In 366,443 UK Biobank participants of European ancestry, diastolic blood pressure (DBP) showed a striking inverted U-shaped relationship with heel bone mineral density (BMD), peaking at 80–90 mmHg (P nonlinear = 3.23×10⁻⁹). Renal biomarker cystatin C and IGF-1 emerged as DBP-dependent mediators of this curve, implicating renal dysfunction as a partial mechanistic bridge. Drug-target Mendelian randomization pinpointed two antihypertensive-relevant genes with opposing skeletal effects: higher MMP9 expression (linked to ACE inhibitor pathways) reduced BMD (β = −0.036), while higher CACNA1G expression (a T-type calcium channel blocker target) increased BMD (β = +0.042).
The finding reframes hypertension management beyond cardiovascular risk alone. Osteoporosis and hypertension frequently co-occur in older adults, yet drug-selection guidelines rarely weigh skeletal consequences. The MMP9 signal is biologically plausible — matrix metalloproteinase-9 degrades collagen scaffolding critical to bone remodeling — while CACNA1G's positive association aligns with calcium-channel biology supporting osteoblast function. The nonlinear DBP–BMD relationship is clinically nuanced: both hypotension and hypertension appear detrimental to bone, complicating aggressive blood-pressure lowering in frail elderly patients.
Limitations are real: the cohort is exclusively European-ancestry, BMD was estimated from heel ultrasound rather than DXA, and Mendelian randomization assumptions require validation. As a preprint posted to medRxiv and not yet peer-reviewed, these findings may change materially. Still, the Mendelian randomization framework adds genuine causal traction to what would otherwise be observational correlation — making this an incrementally important, clinically actionable contribution to precision prescribing for older hypertensive patients.
