Gut bacterial extracellular vesicles in glucocorticoid-associated skeletal complications: evidence boundaries and translational challenges

Long-term or high-dose glucocorticoid (GC) therapy causes major skeletal complications, particularly glucocorticoid-induced osteoporosis (GIOP) and glucocorticoid-associated osteonecrosis of the femoral head (GIONFH). Bacterial extracellular vesicles (BEVs) produced by gut-resident bacteria are candidate inter-organ messengers, but the GC-specific evidence base is extremely limited. In an updated structured narrative search executed on 11–13 October 2026 and bounded to publications through 15 September 2026, one eligible in vivo dataset was identified that jointly incorporated GC exposure, administration of bacterially derived vesicles, and skeletal phenotyping: cultured Lactobacillus animalis -derived BEVs attenuated GC-induced osteonecrosis in mice. Within our operational intestinal-associated bacterial-source scope, 14 primary reports were retained: one directly evaluated GC-associated GIONFH and 13 addressed non-GC skeletal conditions. The core count is bounded by this source criterion and the documented search, rather than representing all bacterial OMV studies with skeletal outcomes. We classify the literature along two independent axes—vesicle source (bacterial versus host) and skeletal context (GC versus non-GC)—while keeping hypothesis-generating mechanisms, non-vesicular microbial products, non-skeletal vesicle evidence, and source-unresolved studies outside the matrix. We also distinguish community-derived gut microbiota-derived extracellular vesicles (GMEVs), cultured commensal-derived BEVs (cBEVs), and engineered BEVs, because these preparations are not biologically interchangeable. The anchor study is critically appraised, and GIOP is separated from GIONFH rather than treated as a single disease entity. Current direct bacterial-vesicle evidence supports proof of concept for GIONFH only; no eligible direct GC–bacterial-vesicle dataset for GIOP was identified within this search and source framework, and no eligible human study directly linking source-resolved circulating GMEVs to GC-associated skeletal outcomes was identified within this search framework. The principal translational barriers are source attribution; isolation and analytical standardization; biomarker analytical and clinical validation; biodistribution, PK–PD, and therapeutic delivery; safety, immunogenicity, and scalable manufacturing; and interspecies and human validation. Gut bacterial EVs should therefore be regarded as candidate mediators of a GC-associated gut–immune–bone–vascular axis rather than established drivers of skeletal injury. Immediate priorities are independent replication, testing of human-prevalent donor taxa, and prospective source-resolved clinical cohorts.