Ultra-Processed Food Intake, Circulating NMR Metabolomic Signatures and Risk of Osteoarthritis in Women.

Purpose: Prospective evidence reporting statistical associations between ultra-processed food (UPF) intake and osteoarthritis (OA) risk in women is sparse, women suffer a disproportionately heavy OA burden with distinct metabolic and inflammatory characteristics, and the circulating biological correlates of UPF intake have not been integrated with OA risk in a unified analytical framework. Patients and Methods: In a prospective multi-omics analysis, we studied women without baseline OA, with NOVA-based UPF intake reconstructed from repeated Oxford WebQ 24-hour dietary records. Cox proportional hazards models (age as time scale) estimated hazard ratios (HRs) per 1-SD UPF increase and across quartiles, adjusting for ethnicity, education, income, smoking, alcohol, physical activity and total energy intake (Model 2); stabilised inverse probability weighting (IPW) addressed UPF availability. Nightingale NMR metabolomic and Olink proteomic features were screened sequentially (UPF-to-omics, omics-to-OA; FDR<0.05); candidate correlates were summarised by principal component analysis into a UPF-related omics signature. We performed two-stage correlational screening for omics markers rather than formal causal mediation analysis. Notably, 61.8% of the female cohort lacked valid UPF dietary records; stabilised inverse probability weighting (IPW) with dual trimming thresholds was applied to mitigate potential selection bias from missing dietary data. Results: Among 13,122 women with UPF data (base female OA cohort 34,322), 528 knee OA, 473 hip OA, 1,908 any OA, 963 knee/hip OA and 57 hand OA events accrued. Model 2 demonstrated per-1-SD UPF increments were associated with higher any OA (HR 1.070, 95% CI 1.023-1.120, P=0.003) and knee/hip OA risk (HR 1.072, 95% CI 1.005-1.143, P=0.035), with the top UPF quartile linked to 28.8% higher knee OA risk; energy-adjusted and IPW-weighted analyses produced consistent estimates, while associations fully attenuated after adiposity adjustment in Model 3. UPF intake was related to 178 NMR features (FDR<0.05), including GlycA, omega-6/linoleic acid percentages and HDL-related lipoprotein indices. The combined PCA NMR signature independently predicted increased knee OA (HR 1.187, 95% CI 1.124-1.253, P<0.001) and any OA risk (HR 1.104, 95% CI 1.070-1.139, P<0.001). In exploratory Olink proteomic analyses, five proteins were associated with UPF intake at FDR<0.05, but no protein passed the pre-specified two-stage FDR screening for both UPF association and OA risk; nominal Olink signals are reported in the Supplementary Materials and interpreted as hypothesis-generating only. Conclusion: Higher UPF intake was associated with modestly increased OA risk in women; NMR signatures of inflammation and lipid metabolism provided exploratory biological context overlapping adiposity pathways.