Context: The relationship between sex steroids and fracture is poorly understood.

Objective: The objective of the study was to examine associations between nonvertebral fracture risk and bioavailable estradiol (bioE2), bioavailable testosterone (bioT), and SHBG.

Design: This was a case-cohort study.

Setting: The Osteoporotic Fractures in Men Study (MrOS) was conducted in a prospective U.S. cohort in 5995 community-dwelling men 65 yr old or older.

Participants: Participants included a subcohort of 1436 randomly chosen white men plus all 446 minorities and all those with incident hip and other nonvertebral fractures.

Main Outcome Measures: Baseline testosterone and estradiol were measured by mass spectrometry (MS) and SHBG by RIA.

Results: Men with the lowest bioE2 (<11.4 pg/ml) or highest SHBG (>59.1 nm) had greater risk of all nonvertebral fractures [adjusted hazard ratio (HR) [95% confidence interval]: 1.5 (1.2–1.9) and 1.4 (1.1–21.8), respectively]. Men with the lowest bioT (<163.5 ng/dl) had no increased fracture risk after adjustment for bioE2 [adjusted HR 1.16 (0.90–1.49)]. A significant interaction between SHBG and bioT (P = 0.03) resulted in men with low bioT and high SHBG having higher fracture risk [HR 2.1 (1.4–3.2)]. Men with low bioE2, low bioT, and high SHBG were at highest risk [HR 3.4 (2.2–5.3)].

Conclusions: Older men with low bioE2 or high SHBG levels are at increased risk of nonvertebral fracture. When SHBG levels are high, men with low bioT levels have higher risk. The strongest association occurred when all measures were considered in combination.

The combination of a low bioavailable testosterone level, low estradiol level, and high sex hormone binding globulin level confers the highest risk of nonvertebral fracture in elderly men.