FRI685 Denosumab Withdrawal Is Associated With Hypercalcemia In Adults With Osteoporosis And Bone Metastases

Disclosure: M.D. Patil: None. S. Thosani: None. R.L. Bassett Jr: None. Z. Wang: None. T.A. Guise: None. Denosumab (dmab) is useful to treat conditions associated with increased bone resorption such as osteoporosis (OP), bone metastases (BM), hypercalcemia of malignancy and giant cell tumor of bone. However, discontinuation of dmab therapy is associated with rebound phenomenon characterized by increase in bone resorption, bone loss and vertebral fractures. Rebound osteoclastic activity as well as osteocyte apoptosis-induced reduction in osteoprotegerin are some of the mechanisms proposed for this rebound phenomenon. Recently, case reports of hypercalcemia following dmab withdrawal have been reported, more frequently in the pediatric population. To understand the association of hypercalcemia following dmab withdrawal in adult patients we conducted a retrospective analysis of patients with OP and with BM. We included adult patients treated with dmab or zoledronate for diagnosis of either OP or BM. We excluded patients with history of hypercalcemia before starting on either of the monotherapies. Subsequently, patients who were found to have other etiologies for hypercalcemia, such as increased PTHrP or calcitriol, multiple myeloma, hyperparathyroidism, or combinations therin, were also excluded. Of the 6181 patients who received dmab treatment, 2004 had OP and 2326 had BM. Among these, 77 experienced hypercalcemia:16 patients had other etiologies for hypercalcemia; 36 patients with BM and 25 patients with OP had no cause for hypercalcemia other than dmab withdrawal. The incidence rates of hypercalcemia in dmab group of patients with OP and BM without any other established cause of hypercalcemia were 1.2% (25/2004) and 1.5% (36/2326) respectively. The median time from last dose of dmab to hypercalcemia was 191 days (95% CI: 182 -295) and 92 days (95% CI: 43 - 170) for patients with OP and with BM, respectively. Of the 4177 patients treated with zoledronate, 666 had OP and 1015 had BM and 16 patients had hypercalcemia. Of these 16 hypercalcemic patients, 6 patients had other etiologies of hypercalcemia; 9 patients with BM and 1 patient with OP had no other etiology for the hypercalcemia other than dmab withdrawal. The incidence rates of hypercalcemia in zoledronate group of patients with OP and BM without any other established cause of hypercalcemia were 0.15% (1/666) and 0.88% (9/1015), respectively. Thus, compared with treatment with zoledronate, treatment with dmab is more likely associated with hypercalcemia (p-value 0.006) in patients with OP and with BM when the drug is discontinued. This is the first study comparing hypercalcemia in context of treatment with dmab and zoledronate which demonstrates significantly higher incidence in adult patients treated with dmab. The results have significant implications for treatment of patients with diseases associated with increased bone resorption. Presentation: Friday, June 16, 2023