Commentary on “The existing evidence for the use of extracellular vesicles in the treatment of osteoporosis: a review” by Geng et al

Dear Editor, We read with great interest the comprehensive review by Geng et al on the therapeutic potential of extracellular vehicles (EVs) in osteoporosis[1]. The review provides a timely synthesis of preclinical evidence showing that EVs from diverse sources can modulate bone remodeling by promoting osteogenesis, inhibiting osteoclastogenesis, enhancing angiogenesis, and improving bone microarchitecture. A notable strength is the integration of mechanistic insights with functional outcomes, offering a clear biological rationale for EV-based therapies. The authors also thoughtfully address EV heterogeneity, emphasizing that source-dependent cargo differences contribute to both therapeutic versatility and biological complexity, an important consideration for future translational applications. As AI-based diagnostic tools are increasingly adopted in clinical practice, maintaining rigorous standards for transparency, validation, and ethical governance is essential to ensure reliability and reproducibility. The TITAN Guidelines 2025 offer a structured framework to support responsible development, assessment, and reporting of medical AI research[2]. Despite these promising findings, several important issues warrant careful consideration. First, the vast majority of evidence remains confined to in vitro experiments and animal models. Robust clinical data in human populations are scarce, leaving critical questions regarding safety, biodistribution, immunogenicity, optimal dosing, and long-term effects unanswered[3]. Addressing these translational gaps will be essential before EV-based therapies can be realistically considered for routine clinical use. Second, methodological heterogeneity represents a significant barrier to reproducibility and clinical translation. Variability in EV isolation, purification, characterization, storage, and delivery methods complicates cross-study comparison and may contribute to inconsistent results[4]. The absence of universally accepted standards underscores the need for harmonized protocols and rigorous quality control measures to ensure reproducibility and regulatory compliance. Third, regulatory and manufacturing challenges remain substantial. EV-based therapeutics occupy a complex regulatory space, intersecting aspects of biologics, cell-derived products, and advanced therapy medicinal products[5]. Clear regulatory frameworks, scalable manufacturing processes, and standardized potency assays will be critical to facilitate safe and efficient clinical development. From a translational standpoint, the review underscores EVs as a promising cell-free therapeutic option with potential safety and logistical advantages over cell-based therapies. EV-based interventions could complement or provide alternatives to existing osteoporosis treatments[6]. The authors emphasize the need for standardized production, rigorous safety evaluation, and well-designed translational and early clinical studies, as well as the exploration of combination strategies to enhance therapeutic efficacy. In conclusion, Geng et al provide a balanced and informative overview of the current evidence supporting the use of extracellular vesicles in osteoporosis treatment. While substantial challenges related to standardization, regulation, and clinical validation remain, the review convincingly illustrates the promise of EV-based approaches as innovative, biologically driven therapies. Their work offers a valuable roadmap for future research and underscores the potential of extracellular vesicles to contribute meaningfully to the evolving landscape of osteoporosis care.