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

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-Trp,Tyr)-PTH(7-34), suggests that such hormone-derived analogs could retain bone-forming activities while having limited effects on bone resorption. IBMS BoneKEy. 2009 December;6(12):470-476. ©2009 International Bone & Mineral Society Introduction: the PTH Paradox Both intermittent and continuous exposure to PTH induce bone formation, however, the net bone mineral balance depends on the magnitude of the concomitant bone resorption. Hence intermittent (daily) administration of PTH(1-84) or the shorter bioactive peptide PTH(1-34) (teriparatide) increases bone mass, bone strength, and reduces fracture risk, and has therefore been approved for treatment of osteoporosis (1). In comparison, continuous exposure to PTH, as seen in primary hyperparathyroidism, may still improve cancellous, but not cortical bone volume (2). The paradox of concomitant PTH anabolism/catabolism has been particularly well-demonstrated by the targeted expression in osteoblasts of a (cAMP) constitutively active PTH/PTHrP receptor mutant (carrying the H223R mutation of Jansen’s chondrometaphyseal dysplasia) (3). In these mice, trabecular bone volume was increased despite a prominent increase in osteoclast number, while cortices appeared thinner and porous. Furthermore, administration of a PTH-Fc fusion molecule characterized by a long circulating half-life and mean residency time, i.e., allowing for weekly rather than daily injections leading to prolonged cycles of intermittent exposure to the hormone, was shown to exert potent anabolic effects on both trabecular and cortical bone in intact and ovariectomized rodents – actually much more potent effects than intermittent PTH(1-34) – despite having hypercalcemic effects that precluded its clinical development (4). Hence PTH stimulates bone formation rather independently of the mode of exposure or pharmacokinetic profile of the derived compounds. However, continuous exposure to the hormone stimulates bone resorption to levels that may eventually exceed its bone-forming effects at the tissue level, IBMS BoneKEy. 2009 December;6(12):470-476 http://www.bonekey-ibms.org/cgi/content/full/ibmske;6/12/470 doi: 10.1138/20090416