Objective: New members of the TNF-signaling superfamily, osteoprotegerin (OPG) and receptor activator of nuclear factor-?B ligand (RANKL), are thought to play an important role in vascular calcification and bone remodeling and might represent the molecular link between arterial calcification and bone resorption. The purpose of this study was to determine whether OPG and/or RANKL mediate the observed association between coronary and bone calcification in postmenopausal women. Methods: Among the members of the Rancho Bernardo longitudinal study, 92 postmenopausal women (aged 58-81 years) taking estrogen therapy (ET) who underwent assessment of bone mineral density (BMD) and coronary artery calcification (CAC) and had serum OPG and RANKL levels measured between 1998-2002 are the basis of this report. Results: Neither OPG nor RANKL levels varied among subjects with and without CAC in multivariate analysis. Increase in BMD at the hip was associated with decrease in CAC (OR=0.52; 95% CI: 0.29-0.93) independent of age, fat-free mass, HDL cholesterol, current smoking, and use of cholesterol-lowering medications. Other skeletal sites demonstrated a similar pattern. Addition of RANKL and/or OPG in the model had minimal effect on the magnitude or statistical significance of the BMD-CAC association. Additionally, a test of interaction indicated that RANKL and OPG are not significant effect modifiers of the association. Conclusion: Serum OPG and RANKL do not account for the observed association between bone and coronary artery calcification among postmenopausal women using ET.