Denosumab is a fully human monoclonal antibody that binds to the receptor activator of nuclear factor kappa-Β ligand, an essential cytokine factor in bone resorption, which reduces bone resorption and has been shown to decrease the incidence of skeletal-related events in patients with malignancy and bone metastasis. Severe hypocalcemia is a rare and life-threatening adverse effect of denosumab therapy. Here, we discuss the case of a patient with stage 4 estrogen receptor-positive, progesterone receptor-negative, human epidermal growth factor receptor 2-negative breast cancer who was on treatment with denosumab for bony metastases and presented with severe refractory hypocalcemia.