Endocrine Abstracts

Hypercalcemia following discontinuation of Denosumab in adults is described in the literature but remains a rare diagnosis. While pediatric cases receiving Denosumab for conditions like giant cell tumor of bone, fibrous dysplasia, osteogenesis imperfecta, central giant cell granuloma, and aneurysmal bone cyst have been discussed extensively, limited information exists regarding this phenomenon in adults. In this context, we present the case of a 77-year-old woman who was admitted to our hospital with hypercalcemia (3.5 mmol/l), confirmed by an ionized calcemia of 1.92 mmol/l. Diagnostic investigations showed normal albumin and phosphorus levels. Parathyroid hormone (PTH) level was normal at 17.9 ng/l (normal values 13.6-85). Further tests showed normal PTH-related protein (PTHrp), vitamin D (25-OH-D), TSH, CEA, and NSE levels. Protein electrophoresis was also normal. A thoraco-abdominal scan revealed a known pseudonodular formation with ground-glass appearance and a non-contrast-taking nodule in a PET-SCAN. The patient was treated with hyperhydration and pamidronate, normalizing her calcemia. However, a month later, calcemia rose to 3.05 mmol/l, necessitating readmission. Further tests to exclude granulomatosis included 1-25-OH-D and angiotensin convertase, both normal. Additional history-taking revealed that the patient had been receiving Denosumab injections every six months for osteoporosis but had missed her last injection, having not received it in the past 10 months. After resuming Denosumab and receiving hyperhydration, her calcemia stabilized. Denosumab, a human monoclonal antibody, inhibits osteoclast activity by targeting RANK ligand (RANKL)¹. It is used to treat conditions like osteoporosis and various bone tumors. Osteoclast activity, essential for bone resorption, is countered by osteoblasts under normal conditions. Denosumab helps restore this balance by preventing bone resorption. Discontinuing Denosumab can lead to rebound hypercalcemia due in part to resumed osteoclast activity. A systematic review by H. Keisuke et al.² (2021) highlighted three adult cases treated for osteoporosis among others, showing treatments for rebound hypercalcemia including rehydration, diuretics, corticoids, and calcitonin. In some cases, bisphosphonates or Denosumab were re-administered. Prophylactic strategies include gradually reducing Denosumab or replacing it with bisphosphonates. This case represents the fourth documented instance of Denosumab cessation-induced hypercalcemia rebound in an adult treated for osteoporosis. It emphasizes considering Denosumab discontinuation in differential diagnoses of hypercalcemia, given its widespread use. Further research is needed to confirm the link between bone resorption and hypercalcemia, using bone resorption markers³ and additional adult cases to improve management strategies for Denosumab discontinuation.

References: 1. Rachner T.D., Khosla S., Hofbauer L.C., 2011. Osteoporosis: now and the future. Lancet 377 (9773), 1276–1287.

2. Keisuke H, Eisuke K, Tsukasa M, Michiro S, Kazuhiro C. Hypercalcemia following discontinuation ofdenosumab therapy: a systematic review. Bone Rep. 2021 November;15:1-6. doi:10.1016/j.bonr.2021.101148.

3. Deodati A., Fintini D., Levtchenko E., Rossi M., Ubertin,G., Segers H., Battafarano G., Cappa M., Del Fattore A., 2021. Mechanisms of acute hypercalcemia in pediatric patients following the interruption of denosumab. J. Endocrinol. Investig. https://doi.org/10.1007/s40618-021-01630-4.