Associations of Serum Testosterone and Sex Hormone-Binding Globulin with Incident Fractures in Middle-Aged to Older Men

Context: As men age, circulating testosterone (T) decreases, circulating sex-hormone binding globulin (SHBG) increases, and risk of fracture increases. It is unclear if circulating T, independently of comorbidities, is associated with fracture risk in men.

Objectives: To determine associations for T and SHBG with incident fractures in men.

Methods: We utilized the large (n=205,973 participants, 11,088 any fracture cases, 1,680 hip fracture cases, 1,366 forearm fracture cases) and well-characterized UK Biobank cohort. Associations were modelled using Cox regressions, adjusting for multiple comorbidities/covariates, imputing for missing information, and assessing non-linearity using cubic splines.

Results: For T, not considering SHBG, there was a non-linear association with hip but not forearm fractures, with the lowest risk in the second quintile. However, in models adjusted for SHBG or using calculated free T, lower T was associated with higher risk for fractures at all evaluated bone sites. Lower SHBG was strongly associated with lower risk of hip and forearm fractures (Q1 vs Q5, hip 0.55, 0.47-0.65; forearm 0.62, 0.52-0.74).

Conclusion: Low circulating SHBG is strongly associated with low risk of fracture at all evaluated bone sites, while the associations of circulating T with fracture risk are of lesser magnitude, non-linear, inconsistent among fracture site, and affected by adjustment for SHBG. These findings demonstrate that circulating SHBG, rather than T, is a major independent biomarker of fracture risk in men. Consequently, both total T and SHBG should be assessed when examining the relationship of endogenous T concentrations with fractures in middle-aged to older men.