Use of Statins and Fracture: Results of 4 Prospective Studies and Cumulative Meta-analysis of Observational Studies and Controlled Trials

Background: The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) are widely used for the treatment of hyperlipidemia, and recent in vitro and animal data suggest that statins promote bone formation and increase bone strength. Methods: To determine whether statin use is associated with a reduced risk for fracture, we analyzed statin use and fracture rates in 4 large prospective studies (the Study of Osteoporotic Fractures, the Fracture Intervention Trial, the Heart and Estrogen/Progestin Replacement Study, and the Rotterdam Study). We searched MEDLINE through January 2002 and abstracts from major scientific meetings and performed a cumulative meta-analysis of published and unpublished observational studies and clinical trials. The meta-analysis included 8 observational studies and 2 clinical trials that reported statin use and documented fracture outcomes. Results: After adjustment for multiple factors, including age, body mass index, and estrogen use, we found a trend toward fewer hip fractures (relative hazards [RHs], 0.19-0.62) and, to a lesser extent, nonspine fractures (RHs, 0.49-0.95) among statin users in each of the 4 prospective studies. The meta-analysis of observational studies was consistent with these findings. The summary odds ratio (OR) for statin use and hip fracture was 0.43 (95% confidence interval [CI], 0.25-0.75), whereas that for nonspine fracture was 0.69 (95% CI, 0.55-0.88). The meta-analysis of clinical trial results did not support a protective effect with statin use for hip fracture (summary OR, 0.87; 95% CI, 0.48-1.58) or nonspine fracture (OR, 1.02; 95% CI, 0.83-1.26). Conclusions: Observational studies suggest that the risk for hip and nonspine fractures is lower among older women taking statin medications for hyperlipidemia, but post hoc analyses of cardiovascular trials do not. Controlled trials specifically designed to test the effect of statins on skeletal metabolism and fracture are needed.