Immunocyte-derived EVs modulate osteoblast and osteoclast activity through macrophage polarization, Treg-associated CD73/adenosine signaling, Th17/Treg balance, and B cell–bone interactions, exerting dual effects by promoting bone formation under physiological conditions while amplifying inflammation and bone resorption in osteoporosis, rheumatoid arthritis, and periodontitis. Here, NT5E is linked to osteoporosis.