Stem cell-based strategies in osteoporosis: Pathophysiological insights and therapeutic perspectives

Osteoporosis is a systemic skeletal disorder marked by reduced bone mass and microarchitectural deterioration, leading to increased fracture risk. Despite the availability of antiresorptive and anabolic agents, current therapies often present limitations such as long-term safety concerns, treatment resistance, and inadequate reversal of established bone loss. Recent advances in stem cell biology offer promising regenerative strategies that target the underlying pathophysiology of osteoporosis. This review provides an in-depth analysis of the dynamic balance between bone formation and resorption, emphasizing the pivotal role of mesenchymal stem cells (MSCs) and hematopoietic stem cells (HSCs) in maintaining bone homeostasis. The disruption of stem cell function, manifested as impaired osteogenic differentiation, increased adipogenesis, senescence, and altered niche interactions, emerges as a key contributor to osteoporotic bone loss. Besides, this review comprehensively summarizes current stem cell-based therapeutic approaches, including MSCs transplantation, endogenous stem cell activation, cell-free therapies utilizing extracellular vesicles and exosomes, and advanced bioengineering techniques that enhance stem cell survival, homing, and osteogenic potential. Furthermore, it identifies major translational challenges such as osteogenesis control, cell source standardization, efficacy assessment, and mechanistic exploration. Future perspectives highlight the integration of single-cell omics, gene editing, biomaterials, senescence-targeting interventions to improve therapeutic precision and efficacy.