Stem Cell-Derived Extracellular Vesicles for the Treatment of Osteoporosis: A Systematic Review of Preclinical Evidence.

Background

Osteoporosis is a prevalent skeletal disorder characterized by reduced bone mass and microarchitectural deterioration, resulting in an increased risk of fractures. Stem cell-derived extracellular vesicles (EVs) have emerged as a promising cell-free therapeutic strategy owing to their inherent advantages, including excellent biocompatibility, low immunogenicity, diverse biological activities, and engineering potential. Despite growing interest in this field, the existing preclinical evidence remains highly heterogeneous in terms of study design, stem cell sources, EV engineering strategies, and delivery approaches. This systematic review aimed to comprehensively synthesize and critically evaluate the available preclinical evidence regarding the therapeutic potential of stem cell-derived EVs for osteoporosis.

Methods

A systematic literature search was conducted in PubMed, Embase, and Web of Science in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Controlled animal studies investigating the therapeutic effects of stem cell-derived EVs in osteoporosis models were included. Data on stem cell sources, EV characteristics, engineering approaches, administration strategies, osteoporosis animal models, therapeutic outcomes, and underlying mechanisms were extracted and qualitatively synthesized.

Results

A total of 64 studies were included. Overall, stem cell-derived EVs demonstrated promising therapeutic potential across various animal models of osteoporosis, exerting pleiotropic effects, including promotion of osteogenesis, inhibition of osteoclastogenesis, enhancement of angiogenesis, modulation of immune responses, and regulation of cellular behaviors. Mechanistically, these effects were largely attributed to the transfer of diverse bioactive cargo, including nucleic acids, proteins, and lipids, which collectively regulate multiple signaling pathways involved in bone remodeling.

Conclusions

Current preclinical evidence supports stem cell-derived EVs as a promising cell-free therapeutic strategy for osteoporosis. However, variability in study design and incomplete reporting in primary studies limit cross-study comparability and translational interpretation, underscoring the need for improved methodological rigor, standardized reporting practices, and robust large-animal validation studies to facilitate future clinical translation.