Association between systemic redox balance and osteoporosis: prospective evidence, polygenic modification, and...

Redox signaling governs bone remodeling, but whether systemic redox balance is associated with incident osteoporosis, genetic susceptibility, and proteomic/inflammatory pathways at population scale remains unclear.

We analyzed UK Biobank participants free of osteoporosis at baseline. Serum redox balance score (SRBS) combined albumin, total bilirubin, and γ-glutamyl transferase. Cox proportional hazards models adjusted for prespecified covariates. Effect modification by an osteoporosis polygenic risk score (PRS) was tested on multiplicative and additive scales. Mediation was evaluated in a proteomics subset and an inflammatory-panel subset using counterfactual mediation with multiple-testing control.

Over a median follow-up of 12.8 years (IQR, 11.7-13.7), 12,893 incident osteoporosis cases were observed. SRBS demonstrated a nonlinear inverse association with osteoporosis, displaying a J-shaped pattern: relative to Q1, multivariable hazard ratios (95% CIs) were 0.82 (0.78-0.86) for Q2, 0.75 (0.71-0.78) for Q3, and 0.72 (0.68-0.75) for Q4; the per-standard-deviation increase corresponded to an HR of 0.85 (0.83-0.87). Cumulative-incidence curves diverged early and showed a stepwise gradient across quartiles. Associations were stronger among men and physically inactive participants. SRBS interacted with the osteoporosis PRS on the multiplicative scale (interaction HR, 1.03; 95% CI, 1.02-1.04), whereas evidence for additive interaction was limited. Proteomic mediation implicated EGFR, TNFRSF10A, CBLN4, CD27, and IGDCC4 (≈8-11% each); inflammatory mediation implicated C-reactive protein (≈8%), platelets (≈4%), and neutrophils (≈4%).

Systemic redox balance values were linked to osteoporosis risk, with partial mediation through plasma-protein and inflammatory pathways and only modest modification by polygenic risk.