Background: 60% of patients with metastatic breast cancer will eventually develop bone metastases during course of disease, bone targeting agents either bisphosphonates or denosumab, through different mechanisms of action, these bone-specific agents block osteoclast function and reduce the risk of skeletal-related events. Objectives: This study aimed to compare monoclonal antibody against receptor activator of nuclear factor _ B (RANK) ligand (denosumab), with zoledronic acid in response, toxicity related to treatment and progression skeletal-related events free survival in boney metastatic breast cancer. Patients and Methods: Patients were assigned to receive either subcutaneous denosumab for six months or intravenous zoledronic acid for six months. The primary end point was difference in response and toxicity between bone targeting agents. The secondary end point was comparing skeletal progression survival analysis and the response in both. Results: Denosumab was not superior to zoledronic acid in delaying skeletal progression survival (log rank test P value: 0.119). Disease progression and rates of adverse events were similar between groups. An excess of renal toxicity occurred with zoledronic acid (P value 0.004), while hypocalcemia occurred more frequently with denosumab (P value 0.004). Conclusions: Denosumab was similar to zoledronic acid in delaying skeletal progression survival in bone metastatic breast cancer (BMBC) and was generally well tolerated. With the convenience of a subcutaneous injection and no requirement for renal monitoring, denosumab represents a potential treatment option for patients with bone metastases. While due to severe hypocalcemia with denosumab, zoledronic acid represent a good treatment option for metastatic patients.