SGLT2 inhibitor, bone metabolism biomarkers, and osteoporosis risk: A Mendelian randomization study

BACKGROUND: Whether sodium-glucose cotransporter 2 (SGLT2) inhibitors elevate osteoporosis risk remains controversial, and the underlying metabolic pathways are unclear. Emerging data suggest these agents influence bone metabolism biomarkers, which may modulate fracture susceptibility. We therefore used Mendelian randomization (MR) to assess the mediating role of bone metabolism markers in the effect of SGLT2 inhibition on osteoporosis. METHODS: A two-sample, two-step MR design evaluated causal associations between genetically proxied SGLT2 inhibition and osteoporosis, with positive-control analyses for type 2 diabetes mellitus (T2DM) and HbA1c. Genetic instruments were SNPs linked to SLC5A2 expression and HbA1c levels. We first quantified SGLT2 inhibition effects on 17 bone biomarkers, then estimated each marker's impact on osteoporosis, and finally performed multivariable MR to derive mediated proportions. RESULTS: Genetically predicted SGLT2 inhibition was associated with a modest increase in osteoporosis risk (OR 1.01 per 1-SD HbA1c decrease; P = 0.002) and higher BMD (β 1.20; P = 0.004). Positive controls confirmed protection against T2DM (OR 0.45; P = 6.95 × 10⁻⁶) and reduced HbA1c (β - 0.37; P < 0.001). Among 17 markers, only total testosterone and interleukin-6 were linked to osteoporosis. Although SGLT2 inhibition significantly lowered total testosterone (β - 0.117; P = 3.22 × 10⁻⁴), its adjusted effect on osteoporosis was nonsignificant (β - 0.002; P = 0.103), mediating a nonsignificant 1.8 % of the total effect (95 % CI -0.6 % to 4.2 %; P > 0.05). CONCLUSION: These findings provide genetic support that SGLT2 inhibition increases osteoporosis risk despite raising BMD. Total testosterone does not appear to mediate this relationship, suggesting other pathways or direct skeletal effects drive the observed bone fragility. Further studies are needed to delineate these mechanisms.