Denosumab-efficacy, safety, persistence and sequential strategies-a systematic review

Denosumab (DMAB), a monoclonal antibody targeting receptor activator of nuclear factor kappa-Β ligand (RANKL), is an effective antiresorptive therapy for osteoporosis that increases bone mineral density (BMD) and reduces the risk of vertebral and non-vertebral fractures. However, its effects are rapidly reversible, and treatment delays or discontinuation are associated with bone turnover overshoot, loss of BMD, and an increased risk of vertebral fractures. Despite generally high treatment persistence, DMAB is frequently discontinued, necessitating appropriate sequential therapy to prevent overshoot in bone turnover. This review summarizes the literature on the efficacy, safety, and persistence of DMAB treatment, as well as strategies for transitioning to other anti-osteoporosis therapies after discontinuation.

A literature search was conducted on September 22, 2025, across multiple databases, including Embase, PubMed, and the Cochrane Library. Randomized controlled trials (RCTs) and observational studies evaluating the efficacy, safety, and persistence of DMAB, as well as clinical outcomes following DMAB discontinuation and subsequent sequential therapy, were included. Data extraction and quality assessment were conducted independently by two authors in accordance with PRISMA guidelines. The efficacy of DMAB compared with placebo and bisphosphonates (BPs) was assessed by meta-analyses of the relevant trials. The remaining outcomes were assessed and described using a narrative synthesis.

A total of 71 studies met the inclusion criteria. Compared with placebo, DMAB consistently increased BMD, reduced BTMs, and lowered the risk of vertebral and non-vertebral fractures. Across included studies, DMAB generally resulted in greater BMD gains and improved fracture outcomes compared with BPs. Changes in BMD were comparable to those observed with teriparatide, while romosozumab resulted in larger gains in the lumbar spine. No data was available on fracture risk when comparing DMAB to osteoanabolic therapies. Real-world studies generally reported high short-term persistence and compliance with DMAB, but treatment persistence declined over longer follow-up periods. Discontinuation of DMAB was associated with rapid increases in BTMs, loss of BMD gains, and an increased risk of vertebral fractures. Sequential treatment with oral or IV BPs attenuated but did not completely prevent bone turnover overshoot and bone loss.

DMAB is an effective treatment for osteoporosis, superior to BPs and comparable to anabolic treatments in improving BMD and superior to BPs in reducing fracture risk, but its discontinuation carries clinically significant risks of bone loss and vertebral fractures. Consequently, discontinuing DMAB requires long-term treatment planning, and the timely initiation of appropriate sequential therapy is essential to optimize patient outcomes.