Association of antihypertensive drugs with fracture and bone mineral density: A comprehensive drug-target Mendelian randomization study

Background Observational studies have investigated the associations between antihypertensive drugs and fracture risk as well as bone mineral density (BMD), but yielding controversial results. Methods In this study, a comprehensive drug-target Mendelian randomization (MR) analysis was conducted to systematically examine the associations between genetic proxies for eight common antihypertensive drugs and three bone health-related traits (fracture, total body BMD [TB-BMD], and estimated heel BMD [eBMD]). The main analysis used the inverse-variance weighted (IVW) method to estimate the causal effect. Multiple MR methods were also employed to test the robustness of the results. Results The genetic proxies for angiotensin receptor blockers (ARBs) were associated with a reduced risk of fracture (odds ratio [OR] = 0.67, 95% confidence interval [CI]: 0.54 to 0.84; P = 4.42 × 10-4; P-adjusted = 0.004), higher TB-BMD (β = 0.36, 95% CI: 0.11 to 0.61; P = 0.005; P-adjusted = 0.022), and higher eBMD (β = 0.30, 95% CI: 0.21 to 0.38; P = 3.59 × 10-12; P-adjusted = 6.55 × 10-11). Meanwhile, genetic proxies for calcium channel blockers (CCBs) were associated with an increased risk of fracture (OR = 1.07, 95% CI: 1.03 to 1.12; P = 0.002; P-adjusted = 0.013). Genetic proxies for potassium sparing diuretics (PSDs) showed negative associations with TB-BMD (β = -0.61, 95% CI: -0.88 to -0.33; P = 1.55 × 10-5; P-adjusted = 1.86 × 10-4). Genetic proxies for thiazide diuretics had positive associations with eBMD (β = 0.11, 95% CI: 0.03 to 0.18; P = 0.006; P-adjusted = 0.022). No significant heterogeneity or pleiotropy was identified. The results were consistent across different MR methods. Conclusions These findings suggest that genetic proxies for ARBs and thiazide diuretics may have a protective effect on bone health, while genetic proxies for CCBs and PSDs may have a negative effect.