Summary <p>We performed a systematic review and meta-analysis of the efficacy of sequential osteoporosis treatment strategies. Sequential strategies resulting in the greatest BMD gain included romosozumab to denosumab or bisphosphonates; teriparatide to romosozumab or denosumab; and bisphosphonates to romosozumab. These findings can help guide sequential medication choice for patients with osteoporosis.</p> Purpose <p>The purpose of this systematic review and meta-analysis was to evaluate the efficacy of sequential osteoporosis medication strategies on bone mineral density (BMD) and fracture outcomes.</p> Methods <p>Pubmed, Embase, and Cochrane Library databases were searched, and pre-specified criteria were applied to select relevant primary studies for inclusion in this systematic review and meta-analysis.</p> Results <p>Thirty-nine primary studies were included. Meta-analysis summary estimates for BMD change on the second medication in a treatment sequence showed robust BMD gain with bisphosphonates followed by 1&#xa0;year of romosozumab at the lumbar spine (10.1%, 95% CI 9.9–10.4), femoral neck (3.1%, 95% CI 2.9–3.4), and total hip (3.1%, 95% CI 2.7–3.5). Moderate BMD gains were found with romosozumab followed by 1&#xa0;year of denosumab, with summary estimates of 4.0% (95% CI 1.2–6.7) at the lumbar spine, 2.2% (95% CI 0.5–3.8) at the femoral neck, and 2.8% (95% CI 0.8–4.9) at the total hip; similar gains were found with teriparatide transitioned to 1&#xa0;year of denosumab. Bisphosphonates followed by 1&#xa0;year of denosumab resulted in significant BMD gain at the lumbar spine (3.5%, 95% CI 2.8–4.2), femoral neck (1.5%, 95% CI 1.2–1.9), and total hip (2.1%, 95% CI 1.8–2.3). However, bisphosphonates transitioned to 1&#xa0;year of teriparatide resulted in significant BMD gain at the lumbar spine (5.1%, 95% CI 4.4–5.9) but not at the hip.</p> Conclusion <p>These findings provide a rigorous summary of the evidence to guide sequential medication choice for patients with osteoporosis.</p>