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DOI 10.1007/s00198-010-1320-4
ORIGINAL ARTICLE
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
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
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
733
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
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
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
735
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
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)
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)
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
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
737
10.
11.
12.
13.
14.
15.
16.
17.
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.
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