Introduction: Bone metastasis affects the majority of patients with advanced breast cancer and no adequate therapy exists. Bisphosphonates, like zoledronic acid, inhibit the osteolytic component of tumor growth in osseous tissues, but these drugs are not curative. The current study evaluated the combination of zoledronic acid with death receptor 5 agonists in an animal model of breast cancer bone metastasis. Results: Combination therapy containing either hTRA8 or mTRA8 with zoledronic acid significantly reduced the number of secondary lesions (7.67 ± 2.2 and 7.5 ± 1.7 lesions/mouse, respectively) compared to saline treated controls (12.1 ± 1.56 lesions/mouse) as assessed by bioluminescence imaging (p < 0.05). Additionally, monotherapy with hTRA8 resulted in a significant reduction in tumor number (8.3 ± 2.9) compared to control animals. Total body tumor burden over time was significantly less in groups treated with hTRA8 + zoledronic and mTRA8 + Zoledronic acid combination as compared with the saline control group. At day 33, both combination therapies and zoledronic acid monotherapy provided significant reduction in total tumor burden and tumor infiltration of hindlimbs by histomorphometry (p < 0.05). Materials and methods: Female athymic nude mice (age 4-6 w, n = 35) were inoculated with 200,000 luciferase-positive MDA-MB-435 cells by injection into the left ventricle. Animals were immediately imaged by bioluminescence technique and placed into one of the following therapy groups: Saline, hTRA8, hTRA8 + zoledronic acid, mTRA8, mTRA8 + zoledronic acid, or zoledronic acid monotherapy. DR5 agonists were given at 200 μg/dose and zoledronic acid 5 μg/dose, with mice treated biweekly for 4.5 weeks and imaged weekly. Conclusion: DR5 agonists in combination with bisphosphonates may be an acceptable combination therapy to reduce breast cancer growth in bone. ©2009 Landes Bioscience.