Extracellular vesicles in osteoporosis and osteoimmunity: a systematic evidence map

Background Osteoporosis extracellular vesicle (EV) research includes many proposed cargoes and therapeutic constructs, but molecular perturbation, vesicle-specific attribution, and evidence in humans answer different questions. Objective We asked 1) where osteoporosis EV studies are concentrated across osteoimmune mechanisms and study stages, 2) how often advanced mechanistic perturbation occurs together with human evidence, and 3) which experiment is missing when a mechanistic, biomarker, or therapeutic claim remains unsupported. Methods Web of Science Core Collection and Scopus supplied the historical set; PubMed and Embase used equivalent osteoporosis/bone-loss and EV/exosome concepts through 16 April 2026. Full-text primary studies were classified by osteoimmune directness, mechanistic-perturbation depth, human linkage, and seven overlapping modules. Risk of bias, reporting completeness, and MISEV2023 reporting were assessed separately. Results The corrected map contained 222 primary studies: 36 (16.2%) were human-linked, 201 (90.5%) contained animal work, and 213 (95.9%) contained in vitro work. Advanced mechanistic perturbation occurred in 115 studies (51.8%); 13 studies combined this category with human linkage, 102 were advanced without human evidence, 23 were human-linked without advanced perturbation, and 84 had neither. The remodeling interface was the largest module (n = 120), followed by non-classical particles (n = 44), engineered delivery (n = 43), macrophage/monocyte biology (n = 35), and ageing/senescence (n = 28). Eight studies entered the T-cell/Treg/Th17 module. One engineered-delivery study linked an osteoblast intervention to B lymphopoiesis; no eligible study establishing an endogenous B cell-derived EV route was identified. Conclusion Candidate cargoes are abundant, but few studies connect a defined donor state and active vesicular fraction to an osteoimmune mediator, a skeletal outcome, and an intended human claim. The map identifies the untested link and the study design needed to evaluate it while keeping separate evidence dimensions distinct. Systematic review registration https://osf.io/zdcj2/ , identifier zdcj2.