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.