SAT-764 - Severe Rebound Hypercalcemia after Denosumab Discontinuation: An Underrecognized Phenomenon in Adults

Denosumab is a medication used for osteoporosis and malignancy-associated bone disease. Osteonecrosis of the jaw (ONJ) is a rare side effect of denosumab, and current International Consensus suggests holding denosumab if ONJ occurs. However, this is at odds with observational data showing rapid bone loss or vertebral compression fractures that occur following denosumab discontinuation. Moreover, hypercalcemia after denosumab discontinuation has been primarily observed in the pediatric population but remains underrecognized in other patient populations. Identifying this condition is important as severe hypercalcemia can result in complications like renal failure.
Our case describes a 64-year-old man with metastatic prostate cancer treated with androgen-deprivation therapy since 2011. His metastases include T11 vertebrae, sacral ala, and 4th rib. He was started on denosumab monthly at a different institution in 2019 without preceding hypercalcemia. Denosumab was inadvertently discontinued with his last dose in July 2024 when he moved to a different province. He was first seen at our institution in February 2025 for severe hypercalcemia (serum calcium 3.37 mmol/L) and an acute kidney injury (creatinine 163 µmol/L from baseline ~100 µmol/L). Complicating his clinical picture was a 1.8 cm lesion in the left submandibular region concerning for ONJ, with no history of preceding dental procedures.
Biochemical evaluation demonstrated low-normal parathyroid hormone (18 ng/L), markedly elevated C-telopeptide (2280 ng/L, ref. 132-752 ng/L), normal 25-hydroxyvitamin D (111 nmol/L), and low 1,25-dihydroxyvitamin D (11 pmol/L) suggesting PTH-independent hypercalcemia due to increased osteoclast-mediated bone resorption. He was referred to otolaryngology for surgery. Although current guidance suggests holding antiresorptive medication in those with active ONJ, given the severe hypercalcemia, denosumab 60 mg was re-administered. This resulted in reduction of serum calcium (1.85 mmol/L) within one week and maintenance of normocalcemia. Six months after denosumab was re-administered, his calcium levels have been slowly increasing (2.61 mmol/L - 2.81 mmol/L). He continues to await surgery with a plan to transition to zoledronic acid for hypercalcemia. His bone mineral density in July 2025 indicated a spine T-score of -2.2, L femoral neck -2.6, and L total hip -1.2. Spine radiographs did not reveal any vertebral compression fractures.
This case highlights rebound hypercalcemia as a rare but clinically significant complication of denosumab discontinuation in adults. Clinicians should consider ongoing monitoring for hypercalcemia following discontinuation, particularly after prolonged or high-dose therapy, such as that used in malignancy-associated bone disease. In some situations, denosumab may need to be continued despite active ONJ, to treat rebound hypercalcemia.

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