Sex hormone-binding globulin increases lumbar fracture risk via bone density, inflammation, and insulin pathways: A Mendelian randomization study.

Circulating sex hormone-binding globulin (SHBG) regulates bioavailable sex hormones that influence bone metabolism. We investigated whether genetically higher SHBG increases lumbar fracture (LF) risk and identified the biological pathways mediating this effect, including bone mineral density (BMD), C-reactive protein (CRP), and insulin use. A two-sample bidirectional and mediation Mendelian randomization (MR) framework was applied using genome-wide significant single-nucleotide polymorphisms (P < 5 × 10-8) from large-scale genome-wide association study datasets (FinnGen, UK Biobank, and IEU OpenGWAS). Instrumental variables were linkage disequilibrium-pruned (r2 < 0.01), and analyses were conducted using inverse-variance weighted, MR-Egger, and Mendelian Randomization Pleiotropy RESidual Sum and Outlier methods. Genetically predicted SHBG was causally associated with higher LF risk (FinnGen: odds ratio [OR] = 1.201; 95% confidence interval, 1.028-1.404; P = .021; UK Biobank: OR = 1.005; 95% confidence interval, 1.002-1.008; P = .002). SHBG showed significant negative effects on lumbar BMD (OR = 0.934; P = .0029) and CRP (OR = 0.921; P = .0065), and a modest decrease in insulin medication use (OR = 0.9963; P = 6.1 × 10-6). Mediation analysis revealed that 64.8% of SHBG's total effect on LF was mediated through BMD, 63.8% through CRP, and 38.7% through insulin pathways. Sensitivity tests confirmed robustness without evidence of pleiotropy. Genetically elevated SHBG increases LF risk mainly through impaired bone density and systemic inflammation. These findings suggest that interventions targeting SHBG-related metabolic pathways may help reduce skeletal fragility.