Combination and sequential therapy for postmenopausal osteoporosis: recent advances and clinical practice

Abstract

Postmenopausal osteoporosis (PMO) is a systemic skeletal disorder caused primarily by estrogen deficiency, leading to impaired bone remodeling, progressive loss of trabecular bone, disruption of bone microarchitecture, increased bone marrow adiposity, and a substantially elevated risk of fragility fractures. As population aging accelerates worldwide, optimizing therapeutic strategies that effectively improve bone strength while ensuring long-term safety and cost-effectiveness has become an important clinical priority. This review summarizes recent advances in combination and sequential therapies for PMO, with a particular focus on their mechanisms of action, clinical efficacy, safety profiles, and practical applications. Current treatment strategies aim to restore the balance between bone formation and bone resorption through the complementary use of anabolic and antiresorptive agents. Emerging evidence indicates that combination therapies, such as receptor activator of nuclear factor-κB ligand inhibitors with platelet-derived growth factor-BB activators, and sequential regimens, including teriparatide followed by denosumab, can improve bone mineral density, reduce fracture risk, and modulate the osteogenic–adipogenic differentiation balance of mesenchymal stem cells. This review also compares the clinical outcomes, economic considerations, and safety concerns associated with different therapeutic approaches, including medication-related osteonecrosis of the jaw and vascular calcification. In addition, the potential roles of genomics, bone metabolism biomarkers, and artificial intelligence in supporting personalized treatment strategies are discussed. Overall, combination and sequential therapies represent promising approaches for improving the management of PMO by maximizing therapeutic efficacy while minimizing adverse effects. Continued clinical research and the integration of precision medicine are expected to further refine individualized treatment strategies and improve long-term patient outcomes.