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This version published online on March 4, 2008
Journal of Clinical Endocrinology & Metabolism, doi:10.1210/jc.2007-1019
A more recent version of this article appeared on May 1, 2008
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Submitted on May 7, 2007
Accepted on February 26, 2008

Osteoprotegerin Lys3Asn Polymorphism and the Risk of Fracture in Older Women

S P Moffett, J I Oakley, J A Cauley, L Y Lui, K E Ensrud, B C Taylor, T A Hillier, M C Hochberg, J Li, S Cayabyab, J M Lee, G Peltz, S R Cummings, J M Zmuda*, and for the SOF Research Group

Department of Epidemiology, University of Pittsburgh, Pittsburgh, PA; San Francisco Coordinating Center, California Pacific Medical Center Research Institute, San Francisco, CA; Center for Chronic Disease Outcomes Research, Veterans Affairs Medical Center, and University of Minnesota, Minneapolis, MN; Kaiser Permanente Center for Health Research Northwest/Hawaii, Portland, Oregon; Department of Medicine and Epidemiology and Preventive Medicine, University of Maryland School of Medicine, Baltimore, MD; Department of Human Genetics, Roche Molecular Systems, Alameda, CA; Genetics and Genomics, Roche Palo Alto, Palo Alto, CA

Context: Osteoprotegerin (OPG) is a soluble decoy receptor for Receptor Activator Nuclear Factor Kappa-{beta} (RANK) 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 years and older participating in the Study of Osteoporotic Fractures (SOF).

Design: BMD was measured using either single-photon absorptiometry (Osteon Osteoanalyzer) or dual-energy X-ray absorptiometry (Hologic QDR 1000). 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 years of 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%CI: 1.13–2.02) and 26% higher risk of hip fracture (95%CI: 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.

Conclusions: These results require confirmation, but suggest a role for the OPG Lys3Asn polymorphism in the genetic susceptibility to hip fractures among older white women.
Key words: Genetics • Polymorphism • Osteoporosis • Osteoprotegerin • Fracture






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