Antipsychotic drug exposure and risk of fracture: a systematic review and meta-analysis of observational studies

To investigate the extent to which exposure to first-generation and second-generation antipsychotics (APs) is associated with an increased risk of fractures, with a particular focus on hip fractures, and to ascertain the risk associated with exposure to individual drugs. We included observational studies that reported data on fractures in individuals exposed to APs compared with unexposed individuals or individuals with previous exposure. We extracted information on study design, source of data, population characteristics, outcomes of interest, matching and confounding factors, and used a modified version of the Newcastle-Ottawa Scale to judge study risk of bias. We pooled adjusted estimates of relative effects to generate pooled odds ratios (ORs) and their 95% confidence interval (CI) using a random-effects model. We rated the quality of evidence using the GRADE approach. Of 36 observational studies, 29 proved to have a low risk of bias and seven were found to have a high risk of bias. The risk of hip fracture (OR: 1.57, 95% CI: 1.42-1.74, low quality of evidence) and of any fracture (OR: 1.17, 95% CI: 1.04-1.31, very low quality of evidence) increased with exposure to APs, with similar increases in risk in the first generation and second generation. The risk was similar among different diagnostic categories. The few studies that provided data were insufficient to allow inferences on individual drugs. AP exposure in unselected populations was associated with a 57% increase in the risk of hip fractures and a 17% increase in the risk of any fractures. Between-study heterogeneity limits the confidence in this estimate.