Transient increase in skeletal-related events after discontinuation of high-dose denosumab in cancer patients

Abstract

Background: Denosumab is widely used to prevent skeletal-related events (SREs) in patients with bone metastases. However, rebound bone resorption after discontinuation is recognized. In osteoporosis, discontinuation of low-dose denosumab increases multiple vertebral fractures, but data on high-dose discontinuation remain limited. Methods: Among 493 patients treated with high-dose denosumab at our institution (2014-2023), 78 met eligibility criteria. SREs during and after treatment were compared using each patient as their own control. SREs were defined as pathological fracture, spinal cord compression, or radiotherapy/surgery for metastatic bone pain. Hypercalcemia, benign fragility fractures, and serum ALP level were also assessed. Results: A total of 11 SREs were observed during denosumab and 24 after discontinuation. Post-discontinuation incidence was 14.1 per 1,000 person-months, 3.3 times higher than during treatment (95 % CI, 1.4-7.8). The increase was significant at 6-15 months, peaking at 12-15 months (IRR 8.7, 95 % CI, 2.8-27.5), and declined thereafter. Fewer denosumab doses were also associated with a higher risk of SREs after discontinuation. Two benign fragility fractures occurred during denosumab and four after discontinuation. Grade ≥ 3 hypercalcemia occurred only after discontinuation (3 cases). Transient ALP elevation at 9-18 months was observed in patients with post-discontinuation SREs, and ALP ≥ 95 U/L at 6 months predicted subsequent SREs (AUC 0.80). Conclusion: SREs increased significantly 6-15 months after high-dose denosumab discontinuation. Elevated ALP was associated with post-discontinuation SREs. These findings emphasize that discontinuation contributes to SRE risk, possibly via rebound bone resorption, and underscore the importance of continuation of therapy whenever possible.