Sequential Versus Step-Therapy Approaches for Osteoporosis Management in Orthopedic Subspecialties

Osteoporosis affects more than 53 million Americans and contributes to nearly 2 million fragility fractures each year, yet most patients who sustain fractures never receive guideline-recommended pharmacotherapy. Traditional step-therapy typically begins with bisphosphonates and reserves anabolic agents for later-line use, whereas sequential therapy prioritizes anabolic treatment followed by antiresorptive consolidation. This review synthesizes the evidence comparing these treatment paradigms and examines their relevance to orthopedic populations, in whom bone quality directly influences fracture healing, fixation, fusion, and implant-related outcomes.

Among 37 studies meeting PRISMA-ScR inclusion criteria, anabolic-first sequential therapy generally produced greater gains in bone mineral density and greater fracture risk reduction than step-therapy or antiresorptive monotherapy. In one representative trial, romosozumab followed by denosumab achieved a 16.8% increase in lumbar spine bone mineral density versus 7.5% with monotherapy, and 92% versus 47% of patients reached treatment targets. In ARCH, anabolic-first therapy was associated with 48% lower vertebral fracture risk and 38% lower hip fracture risk. In orthopedic settings, emerging evidence suggests that sequential protocols may improve postoperative bone mineral density after hip fracture, support spinal fusion, and mitigate periprosthetic bone loss after arthroplasty. Prior antiresorptive exposure appeared to attenuate subsequent anabolic response, particularly at the hip, supporting the rationale for earlier anabolic use. Economic analyses also suggest that, despite higher upfront drug costs, sequential therapy may be cost-effective in patients at high fracture risk. Current evidence supports anabolic-first sequential therapy as a more effective strategy than step-therapy for improving bone mineral density and reducing fracture risk in appropriately selected high-risk patients. For orthopedic populations, the available data suggest meaningful potential benefits in hip fracture care, spinal reconstruction, and arthroplasty, although subspecialty-specific evidence remains more limited than the broader osteoporosis literature. These findings support reconsideration of formulary and treatment policies that delay anabolic therapy in patients most likely to benefit.