Acute hypercalcemia and excessive bone resorption following anti-RANKL withdrawal: Case report and brief literature review

Denosumab is an anti-RANKL antibody that is commonly used for the treatment of osteoporosis; in oncology, bisphosphonates and denosumab have become the standard therapies for the treatment and prevention of skeletal complications in patients with myeloma and solid tumors. In recent years, excessive bone remodeling following the discontinuation of denosumab has raised concerns. Several cases of hypercalcemia have been reported after the discontinuation of high-dose denosumab (120 mg every 4 weeks), mainly in children. In this study, we report a new case of severe refractory hypercalcemia in a 54-year-old woman who received high-dose denosumab for 5 years as an adjuvant therapy for breast cancer. She is currently in remission and undergoing treatment with anastrazole, an aromatase inhibitor. The peculiarities of this case are the presence of associated bone pain with subperiosteal bone resorption on hand X-rays, and diffuse, long bone diaphyseal uptake on a bone scan. Hyperparathyroidism has been ruled out, and existing evidence suggests that this high-level of bone remodeling could be due to a rebound hyperactivation of the RANKL pathway. In addition to rehydration, repeated use of i.v. bisphosphonates was required to control recurrent hypercalcemia. As hypercalcemia is a serious metabolic complication, a gradual dose reduction should be considered when interruption of high dose denosumab therapy is planned.