Dissecting the comprehensive relationship between blood pressure and bone mass: the observational association and pleiotropic drug targets

Background Hypertension is a major global health challenge with well-established cardiovascular risks, yet its relationship with bone mineral density and the skeletal relevance of antihypertensive-related targets remain unclear. Methods Based on individual-level data from 366,443 European-ancestry participants in the UK Biobank, this study adopted restricted cubic spline models to explore linear and nonlinear associations between systolic/diastolic blood pressure (SBP/DBP) and heel estimated bone mineral density (BMD). We stratified participants by median DBP to conduct systematic biomarker analyses covering renal, endocrine, inflammatory and metabolic indicators. Drug-target Mendelian randomization (MR) combined with colocalization and mediation analyses was further performed to identify and validate causal antihypertensive-related target genes associated with BMD. Results A significant inverted U-shaped association was identified between DBP and BMD (P non-linear=3.23e-9), with peak BMD observed at a DBP of 80-90 mmHg, while SBP showed a trend of nonlinear correlation. Biomarker analyses revealed that renal biomarker cystatin C and endocrine biomarker IGF-1 exhibited DBP-dependent associations with BMD, mediating the nonlinear DBP-bone density relationship. Drug-target MR demonstrated that genetically proxied MMP9 expression (ACE inhibitor-related) was negatively correlated with BMD (beta=-0.036, P=5.29e-6), whereas CACNA1G expression (T-type calcium channel blocker target) was positively associated with BMD (beta=0.042, P=1.57e-9). Conclusion The inverted U-shaped association between blood pressure and bone mass might partly reflected by renal dysfunction. Antihypertensive pathways mediated by MMP9 and CACNA1G exert opposing effects on bone mass, implying that skeletal health should be considered when selecting antihypertensive agents for vulnerable older populations.