The impact of bone mineral density on the risk of falling: evidence from genetic correlation and Mendelian randomization analysis.

BACKGROUND:Falls are the most common consequence of low bone mineral density (BMD). However, due to limitations inherent in observational studies, the causal relationship between the two remains unestablished. METHODS:This study utilized Mendelian Randomization (MR) analysis to explore the causal relationship between BMD and the risk of falling, incorporating linkage disequilibrium score (LDSC) regression for genetic correlation assessment. The primary method was inverse-variance weighted (IVW), supplemented with sensitivity analyses and the causal analysis using summary effect estimates (CAUSE) to address heterogeneity and pleiotropy biases. RESULTS:LDSC analysis indicated significant genetic correlations between BMD at various sites and falling risk (rg range: -0.82 to 0.76, all P < 0.05). IVW analysis, with False Discovery Rate (FDR) correction, showed a protective causal effect of total body BMD (OR = 0.85, 95% CI 0.82-0.88, P = 7.63 × 10-17, PFDR = 1.91 × 10-16), femoral neck BMD (OR = 0.81, 95% CI 0.75-0.88, P = 3.33 × 10-7, PFDR = 5.55 × 10-7), lumbar spine BMD (OR = 0.85, 95% CI 0.79-0.91, P = 9.56 × 10-7, PFDR = 1.20 × 10-6), and heel BMD (OR = 0.82, 95% CI 0.79-0.81, P = 1.69 × 10-39, PFDR = 8.45 × 10-39) on falling risk. No causal relationship was found for forearm BMD (OR = 1.02, 95% CI 0.94-1.11, P = 0.64, PFDR = 0.64). Replication datasets and CAUSE analysis provided causal evidence consistent with the main findings. CONCLUSION:The study established a causal relationship between BMD at four different sites and the risk of falling, highlighting potential areas for targeted prevention strategies.