Testosterone, sex hormone-binding globulin, and fracture risk in men: evidence from observational and Mendelian randomization analyses.

UNLABELLED

Both observational and factorial Mendelian randomization analysis revealed that the combined exposure to higher TT and lower SHBG was associated with decreased risk of fracture. These findings suggest that considering both TT and SHBG-rather than focusing on testosterone alone-may improve fracture risk assessment.

PURPOSE

Lower total testosterone (TT) levels have been associated with increased fracture risk in aging men, yet the benefits of testosterone supplementation remain uncertain. This study aimed to assess the joint contributions of TT and sex hormone-binding globulin (SHBG) to fracture risk using both observational and genetic approaches.

METHODS

We included 162,786 men from the UK Biobank, with baseline serum TT and SHBG measurements and genetic data. Cox proportional hazards models were used to estimate associations of TT and SHBG with incident fractures. A 2 × 2 factorial Mendelian randomization (MR) analysis was conducted to evaluate the combined genetic effects of increased TT and decreased SHBG on fracture risk.

RESULTS

The median age at baseline was 59.0 years, and 7493 men experienced fractures during 13.3 years follow-up. The association between serum TT levels and incident fracture was significantly affected by adjustment for SHBG. Compared to the lowest quintile of Bio-T levels, the adjusted hazard ratio (HR) for total fracture in the highest quintile was 0.72 (95% CI: 0.67, 0.78). In factorial MR analysis, men with genetically higher TT and lower SHBG had significantly lower odds of total fracture (OR: 0.87, 95% CI: 0.80-0.95) compared to those with genetically lower TT and higher SHBG. No association was observed in groups with only high TT or only low SHBG.

CONCLUSION

Our findings suggest that the interplay between TT and SHBG is important in determining fracture risk, highlighting the potential clinical value of jointly assessing them to improve fracture risk stratification in men.