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Direct Comparison of Sustained Infusion of Human Parathyroid Hormone-Related Protein-(1–36) [hPTHrP-(1–36)] Versus hPTH-(1–34) on Serum Calcium, Plasma 1,25-Dihydroxyvitamin D Concentrations, and Fractional Calcium Excretion in Healthy Human Volunteers

Division of Endocrinology, University of Pittsburgh School of Medicine (M.J.H., M.B.T., A.G.-O., A.F.S.), and Graduate School of Public Health (S.M.S.), Pittsburgh, Pennsylvania 15213; and Department of Pediatrics, Medical University of South Carolina (B.W.H.), Charleston, South Carolina 29425

Address all correspondence and requests for reprints to: Mara J. Horwitz, M.D., Division of Endocrinology, Falk 580, University of Pittsburgh School of Medicine, 3601 Fifth Avenue, Pittsburgh, Pennsylvania 15213. E-mail: horwitz+{at}pitt.edu.

PTH and PTH-related protein (PTHrP) cause primary hyperparathyroidism and humoral hypercalcemia of malignancy (HHM), respectively. These syndromes are similar in several important ways, but differ in several characteristic, yet unexplained, ways. Two of the unresolved questions in HHM and hyperparathyroidism involve renal physiology. 1) Why does renal proximal tubular production of 1,25-dihydroxyvitamin D [1,25-(OH)₂D] differ between the two syndromes? 2) Do distal tubular calcium responses to PTH and PTHrP differ in the two syndromes? To address these questions, we compared the two peptides, human PTH-(1–34) and PTHrP-(1–36), in a direct, head to head study using a continuous, steady state infusion of each peptide at the same dose in normal human volunteers for 46 h. We had previously described such methods as applied to PTHrP, but a direct multiday comparison of PTHrP to PTH has not previously been reported.

In two groups (seven subjects each) of healthy young (25- to 35-yr-old) normal volunteers, PTH and PTHrP infused at 8 pmol/kg·h displayed similar calcemic effects, although PTH was slightly more potent in this regard. Both peptides also displayed similar phosphaturic effects. In addition, both peptides had similar effects on renal tubular calcium handling, yielding fractional calcium excretion values of approximately 3.5%, some 50% below the values (6.5%) observed in subjects rendered similarly hypercalcemic by the infusion of calcium. In contrast to these several quantitatively similar effects of PTH and PTHrP, PTH tended to be selectively more effective than PTHrP in stimulating renal production of 1,25-(OH)₂D.

These studies indicate that renal tubular calcium reabsorption is likely to contribute to hypercalcemia in patients with HHM. In addition, PTH may be selectively more effective than PTHrP in stimulating 1,25-(OH)₂D production, in contrast to its phosphaturic, calcemic effects and its effects to stimulate nephrogenous cAMP excretion and renal tubular calcium reabsorption.

This work was supported by NIH Grants NIDDK R-0155081 and RR-00056.

Abbreviations: 1,25-(OH)₂D, 1,25-Dihydroxyvitamin D; FECa, fractional calcium excretion; h, human; HHM, humoral hypercalcemia of malignancy; HPT, hyperparathyroidism; PTHrP, PTH-related protein; TmP/GFR, tubular maximum for phosphorus/glomerular filtration rate.

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