60 Background: Bone-modifying agents (BMAs) are standard in metastatic prostate cancer, preventing skeletal complications but risking medication-related osteonecrosis of the jaw (MRONJ). Evidence guiding prostate-specific management remains sparse. We investigated real-world MRONJ risk, systemic outcomes, and bone metabolism with RANKL inhibitors (RANKLi) versus bisphosphonates (BP). Methods: Men with metastatic prostate cancer (TriNetX Global, 2000–2024) receiving RANKLi or BP were propensity-matched 1:1 (n = 10,964) for key clinical and treatment factors, including baseline corticosteroid use, osteoporosis, osteopenia, and vitamin D levels. Primary endpoints included MRONJ incidence and hazard; secondary outcomes included antibiotic use (≤2 years), survival, and metabolic bone indices. Results: RANKL inhibition was associated with a significantly higher MRONJ incidence (1.30% vs 0.64%; OR 2.05, 95% CI 1.35–3.13; HR 1.82, 95% CI 1.18–2.79; both p < 0.01). Antibiotic use within 2 years was greater with RANKLi (38.5% vs 34.1%; p < 0.001). Despite these toxicities, RANKLi conferred superior overall survival (37.4 vs 32.5 months; HR 0.89, 95% CI 0.83–0.95; p < 0.0001) and reduced hypercalcemia (0.21% vs 0.46%; p = 0.0278). Conclusions: RANKL inhibition nearly doubled MRONJ risk compared with bisphosphonates but provided clear survival and metabolic advantages. The absolute MRONJ risk remained low yet clinically meaningful, reinforcing the importance of proactive dental surveillance and multidisciplinary care. These findings highlight a critical therapeutic balance of greater skeletal and survival benefit at the cost of increased MRONJ risk while managing metastatic prostate cancer. Outcomes with RANKL inhibitors versus bisphosphonates. Outcome RANKL Inhibitors Bisphosphonates p-value Effect Estimate (95% CI) Medication-related osteonecrosis of the jaw (MRONJ) 1.30% (71/5,460) 0.64% (35/5,460) 0.0008 OR 2.05 (1.35–3.13); HR 1.82 (1.18–2.79) Antibiotic use (≤2 years) 38.5% 34.1% <0.001 — Median overall survival (months) 37.4 32.5 <0.0001 HR 0.89 (0.83–0.95) Hypercalcemia incidence 0.21% 0.46% 0.0278 —
Syed et al. (2026) studied this question.