Osteoporosis (OP) remains a significant global health challenge, marked by high prevalence
and considerable economic burden, yet effective therapeutic options remain limited. Central to
the pathogenesis of OP is mitochondrial dysfunction, which adversely impacts bone formation and
resorption. This review provides an in-depth analysis of the complex relationship between mitochondrial
function and OP, elucidating critical molecular mechanisms and identifying promising therapeutic
agents. Among these, zoledronic acid and resveratrol stand out, demonstrating significant efficacy
in enhancing mitochondrial functions and enhancing bone density in both preclinical models
and clinical trials. Moreover, innovative drug delivery systems, such as mitochondrial-targeted
nanodelivery systems and localized delivery methods, have been developed to ensure precise targeting
and reduce systemic side effects, thereby enhancing bioavailability and therapeutic outcomes. By
delving into these advancements, this review seeks to facilitate the translation of mitochondrial-targeted
therapies from preclinical research to clinical application, ultimately advancing OP management
and improving patient outcomes.