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Parathyroid Hormone-Related Protein-(1–36) Is Biologically Active When Administered Subcutaneously to Humans¹

Divisions of Endocrinology, Veterans Administration Connecticut Healthcare System, West Haven, Connecticut 06516; and Yale University School of Medicine, New Haven, Connecticut 06520

Address all correspondence and requests for reprints to: Andrew F. Stewart, M.D., Research 151/C, Veterans Administration Medical Center, 950 Campbell Avenue, West Haven, Connecticut 06516.

Abstract

PTH-related protein (PTHrP) is responsible for most cases of humoral hypercalcemia of malignancy (HHM). It mimics the actions of PTH as a result of its structural homology with PTH and its ability to bind to and signal via the PTH/PTHrP receptor in bone and kidney. PTHrP-(1–36) appears to be one of several secretory forms of PTHrP. This peptide has been administered iv to normal volunteers previously and has been shown to produce effects that are qualitatively and quantitatively the same as those produced by PTH-(1–34). To determine whether PTHrP-(1–36) could be used sc in humans as a diagnostic reagent for elucidating the differences between HHM and hyperparathyroidism, we performed a 12-h dose-finding study examining whether sc PTHrP-(1–36) could elicit effects on mineral homeostasis.

PTHrP-(1–36) administered sc in three doses (0.82, 1.64, and 3.28 µg/kg) to 21 normal women produced increases in circulating PTHrP-(1–36), reductions in serum phosphorus and the renal phosphorus threshold, increments in fractional calcium excretion and nephrogenous cAMP excretion, and increases in plasma 1,25-dihydroxyvitamin D. These changes were highly significant in statistical terms and were observed at doses that had no effect on serum calcium or endogenous PTH.

These studies demonstrate the feasibility of using PTHrP-(1–36) as a diagnostic probe for future studies aimed at elucidating the differing pathophysiologies of HHM and hyperparathyroidism.

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