The Knee Osteoarthritis Sex Gap Is Not a Biological Constant: A Global Ecological Study Across 204 Countries Revealing a Nine-Fold Range Shaped by Development, Climate, and Ageing

Background. Knee osteoarthritis exhibits one of the largest sex disparities of any chronic disease, yet the global distribution, determinants, and trajectory of this gap remain poorly characterized. The assumption that KOA universally affects women more than men has not been systematically tested at the global scale. Methods. We integrated GBD 2023 KOA data (204 countries, 1990–2023) with climate (WorldClim 2.1), socioeconomic (World Bank, UNDP), and sex-stratified metabolic risk factor data. The analysis was pre-registered (OSF: osf.io/t7246). Six analytical modules were applied: Kitagawa non-parametric decomposition of the female-male prevalence gap [24], mixed-effects ecological regression, age-period-cohort decomposition, climate-zone-stratified analysis, six pre-registered prediction directions with quantitative selection thresholds, and clinical translation modeling. Safeguards included diagnostic ascertainment sensitivity analysis, variance inflation factor diagnostics, residual orthogonality testing, and Monte Carlo uncertainty propagation. Results. The female-to-male KOA prevalence ratio (FMR) ranged from 0.38 (Burkina Faso) to 3.34 (Mongolia), with only 23% of countries showing FMR above 1.0. The FMR-SDI association was regionally heterogeneous (Cochrane Q = 23.7, P = 0.0006). Global net drift was 0.58% per year for females versus 0.40% for males. Kitagawa decomposition attributed 94% of the sex gap to rate effects (females having higher KOA within the same obesity level). Mixed-effects models yielded SDI (beta = 5210, P < 0.001) and aging rate (beta = 232, P < 0.001) as dominant predictors (marginal R-squared = 0.733), while sex-by-obesity interaction was not significant (P = 0.682). Controlling for UHC Service Coverage Index attenuated the SDI-FMR coefficient by 1.6%. Climate-zone-stratified FMR ranged from 0.81 (Tropical) to 1.50 (Continental; P < 0.0001). A 10% reduction in female obesity prevalence would close 43.6% of the FMR gap (95% CI: 42.5–44.7%). Global female KOA cases are projected to rise from 139 million to 226–264 million by 2050. Screening at age 45 yields a number needed to screen of 30 for women. Conclusions. The KOA sex gap is not a fixed biological constant but a dynamic, context-dependent gradient. Differential vulnerability, not differential exposure, drives the gap, with menopause timing, cold climate, and development stage as key modifying factors. Under a pre-registered analytical framework, a 10% reduction in female obesity could close 44% of the sex gap by 2050, averting approximately 17 million cases. Female-specific screening from age 45, combined with differentiated country strategies based on a four-quadrant risk matrix, offers a quantitative evidence base for KOA prevention policy.