{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,5]],"date-time":"2026-11-05T17:35:11Z","timestamp":1793900111971,"version":"4.8.0"},"reference-count":47,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,9,16]],"date-time":"2025-09-16T00:00:00Z","timestamp":1757980800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Endocrinol."],"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>Traditional pharmacological treatments for osteoporosis face challenges due to various limitations, including long-term safety concerns and limited bone anabolic effects. Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) have emerged as a promising cell-free alternative therapy. However, their preclinical efficacy and the factors driving heterogeneity still require systematic evaluation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>A systematic search was conducted in PubMed, EMBASE, Cochrane Library, and Web of Science (from inception to February 2025). Two independent authors performed literature screening, data extraction, and risk of bias assessment. A random-effects model was used to pool and analyze bone mineral density (BMD), bone volume fraction (BV\/TV), trabecular\/cortical structural parameters, and biomechanical test results. Publication bias was assessed using funnel plots and Egger\u2019s test, while leave-one-out sensitivity analysis was performed to evaluate the stability of the results. Subgroup analyses were conducted based on animal type, EVs source, synthesis method, engineering approach, intervention route, frequency, and treatment duration.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>A total of 17 studies were included. The results demonstrated that, compared to the control group, MSC-EVs significantly increased BMD, BV\/TV, trabecular number (Tb.N), trabecular thickness (Tb.Th), cortical thickness (Ct.Th), mineral apposition rate (MAR), and the ultimate load-bearing capacity of the femur, while reducing trabecular separation (Tb.Sp). Significant heterogeneity and publication bias were observed in all analyses. Sensitivity analysis confirmed the robustness of all results.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>MSC-EVs demonstrate significant improvements in preclinical osteoporosis models, highlighting its potential for clinical translation. However, further standardized studies are needed to evaluate the long-term efficacy and safety of MSC-EVs.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fendo.2025.1625969","type":"journal-article","created":{"date-parts":[[2025,9,16]],"date-time":"2025-09-16T04:14:18Z","timestamp":1757996058000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":4,"title":["Therapeutic effects of mesenchymal stem cell-derived extracellular vesicles in osteoporosis models: a systematic review and meta-analysis of preclinical studies"],"prefix":"10.3389","volume":"16","author":[{"given":"Ying","family":"Zhang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shaoyun","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chao","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,9,16]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mcna.2020.06.004","article-title":"Osteoporosis in older adults","volume":"104","author":"Johnston","year":"2020","journal-title":"Med Clin North Am"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1097\/SMJ.0b013e31818be99b","article-title":"New guidelines for the prevention and treatment of osteoporosis","volume":"102","author":"Lewiecki","year":"2009","journal-title":"South Med J"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1002\/jbmr.2269","article-title":"The recent prevalence of osteoporosis and low bone mass in the United States based on bone mineral density at the femoral neck or lumbar spine","volume":"29","author":"Wright","year":"2014","journal-title":"J Bone Miner Res"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1007\/s00198-006-0172-4","article-title":"An estimate of the worldwide prevalence and disability associated with osteoporotic fractures","volume":"17","author":"Johnell","year":"2006","journal-title":"Osteoporos Int"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1007\/s00198-016-3865-3","article-title":"The impact of the new National Bone Health Alliance (NBHA) diagnostic criteria on the prevalence of osteoporosis in the USA","volume":"28","author":"Wright","year":"2017","journal-title":"Osteoporos Int"},{"key":"B6","doi-asserted-by":"publisher","first-page":"46","DOI":"10.5152\/eurjrheum.2016.048","article-title":"An overview and management of osteoporosis","volume":"4","author":"S\u00f6zen","year":"2017","journal-title":"Eur J Rheumatol"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1093\/ageing\/afp221","article-title":"Excess mortality in men compared with women following a hip fracture. National analysis of comedications, comorbidity and survival","volume":"39","author":"Kannegaard","year":"2010","journal-title":"Age Ageing"},{"key":"B8","doi-asserted-by":"publisher","first-page":"2557","DOI":"10.3390\/ijms20102557","article-title":"Molecular-based treatment strategies for osteoporosis: A literature review","volume":"20","author":"Ukon","year":"2019","journal-title":"Int J Mol Sci"},{"key":"B9","doi-asserted-by":"publisher","first-page":"dgaa048","DOI":"10.1210\/clinem\/dgaa048","article-title":"Pharmacological management of osteoporosis in postmenopausal women: an endocrine society guideline update","volume":"105","author":"Shoback","year":"2020","journal-title":"J Clin Endocrinol Metab"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2010.1360","article-title":"Atypical fractures as a potential complication of long-term bisphosphonate therapy","volume":"304","author":"Sellmeyer","year":"2010","journal-title":"Jama"},{"key":"B11","doi-asserted-by":"publisher","first-page":"76","DOI":"10.1016\/j.molmed.2004.12.004","article-title":"Osteoclast-derived activity in the coupling of bone formation to resorption","volume":"11","author":"Martin","year":"2005","journal-title":"Trends Mol Med"},{"key":"B12","doi-asserted-by":"publisher","first-page":"669","DOI":"10.1038\/nrd.2016.207","article-title":"Merck &Co. drops osteoporosis drug odanacatib","volume":"15","author":"Mullard","year":"2016","journal-title":"Nat Rev Drug Discov"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2021.09.006","article-title":"Mesenchymal stromal cells: Putative microenvironmental modulators become cell therapy","volume":"28","author":"Krampera","year":"2021","journal-title":"Cell Stem Cell"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2018.05.004","article-title":"Mesenchymal stromal cells: clinical challenges and therapeutic opportunities","volume":"22","author":"Galipeau","year":"2018","journal-title":"Cell Stem Cell"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1016\/j.biomaterials.2010.12.032","article-title":"Homing of endogenous stem\/progenitor cells for in situ tissue regeneration: Promises, strategies, and translational perspectives","volume":"32","author":"Chen","year":"2011","journal-title":"Biomaterials"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1172\/JCI81423","article-title":"Mucosally transplanted mesenchymal stem cells stimulate intestinal healing by promoting angiogenesis","volume":"125","author":"Manieri","year":"2015","journal-title":"J Clin Invest"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.110.239848","article-title":"Malignant tumor formation after transplantation of short-term cultured bone marrow mesenchymal stem cells in experimental myocardial infarction and diabetic neuropathy","volume":"108","author":"Jeong","year":"2011","journal-title":"Circ Res"},{"key":"B18","doi-asserted-by":"publisher","first-page":"63","DOI":"10.1186\/s13287-018-0791-7","article-title":"Mesenchymal stem cell-derived extracellular vesicles: novel frontiers in regenerative medicine","volume":"9","author":"Keshtkar","year":"2018","journal-title":"Stem Cell Res Ther"},{"key":"B19","doi-asserted-by":"publisher","first-page":"113836","DOI":"10.1016\/j.addr.2021.113836","article-title":"Extracellular vesicles from mesenchymal stromal cells: Therapeutic perspectives for targeting senescence in osteoarthritis","volume":"175","author":"Boulestreau","year":"2021","journal-title":"Adv Drug Delivery Rev"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.2147\/IJN.S263756","article-title":"Bone-targeted extracellular vesicles from mesenchymal stem cells for osteoporosis therapy","volume":"15","author":"Wang","year":"2020","journal-title":"Int J Nanomed"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1007\/s10753-021-01583-z","article-title":"Mesenchymal stem cell-derived extracellular vesicles inhibit osteoporosis via microRNA-27a-induced inhibition of DKK2-mediated wnt\/\u03b2-catenin pathway","volume":"45","author":"Wang","year":"2022","journal-title":"Inflammation"},{"key":"B22","doi-asserted-by":"publisher","first-page":"1450","DOI":"10.3390\/ijms18071450","article-title":"Mesenchymal stem\/stromal cell-derived extracellular vesicles and their potential as novel immunomodulatory therapeutic agents","volume":"18","author":"B\u00f6rger","year":"2017","journal-title":"Int J Mol Sci"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1016\/j.jconrel.2017.08.022","article-title":"Extracellular vesicles from mesenchymal stem cells activates VEGF receptors and accelerates recovery of hindlimb ischemia","volume":"264","author":"Gangadaran","year":"2017","journal-title":"J Control Release"},{"key":"B24","doi-asserted-by":"publisher","first-page":"n71","DOI":"10.1136\/bmj.n71","article-title":"The PRISMA 2020 statement: an updated guideline for reporting systematic reviews","volume":"372","author":"Page","year":"2021","journal-title":"Bmj"},{"key":"B25","doi-asserted-by":"publisher","first-page":"9636897211057465","DOI":"10.1177\/09636897211057465","article-title":"The role and mechanism of exosomes from umbilical cord mesenchymal stem cells in inducing osteogenesis and preventing osteoporosis","volume":"30","author":"Yahao","year":"2021","journal-title":"Cell Transplant"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.2147\/IJN.S433511","article-title":"Bone-targeting peptide and RNF146 modified apoptotic extracellular vesicles alleviate osteoporosis","volume":"19","author":"Gui","year":"2024","journal-title":"Int J Nanomed"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.7150\/thno.39238","article-title":"Human umbilical cord mesenchymal stromal cells-derived extracellular vesicles exert potent bone protective effects by CLEC11A-mediated regulation of bone metabolism","volume":"10","author":"Hu","year":"2020","journal-title":"Theranostics"},{"key":"B28","doi-asserted-by":"publisher","first-page":"119208","DOI":"10.1016\/j.lfs.2021.119208","article-title":"Extracellular vesicles from GPNMB-modified bone marrow mesenchymal stem cells attenuate bone loss in an ovariectomized rat model","volume":"272","author":"Huang","year":"2021","journal-title":"Life Sci"},{"key":"B29","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1186\/s13018-020-02160-0","article-title":"Exosomal miR-186 derived from BMSCs promote osteogenesis through hippo signaling pathway in postmenopausal osteoporosis","volume":"16","author":"Li","year":"2021","journal-title":"J Orthop Surg Res"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1002\/jor.25776","article-title":"Exosomal circFAM63Bsuppresses bone regeneration of postmenopausal osteoporosis via regulating miR-578\/HMGA2 axis","volume":"42","author":"Li","year":"2024","journal-title":"J Orthop Res"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.7150\/thno.96174","article-title":"Extracellular vesicles from apoptotic BMSCs ameliorate osteoporosis via transporting regenerative signals","volume":"14","author":"Li","year":"2024","journal-title":"Theranostics"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2020.608521","article-title":"BMSC-derived exosomal miR-29a promotes angiogenesis and osteogenesis","volume":"8","author":"Lu","year":"2020","journal-title":"Front Cell Dev Biol"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.2147\/IJN.S335757","article-title":"Multiplexed molecular imaging strategy integrated with RNA sequencing in the assessment of the therapeutic effect of wharton\u2019s jelly mesenchymal stem cell-derived extracellular vesicles for osteoporosis","volume":"16","author":"Lu","year":"2021","journal-title":"Int J Nanomed"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.7150\/ijbs.14809","article-title":"Exosomes secreted by human-induced pluripotent stem cell-derived mesenchymal stem cells repair critical-sized bone defects through enhanced angiogenesis and osteogenesis in osteoporotic rats","volume":"12","author":"Qi","year":"2016","journal-title":"Int J Biol Sci"},{"key":"B35","doi-asserted-by":"publisher","first-page":"250","DOI":"10.1186\/s13018-023-03660-5","article-title":"ERK-estrogen receptor \u03b1 signaling plays a role in the process of bone marrow mesenchymal stem cell-derived exosomes protecting against ovariectomy-induced bone loss","volume":"18","author":"Qi","year":"2023","journal-title":"J Orthop Surg Res"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1089\/hum.2020.005","article-title":"Bone marrow mesenchymal stem cells-derived exosomal microRNA-150-3p promotes osteoblast proliferation and differentiation in osteoporosis","volume":"32","author":"Qiu","year":"2021","journal-title":"Hum Gene Ther"},{"key":"B37","doi-asserted-by":"publisher","first-page":"115829","DOI":"10.1016\/j.bcp.2023.115829","article-title":"Extracellular vesicles from bone marrow mesenchymal stem cells alleviate osteoporosis in mice through USP7-mediated YAP1 protein stability and the Wnt\/\u03b2-catenin pathway","volume":"217","author":"Wang","year":"2023","journal-title":"Biochem Pharmacol"},{"key":"B38","doi-asserted-by":"publisher","first-page":"798","DOI":"10.21037\/atm-21-1838","article-title":"Exosomes derived from cyclic mechanical stretch-exposed bone marrow mesenchymal stem cells inhibit RANKL-induced osteoclastogenesis through the NF-\u03baB signaling pathway","volume":"9","author":"Xiao","year":"2021","journal-title":"Ann Transl Med"},{"key":"B39","doi-asserted-by":"publisher","first-page":"121438","DOI":"10.1016\/j.biomaterials.2022.121438","article-title":"Bioactive glass nanoparticles inhibit osteoclast differentiation and osteoporotic bone loss by activating lncRNA NRON expression in the extracellular vesicles derived from bone marrow mesenchymal stem cells","volume":"283","author":"Yang","year":"2022","journal-title":"Biomaterials"},{"key":"B40","doi-asserted-by":"publisher","first-page":"1","DOI":"10.4158\/GL-2020-0524SUPPL","article-title":"AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS\/AMERICAN COLLEGE OF ENDOCRINOLOGY CLINICAL PRACTICE GUIDELINES FOR THE DIAGNOSIS AND TREATMENT OF POSTMENOPAUSAL OSTEOPOROSIS-2020 UPDATE","volume":"26","author":"Camacho","year":"2020","journal-title":"Endocr Pract"},{"key":"B41","doi-asserted-by":"publisher","first-page":"115558","DOI":"10.1016\/j.bone.2020.115558","article-title":"Composition and characteristics of trabecular bone in osteoporosis and osteoarthritis","volume":"140","author":"Tamimi","year":"2020","journal-title":"Bone"},{"key":"B42","doi-asserted-by":"publisher","first-page":"117373","DOI":"10.1016\/j.bone.2024.117373","article-title":"Combining systemic and local osteoporosis treatments: A longitudinal in vivo microCT study in ovariectomized rats","volume":"192","author":"Stadelmann","year":"2025","journal-title":"Bone"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1016\/S8756-3282(02)00830-X","article-title":"Contribution of trabecular and cortical components to the mechanical properties of bone and their regulating parameters","volume":"31","author":"Ito","year":"2002","journal-title":"Bone"},{"key":"B44","doi-asserted-by":"publisher","first-page":"390","DOI":"10.1002\/jmri.20807","article-title":"Structural and functional assessment of trabecular and cortical bone by micro magnetic resonance imaging","volume":"25","author":"Wehrli","year":"2007","journal-title":"J Magn Reson Imaging"},{"key":"B45","doi-asserted-by":"publisher","first-page":"12750","DOI":"10.3390\/ijms222312750","article-title":"Mesenchymal stem cell-derived extracellular vesicle: A promising alternative therapy for osteoporosis","volume":"22","author":"Lu","year":"2021","journal-title":"Int J Mol Sci"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.26355\/eurrev_201806_15280","article-title":"Exosomes derived from bone marrow mesenchymal stem cells improve osteoporosis through promoting osteoblast proliferation via MAPK pathway","volume":"22","author":"Zhao","year":"2018","journal-title":"Eur Rev Med Pharmacol Sci"},{"key":"B47","doi-asserted-by":"publisher","first-page":"30","DOI":"10.1186\/s13287-018-1121-9","article-title":"BM-MSC-derived exosomes alleviate radiation-induced bone loss by restoring the function of recipient BM-MSCs and activating Wnt\/\u03b2-catenin signaling","volume":"10","author":"Zuo","year":"2019","journal-title":"Stem Cell Res Ther"}],"container-title":["Frontiers in Endocrinology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2025.1625969\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,9,16]],"date-time":"2025-09-16T04:14:19Z","timestamp":1757996059000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2025.1625969\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,9,16]]},"references-count":47,"alternative-id":["10.3389\/fendo.2025.1625969"],"URL":"https:\/\/doi.org\/10.3389\/fendo.2025.1625969","relation":{},"ISSN":["1664-2392"],"issn-type":[{"value":"1664-2392","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,9,16]]},"article-number":"1625969"}}