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Tumor Necrosis Factor- Polymorphism, Bone Strength Phenotypes, and the Risk of Fracture in Older Women

Department of Epidemiology (S.P.M., J.M.Z., J.I.O., J.A.C.), University of Pittsburgh, Pittsburgh, Pennsylvania 15261; Department of Radiology (T.J.B.), The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205-2196; Department of Medicine (K.L.S., L.-Y.L.), University of California, San Francisco, San Francisco, California 94143; Department of General Internal Medicine (K.E.E.), Veterans Affairs Medical Center, Minneapolis, Minnesota 55417; Kaiser Permanente Center for Health Research Northwest/Hawaii (T.A.H.), Portland, Oregon 97227; Department of Medicine and Epidemiology and Preventive Medicine (M.C.H.), University of Maryland School of Medicine, Baltimore, Maryland 21201; Axys Pharmaceuticals (P.M.), La Jolla, California 92037; Roche Palo Alto (G.P.), Palo Alto, California 94304-1397; Roche Molecular Systems (D.G.), Alameda, California 94588; and Research Institute (S.R.C.), California Pacific Medical Center, San Francisco, California 94120-7999

Address all correspondence and requests for reprints to: Susan P. Moffett, Ph.D., Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, 130 DeSoto Street, Pittsburgh, Pennsylvania 15261. E-mail: susan.moffett{at}hgen.pitt.edu.

TNF is a proinflammatory cytokine that promotes osteoclastic bone resorption. We evaluated the association between a G-308A polymorphism (rs1800629) at the TNFA locus and osteoporosis phenotypes in 4306 older women participating in the Study of Osteoporotic Fractures. Femoral neck bone mineral density (BMD) and structural geometry were measured using dual-energy x-ray absorptiometry and hip structural analysis. Incident fractures were confirmed by physician adjudication of radiology reports. Despite similar femoral neck BMD, women with the A/A genotype had greater subperiosteal width (P = 0.01) and endocortical diameter (P = 0.03) than those with the G/G genotype. The net result of these structural differences was that there was a greater distribution of bone mass away from the neutral axis of the femoral neck in women with the A/A genotype, resulting in greater indices of bone bending strength (cross-sectional moment of inertia: P = 0.004; section modulus: P = 0.003). Among 376 incident hip fractures during 12.1 yr of follow-up, a 22% decrease in the risk of hip fracture was seen per copy of the A allele (relative risk 0.78; 95% confidence interval 0.63, 0.96), which was not influenced by adjustments for potential confounding factors, BMD, or bone strength indices. The G-308A polymorphism was not associated with a reduced risk of other fractures. These results suggest a potential role of genetic variation in TNF in the etiology of osteoporosis.