Context: Endogenous estradiol, testosterone, and sex hormone-binding globulin (SHBG) may influence the risk of hip fracture.

Design and Methods: From the Women's Health Initiative Observational Study, 39,793 eligible postmenopausal women did not have a previous hip fracture and were not using estrogen or other bone-active therapies. Of these, 400 who had a first-time non-pathological hip fracture (median follow up=7 years) were matched to 400 controls by age, ethnicity, and baseline blood draw date. Estradiol, testosterone, and SHBG were measured in banked baseline serum.

Results: Compared with women in the lowest tertiles, those with bioavailable testosterone in the highest tertile had a lower risk (odds ratio, OR = 0.62; 95% CI: 0.44, 0.88); those with bioavailable estradiol in the highest tertile had a lower risk (OR = 0.44; 95% CI: 0.29, 0.66); and those with SHBG in the highest tertile had a higher risk (OR = 1.90; 95% CI: 1.31, 2.74) of hip fracture. In models with all three hormones and potential confounders, high SHBG remained a strong independent risk factor (OR = 1.76; 95% CI: 1.12, 2.78), high bioavailable testosterone remained protective (OR = 0.64; 95% CI: 0.40, 1.00), but estradiol no longer was associated (OR = 0.72; 95% CI: 0.42, 1.23).

Conclusions: High serum SHBG is associated with an increased risk of subsequent hip fracture and high endogenous testosterone with a decreased risk, independent of each other, serum estradiol concentration, and other putative risk factors. But endogenous estradiol has no independent association with hip fracture.