The causal effect of schizophrenia on fractures and bone mineral density: a comprehensive two-sample Mendelian randomization study of European ancestry

Abstract Background Schizophrenia was clinically documented to co-occur with fractures and aberrant bone mineral density (BMD), but the potential causal relationship remained unclear. This study aimed to test the causal effects between schizophrenia and fractures as well as aberrant BMD by conducting Mendelian randomization (MR) analyses. Methods Two-sample MR was utilized, based on instrumental variables from large genome-wide association studies (GWAS) of schizophrenia as exposure, to identify the causal association of schizophrenia with mixed fractures, fractures at different body sites (including skull and facial bones, shoulder and upper arm, wrist and hand, and femur) and BMDs of forearm (FA), femoral neck (FN), lumbar spine (LS) and estimated BMD (eBMD). Multivariable Mendelian randomization (MVMR) analysis was performed to minimize the confounding effect of body mass index (BMI). Results Result from inverse variance weighting (IVW) method provided evidence schizophrenia increased the risk of fractures of skull and facial bones [odds ratio (OR) = 1.0006, 95% confidence interval (CI): 1.0003 to 1.0010] and femur [OR =1.0007, 95% CI: 1.0003 to 1.0011], whereas, decreased the level of eBMD [β (95%CI): -0.013 (-0.021, -0.004)]. These causal effects still existed after adjusting for BMI. Sensitivity analyses showed similar results. However, no causal effect of schizophrenia on fracture or BMD in other parts was detected. Conclusion The current finding confirmed that schizophrenia was causally associated with the fractures of skull, face and femur as well as eBMD, which might remind psychiatrists to pay close attention to the fracture risk in schizophrenic patients when formulating their treatment strategies.