JOURNAL OF BONE AND MINERAL RESEARCH

Volume 16, Number 5, 2001

2001 American Society for Bone and Mineral Research

Classification of Osteoporosis Based on Bone

Mineral Densities

YING LU,1 HARRY K. GENANT,1 JOHN SHEPHERD,1 SHOUJUN ZHAO,1 ASHWINI MATHUR,2
THOMAS P. FUERST,1 and STEVEN R. CUMMINGS3

ABSTRACT

In this article we examine the role of bone mineral density (BMD) in the diagnosis of osteoporosis. Using
information from 7671 women in the Study of Osteoporotic Fractures (SOF) with BMD measurements at the
proximal femur, lumbar spine, forearm, and calcaneus, we examine three models with differing criteria for the
diagnosis of osteoporosis. Model 1 is based on the World Health Organization (WHO) criteria using a T score
of 2.5 relative to the manufacturers young normative data aged 20 29 years, with modifications using
information from the Third National Health and Nutrition Examination Survey (NHANES). Model 2 uses a
T score of 1 relative to women aged 65 years at the baseline of the SOF population. Model 3 classifies women
as osteoporotic if their estimated osteoporotic fracture risk (spine and/or hip) based on age and BMD is above
14.6%. We compare the agreement in osteoporosis classification according to the different BMD measure-
ments for the three models. We also consider whether reporting additional BMD parameters at the femur or
forearm improves risk assessment for osteoporotic fractures. We observe that using the WHO criteria with the
manufacturers normative data results in very inconsistent diagnoses. Only 25% of subjects are consistently
diagnosed by all of the eight BMD variables. Such inconsistency is reduced by using a common elderly
normative population as in model 2, in which case 50% of the subjects are consistently diagnosed as
osteoporotic by all of the eight diagnostic methods. Risk-based diagnostic criteria as in model 3 improve
consistency substantially to 68%. Combining the results of BMD assessments at more than one region of
interest (ROI) from a single scan significantly increases prediction of hip and/or spine fracture risk and
elevates the relative risk with increasing number of low BMD subregions. We conclude that standardization
of normative data, perhaps referenced to an older population, may be necessary when applying T scores as
diagnostic criteria in patient management. A risk-based osteoporosis classification does not depend on the
manufacturers reference data and may be more consistent and efficient for patient diagnosis. (J Bone Miner
Res 2001;16:901910)

Key words: bone densitometry, classification, osteoporosis, diagnostic agreement

INTRODUCTION
ONE MINERAL density (BMD) and bone mineral content
B (BMC) values are used to diagnose osteoporosis.(1)
According to the World Health Organization (WHO) work-
ing group,(2) white women whose BMD or BMC values are
below 2.5 T score compared with young normal adults are
considered to have osteoporosis. Although based on the
properties of dual X-ray absorptiometry (DXA) scans of
spine and hip, this diagnostic approach does not specify the

1
Osteoporosis and Arthritis Research Group, Department of Radiology, University of California San Francisco, San Francisco,
California, USA.
2
Statistical Sciences, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania, USA.
3
Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, California, USA.

901
902
anatomic measurement sites and/or techniques and, there-
fore, as the WHO working group notes, individuals will be
categorized differently according to the site and technique
of measurements and the equipment and the reference pop-
ulation used.(2) The choice of bone measurement technol-
ogy, the corresponding reference population, and the mea-
surement sites will have a direct impact on the management
of individual patients in clinical practice.
Although there is a wide array of bone mineral measure-
ment techniques available or under development, the most
commonly used is X-ray absorptiometry, either single X-ray
absorptiometry (SXA) or dual X-ray absorptiometry
(DXA). DXA and/or SXA scanners can measure many
anatomic sites.(3) The most common sites are the lumbar
spine, proximal femur, forearm, and calcaneus. Each pro-
vides a reasonable capacity for generic fracture risk predic-
tion,(1) and each correlates moderately well to the others.(4,5)
However, this modest correlation does not necessarily lead
to consistent diagnostic classification of individual patients
when threshold-based criteria are used.(513) These incon-
sistencies may be caused by differences in reference data,
differences in peak bone levels and rates of bone loss, in
technique-related sources of error, and in individual ana-
tomic interrelationships.(3) These inconsistencies also make
it unclear whether combining the results of several measure-
ment techniques and/or sites reduces misclassification or
improves fracture risk assessment.(7,9 11,14) Furthermore,
inconsistencies in patient diagnosis make it difficult to de-
velop treatment and reimbursement standards.(15)
The use of bone densitometry in patient management
differs from its use in mass screening or epidemiological
study. Under managed care, physicians are obligated to
reduce the cost of examinations by eliminating unnecessary
scans. At the same time, they are responsible for accurately
diagnosing their patients; a truly osteoporotic patient must
not go undiagnosed, and a healthy patient must not be
falsely diagnosed as osteoporotic. Using only one diagnos-
tic technique and/or one BMD parameter may fail to detect
patients who might be diagnosed with another method.
Measuring multiple sites reduces the likelihood of missing
an osteoporotic patient but increases expense; false-positive
rates will increase, resulting in some normal subjects re-
ceiving treatment. The choice of technique and site will
affect the diagnostic conclusions as well as the cost, directly
affecting the choice of intervention strategy for an individ-
ual patient.
Given these conditions, we attempted to distinguish the
differences in the diagnosis of osteoporosis based on dif-
ferent BMD sites and to examine their clinical ramifications.
Using a prospective cohort from the Study of Osteoporotic
Fractures (SOF), we applied three approaches to investigate
the magnitude of discordance in the diagnosis of osteopo-
rosis. Model 1 was based on the WHO criteria and the
manufacturers young normative data for different measure-
ment sites. Model 2 used a standardized older reference
population to derive a T scorelike measure. Model 3 used
a cut-off threshold based on osteoporotic fracture risk. Fi-
nally, we considered whether assessing more than one BMD
region of interest (ROI) from a single scan site helps predict
hip and/or spinal fractures in a clinical setting.
LU ET AL.
MATERIALS AND METHODS
Subjects
From 1986 to 1988, the SOF recruited 9704 white women
aged 65 years or older from population-based listings in
four areas of the United States. At baseline, BMD was
measured at the calcaneus, distal radius, and proximal ra-
dius, using single photon absorptiometry (SPA). At the
second visit (1988 1989), surviving participants had BMD
measurements of the postero-anterior (PA) spine (L1L4)
and proximal femur (neck, trochanter, Wards triangle, and
total hip ROIs) using DXA. Fractures of the hip and spine
were recorded for each subject at each visit. Details of the
study design and the data have been published.(16,17)
We included 7671 women from the study for whom all
the BMD measurements were available. All analyses of the
classification of osteoporosis according to BMD measure-
ments in this article were based on this study population.
Fractures
All women who had fractures of the hip and/or spine were
included, whether they were followed for 5 years or not. We
also included all women who actually were followed for 5
years, whether they had fractures in that time or not.
Women who were followed for less than 5 years and had no
fractures were excluded. These parameters gave us the
records of 5568 women that were suitable for analyses
related to hip fracture.
Lateral spine radiographs were obtained at baseline and
about 3 years later. Incident vertebral deformities were
defined by quantitative morphometry as a 20% reduction
and at least 4-mm loss in the height of anterior, posterior, or
midheight of any vertebra between L4 and T4, during the
time between baseline and follow-up visits.(18,19) The aver-
age time between the baseline and follow-up radiographs
was about 3.7 years. An experienced radiologist provided
visual confirmation of the diagnoses. The records of 6561
women were suitable for the analyses related to spinal
fractures.
By combining hip and spine fractures, 5066 women met
our inclusion criteria of at least one fracture or completion
of 5 years follow-up. We considered hip and/or spine frac-
tures in the SOF because they are probably the most rele-
vant osteoporotic fractures. Unless specified otherwise, in
this article fracture will refer to osteoporotic fractures of
the hip and/or the spine.
BMD based classification of patients
The DXA scanners used in the SOF were the Hologic
QDR 1000 (Hologic, Inc., Waltham, MA, USA). The SPA
scanners were from OsteoAnalyzer (Siemens-Osteon, Wa-
hiawa, HI, USA). The unit of BMD measurement was in
grams per square centimeter. Lumbar spine BMD was mea-
sured at L1L4. The reference parameters (peak mean and
SD of young women aged 20 29 years) for hip, spine, and
calcaneus were provided by the manufacturers. The hip
BMD normative data represent the new version based on
results from the National Health and Nutrition Examination
Survey (NHANES) study.(20,21) The forearm reference data
BMD CLASSIFICATIONS FOR OSTEOPOROSIS 903

TABLE 1. MEAN AND SDS OF NORMATIVE BMD VALUES (g/cm2) FROM MANUFACTURERS (MODEL 1), SOF 65 (MODEL 2),
AND OVERALL SOF DATA

Reference values for model 1 Reference values for model 2

(young women aged 2029 (564 SOF women aged 65 Descriptive statistics of SOF
years) years at baseline) participants (n 7671)
Peak Mean (Peak SD) Mean (SD) Mean (SD)

Age at baseline 65 (0) 71.26 (5.04)

Total hip, BMD 0.942 (0.122)a 0.796 (0.13) 0.758 (0.131)
Trochanteric, BMD 0.703 (0.101)a 0.585 (0.10) 0.558 (0.102)
Femoral neck, BMD 0.849 (0.111)a 0.680 (0.11) 0.650 (0.110)
Wards triangle, BMD 0.734 (0.117)a 0.462 (0.11) 0.428 (0.110)
Calcaneus, BMD 0.425 (0.07)b 0.435 (0.09) 0.407 (0.093)
Distal radius, BMD 0.38 (0.05)c 0.383 (0.08) 0.363 (0.084)
Proximal radius, BMD 0.79 (0.05)c 0.670 (0.10) 0.637 (0.103)
Lumbar spine, BMD 1.047 (0.11)b 0.872 (0.17) 0.857 (0.169)
a
New Hologic reference values for model 1 were from NHANES study.20
b
Reference values for model 1 were from the manufacturers.
c
Reference values for forearms for model 1 were from Davis et al.22

were derived from Davis et al.(22) These reference values are
listed in the first column of Table 1.
We used the WHO criteria to classify women as osteo-
porotic based on the young normative values.(2) We consid-
ered a woman to be osteoporotic if her BMD T score was
less than 2.5. (A T score is defined as the BMD value
minus the sex-matched young reference BMD divided by
the sex-matched young reference SD at the corresponding
anatomical site.) We refer to this classification as model 1.
In model 2, we substituted the peak young reference
values in the T score with reference values from the SOF
women aged 65 years at baseline. We refer to this alterna-
tive T score definition as T (T prime). The midcolumn of
Table 1 lists reference values for this cohort. To make
classifications based on this reference cohort comparable
with model 1, we used a T score of 1 as the cut-off
point for the SOF 65 group, which derived a comparable
prevalence of osteoporosis based on the femoral neck
BMD.
Model 3 was based on the estimated risk of osteoporotic
fracture of the hip and/or spine for a given BMD measure-
ment. The estimated risk was determined with a logistic
regression equation derived from the SOF fracture data.
Because age is always available without cost, we used both
age and BMD values in the regression equations. In this
model, classifications of osteoporosis were based on a
threshold of the estimated fracture probability as illustrated
in the Appendix, that is, patients with a fracture risk above
the cut-off values were designated as osteoporotic. The
cut-off values for fracture risk were 14.6% for model 3,
based on follow-up periods of 5 years for the hip and 3.5
years for the spine. The fracture risk value of 14.6% was
chosen to generate a prevalence of osteoporosis similar to
models 1 and 2 according to neck BMD so that comparisons
among models would be possible.
Statistics
Descriptive statistics were used to summarize the study
population. Pearsons correlation coefficients were used to
evaluate the association of BMD values from different
anatomic measurement sites. -Statistics and percentage
agreements were used to study the agreement in classifica-
tions.
To evaluate the diagnostic agreement for model 3, we
used a 10-fold cross-prediction method to classify the
women. We randomly divided the SOF data into 10 subsets.
We derived cut-off values from nine of the subsets and used
those values to classify women in the remaining subset. We
rotated the target subset among all subsets so that all pa-
tients in the SOF study were classified based on other
women. This was done to reduce the bias in classification
because the classification rules and results to be compared
are based on the same data.
Logistic regression analysis was used to assess the risk of
fractures. All statistical analyses were carried out using a
statistical software package (SAS 6.09; SAS Institute, Cary,
NC, USA). The statistically significant level was set at 0.05
throughout the study.
RESULTS
Classification of osteoporosis
Descriptive statistics of the study participants used in this
article are shown in the last column of Table 1. Correlation
coefficients between BMD parameters measured at different
sites are shown in Table 2. The correlation coefficients
ranged from 0.51 between proximal radius and Wards
triangle BMD to 0.90 between total hip and trochanteric
BMD. Measurements from the same anatomic sites tended
to have higher correlations than those from different sites.
Correlation coefficients between two different sites were
moderate (around 0.6).
In model 1, using the WHO criteria and the manufactur-
ers reference values, the prevalence of osteoporosis ranged
from 3% based on calcaneal BMD to 60% based on the
BMD of the proximal radius (Fig. 1). Examination of the
cross-tables of classifications of osteoporosis, specifically
904
TABLE 2. CORRELATION COEFFICIENTS AMONG BMD MEASUREMENTSa
Femoral Wards
Trochant neck triangle
Total hip 0.901 0.861 0.838
Trochant 0.760 0.766
Femoral neck 0.868
Wards triangle
Calcaneal
Distal radius
Proximal radius
a
n 7671; p 0.0001.
FIG. 1. Prevalence of osteoporosis based on eight BMD measure-
ments.
the upper triangle of Table 3, shows that the percentages of
agreement in the diagnosis of osteoporosis ranged from
43% between proximal radius and calcaneal BMD to 92%
between total hip and trochanter BMD. Overall, the percent-
ages of agreement varied greatly, indicating poor agreement
in diagnosis. This is also evident in the very low -statistics
given in the lower triangle of Table 3. The percentage of
women who were consistently classified by all eight mea-
surement sites was only 25%: 24% were classified as nor-
mal and 1% as osteoporotic (Fig. 2). These results suggest
that using the WHO criteria and the manufacturers refer-
ence data could result in very different diagnoses depending
on the anatomic site and method used.
Model 2 further examined whether the differences were
caused by the use of younger reference values or by the use
of threshold-based diagnostic criteria in general. The prev-
alence of osteoporosis classified in model 2 was substan-
tially more consistent than in model 1 (Fig. 1). The most
noticeable changes were for osteoporosis at Wards triangle,
calcaneus, and forearm. The upper triangle of Table 4 shows
the percentages of agreement in classifications based on two
BMD measurements. The percentages ranged from 75%
between femoral neck and proximal radius to 89% between
total hip and trochanter BMD. The -statistics for pairwise
agreement in diagnosis ranged from 0.33 to 0.70, given in
the lower triangle of Table 4. Overall, model 2 showed
LU ET AL.
Distal Proximal
Calcaneal radius radius Spine
0.693 0.599 0.597 0.662
0.669 0.555 0.539 0.646
0.617 0.532 0.516 0.603
0.583 0.535 0.514 0.580
0.667 0.634 0.638
0.757 0.566
0.551
substantially improved agreement in classifications, partic-
ularly among classifications based on different femoral
BMD measurements and when comparing calcaneal BMD
to other locations. The percentage of women who were
classified consistently by all eight BMD measurements was
49%: 45% as normal and 4% as osteoporotic (Fig. 2). Even
with this improvement over model 1, more than 50% of the
women were diagnosed differently depending on the ana-
tomic sites measured. Most of the percentage agreements
between two sites were above 80%, indicating that a fifth of
the women would be classified differently if they were
diagnosed based on two different BMD measurement sites.
Except for measurements of hip BMD sites, the -statistics
of other combinations were mostly less than 0.5, suggesting
only moderate agreement among different sites after adjust-
ing for agreement by chance.
Model 3 used a risk-based approach and further improved
the agreement in classifications. The prevalence of osteo-
porosis by this model ranged from 22% to 26%, as shown in
Fig. 1. The model substantially improved the -statistics
(lower triangle of Table 5) as well as the percentage agree-
ment (upper triangle of Table 5), although moderate dis-
crepancies remained. The percentage of women who were
classified consistently by all eight BMD measurements was
69%: 59% as normal and 10% as osteoporotic (Fig. 2) based
on our 10-fold cross-prediction. We found that low hip
BMD missed only 6% of women diagnosed as low by other
BMD measurements in model 3.
Fracture outcome in the diagnostic classification of
osteoporotic patients
Agreement in diagnostic classification is one aspect of the
comparison of diagnostic criteria. Equally important is
whether a diagnostic method reflects patient prognosis.(23)
Figure 3 shows the sensitivity, specificity, and the posi-
tive and negative predictive values for hip and/or spine
fracture for each measurement in the three classification
models. Although sensitivities and specificities varied most
in model 1 and were most consistent in model 3, the
variations in positive and negative predictive values in
model 1 and the improvement in model 3 were not substan-
tial. This is because both positive and negative predictive
values were regulated by the low prevalence of fracture,
which was 7%. Still, model 1 had the most variations, with
positive predictive values ranging from 12% Wards trian-
BMD CLASSIFICATIONS FOR OSTEOPOROSIS 905

TABLE 3. PERCENTAGE AGREEMENT (UPPER TRIANGLE) AND -STATISTICS (LOWER TRIANGLE IN PERCENTAGE) IN
OSTEOPOROSIS DIAGNOSIS FOR MODEL 1a
Femoral Wards Distal Proximal
Percent (%) Total hip Trochant neck triangle Calcaneal radius radius PA spine

Total hip 92 86 58 85 84 54 75
Trochant 68 83 55 88 86 51 74
Femoral neck 59 45 66 77 77 57 74
Wards triangle 25 19 38 45 49 69 64
Calcaneal 20 24 14 4 91 43 69
Distal radius 29 30 22 10 24 48 71
Proximal radius 18 15 23 37 4 11 63
PA spine 35 29 36 32 9 20 31

The upper triangle of the table is the percentage of agreement in classification of osteoporosis by two BMD measurements. The lower
triangle of the table is the -statistics of classification of osteoporosis by two BMD measurements. The row and column titles are the two
BMD sites to be measured.
a
n 7671.

by Wards triangle, calcaneal, and distal radius BMD in

model 1 were higher than the relative risks in model 2.
However, given the very high prevalence of Wards
triangle osteoporosis and very low prevalence of calca-
neus and distal radius osteoporosis in model 1, such
advantages in relative risk were of no practical use.
Model 3 had consistently higher relative risks and rela-
tive risks across all eight measurements sites, compared
with both models 1 and 2. Thus, model 3 was most
relevant to the prognosis of the classified subjects.

FIG. 2. Pie chart for the distribution of the number of low BMD sites.
The pie chart consists of SOF participants in nine categories according
to their number of osteoporotic sites. The area of each category repre-
sents the percentage of participants in it. Participants who are classified
consistently by eight BMD measurement sites had either no low BMD
sites or eight low BMD sites.
gle (WARDS) to 34% calcaneus (CALC). In contrast, the
ranges of positive predictive values were from 17% (both
forearm BMDs) to 24% (WARDS) for model 2 and 22%
(PRAD) to 25% (all hip BMDs) for model 3. Negative
predictive values were all above 90%.
Figure 4 shows the relative risks for fracture for os-
teoporotic women (those with lower BMD) compared
with all the nonosteoporotic women (those with higher
BMD) in the study, according to the three different
diagnostic models. Relative risk here is for 5-year hip
and/or spine fracture and compares two groups rather
than traditional 1 SD change in BMD. Osteoporotic
women had significantly elevated risks of fracture in each
model. Although model 2 provided significantly better
agreements in classification and homogeneity of sensitiv-
ity and specificity, the relative risks were not all higher
than those in model 1. The relative risks for classification
Combination of measurements
The disagreement in patient classification and the multi-
ple BMD parameters measured in hip and forearm scans
lead to the question of whether additional BMD parameters
derived from different ROIs of the same scan would be
beneficial in patient management, without additional mea-
surement cost. We examined the benefits of combining
multiple BMD results from the hip or from the forearm scan
measurements.
The relative risk of osteoporotic fracture as a function of
the number (0) of osteoporotic ROIs in a hip or forearm
scan, in reference to women without osteoporotic ROIs in
the corresponding site, is listed in Table 6. The risk in-
creased with the number of osteoporotic ROIs assessed for
either hip or forearm scans in all three models (Armitage
trend test, p 0.001). This suggests that the combination of
osteoporotic status of all BMD ROIs from a hip or a forearm
scan could help physicians better assess the prognosis of a
patient without increasing diagnostic expense. Therefore, it
may be beneficial to combine BMD information from dif-
ferent ROIs in the same hip or forearm scan in reporting
patient bone status.
DISCUSSION
A number of important conclusions can be drawn from
this study. The correlation between BMD measures is good,
but the agreement in threshold-based classifications is only
906 LU ET AL.

TABLE 4. PERCENTAGE OF AGREEMENT (UPPER TRIANGLE) AND -STATISTICS (LOWER TRIANGLE IN PERCENTAGE) IN
OSTEOPOROSIS DIAGNOSIS FOR MODEL 2a
Femoral Wards Distal
Percent (%) Total hip Trochant neck triangle Calcaneal radius Proximal radius PA spine

Total hip 89 87 85 79 77 77 80
Trochant 70 83 83 79 76 76 80
Femoral neck 65 54 87 77 76 75 78
Wards triangle 59 52 64 76 75 75 78
Calcaneal 46 45 41 37 78 77 78
Distal radius 39 35 34 33 44 83 77
Proximal radius 39 36 33 34 42 55 77
PA spine 42 41 36 35 40 34 34

The illustration of this table is the same as those in Table 3.

a
n 7671.

TABLE 5. PERCENTAGE OF AGREEMENT (UPPER TRIANGLE) AND -STATISTICS (LOWER TRIANGLE IN PERCENTAGE) IN
OSTEOPOROSIS DIAGNOSIS FOR MODEL 3a
Femoral Wards Distal Proximal
Percent (%) Total hip Trochant neck triangle Calcaneal radius radius PA spine

Total hip 92 90 89 87 86 86 86
Trochant 77 87 87 87 85 85 86
Femoral neck 74 65 91 86 85 85 85
Wards triangle 71 65 76 85 85 85 85
Calcaneal 64 64 61 59 89 89 88
Distal radius 60 59 60 59 70 92 88
Proximal radius 60 58 58 58 69 78 88
PA spine 62 61 60 59 66 66 67

The illustration of this table is the same as those in Table 3.

a
n 7671.

modest. Threshold-based classifications depend heavily on
the reference data used. Standardization of the reference
data will reduce but not eliminate inconsistencies in osteo-
porosis diagnosis. Risk-based classifications further im-
prove the consistency among different measurement sites
and result in nearly 70% agreement among the eight BMD
sites studied. Reporting the status of all ROIs at the hip or
forearm enhances fracture risk prediction.
The ideas and models in this article are not new. The
conclusions are not surprising. Many authors have reported
inconsistency in WHO classifications.(510,12) There has
been considerable effort to determine new definitions that
will lead to more consistent classification.(23,24) Our article
is the first to evaluate the impact of diagnostic classification
using data from a large prospective study. Our results sup-
port previous observations based on small data sets and
reinforce the suggestions that classification of osteoporosis
should focus on risk of fracture rather than on T scores
selected to provide a certain prevalence.(24 27)
Although consensus is forming that the diagnosis and
treatment of osteoporosis should not be based solely on
BMD but should include other considerations and risk fac-
tors,(1,24) BMD values are still the most frequently used and
important factor. The WHO criteria produce inconsistent
diagnoses of osteoporosis and are better applied in epide-
miological and population-based studies than in individual
diagnostic procedures or as thresholds for therapeutic deci-
sions. This inconsistency has more consequences in clinical
practice than in epidemiological studies. Physicians face the
dilemma of deciding which patients should receive long-
term treatments. Our study suggests that many of the incon-
sistencies are methodological and can be reduced by stan-
dardization to an older reference population and by using
risk-based criteria. With increasing therapeutic choices in
patient management, such information also can be used in
choosing the optimal treatment strategies based on patient
prognosis.
Because of logistical and proprietary concerns, manufac-
turers do not codevelop or share their reference populations.
Device manufacturers typically use different reference pop-
ulations for different machines. Our study supports the
notion that different normative populations within and
among manufacturers are a source of inconsistencies in
classification based on T scores.(8,12,13) However, it seems
that age may play a more dominant role in the disagreement.
The disagreement in classifications could be reduced by
using a unified elderly normative population in which the
differences in age-related bone losses have been negated.
Unfortunately, the current study cannot explicitly separate
the effect of a standardized reference population and of
BMD CLASSIFICATIONS FOR OSTEOPOROSIS
FIG. 4. Relative fracture risk for hip and/or spine fracture based on
eight BMD measurements. Relative risks for hip and/or spine fracture
for osteoporotic women (lower BMD) compared with all the nonos-
teoporotic women (higher BMD) in the study.
differential aging effects because we do not have complete
manufacturer-based reference data for age 65 years for all
measured sites. The greatest disagreements in model 1 were
between peripheral BMD and central BMD measures. Be-
cause of changes in technology, we are not able to obtain
reliable references for 65-year-old white women from man-
ufacturers for forearm and calcaneal BMD. The Interna-
tional Committee for Standards in Bone Measurement has
recommended the adoption of hip BMD measurements from
the NHANES(20,21) as the standardized reference population
for white women. Developing a universal reference popu-
lation for all bone measurement sites and technologies
907
FIG. 3. Sensitivity, specificity, and positive
and negative predictive values for osteoporotic
fracture based on eight BMD measurements.
would be a formidable task. However, there are efforts
underway as proposed by Miller.(25) As diagnostic and
treatment options increase, the importance of studying
methodologies to calibrate future BMD measurements to
the same reference population increases also.
Currently, the T score based threshold approach for de-
fining osteoporosis is widely applied. However, there are
many advantages to a risk-based approach rather than T
scores. We have previously underscored some of the pitfalls
of using T scores for patient diagnosis.(9,10,26) Black et al.
suggested avoiding the use of T scores as classification tools
altogether and proposed including the relative risk of frac-
tures as a standard tool in reporting bone densitometry
results.(27) This article supports these arguments. Because
relative risk depends on the definition of baseline fracture
risk, it is much easier to define osteoporosis based on
absolute fracture risks within a defined time window.
The risk-based diagnostic criteria used in this study
showed strong and consistent separation of osteoporotic
women from normal women. The better agreement, to a
certain degree, could be attributed to the use of age as a
variable in estimating risk and perhaps because the logistic
regression model used information of fracture risks over the
whole age range. Because age is a known risk factor for
osteoporosis and costs nothing to obtain, it is beneficial to
include it in our diagnostic criteria. Dropping age in the
estimation of fracture risks in model 3 would result in a
classification scheme very similar to model 2. Using age in
the model to estimate the fracture risks causes the BMD
cut-off values to vary with age. This should not be a
problem in practice because the manufacturers could pro-
gram the logistic regression equations and report such risks
to physicians. It is already being used in a limited way. It is
important to point out that model 3 offers significantly
908 LU ET AL.

TABLE 6. RELATIVE OSTEOPOROTIC FRACTURE RISK AS A FUNCTION OF NUMBER OF OSTEOPOROTIC ROIs IN HIP
OR FOREARM SCANS

No. of Trend test

osteoporotic Prevalence Relative risk*
Model Scan sites (%) (95% CI) 2 p Value

1 Hip 1 30 2.43 (1.86, 3.19) 83.14 0.0001

2 12 4.47 (3.37, 5.93)
3 7 5.34 (3.95, 7.23)
4 9 8.65 (6.71, 11.16)
Forearm 1 52 1.92 (1.57, 2.36) 55.19 0.0001
2 9 3.83 (3.00, 4.89)
2 Hip 1 10 2.19 (1.64, 2.93) 73.15 0.0001
2 8 3.06 (2.32, 4.03)
3 8 4.17 (3.26, 5.35)
4 12 5.73 (4.71, 6.98)
Forearm 1 17 1.73 (1.40, 2.13) 41.47 0.0001
2 17 2.70 (2.25, 3.24)
3 Hip 1 7 2.60 (1.88, 3.59) 77.97 0.0001
2 6 3.19 (2.37, 4.28)
3 6 4.61 (3.54, 6.00)
4 16 5.97 (4.95, 7.21)
Forearm 1 8 2.34 (1.81, 3.04) 52.36 0.0001
2 19 3.56 (3.01, 4.21)

Relative risks were calculated for women with a given number (0) of osteoporotic ROIs in a hip or forearm scan in comparison to
those without osteoporotic ROI in the corresponding site.
a
Relative risk was for either hip or spine fracture during the study and relative to subjects with zero osteoporotic ROI.

better prediction of osteoporotic fractures than does age
alone, and may be more relevant to classification. An addi-
tional advantage of the risk-based diagnostic criteria is that
risk information from multiple sources can be integrated
into the estimation of global risk of fractures.
Using an older rather than younger reference age in T score
calculations reduces age-related loss discrepancies between
sites for postmenopausal women. Prevalence is still not equal
because each manufacturers T score is normalized by unique
population SDs. To compensate, site and technology-specific T
score thresholds for osteopenia and osteoporosis could be
developed that, for large populations, would produce equiva-
lent prevalence to a reference site such as the femoral neck.
This approach is being considered by the joint committees of
the NOF and ISCD and is outlined in Faulkner et al.(13)
Although this approach could be implemented with existing
reference curves, prevalence-based approaches generally are
intended for epidemiological study. Also, this type of approach
does not explicitly take into account fracture risk estimates that
can differ by more than a factor of 2. It is not clear how well
this approach would work to reduce inconsistent diagnoses in
individual patients when different measurement techniques are
used.
As expected, the risk-based diagnostic criteria used in this
study were shown to be preferable based on the consistency
among different BMD measurements. This supports the
proposal by Kanis and Gluer for the Committee of Scientific
Advisors of IOF.(24) The risk-based approach of model 3 is
still dependent on the population used to derive the esti-
mates of fracture probability. Although we do not have data
to confirm it, we can speculate that the estimation equations
derived from different populations will result, somewhat, in
inconsistent osteoporosis diagnoses. The use of risk-based
diagnostic criteria does not reduce the need for a standard
reference population.
A substantial disadvantage of a risk-based approach in
clinical use is that it requires prospective clinical studies for
the risk of fractures, which are expensive and time consum-
ing. Almost all of the prospective data available to link
BMD and fracture pertain to elderly white women; yet
interest is growing in assessing osteoporosis risk in women
under the age of 65 years, in nonwhite women, and in men.
Thus, it will be difficult to establish clinical thresholds for
new techniques and populations other than white women.
Also, risk estimates based on BMD may not be very accu-
rate because BMD is only one of many factors that influence
fracture risks.(17) The use of cross-sectional studies has been
proposed to evaluate diagnostic cut-off values based on
observed odds ratios (ORs). Possible limitations of such an
approach are that selection of fracture cases can produce biases
and, further, the observed BMD already may be affected by the
fracture and may differ from the prospective studies.
The selection of hip and/or spine fracture as the osteo-
porotic fractures in this study was based on their relative
clinical importance and abundance. In unpublished work
and other conference presentations,(9,10) we have performed
similar analyses using only hip or spine fracture as the
endpoints. The results were very similar to the results in this
article and are available through the corresponding author.
The cut-off value of 14.6% for osteoporotic fracture in
model 3 was derived to make the prevalence of osteoporosis
at the femoral neck comparable with the other two models
so that comparison among models would be possible. It was
not optimally selected and was not based on any clinical
BMD CLASSIFICATIONS FOR OSTEOPOROSIS
validation. Such a cut-off value requires further careful
study and should not be used directly for clinical applica-
tions without further validation. In the Appendix, we pro-
vide a formula and corresponding parameters for calculating
the corresponding BMD value for given percentages of
cut-off points. This allows the reader to select the risk levels
and derive BMD cut-off values accordingly.
Regardless of which definition of osteoporosis is used, we
should always expect inconsistencies when measuring dif-
ferent body sites because of biological and technical varia-
tions. However, it is important to examine whether the
proportion of misdiagnosed patients is small enough to
offset the cost of identifying them and whether this addi-
tional knowledge enhances the prognostic information and
changes the treatment strategy. Although there have been
limited studies of the cost-effectiveness of the use of
BMD,(1,28) Black et al.(14) compared the risk of hip fractures
using BMD of the femoral neck and lumbar spine. They
found that by altering the cut-off values of the T score to
2.2 for femoral neck BMD, they could get a classification
with the same risk prediction power as using either a neck
or spine BMD with a T score less than 2.5. They con-
cluded that the additional spine scan was unjustified.
Our approach of combining BMD parameters from a
given site has several differences from that study. First, we
used a combination of a scan of the hip or forearm, which
gives more information than assessment of a single param-
eter. Second, our comparison was based on individual pa-
tients, not the similarity in statistical properties of popula-
tions. Although diagnosis and risk assessment are two
different concepts with different uses, we only wish to
emphasize that combining available information on diagno-
sis from the same scan can provide prognostic information
and should not be ignored.
This study has several limitations. First, our conclusions
are limited to women over the age of 65 years, to BMD
measured by DXA/SPA, and to hip and/or spinal fractures,
and may not apply to other bone measures, other osteopo-
rotic fractures, or other populations. With the rapid devel-
opment of new bone mineral measurement technologies,
including quantitative ultrasound, it is important to deter-
mine the appropriate selection of single and/or multiple
technologies and to integrate this information and its appro-
priate use into patient management.
Second, the hip and spinal fractures used in this article
had different time windows. Hip fractures occurred within 5
years after all BMD measurements. However, spinal frac-
tures could have occurred before the hip and spine DXA
scans. Thus, the risk of incident spinal fractures for some
participants may not be evaluated prospectively, as were the
hip fractures. The window of spinal fractures averaged
about 3.7 years, which is different from hip fractures. Thus,
fracture outcomes may be weighted more toward hip frac-
tures than spine fractures. Given the relative clinical impor-
tance of hip fractures, a slight overemphasis on hip fractures
may be reasonable. Our osteoporotic fracture risk estimation
only serves as a surrogate measure of the risk of future
fractures. However, separate analyses indicated that our
conclusions remained the same regardless of whether we
studied only hip fracture or only spine fracture based on the
same population.(9,10)
909
Third, the calcaneal and forearm BMD measures were
obtained 2 years before the hip and spine BMD. Although it
seems unlikely, we do not know whether the difference in
measurement time would affect the conclusions.
Fourth, the statistical method used in this article may
introduce some biases in favor of model 2 and model 3 over
model 1. Model 2 used women aged 65 years at baseline of
the SOF study as reference. Thus, the reference data used in
model 2 is part of the SOF data to be evaluated and is more
consistent for other age groups than the reference data used
in model 1. Using the 10-fold cross-prediction, model 3
built classification rules using data different from the data to
be evaluated. Nevertheless, it still used SOF data of all age
ranges. Such biases are not thought to be substantial enough
to change the conclusions. The observed differences among
the three models can be attributed mainly to the method-
ological differences in patient classifications.
In summary, we conclude that standardization of normative
data, perhaps referenced to an older population, may be nec-
essary for applying T scores as diagnostic criteria in patient
management. A risk-based osteoporosis classification does not
depend on the manufacturers reference data and may be more
consistent and efficient in patient diagnosis.
ACKNOWLEDGMENT
We thank David Breazeale for editorial assistance and
manuscript preparation. We also thank both reviewers and
editors for their comments and suggestions.
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