Osteoporosis constitutes a major worldwide public health burden characterized by enhanced skeletal fragility. Bone metabolism is the combination of bone resorption by osteoclasts and bone formation by osteoblasts. While increase in bone resorption is considered as the main contributor of bone loss that may lead to osteoporosis, this loss is accompanied by increased bone marrow adiposity. Osteoblasts and adipocytes share the same precursor cell and an inverse relationship exists between the two lineages. Therefore, identifying signaling pathways that stimulates mesenchymal stem cells osteogenesis at the expense of adipogenesis is of major importance in order to develop new therapeutic treatments. For this purpose, we identified by transcriptomic analysis the oxytocin receptor pathway as a potential regulator of the osteoblast/adipocyte balance of human multipotent adipose-derived stem (hMADS) cells. Both oxytocin (OT) and carbetocin (Cb, a stable OT analogue) negatively modulate adipogenesis while promoting osteogenesis in both hMADS cells and human bone marrow mesenchymal stromal cells (hBMSC). Consistent with these observations ovariectomized (OVX) mice and rats, which become osteoporotic and exhibit disequilibrium of this balance, have significant decreased OT levels compared to sham-operated controls. Subcutaneous OT injection reverses bone loss in OVX mice and reduces marrow adiposity. Clinically, plasma OT levels are significantly lower in postmenopausal women developing osteoporosis than in their healthy counterparts. Taken together, these results suggest that plasma OT levels represent a novel diagnostic marker for osteoporosis and that OT administration holds promise as a potential therapy for this disease. ______________________________________________________________________________ Author contributions: C.E.: carried out most of the experiments, data analysis and interpretation, collection and assembly of data; A.B., H.B. and C.B.: analysis of bone micro-architecture and biomechanical parameters of mice, manuscript writing; L.Z., M.S. and Z.T.: microarray analysis, data analysis and interpretation; F.M.: contribution to the mice study, data analysis and interpretation; V.B., G.F.C. and L.E.: provision of patients, data analysis and interpretation; N.W.: histological analysis of mice tissues, data analysis and interpretation; E.L.: provision of study material, data analysis and interpretation; C.D.: data analysis and interpretation, manuscript writing; G.A.: conception and design, data analysis and interpretation, manuscript writing; E.A.: conception and design, collection and assembly of data, data analysis and interpretation, manuscript writing.