Osteoprotegerin Is a Risk Factor for Progressive Atherosclerosis and Cardiovascular Disease

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Abstract
Background— Osteoprotegerin is a novel member of the tumor necrosis factor receptor superfamily and a soluble decoy receptor of the receptor activator of nuclear factor-κB ligand. Recent experimental research has implicated osteoprotegerin in atherogenesis, but epidemiological confirmation of this concept is sparse. Methods and Results— As part of the prospective, population-based Bruneck Study, severity, initiation, and progression of atherosclerosis were assessed in carotid arteries. Cases of incident cardiovascular disease and vascular mortality were carefully recorded over a 10-year period (1990 to 2000). Osteoprotegerin levels were measured in samples obtained at baseline and during follow-up. Serum osteoprotegerin showed a strong association with numerous vascular risk factors, including age, diabetes, markers of systemic inflammation, chronic infection, and smoking. In multivariate analyses, osteoprotegerin was significantly related to severity and 10-year progression of carotid atherosclerosis. Furthermore, a high level of osteoprotegerin was an independent risk factor for incident cardiovascular disease (adjusted relative risk for the top versus bottom tertile group for osteoprotegerin 2.2 [1.3 to 3.8]; P =0.001) and vascular mortality (adjusted relative risk for the top versus bottom tertile group for osteoprotegerin 3.1 [1.2 to 8.2]; P =0.010) but not for mortality due to nonvascular causes. Conclusions— Osteoprotegerin is an independent risk factor for the progression of atherosclerosis and onset of cardiovascular disease.