Plasma proteins mediate the protective association between physical activity and osteoporosis risk: A prospective study in the UK biobank

BACKGROUND: This study examined the association between physical activity (PA) and osteoporosis risk and, using plasma proteomics and mediation analysis, identified circulating proteins and pathways that mediate this relationship. METHODS: We included 39,799 UK Biobank participants free of osteoporosis at baseline. Cox regression models assessed associations between PA and incident osteoporosis. Linear regression identified PA-associated proteins, and enrichment analysis characterised their functional pathways. Taking moderate-to-vigorous physical activity (MVPA) categories as the exposure, causal mediation analysis within a Cox framework estimated the total effect (TE), pure natural direct effect (PNDE), pure natural indirect effect (PNIE), and proportion mediated (PM). Proteins with significant mediation effects underwent pathway enrichment analysis. RESULTS: Over a mean follow-up of 13.1 years, 1589 participants developed osteoporosis. After multivariable adjustment, moderate and high MVPA were associated with lower osteoporosis risk (HR=0.75, 95% CI 0.64-0.88; HR=0.74, 95% CI 0.63-0.87), whereas the association for low MVPA was weaker. Restricted cubic splines showed that, compared with 0 MET-min/week, MVPA in the range of approximately 500-7000 MET-min/week was associated with the lowest risk, with little additional benefit at higher levels. We identified 60 proteins (PM ≥ 5%) that mediated the MVPA-osteoporosis association, mainly enriched in cytokine-cytokine receptor interaction and PI3K-Akt signaling. CONCLUSION: PA is inversely associated with osteoporosis risk. Plasma proteins involved in immune/inflammatory regulation, mechanotransduction signaling, and the PI3K-Akt signaling pathway exerted significant mediating effects in this association. These proteins represent candidates for further investigation in studies designed to establish causality and clinical utility.