Oral statins and increased bone-mineral density in postmenopausal women

Lancet 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.

The 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 systems.

Experimental 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.

We 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 since 1989.2

We 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).

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. 

Comparison of characteristics and bone-mineral density for controls and statin users

A 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.

The 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 observations.

REFERENCES

1 Mundy G, Garrett R, Harris S, et al. Stimulation of bone formation in vitro and in rodents by statins. Science 1999; 286: 1946-49 [PubMed].

2 Lloyd ME, Hart DJ, Nandra D, et al. Relation between insulin-like growth factor-I concentrations, osteoarthritis, bone density, and fractures in the general population: the Chingford study. Ann Rheum Dis 1996; 55: 870-74 [PubMed].

3 Bauer D, Mundy G, Jamal S, et al. Statin use, bone mass and fracture: an analysis of two prospective studies. J Bone Miner Res 1999; 14 (suppl): S179 (abstr).

4 Alberts AW, Chen J, Kuron G, et al. Mevinolin: a highly potent competitive inhibitor of hydroxymethylglutaryl-coenzyme A reductase and a cholesterol-lowering agent. Proc Natl Acad Sci USA 1980; 77: 3957-61 [PubMed].

5 Fisher JE, Rogers MJ, Halasy JM, et al. Alendronate mechanism of action: geranylgeraniol, an intermediate in the mevalonate pathway, prevents inhibition of osteoclast formation, bone resorption, and kinase activation in vitro. Proc 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)