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The Effects of Serum Testosterone, Estradiol, and Sex Hormone Binding Globulin Levels on Fracture Risk in Older Men

Bone and Mineral Unit (E.S.L., C.M.N., L.M.M., J.A.L., E.S.O.), Oregon Health and Science University, Portland, Oregon 97239; Department of Family and Preventive Medicine (E.B.-C., G.L.), University of California, San Diego, San Diego, California 92093; Departments of Medicine and Epidemiology & Community Health (K.E.E.), University of Minnesota and Department of Medicine (K.E.E.), Veterans Affairs Medical Center, Minneapolis, Minnesota 55417; Department of Medicine (A.R.H.), Stanford University, Palo Alto, California 94305; and Department of Internal Medicine (C.O.), Center for Bone Research at the Sahlgrenska Academy, SE-416 85 Göteborg, Sweden

Address all correspondence and requests for reprints to: Eric Orwoll, M.D., Bone and Mineral Unit (CR 113), Oregon Health and Science University, 3181 SW Sam Jackson Park Road, Portland Oregon 97239. E-mail: orwoll{at}ohsu.edu.

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.