Risk of Symptomatic Skeletal Events After Discontinuation of Long-term Denosumab in Patients With Bone Metastases: A...

The optimal duration of denosumab (Dmab) therapy for patients with bone metastases remains uncertain, particularly regarding the balance between preventing skeletal-related events and the risk of medication-related osteonecrosis of the jaw (MRONJ) after treatment discontinuation. This study evaluated the incidence and risk factors of symptomatic skeletal events (SSEs) following Dmab discontinuation.

We retrospectively analysed 178 patients with bone metastases who discontinued Dmab after ≥6 doses and had ≥3 months of follow-up. Incidence, timing, and risk factors of SSEs were assessed using Cox regression. A landmark analysis was performed in patients treated for ≥2 years (n = 152), with SSE-free survival compared between discontinuation and continuation groups, with and without propensity score matching (PSM). Incidence rates of SSEs and MRONJ were compared between patients treated for <2 and ≥2 years.

SSEs occurred in 16.9% of patients, with 77% developing within one year after discontinuation, particularly within six months. Longer Dmab treatment duration was associated with reduced SSE risk (HR, 0.96; 95% CI, 0.93-0.99). The incidence of SSEs was lower in the ≥2-year group compared with the <2-year group (0.044 vs. 0.201 per person-year), whereas MRONJ incidence was higher (0.091 vs. 0.055 per person-year, P < 0.001). In the ≥2-year landmark cohort, the number of prior SSEs was the only independent predictor of subsequent SSEs. After ≥2 years, SSE-free survival was not significantly different between discontinuation and continuation groups after PSM (P = 0.074). Median overall survival from Dmab initiation was 41 months, with 1- and 2-year survival rates of 96% and 72%, respectively.

Discontinuation of Dmab after ≥2 years may be a reasonable option for selected patients with stable disease. However, decisions must balance the benefit of reduced SSE risk with the increased likelihood of MRONJ. Patients with a history or greater burden of SSEs remain at increased risk and require close monitoring.