Causal inference of modifiable lifestyle and birth traits on osteonecrosis risk: A bidirectional 2-sample Mendelian randomization study

Osteonecrosis (ON) is a progressive skeletal disorder caused by impaired bone perfusion and cell viability. While corticosteroid use and alcohol intake are established risk factors, the causal effects of modifiable lifestyle behaviors and early developmental traits on ON remain unclear. We conducted a bidirectional 2-sample Mendelian randomization (MR) study to assess the causal impact of grape intake, cereal intake, water intake, physical activity amplitude, birth weight, and birth length on ON risk. Summary-level genetic data were obtained from large genome-wide association studies. The inverse-variance weighted method was primary, with MR-Egger and weighted median approaches for sensitivity analyses. False discovery rate (FDR) correction was applied. Forward MR showed that genetically predicted higher grape intake (odds ratios [OR] = 0.16, 95% confidence interval [CI]: 0.03-0.83, FDR-adjusted P = .044), cereal intake (OR = 0.18, 95% CI: 0.04-0.79, FDR-adjusted P = .044), physical activity amplitude (OR = 0.13, 95% CI: 0.02-0.76, FDR-adjusted P = .044), and birth weight (OR = 0.56, 95% CI: 0.35-0.91, FDR-adjusted P = .044) were significantly associated with a lower risk of ON. Water intake showed a suggestive inverse association (OR = 0.19, 95% CI: 0.04-0.96, P = .045, FDR-adjusted P = .054), whereas birth length was not associated (OR = 0.67, 95% CI: 0.34-1.32, P = .245, FDR-adjusted P = .245). Results were robust across sensitivity analyses. Reverse MR analyses indicated no significant effect of ON on these exposures, supporting a unidirectional causal pathway from these modifiable and developmental factors to disease susceptibility. This study provides novel genetic evidence implicating dietary patterns, physical activity, and early-life developmental traits as protective factors against ON. These findings highlight modifiable risk factors that may inform preventive measures and guide future translational research aimed at reducing ON incidence and improving bone health outcomes.