Bone Health in Prostate Cancer: Two Clinical Paradigms and the Evolving Role of Bone-Protecting Agents

Men with prostate cancer (PCa) face two distinct but partially overlapping bone-health problems: treatment-induced loss of bone mineral density (BMD) with consequent fragility-fracture risk, and metastasis-driven skeletal morbidity manifesting as skeletal-related events (SREs). Because the literature and contemporary recommendations frequently conflate these paradigms — blurring the indications, doses, schedules and endpoints of bone-protecting agents (BPAs) — this narrative review synthesises current evidence under an explicit two-paradigm framework: Paradigm A, androgen-deprivation therapy (ADT)-induced fragility; and Paradigm B, bone metastases and SREs. We reviewed pivotal randomised trials, systematic reviews and meta-analyses, guidelines (EAU 2026, NCCN 2026, AUA/SUO 2023, ASCO/CCO 2020, MASCC/ISOO/ASCO 2019), and 2024–2026 practice-changing evidence including PEACE-3, ERA-223 follow-up. ADT and androgen receptor pathway inhibitor (ARPI) intensification sharply raise fracture risk, yet risk assessment remains incompletely implemented. In Paradigm A, denosumab (DNB) (60 mg every 6 months) carries the strongest fracture-prevention evidence in PCa trials, whereas bisphosphonates preserve BMD with less robust fracture-endpoint data. In Paradigm B, DNB (120 mg) and zoledronic acid (ZA) (4 mg) every 4 weeks delay SREs in metastatic castration-resistant PCa — DNB modestly superior for time to first SRE, neither prolonging survival; early oncology-dose treatment of castration-sensitive disease did not reduce SREs (CALGB 90202), though the high fracture burden of intensified disease often still warrants prevention. When radium-223 is combined with an ARPI, PEACE-3 established mandatory BPA co-administration. Critically, the agents are not interchangeable at discontinuation: stopping DNB provokes rebound bone loss and fracture, demanding a planned transition. Agent selection turns on clinical criteria — renal function, medication-related osteonecrosis of the jaw (MRONJ) risk, discontinuation strategy and dosing convenience. A useful approach starts by naming the paradigm: identify the clinical state, match the bone-health objective, then select agent, dose and duration. The two paradigms guide different decisions and should not be merged.