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

Xin Huang; Tianxin Zhang; Ping Guo; Weiming Gong; Hengchao Zhu; Meng Zhao; Zhongshang Yuan

doi:10.3389/fendo.2023.1164387

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

Front Endocrinol (Lausanne). 2023 Mar 28:14:1164387. doi: 10.3389/fendo.2023.1164387. eCollection 2023.

Authors

Xin Huang^{1

2}, Tianxin Zhang^{1

2}, Ping Guo^{1

2}, Weiming Gong^{1

2}, Hengchao Zhu³, Meng Zhao⁴, Zhongshang Yuan^{1

2}

Affiliations

¹ Department of Biostatistics, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China.
² Institute for Medical Dataology, Shandong University, Jinan, Shandong, China.
³ Department of Biostatistics, School of Public Health, Yale University, New Haven, CT, United States.
⁴ Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China.

Abstract

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.

Keywords: antihypertensive drugs; bone mineral density; causal effect; drug-target mendelian randomization; fracture.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Angiotensin Receptor Antagonists
Angiotensin-Converting Enzyme Inhibitors
Antihypertensive Agents / therapeutic use
Bone Density* / genetics
Calcium Channel Blockers
Fractures, Bone* / genetics
Humans
Mendelian Randomization Analysis / methods
Sodium Chloride Symporter Inhibitors

Substances

Antihypertensive Agents
Sodium Chloride Symporter Inhibitors
Angiotensin Receptor Antagonists
Angiotensin-Converting Enzyme Inhibitors
Calcium Channel Blockers

Grants and funding

This research was funded by the Natural Science Foundation of Shandong Province (ZR2019ZD02) and the National Natural Science Foundation of China (82173624 and 81872712).