Exosomes are secreted into the blood by various types of cells. These small vesicles are involved in bone remodeling by mediation of intercellular communication in osteoblasts, osteoclasts or their precursors. Alterations in exosomal proteins are related to the failure of bone remodeling, which results in progressive loss of bone mass and poor quality of bone structure. However, the molecular changes in serum-derived exosomes (SDEs) from patients with low bone density and their functions in bone remodeling remain to be fully elucidated. We present a quantitative proteomics analysis of exosomes purified from the serum of patients with osteoporosis/osteopenia and normal volunteers; these data are available via Proteome Xchange with the identifier PXDXXXXX. Overall, 1,371 proteins were identified with an overlap of 1,160 Gene IDs among the ExoCarta proteins. In vitro studies and bioinformatics analysis revealed that the main changes in the SDEs of osteoporosis patients were proteins playing critical roles in integrins-mediated mechanosensation and signaling cascades, which are implicated in aggravating the failure of bone remodeling, including the enhancement of osteoclast differentiation and inhibition of bone mineralization. In contrast, the main changes in SDEs of osteopenia patients were proteins known to facilitate both osteoclast differentiation and osteoblastic bone formation, which resulted in a compensatory elevation of bone remodeling. In addition, bioinformatics analysis indicated that SDEs from elderly volunteers mediate negative regulation of bone remodeling via selenium deficiency-associated oxidative stress. This information will be helpful in elucidating the pathophysiological functions of SDEs and aid in the development of osteoporosis diagnostics and therapeutics.