Abstract
Osteoporosis, a global health crisis marked by compromised bone mineral density and heightened fracture susceptibility, demands innovative therapeutic strategies beyond conventional anti-resorptive approaches. Mitochondrial dysfunction, characterized by impaired bioenergetics, oxidative stress overload, and calcium dysregulation, has emerged as a central driver of osteoblast-osteoclast imbalance. Recent breakthroughs in mitochondrial transplantation (MT)-a revolutionary modality involving the transfer of functional mitochondria to metabolically compromised cells-have demonstrated unprecedented efficacy in preclinical osteoporosis models, restoring bone mass, microarchitecture, and mechanical strength. This review synthesizes cutting-edge insights into mitochondrial dynamics in bone homeostasis, dissects the molecular cascades linking mitochondrial failure to osteoporotic pathogenesis, and critically evaluates MT's potential to redefine osteoporosis management. We also discuss novel mechanisms of intercellular mitochondrial trafficking within the osteocyte dendritic network, explore bioengineered delivery platforms (eg, immunomodulatory hydrogels, nanoparticle-encapsulated mitochondria), and address emerging challenges in clinical translation, including donor source optimization, immune compatibility, and CRISPR-engineered mitochondrial genomes. By integrating single-cell omics data and AI-driven mitochondrial viability predictors, this work charts a roadmap for personalized mitochondrial medicine, positioning MT as a cornerstone of next-generation osteoporosis therapeutics.