Longitudinal osteoporosis therapy: treat-to-target and sequential strategies-a narrative review

Osteoporosis is a chronic skeletal disorder in which reduced bone strength confers sustained fracture risk, often necessitating long-term pharmacotherapy with a multi-phase approach rather than a single "one and done" drug choice. Contemporary guidelines increasingly advocate a treat-to-target (TTT), goal-directed approach: clinicians define an explicit target, most often a total hip T-score threshold that corresponds to a lower fracture risk than baseline; select initial therapy according to baseline risk; and reassess and adjust treatment intensity until that target is achieved and maintained. Within this framework, sequential strategies are central. Anabolic-first sequences (e.g., abaloparatide or teriparatide followed by alendronate, or romosozumab followed by alendronate or denosumab) consistently produce larger and more durable gains in bone mineral density and fracture risk reduction in very-high-risk patients than antiresorptive monotherapy. Transitions from long-term bisphosphonates to teriparatide are complicated by transient increased remodeling and modest hip BMD responses, whereas switching to romosozumab yields more robust bone mineral density (BMD) gains at the hip. Notably, denosumab discontinuation demands structured bisphosphonate "exit" therapy to avoid rebound bone loss and multiple vertebral fractures. Across all pathways, rare but serious adverse events (e.g., atypical femoral fractures, medication-related osteonecrosis of the jaw, cardiovascular events), patient adherence and persistence, and insurance coverage constraints strongly shape the feasibility and desirability of specific regimens. This narrative review synthesizes mechanistic and clinical evidence underlying TTT osteoporosis care, summarizes the evidence base for sequential osteoporosis pharmacotherapy, and proposes practical strategies to help clinicians choose, transition, and discontinue therapies while preserving skeletal gains and minimizing harm over decades of longitudinal osteoporosis care.