Statin use and fracture risk: can we quantify the healthy-user effect?

Numerous observational studies show that statin use is associated with lower risk of osteoporotic fractures. However, a causal relationship is not supported by data from randomized trials. Unmeasured confounding is implicated as a likely culprit for the controversy because of failure to measure and adjust for patient-level tendencies to engage in healthy behaviors. However, an alternative explanation is selection bias because of the inclusion of prevalent users of statins in the analysis. The relative importance of either bias has not been investigated in a quantitative sensitivity analysis.

We conducted a systematic review to summarize the pattern of association between statin use and fracture risk in observational studies. Our objective was to quantify the magnitude of unmeasured confounding and selection bias in a sensitivity analysis.

In 17 published studies, the pooled relative risk for the association between current use of statins and fracture risk was 0.75 (95% confidence interval = 0.66-0.85). Upon adjustment for individual-level use of preventative health services, the pooled relative risk shifted by less than 5% on the log scale. However, a sensitivity analysis for selection bias revealed that moderate levels of bias could eliminate the association between statins and fracture risk.

It appears that confounding from unmeasured variables cannot explain the protective association between statins and fractures that has been observed in the literature.