Serum Testosterone and SHBG Levels Linked to Fracture Risk in Older Men

Overview

In a large UK Biobank cohort study of over 200,000 men, low serum sex hormone-binding globulin (SHBG) levels were strongly associated with reduced fracture risk, while associations between testosterone (T) levels and fracture risk were weaker, nonlinear, and influenced by SHBG adjustment. These findings highlight SHBG as a major independent biomarker for fracture risk in middle-aged and older men.

Background

Osteoporotic fractures increase with age due to declining bone mass and increased fall risk, with men experiencing higher mortality post-fracture than women. Circulating testosterone decreases and SHBG increases with age, but the independent role of testosterone in fracture risk remains unclear. Previous smaller studies have shown inconsistent results regarding testosterone's association with fractures, whereas high SHBG and low free testosterone have been more consistently linked to increased fracture risk. Testosterone treatment trials have shown mixed effects on bone mineral density and fracture risk, underscoring the need for large-scale analyses.

Data Highlights

Key Findings

• Lower circulating SHBG was strongly associated with a lower risk of hip and forearm fractures (Q1 vs Q5 hazard ratio for hip fractures 0.55, 95% CI 0.47-0.65; forearm fractures 0.62, 95% CI 0.52-0.74).
• Testosterone showed a nonlinear association with hip fractures when SHBG was not considered, with the lowest risk in the second quintile.
• When adjusted for SHBG or using calculated free testosterone, lower testosterone was associated with higher fracture risk at all evaluated bone sites.
• Associations of testosterone with fracture risk were weaker, inconsistent across fracture sites, and influenced by SHBG adjustment.
• SHBG is a major independent biomarker of fracture risk in men, more so than total testosterone.
• Both total testosterone and SHBG should be assessed when evaluating fracture risk related to endogenous testosterone levels in middle-aged and older men.

Clinical Implications

Assessment of fracture risk in middle-aged and older men should include measurement of both serum total testosterone and SHBG levels, as SHBG is a stronger independent predictor of fracture risk. Clinicians should be cautious interpreting testosterone levels alone without considering SHBG, given the complex and nonlinear associations with fracture risk. These findings may inform risk stratification and guide decisions on monitoring and potential interventions to reduce fracture risk.

Conclusion

In middle-aged and older men, circulating SHBG levels are a robust independent biomarker for fracture risk, whereas testosterone's association is less consistent and influenced by SHBG. Comprehensive hormonal assessment including both SHBG and testosterone is essential for accurate fracture risk evaluation.

References

1. UK Biobank Study 2024 -- Links Between Serum Testosterone and SHBG Levels and the Risk of Fractures in Middle-aged and Older Men