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Osteoprotegerin Lys3Asn Polymorphism and the Risk of Fracture in Older Women

Department of Epidemiology (S.P.M., J.I.O., J.A.C., J.M.Z.), University of Pittsburgh, Pittsburgh, Pennsylvania 15261; San Francisco Coordinating Center (L.Y.L., S.R.C.), California Pacific Medical Center Research Institute, San Francisco, California 94115; Center for Chronic Disease Outcomes Research (K.E.E., B.C.T.), Veterans Affairs Medical Center, and University of Minnesota, Minneapolis, Minnesota 55455; Kaiser Permanente Center for Health Research Northwest/Hawaii (T.A.H.), Portland, Oregon 97227-1098; Department of Medicine and Epidemiology and Preventive Medicine (M.C.H.), University of Maryland School of Medicine, Baltimore, Maryland 21201; Department of Human Genetics (J.L., S.C., J.M.L.), Roche Molecular Systems, Alameda, California 94501; and Genetics and Genomics (G.P.), Roche Palo Alto, Palo Alto, California 94304

Address all correspondence and requests for reprints to: Joseph M. Zmuda, Ph.D., Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, 130 DeSoto Street, Pittsburgh, Pennsylvania 15261. E-mail: zmudaj{at}edc.pitt.edu.

Context: Osteoprotegerin (OPG) is a soluble decoy receptor for receptor activator nuclear factor -β that blocks osteoclastic bone resorption.

Objective: We investigated the association between a Lys3Asn polymorphism in the OPG gene and bone mineral density (BMD), and the risk of fracture in 6695 women aged 65 yr and older participating in the Study of Osteoporotic Fractures.

Design: BMD was measured using either single-photon absorptiometry (Osteon Osteoanalyzer; Dove Medical Group, Los Angeles, CA) or dual-energy x-ray absorptiometry (Hologic QDR 1000; Hologic, Inc., Bedford, MA). Incident fractures were confirmed by physician adjudication of radiology reports. Genotyping was performed using an immobilized probe-based assay.

Results: Women who were homozygous for the minor G (Lys) allele had significantly lower BMD at the intertrochanter, distal radius, lumbar spine, and calcaneus than those with the C (Asn) allele. There were 701 incident hip fractures during 13.6-yr follow-up (91,249 person-years), including 362 femoral neck and 333 intertrochanteric hip fractures. Women with the C/C (Asn-Asn) genotype had a 51% higher risk of femoral neck fracture (95% confidence interval, 1.13–2.02) and 26% higher risk of hip fracture (95% confidence interval, 1.02–1.54) than those with the G/G (Lys-Lys) genotype. These associations were independent of BMD. Intertrochanteric fractures were not associated with the Lys3Asn polymorphism.

Conclusion: These results require confirmation but suggest a role for the OPG Lys3Asn polymorphism in the genetic susceptibility to hip fractures among older white women.