Pathophysiology of PTH-related Protein (1-36) in Humans

University Of Pittsburgh At Pittsburgh, Pittsburgh PA

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Abstract

DESCRIPTION (Adapted from the Applicant's Abstract): This application is a hormone-related protein (PTHrP) in the syndrome of humoral hypercalcemia of malignancy (HHM) and its potential therapeutic role in osteoporosis. PThrP is responsible for HHM. Patients with HHM resemble those with primary hyperparathyroidism (HPT) in that both groups are hypercalcemic, both display increases in osteoclastic bone resorption, both display renal phosphorus wasting and hypophosphatemia, and increases in nephrogenous cydic AMP excretion. Both HPT and HHM are humoral syndromes. The two syndromes differ with regard to regulation of 1,25(OH)2D (in that this vitamin D metabolite is increased in HPT and reduced in HHM) and in renal calcium handling (with some groups reporting that renal calcium reabsorption is increased, while others suggest that the syndrome is associated with increased renal calcium excretion). In the prior period of funding, we have shown that PTHrP(1-36) stimulates renal calcium conservation in normal human volunteers, and appears to transiently up-regulate, then down regulate, 1,25(OH)2D production. Moreover, we have demonstrated in rats that daily subcutaneous administration of PTHrP is markedly anabolic for the skeleton, leading to increases in bone mass as well as in biomechanical strength. Preliminary studies in humans demonstrate that PTHrP may be a pure anabolic agent," selectively stimulating bone formation without stimulating bone resorption. The studies in this proposal, then, have two Specific Aims: 1. To further define the relative potencies and mechanisms of action of PThrP vs. PTH in humans as regulators of renal calcium reabsorption and 1,25(OH)2D biosynthesis. 2. To complete a pilot study, currently in progress, designed to determine the efficacy of PTHrP(1-36) in the treatment of postmenopausal osteoporosis. These studies represent an extension of an ongoing, longstanding research program in humans, targeted at understanding the physiology and pathophysiology of PTHrP, and at developing strategies which might employ PTHrP as an anabolic agent in the treatment of osteoporosis. The studies described in the application strongly suggest that PTHrP may have a unique role as an anabolic agent in the treatment of osteoporosis.