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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2009;29:975.)
© 2009 American Heart Association, Inc.

Clinical and Population Studies

Osteoprotegerin and Soluble Receptor Activator of Nuclear Factor-B Ligand and Risk for Coronary Events

A Nested Case–Control Approach in the Prospective EPIC-Norfolk Population Study 1993–2003

Anne G. Semb; Thor Ueland; Pål Aukrust; Nicholas J. Wareham; Robert Luben; Lars Gullestad; John J.P. Kastelein; Kay-Tee Khaw; S. Matthijs Boekholdt

From the Department of Rheumatology (A.G.S.), Diakonhjemmet Hospital, Research Institute for Internal Medicine (T.U., P.A.), Section of Clinical Immunology and Infectious Diseases (P.A.), and the Department of Cardiology (L.G.), Oslo University Hospital, Rikshospitalet, University of Oslo, Norway; MRC Epidemiology Unit (N.J.W.), Department of Public Health and Primary Care (R.L., K.-T.K.), Institute of Public Health, University of Cambridge, UK; the Department of Cardiology (S.M.B.), and the Department of Vascular Medicine (M.B.), Academic Medical Center, Amsterdam, the Netherlands.

Correspondence to Anne G. Semb, Department of Rheumatology, Diakonhjemmet Hospital, N-0319 Oslo, Norway. E-mail a-semb{at}diakonsyk.no

Objective— The purpose of this study was to examine the association between serum levels of osteoprotegerin (OPG) and receptor activator of nuclear factor-B ligand (RANKL) and future coronary artery disease (CAD) in apparently healthy individuals. The identification of OPG as a novel cardiovascular risk marker suggests an association between mediators of bone homeostasis and cardiovascular disease.

Methods and Results— Serum levels of OPG and RANKL were analyzed in a prospective case–control study nested in the European Prospective Investigation into Cancer and Nutrition (EPIC-Norfolk) study, a cohort study of 25 663 men and women, where 951 apparently healthy individuals who developed a coronary event during 6 years’ follow-up were matched by sex and age with 1705 healthy controls. Baseline OPG, but not RANKL, was higher in cases than in controls, and OPG was higher in women than in men. Both men and women in the highest OPG quartile had a higher risk for future CAD. These associations were independent of established cardiovascular risk factors, and when using OPG as a continuous variable, also after adjustment for CRP. In contrast, RANKL showed no association with coronary events.

Conclusion— OPG is associated with the risk of future CAD in apparently healthy men and women, independent of established cardiovascular risk factors.

In the EPIC-Norfolk study, of 951 healthy individuals, matched with 1705 healthy controls (followed 6.7 years), those within the highest osteoprotegerin quartile had significant higher risk for future coronary events, independent of established cardiovascular risk factors. In contrast, receptor activator of nuclear factor-B ligand was not associated with coronary events.

Key Words: osteoprotegerin • CRP • coronary artery disease • case–control study • risk factors • inflammation

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