In multiple myeloma (MM), bone disease is a major source of morbidity, making bone-protective agents like zoledronic acid (ZOL) and denosumab essential to care. ZOL has shown strong efficacy in reducing skeletal-related events (SREs), including in patients without evident bone lesions. Denosumab is non-inferior to ZOL and preferred in patients with renal impairment. Long-term ZOL treatment beyond two years continues to reduce SRE risk with minimal added toxicity. After one year of monthly ZOL, extending dosing to every 12 weeks has proven effective in multiple studies. Although denosumab interval extension is promising in other diseases, data in MM are limited, and discontinuation carries a risk of rebound bone loss, particularly vertebral fractures.

Evidence supports reinitiating bone protection at relapse, even without symptoms, though lifetime bisphosphonate exposure should be considered. Bone markers, like urinary N-telopeptide, have been explored for treatment individualization, but clinical utility remains unproven. Importantly, even patients in deep remission (very good partial response or complete response) remain at risk for SREs, suggesting ongoing treatment may still be needed. A practical approach is monthly ZOL for at least a year, followed by dosing every 12 weeks up to four years if VGPR or better is achieved. Bone-protective therapy should resume at relapse or new SREs, with adjustments based on disease status, imaging, and individual risk factors.

Reference: Gundesen MT, Schjesvold F, Lund T. Treatment of myeloma bone disease: When, how often, and for how long? J Bone Oncol. 2025;52:100680. doi: 10.1016/j.jbo.2025.100680.