Osteoporos Int (2011) 22:731737

DOI 10.1007/s00198-010-1320-4

ORIGINAL ARTICLE

Risk of fractures associated with treatment for benign

prostate hyperplasia in men
P. Vestergaard & L. Rejnmark & L. Mosekilde

Received: 10 March 2010 / Accepted: 1 June 2010 / Published online: 15 June 2010
# International Osteoporosis Foundation and National Osteoporosis Foundation 2010

Abstract
Summary Treatment of benign prostate hyperplasia with blockers may affect blood pressure while treatment with 5-reductase inhibitors may affect conversion of testosterone
potentially leading to osteoporosis. In our study, neither 5-reductase inhibitors nor -blockers were associated with
negative effects on fractures, -blockers perhaps being
associated with a limited decrease in fractures.
Introduction The objective is to study fracture risk associated
with drugs for benign prostate hyperplasia. The hypotheses
were that (1) -blockers may elevate fracture risk by causing
presyncope/falls and (2) 5--reductase inhibitors may elevate
fracture risk by lowering dihydrotestosterone.
Methods This is a nationwide case-control study using all
9,719 male fracture patients aged 60 years in the year 2000
as cases and drawing 29,156 age- and gender-matched
controls. The main exposure was the use of the drugs
mentioned above for benign prostate hyperplasia. Confounder
control included social variables, contacts to hospitals and
general practitioners, alcoholism and other variables.
Results For the 5--reductase inhibitors, no change in
overall risk of fractures was seen. No change in risk of
hip, spine and forearm fractures was present. For the blockers, a decrease in overall risk of fractures was seen, as
well as a decrease in the risk of hip and spine fractures, but
only at average doses >0.5 defined daily doses per day. No
P. Vestergaard : L. Rejnmark : L. Mosekilde
Department of Endocrinology and Internal Medicine,
Aarhus University Hospital,
Aarhus, Denmark
P. Vestergaard (*)
The Osteoporosis Clinic, Aarhus University Hospital,
Tage Hansens Gade 2,
8000 Aarhus C, Denmark
e-mail: p-vest@post4.tele.dk

decrease was seen for forearm fractures. A decreasing risk

of any fracture, hip fractures and spine fractures were seen
with increasing dose of -blockers, while no such association was seen for the forearm fractures.
Conclusion Neither the 5--reductase inhibitors nor blockers were associated with negative effects on fracture
risk. A small trend towards a decrease in fracture risk may
be present for the -blockers. However, more research is
needed to confirm if this trend is real.
Keywords 5--reductase inhibitors . Benign prostate
hyperplasia . Fracture . -blockers

Introduction
Benign prostate hyperplasia (BPH) is a frequent condition in elderly men [1]. Little is known on the effects of
drugs to treat BPH on the skeleton. Treatment with 5-reductase inhibitors (finasteride, dutasteride) may in
theory reduce the conversion of testosterone to dihydrotestosterone [2] but apparently does not increase the risk of
sexual dysfunction or gynecomastia compared to controls
[3]. However, it is not clear if such treatment may be
associated with an increase in the risk of fractures. One
prior study failed to show an excess risk of hip fractures in
users of finasteride [4]. However, the number of men
exposed to finasteride was limited (109 and 141 in the
case and control group, respectively) [4]. Three randomised controlled trial of finasteride and dutasteride failed
to show any effect of 5--reductase inhibition on bone
mineral density (BMD) [57], even after 4 years of followup [7]. Also, no detrimental effects of dutasteride on
biochemical markers of bone turnover have been demonstrated [2, 8].

732

However, besides the 5--reductase inhibitors, adrenergic

-receptor blockers are also widely used to alleviate the
symptoms of BPH. The -receptor blockers have the
added effect that they may lower blood pressure [9],
which could lead to dizziness [10] and thus an increased
risk of falls and fractures. One prior study failed to show
any association between -blocker exposure and risk of
fractures [11], while another reported an increased risk of
fractures [12]. A further study showed that the fracture risk
associated with -receptor blockers seemed limited to
those who used them for cardiovascular disease [13]. A
meta-analysis of drugs used for hypertension failed to
show an association between use of -receptor blockers
and risk of fractures [14]. Besides the effects on blood
pressure, no evidence exists for an effect of the -blockers
on bone turnover and BMD. Only indirect evidence exists
for an effect of agonists on the osteoclast differentiation,
and thus a potential effect of the -blockers [15].
Thus, only one prior study on 5--reductase inhibitors
exists, covering only hip fractures [4]. The study addressed
the cumulative dose of drugs and not measures of daily
dose. Also, the study was limited in size.
For the -blockers, one study addressed both -blockers
used for hypertension and for BPH [13]. It did thus not
specifically address the -blockers used for BPH. One
further study used a composite end point of falls, fractures
and hypotension related events, i.e. not looking at fractures
per se [9]. The meta-analysis did mainly look at -blockers
used for hypertension [14].
The current study thus aimed at assessing the association
of 5--reductase inhibitors and -blockers used specifically
for BPH and their effect on:
1. the overall risk of fractures, the risk of hip, spine and
forearm fractures,
2. the average daily dose on risk of fractures and
3. the duration of treatment on risk of fractures.

Material and methods

Study design
The study was designed as a case-control study. All male
subjects aged 60 years or above sustaining a fracture
during the year 2000 in Denmark were included as cases
(n=9,719), and for each case, three subjects of the same
age (same birth year) and gender were randomly selected
from the background population as controls (n=29,156).
Fracture risk increases with age especially after the age of
60 in men [16] and also the prevalence of BPH, and thus,
the use of drugs against this is rare below the age of 60. A
cut-off value of 60 years was thus chosen.

Osteoporos Int (2011) 22:731737

End points
The study end points were occurrence of any fracture (ICD10
codes: S02.0S02.9, S07.0S07.9, S12.0S12.9, S22.0
S22.9, S32.0S32.8, S42.0S42.9, S52.0S52.9, S62.0
S62.9, S72.0S72.9, S82.0S82.9, S92.0S92.9) between
January 1 2000 and December 31, 2000. In Denmark, almost
all patients with fractures are managed in the hospital system
(also including the emergency rooms) [17], even fractures
sustained abroad are registered upon return for insurance
reasons. The capture of fractures is thus high [18, 19]. The
vertebral fractures included were clinical fractures collected
from hospital records of patients referred to emergency
rooms or other departments and patients who had a vertebral
fracture diagnosed.
Exposure variables
The primary exposure variables were use of either 5-reductase inhibitors (finasteride or dutasteride) or -blockers
(alfuzosin, doxazosin, tamsulosin, terazosin). In Denmark,
these drugs are only licensed to use for BPH. The -blockers
mentioned are not licensed to treat say hypertension, and
prescription is thus limited to benign hypertension.
The exposure was defined as ever use of these drugs
or not. Duration was calculated from the first use after
January 1, 1996 and the occurrence of a fracture during
the year 2000 among the fracture patients or the
corresponding dummy date among the controls. The total
dose was calculated as the total number of redeemed
daily doses of the drug in question from the first day of
use to the date of fracture or corresponding dummy date
among the control subjects. Average daily dose was
calculated as total dose divided by time from first use to
the date of fracture or corresponding dummy date among
the controls. Regarding recency, this was defined as the
last date where a prescription of the drug in question was
made.
The other exposure variables were occurrence of (1) the
use of drugs known to be associated with fracture risk
(corticosteroids, anti-epileptic drugs, LHRH agonists), (2)
the number of contacts to the health service (hospitals,
general practitioners or specialists) as a proxy variable for
disease severity [20], and the Charlson index, which is an
index of 19 comorbid conditions [21], and (3) social
variables [22]. These factors were chosen as they were
known to potentially affect fracture risk, and were regarded
as important potential confounders in a setting where many
variables besides the main factor may influence the risk of
fractures (confounding by indication). The variables were
entered into the statistical analysis, and analyses for
interaction were performed. Other important disease confounders included (1) alcoholism [23], (2) occurrence of a

Osteoporos Int (2011) 22:731737

prior fracture or not [24], (3) prostate cancer and (4)

orchiectomy.
The social variables were: (1) working or not, (2) income
in the year of the fracture (dichotomised by average
income) and (3) living alone or together with another
person. These factors were included as prior studies have
indicated that living in a relationship rather than living
alone may be associated with a decreased risk of fractures,
and that having a job may be associated with fewer
fractures than being retired or out of a job, and that income
in some settings may be a predictor of fracture risk [22].
Registers used
The information on fracture occurrence and occurrence of
other diseases, prior fractures, alcoholism came from two
registers: (1) The National Hospital Discharge Register [18]
and (2) The Psychiatric Central Register [25].
The National Hospital Discharge Register was founded
in 1977 [18]. It covers all in-patient contacts from 1977 to
1994, and also from 1995, all outpatient visits to hospitals,
outpatient clinics and emergency rooms [18]. Upon
discharge, the physician codes the reason for the contact
using the ICD system. The code used is at the discretion of
the individual physician. The register has a nationwide
coverage and an almost 100% capture of contacts [18]. In
general, the validity of registrations is high [19] especially
for fractures where a precision of 97% has been reported
both for fractures treated on an in-patients basis and for
fractures treated on an outpatient basis via emergency
rooms (say a forearm fracture) [26]. The cases occurred
only once in the analyses with the first occurrence of an
incident fracture during the year 2000.
The National Health Service keeps a register of all
contacts to general practitioners for reimbursement purposes. The register does not contain ICD codes for the
contacts but codes for the nature of the contact (regular
check-up visit, routine vaccination in children).
The number of bed days in the year 1999 was counted as
the number of days the patient spent on an in-patient basis
in any hospital in 1999. The number of contacts to general
practitioner or specialist was counted as the total number of
reimbursement codes issued by the general practitioner or
specialist in the year 1999 for each patient.
The Danish Medicines Agency keeps a nationwide
register of all drugs sold at pharmacies throughout the
country from 1996 and onwards (The National Pharmacological Database run by the Danish Medicines Agency,
http://www.dkma.dk). Any drug bought is registered with
ATC code, dosage sold and date of sale for the period
January 1 1996 to December 31, 2000. As all sales are
registered to the individual who redeemed the prescription,
the capture and validity is high.

733

The psychiatric central register along with the National

Hospital Discharge Register and the database on drugs sold
formed the basis of classification as having a diagnosis of
alcoholism or using drugs against alcoholism.
Information on income was obtained from the Tax
authorities, and information on working status and marital
status from the National Bureau of Statistics (Statistics,
Denmark).
It is possible to link these sources of information through
the Central Person Register Number, which is a unique
registration code given to every inhabitantto some degree
similar to the American social security numberthat
allows registration on an individual basis.
The project was approved and controlled by the National
Board of Health, the Danish Data Protection Agency and
the Directory Board of the Psychiatric Central Register.
Statistical analyses
Mean and standard deviation were used as descriptive
statistics. Crude and adjusted odds ratios (ORs), and 95%
confidence intervals were calculated. A conditional logistic
regression analysis was used to assess the association
between any fracture and the exposure variable. Crude
and multiply adjusted ORs were calculated. Analyses were
performed using STATA 8.2 (STATA Corp., College
Station, TX) and SPSS 14.0 (SPSS Inc., Chicago, IL), both
in the UNIX version.

Results
Table 1 shows baseline characteristics of the patients and
controls. The patients and controls were well matched
concerning age and gender. Fracture cases more often than
controls had comorbid conditions, had a diagnosis of
alcoholism and had prior fractures. The frequency of use
of 5--reductase inhibitors or use of -blockers was higher
among fracture cases than among controls.
Table 2 shows the crude risk of any fracture associated
with 5--reductase inhibitors and -blockers. There was a
small excess risk of any fracture with both the 5-reductase inhibitors and the -blockers. No doseresponse
relationship was present for the 5--reductase inhibitors,
while for the -blockers a decreasing risk of fractures was
present with increasing average daily dose (for trend,
p<0.01).
Table 3 shows the adjusted risk of any fracture
associated with the 5--reductase inhibitors and blockers. After adjustment, no significant decrease in the
risk of any fracture was present for the 5--reductase
inhibitors, while a significant decrease was seen for the blockers. At average doses larger than 0.5 defined daily

734
Table 1 Baseline characteristics
of fracture cases and controls
only men 60 years

GP general practitioner, DKR

Danish crowns (5.5 DKRUS
$1), ACE angiotensinconverting enzyme, ARB Angiotensin II receptor blockers
a

A composite index of 19 comorbid conditions (see text)

Osteoporos Int (2011) 22:731737

Variable

Cases (n=9,719)

Controls (n=29,156)

Age (years)
Annual income (DKR)
Previous fracture
Number of bed days in hospital in 1999
Charlson indexa
0
12
34
5
No. of contacts to GP or specialists in 1999
Living with someone
Working
Duration of follow-up before the index date
Alcoholism
Ever use of anti-epileptic drugs

74.59.6
169.209156.137
3,192 (32.8%)
7.829.3

74.59.6
180.818309.360
3,185 (10.9%)
20.243.2

<0.01
<0.01

4,588 (47.2%)
3,210 (33.0%)
1,261 (13.0%)
660 (6.8%)
37.656.9
5,548 (57.5%)
1,204 (12.5%)
43,250 years
1,004 (10.3%)
941 (9.7%)

18,122 (62.2%)
8,169 (28.0%)
2,098 (7.2%)
767 (2.6%)
25.840.2
19,246 (66.4%)
4,401 (15.2%)
129,744 years
957 (3.3%)
1,363 (4.7%)

<0.01
<0.01
<0.01

<0.01
<0.01

6,243 (64.2%)
2,925 (30.1%)
2,286 (23.5%)
615 (6.3%)
643 (6.6%)
1,800 (18.5%)
138 (1.4%)
1,372 (14.1%)
2,020 (20.8%)
7,694 (79.2%)
5,208 (53.6%)
663 (6.8%)
1,356 (14.0%)
395 (4.1%)
26 (0.3%)
230 (2.4%)

17,063 (58.5%)
5,555 (19.1%)
6,262 (21.5%)
1,005 (3.4%)
1,918 (6.6%)
5,016 (17.2%)
418 (1.4%)
4,219 (14.5%)
5,608 (19.2%)
17,941 (61.5%)
7,506 (25.7%)
1,806 (6.2%)
3,663 (12.6%)
613 (2.1%)
25 (0.1%)
377 (1.3%)

<0.01
<0.01
<0.01
<0.01
0.90
<0.01
0.92
0.39
<0.01
<0.01
<0.01
0.03
<0.01
<0.01
<0.01
<0.01

Ever use of any glucocorticoid

Loop diuretics
Thiazide diuretics
Potassium-sparing diuretics
Other diuretics
ACE inhibitors/ARB
-blocking agents for hypertension
Beta blockers
Calcium channel blockers
Weak analgesics
Strong analgesics
Ever use of 5--reductase inhibitors
Ever use of -blocking agents for BPH
Prior prostate cancer
LHRH agonists
Orchiectomy

Table 2 Crude OR for any fracture among users of 5--reductase

inhibitors or -blockers
Drug

OR (95% CI)

-blockers
Average daily dose of -blocker
0.1 DDD per day (532/1268)
0.110.5 DDD per day (408/1069)
>0.5 DDD per day (416/1326)
5--reductase inhibitors
Average daily dose of 5--reductase inhibitors
0.1 DDD per day (203/559)
0.110.5 DDD per day (242/558)
>0.5 DDD per day (218/689)

1.13 (1.061.21)*

*: 2p<0.05

1.28
1.16
0.96
1.11

(1.151.42)*
(1.041.31)*
(0.851.07)
(1.011.22)*

1.10 (0.931.29)
1.31 (1.121.53)*
0.96 (0.821.11)

<0.01

doses (DDD) per day, a statistically significant decrease

was seen for both 5--reductase inhibitors and -blockers.
No trend with dose was seen for the 5--reductase
inhibitors, while a decreasing trend with increasing dose
was seen for the -blockers (for trend, p<0.01).
Table 4 shows the results for hip, forearm and spine
fractures. For the hip fractures, no reduction in overall risk
was seen for the 5--reductase inhibitors, while a decrease
was seen for the -blockers. For the -blockers, a small
reduction in risk of hip fractures was present for the highest
doses, while for the 5--reductase inhibitors, a reduction was
seen for the lowest doses. For the hip fractures, a significant
decrease in fracture risk was present with dose for the blockers, but not for the 5--reductase inhibitors. For the
forearm fractures, no significant change in fracture risk was
present.For the spine fractures, a pattern similar to the hip
fractures was present with a decrease at the highest doses of
the -blockers and a decrease with increasing dose. For the

Osteoporos Int (2011) 22:731737

735

Table 3 Adjusted OR for any fracture among users of 5--reductase

inhibitors or -blockers

Table 5 Effect of duration of treatment on risk of any fracture

Duration (years)

Drug

OR (95% CI)

-blockers
Average daily dose of -blocker
(DDD per day)
0.1
0.110.5
>0.5
5--reductase inhibitors

0.93 (0.861.00)

1.05
0.91
0.83
0.93

Average daily dose of 5--reductase

inhibitors (DDD per day)
0.1
0.110.5
>0.5

0.88 (0.741.05)
1.08 (0.911.28)
0.84 (0.710.99)*

(0.931.17)
(0.801.04)
(0.740.94)*
(0.841.03)

Adjusted for prior fracture, ever use of corticosteroids, ever use of

drugs against epilepsy, ever use of strong analgesics, ever use of weak
analgesics, Charlson index, number of bed days in 1999, number of
contacts to GP or specialist in 1999, alcoholism, income, working or
not, living with someone or living alone, use of beta blockers, use of
calcium channel blockers, use of ACE inhibitors/angiotensin II
receptor blockers, -blockers as antihypertensives, loop diuretics,
thiazide diuretics, potassium-sparing and other types of diuretics,
prostate cancer, orchiectomy and use of LHRH agonists
*: 2p<0.05

5--reductase inhibitors, an increase was present at the

lowest doses, and no doseresponse was present.
Table 5 shows the effect of treatment duration on risk of
any fracture. For the 5--reductase inhibitors, no trend with
duration was present. For the -blockers, the time interval
13 years of treatment was associated with a decrease in the
risk of fractures.

OR (95% CI)

-blocker
1
1.13
>3
5--reductase inhibitors
3
3.15
>5

0.93 (0.831.05)
0.86 (0.750.98)*
0.98 (0.871.11)
0.91 (0.761.09)
1.01 (0.851.19)
0.88 (0.751.03)

Adjusted for prior fracture, ever use of corticosteroids, ever use of

drugs against epilepsy, ever use of strong analgesics, ever use of weak
analgesics, Charlson Index, number of bed days in 1999, number of
contacts to GP or specialist in 1999, alcoholism, income, working or
not, living with someone or living alone, use of beta blockers, use of
calcium channel blockers, use of ACE inhibitors/angiotensin II
receptor blockers, -blockers as antihypertensives, loop diuretics,
thiazide diuretics, potassium-sparing and other types of diuretics,
prostate cancer, orchiectomy, and use of LHRH agonists.
*: 2p<0.05

Table 6 shows the effects of age. No trend with age was

present for the 5--reductase inhibitors while for the blockers, the effect tended to be more pronounced in those
older than 80 years than in younger men but only for the
average doses >0.5 DDD per day.
The effect of -blockers on overall risk of fractures
disappeared more than 3 month after last use (for any
fracture: for 3 months, adjusted OR=0.76, 95% confidence
of intervals (CI): 0.670.86; for 3 months2 years after last
use, crude OR=1.05, 95% CI: 0.931.18; >2 years since last
use, crude OR=1.03, 95% CI: 0.911.16). For the 5--

Table 4 Adjusted OR for hip, forearm and spine fractures

Drug

Hip

Forearm

Spine

-blockers
Average daily dose of -blocker (DDD per day)
0.1
0.110.5
>0.5
5--reductase inhibitors
Average daily dose of 5--reductase inhibitors (DDD per day)
0.1
0.110.5
>0.5

0.86 (0.740.99)*

0.89 (0.681.16)

0.99 (0.711.39)

0.99
0.89
0.71
0.92

1.17
0.71
0.73
1.21

1.52
1.10
0.56
1.15

(0.801.22)
(0.701.12)
(0.570.90)*
(0.771.11)

0.57 (0.400.82)*
1.25 (0.931.68)
0.99 (0.741.32)

(0.811.69)
(0.441.16)
(0.461.15)
(0.851.72)

1.14 (0.642.04)
1.13 (0.632.04)
1.39 (0.772.50)

(0.932.48)
(0.621.95)
(0.320.97)*
(0.741.77)

2.48 (1.155.32)*
0.97 (0.471.98)
0.79 (0.401.56)

Adjusted for prior fracture, ever use of corticosteroids, ever use of drugs against epilepsy, ever use of strong analgesics, ever use of weak
analgesics, Charlson index, number of bed days in 1999, number of contacts to GP or specialist in 1999, alcoholism, income, working or not,
living with someone or living alone, use of beta blockers, use of calcium channel blockers, use of ACE inhibitors/angiotensin II receptor blockers,
-blockers as antihypertensives, loop diuretics, thiazide diuretics, potassium-sparing and other types of diuretics, prostate cancer, orchiectomy and
use of LHRH agonists
*: 2p<0.05

736

Osteoporos Int (2011) 22:731737

Table 6 Effects of age group on risk of any fracture

Average daily drug dose
-blockers (DDD per day)
0.1
0.110.5
>0.5
5--reductase inhibitors (DDD per day)
0.1
0.110.5
>0.5

6069years

7079years

80years

1.05 (0.811.35)
0.84 (0.641.12)
0.85 (0.641.11)

1.17 (0.961.42)
0.91 (0.731.13)
1.02 (0.831.24)

1.01 (0.851.20)
0.99 (0.811.20)
0.72 (0.600.88)*

0.88 (0.571.36)
0.69 (0.441.07)
0.66 (0.411.08)

0.84 (0.631.13)
0.98 (0.751.30)
0.85 (0.641.12)

0.94 (0.731.22)
1.41 (1.101.80)*
0.93 (0.741.18)

Adjusted for prior fracture, ever use of corticosteroids, ever use of drugs against epilepsy, ever use of strong analgesics, ever use of weak
analgesics, Charlson index, number of bed days in 1999, number of contacts to GP or specialist in 1999, alcoholism, income, working or not,
living with someone or living alone, use of beta blockers, use of calcium channel blockers, use of ACE inhibitors/angiotensin II receptor blockers,
-blockers as antihypertensives, loop diuretics, thiazide diuretics, potassium-sparing and other types of diuretics, prostate cancer, orchiectomy and
use of LHRH agonists.
*: 2p<0.05

reductase inhibitors, any effects were also only seen with use
within the last 6 months: adjusted OR=0.80, 95% CI: 0.67
0.95; 6 month3 years, OR=1.01, 95% CI: 0.851.21;
>3 years since last use OR=0.99, 95% CI: 0.851.16).

Discussion
In this large-scale population-based case-control study, no
increase in the risk of fractures at any of the sites studied was
seen for the 5--reductase inhibitors. Also, no doseresponse
relationship was present for the 5--reductase inhibitors. The
few significant findings for the 5--reductase inhibitors did
not show any pattern and may be due to chance findings. For
the -blockers, a trend towards fewer fractures was seen both
for overall risk of fractures, hip fractures and spine fractures,
while no trend was present for the forearm fractures. In the
interpretation of the results, it should be noted that only a few
subgroup analyses showed statistical significance and chance
findings are a possibility.
None of the prior studies have specifically addressed the
-blockers used for BPH, but the study by Souverein et al.
[13] which addressed all -blockers, both those for
cardiovascular disease and those for BPH, failed to show a
decreasing trend in hip fracture risk with cumulated dose.
The study observed an excess hip fracture risk for the blockers used for cardiovascular disease early after treatment
initiation. This may signal that the -blockers used for BPH
may have a particular effect, which may differ from those
used against hypertension. However, a selection bias may
also be a possibilitythose with a high risk of falls are not
treated with the -blockers of fear from falls [9]. This is the
first major study on -blockers used specifically for BPH
with fractures as end point. The dose dependent decrease in
risk of fractures for several fracture types with -blockers

may indicate that the relationship may be causal. If the

relationship was spurious, those falling would terminate the
drugs and thus those with low exposures should have an
excess risk of fractures, and those who tolerate the drugs
should not have any decrease in the risk of fractures. Only
for the spine fracture was an excess risk of fractures seen
with low doses, while a decrease was seen for hip fractures.
This speaks against a spurious relationship. However, more
studies are needed to confirm the effect. The blood pressurelowering effect of the -blockers used for BPH may
decrease urine calcium loss [27], and the effect on fracture
risk may thus be the same as seen for other drugs used
against hypertension [28]. If this truly is the mechanism, the
effect should be limited to patients with high blood pressure.
More research is needed to determine the limits above which
blood pressure lowering may prevent fractures as well as
establish the limits below which blood pressure should not
be lowered. Analyses of secondary end points from the large
randomised controlled trials on antihypertensives may prove
a good source for such studies.
It also needs to be established if the fracture prevention
is solely limited to a blood pressure effect or whether a
direct effect on the -receptors may also play a role.
Treatment with epinephrine, an -receptor agonist, has
shown to increase osteoclast differentiation factor [15]. It
may thus be that inhibition of this signal may decrease
osteoclast activity, bone remodelling and bone loss.
However, more work is needed to confirm this hypothesis.
The absence of a decrease in risk of any fracture less than
1 year after the start of the -blockers followed by a decrease
13 years after the start and a reversal to no increase or
decrease in risk of any fracture more than 3 years after start of
the -blocker may signal a double effect. First of all, it may
take some time for the blood pressure to decrease and urine
calcium excretion to adapt, therefore an effect is first seen after

Osteoporos Int (2011) 22:731737

some time. However, this time dependency could also signal

an effect mediated over BMD, which takes some time to set
in. Secondly, the lack of an effect with more than 3 years of
treatment may be the effect of lack of adherence or an
adaption to the effects of the -blockers, so that some of the
initial effect is lost. The age effect with a more pronounced
effect in older men may be due to a higher risk of hypertension
with age [29], and perhaps also a higher risk of osteoporosis
and fractures with age [16].
The main advantage of the study is the large study size,
the long duration of follow-up and the completeness and
quality of diagnoses during follow-up. The major drawbacks are lack of information on individual parameters such
as weight, height, blood pressure, and smoking.
In conclusion, neither the 5--reductase inhibitors nor blockers were associated with negative effects on fracture
risk. A small trend towards a decrease in fracture risk may
be present for the -blockers. However, more research is
needed to confirm if this trend is real.

737

10.
11.

12.

13.

14.

15.

16.

17.

Conflicts of interest None.

18.

References
1. Bushman W (2009) Etiology, epidemiology, and natural history of
benign prostatic hyperplasia. Urol Clin N Am 36:403415, v
2. Tollin SR, Rosen HN, Zurowski K, Saltzman B, Zeind AJ, Berg
S, Greenspan SL (1996) Finasteride therapy does not alter bone
turnover in men with benign prostatic hyperplasiaa Clinical
Research Center study. J Clin Endocrinol Metab 81:10311034
3. Djavan B, Chapple C, Milani S, Marberger M (2004) State of the
art on the efficacy and tolerability of alpha1-adrenoceptor
antagonists in patients with lower urinary tract symptoms
suggestive of benign prostatic hyperplasia. Urol 64:10811088
4. Jacobsen SJ, Cheetham TC, Haque R, Shi JM, Loo RK (2008)
Association between 5-alpha reductase inhibition and risk of hip
fracture. JAMA 300:16601664
5. Amory JK, Anawalt BD, Matsumoto AM, Page ST, Bremner WJ,
Wang C, Swerdloff RS, Clark RV (2008) The effect of 5alphareductase inhibition with dutasteride and finasteride on bone mineral
density, serum lipoproteins, hemoglobin, prostate specific antigen
and sexual function in healthy young men. J Urol 179:23332338
6. Matzkin H, Chen J, Weisman Y, Goldray D, Pappas F, Jaccard N,
Braf Z (1992) Prolonged treatment with finasteride (a 5 alphareductase inhibitor) does not affect bone density and metabolism.
Clin Endocrinol (Oxf) 37:432436
7. Matsumoto AM, Tenover L, McClung M, Mobley D, Geller J,
Sullivan M, Grayhack J, Wessells H, Kadmon D, Flanagan M,
Zhang GK, Schmidt J, Taylor AM, Lee M, Waldstreicher J (2002)
The long-term effect of specific type II 5alpha-reductase inhibition
with finasteride on bone mineral density in men: results of a 4year placebo controlled trial. J Urol 167:21052108
8. Andriole GL, Kirby R (2003) Safety and tolerability of the dual
5alpha-reductase inhibitor dutasteride in the treatment of benign
prostatic hyperplasia. Eur Urol 44:8288
9. Chrischilles E, Rubenstein L, Chao J, Kreder KJ, Gilden D, Shah
H (2001) Initiation of nonselective alpha1-antagonist therapy and
occurrence of hypotension-related adverse events among men

19.

20.
21.

22.

23.

24.

25.
26.

27.

28.

29.

with benign prostatic hyperplasia: a retrospective cohort study.

Clin Ther 23:727743
Dutkiewics S (2001) Efficacy and tolerability of drugs for treatment
of benign prostatic hyperplasia. Int Urol Nephrol 32:423432
Hall GC, McMahon AD (2007) Comparative study of modified
release alpha-blocker exposure in elderly patients with fractures.
Pharmacoepidemiol Drug Saf 16:901907
Lee J, Choi NK, Jung SY, Kim YJ, Seong JM, Oh SJ, Park BJ (2009)
The risk of fracture with taking alpha blockers for treating benign
prostatic hyperplasia. J Prev Med Public Health 42:165170
Souverein PC, Van Staa TP, Egberts ACG, De la Rosette JJMCH,
Cooper C, Leufkens HGM (2003) Use of alpha-blockers and the
risk of hip/femur fractures. J Intern Med 254:548554
Wiens M, Etminan M, Gill SS, Takkouche B (2006) Effects of
antihypertensive drug treatments on fracture outcomes: a metaanalysis of observational studies. J Intern Med 260:350362
Takeuchi T, Tsuboi T, Arai M, Togari A (2001) Adrenergic
stimulation of osteoclastogenesis mediated by expression of
osteoclast differentiation factor in MC3T3-E1 osteoblast-like
cells. Biochem Pharmacol 61:579586
Vestergaard P, Rejnmark L, Mosekilde L (2005) Osteoporosis is
markedly underdiagnosed: a nationwide study from Denmark.
Osteoporos Int 16:134141
Vestergaard P, Emborg C, Stving R, Hagen C, Mosekilde L,
Brixen K (2002) Fractures in patients with anorexia nervosa,
bulimia nervosa, and other eating disorders a nationwide
register study. Int J Eat Disord 32:301308
Andersen T, Madsen M, Jrgensen J, Mellemkjr L, Olsen J (1999)
The Danish National Hospital Register. Dan Med Bull 46:263268
Mosbech J, Jrgensen J, Madsen M, Rostgaard K, Thornberg K,
Poulsen T (1995) The Danish National Patient Register: evaluation of data quality. Ugeskr Laeger 157:37413745
Vestergaard P, Rejnmark L, Mosekilde L (2004) Fracture risk
associated with use of anti-epileptic drugs. Epilepsia 45:13301337
Charlson M, Pompei P, Ales K, MacKenzie C (1987) A method of
classifying prognostic comorbidity in longitudinal studies: development and validation. J Chron Dis 40:373383
Vestergaard P, Rejnmark L, Mosekilde L (2006) Socioeconomic
aspects of fractures within universal public healthcare: a nationwide
case-control study from Denmark. Scand J Public Health 34:371377
Kanis J, Johansson H, Johnell O, Oden A, De Laet C, Eisman J,
Pols H, Tenenhouse A (2005) Alcohol intake as a risk factor for
fracture. Osteoporos Int 16:737742
Klotzbuecher C, Ross P, Landsman P, Abbott T III, Berger M
(2000) Patients with prior fractures have an increased risk of
future fractures: a summary of the litterature and statistical
synthesis. J Bone Miner Res 15:721739
Munk-Jrgensen P, Mortensen P (1997) The Danish Psychiatric
Central Register. Dan Med Bull 44:8284
Vestergaard P, Mosekilde L (2002) Fracture risk in patients with
celiac disease, Crohn's disease, and ulcerative colitis: a nationwide follow-up study in 16,416 patients in Denmark. Am J
Epidemiol 156:110
Strazzullo P, Galletti F, Cirillo M, Siani A, Nunziata V,
Giannattasio R, Mancini M (1986) Altered extracellular calcium
homoeostasis in essential hypertension: a consequence of abnormal cell calcium handling. Clin Sci (Lond) 71:239244
Rejnmark L, Vestergaard P, Mosekilde L (2006) Treatment with
beta-blockers, ACE inhibitors, and calcium-channel blockers is
associated with a reduced fracture risk: a nationwide case-control
study. J Hypertens 24:581589
Burt VL, Cutler JA, Higgins M, Horan MJ, Labarthe D, Whelton
P, Brown C, Roccella EJ (1995) Trends in the prevalence,
awareness, treatment, and control of hypertension in the adult
US population. Data from the health examination surveys, 1960 to
1991. Hypertension 26:6069

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