Revealing the mediating mechanisms between BMI and osteoarthritis: a Mendelian randomization and mediation analysis

Background: Despite well-documented associations between Body mass index (BMI) and Osteoarthritis (OA), the specific biological pathways and mediators involved remain poorly understood. This study aims to explore mediators through which BMI influences OA risk, particularly knee osteoarthritis (KOA), using Mendelian Randomization (MR) and mediation analysis. Methods: We used a two-step MR approach with data from the IEU OpenGWAS and FinnGen version 7 databases. BMI (N = 322,154) was the primary exposure, with knee disorders (KD), total bone mineral density (TBMD), metabolic disorders (MD), and anxiety disorders (AD) as potential mediators. Outcomes included KOA (N = 22,347), hip OA (HOA) (N = 11,989), and all OA (AllOA) (N = 50,508). Univariate MR evaluated causal relationships, followed by multivariate MR to quantify mediation effects. Multiple sensitivity analyses were conducted to validate robustness, while horizontal pleiotropy and heterogeneity were assessed using MR-Egger intercept and Cochran’s Q statistic. Results: BMI significantly increased the risk of KOA (odds ratio [OR]: 2.00, 95% confidence interval [CI]: 1.56–2.56), HOA (OR: 2.05, 95% CI: 1.40–2.98), and AllOA (OR: 1.66, 95% CI: 1.41–1.95). KD and TBMD significantly mediated the effect on KOA, with mediation proportions of 20.89% and 3.59%, respectively. MD and AD showed no significant effects. Sensitivity analyses supported the robustness of these findings. Horizontal pleiotropy and heterogeneity tests indicated minimal evidence of bias, supporting the reliability of our results. Conclusions: BMI increases OA risk, with KD and TBMD partially mediating the effect, particularly for KOA. The direct impact of BMI remains predominant, emphasizing the importance of weight reduction, joint protection, and physical activity as preventive measures. © The Author(s) 2025.