The roles of parathyroid hormone in bone remodeling: prospects for novel therapeutics.

The aim of this review is to focus on the roles of PTH in bone remodeling. PTH plays a central role in regulating calcium-phosphate metabolism and its production increases in response to low serum calcium levels. A continue hypersecretion of PTH, as occurs in primary hyperparathyroidism, leads to bone resorption. On the other hand, there is clear evidence of the anabolic properties of PTH.When administered at a low dose and intermittently, this hormone seems to be able to exert positive effects on bone volume and microarchitecture. The effects of PTH are mediated by PTH/PTH-related protein receptor, a G protein that can activate the cAMP-dependent protein kinase (PK)A and calcium-dependent PKC; the activation of PKA account for most of the PTH anabolic action. The anabolic actions of PTH involve direct effects on osteoblasts and indirect effects mediated by activation of skeletal growth factors (IGF-I) and inhibition of growth factor antagonists, such as sclerostin. PTH enhances the number and the activation of osteoblast through 4 pathways: increasing osteoblast proliferation and differentiation, decreasing osteoblast apoptosis and reducing the negative effects of peroxisome proliferator activator (PPAR)γ receptor on osteoblast differentiation. Moreover PTH enhances the Wnt-β catenin pathway, that is central to osteogenesis and bone formation, inhibiting sclerostin. Finally, PTH induces the synthesis of IGF-I and, due to its prodifferentiating and pro-survival effects on osteoblasts, this could be a key mediator of PTH effect on osteoblasts. In conclusion, the intermittent administration of PTH has a pleiotropic anabolic effect on bone; further studies about mechanisms of action of PTH could be a starting point to new osteoporosis treatments.