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Associations of Serum Sex Hormone-Binding Globulin and Sex Hormone Concentrations with Hip Fracture Risk in Postmenopausal Women

Divisions of Endocrinology, Clinical Nutrition, and Vascular Medicine (J.S.L.) and General Medicine (J.R.), Department of Internal Medicine, University of California Davis, Sacramento, California 95817; Fred Hutchinson Comprehensive Cancer Center (A.Z.L., L.W., C.K.), University of Washington, Seattle, Washington 98109; Department of Epidemiology (J.A.C.), University of Pittsburgh, Pittsburgh, Pennsylvania 15261; Division of Endocrinology (R.D.J.), Department of Medicine, Ohio State University, Columbus, Ohio 43210; Brigham and Women’s Hospital and Harvard Medical School (M.S.L.), Boston, Massachusetts 02115; Division of Preventive Medicine (C.E.L.), University of Alabama-Birmingham School of Medicine, Birmingham, Alabama 35205; San Francisco Coordinating Center (D.C.B., S.R.C.), California Pacific Medical Center Research Institute, San Francisco, California 94107; and Departments of Medicine and Epidemiology (D.C.B., S.R.C.), University of California San Francisco, San Francisco, California 94117

Address all correspondence and requests for reprints to: Jennifer S. Lee, M.D., Division of Endocrinology, Clinical Nutrition, and Vascular Medicine, Department of Internal Medicine, PSSB Suite G400, Sacramento, California 95817. E-mail: jswlee{at}ucdavis.edu.

Context: Endogenous estradiol, testosterone, and 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 nonpathological hip fracture (median follow-up, 7 yr) 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% confidence interval (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.