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

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.

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.

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.

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.