The physiological maintenance of bone mass is ensured by bone tissue renewal, allowing old bone tissue to be replaced by an equivalent mass of bone matrix. After mechanical or hormonal stress activation, a phase of resorption by osteoclasts occurs, followed by a phase of bone formation by osteoblasts. Among the multiple factors involved in osteoblastic differentiation are the following: Cbfa1 (transcription factor); low density lipoprotein receptor-related protein-5 (LRP-5), a membrane lipoprotein receptor and protein Wnt co-receptor, which plays an important role during development. It is possible that osteoblastic proliferation and differentiation are regulated by distinct pathways. Osteoclastic differentiation is also regulated by numerous factors: osteoprotegerin (OPG); RANK-L (receptor activator of nuclear factor kappa B ligand, a transmembrane protein related to tumour necrosis factor [TNF], the binding of which to its RANK receptor induces osteoclastic differentiation); and soluble TNF receptors. Local regulation of the OPG/RANK-L ratio could explain postmenopausal loss of bone mass. OPG could play a major role in myeloma and Paget disease. Osteolysis together with bone metastasis could also be related to the local production of RANK-L. OPG decreases osteolysis and offers an interesting therapeutic perspective for the treatment of osteoporosis and other diseases associated with bone hyper-resorption.