Purpose: We assessed serum concentrations of the recep-levels were associated with a higher risk of death from breast tor activator of NFkB ligand (RANKL) and its decoy recep-cancer [HR 1.94; 95% confidence interval (CI) 1.23–3.07; tor, osteoprotegerin (OPG), two proteins implicated in the P = 0.005] and OPG was an independent prognostic marker development and progression of breast cancer, in 509 for breast cancer–specific survival (BCSS; multivariate patients with primary, nonmetastatic breast cancer. Then analyses, P = 0.035). RANKL levels were 33% higher the results were evaluated with regards to the occurrence of (P < 0.0001) in DTC ^pos patients (41%), whereas high levels bone metastases, the presence of disseminated tumor cells were associated with a significantly better BCSS in DTC ^neg (DTC) in the bone marrow, survival, and risk of developing patients as compared with low levels (HR 0.524; 95% CI metastatic disease. 0.30–0.95; P = 0.04). RANKL serum levels were significantly Experimental Design: Before surgery, two bone marrow increased in patients who developed bone metastases aspirates were analyzed for DTC using density centrifugation (P = 0.01) and patients within the highest quartile of followed by immunocytochemistry (pan-cytokeratin anti-RANKL had a significantly increased risk of developing bone body A45-B/B3). RANKL and OPG levels in the serum were metastases compared with those in the lowest (HR 4.62; measured by ELISA. 95% CI 1.49–14.34; P = 0.03). Results: RANKL levels were significantly lower in women Conclusions: These findings warrant further investigation >60 years (P < 0.0001) and RANKL/OPG ratios higher in as they provide a rationale for novel diagnostic or therapeutic lymph node–positive patients (P < 0.05). High OPG serum approaches.