Discontinuing Long-Term Denosumab in Treating Fragile Bone: Why, for Whom, and How?

Discontinuation of denosumab (Dmab) may be necessary due to adverse events or an unfavorable long-term risk-benefit profile. However, accumulating evidence demonstrates pronounced rebound phenomena after withdrawal, most notably a marked increase in multiple vertebral fractures, and, in some reports, elevated mortality. This review addresses three key clinical considerations: (1) the mechanistic and clinical evidence for rebound effects and indications for Dmab cessation ("Why?"); (2) patient populations in whom Dmab initiation or continuation may be inappropriate and who therefore require careful transition planning ("For whom?"); and (3) optimal discontinuation and sequential treatment strategies, including scenarios in which continued or lifelong therapy may be advisable ("How?"). Emerging data suggest that concurrent teriparatide and zoledronate may attenuate rebound risk in long-term Dmab users requiring urgent discontinuation, although prospective validation is needed before routine adoption.