Association Between Lipid-Lowering Drugs and Bone Mineral Density: A Study Employing Drug-Target Mendelian Randomization

Purpose: This study aimed to evaluate the causal association between lipid phenotypes mediated by drug targets and bone mineral density using a two-sample Mendelian randomization approach. Methods: Mendelian randomization analysis was conducted utilizing publicly available pooled-level GWAS data for lipid traits. Instrumental variables were selected based on specific lipid-lowering targets, and inverse variance weighting, weighted median, and MR Egger methods were employed. Sensitivity analyses were performed to ensure the robustness of the results. Results: This study aimed to investigate the association between LDL cholesterol levels mediated by specific genes and bone mineral density (BMD) outcomes. Firstly, HMGCR-mediated LDL cholesterol showed a significant association with both H-BMD (β = -0.086, 95%CI: 0.117 to 0.055, p = 5.420 × 10 -8 ) and TB-BMD (β = 0.193, 95%CI: 0.288 to 0.098, p = 7.350× 10 -5 ). APOB-mediated LDL cholesterol demonstrated suggestive associations with FA-BMD (β = 0.210, 95%CI: 0.044 to 0.376, p = 0.013) and H-BMD (β = -0.032, 95%CI: -0.061 to -0.004, p = 0.027). Similarly, CETP-mediated LDL cholesterol showed suggestive relationships with FA-BMD (β = 0.315, 95%CI: 0.102 to 0.528, p = 0.004) and H-BMD (β = 0.055, 95%CI: -0.092 to -0.018, p = 0.027). LDLR-mediated LDL cholesterol was associated with H-BMD (β = -0.022, 95%CI: 0.041 to 0.003, p = 0.025) and LS-BMD (β = 0.124, 95%CI: 0.017 to 0.231, p = 0.023). However, no substantial evidence was found for an association between PCSK9-mediated LDL cholesterol, NPC1L1-mediated LDL cholesterol, and BMD outcomes. Conclusion: Our study provides significant findings supporting the protective effect of HMGCR inhibitors on BMD. Associations were also observed between APOB, CETP, and LDLR-mediated LDL cholesterol and BMD at different skeletal sites. These results contribute to our understanding of the relationship between cholesterol-related genes and bone health, suggesting potential therapeutic targets for improving bone density.