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. This evidence concerns the gene NT5E and rheumatoid arthritis.