Other primary causes are alcoholism and hypogonadism. On a more anecdotal level, we should also not forget

hyperthyroidism and minor tubulopathy (eg, moderate idiopathic proximal tubulopathy), which can cause low-grade hypercalciuria and/or phosphate diabetes. Overall, osteoporosis in men is secondary in around 6 cases in 10. In addition to these direct causes, there are also a number of risk factors. Once youve excluded secondary osteoporosis, the remaining 40% of cases can be considered idiopathic. Two factors need to be borne in mind here in terms of pathophysiology. The first is estrogen deficiency. As weve seen, what little impact testosterone has on bone is indirect, mediated by estrogen. In unselected men, it has been shown that circulating estradiol levels (which are naturally very low and can only be detected using ultrasensitive kits) correlate with BMD and thus help to explain agerelated bone loss. No such correlation or at least a much lower correlation is found with circulating testosterone levels. In osteoporotic men, on the other hand, the data are less clear-cut, with some investigators finding no difference in circulating estradiol levels between osteoporotic men and controls. One explanation is that most studies measured total estradiol and not the active form, namely free estradiol. On the other hand, there is convincing evidence to show that sex hormone binding globulin (SHBG) is higher in osteoporotic men than in controls. Overall fracture risk doubles with every standard deviation in SHBG level. The second factor to bear in mind in the pathophysiology of idiopathic osteoporosis in men is osteoblast dysfunction. Preliminary histomorphometry data suggest that although osteoblasts are quantitatively normal in osteoporosis in men, their capacity for synthesis is impaired. These findings require confirmation. Lastly, we now know that the microarchitecture of bone, which is a major aspect in female osteoporosis, is also a key factor in osteoporosis in men. This has been clearly demonstrated by Maurice Audran and his group in Angers, France, with particular regard to both steroidand hypogonadism-induced osteoporosis in men. What are the significant risk factors for osteoporosis and osteoporotic fractures in men? n addition to the causes already mentioned, there is an important risk factor to be considered in men, namely, smoking. Overall risk factors for osteoporosis and osteoporotic fractures are similar in men and women. As in

women, some risk factors relate solely to fractures and are independent of BMD. But data on this subject are much fewer than in women. In addition, some risk factors are more frequent in men for lifestyle reasons: the steroid therapy already mentioned, and also alcoholism, which some investigators classify as a direct cause, and others as simply a risk factor, as in women. Are the significant risk factors for osteoporosis and osteoporotic fractures different in men from those in women ? ot overall. However, some risk factors are commoner in men: alcoholism, smoking and, to a lesser extent, steroid therapy.

Is it easy to diagnose osteoporosis in men? vidence shows that broadly speakingand somewhat paradoxically, given its frequency osteoporosis often goes undiagnosed. In men, the diagnosis is not always easy (this can also apply in women) in so far as physicians do not always suspect osteoporosis when faced with fracture. It is important to remember that although trauma may be responsible for the great majority of osteoporotic fractures it tends to be disproportionately minorthe revelatory event rather than the true cause. It is therefore important to diagnose osteoporosis before fracture occurs. From this point of view, bone densitometry is a useful investigation in women, in particular because of the correlation shown between decreasing bone density and increasing fracture risk. To what extent does this apply in men? Again, the data are far fewer than in women. However, a number of longitudinal studies are available, including one very recent meta-analysis pooling 12 cohorts into a total of 9891 men and 29 082 women. The authors showed that at age 65, every standard deviation decrease in femoral bone density multiplied the general fracture risk by 2.88 in women and 2.94 in men, confirming earlier longitudinal studies that it doubled vertebral fracture risk. Having shown that densitometry is an important tool in assessing fracture risk in men, the next question is to decide whether the World Health Organization definition of osteoporosis, which dates back over a decade, should apply to men. Strictly speaking, the answer is No, in that the original definition was stated to apply only to women. However, there is

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evidence to justify an identical threshold in men. A UK group used DXA to compare BMD in men and women with vertebral fractures. As wed expect, mean BMD was higher in men. However, by expressing the results as mean T-scores referred to the young male population rather than in absolute terms, the authors showed that they were similar in both sexes, and very close to the 2.5 threshold (2.42 in men versus 2.40 in women).

A more direct method for defining a relevant threshold is to attempt a match between the epidemiological fracture and densitometry data. One reason for choosing a T-score threshold of 2.5 in women to define osteoporosis was that it gave a prevalence of osteoporosis in women over 50 as 30%, which approximated to the percentage of osteoporotic fractures observed in this population. A Mayo Clinic study applying this approach in a vast male cohort showed that 19%

had T-scores <2.5 (spine, hip, or wrist), a percentage approximating to that of osteoporotic fractures in men over 50 (13%). A final point is that while this definition is probably applicable, it is essential to use young men, and not young women, as the reference population. If young women are used, the prevalence of densitometric osteoporosis would only be 3%, which is much lower than the figure derived from fracture epidemiology.

LES

PROFILS DE FACTEUR DE RISQUE DANS LES FRACTURES OSTOPOROTIQUES DIFFRENT-ILS CHEZ LA FEMME ET CHEZ LHOMME ?

ien quil sagisse avant tout dune maladie touchant la femme, lostoporose nen pose pas moins un problme important chez lhomme, avec une prvalence 13 % pour les fractures ostoporotiques dans la population masculine de plus de 50 ans, touchant les mmes sites que chez la femme, savoir le poignet, la vertbre et la hanche. Chez lhomme, la fracture du poignet ncessite toujours une valuation de lostoporose, car si cette dernire est en cause, la fracture du poignet est prdictive dun risque multipli par 10 de fracture vertbrale (contre 5 chez la femme) et dun risque multipli par 2 ou 3 de fracture de hanche (contre seulement 40 50 % chez la femme). Chez lhomme, la fracture de hanche est associe une mortalit double ou triple de celle chez la femme, en partie en raison de la frquence plus leve du tabagisme et de lalcoolisme. Hormis ces facteurs, les diffrences principales lie au sexe ont trait au pic de masse osseuse et lpaisseur des pices squelettiques, la valeur de ces deux paramtres tant plus leve chez lhomme et conditionnant directement la rsistance mcanique osseuse. Ces

deux paramtres auxquels sajoute labsence dun quivalent rel masculin de la mnopause, expliquent la relative raret de lostoporose chez lhomme. Dans ce contexte, il est particulirement important dliminer une ostoporose secondaire, prsente dans 6 cas sur 10. Les causes principales en sont malignes (mtastases osseuses ou mylome multiple), mais surtout lhypercorticisme, en particulier dorigine exogne (glucocorticodes prescrits pour une bronchopathie chronique obstructive, plus frquemment observe dans la population masculine que fminine). La densitomtrie osseuse savre aussi utile dans les deux sexes pour le dpistage de lostoporose. Il faut vraisemblablement appliquer la mme valeur seuil (T-score -2.5) chez lhomme que chez la femme, condition que la population de rfrence soit reprsente par des hommes jeunes, et non des femmes jeunes, faute de quoi la prvalence de lostoporose densitomtrique se verrait abaisse une valeur de seulement 3%, en opposition ce que laissent apparatre les donnes pidmiologiques fracturaires.

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MUSCULOSKELETAL REHABILITATION IN
POSTMENOPAUSAL OSTEOPOROSIS
by S. Boonen, Belgium

steoporosis is a common and serious health problem, particularly among postmenopausal women. Of great concern is the increased likelihood of fractures in these patients. In fact, the incidence of osteoporotic fractures is greater than that of myocardial infarction, stroke, or breast cancer.1 Osteoporotic fractures tend to occur most frequently in the spine and hip, and less frequently in the pelvis, wrist, and upper arm. Fractures in these mostly elderly women can greatly reduce quality of life and functional abilities and often result in institutionalization and even mortality.2,3 Several musculoskeletal factors are implicated in osteoporotic fractures in the elderly. Among them are loss of bone mass (low bone mineral density [BMD]) and an increased propensity to falls.4 Historically, BMD has been regarded as the main risk factor for osteoporotic fracture. Low BMD, as measured by dual x-ray absorptiometry, is specific for osteoporotic fractures: low BMD is associated with a high risk of fracture. Because it is so specific, absorptiometry is a powerful diagnostic tool. However, it is not very sensitive: patients with normal BMD may be osteoporotic, because the damage to the microarchitecture is not fully reflected in absorptiometry measurements. In fact, only a modest proportion of fracturesbetween 10% and 44% occur in women with absorptiometry-defined osteoporosis (a BMD value 2.5 standard deviations below normal for young adults).5

Steven BOONEN, MD, PhD Leuven University Center for Metabolic Bone Disease and Division of Geriatric Medicine Katholieke Universiteit Leuven Leuven, BELGIUM

There is also a large overlap in BMD values between patients with and without fractures.6 In addition, increasing BMD with antiresorptive therapies does not substantially reduce the risk of fracture. Clearly, additional factors are involved. Although bone remodeling and bone microarchitecture must be considered, the largest and most important contribution is the increased propensity for falling.7 For predicting hip fracture, risk factors for falls and low BMD are independent and additive.8 Physicians, particularly bone specialists but also general practitioners, tend to treat these patients only with antiresorptive or anabolic drugs. However, osteoporosis is a musculoskeletal disease, so other factors, such as muscle strength and falls, are also important and need to be understood. In fact, these extraskeletal factors have been largely ignored by clinicians when considering how to prevent fractures and how to rehabilitate patients after fractures have occurred. The aim of this chapter is to describe several nonpharmacological approaches to musculoskeletal rehabilitation for fractures in postmenopausal women with osteoporosis. Preventing falls and fall-related fractures Falls are the single largest cause of injury in older people, and they are quite common: about a third of people over 65 years old fall each year.9 In this population, about half of all falls cause minor trau-

ost antifracture strategies have focused on increasing bone strength by reducing bone turnover. The efficacy of these interventions in reducing the risk of fracture has been consistently documented in well-defined patients with confirmed osteoporosis (low bone mineral density or prevalent vertebral fracture). However, fractures result from both a loss of skeletal integrity and an increased risk of falls. Nevertheless, little attention has been given to the targeting of extraskeletal factors to prevent fractures in selected individuals. In the management of patients with increased risk of fracture due to osteoporosis or extraskeletal risk factors, measures of musculoskeletal rehabilitation should be considered (along with pharmacotherapy) to optimize musculoskeletal health, improve quality of life, and re66 MEDICOGRAPHIA, VOL 28, No. 1, 2006

duce the risk of fracture and fracture recurrence. Given the importance of muscle function to bone quality and to the risk of falls and fall-related injuries, this article emphasizes the role of elements of muscle function, such as strength and coordination, in the prevention of fracture and postfracture rehabilitation in patients with osteoporosis.
Medicographia. 2006;28:66-71. (see French abstract on page 71)

Keywords: rehabilitation; osteoporosis; fall; physical activity

Address for correspondence: Prof Steven Boonen, Leuven University Center for Metabolic Bone Disease and Division of Geriatric Medicine, Katholieke Universiteit Leuven, Herestraat 49, B-3000 Leuven, Belgium (e-mail: steven.boonen@uz.kuleuven.ac.be)

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ma, up to 6% of falls result in fractures, and between 1% and 2% are associated with hip fractures.9 However, more than 90% of all hip fractures are associated with falls.10 Multiple factors predispose elderly patients to falls: muscular weakness, disability of the legs, reduced visual acuity, balance and gait abnormalities, sedative use, cognitive impairment, and foot problems.11 The risk of falling rises directly as the number of these risk factors increases.11 The PIDmiologie de lOStoporose (EPIDOS) study, a prospective cohort study of risk factors for hip fractures conducted in France, found a relationship between falls and risk factors for falls (low physical activity or disturbed body balance) and the occurrence of fractures of the humerus in patients with osteoporosis. This relationship was not found in participants with normal BMDs.12 In keeping with these findings, a retrospective study of postmenopausal women reported an increased risk for fractures during the preceding year in women who reported a fall during that period and who had low BMDs, but not in women with a history of falling and normal BMDs or in women who reported no falls, irrespective of their BMD.4 These results suggest that the risk for fractures is increased, particularly in women with low BMD who fall (Table I). These results could also explain why even women with osteopenia might have an increased risk of fracture, if they fall. Although treatment for elderly people can reduce the risk of falls, no study has reported an effect on the incidence of fall-related osteoporotic fractures.13 This issue will require clinical trials specifically designed to study fall-related osteoporotic fractures, and their findings may inform the design and implementation of strategies to prevent falls in patients with hip fracture.
x Multifactorial intervention programs to reduce

ous activities, but no effect was observed on wrist or vertebral fractures. A multidisciplinary program tested a comprehensive combination of general and resident-specific tailored strategies to reduce falls in persons over the age of 65 living in residentialcare facilities. The interventions included individual exercise programs in conjunction with staff education, environmental modification, mobility aids, medication review, hip protectors, and problemsolving conferences after falls.18 Both falls and fallrelated injuries were reduced. Similar, positive findings were observed in a pooled analysis from studies
No. of women 1145 705 289 208 189 113 Adjusted risk* 1.0 2.8 2.8 1.1 21.0 24.8 95% confidence interval 0.9-8.9 0.6-12.8 0.1-9.6 7.1-62.3 6.9-88.6

Bone mineral density No recent fall Normal Osteopenia Osteoporosis Recent fall Normal Osteopenia Osteoporosis

* Adjusted for age and body mass index, both included in logistic model as continuous variable. T score >-1.0. T score between -1.0 and -2.5. T score <-2.5.

Table I. Association between osteopenia, osteoporosis, history of falls, and fracture in the preceding year in postmenopausal women.
Modified from reference 4: Geusens P, Autier P, Boonen S, Vanhoof J, Declerck K, Raus J. The relationship among history of falls, osteoporosis, and fractures in postmenopausal women. Arch Phys Med Rehabil. 2002;83:903-906. With permission from the American Congress of Rehabilitation Medicine and the American Academy of Physical Medicine and Rehabilitation.

falls and fractures Reduced muscle strength, lack of coordination, hyperkyphosis, increased postural sway, slow walking velocity, and poor functional performance are important risk factors for falls.5,14 Addressing these risk factors can reduce the incidence of falls. In particular, falls may be prevented with multidisciplinary intervention programs, including education, exercise, environmental modifications, mobility aids, and individually tailored exercise programs. However, it remains to be clarified whether and to what extent these strategies will reduce the risk of fallrelated fractures.15
x Physical training programs to reduce falls and

fractures The positive effects of physical activity on the rate of falls have been confirmed in a number of studies.15-19 Increased physical activity can even potentially reduce the risk of fracture, but antifracture efficacy has not been consistently documented. In a prospective cohort study of 9704 women 65 years of age, high-level physical activity reduced the risk of hip fracture.16 The risk of hip fracture was reduced among women who performed moderate-to-vigor-

including a total of 566 community-dwelling women at least 80 years old who participated in the same program of progressive muscle strengthening, balance retraining, and walking. This intervention reduced the number of women who fell over a 1-year period by some 20%.15 The number of injurious falls was also reduced, by 33%. Body sway is a well-documented risk factor for falls and fall-related fractures.5 Proprioceptive dynamic posture training minimizes body sway, as well as decreases kyphosis by strengthening the back extensors, and thus reduces pain and increases mobility. In a controlled trial, proprioceptive dynamic posture training improved balance in osteoporotic patients with kyphosis and reduced the risk of falls.19 These findings contrast with those from a systematic review of randomized trials testing whether physical exercise or physical therapy could prevent falls in elderly people.15 Pooled data showed no significant differences between intervention and control groups in the number of persons who fell. One of the studies even reported that brisk walking significantly increased falls.
x Vitamin D to reduce falls and fractures Vitamin D supplementation can improve muscle function in older persons with vitamin D deficiency. In women between 63 and 99 years old given calcium (1200 mg/day) plus vitamin D (800 IU/day) for

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3 months, muscle strength improved by 5% to 11% over that of a control group receiving only calcium (1200 mg/day).20 However, in a 6-month study of high-dose vitamin D therapy (a single 300 000 IU dose), frail elderly men and women showed no improvement in quadriceps strength or leg function, suggesting that this regimen may not be effective, at least in frail patients.21 Several randomized controlled trials have reported that vitamin D supplementation, with or without calcium, reduced falls in at-risk patients. Calcium (1200 mg/day) plus vitamin D (800 IU/day) given for 3 months reduced the rate of falling by 49% compared with patients receiving only calcium.20 In another study of the same treatment applied over 8 weeks, the risk of falling over the next year was reduced from 45% to 24%.22 The incidence of fracture dropped from 9% to 4%, but the difference was not statistically significant. A meta-analysis combined the results from 5 randomized, double-blind clinical trials that evaluated any form of vitamin D treatment in patients older than 60 years and in stable health (1237 patients; 81% women; mean age 70 years).23 Treatment ranged from 2 months to 3 years. The risk of falling was significantly reduced by 22% in patients receiving any form of vitamin D compared with those receiving calcium alone or placebo, and the number needed to treat to prevent 1 fall was 15. The question remains whether, and to what extent, vitamin D reduces the risk of fracture by preventing falls. The inconsistencies among studies are probably caused by differences in the type of supplement, the concomitant use of a calcium supplement, and the degree of vitamin D deficiency at baseline, in addition to differences in patient populations and study design.
x Hip protectors to reduce the impact of falls and to prevent fractures An external hip protector is a polypropylene or polyethylene shell that fits around the hip. It is designed to absorb the energy from a fall and especially to shunt the energy to the soft tissues around the hip. Several studies have found that hip protectors lower the incidence of hip fractures in nursinghome residents.24 Other studies have found no such protective effect.25 In these negative studies, shunting the impact away from the greater trochanter at least did not increase the risk of nonhip fractures. However, most of the residents who experienced a hip fracture in these negative studies were not wearing the protector at the time of the fall. Thus, adherence is a factor that could potentially be improved with good results. The effect of wearing a hip protector on activity levels and, hence, its effectiveness in preventing fractures, also needs to be studied.

of vertebral fractures. In one study, progressive, resistive back strengthening reduced the risk for vertebral fractures in women 58 to 75 years old.27 Several studies have found that intensive physical training does improve strength and functional performance in older people, even in frail nursing home residents.28 In postmenopausal women, progressive resistance training to strengthen the paraspinal muscles maintains or increases BMD.29 Backstrengthening exercises can also reduce thoracic hyperkyphosis, vertebral fracture, loss of height, and pain of the anterior rib cage, which are the most disfiguring consequences of osteoporosis.27 Increased back strength reduces the kyphotic posture that can occur with osteoporosis and aging.30 A hyperkyphotic posture can also increase the risk of falls when hip motion, rather than ankle motion, is used to compensate for moments of offbalance.14 Stronger back muscles may decrease the angle of kyphosis and thus improve body height.30 This result may be associated with better posture and a correction of the center of gravity, which then results in less body sway.19 In severe kyphosis, the lower part of the rib cage can press on the pelvic rim, causing considerable pain and tenderness and even compromised breathing. Therefore, decreasing the kyphosis through recruitment of back extensors provides better dynamic-static posture and can reduce pain, increase mobility, reduce depression, and improve the patients quality of life.31 Hyperkyphosis is also a common disfiguration after vertebral fracture.
x Spinal orthoses in vertebral fracture patients Orthoses increase back extensor strength and decreases body sway, which are both risk factors for falls and fall-related fractures. Kaplan et al found that rigid bracing is not necessary for managing postural osteoporotic back pain and that a weighted kypho-orthosis was better tolerated by patients and provided better pain relief.32 Moreover, the use of rigid thoracolumbar braces in osteoporosis is limited by factors such as short stature, atrophied trunk muscles, hiatus or inguinal hernia, moderate to severe obesity, scoliosis caused by osteoporosis and compression fractures, and restricted respiration, all of which can lead to low adherence in wearing the orthosis. Most recently, Pfeifer et al 33 reported the effectiveness of orthoses for stabilizing osteoporotic vertebral fractures. In that study, the use of one particular orthosis was associated with a significant increase in trunk muscle strength, most likely because of increased muscular activity while wearing the orthosis. x Vertebro- or kyphoplasty In percutaneous transpedicular polymethylmethacrylate vertebroplasty (PTPV), acrylic cement (usually polymethylmethacrylate) is injected into a partially collapsed vertebral body. The objective is to relieve the associated back pain and improve the mechanical stability of the vertebra.34 In one study of patients with osteoporotic fractures, PTPV reduced the use of narcotics and analgesics in 63%

Rehabilitation strategies in fracture patients

x Strength training and vertebral fractures Back strength is significantly lower in persons with osteoporosis than in healthy persons.26 Strengthening the paraspinal muscles can reduce the risk

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Hip fracture Initial score Physical function Role physical Bodily pain General health Vitality Social functioning Role emotional Mental health 0 25 50 SF-36 Score
* * * * * * * *

Control One-year score Physical function Role physical Bodily pain General health Vitality Social functioning Role emotional Mental health
* * * * * * * *

75

100

25

50 SF-36 Score

75

100

Figure 1. Impact of hip fracture occurrence on different domains of quality of life: scores on the 36-item Short-Form Health Survey (SF-36) at hospital discharge (initial score) and 1 year after hospital discharge (1-year score). *P<0.05 between fracture patients and controls.
Modified from reference 2: Boonen S, Autier P, Barette M, Vanderschueren D, Lips P, Haentjens P. Functional outcome and quality of life following hip fracture in elderly women: a prospective controlled study. Osteoporos Int. 2004;15:87-94. Copyright 2004, International Osteoporosis Foundation and National Osteoporosis Foundation.

of patients, increased it in 7%, and had no apparent effect in 30%. Ambulation and mobility improved in 50% of the patients, worsened in 1%, and did not change in 48%.7 Complications associated with PTPV may include pressure on the spinal cord or nerve roots, pain and weakness, pulmonary embolism (if cement enters the blood and travels to the lungs), rib fracture (after lying prone for a prolonged period during the procedure), infection, and bleeding. The presence of methylmethacrylate in fractured vertebrae may also cause adjacent vertebrae to fracture more easily. Thus, PTPV can relieve pain in a high percentage of patients with refractory pain caused by spinal compression fractures.35 However, it is not a substitute for other rehabilitative measures.
x Rehabilitation in hip fracture patients

By any measure, hip fracture is the most devastating complication of osteoporosis (Figure 1). The mortality rate in patients with hip fracture is between 12% and 20% higher than in persons of similar age and sex who have not had a fracture.36 Of those who survive surgery for an osteoporotic hip fracture, less than one third return to their prefracture functional state, and both those with and those without restored status require some form of ambulatory support or even institutionalized care.37 Clinicians may not consistently treat patients for osteoporosis, even after a hip fracture, because the most common drugs have been tested and are marketedfor the primary prevention of hip fractures. No studies have yet evaluated either pharmacological or nonpharmacological measures for the secondary prevention of hip fractures. For example, it is unknown whether calcium supplementation after a hip fracture can reduce the subsequent loss of bone mineral from the contralateral hip and, in turn, diminish the risk of another hip fracture. However, data from patients with hip fracture have shown a significant relationship between calcium intake and bone loss from the proximal femur.38

Prospective randomized trials to assess interventions targeted at this critical time period are warranted. The evidence that exercise programs can improve strength and mobility in patients with hip fracture is strong.39 However, further research is needed to determine whether the extent of improvement in these risk factors is sufficient to prevent additional falls and any associated fractures in this high-risk population. In the year after a vertebral fracture, almost 20% of women will experience an additional vertebral fracture.40 The risk of subsequent hip fracture over the next 3 to 4 years also increases, by two to four times, compared with the risk in patients without vertebral fractures.41 In the years after a hip fracture, the risk of a second hip fracture is 10%, and that of any additional fracture ranges from 2% to 8%.42 Most studies of rehabilitation on functional recovery after hip fracture have taken place in acute or subacute rehabilitation facilities and have enrolled patients on wards and in outpatient settings. The aims, interventions, and outcome measures used in these studies differ considerably, and the studies themselves have produced inconsistent and conflicting results. According to a recent meta-analysis,43 there is no conclusive evidence that coordinated, multidisciplinary inpatient rehabilitation is more effective than conventional hospital care (with no rehabilitation professionals involved) for older patients with hip fracture. Most hip fractures result from a fall and, thus, all patients who sustain a hip fracture should be assessed for the presence of risk factors for falls. Subsequently, different interventions that target multiple intrinsic and extrinsic risk factors of individual patients should be considered. Because many community-living older persons who fracture a hip eventually return home, much postfracture rehabilitation occurs at home, so little is known about effective ambulatory strategies for the rehabilitation of geriatric patients after hip surMEDICOGRAPHIA, VOL 28, No. 1, 2006 69

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gery. A recent randomized controlled trial found that a home-based systematic multicomponent rehabilitation strategy was no more effective for promoting recovery than usual home-based rehabilitation.44 Conclusions Patients who have both low BMD and a propensity to fall will benefit most from specific exercise programs, as well as from the use of hip protectors in some instances. Low BMD and the propensity to fall both contribute to osteoporotic fractures, particularly in the elderly. Professionally prescribed, homebased balance retraining, muscle strengthening, and walking, as well as tai chi group exercises, and a multidisciplinary, multifactorial risk factor screening and intervention program, are likely to be benREFERENCES 1. Cummings SR, Black DM, Rubin SM. Lifetime risks of hip, Colles, or vertebral fracture and coronary heart disease among white postmenopausal women. Arch Intern Med. 1989;149:2445-2448. 2. Boonen S, Autier P, Barette M, Vanderschueren D, Lips P, Haentjens P. Functional outcome and quality of life following hip fracture in elderly women: a prospective controlled study. Osteoporos Int. 2004;15: 87-94. 3. Autier P, Haentjens P, Bentin J, et al. Costs induced by hip fractures: a prospective controlled study in Belgium. Belgian Hip Fracture Study Group. Osteoporos Int. 2000;11:373-380. 4. Geusens P, Autier P, Boonen S, Vanhoof J, Declerck K, Raus J. The relationship among history of falls, osteoporosis, and fractures in postmenopausal women. Arch Phys Med Rehabil. 2002;83:903-906. 5. Nguyen T, Sambrook P, Kelly P, et al. Prediction of osteoporotic fractures by postural instability and bone density. BMJ. 1993;307:1111-1115. 6. Marshall D, Johnell O, Wedel H. Meta-analysis of how well measures of bone mineral density predict occurrence of osteoporotic fractures. BMJ. 1996;312: 1254-1259. 7. Jensen ME, Evans AJ, Mathis JM, Kallmes DF, Cloft HJ, Dion JE. Percutaneous polymethylmethacrylate vertebroplasty in the treatment of osteoporotic vertebral body compression fractures: technical aspects. AJNR Am J Neuroradiol. 1997;18:1897-1904. 8. Cummings SR, Nevitt MC, Browner WS, et al., the Study of Osteoporotic Fractures Research Group. Risk factors for hip fracture in white women. N Engl J Med. 1995;332:767-773. 9. Tinetti ME, Williams CS. Falls, injuries due to falls, and the risk of admission to a nursing home. N Engl J Med. 1997;337:1279-1284. 10. Melton LJI, Chao EYS, Lane J. Biomechanical aspects of fractures. In: Riggs BL, Melton LJ, eds. Osteoporosis: Etiology, Diagnosis, and Management. New York, NY: Raven Press; 1998:111-131. 11. Fiatarone MA, ONeill EF, Ryan ND, et al. Exercise training and nutritional supplementation for physical frailty in very elderly people. N Engl J Med.1994; 330:1769-1775. 12. Lee SH, Dargent-Molina P, Breart G, for the EPIDOS Group. Risk factors for fractures of the proximal humerus: Results from the EPIDOS prospective study. J Bone Miner Res. 2002;17:817-825. 13. Tinetti ME. Clinical practice: preventing falls in elderly persons. N Engl J Med. 2003;348:42-49. 14. Lynn SG, Sinaki M, Westerlind KC. Balance characteristics of persons with osteoporosis. Arch Phys Med Rehabil. 1997 ;78:273-277. 15. Gillespie LD, Gillespie WJ, Robertson MC, Lamb SE, Cumming RG, Rowe BH. Interventions for preventing falls in elderly people. Cochrane Database Syst Rev. 2001;3:CD000340.

eficial for preventing falls in elderly people. Rehabilitation after vertebral fractures caused by osteoporosis consists of improving muscle strength (particularly of the legs) to decrease the risk of falls and fractures, back-strengthening exercises to improve posture and decrease hyperkyphosis, and sedative physical therapy to decrease postural deficit-related pain. Among other factors, a loss of musculoskeletal integrity after hip fracture is likely to have a major impact on the outcome of rehabilitation and on the risk of fracture recurrence. However, it remains to be clarified whether targeted interventions (pharmacological or nonpharmacological) might be able to modify this process by enhancing bone and muscle mass and thus facilitate postsurgical rehabilitation and reduce the risk of recurrent fractures.
in calcium-replete postmenopausal women. J Bone Miner Res. 2001;16:175-181. 30. Itoi E, Sinaki M. Effect of back-strengthening exercise on posture in healthy women 49 to 65 years of age. Mayo Clin Proc. 1994;69:1054-1059. 31. Malmros B, Mortensen L, Jensen MB, Charles P. Positive effects of physiotherapy on chronic pain and performance in osteoporosis. Osteoporos Int. 1998; 8:215-221. 32. Kaplan RS, Sinaki M, Hameister M. Effect of back supports on back strength in patients with osteoporosis: a pilot study. Mayo Clin Proc. 1996;71:235-241. 33. Pfeifer M, Begerow B, Minne HW. Effects of a new spinal orthosis on posture, trunk strength, and quality of life in women. Med Rehabil. 2004;83:177-186. 34. Amar AP, Larsen DW, Esnaashari N, Albuquerque FC, Lavine SD, Teitelbaum GP. Percutaneous transpedicular polymethylmethacrylate vertebroplasty for the treatment of spinal compression fractures. Neurosurgery. 2001;49:1105-1114. 35. Lieberman IH, Dudeney S, Reinhardt MK, Bell G. Initial outcome and efficacy of kyphoplasty in the treatment of painful osteoporotic vertebral compression fractures. Spine. 2001;26:1631-1638. 36. Parker MJ, Palmer CR. Prediction of rehabilitation after hip fracture. Age Ageing. 1995;24:96-98. 37. Greendale GA, Barrett-Connor E, Ingles S, Haile R. Late physical and functional effects of osteoporotic fracture in women: The Rancho Bernardo Study. J Am Geriatr Soc. 1995 ;43:955-961. 38. Dirschl DR, Henderson RC, Oakley WC. Accelerated bone mineral loss following a hip fracture: a prospective longitudinal study. Bone. 1997;21:79-82. 39. Sherrington C, Lord SR. Home exercise to improve strength and walking velocity after hip fracture: a randomized controlled trial. Arch Phys Med Rehabil. 1997;78:208-212. 40. Lindsay R, Silverman SL, Cooper C, et al. Risk of new vertebral fracture in the year following a fracture. JAMA. 2001;285:320-323. 41. Ismail AA, Cockerill W, Cooper C, et al. Prevalent vertebral deformity predicts incident hip though not distal forearm fracture: results from the European Prospective Osteoporosis Study. Osteoporos Int. 2001; 12:85-90. 42. Colon-Emeric C, Kuchibhatla M, Pieper C, et al. The contribution of hip fracture to risk of subsequent fractures: data from two longitudinal studies. Osteoporos Int. 2003;14:879-883. 43. Cameron I, Crotty M, Currie C, et al. Geriatric rehabilitation following fractures in older people: A systematic review. Health Technol Assess. 2000;4: 1-111. 44. Tinetti ME, Baker DI, Gottschalk M, et al. Homebased multicomponent rehabilitation program for older persons after hip fracture: A randomized trial. Arch Phys Med Rehabil. 1999;80:916-922.

16. Gregg EW, Cauley JA, Seeley DG, Ensrud KE, Bauer DC, for the Study of Osteoporotic Fractures Research Group. Physical activity and osteoporotic fracture risk in older women. Ann Intern Med.1998; 129:81-88. 17. Wolff SL, Barnhart HX, Kutner NG, McNeely E, Coogler C, Xu T, the Atlanta FICSIT Group. Reducing frailty and falls in older persons: an investigation of tai chi and computerized balance training. J Am Geriatr Soc. 1996;44:489-497. 18. Jensen J, Lundin-Olsson L, Nyberg L, Gustafson Y. Fall and injury prevention in older people living in residential care facilities: a cluster randomized trial. Ann Intern Med. 2002;136:733-741. 19. Sinaki M, Lynn SG. Reducing the risk of falls through proprioceptive dynamic posture training in osteoporotic women with kyphotic posturing: a randomized pilot study. Am J Phys Med Rehabil. 2002; 81:241-246. 20. Bischoff HA, Stahelin HB, Dick W, Akos R, Knecht M, Salis C, et al. Effects of vitamin D and calcium supplementation on falls: a randomized controlled trial. J Bone Miner Res. 2003;18:343-351. 21. Latham NK, Anderson CS, Lee A, Bennett DA, Moseley A, Cameron ID. A randomized, controlled trial of quadriceps resistance exercise and vitamin D in frail older people: the Frailty Interventions Trial in Elderly Subjects (FITNESS). J Am Geriatr Soc. 2003; 51:291-299. 22. Pfeifer M, Begerow B, Minne HW, Abrams C, Nachtigall D, Hansen C. Effects of a short-term vitamin D and calcium supplementation on body sway and secondary hyperparathyroidism in elderly women. J Bone Miner Res. 2000;15:1113-1118. 23. Bischoff-Ferrari HA, Dawson-Hughes B, Willett WC, et al. Effect of Vitamin D on falls: a meta-analysis. JAMA. 2004;291:1999-2006. 24. van Schoor NM, Deville WL, Bouter LM, Lips P. Acceptance and compliance with external hip protectors: a systematic review of the literature. Osteoporos Int. 2002;13:917-924. 25. van Schoor NM, Smit JH, Twisk JW, Bouter LM, Lips P. Prevention of hip fractures by external hip protectors: a randomized controlled trial. JAMA. 2003; 289:1957-1962. 26. Sinaki M, Khosla S, Limburg PJ, Rogers JW, Murtaugh PA. Muscle strength in osteoporotic versus normal women. Osteoporos Int. 1993;3:8-12. 27. Sinaki M, Itoi E, Wahner HW, et al. Stronger back muscles reduce the incidence of vertebral fractures: a prospective 10 year follow-up of postmenopausal women. Bone. 2002;30:836-841. 28. Mulrow CD, Gerety MB, Kanten D, et al. A randomized trial of physical rehabilitation for very frail nursing home residents. JAMA. 1994;271:519-524. 29. Kerr D, Ackland T, Maslen B, Morton A, Prince R. Resistance training over 2 years increases bone mass

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Rehabilitation in osteoporosis Boonen

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C U S

RADAPTATION

MUSCULOSQUELETTIQUE DANS LOSTOPOROSE POSTMNOPAUSIQUE

a plupart des stratgies antifracturaires ont ax leurs efforts sur laugmentation de la rsistance osseuse par diminution du renouvellement de los. Lefficacit de ces traitements pour rduire le risque de fracture a t rgulirement prouve chez des patientes bien dfinies prsentant une ostoporose confirme (densit minrale osseuse basse ou fracture vertbrale prvalente). Cependant, les fractures sont provoques la fois par une perte de lintgrit du squelette et par une augmentation du risque de chutes. Nanmoins, les facteurs extrasquelettiques dans la prvention des fractures chez des sujets slectionns ont peu retenu lattention. On devrait envisager des

mesures de radaptation musculosquelettique (et de pharmacothrapie) pour optimiser la sant au niveau musculosquelettique, amliorer la qualit de vie, et rduire le risque de fractures et de rcurrence de fractures dans la prise en charge des patientes qui prsentent un risque accru de fractures cause de lostoporose ou des facteurs de risque extrasquelettiques. tant donn limportance de la fonction musculaire vis--vis de la qualit osseuse et du risque de chutes ou de lsions dues aux chutes, cet article met laccent sur le rle des diffrents aspects de la fonction musculaire, tels que la force et la coordination, dans la prvention des fractures et la radaptation des patientes ostoporotiques.

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P D A T E

DETERMINANTS OF BONE QUALITY

b y G . B o i v i n a n d P. J . M e u n i e r , F r a n c e

one strength and fracture risk are generally assessed by measuring bone mineral density (BMD). Fracture risk increases with age, partly as a function of changes in BMD. However, the risk of fracture in a 75-year-old woman is 4 to 7 times that in a 45-year-old woman with an identical BMD.1 This demonstrates that there is a component of bone fragility that is independent of bone mass, and is associated with bone quality. This has been recently emphasized by the observation that major treatments for osteoporosis all have about the same fracture efficacy, though there is a 7-fold difference in their effect on BMD. The drugs used to treat bone fragility aim to improve bone strength, and thus decrease the risk of fracture. In humans, the end point used to evaluate bone strength is the fracture rate, but large numbers of patients are required to demonstrate significant reductions as a result of therapeutic intervention. Furthermore, fracture is not only caused by decreased bone mineral mass, or alteration of the microarchitecture, but also by falls, which can occur as a result of loss of balance, inappropriate protective responses, or muscle weakness. Bone strength corresponds to the maximal load that can be applied before a fracture occurs. It is influenced by a variety of determinants, such as mass, size, geometry, microarchitecture, as well as by the intrinsic properties of bone tissue, such as the degree of mineralization of bone (DMB) and the organic matrix characteristics (orientation and chemical structure of the collagen fibers), as well as the accumulation of microdamage (initiation and pro-

Georges BOIVIN, PhD Director of Research INSERM Unit 403

gression of microcracks), and the apoptosis of osteocytes. Bone quality is deeply influenced by the rate of bone turnover.2 Changes in fracture risk and BMD were recently evidenced in osteoporotic patients treated with alendronate, without any modification in bone matrix volume or bone microarchitecture.3 Thus, mineralization and mineral characteristics should not be neglected among the factors determining the mechanical competence of bone. Bone mineral density (BMD) Currently, areal BMD is measured by dual-energy x-ray absorptiometry (DXA). BMD is a major determinant of bone strength, and BMD values obtained at the proximal femur and lumbar spine are used to diagnose osteoporosis by applying the criteria established by the World Health Organization (WHO). Most of the clinical studies carried out on bone resorption inhibitors, such as bisphosphonates, selective estrogen receptor modulators (SERMs), or estrogen, have shown some association
SELECTED
BMD BMU BSU DXA DMB PTH SERM
ABBREVIATIONS AND ACRONYMS

Pierre J. MEUNIER, MD Professor of Medicine Ren Laennec Faculty of Medicine, Claude Bernard University, Lyon FRANCE

bone mineral density basic multicellular unit basic structural units dual energy x-ray absorptiometry degree of mineralization of bone parathyroid hormone selective estrogen receptor modulator

one strength is defined as the maximal load that can be applied before a fracture occurs. It is influenced by a number of determinants, such as mass, size, geometry, microarchitecture, as well as by intrinsic bone tissue properties. The latter include the degree of mineralization of bone, the characteristics of the organic matrix (collagen fiber orientation and chemical structure), bone microdamage accumulation (initiation and progression of microcracks), and osteocyte apoptosis. Bone quality in general as well as the degree of mineralization of bone are both deeply influenced by the rate of bone turnover. This may explain the changes in fracture incidence and the increase in bone mineral density and bone strength observed independently of changes in bone matrix volume and bone microarchitecture. The growing interest in the evaluation of the determinants of bone quality reflects the importance of bone mineral substance in the MEDICOGRAPHIA, VOL 28, No. 1, 2006

pathophysiology of osteoporosis and other bone conditions, and has led to the rediscovery of the mineral dimension of bone, which had been all but forgotten for many years, and which is assessed by means of the following parameters: degree of mineralization of bone; heterogeneity index of bone mineralization; mechanical properties of bone tissue (microhardness tester); size and maturity of crystals; and the degree of collagen maturation (Fourier transform infrared microspectroscopy).
Medicographia. 2006;28:72-77. (see French abstract on page 77)

Keywords: bone strength; bone quality; microarchitecture; mineralization; hardness; bone remodeling
Address for correspondence: Georges Boivin, Director of Research, INSERM Unit 403, Facult de Mdecine Ren Laennec, Universit Claude Bernard Lyon1, 69372 Lyon Cedex 08, France (e-mail: Georges.Boivin@sante.univ-lyon1.fr)

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between the increment in areal BMD and the decrease in risk of fracture, but the relationship between the two is not always straightforward.4 Thus, raloxifene and alendronate treatment are both associated with a reduction in vertebral fracture, but the effect on BMD is less pronounced with raloxifene (+3%) than with alendronate (+8%).5 In untreated bone, ex vivo studies performed on human samples have evidenced an excellent correlation between BMD of the proximal femur and bone strength, as evaluated by the shear test applied to the femoral neck6 or by compression of the vertebrae.7 According to these ex vivo studies, BMD predicts approximately 60% to 70 % of the variance of bone strength. BMD is not a volumetric (mass per volume) density, but an areal density (mass per area). The high level of prediction of bone strength by areal BMD could be explained, at least in part, by the fact that bone size is integrated in this measurement. Bone geometry Among the determinants of bone strength, dimensions such as external diameters and cortical thickness play a major role. Mechanical studies have demonstrated that increasing the external diameter of a cylinder greatly increases its resistance to flexion. Increase in cortical thickness also improves bone strength, but to a lesser extent. The outer diameter of the long bones predicts up to 55% of the variance of bone strength.8-12 Stimulators of bone formation, such as insulinlike growth factor I, growth hormone,13 and parathyroid hormone (PTH), stimulate periosteal apposition14 and increase the external diameter of long bones. This expansion of the outer diameter of long bones is associated with a marked increment in bone strength. An increase in cortical thickness may also be observed with antiresorptive therapies, and results from inhibition of endosteal bone resorption, thereby contributing to the increase in bone strength. Expansion of bone diameter is also observed in humans.12 During growth, bone diameter is influenced by nutritional factors such as calcium and phosphate salt supplements. In elderly men, an expansion of bone outer diameter occurs, and with PTH treatment an increased bone area can be detected. An excess of growth hormone, as in acromegaly, also increases bone size. Thus, an increase in bone size is possible in adults, but its specific role as a determinant of fracture risk remains to be determined. Bone microarchitecture If cancellous bone is more plate-like, with thicker and more numerous trabeculae, there is an enhancement of strength. Trabecular architecture, which is more isotropic, having similar mechanical properties in all directions, may further lower fracture risk. This could provide a rationale for the clinical observation that fracture risk decreases by 50% to 60% in the first year of bisphosphonate ther-

apy with only a 5% increase in BMD. Teriparatide increases trabecular number and connectivity via longitudinal tunneling, converting thickened trabeculae to multiple struts of normal thickness.15 Although its increases cortical porosity, the porosity is located close to the marrow cavity where its mechanical effect is small.16,17 Simultaneously, teriparatide favors periosteal apposition, which maintains or improves cortical bone strength.18 Among the invasive methods that preserve tissue structure, bone histomorphometry allows the direct measurement of the amount of bone matrix in a given volume of biopsied bone, in particular through measurements of cancellous or total bone volume, expressed as a percentage of either spongy bone tissue or core volume.19 Bone histomorphometry is performed on undecalcified transiliac bone biopsies embedded in methyl methacrylate. This method is used to measure: (i) static parameters reflecting bone structure and microarchitecture in cancellous and compact bone; (ii) bone remodeling (resorption and formation); and (iii) dynamic parameters such as the rate of osteoblast activity, after double tetracycline labeling. It is the only method suited to evaluate tissue and cell changes at the level of the intermediary organization of bone, ie, the basic structural units (BSU), of which there are two varieties, the osteon in cortical bone and the cancellous bone packet in spongy bone. Bone histomorphometry allows good discrimination of completely nonmineralized matrix, but this method is in no way capable of providing information on the individual DMB of each BSU. Sex hormone deficiency is associated with alterations in the connectivity of trabecular structures, ie, decrease in the number of trabeculae, increase in trabecular separation, changes in trabecular shape from plate-like to rod-like, and various alterations in parameters of connectivity evidenced by histomorphometry.20,21 These alterations in trabecular structure may contribute to changes in bone strength. Ovariectomy can reduce bone strength and bone mass; however, significant modifications of vertebral bone strength can be detected before any decrease in BMD. Dissociation between these two variables may be due to early alteration of the microarchitecture (perforation and/or disappearance of trabeculae) without major effects on BMD. Therefore, the mechanical properties of trabecular bone are dominated by bone volume fraction and the extent of anisotropy. In fact, most morphologic properties calculated from three-dimensional microcomputed tomography images, such as trabecular thickness, trabecular spacing, connectivity, and structural index, are to some extent correlated with bone volume fraction. Intrinsic determinants of bone quality other than bone mineralization Microdamage accumulation reduces bone strength, stiffness, and toughness.22 Bone from older women is more subject to microcracks and is inherently more fragile than bone from younger women. This may be why there is a significant accumulation of MEDICOGRAPHIA, VOL 28, No. 1, 2006 73

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microdamage at several anatomical sites with age.23 The pharmacological suppression of remodeling also increases microdamage accumulation,24 and the extent of this increase is probably dependent on the magnitude of the suppression.25 The collagen matrix exerts a profound influence on bone mechanical properties.26 The risk of vertebral fracture is significantly increased in subjects with the Sp1 polymorphism of the COL1A1 gene. Changes in collagen with aging are known to affect the amount of energy required to cause fracture.27 This may be related either to the amount of collagen in the matrix or to the extent or nature of its cross-linking. Antiresorptive treatments probably increase the amount of cross-linking, but whether this is a positive or a negative change is unclear at this time.

Figure 1. Microradiograph of a section from an iliac bone sample (control man 76-year-old, mean degree of mineralization of bone tissue (DMB) = 1.330.16 g/cm3 and heterogeneity index of mineralization = 0.35 g/cm3). The heterogeneity of the mineralization is illustrated by the wide distribution from dark grey young basic structural units (BSU) to clear grey old BSU.

Both hypo- and hypermineralization of bone tissue reduce the amount of energy that can be absorbed before fracture.28,29 As discussed later on in this paper, suppression of remodeling favors tissue mineralization by increasing the period of time over which secondary mineralization can occur. This may increase the tendency for microcracks to initiate. Suppression of remodeling increases tissue homogeneity, possibly making crack growth easier as well. However, the magnitude of the effect is probably determined by the amount of suppression. Degree of mineralization of bone (DMB) Although there is widespread consensus on the fact that bone strength depends on the volume of bone matrix and the microarchitectural distribution of this volume, DMB is rarely mentioned as a determinant of bone strength. Yet, not only does DMB strongly influence the mechanical resistance of bones,30 but this is also true of BMD.3 Microradio74 MEDICOGRAPHIA, VOL 28, No. 1, 2006

graphic observations made in the 70s clearly show that DMB is heterogeneously distributed in the BSU (both in the osteons in cortical bone and in the trabecular packets in cancellous bone), the recently deposited BSU being much less mineralized than the older ones. Young BSU appear in dark grey on microradiographs, whereas the old BSU are whiter (Figure 1). This heterogeneity in DMB is explained by the fact that the bone formation that follows bone resorption in the remodeling sequence is a multistep process: the new matrix begins to mineralize after about 5 to 10 days from the time of deposition and the linear rate of this primary mineralization can be measured directly in vivo by means of double tetracycline labeling. After full completion of the BSU, a phase of secondary mineralization sets in.31 This process consists of a slow and gradual maturation of the mineral component, including an increase in the amount of crystals and/or an augmentation of crystal size toward their maximum dimensions. This secondary mineralization progressively augments the mineral content on bone matrix. At the end of the primary mineralization phase, the mineral content is only about 50% to 60% of the maximum degree of mineralization achieved at the end of the secondary mineralization phase. DMB is commonly measured by x-ray attenuation experiments. Most studies have used contact microradiography, which yields a high linear resolution. Quantitative microradiography using a computerized microdensitometric method allows the measurement of the focal DMB of each BSU within the limits imposed by the thickness of the section.31-33 Microscopic mineral variations and mineral density distributions have also been evaluated by quantitative backscattered electron imaging, as previously reviewed.34 DMB has also been measured using synchrotron radiation microtomography,35,36 which may also provide 3-D images with a spatial resolution as high as 1 micrometer, which is very accurate for quantifying human bone microarchitecture. The DMB values measured by the two different techniques show an extensive overlap of distributions and exhibit the same range of variation (0.5 to 1.6 g. mineral/cm3). Quantitative microradiography has been used to determine control values in 43 iliac bone samples taken at necropsy from 30 women and 13 men who died suddenly and in whom no apparent bone disorder was found.32 In terms of mean values, distribution, and evolution with age, the DMB was not significantly different between both sexes and did not change significantly with age. The mean (SEM) DMB expressed in g mineral/cm3 was 1.090.02 in total bone. The distributions of DMB revealed a small shift towards the high values in cancellous bone compared with compact bone (maximum DMB was 1.10 and 1.05 g/cm3, respectively, and the index of heterogeneity was 0.28 and 0.34 g/cm3, respectively). This may reflect either the presence in cancellous bone of a higher proportion of interstitial bone than in compact bone, or an edge effect (100-m thick sections) with suppression of the measurements in the least mineralized parts of the trabeculae.

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In adult bone, the major biological determinant of mineralization is the rate of turnover. Thus, in our model (Figure 2),37 any agent (PTH) or event (menopause, ovariectomy) that causes an increase in the birthrate or activation frequency of basic multicellular units (BMU), induces a decrease in the life-

Bone remodeling
Formative effects: OVX, PTH

Birthrate of BMU

Lifespan of BSU

Bone remodeling
Anti-resorptive effects: biphosphonates, estrogen, raloxifene

Duration of secondary mineralization

Degree of mineralization of bone tissue (DMB)

Figure 2. Diagram summarizing the effects of the rate of bone remodeling activity on the secondary mineralization and consequently on the degree of mineralization of bone. The black arrows relate to decreased bone remodeling activity, and the green arrows to increased bone remodeling activity.
Abbreviations: BMU, basic multicellular unit, BSU, basic structural unit; DMB, degree of mineralization of bone tissue; OVX, ovariectomy; PTH, parathyroid hormone. Adapted from reference 37: Boivin G, Meunier PJ. The mineralization of bone tissue: a forgotten dimension in osteoporosis research. Osteoporos Int. 2003;14(suppl 3)S19S24. Copyright 2003, Springer Verlag USA.

span of BSU, in other words, in the time available for secondary mineralization. This leads to new BSU being resorbed before they have fully completed their secondary mineralization, as proven by the presence of a large amount of incompletely mineralized BSU and a low mean DMB. In primary hyperparathyroidism, a shift of DMB toward the low values was observed (mean 0.920.07 g/cm3; DMB max 0.90), but the index of heterogeneity was unchanged (0.30 g/cm3). In patients treated with teriparatide, the DMB was decreased, but with an increased heterogeneity of the values,38,39 as expected after a short prolongation of bone formation activity. Conversely, antiresorptive agents (bisphosphonates, estrogen, SERMs), which cause a marked reduction in the birthrate of BMU, prolong the lifespan of the BSU, allowing a more complete secondary mineralization. This should finally lead to an increase in DMB. Recently, mean DMB was measured by quantitative microradiography3 on transiliac bone biopsies taken from 53 postmenopausal osteoporotic women who had been treated with alendronate (10 mg/day) for 2 or 3 years, or with placebo. In the same patients, BMD values were obtained at lumbar spine level. After 2 years on alendronate, mean DMB in total bone was 7.5% higher than on placebo (P=0.0026). After 3 years on alendronate, mean DMB in total bone was 10.7% higher than on placebo (P=0.0001). After alendronate, the distribution of the DMB in total bone showed a clear shift toward the highest mineralization values concomitantly with a decrease in the number of BSU having low values of mineralization. The betweengroup differences in mean DMB were similar to those in BMD at lumbar spine level (+8.7% after 2 years and +9.6% after 3 years, respectively), sug-

gesting that the mean DMB increase probably accounts for the major part of the increase in BMD seen with alendronate. After 2 and 3 years of alendronate, the index of heterogeneity was smaller than after placebo. This illustrates the fact that with alendronate, which achieves a more complete secondary mineralization, the homogeneity of mineralization is better. Similar data have been reported after etidronate treatment for 1 and 2 years.36 Treatments with other bisphosphonates like risedronate40 and zoledronate41 also revealed decreases in vertebral fractures and increases in BMD without any significant changes in bone mass and microarchitecture, but marked reduction in activation frequency. Another antiresorptive agent, the SERM raloxifene, whose action on the decrease of remodeling rate is less potent than that of alendronate, has also been tested.42 Raloxifene induces a mild increase in BMD, a moderate decrease in the biochemical markers of bone turnover, and decreases the risk of vertebral fractures in postmenopausal women. In the absence of significant changes in bone mass and microarchitecture, the changes in BMD reflect even mild modifications in DMB.43 Similar changes in DMB have been reported after administration of high doses of estrogen.44 Finally, strontium ranelate (Protelos), a new orally effective and safe treatment of postmenopausal osteoporosis, has been shown to decrease vertebral and hip fractures and increase BMD.45,46 The mechanism of action of strontium ranelate is unique in that it acts as a decoupling agent that decreases bone resorption and increases bone formation. Its effects at bone tissue level have recently been investigated in animals47 and in women.37 Conclusions The methods used for the evaluation of bone strength depend on the part of the skeleton being investigated48: compression for the vertebral body or of proximal tibia; 3- or 4-point bending test for the long bones (tibia, femur); and shear test for the femoral neck. Recently, racial and sex differences have been reported to explain differences in bone strength, bone loss, and bone geometry.49,50 Biomechanical tests are used to record a load-deflection curve, allowing the calculation of various components: stiffness by measuring the slope of the linear part of the curve; ultimate strength by measuring the highest load obtained before fracture; and energy absorbed (toughness) by measuring the area under the curve. Other parameters can be derived, for example, the yield point, which corresponds to the transition from an elastic to a plastic, ie, irreversible, deformation of the sample. All these tests are well described, and their reproducibility has been evaluated (3% to 5 %). These measurements can be used to evaluate the severity of bone fragility as well as the integrate effect of treatment on the various determinants of bone strength. However, in clinical studies based on bone biopsies, the amount of bone available is too small to investigate the biomechanical properties. Recently, a nanoindentation technique has been applied to investigate tissue MEDICOGRAPHIA, VOL 28, No. 1, 2006 75

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quality by measuring both hardness and elasticity of dry and wet bone tissue with a high spatial resolution.51,52 Nanoindentation involves compressing a pyramidal diamond tip into a material, and simultaneously recording the resulting force and displacement. From the force-displacement curves obtained, hardness (the maximal force per unit area), and indentation modulus (a purely elastic property) can be calculated. The nanoindentation method allows the mechanical properties of bone lamellae to be quantified. To study the mechanical properties of bone tissue at the level of each BSU the true intermediate level of organization allowing a correct approach to remodelingwe are developing investigation techniques using microhardness testers (Vickers and Knoop). Finally, the correlation between mineralization, hardness, and the classic mechanical tests is being actively investigated. Changes in bone remodeling activity directly influence the degree of mineralization of bone. This
REFERENCES 1. Hui S, Slemenda CW, Jonhston CC. Age and bone mass as predictors of fracture in a prospective study. J Clin Invest. 1988;81:1804-1809. 2. Dempster DW. The impact of bone turnover and bone-active agents on bone quality: focus on the hip. Osteoporos Int. 2002;13:349-352. 3. Boivin G, Chavassieux PM, Santora AC, et al. Alendronate increases bone strength by increasing the mean degree of mineralization of bone tissue in osteoporotic women. Bone. 2000;27:687-694. 4. Hauselmann HJ, Rizzoli R. A comprehensive review of treatments for postmenopausal osteoporosis. Osteoporos Int. 2003;14:2-12. 5. Riggs BL, Melton LJ III. Bone turnover matters: the raloxifene treatment paradox of dramatic decreases in vertebral fractures without commensurate increases in bone density. J Bone Miner Res. 2002;17:11-14. 6. Dalen N, Hellstrom LG, Jacobson B. Bone mineral content and mechanical strength of the femoral neck. Acta Orthop Scand. 1976;47:503-508. 7. Granhed H, Jonson R, Hansson T. Mineral content and strength of lumbar vertebrae. A cadaver study. Acta Orthop Scand. 1989;60:105-109. 8. Turner CH, Burr DB. Basic biomechanical measurements of bone: a tutorial. Bone.1993;14:595-608. 9. Ammann P, Rizzoli R, Bonjour JP. Preclinical evaluation of new therapeutic agents for osteoporosis. In: Meunier PJ, ed. Osteoporosis: Diagnosis and Management. London, UK: Martin Dunitz; 1998:257-273. 10. Bonjour JP, Ammann P, Rizzoli R. Importance of preclinical studies in the development of drugs for treatment of osteoporosis: a review related to the 1998 WHO guidelines. Osteoporos Int. 1999;9:379-393. 11. Turner CH. Biomechanics of bone: determinants of skeletal fragility and bone quality. Osteoporos Int. 2002;13:97-104. 12. Seeman E. Pathogenesis of bone fragility in women and men. Lancet. 2002;359:1841-1850. 13. Andreassen TT, Jorgensen PH, Flyvbjerg A, et al. Growth hormone stimulates bone formation and strength of cortical bone in aged rats. J Bone Miner Res. 1995;10:1057-1067. 14. Ejersted C, Andreassen TT, Oxlund H, et al. Human parathyroid hormone (1-34) and (1-84) increase the mechanical strength and thickness of cortical bone in rats. J Bone Miner Res. 1993;8:1097-1101. 15. Jerome CP, Burr DB, van Bibber T, Hock JM, Brommage R. Treatment with human parathyroid hormone (1-34) for 18 months increases cancellous bone volume and improves trabecular architecture in ovariectomized cynomolgus monkeys (Macaca fascicularis). Bone. 2001;28:150-159. 16. Hirano T, Burr DB, Turner CH, Sato M, Cain RL, Hock JM. Anabolic effects of human biosynthetic parathyroid hormone fragment (1-34), LY333334, on remodeling and mechanical properties of cortical bone

may explain the observation of modifications in fracture incidence and the increase in the BMD and in bone strength independently of changes in bone matrix volume and bone microarchitecture. This new approach to the determinants of bone quality emphasizes the importance of bone mineral substance in the pathophysiology of osteoporosis and other bone conditions, and of taking a fresh look at the long forgotten mineral dimension of bone. In addition to parameters of DMB such as the heterogeneity index of the distribution of mineralization, we are now able to evaluate the mechanical properties at tissue level, by means of microhardness testers, and the role of the size/maturity of crystals and of the maturation of collagen, by means of Fourier transform infrared microspectroscopy.
The expert technical assistance of Delphine Farlay, Catherine Simi and Yohann Bala (INSERM Unit 403, Facult de Mdecine R. Laennec, Lyon, France) is gratefully acknowledged.
strength. A study on human calcaneus. Bone. 2004; 34:783-789. 31. Meunier PJ, Boivin G. Bone mineral density reflects bone mass but also degree of mineralization of bone: therapeutical implications. Bone. 1997;21:373-377. 32. Boivin G, Meunier PJ. The degree of mineralization of bone tissue measured by computerized quantitative contact microradiography. Calcif Tissue Int. 2002;70:503-511. 33. Boivin G, Meunier PJ. Effects of bisphosphonates on matrix mineralization. J Musculoskel Neuron Interact. 2002;2:538-543. 34. Boivin G, Meunier PJ. Methodological considerations in measurement of bone mineral content. Osteoporos Int. 2003;14(suppl 5):22-28. 35. Nuzzo S, Peyrin F, Cloetens P, Bachurel J, Boivin G. Quantification of the degree of mineralization of bone in three dimension using synchrotron radiation microtomography. Medical Physics. 2002;29:26722681. 36. Nuzzo S, Lafage-Proust MH, Martin-Badosa E, et al. Synchrotron radiation microtomography allows the analysis of three-dimensional microarchitecture and degree of mineralization of human iliac crest biopsies: effects of etidronate treatment. J Bone Miner Res. 2002;17:1372-1382. 37. Boivin G, Meunier PJ. The mineralization of bone tissue: a forgotten dimension in osteoporosis research. Osteoporos Int. 2003;14(suppl 3):S19-S24. 38. Misof BM, Roschger P, Cosman F, et al. Effects of intermittent parathyroid hormone administration on bone mineralization density in iliac crest biopsies from patients with osteoporosis: a paired study before and after treatment. J Clin Endocrinol Metab. 2003; 88:1150-1156. 39. Arlot ME, Meunier PJ, Boivin G, et al. Differential effects of teriparatide and alendronate on bone remodeling in postmenopausal women assessed by histomorphometric parameters. J Bone Miner Res. 2005; 20:1244-1253. 40. Borah B, Ritman EL, Dufresne TE, et al. The effects of risedronate on bone mineralization as measured by micro-computed tomography with synchrotron radiation: correlation to histomorphometric indices of turnover. Bone. 2005;37:1-9. 41. Boivin G, Arlot M, Trechsel U, Meunier PJ. Effects of intravenous zoledronic acid on the degree of mineralization of bone in post-menopausal osteoporosis: a quantitative microradiographic analysis of transiliac biopsies after one year. J Bone Miner Res. 2003;18 (suppl 2):S261. 42. Ott SM, Oleksik A, Lu Y, Harper K, Lips P. Bone histomorphometric and biochemical marker results of a 2-year placebo-controlled trial of raloxifene in postmenopausal women. J Bone Miner Res. 2002;17: 341-348.

in rabbits. J Bone Miner Res. 1999;14:536-545. 17. Burr DB, Hirano T, Turner CH, Hotchkiss C, Brommage R, Hock JM. Intermittently administered human parathyroid hormone (1-34) treatment increases intracortical bone turnover and porosity without reducing bone strength in the humerus of ovariectomized cynomolgus monkeys. J Bone Miner Res. 2001;16:157-165. 18. Zanchetta JR, Bogado CE, Ferretti JL, et al. Effects of teriparatide (recombinant human parathyroid hormone (1-34) on cortical bone in postmenopausal women with osteoporosis. J Bone Miner Res. 2003;18: 539-543. 19. Chavassieux P, Arlot M, Meunier PJ. Clinical use of bone biopsy. In: Marcus R, Feldman D, Kelsey J, eds. Osteoporosis. 2nd edition. San Diego, Ca: Academic Press Inc; 2001;2:501-509. 20. Compston JE. Sex steroids and bone. Physiol Rev. 2001;81:419-447. 21. Gallagher JC. Effect of estrogen on bone. In: Favus MJ, ed. Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism. Fifth edition. Chapter 23. Washington, DC: ASBMR; 2003:327-330. 22. Burr DB, Forwood MR, Fyhrie DP, Martin RB, Schaffer MB, Turner CH. Bone microdamage and skeletal fragility in osteoporotic and stress fractures. J Bone Miner Res. 1997;12:6-15. 23. Burr DB. Bone quality: understanding what matters. J Musculoskel Neuron Interact. 2004;4:184186. 24. Mashiba T, Turner CH, Hirano T, Forwood MR, Johnston CC, Burr DB. The effects of suppressed bone turnover by bisphosphonates on microdamage accumulation and biomechanical properties in clinically relevant skeletal sites of beagles. Bone. 2001;28:524531. 25. Mashiba T, Hirano T, Turner CH, Forwood MR, Johnston CC, Burr DB. Suppressed bone turnover by bisphosphonates increases microdamage accumulation and reduces some biomechanical properties in dog rib. J Bone Miner Res. 2000;15:613-620. 26. Burr DB. The contribution of the organic matrix to bones mechanical properties. Bone. 2002;31:8-11. 27. Burr DB, Turner CH. Biomechanical measurements in age-related bone loss. In: Rosen CJ, Glowacki J, Bilezikian JP, eds. The Aging Skeleton. San Diego, Ca: Academic Press Inc; 1999:301-311. 28. Currey JD. The effect of strain rate, reconstruction and mineral content on some mechanical properties of bovine bone. J Biomech. 1975;8:81-86. 29. Currey JD, Brear K, Zioupos P. The effects of aging and changes in mineral content in degrading the toughness of human femora. J Biomech. 1996;29: 257-260. 30. Follet H, Boivin G, Rumelhart C, Meunier PJ. The degree of mineralization is a determinant of bone

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43. Boivin G, Lips P, Ott SM, Harper KD, Sarkar S, Pinette KV, Meunier PJ. Contribution of raloxifene and calcium and vitamin D3 supplementation to the increase of the degree of mineralization of bone in postmenopausal women. J Clin Endocrinol Metab. 2003; 88:4199-4205. 44. Boivin G, Vedi S, Purdie DW, Compston JE, Meunier PJ. Influence of estrogen therapy at conventional and high doses on the degree of mineralization of iliac bone tissue: a quantitative microradiographic analysis in postmenopausal women. Bone. 2005;36: 562-567. 45. Meunier PJ, Roux C, Seeman E, et al. The effects of strontium ranelate on the risk of vertebral fracture in women with postmenopausal osteoporosis. N Engl

J Med. 2004;350:459-468. 46. Reginster JY, Seeman E, De Vernejoul MC, et al. Strontium ranelate reduces the risk of nonvertebral fractures in postmenopausal women with osteoporosis: Treatment of Peripheral Osteoporosis (TROPOS) study. J Clin Endocrinol Metab. 2005;90:28162822. 47. Farlay D, Boivin G, Panczer G, Lalande A, Meunier PJ. Long-Term strontium ranelate administration in monkeys preserves characteristics of bone mineral crystals and degree of mineralisation of bone. J Bone Miner Res. 2005;20:1569-1578. 48. Ammann P, Rizzoli R. Bone strength and its determinants. Osteoporos Int. 2003;14(suppl 3):13-18. 49. Wang XF, Duan Y, Beck TJ, Seeman E. Varying

contributions of growth and ageing to racial and sex differences in femoral neck structure and strength in old age. Bone. 2005;36:978-986. 50. Duan Y, Wang XF, Evans A, Seeman E. Structural and biomechanical basis of racial and sex differences in vertebral fragility in Chinese and Caucasians. Bone. 2005;36:987-998. 51. Zysset PK, Guo XE, Hoffler CE, et al. Elastic modulus and hardness of cortical and trabecular bone lamellae measured by nanoindentation in the human femur J Biomech. 1999;32:1005-1012. 52. Hengsberger S, Boivin G, Zysset PK. Morphological and mechanical properties of bone structural units: a two cases study. Int J Japan Soc Mechanical Engineers. 2002. Series C;45:936-943.

DTERMINANTS

DE LA QUALIT OSSEUSE

a rsistance osseuse est dfinie comme la charge maximale applicable avant la survenue dune fracture. Celle-ci varie en fonction dun certain nombre de facteurs, tels que la masse, la taille, la gomtrie, la microarchitecture, mais galement les proprits matrielles intrinsques du tissu osseux. Ces dernires comprennent le degr de minralisation osseuse et les caractristiques de la matrice organique (orientation et structure chimique des fibres de collagne), laccumulation de microlsions osseuses (apparition et progression de microfissures) ainsi que lapoptose des ostocytes. La qualit osseuse en gnral et le degr de minralisation osseuse sont tous deux profondment influencs par le taux de remodelage osseux. Ceci peut expliquer les modifications de lincidence des fractures et laugmentation de la densit minrale osseuse et de la rsistance osseuse appa-

raissant indpendamment de toute modification de la microarchitecture osseuse et du volume de la matrice. Lintrt croissant port lvaluation des dterminants de la qualit osseuse reflte limportance de la substance minrale osseuse dans la physiopathologie de lostoporose et dautres pathologies osseuses et a conduit la redcouverte de la dimension minrale de los qui avait t relgue dans loubli pendant de nombreuses annes. Cette dimension fait intervenir des paramtres tels que le degr de minralisation osseuse ; lindice dhtrognit de distribution de la minralisation ; les proprits mcaniques du tissue osseux (testeur de microduret) ; la taille et la maturit des cristaux ; ainsi que le degr de maturation du collagne (microspectroscopie infrarouge par transforme de Fourier).

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Christian RGNIER, MD Praticien Attach des Hpitaux de Paris Socit Internationale dHistoire de la Mdecine 9, rue Bachaumont 75002 Paris, FRANCE (e-mail: dr.christian.regnier@wanadoo.fr)

French medicine in Russia

A tale of passion
b y C . R g n i e r, F r a n c e

he first Russian to obtain his degree of doctor of medicine was a certain Posnikov who received his degree at Padua in 1692.1 This anecdotal and controversial event marks the beginning of the history of Russian medicine. Up until the 18th century, there was no organized medical teaching in Russia. In the absence of traditional Russian medicine, foreign doctors practiced at the imperial court, and also looked after the families of aristocrats and the wealthy bourgeois. At the beginning of the Age of Enlightenment, and encouraged by the enlightened czars, Russia became a land of knowledge and expertise. The first Russian doctors were now taught in their own country, but still had to go abroad to perfect their knowledge and defend their theses. These doctors had a good reputation and specialized in certain fields of which they became masters: neurology, physiology, ophthalmology, epidemiology, pediatrics, and hygiene. Russian doctors in the face of German competition At the beginning of the 18th century, during the reign of Peter 1, a network of lazarets, apothecaries, hospitals, and medical schools began to spread across the Russian landscape. Organized, regulated, and financed by the state, medicine began to be taught in Moscow in 1706, to be followed by Saint Petersburg, Kronstadt, Barnaul, and Elizabethgrad. These institutions produced mainly military doctors, and taught Western medicine with the accent on practicality, but they did not award doctoral degrees. Everything changed in 1776 when the czarina Catherine II the Great transformed the Moscow medical school into a faculty. In order to launch this new project along western lines, the czarina consulted the French philosopher Denis Diderot who in 1775 sent her a Plan for a university [of medicine] in which he recommended

F
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or a long while medicine in Russia was the stamping ground of European doctors, then, at the beginning of the 18th century, medical schools were established in Moscow and Saint Petersburg. The first Russian doctors could now practice their art in their own country, but they still had to go abroad to acquire their doctorates. The czars and czarinas in the Age of Enlightenment were open to foreign influences, and wanting to modernize Russia they sought the assistance of German and French professors to teach in the newly created medical schools. The choice of either German or French instructors was more or less haphazard, and could depend on family history, personal affinity, or the origins of the Russian sovereigns. Medico-scientific exchanges between France and Russia flourished in the Age of Enlightenment, were almost nonexistent under Napoleon I, and took off in the middle of the 19th century under the influence of the great French scientists like Claude Bernard, Jean-Martin Charcot, and Louis Pasteurall of them strongly pro-Russian. However, Franco-Russian relations, including in the field of medicine, always seem to have been subject to hazard. With the exception of the short-lived Franco-Russian alliance of 1891, nothing was organized or programmed officially. Everything was a question of intuition, enthusiasm, disappointment, or sudden impulse.
(see French abstract on page 87)

Medicographia. 2004;26:78-87.

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Czar Peter I the Great (1672-1725), portrait in glass mosaic, by Mickhail Lomonosov. Lomonosov, the son of a fisherman who became a self-taught scientist, founded Moscow University in 1755. Hermitage Museum, St Petersburg. Hermitage Museum.

that there should be seven chairs of which two should be devoted to practical medicine. When the faculty opened, six chairs had been assigned to professors from Holland, Germany, and England (the French professor declined to accept the honor). The Russian faculty decided to adopt Latin nomenclature for anatomy, thus forcing Western works to be adapted. Around 1780, the first Russian professors of medicine began to replace their European counterparts. Nonetheless, a considerable number of foreign practitioners remained in Russia until the first half of the 19th century. In 1809, a census revealed that out of 2596 doctors in the empire only 1187 (45%) were of Russian origin.2-8 In 1888, Doctor Georges Dujardin-Beaumetz, aided by his Russian student Winocourov, drew up a register of medical schools in Russia. He listed nine active medical faculties: Moscow, Karlov, Kiev, Odessa, Kazan, Dorpat, Warsaw, Tomsk, and Saint Petersburg. Students had to pay for tuition, and the curriculum lasted 5 years for basic medicine (the lekars). Doctor Dujardin-Beaumetz estimated the number of Russian doctors to be about 15 000, of which 750 were women.9 The foreign doctors were usually German or Dutch. The fact that the czars did not speak Russian, the pro-German policy of Peter I the Great, and the reigns of the German-born czars like Peter III who was raised in Kiel, and that of his wife Catherine the Great (born in Stettin, the daughter of the Prince of Anhalt-Zerbst), favored the establishment and spread of German medicine in Russia. Up until 1785, Russian medical students had to finish their studies and defend their theses at the Open University of Strasbourg (Straburg in German), which accepted students from Alsace, Switzerland, and Germany. The Russian doctor Lepekhin who studied in Strasbourg from 1762 to 1767, wrote:
As far as medicine is concerned, I could not wish for better; here, in Straburg, there are great advantages for medical students compared with other universities () There are two hospitals, one military and the other civilian, where students are welcomed and can study diseases.

The reputation of Strasbourg was based on the quality of its practical teaching, particularly the dissections and experiments in physiology. From 1785 to 1787, there were 44 Russian medical students out of a total of 125 undergraduates. A great many of the Russian medical pioneers studied and defended their theses in Strasbourg. However, during the Revolution, teaching of medicine in France collapsed and

Map of Saint Petersburg (1737, anonymous). Founded in 1713 by Peter I the Great, the Venice of the Norththus called because of its numerous canals and over 500 bridgesbecame the capital of the Russian Empire in 1715, though the period of its greatest development took place under empresses Anna Ivanovna (1730-1740) and Elizabeth Petrovna (1741-1762). In 1725, the czar founded the first Academy of Sciences, which was to be transferred to Moscow in 1934. Courtesy of Historic Cities Research Project http://historic-citiesKhuji.ac.il. The Hebrew University of Jerusalem & The Jewish National and University Library.

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Strasbourg did not escape the slaughter, especially since its statute of political autonomy vanished in the upheaval. For Russian medical students, the new pole of attraction was Berlin where an institute was specially created for their needs. In 1802, Czar Alexander I decided to reopen the faculty of medicine in Dorpat (now Tartu in Estonia) where teaching was conducted in German, the scientific language of the 19th century. Dorpat was noted for medical and scientific exchanges between Russian- and German-speaking Slavs. In 1871, after the defeat of the French by Prussia, Russian students returned to Strasbourg to complete their studies (Alsace was occupied by Germany until 1918).2,3,5,7,9-11 In the 19th century, the omnipresence of German doctors was often depicted with irony by Russian writers. In The Dead Souls, Nicolas Gogol mocked Christian Ivanovitch, a German doctor in a provincial Russian hospital, who could not speak Russian:
Man is not very complicated: if he has to die, he will die anyway; if he is going to get better, he will get better anyway. In any case, Christian Ivanovitch would have had difficulty explaining anything to his patients, since he can only gabble in German.12

Medical Faculty of Straburg (German spelling), which attracted many aspiring Russian doctors. Engraving by Perrin (1840), showing the University premises, formerly the Foundlings Hospice. Coll. Inter-Activits.

Another Russian author, Alexandre Ghertsen, described in Who is Guilty? the sad fate of Doctor Cruciferski, a Russian doctor who never had sufficient clients:

Cruciferski dragged himself from one end of Russia to the other and finally settled in a country town. To begin with he had enough clients. The dignitaries and landed gentry would have preferred to be treated by a German doctor. But, fortunately for Cruciferski, there was no German on hand (except for a clockmaker).13

In War and Peace (1869), Leo Tolstoy also alluded to German doctors who could not speak Russian. After breaking off her engagement, Natacha became ill:
the doctors who came to treat her, sometimes alone, sometimes in a group, discussed furiously in French, German, and Latin, criticized each other, prescribed medicines of every sort against all the diseases they knew, but it never occurred to any of them that they hadnt a clue abouch which disease Natacha was suffering from.14

Franco-Russian relations: between enthusiasm and deception Aware of the archaic state of Russian society, still too feudal and under the thumb of a powerful bureaucratic hierarchy, Czar Peter I the Great decided to breathe a touch of modernism into his vast empire. Wishing to give Russia a window on Europe, he built Saint Petersburg on the banks of the Baltic. Drawing inspiration from Amsterdam, where he had studied navigation, Peter I wanted his capital to be as sumptuous as Versailles, and naturally chose French architects. In his History of Russia Under Peter the Great, Voltaire explained that the czars sobriquet was given to him because he had the courage to take on the enormous tasks that had never even entered the minds of his predecessors. Hoping to form an alliance against Sweden, and wanting to marry his daughter Elizabeth, aged 7, to little Louis XV, aged 6, the czar remained in Paris from 4 May to 20 June 1717. He visited hospitals, the Jardin des Plantes, the Academy of Science, and witnessed an operation for cataract. Not bothering much about protocol, he shocked the court with his unpolished manners. Despite initial hopes, the visit did not stimulate scientific exchanges between the two countries, nor did it foster political relations (there was no marriage), perhaps because the czar could not speak French, which became mandatory at the Russian court in the reign of his daughter, Czarina Elizabeth. The Saint Petersburg Academy of Science was established towards the end of the reign of Peter I the Great, and became a meeting place for European academics. In 1721, the king dispatched Schumacher, the academy librarian, to Paris with instructions to acquire surgical instruments, medical samples, and anatomical models. Schumacher was also to recruit experienced doctors and surgeons, among whom Duvernoy, a celebrated Parisian anatomist. However, not knowing much about this large rather rugged country and its customs, the doctors declined. During this period, the French Jesuits in Peking maintained close links with the Saint Petersburg Academy of Science (which inherited their library). The Jesuits, under Father Parennin, sent the academy samples of Chinese plants with antivenereal qualities. The daughter of Peter the Great, Elizabeth Petrovna, ascended the throne in November 1741 after a coup dtat fomented by the Marquis de la Chtardie, the representative of the king of France in Saint Petersburg. The marquis was backed up by Armand Lestocq, an adventurous doctor who bled the young czarina 80 MEDICOGRAPHIA, VOL 28, No. 1, 2006

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French man of letters and philosopher Denis Diderot (1713-1784) by Louis Michel Van Loo. Oil on canvas 81i 65 cm, 1767, Louvre Museum, Paris. Diderot was the Father of the Encyclopedia, the first volume of which appeared in 1751 and the 31st and last in 1776. In his later years, he was rescued from financial difficulties by Catherine II the Great. RMN.

(and taught her French). In 1759, the czarina acquired a surgical arsenal in Paris, which included an obstetrical manikin and numerous instruments covering all aspects of surgery. The inventory covered 44 pages and is conserved in the French National Library.3,8,15-17 Medical exchanges with France increased under Catherine II who enjoyed the services of a French doctor, Pierre Isaac Poissonnier, whose political mission seems to have occupied more of his time than his medical activity. Indeed, it was to her friend Voltaire passionately interested in medicine that the czarina turned for advice in 1768 on whether to be inoculated against smallpox. Catherine the Great could speak and write in French with elegance.
One speaks a purer French at the Empresss court than at Versailles, because there our beautiful ladies do not bother to learn the grammar

wrote Voltaire diplomatically. Aware of the modernizing influence of thought in the Age of Enlightenment, the czarina proposed unsuccessfully to dAlembert and Diderot that they should choose Riga or any other town in the empire for the printing of their Encyclopdie Raisonne des Sciences et des Arts (Rational Encyclopedia of Sciences and Art). In 1773-4, Diderot resided in Saint Petersburg for six months deluding himself that he could influence Catherine the Great and make her change her politics in Poland. However, the czarina contented herself with purchasing the philosophers library and in return he recruited French artists and doctors for her. Two historic events sapped the development of relations between France and Russia: the French Revolution and the invasion of Moscow by Napoleons Grande Arme in 1812. The beheading of Louis XVI appalled Catherine the Great, and the invasion of Russia by Napoleon was strongly resented by the Russian intellectuals who had been rather favorable to the ideas of the Revolution. Moreover, 1812 marked a turning point in Russia when all hope of reforming the regime went up in smoke with the burning of Moscow. In 1801, at the beginning of the reign of Alexander I, the czar had aroused considerable enthusiasm among the liberals for his efforts to reform serfdom and autocracy; however, in 1812, after the war with France, the Russian king adopted authoritarian politics before sinking into mysticism.1,4,6,17-19 In the first half of the 19th century, at a time when the anatomicoclinical method spread abroad by the Paris School was dominating medicine, in Russia the medical and scientific influence of France had grown more or less non-existent. Even the great military surgeon trained in Dorpat, Nicolas Ivanovitch Pigorov, who visited Paris in 1837, was not enthusiastic: From a surgical point of view, Paris did not impress me. The hospitals were gloomy and mortality was high. 2 Claude Bernard and Jean-Martin Charcot: the Russomania period In the second half of the 19th century, Claude Bernard, Louis Pasteur, and JeanMartin Charcot, three universally recognized representatives of French science and medicine, attracted young Russian doctors and scholars to Paris. As was usual in France at that time, the three men were profoundly Russophile. This sympathy for Russia and Russians was nursed by the presence of numerous exiled Russian writers who had MEDICOGRAPHIA, VOL 28, No. 1, 2006 81

Meeting between Napoleon I and Czar Alexander I and the sovereign vassals of Germany, at Erfurt (27 September to 14 October 1808). The Czar agreed to lend Napoleon his support in the event Austria declared war to France. In exchange, Russia would annex Finland and the Romanian provinces of Moldavia and Walachia. Painting by Nicolas Gosse. Museum of French History, Versailles. Muse de lHistoire de France, Versailles.

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settled in Paris, among them Turgenev. Claude Bernard, the founder of experimental medicine, was the most famous of the French physiologists; however, his works were competing with those of the German experimenters such as Karl Ludwig and Justus von Liebig, the founder of organic chemistry. In this climate of increasing rivalry, Claude Bernard enjoyed receiving in his laboratory at the Collge de France young Russian savants. Among them was Ivan Mikhailovitch Setchenov, pioneer of Russian neurophysiology, who identified the inhibitory centers of spinal reflexes in 1865. His popular work, The Reflexes of the Brain (1863), was a great success in Russia and pointed the way for numerous researchers such as Pavlov. Other residents at Claude Bernards laboratory included the young Sergei Petrovitch Botkin who later taught experimental medicine at the Saint Petersburg Academy, and lie de Cyon who studied experimental physiology, focusing on the regulation of heartbeat by the sympathetic nervous system. From 1869, Claude Bernard had as assistant and confidante, Marie Sarah Raffalovitch, who was born into a family of Russian financiers in Odessa. She could speak eight languages and translated his scientific and medical articles. Bernard wrote nearly 480 letters to the young woman whom he met during one of his courses at the Collge de France. The letters are conserved in the Claude Bernard Museum in Saint Julien-en-Beaujolais and portray the solitude of this great scientist who could always rely on the comprehension and disinterested friendship of Marie Raffalovitch.10,15,18,20

Louis Pasteur (1822-1895). The iconic French chemist, father of modern bacteriology. Painting by Edelfeldt. Institut Pasteur, Paris.

The rabid Russians from Smolensk, at Pasteurs laboratory at the cole Normale, in the rue dUlm, in Paris, in 1886: the early days of international humanitarian medicine. Muse de lInstitut Pasteur, Paris.

Famous for his lessons on hysteria and hypnosis, the neurologist Jean-Martin Charcot attracted Russian doctors to the Salptrire Hospital who went on to found the highly respected Russian schools of neurology and psychiatry. One of them was Vladimir Bechterev, who held the position of professor and chair of mental and nervous diseases in Saint Petersburg, and described the cortical localization of motor functions in 1887. Another Russian student, Alexis Kojevnikov, frequented Charcots department, and later in 1893 described focal epilepsy. Charcot, a connoisseur of Russia and friend of Grand Duke Nicholas, was summoned to Russia to treat the royal family. He was regularly invited to dinner parties by the Daudets where Turgenev, inspired by champagne, enthusiastically declaimed Russian folk tales.18,21 Pasteur at the time of the Franco-Russian alliance Louis Pasteur played an important role in the strengthening of scientific relations between France and Russia. A fervent patriot, considering the 1870 defeat at the hands of Germany a profound humiliation, and now constantly having to compete with German bacteriologists, Pasteur was as passionately pro-Russian as he was anti-German. Already in 1881, Pasteur contemplated going to Russia to study an infection known as Siberian plague that he suspected to be quite simply anthrax. On July 1, in a letter to Count Orloff, Russian Ambassador in Paris, he wrote: I take the liberty to inform Your Excellency that I have discovered the vaccine against anthrax. In November, 1883, Pasteur wrote to the Saint Petersburg Academy of Science proposing that they join forces to study diseases of the silkworm.4 When Pasteurs rabies vaccine had proved its efficacy after the first two successful tests in July and October 1885, the news traveled the length and breadth of Russia where the disease was a permanent menace. On March 1, 1886, Pasteur published the first statistics based on 350 humans vaccinated against rabies. The same month, 19 Russians from the region of Smolensk were dispatched to Paris after having been bitten by a rabid wolf. On their arrival in the capital, five of them, in a very serious state, were hospitalized at the 82 MEDICOGRAPHIA, VOL 28, No. 1, 2006

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Czar Nicholas II (1868-1918) and his wife, the Princess of Hesse (ne Alexandra Feodorovna), and their children. Engraving published in Le Petit Journal, a French newspaper, in July 1901. The oval framedpainting behind the Nicholas II shows his father, Alexander III (one of Paris most beautiful bridges is named after him). Coll. Inter-Activits.

Htel Dieu. Pasteur immediately applied his vaccination protocol and saved sixteen of the patients. Their long voyage, their strange garments, and their successful treatment made the Russians from Smolensk a sensation and everyone wanted to interview them.22-24 Since the efficacy of the rabies vaccine seemed proven, prince Alexander of Oldenburg decided to found an antirabies laboratory in Saint Petersburg and thus produce the vaccinations on site using Pasteurs method. On July 14, 1886, Adrien Loir, Pasteurs nephew, set sail for the imperial city with a cage containing two rabbits with rabies. The first two Russian antirabies centers were established in conjunction with the Pasteur Institute at Saint Petersburg and Odessa in 1886. Stimulated by research on the antirabies vaccine, many medical and scientific ideas were exchanged between the Russian and French biologists.22,23 On November 14, 1888, the Pasteur Institute was inaugurated in Paris in the presence of Prince Oldenburg and the Grand Dukes Vladimir and Alexis of Russia who had contributed generously to the public subscription for the foundation of the institute. During the ceremony, Pasteur wore the grand cross of Saint Anne of Russia awarded him by the czar for saving the Smolensk Russians. Pasteur had written to Nikolai Federovitch Gamaleia, the future head of the Russian Institute:
You are going to direct Russian research, which I hope will prosper. You know my warm feelings for your country which extend well beyond the walls of the laboratory.

Russian researchers were the first foreigners to be invited to work at the Pasteur Institute.4,25 This blossoming of scientific relations between France and Russia was officially reinforced in 1891 with the signing of the Franco-Russian treaty. This pact freed the two countries from a certain diplomatic isolation. In addition, France hoped that the treaty would put pressure on Germany. However, Czar Alexander III was far from being an enlightened sovereign. Having been traumatized by the assassination of his father

XAVIER GALEZOWSKI, A MASTER OF OPHTHALMOLOGY

Born in Lipowice (Poland), Xavier Galezowski (1833-1907) studied medicine in Saint Petersburg where he defended his thesis on the use of von Helmholtzs ophthalmoscope, for which he received a gold medal (and later perfected the instrument). In 1859, he accompanied his uncle, Sverin Galezowski, who was also a doctor, to Paris. For the next five years, the young Xavier was assistant to the famous Parisian ophthalmologist, Louis-Auguste Desmarres. In 1865, he presented his dissertation, An Ophthalmoscopic Study on the Alterations of the Optic Nerve and the Cerebral Alterations on Which They Depend. In 1867, he opened his own private ophthalmological clinic in the rue Dauphine. In thirty years, nearly 260 000 patients were treated in this clinic, which served as a model for French ophthalmology. Galezowski was decorated with the Lgion dhonneur after the Franco-Prussian war, and in 1872 founded the Journal of Ophthalmology, the first French journal devoted to this specialty, which later became the Ophthalmology Collection. In 1886, he invented plaques of gelatin moistened with a mercury salt (the forerunner of contact lenses) to protect the cornea after operations for cataract. He also gave his name to a round-ended catheter for exploring the lachrymal glands. In 1872, he published a Treatise on the Diseases of the Eye (464 figures), in 1876 an Illustrated Treatise on Ophthalmoscopy, and in 1902 Clinical Lessons in Ophthalmology. Finally, in 1883, he proposed the use of optometric and chromatic scales to measure visual acuity.28

Galezowskis ophthalmoscope: method of use. Extracted from: Trait des Maladies des Yeux [Treatise on the Diseases of the Eye], 1875, by Xavier Galezowski. BIUM.

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Cover of the Russian-language version of the monthly medical journal Paris-Mdical, 1913, published in France and Russia. Paris-Mdical, later merged with the Journal des Praticiens to become the Revue du Praticien. In the central box, the last line states that that the entry of this journal into Russia is authorized by circular No. 235 of the Interior Ministry. Coll. Inter-Activits.

Alexander II, he adopted a harsh authoritarianism, kept Russian society under his thumb, and imposed a forced russianization on the country. Despite that, official medical links between France and Russia kept flourishing. Thus, from 1896 to 1902, the Russian Archives for Pathology, Clinical Medicine, and Bacteriology were published in Saint Petersburg in several languages including French; France was instrumental in getting the Twelfth International Medical Congress held in Moscow in 1897; a Russian edition of the journal Paris Mdical was published from 1910. Though France had succeeded in imposing its superiority in scientific research on Russian savants, the medical field was still dominated by the Germans. Very few French doctors settled in Russia; however, in 1903, Doctor Marcou, senior doctor at the French Hospital in Petrograd, was called to the bed of a young patient:
With rather startling frankness, she told me she was astonished to see a French doctor working in Russia. A dancer, a hairdresser, or a good cook, those were the three trades exported to Russia and elsewhere () It was with these words, which were rather unflattering for my self-esteem, that my patient greeted me. () For them [the Russians], good medical care and doctors exist only in Germany () The microscopes and all the laboratory paraphernalia impress them enormously.

It is true that medical works published in France were known to the Russians thanks only to German reviews, since French medical journals could not be found outside Saint Petersburg. Marcou deplored the lack of audacity of the French:
the German suppliers provide everything up front (medical material and books), and are happy to be paid later; whereas French suppliers demand down payment. () German interests are winning in all countries thanks to their admirable organization.10,11

Mechnikov, the most French of the Russian scientists Born in 1845 in Ivanoska, near Kharkov, the son of a policeman and a Jewish mother, Ilya Ilich Mechnikov studied zoology in Saint Petersburg, then microbiology in Giessen, Gttingen, and Munich. As a result he had perfect mastery of the microscopic techniques at which the German bacteriologists excelled: cellular coloration, studies of artificial milieus, and optics. He had also carried out zoological experiments in Naples and Denmark. In 1882, fleeing the pogroms perpetrated by the police of Alexander III, Mechnikov and his family moved to Italy, France, and North Africa. In Messina, he discovered phagocytosis, the foundation of modern immunology.
One day when the whole family was at the circus, I was observing the life of mobile cells of a transparent starfish larva when I was struck by a sudden thought. The idea came to me that similar cells could serve as a defense for the organism against harmful intruders.

He then pierced the starfish larvae with rose thorns and observed cellular digestion. Transposing his findings to man, he realized that the phagocytosis served to combat infection. Mechnikov communicated the results of his experiments to his former teachers at the German universities: the reception was lukewarm and even hostile.22,24,26 Later, when directing the Institute of Microbiology in Odessa, and again a victim to anti-Jewish persecution, Elie Mechnikov set off in 1887 on another voyage to Europe. His main stop was Paris where after a decisive meeting with Pasteur he planned to settle permanently. The two men had at least two points in common: they both possessed an exceptional scientific intuition and both had suffered from the hostile reactions of the medical profession. By nature austere and reserved, Pasteurwho knew the work of Mechnikov on phagocytosiswas immediately won over by the strong personality of the Russian scientist, whom he received at home with his wife Olga. Though it was not easy to make friends with Pasteur, the two men esteemed each other very highly. Moreover, the French savant was not averse at receiving an enemy of Robert Koch, his archrival on the bacteriological battlefield.22,23,25,26 In his newly inaugurated institute, Pasteur proposed in 1888 that Mechnikov should direct the morphological microbial forms department that occupied the whole of the 4th story. Louis Pasteur Vallery-Radot, Pasteurs son-in-law, described the Russian scientist in action: 84 MEDICOGRAPHIA, VOL 28, No. 1, 2006

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SERGE VORONOFF: CRAZY SCIENTIST OR PRECURSOR OF GENIUS?

Between the two Great Wars, Doctor Serge Voronoff (18661951) hit the headlines. The expression going to see Voronoff meant going to be rejuvenated or wanting to recover ones virility. Samuel Abrahamovitch (aka, Sergey, Serge) Voronoff was born into a rich Jewish family at Voronezh, some 600 miles south of Moscow. Suspected of being a political agitator, the young Voronoff, who spoke excellent French, abandoned his village in February 1885 to study medicine in Paris (he was naturalized French in 1895), with his brother George, who was to die at Auschwitz. He became assistant to the famous surgeon Jules Pan and defended his medical thesis in 1893. After spending seven years in Egypt, where he reorganized surgery, he embarked in 1910 on a ship to New York. There he joined the famous Rockefeller Institute where he made friends with the French surgeon Alexis Carrel, who taught him the technique of transplanting. On his return to France at the beginning of the Great War, Voronoff performed bone autografts on soldiers at the Russian Hospital that Nicholas II had put at Frances disposal. To general skepticism, Voronoff succeeded in November 1915 in grafting fetal membranes on badly burned soldiers. Convinced that the role of the testicles was not confined to reproduction, but that they acted on skeletal, muscular, nervous, and psychological development as well, he started on a 10-year course of experimentation on animals and, on October 5, 1922, at the thirty-first Surgical Congress, Voronoff, photos in hand, presented his surgical technique for rejuvenating patients. His anthropoid-anthropic grafting technique consisted in transplanting the testicle of a chimpanzee into the
Monkey business? In spite of the apparent incongruity, Voronoff carried out what in effect was the first xenograft. He made important contributions to such current hot topics as gerontology and the biology of aging, endocrinology, hormone replacement therapy, and organ transplants. Learned articles on this fascinating pioneer are being published to this day. Engraving from Le Petit Journal in October 1922.

ual hormones for an extended period of time, as opposed to opotherapy, which required repeated injections with unconvincing results. The first (official) transplant took place on June 12, 1920, to be followed by upwards of 50 operations, carried out at private clinics in Auteuil, Neuilly, and Paris. Louis Dartigues, President of the Paris Surgeons, and an admirer of Voronoff, reported in June 1924:
The renewal of vitality is marked by the reawakening of intelligence, a more vivid imagination, a sharper memory, an increased speed of action, and a feeling of euphoria.

Voronoffs split n splice technique of grafting monkey testicle slices to human testicles drew both interest from his peers, and ridiculeas here in a satirical medical journal called Chanteclair dated 1910 (No. 59), but it also made international headlines. Time magazine devoted two articles to the famed gland-grafter in 1923 and again in 1926.

subject to be rejuvenated. After administering a local anesthetic (Novocain), Voronoff cut the chimpanzees testicle into six parts, which remained attached to the spermatic cord. Each of the 6 grafts was then inserted into the patients testicle. The patient remained recumbent for several days, then two or three months later the alleged miracle occurred. According to Voronoff, glandular transplants would allow the production of sex-

By 1925, the revitalizing grafts were already a great success. Politicians, intellectuals, industrialists, scientists, doctors, and artists flocked to Voronoff to get themselves rejuvenated. The demand for chimpanzees to satisfy the laboratory of Experimental Surgery at the Collge de France directed by Voronoffsoon exceeded supply. Mr Carde, governor of French West Africa, was obliged to regulate the exportation of chimpanzees in order to curb poaching. Voronoff was already planning the creation of a farm in the south of France for the breeding of chimpanzees, which he built in Menton. In 1926, Voronoff was decorated with the Lgion dhonneur (Legion of Honor). By the early 30s, more than 500 men had been operated on in France, and thousands of others throughout the world. Despite this success, the proliferation of emulators abroad and the numerous journals praising the method in France finally began to worry the medical community. Serious reservations were voiced concerning the scientific basis of the procedure, whose claims of success were based only on the presentation of photographs taken before and after. Turning his attention to women, Voronoff implanted monkey ovaries to women. Standing on increasingly shaky ethical ground, he also transplanted a womans ovary in Nora, a female monkey, which he then proceded to inseminate with human sperm (his own?)fortunately to no avail. The use of surgery for rejuvenation gradually went out of fashion, but Serge Voronoff pursued his studies on the grafting of endocrine tissues. In 1928, he wanted to graft the kidney of a decapitated prisoner on a young girl suffering from renal failure due to tuberculosis, but the state prosecutor did not allow it.27

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with his imagination working overtime, living, like Doctor Faust, in a laboratory swamped with books, notes, and drawings, in the middle of which guinea pigs and rabbits scamper around, while in the aquariums axolotls dream of their tropical seas, and in a nearby research room giant crocodiles languish.

Ilya Ilich Mechnikov (1845-1916), in his laboratory in Paris. Muse de lInstitut Pasteur.

Charles Nicolle, Nobel prize in medicine (1928) for his work on the transmission of typhus, rubbed shoulders with the Russian scientist and noted: I cannot say whether he was a poet or a scientist, since his ideas were so extravagant. The Belgian doctor Jules Bordet, Nobel Prize in 1919 for his discovery of humoral immunity, also worked in Mechnikovs laboratory.23,24,26 With great ease, Mechnikov switched from zoology to human pathology, and dubbed himself the zoologist who got lost in medicine. Returning to his studies on phagocytosis, he applied his theories on cellular immunity to the pathogenesis of cholera, leprosy, typhus, anthrax, tuberculosis, and syphilis. As early as 1889, Mechnikovs theory of cellular immunity was accepted by the Pasteur Institute, which made it its official doctrine that a system of phagocytes kept permanent watch to prevent infection. Mechnikov distinguished microphages (white corpuscles) and macrophages (cells located in certain organs). The results of his studies were published in two landmark works in the history of immunology: Lessons on the Comparative Physiology of Inflammation (1892) and Immunity in Infectious Diseases (1901). In 1904, he became assistant director of the Pasteur Institute, in charge of scientific studies. In 1908, he shared the Nobel Prize in medicine, for works on immunization, with the German biologist Paul Ehrlich who pioneered humoral immunity.24-26 Mechnikov encouraged several of his Odessa students to join him, among them Waldemar Khavkine, a young zoologist (and active opponent of the czarist regime) who was given the post of Institute librarian. He worked evenings in the laboratory of his mentor on vibrions, and in 1892 developed the first vaccine against cholera. Just like Pasteur, Mechnikov had a paternalistic approach to his students. In 1917, despite financial difficulties at the Institute due to the war, most of the Russian students remained in Paris and pursued the immunological work of their mentor. These included Alexandre Besredka, who became Mechnikovs successor at the Institute, as well as Nicolas Gamaleia, Serge Metalnikov, and Serge Winogradsky.23-26 The strong links between scientists based in Russia and the Pasteurians was reflected in the large number of articles published in Russia supporting the work of Pasteur and his students, and, more anecdotally, in the spate of Russian towns that boasted a Pasteur street. A highly symbolic testimony to the strong medical ties between Russia and France was, so to speak, carved in stone in the heavens, when the Russian Academy of Science gave Pasteurs name to site N 393 of their Cartographic Atlas of the Moon.
REFERENCES 1. Gantt HW. Russian Medicine. New York, NY: Paul B. Hoeber; 1935. 2. Debono L. La Mdecine en Russie de 1801 1917. Medical thesis. Besanon, France. 1997. 3. Huard P, Wong M. Les Activits Mdicales en Russie au XVIIIe Sicle. Concours Med. 1967;89:9033-9038. 4. Efremenko A. Histoire de la collaboration scientifique francorusse. In: Histoire des Sciences Mdicales. 1972;6(chap 3):173186. 5. Efremenko A. Relations mdicales franco-russes luniversit de Strasbourg. In: Comptes Rendus du 92e Congrs National des Socits Savantes Strasbourg et Colmar en 1967. Paris, France: Bibliothque Nationale; 1969 ;1. 6. Garrison FH. Russian medicine under the old regime. Bull N Y Acad Med. 1931;7,9:693-734. 7. Grmek MD. Les bases historiques de l'enseignement mdical en Russie. Episteme. 1970;4:131-145; 334-356. 8. Goldwin RM. Peter the Great and Russian medicine. Surg Gynecol Obstet. 1960;3:523-525. 9. Dujardin-Beaumetz G. De l'enseignement mdical et de la pratique mdicale en Russie. Gazette Hebdomadaire Med Chir.1888; 51:809-811 ; 52:821-623. 10. Marcou. LAllemagne mdicale en Russie. Arch Gen Med. 1903;80:1825-1828. 11. Fuster. Organisation des tudes mdicales en Russie. Montpellier Med. 1904;19:455-463. 12. Gogol N. Les mes Mortes [Dead Souls] Paris, France: Gallimard; 1996 (1st ed 1842) 13. Herzen A. Qui la Faute ? Moscow, Russia: Progress Eds, 1970 (premire dition 1848).

14. Tolstoy L. Guerre et Paix [War and Peace]. Paris, France: Gallimard; 1993 (1st ed 1869). 15. Rgnier C. La mdecine russe au XVIIIe sicle. Panorama Med. 1986;2375:41. 16. Huard P, Wong M. Mdecins trangers et mdecine russe au XVIIIe sicle. Ouest Med. 1964;17:705-711. 17. Fron B. La Galerie des Tsars: Dictionnaire des Chefs Suprmes de la Russie. Paris, France: Les ditions Noir sur Blanc; 2004. 18. Taton R. Sur lhistoire des relations scientifiques francorusses. Rev Hist Sci. 1970;23:257-264. 19. Fumaroli M. Quand LEurope Parlait Franais. Paris, France: ditions de Fallois; 2001. 20. Bernard C. Lettres Madame R. Saint Julien-en-Beaujolais, France: Fondation Mrieux et Jacqueline Sonolet; 1974. 21. Thuillier J. Monsieur Charcot de la Salptrre. Paris, France: Robert Laffont; 1993. 22. Hutchinson JF. Tsarist Russia and the bacteriological revolution. J Hist Med Allied Sci. 1928;21:1406-1408. 23. Moulin AM. LAventure de la Vaccination. Paris, France: Fayard; 2003. 24. Dubos R. La Leon de Pasteur. Paris, France: Albin Michel; 1987. 25. Debr P. Louis Pasteur. Paris, France: Flammarion; 1994. 26. Moulin AM. Le Dernier Langage de la Mdecine. Histoire de lImmunologie de Pasteur au Sida. Paris, France: PUF; 1991. 27. Real J. Voronoff. Paris, France: Stock; 2001. 28. Amalric P. The Galezowski tradition in Paris. Documenta Ophtalmologica. 1999;98: 105-113.

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MDECINE FRANAISE ET LA RUSSIE UNE HISTOIRE PASSIONNELLE

ongtemps la mdecine fut exerce en Russie par des mdecins europens. Au dbut du XVIIIe sicle, des coles de mdecine furent fondes Moscou et Saint-Ptersbourg; les premiers mdecins russes purent alors exercer leur art chez eux mais ils devaient encore soutenir leur doctorat ltranger. Ouverts aux changes avec ltranger, souhaitant moderniser la Russie, les tsarines et les tsars du sicle des Lumires sassurrent du concours de professeurs de mdecine allemands et franais pour enseigner dans ces coles nouvellement cres. Ce furent les alas de lhistoire, le jeu des alliances, les affinits personnelles ou les origines familiales des souverains russes qui dterminrent souvent ces choix germanophiles ou francophiles. Intenses au sicle des Lumires, distants sous Napolon Ier, les changes mdico-scientifiques entre la France et la Russie se dvelopprent au milieu du XIXe sicle sous limpulsion de grands savants franais comme Claude Bernard, Jean-Martin Charcot ou Louis Pasteur anims de puissants sentiments russophiles. Les relations franco-russes y compris dans le domaine mdical semblent avoir toujours t soumises des alas passionnels ; lexception de lphmre trait dalliance franco-russe de 1891, rien ne fut vraiment organis ni programm. Tout ne fut quintuitions, exaltations, dceptions et coups de cur

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Isabelle SPAAK, journalist 37 rue des Plantes, 75014 Paris, FRANCE (e-mail: isabelle.sppak@wanadoo.fr)

When Russia spoke French

by I. Spaak, France

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uring a party on the banks of the Neva, the poet Pushkin was asked whether the woman he had been talking to for some time was intelligent. Ive no idea, replied the poet, we were talking French. This was in no way intended to be ironic, nor to express scorn. But is due to the fact that at the beginning of the 19th century French served as a special language. At that period it was used for conversation, but not to express ones feelings. In Saint Petersburg in 1807, Czar Alexander I concluded a treaty with Napoleon I in which they agreed to split Europe between them, while ignoring England entirely. The two powers signed the Treaty of Tilsit, with France taking the West and Russia the East. The treaty lasted for only a short period since Napoleon, blinded by his lust for conquest, set out a few years later on his ill-fated march to Moscow. However, at the time, France, its fashions, its art, and its language carried away the hearts in the Russian capital. The aristocracy ate, drank, dressed, flirted, and cultivated themselves in French, while the Russian language was reserved for ordinary people and personal matters. Though official correspondence and
The fame of the new city on the edge of the Baltic spreads in all directions, to Europe and Asia. View of St Petersburg: Japanese lacquered plaque copied from a painting by Mihail Ivanovich Mahaev (1717-1770). Chido museum. Courtesy of the National Museum of Japanese History (http://rekihaku.ac.jp). All rights reserved.

aint Petersburg was founded in 1703 by Czar Peter I who wanted to open up Russia to Western progress. By battling the Swedes and winning the swampy territory at the mouth of the Neva to build a port that would bear his name, Peter the Great opened up a trade route to the Baltic that gave him access to Europe and France. The French architect Jean-Baptiste Alexandre Leblond was entrusted with the task of designing the city along the lines of Versailles, and it is to him that we owe the lakeside scenery and the numerous canals. Peters daughter, Elizabeth, crowned empress in 1741, was like her father, an unconditional admirer of France and its arts. Architects, philosophers, actors, and musicians were invited to the burgeoning port or were consulted. The French Theater became the favorite rendezvous of the Petersburg aristocrats by the middle of the 18th century, and speaking French became a must for the nobility. From the beginning of her reign in 1762, Catherine II confirmed this predilection for European ways and particularly for the philosophy of the Enlightenment. Voltaire, Diderot, and Montesquieu were reference personalities for this enlightened but ironhanded czarina. Henceforth, in Saint Petersburg one spoke, thought, and amused oneself in French. This custom was continued under the reign of Alexander I (1801-1825) who, despite being a relentless opponent of Napoleon on the battlefield, kept up a mutually admiring relationship with his rival that was based on the French way of life. The vast majority of the aristocracy of the Russian capital chose to be Francophile long after the reign of Nicholas I who became emperor in 1825.
Medicographia. 2004;26:88-94. (see French abstract on page 94)

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social conversations were carried out in the language of Voltaire and Diderot, so close to the heart of Catherine II, a fervent believer in the philosophy of the Enlightenment, billets-doux and family letters were written in Russian. This complicated duality was mocked irreverently by Astolphe de Custine in his travel-journal cum scathing attack on Russia. Without any regard for Czar Nicholas I whose hospitality he had enjoyed from May to September 1839, and egged on by Balzac and the perfidious Talleyrand, the eccentric marquis penned Russia in 1839. The book mocked the Tatars who used two languages, but neither of them perfectly: one for social relations, the other for informal situations. Ironically, the first edition in 1843 was an immediate success in Russia as well as in France. In fact, this linguistic duality was used as a faade that enabled the nobility to mask their true feelings, which suited the Russian mentality perfectly. However, unaware of the future criticisms of the caustic Custine, Pushkin and his friends indulged themselves with Bordeaux wines and Veuve Clicquot champagne when they dined chez Dum, a famous restaurant that had succeeded in subtly marrying Russian and French dishes. In fact, though the nobility swore only by Paris, it was also in order to adapt the style to the Russian way of life. They copied and borrowed while at the same time insisting on the specificity of their own language. Indeed, there was no question of slavishly copying Gold snuff box with miniature portrait of Peter the Great (1727). French fashions. On the contrary. Those who did Kremlin Museums, Moscow. The Brigdeman Art Library. not know how to strike the happy medium were mercilessly mocked and dubbed copycats. Peter the Greats flowery French Though in the time of Catherine II the nobility had begun to take an interest in French ideas and art, it was nevertheless much earlier that Saint Petersburg had begun to gaze in the direction of France. Created by Peter the Great, the imperial city opened up the Baltic and gave Russia access to Europe. The city was officially born on May 16, 1703 when the two fortresses, Peter and Paul, were founded. But the vast building site was surrounded by swamps, at the center of which Peter the Great established his headquarters in a modest wooden house while the Peterhof Palace was being built. The czar had great ambitions for his city and planned to model it on the great Western cities and make Saint PetersMap of St Petersburg, 1738. Rue des Archives/The Granger Coll. burg a model of harmony. An enthusiastic traveler interested in marine matters and the art of war, he had visited naval shipyards in Holland and at Deptford in England (where he even did a stint, incognito, as a shipwright) and studied navigation in the Kremlin Naval Museum. Meanwhile, under appalling conditions, Russian peasants, and Finnish, Estonian, and Swedish prisoners toiled to create Peters dream port. The czar enjoyed wandering in the streets talking to strangers, whether noblemen or valets, and in this manner picked up some knowledge of various languages including French. Up to a point. Dubois, the minister of foreign affairs under Philip of Orleans, who met the emperor when he came to Paris in 1717, noted: When I speak to the emperor in French, I have to ask myself who on earth could have taught him our language. He does not know a single everyday word, but he uses expressions that would make a guardsman flinch. In Versailles, he swore so profusely, with such profanities, that even the grooms gaped. During a disastrous famine that raged in Russia, Peter I did not hesitate to abandon his fellow countrymen for the delights of Paris. And he enjoyed himself accosting strangers, investigating boutique backrooms, visiting museums, and inspecting the Louvres marble stores and the Gobelins tapestry workshops. He also enjoyed immersing himself in classical architecture, as well as chasing the pretty ladies in the alleys of the Versailles park. From Marly-le-Roi to the Invalides via Saint-Cyr, he visited all the centers of culture and the art of living. He also tried without success to marry off his daughter, Elizabeth, to the MEDICOGRAPHIA, VOL 28, No. 1, 2006 89

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Layout of the gardens and waterworks of the Peterhof Palace, by Jean-Baptiste Leblond. The center of the fountain features a water pyramid. Colored engraving by P. A. de St-Hilaire, 1774. AKG-images.

young Louis XV. To sum up, Peter I wanted France both for its cultural distinction and as a political ally. On his return to Saint Petersburg, he obliged men and women of social standing to club together as in Paris and organize pageants like those he had seen in Versailles. A French architect for Saint Petersburg Despite the fact that Italian, German, and Dutch architects had been requested to draw up plans for construction, the czar decided in 1716 to entrust the planning of his dream city to the Frenchman Jean-Baptiste Alexandre Leblond. The architect got to work immediately, set up workshops to provide planks, carved stones, metal castings, and locks. Above all he designed an aquatic labyrinth in the muddy earth snatched from the marshes over which blew a wind that nothing could stop. It is freezing cold in this lakeside city on the edge of the Baltic. Slowly the face of Saint Petersburg emerged. It was on the scale of the absolute power wielded by the sovereign who demanded pure lines, totally visible buildings, and rigorously majestic alignments to contrast with the medieval chaos of Moscow. He wanted to attract as much scientific, artistic, and intellectual knowledge as possible into his city destined for a glittering future. But much work remained to be done to establish this The Hermitage Theater, as seen from the Vassily Island, 1822. Color lithoorder, this vision of a perfect world that was being cregraph. Anonymous. Pushkin Museum, Moscow. The Bridgeman Art Library. ated ex nihilo. In winter the fog penetrated everywhere. In 1725, the year Peter the Great died, one hundred and fifty thousand men were sacrificed in the construction of four neighborhoods that were won from the forests, fields, and swamps. The apotheosis of Saint Petersburg and the peak of its diplomatic relations with France still lay in the future. After a succession of four sovereigns who reigned briefly, in 1741, Elizabeth Petrovna followed in the footsteps of her father and mounted the throne, thanks, it is said, to the French ambassador, who was not averse to supplement his diplomatic counseling with a little bit of courting of the future empress on the side. Czarina Elizabeth imposes French on the Russian nobility Elizabeth undertook vast works in the insalubrious city that had been the dream of her father. Its once sumptuous facades were already nearly in ruins and seem to have been built hastily simply to satisfy the insatiable appetite of a megalomaniac emperor. Elizabeth busied herself perfecting the image of the imperial city, giving priority to the construction of magnificent palaces among them the Winter Palaceand several churches, witnesses to her religious faith. Greatly influenced by French culture she built the French Theater and invited stars of the Comdie Franaise to perform. Elizabeth succeeded in imposing the language of Voltaire on Russian society, and even had Voltaire elected to the Saint Petersburg Academy of Science after he had publicly expressed his admiration for her:
View of the south faade of the Winter Palace, from Palace Square, by Bartolomeo Francesco Rastrelli (1700-1771). St Petersburg. The Bridgeman Art Library. I have praised Elizabeth of England, but what can I say of the empress who exceeds the queen in magnificence and equals her in virtue?

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In his acception speech on the occasion of his entry into another academy, this time on home turf, the French Academy, and after having expressed his affection for the city of Peter the Great, Voltaire praised in more than laudatory terms the influence of his fellow academicians on the court of Elizabeth.
Your writings, Gentlemen, have penetrated to the capital of the most remote empire in Europe and the largest in the world. In this city, that forty years ago was nothing but a wilderness inhabited by savage beasts, your dramas are now presented, and the same natural good taste that enables Italian music to be enjoyed in the city of Peter the Great and his worthy daughter, also enables your eloquence to be appreciated.

The reign of Elizabeth and her love of France has given rise to a dubious story of purported romance between Elizabeth and a mysterious emissary sent by Louis XV. It is said that the young and handsome knight succeeded in introducing himself into the czarinas court disguised as a woman and won her favors. The anecdote was recounted by the knight himself in his memoirs. Without any delicacy he elaborated on a wealth of details concerning the physical aging of a woman in search of young flesh.

Voltaire (1694-1778), admirer of czarina Elizabeth Petrovna, the younger daughter of Peter the Great. Pastel by Maurice Quentin de la Tour, 1736, Chteau de Ferney, FerneyVoltaire. Rue des Archives.

The czarina, he wrote, had turgid bluish lips, shiny cheekbones, swollen eyelids, and watery eyes Her skin was sweaty and discharged wantonness from all its pores I said to myself that this woman in front of me had taken into her arms innumerable men, picked up by chance in the streets, and that her mouth, her neck, and her breasts had been stained and withered by the kisses of soldiers

Catherine II the Great in full imperial regalia. Oil on canvas, by Stefano Torrelli, towards 1780. St Petersburg. Rue des Archives/ The Granger Coll.

Catherine II and the French Enlightenment Whether or not the story is true, the fact remains that the secret agent contributed to the Franco-Russian reconciliation and that he returned to Versailles in 1755, bearing a letter from Elizabeth to My brother Louis XV, to whom her father had dreamed of marrying her twenty-five years before. In fact, the czarina who did the most for Franco-Russian relations was Catherine II. Married very young to Peter III, the adopted son of Elizabeth, she came from the minor German aristocracy, had spoken French since her childhood, and was an adept of the philosophy of the Enlightenment. Armed with this knowledge she settled down rapidly. Her reign (1762-1796) was one long sequence of correspondence and of quest for knowledge. Her mentor was Voltaire, biographer of Peter the Great, and she cherished a bust of Rousseau in her apartments. She invited Diderot to spend several months in Saint Petersburg, and the philosopher, alarmed by her firm-handed ruling and her political absolutism on the lines of Peter I, dubbed her the Semiramis of the North (a semilegendry Assyrian Queen who convinced Ninus to make her Regent for the day, and then promptly had him executed). Nevertheless, he presented her with a bookcase, and on his return to Paris helped her put together a collection of paintings by Watteau, Le Lorrain, and Poussin that formed the nucleus of the Hermitage Museum inaugurated in 1764. To justify her acts, she explained to the author of The Nun: You Mr Diderot, work on paper. But I work on the skin of man. A lucid reflection that says much on the lack of liberty and the suffering of her people. Yet, Catherine II was considered a civilized sovereign in the eyes of the European elite, and was largely inspired by Montesquieu when drawing up her first legislative treatise. His comparative study of legal and political issues, De lEsprit des Lois [The Spirit of Laws], made her dream of reforming Russia inMEDICOGRAPHIA, VOL 28, No. 1, 2006 91

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The poet Alexander Sergevich Pushkin (1799-1837), the Russian Shakespeare. Rue des Archives.

Bronze equestrian statue of Peter the Great, by tienne Falconet, offered by Catherine: Petro Primo, Catharina Secunda To Peter the First, from Catherine the Second (dated 1782). AKG-images.

spired by the philosophy of the Enlightenment. Yet, notwithstanding such generous principles, she published in 1785 a Charter of Nobility, which codified even further the social differences and enclosed the aristocracy in a hermetic bubble with codes of value and an attachment to the French language that completely isolated them from the rest of Russia. An error the empress would become aware of a few months before her death. Nevertheless, it is thanks to her that Russia was finally saved from obscurantism and became impregnated with Western practices that would eventually bring order and a better future. A French statue for Peter the First from Catherine the Second Peter I had already sought to domesticate society symbolically by converting the swamps into well-ordered canals that in 1774 occupied a fifth of the urban space, according to Leblonds plans. Under Catherine II, the city was smartened up and the czarina marked her admiration for the founder of the city by commissioning a French sculptor, Etienne Falconnet, to create a statue of Peter the Great and gave it a rather revealing inscription: To Peter the First, from Catherine the Second. Thanks to her, the nobility acquired an independent spirit and a taste for education based on the French method, which was taught in a few expensive private institutes and by tutors who were more or less competent. Described by Diderot as riffraff, they were often jailbirds or charlatans come to try their luck in the countries of the North. It was not until the end of the 18th century that genuine tutors began to arrive in the Russian capital. One of them, Boudry, the brother of Marat (French politician stabbed to death in his bath by Charlotte Corday during the Revolution), became a friend of Pushkin who had been brought up on French culture. Boudry was appointed Professor of French at Tsarskoe Selo (the sprawling architectural ensemble that was the beloved summer residence of the Russian czars and an inspiration to many celebrated Russian poets, painters, and musicians), and requested Catherine II to change his name by prefixing it with the aristocratic dethus improving his social status. The nobility became an educated minority who enjoyed all the privileges and it became more natural for them to express themselves in French rather than in their mother tongue, even if Paul I, who succeeded his mother Catherine II, rebelled against the pervading Francophilia and ordered the collars of tail coats to be cut off because he thought they were the uniform of the French Jacobins. Nonetheless, Paul spoke perfect French and recited verses of Racine. His reign was short (1796-1801), but he had time to conclude a treaty with Napoleon against all advice that led to the war with England, a long-standing commercial partner of Russia. This led to discontent, and hearsay has it that when conspirators entered his bedroom to strangle him, he harangued them unsuccessfully in French.
Treaty of Tilsit (1807): Czar Alexander I and Emperor Napoleon I. Rue des Archives.

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Alexander I: staunch francophile despite the war with Napoleon Paul Is son, Alexander I, his successor and probable murderer, continued to support the influence of France. Even fashion was modeled on the latest Parisian creations, and elegant Russian ladies wore the same simple and diaphanous dresses inspired by Greece that were reborn on the Seine and copied on the Neva. After having been officially forgotten under Paul I, French art was revived as a source of inspiration under Alexander I. From 1805 to 1807, the czar joined a coalition against France at the side of Austria, England, and Prussia. However, the victories of Napoleon at Austerlitz, Jena, Eylau, and Friedland soon encouraged him to seek a separate peace. The two men met at Tilsit to sign the treaty. It was the start of the French Follies that invaded the court, the streets, the interior of palaces, and architecture. Carrying mimicry to the ridiculous, Alexander I courted Mlle George, a buxom actress whom Napoleon had probably seduced before him, and let slip: I wanted to taste the water at the same well at which my rival had satisfied his thirst. He ordered the French architects Percier and Fontaine to provide him with a summary of all the works of art with which the French Emperor had embellished the capital of his empire. The French colony at the beginning of the 19th century numbered more than four thousand persons, and the boutiques were named Madame Louise, Fleur de Nice, Vrai savon de Marseille, etcetera. In short, Francophilia was top of the pops up until Napoleons troops entered Moscow on September 14, 1812, thus sounding the knell of this excessive infatuation. For the first time in their life, numerous women donned traditional dress and spurned the French language. But this rejection was only temporary. The victory of Russia over the Napoleonic armies made Empire style fashionable again. On the orders of Alexander I, who wanted the capital of his empire that had defeated Napoleon to have an imperial dimension, work started up again. Just as if nothing had happened, French engineers (Btancourt and Basin), decorators, architects (Auguste Ricard de Montferrand), and financiers once again contributed to the blooming of Saint Petersburg, symbol of a Europe that refused to be subdued.
FURTHER READING Vladimir Fdorovski: Le Roman de SaintPtersbourg. Paris, France: Editions du Rocher. Catalog of the exhibition at the Muse de lArme on May 21 to August 31, 2003: Paris Saint-Ptersbourg 1800-1830: Quand la Russie Parlait Franais. Paris, France: Editions RMN; 2003.

Kazan Cathedral, St Petersburg. Color lithograph printed by Lemercier (1840s), Paris, after a painting by Louis Jules Arnout. Pushkin Museum, Moscow. The Bridgeman Art Library.

MILESTONES

1682 Ten-year-old Peter I is proclaimed czar 1703 Foundation of Saint Petersburg 1712 Saint Petersburg becomes the capital of Russia 1717 Peter I travels to Paris 1725 Death of Peter I 1725-1727 Reign of Catherine I 1727-1730 Reign of Peter II 1730-1740 Reign of Anna Ivanovna 1741-1761 Reign of Elizabeth Petrovna 1747-1762 Russia participates in the Seven Years War

1761-1762 Reign of Peter III 1762-1796 Reign of Catherine II 1796-1801 Reign of Paul I 1801-1825 Reign of Alexander I 1805 Victory of Napoleon I over the AustroRussian coalition at Austerlitz 1807 Treaty of Tilsit between Napoleon and Alexander I 1812 Napoleon enters Moscow 1814 Allied troops enter Paris 1815 Waterloo 1825-1855 Reign of Nicholas I 1837 Death of Pushkin

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EMPIRE STYLE
Named after a political organization and not in honor of a crowned head, Empire style appeared in France at the time of the 1789 revolution and ended with the fall of Napoleon. Arriving at the same time in Russia, Alexander style survived until 1825. Though the two monarchs fought each other mercilessly on the battlefield, they nonetheless maintained close relations in time of peace, and Russia enthusiastically adopted the Parisian way of life, the city at that time being the capital of the world. Whereas classicism embodied simplicity, soft colors, and pure lines, Empire style expressed the cool and virile, drawing from ancient Greece and Egypt to suggest power and force. Silhouettes of Egyptians carrying vessels, sphinxes, crowned maidens bearing lyres, warriors, eagles, and griffins, the source of inspiration was the same in France and Russia. But it was the painter David, the architects Percier and Fontaine, and the cabinetmakers Franois-Honor-Georges and JacobDesmelter who set the tone for this way of life that exalted victory and honor. Vases, plates, table settings, silverware, furniture, and ladies and mens wear, everything was a pretext for Russians and French to correspond and discuss the tastes and styles decreed by the Empress Josephine with whom Alexander I had an excellent relationship and often visited in her Malmaison residence. The symbolic figures that can be seen on the everyday objects of that timecups, plates, cameosillustrate the extent to which the language had imitated this unity of cultures.

Empire style furniture at the Chteau de Fontainebleau: in the forefront, Napoleon Is desk. Rue des Archives/ Talliandier.

Symbol of Empire style: the Austerlitz Table, inlaid with Sevres plaques, commemorating Napoleons victory at Austerlitz (1808-1810). French School. Muse National du Chteau de Malmaison, Rueil-Malmaison. The Bridgeman Art Library.

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onde en 1703 par Pierre 1er, Saint-Ptersbourg est ne de la volont du tsar dinscrire la Russie dans le progrs occidental. En arrachant de haute lutte aux Sudois ce morceau de terre marcageux lembouchure de la Neva pour y installer un port baptis en son honneur, Pierre le Grand soffrait un balcon sur la Baltique et une fentre sur lEurope, donc sur la France. Cest un architecte franais, Jean-Baptiste Alexandre Leblond, que Pierre confia le soin de dessiner les jardins de la ville limage de ceux de Versailles et cest lui que lon doit le paysage lacustre faonn par dinnombrables canaux. son tour, sa fille Elisabeth, sacre impratrice en 1741, fut une admiratrice inconditionnelle de la France et de ses arts. Architectes, philosophes, acteurs et musiciens sont invits ou consults. Le thtre franais devient lendroit le plus pris des aristocrates ptersbourgeois au milieu du XVIIIe sicle et la langue franaise simpose dans la noblesse. Ds le dbut de son rgne en 1762, Catherine II confirme cette disposition envers lEurope et particulirement la philosophie des Lumires. Voltaire, Diderot, Montesquieu font partie des personnalits de rfrence de cette souveraine la poigne de fer mais aux ides claires. A Saint-Ptersbourg on parle, on pense et on samuse dornavant en franais. Une habitude poursuivie sous le rgne dAlexandre 1er (1801-1825), qui malgr les combats acharns qui lopposaient Napolon sur les champs de bataille, entretenait avec son rival des relations dadmiration rciproque inscrites dans un style de vie la franaise revendiqu par la plus grande partie de laristocratie de la capitale russe bien au-del du rgne de Nicolas 1er sacr empereur en 1825.

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