Challenges in Sequential Antiresorptive Therapy After Long-Term Denosumab Discontinuation: A Case Report and Narrative Review of the Literature

Background/Objectives: Discontinuation of long-term denosumab (Dmab) remains a major clinical challenge because of rebound activation of bone remodeling and increased vertebral fracture risk. Intravenous zoledronate (ZOL) is widely recommended as sequential therapy, although evidence after very prolonged Dmab exposure is limited. We report a patient who developed two rare adverse events—acute hepatocellular injury and delayed inflammatory polyarthritis—following a single ZOL infusion administered after 12 years of continuous Dmab treatment. The subsequent management of persistent rebound bone turnover with oral alendronate (ALN) highlights the therapeutic challenges encountered when repeat ZOL administration is not feasible. Methods: A 65-year-old woman with postmenopausal osteoporosis received a single 5 mg ZOL infusion 6 months after her final Dmab injection following 12 years of continuous therapy. Within 24 h, she developed a typical acute phase response. Three days later, marked hepatocellular injury was detected, characterized by substantial elevations in transaminases and gamma-glutamyl transferase, while viral and autoimmune hepatitis were excluded. Liver enzymes normalized within five days with supportive management. Thirty-two days after ZOL administration, she developed inflammatory polyarthritis in the absence of previous rheumatologic disease and with negative immunologic testing. Treatment with low-dose prednisone (5 mg/day) resulted in rapid clinical and biochemical remission. At 6 months, bone turnover markers remained markedly elevated (CTX 0.82 ng/mL, P1NP 95 ng/mL), indicating insufficient suppression of rebound bone turnover after Dmab discontinuation. Because of the adverse events, the patient declined repeat ZOL administration. Results: Weekly oral alendronate (ALN) (70 mg) was initiated and was associated with partial suppression of bone turnover markers. Despite a decline in bone mineral density (BMD) of approximately 5% at both the lumbar spine and total hip over 12 months, BMD remained within the osteopenic range, and no new fragility fractures occurred during follow-up. Conclusions: This case illustrates two rare sequential immune-mediated adverse events following ZOL infusion and underscores the therapeutic challenges of managing Dmab discontinuation after long-term treatment when repeat ZOL administration is contraindicated. Sequential intravenous ZOL and oral ALN therapy was associated with partial suppression of bone turnover markers and protection from incident fractures during follow-up, despite a modest decline in BMD of approximately 5%.