Oral statins and increased bone-mineral density in postmenopausal women
2000; 355: 2218 - 2219
C J Edwards, D J Hart, T D Spector
Experimental evidence suggests that the cholesterol-lowering drugs statins increase bone formation. We report a significant increase of bone-mineral density associated with taking statins in postmenopausal women.
treatment of osteoporosis remains a major challenge, despite an increasing array
of therapeutic agents, including bisphosphonates, hormone replacement therapy,
and selective oestrogen receptor
modulators. Despite widespread use, however, these agents all rely on decreasing
osteoclastic absorption of bone for their effect. No widely used licensed
treatment that increases bone
formation exists yet. The most potent bone-inducing factors are growth factors,
such as bone morphogenetic proteins, but the therapeutic use of such factors is
hampered by difficulty in
delivering these agents to bone and their by widespread effects on other organ
evidence has shown that the statins, a class of cholesterol-lowering drugs,
might increase bone formation.1 The statins lovastatin and simvastatin increased
new bone formation in rodents
associated with increased expression of the bone morphogenetic protein-2 gene.
This finding was true when statins were added to bone cultures in vitro, by
subcutaneous injection to sites overlying bone, and after oral
administration in normal and ovariectomised animals.
investigated the possibility that bone formation would increase in
postmenopausal women taking statins for hypercholesterolaemia. The women studied
were participants of the Chingford
study, a population-based cohort of 1003 women living in the UK, seen annually
measured bone-mineral density at the spine and hip with a DXA QDR 2000 scanner (Hologic)
during the same visit at which statin status was established. Records showed
that 41 women were taking statins
at the time of the scan. The most commonly used statin was simvastatin (21
women, 51%), followed by pravastatin (ten women, 24%), atorvastatin (six women,
15%), and fluvastatin (four women, 10%). The median (IQR) length of
statin use was 48 (9-78) months. Each woman was matched with two or three
controls, selected from the same population, who were closest in age and the date on which
examination took place. We compared bone-mineral density at the hip and spine
between the two groups and analysed the data by independent t test and ANCOVA (table).
Bone-mineral density at the spine and the hip (femoral neck) remained significantly higher in the 41 statin users than in the 100 controls (table), and remained higher at the spine and hip after adjustment for age, height, and weight. Different areas of the hip, including trochanter and total hip, yielded similar crude results to the femoral neck (trochanter 0…65 vs 0…7, p=0…02; total hip 0…83 vs 0…89, p=0…008). Since hormone replacement therapy has a major effect on bone-mineral density, we also did an analysis excluding individuals taking hormone replacement therapy (71 controls, 23 statin users). The results for the spine bone-mineral density were similar and remained significant (0…89 vs 0…97, p=0…01). In 46 women whose lipid concentrations were higher than 7…5 mmol at baseline, excluding those taking statins, bone-mineral density did not differ at the spine or hip. (spine 0…89 vs 0…90, p=0…43; hip 0…69 vs 0…70, p=0…51).
|Controls (n=100)||Statins (n=41)||P|
|Age (years)||66…9 (5…4)||66…4 (5…3)||0…6
|Height (cm)||161…5 (6…1)||161…2 (5…9)||0…54|
|Weight (kg)||66…3 (10…6)||71…3 (12…8)||0…02|
|Years since menopause||18…9 (6…0)||18…7 (6…1)||0…86|
|Number on HRT||20 (20%)||13 (32%)||0…14|
|Number of smokers||21 (26%)||6 (23%)||0…7
|Prevalence||21 (21%)||7 (17%)||0…49|
|HRT duration (months)||19…3 (30…0)||27…8 (23…1)||0…40|
|Spine BMD (g/cm2)||0…89 (0…14)||1…00 (0…16)||0…
|Spine BMD adjusted*||0…91 (0…13)||0…99 (0…16)||0…001|
|Hip BMD (g/cm2)||0…70 (0…13)||0…76 (0…13)||0…002|
|Hip BMD adjusted||0…68 (0…15)||0…76 (0…13)||0…05|
HRT=hormone replacement therapy; BMD=bone-mineral density. Mean (SD) shown unless otherwise indicated. *Smokers based on 106 women, excluding ex-smokers; adjusted with ANCOVA for age, height, weight, HRT, and smoking status.
of characteristics and bone-mineral density for controls and statin users
preliminary abstract suggests that statins protect against fracture,3 but our
data do not support such findings. Although our study was cross-sectional, major
confounders were unlikely to have
caused the degree of association we saw.
Some caution is needed, however, when interpreting these results. Although
we showed no clear differences between controls and women not on statins who had
high cholesterol concentrations, it is still possible that hypercholesterolaemia
or a related trait might be associated with increased bone-mineral density.
exact mechanism of action of statins is unclear, but they have been shown to
decrease the production of mevalonate, a precursor of cholesterol production, by
inhibiting the enzyme HMG-CoA reductase.4 This pathway is important in the
action of certain antiresorptive bisphosphonates used to treat osteoporosis.5
Our findings may have major implications for the design of future treatments for
osteoporosis aimed at increasing bone-mineral density by inducing bone
formation. Randomised controlled trials of statins are needed to confirm these
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Natl Acad Sci USA 1999; 96: 133-38. Twin Research and Genetic Epidemiology Unit,
St Thomas's Hospital, London SE1 7EH, UK (C J Edwards MRCP, D J Hart PhD, T D
Spector FRCP) and Kennedy Institute of Rheumatology, Imperial College of
Science, Technology and Medicine, London W6 8LH, UK (C J Edwards MRCP)