Stem Cell-Based Regenerative Strategies for Bone Aging: Current Advances and Future Perspectives

Bone aging is characterized by a progressive decline in skeletal regenerative capacity, driven by stem-cell senescence, chronic inflammation, impaired vascularization, metabolic dysfunction, and alterations in the bone marrow niche. These changes contribute to osteoporosis, delayed fracture healing, and reduced bone quality in older individuals. Stem cell-based therapies have emerged as promising strategies to restore bone regeneration, with investigations focusing on mesenchymal stromal cells, skeletal stem cells, adipose-derived stromal cells, induced pluripotent stem cell-derived osteogenic progenitors, and cell-free approaches such as extracellular vesicles and secretomes. This narrative review examines the biological mechanisms underlying bone aging, the impact of the aged microenvironment on stem-cell function, and current approaches to rejuvenate skeletal regeneration. We discuss advances in tissue engineering, including biomaterials, 3D-printed scaffolds, controlled-release systems, and multifunctional constructs designed to modulate inflammation, enhance angiogenesis, and improve osteogenesis. Preclinical studies consistently demonstrate beneficial effects on bone formation, microarchitecture, and repair; however, translation to clinical practice remains limited. Human studies have primarily focused on fracture nonunion and focal bone defects, showing encouraging safety and feasibility but insufficient evidence for systemic treatment of age-related skeletal fragility. Major barriers include cellular heterogeneity, manufacturing and regulatory challenges, inadequate potency assays, and the complexity of the aged bone niche. Future success will likely depend on integrated therapeutic strategies that simultaneously target progenitor-cell dysfunction and the local microenvironment while ensuring reproducible, scalable, and clinically meaningful outcomes. These advances may pave the way toward effective regenerative therapies for osteoporosis and age-related bone loss.