THE USE OF ORAL BISPHOSPHONATES IN REFRACTORY SEVERE HYPERCALCEMIA AFTER DENOSUMAB CESSATION.

Denosumab,a monoclonal IgG2 antibody directed against RANK-L,is used as a neoadjuvant therapy for inoperable or metastatic giant cell tumor of bone. Many side effects like as hypocalcemia during treatment and rarely severe hypercalcemia especially in children after discontinuation of denosumab occurred. The unpredictable onset and recurrent episodes of severe hypercalcemia increase the duration of hospitalization and the risk of complications. Persistent hypercalcemia and difficulties in management have prompted the search for different more effective therapeutic options.

Objectives: To share our experience with the use of oral bisphosphonate in acute and long-term therapy of severe hypercalcemia following high-dose denosumab therapy and to review the literature on this subject.

Case: We report the management of a case of severe hypercalcemia that developed 4 months after the completion of 18-month denosumab treatment in a 9-year-old girl who was followed up with a giant cell bone tumor for 6 years. Based on an evaluation aiming to determine etiology, hypercalcemia was considered as "rebound-linked" upon denosumab discontinuation. Severe hypercalcemia attacks recurring with an interval of 2 weeks were treated with IV bisphosphonate, but when mild hypercalcemia developed again, treatment with 70 mg per week of oral bisphosphonate was planned. After the second dose of alendronate, the calcium level always remained below 10.5 mg/dl. In the 14-month follow-up, no hypercalcemia attack was observed again.

Results: Rebound hypercalcemia can occur as an unpredictable recurrent episode at any time after denosumab cessation. Thus, the patient should be closely monitored especially in childhood due to rapid bone cycle. In long-term follow-up, oral biphosphonates can be used effectively to reduce hospitalization time and the management of especially life-threatening recurrent attacks.