IBMS BoneKEy | Perspective

Coupling PTH and arrestins to uncouple bone formation from resorption: A new road to osteoporosis anabolic therapy?

Serge L Ferrari
Mary L Bouxsein

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DOI:10.1138/20090416

Abstract

The main physiological role of PTH is to maintain serum calcium homeostasis, which is achieved by increasing tubular calcium reabsorption and bone resorption. The latter supposes that increases in PTH levels induce activation of osteoclasts, which is mediated primarily by intracellular cAMP and increased RANKL over OPG expression in osteoblasts. Hence even intermittent (daily) administration of PTH for osteoporosis treatment is often accompanied by a transient increase in serum calcium levels and/or urinary calcium excretion. Stimulated bone resorption may ultimately limit the net anabolic effects of intermittent PTH on the skeleton, particularly through Haversian bone remodeling of the cortical compartment. Nevertheless, the PTH mechanisms leading to bone loss are normally regulated by coupling the activated PTH/PTHrP receptor with intracellular β-arrestins. In turn, the development of a “β-arrestin-biased” PTH ligand, (D-Trp12,Tyr34)-PTH(7-34), suggests that such hormone-derived analogs could retain bone-forming activities while having limited effects on bone resorption.

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