ArticlesEffect of pravastatin on frequency of fracture in the LIPID study: secondly analysis of a randomised controlled trial
Introduction
Two recent, independent observations have suggested that the statins, a class of drugs used in the management of hypercholesterolaemia, may be valuable in the management of osteoporosis. First, studies of aminobisphosphonates, widely used in the management of osteoporosis, have suggested that they have a similar mechanism of action to the statins. The aminobisphosphonates are potent antiresorptive agents that cause osteoclast apoptosis, apparently by inhibiting an enzyme (farnesyl diphosphate synthase) in the mevalonate pathway, which is involved in the synthesis of cholesterol.1, 2 Byproducts of this pathway are necessary for the linkage of lipid moieties to cytosolic proteins (protein prenylation), such linkages being necessary for normal osteoclast function. The statins also interfere with the mevalonate pathway, inhibiting its first step, the enzyme 3-hydroxy-3-methylglutaryl coenzyme A reductase. These observations suggest that statins may also act as inhibitors of osteoclasts, and this effect has been confirmed in vitro.3
More recently, a programme involving the screening of a large number of chemical species for anabolic effects on osteoblasts identified the statins as having this action. In-vivo studies have shown that these drugs can increase bone density in mice after both subcutaneous administration over the calvaria and systemic oral dosing.4
As a result of these findings, the association of statin use with bone density and fracture incidence has been assessed in observational studies (table 1). Bauer and colleagues5 reported trends for hip bone density to be higher by 0·2–1·1% in statin users and for fracture frequency to be lower in these groups, though neither of these differences was statistically significant. Chung and co-workers6 reported that diabetic men using statins showed more positive changes in bone density than diabetic men not requiring this therapy. No significant effect was found in diabetic women, even though greater numbers of women were studied. Edwards and colleagues7 reported that bone density was almost 10% higher in 41 women using statins than in 100 controls. Meier and colleagues8 found an odds ratio for fracture of 0·55 among statin users, in a nested case-control study that used the UK General Practice Research Database. Wang and co-workers9 confirmed these findings in a similar study of hip fractures based on reimbursement databases from the USA, as did Chan and colleagues,10 using data from health-maintenance organisations in that country. These positive findings may lead some doctors to prescribe statins for their osteoporotic patients. However, two further observational studies,11, 12 including a reanalysis of the UK General Practice Database,11 have not confirmed these findings.
Observational studies are always potentially subject to biases whatever measures are taken to adjust for confounding factors, so any effect of statins on bone density and fracture risk must also be assessed in randomised controlled trials.13, 14 We report fracture data from our randomised controlled trial on the effect of statin use on mortality due to coronary heart disease, the Long-term Intervention with Pravastatin in Ischaemic Disease (LIPID) study.15
Section snippets
Methods
The LIPID study was a double-blind, randomised, controlled trial comparing pravastatin 40 mg daily with placebo over a mean follow-up period of 6·0 years. Patients entering the study had a history of myocardial infarction or hospital admission for unstable angina, and their initial cholesterol concentrations were between 4·0 and 7·0 mmol/L. 9014 patients entered the study (table 2). The primary study outcome was mortality from coronary heart disease.
The frequency of fractures in this study was
Results
Table 3 sets out the number of fractures resulting in hospital admission, classified by skeletal region. Because some individuals had more than one fracture, the numbers of patients having fractures were slightly lower (table 4). Table 4 also gives the hazard ratios for fracture and information on fractures not necessitating hospital admission. Separate analyses were done for women alone and for people aged 65 years or older. Fracture risks were similar in both treatment groups across these
Discussion
Our data show no evidence of a reduced frequency of fracture in patients treated with pravastatin. The 95% CI around the relative risk of fracture show that a small effect cannot be completely ruled out, but this agent is unlikely to have clinically significant efficacy against fractures. It certainly does not have an effect equal to that of the therapies currently used in the management of osteoporosis, bisphosphonates and hormone replacement therapy, which lower fracture risk by about 50%.16,
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2021, InjuryCitation Excerpt :Some RCTs investigating the benefits of statins for cardiovascular system have later been examined for the influence of oral statins on osteoporosis and fracture risk. In a secondary analysis of an RCT on the effects of pravastatin application in ischemic disease (LIPID study) the daily intake of 40 mg pravastatin did not reduce fracture risk compared to control group [57]. Also in the Heart Protection Study [58] including over 20,000 subjects, no difference between the simvastatin and placebo group regarding hip, wrist or spine fractures could be detected over the period of 5 years.
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