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.