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Statin Use, Bone Mineral Density, and Fracture Risk
Geelong Osteoporosis Study
Julie A. Pasco, PhD;
Mark A. Kotowicz, MBBS, FRACP;
Margaret J. Henry, PhD;
Kerrie M. Sanders, MNutr, PhD;
Geoffrey C. Nicholson, MBBS, PhD, FRACP, FRCP
Arch Intern Med. 2002;162:537-540.
ABSTRACT
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Background Recent data suggest that 3-hydroxy-3-methylglutaryl coenzyme A reductase
inhibitors (statins) decrease fracture risk and increase bone mineral density
(BMD).
Methods This cross-sectional study is set in southeastern Australia. We evaluated
the association between statin use, fracture risk, and BMD in 1375 women (573
with incident fractures and 802 without incident fracture, all drawn from
the same community). Fractures were identified radiologically. Medication
use and lifestyle factors were documented by questionnaire.
Results Unadjusted odds ratio for fracture associated with statin use was 0.40
(95% confidence interval [CI], 0.23-0.71). Adjusting for BMD at the femoral
neck, spine, and whole body increased the odds ratio to 0.45 (95% CI, 0.25-0.80),
0.42 (95% CI, 0.24-0.75), and 0.43 (95% CI, 0.24-0.78), respectively. Adjusting
for age, weight, concurrent medications, and lifestyle factors had no substantial
effect on the odds ratio for fracture. Statin use was associated with a 3%
greater adjusted BMD at the femoral neck (P = .08),
and BMD tended to be greater at the spine and whole body but did not achieve
statistical significance.
Conclusion The substantial 60% reduction in fracture risk associated with statin
use is greater than would be expected from increases in BMD alone.
INTRODUCTION
THE 3-HYDROXY-3-METHYL glutaryl coenzyme A (HMG-CoA) reductase inhibitors
(statins) stimulate bone formation in vitro and in rodents, an effect associated
with increased expression of the bone morphogenic protein-2 (BMP-2) gene in bone cells.1 Recent data
suggest that statins used in the treatment of hypercholesterolemia decrease
fracture risk2-4
and increase bone mineral density (BMD).5 Furthermore,
treatment with statins has been associated with increased BMD in patients
with diabetes mellitus.6 Our objective is to
determine whether statins decrease the risk of fracture and to evaluate the
association between statin use and BMD in Australian women.
SUBJECTS AND METHODS
Subjects in this case-control study were drawn from the Barwon Statistical
Division in southeastern Australia for participation in the Geelong Osteoporosis
Study; details about participants have been described elsewhere.7-8
Of 1443 women aged between 50 and 95 years, 68 were excluded because of incomplete
medication histories. Current statin use was evaluated in 573 women with nonpathological
incident fractures (all causes) during the 2-year period from February 1994
through February 1996 and in an age-stratified random sample of 802 women
without incident fractures. All fracture cases were identified from radiological
reports of the 2 radiological practices that service the region. This method
of fracture case ascertainment has been validated.9
Self-reported use of statins and other medications, together with details
about diet and lifestyle, were documented by questionnaire. Statin use was
classified as current if the subjects were using statins at the time of assessment.
Duration of statin use was documented in years, but the dosage remained unspecified.
Calcium intake was estimated for 1370 subjects using a validated food frequency
questionnaire.10 Subjects were classified as
alcohol consumers if they regularly consumed more than 2 standard drinks per
week (1 standard drink is equivalent to approximately 10 g of alcohol); regular
cigarette smoking was classified as current/not current and ever/never; current
exercise levels were classified as active if exercise was performed regularly,
otherwise they were designated as sedentary. Bone mineral density was measured
at the femoral neck (n = 1354), spine (L2-4, anterior-posterior projection;
n = 1373), and whole body (n = 1311) (Lunar DPX-L, software version 1.31;
LUNAR Corporation, Madison, Wis). Short-term precision in vivo at these sites
was 1.6%, 0.6%, and 0.4%, respectively. The median time between the fracture
event and assessment was 59 days. Questionnaire data collection and BMD assessments
were performed concurrently. Written informed consent was obtained from all
participants. The study was approved by the Barwon Health Research and Ethics
Advisory Committee.
Between statin users and nonusers or between fracture and nonfracture
groups, differences in exposure to other medications, consumption of alcohol,
cigarette smoking, activity levels, or fracture site were determined with
the  2 test (and Yates adjustment when applicable), whereas
differences in BMD, age, weight, height, and dietary calcium intake were determined
with 2-sample t tests. Differences in duration of
exposure among statin users with and without fracture were determined using
a Mann-Whitney test. Odds ratios for fracture associated with statin use have
been expressed with 95% confidence intervals before and after adjusting for
BMD, age, weight, dietary calcium, alcohol use, smoking (current and ever),
activity levels, and exposure to hormone replacement therapy, glucocorticoids,
and calcium and/or vitamin D supplements. Differences in BMD adjusted for
age, weight, fracture/nonfracture status, and confounders were assessed using
analysis of covariance. In validating the models, interaction terms were tested
for significance. All statistical analyses were performed using Minitab software
(release 12; Minitab, State College, Pa).
RESULTS
There were 16 statin users in the fracture group and 53 in the nonfracture
group. There was no difference in the distribution of fractures by site: the
percentage of hip, spine, Colles, and other fractures in the statin users
vs nonusers was 6% (n = 1) vs 12% (n = 70), 24% (n = 4) vs 19% (n = 116),
18% (n = 3) vs 17% (n = 104), and 53% (n = 9) vs 52% (n = 310), respectively
(P = .8). There was no difference between statin
users and nonusers in age, weight, height, or dietary calcium intake, or in
the proportion of subjects who consumed alcohol or were cigarette smokers
(current or ever), active, or users of hormone replacement therapy, glucocorticoids,
or calcium and/or vitamin D supplements (P>.05) (Table 1). Among the statin users, duration
of exposure did not differ significantly between the fracture and nonfracture
groups (median, 3.0 vs 2.0 years; P = .3). Exposure
to hormone replacement therapy was less common and exposure to glucocorticoids
and calcium and/or vitamin D supplements more common in the fracture group,
whereas other characteristics between the fracture and nonfracture groups
were similar (Table 1). In univariate
analysis, statin use was associated with a 60% reduction in fracture risk
(Table 2). The effect was not
entirely explained by BMD, and adjusting for individual potential confounders
had little effect on the odds ratio for fracture (Table 2).
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Table 1. Characteristics of Statin Users and Nonusers and Fracture
and Nonfracture Groups*
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Table 2. Odds Ratios for Fracture Associated With Statin Use*
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After adjusting for age, weight, and fracture status, statin use was
associated with a 3% greater BMD at the femoral neck (P = .08) (Table 3). Statin
use remained in the model with only minor changes to the coefficient after
the addition of potential confounders including smoking (current and ever),
use of hormone replacement therapy, use of calcium and/or vitamin D supplements,
and activity levels to the regression model. There was a pattern of greater
BMD at the other sites among statin users; however, adjusted differences did
not achieve significance (Table 3).
At  = .05, we had 80% power for detecting differences in BMD equal
to or greater than 19%, 20%, and 12% at the femoral neck, spine, and whole
body, respectively. Thus, the small number of statin users may have limited
the power to detect differences in BMD at the spine and whole body. No effect
of duration of exposure on BMD was detected.
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Table 3. Bone Mineral Density for Statin Users and Nonusers*
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COMMENT
We confirm observations that statin use is associated with a reduction
in fracture risk.2-4
This risk reduction is not explained by the effects of BMD as indicated by
the small change in odds ratio after adjustment for BMD. Although there were
differences in exposures to other medication and lifestyle factors, these
potential confounders had no impact on the odds ratio for fracture.
In addition to statin use, BMD measurements were obtained for fracture
and nonfracture cases, making this study unique. The effect of statin use
on BMD was small after adjusting for age and weight. Statin users tended to
be younger and heavier within the fracture cohort, whereas a reverse pattern
occurred for age in the nonfracture group. The apparent 13% and 10% differences
in unadjusted BMD between statin users and nonusers at the femoral neck and
spine in the fracture group were likely affected by differences in distribution
of age and weight.
The 60% reduction in fracture risk associated with statin use is consistent
with other case-control studies in different populations.2-4
An exception to this finding reports no effect of pravastatin use on fracture
frequency.11 In contrast to other statins,
pravastatin does not induce bone morphogenetic protein-2 in human osteosarcoma
cells,12 which may explain the negative finding.
The apparent, substantial statin-related differences in BMD reported recently5 suggest that reductions in fracture risk could operate
entirely through increased BMD. However, results from our study suggest that
increases in BMD associated with statin use may be too small to account for
the observed reduction in fracture risk. Furthermore, the fracture risk reduction
conferred by adjusting the odds ratio for BMD supports this notion. Unless
confounded by unrecognized factors, statin use is associated with substantial
protection against fracture, but the mechanisms of action remain unclear.
Even with increased power to detect smaller changes in BMD, the bone densitometry
technology is limited in its ability to detect changes on bone surfaces that
might protect against fracture.13 Studies focused
on the effects of statins on bone architecture by histomorphometry or noninvasive
techniques are needed to clarify the mechanism of action.
AUTHOR INFORMATION
Accepted for publication July 17, 2001.
This work was supported by the Victorian Health Promotion Foundation,
Carlton, Australia.
We thank Belinda Burgess for her assistance in collating the data.
Corresponding author: Julie A. Pasco, PhD, Department of Clinical
and Biomedical Sciences–Barwon Health, The University of Melbourne,
Geelong Hospital, Barwon Health, PO Box 281, Geelong 3220, Australia (e-mail: juliep{at}barwonhealth.org.au).
From the Department of Clinical and Biomedical Sciences–Barwon
Health, The University of Melbourne, Geelong Hospital, Geelong, Australia.
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