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Dissociation of Bone Formation from Resorption during 2-Week Treatment with Human Parathyroid Hormone-Related Peptide-(1–36) in Humans: Potential as an Anabolic Therapy for Osteoporosis¹

Division of Endocrinology, University of Pittsburgh Medical Center (A.F.S.), Pittsburgh, Pennsylvania 15213; the Departments of Orthopedics (C.G.) and Endocrinology (H.P., M.M., A.F.S.), Yale University School of Medicine, New Haven, Connecticut 06520; and the Department of Veterans Affairs (A.F.S.), Pittsburgh, Pennsylvania 15213

Address all correspondence and requests for reprints to: Andrew F. Stewart, M.D., Division of Endocrinology, E-1140 Biomedical Sciences Tower, University of Pittsburgh Medical Center, 3550 Terrace Street, Pittsburgh, Pennsylvania 15213. E-mail: stewart{at}med1.dept-med.pitt.edu

PTH administration increases bone mass in rodents and in humans. PTH-related protein (PTHrP) binds to and signals via the skeletal PTH receptor. Administration of PTHrP on a once daily basis increases bone mineral content in rats. In humans, PTHrP-(1–36) is equipotent to PTH-(1–34) and is active when administered sc. These findings suggest that PTHrP might have therapeutic benefit in the treatment of osteoporosis. In this study, 13 postmenopausal estrogen-deficient women received a single daily sc dose of PTHrP-(1–36) for a 14-day period to determine whether PTHrP-(1–36) 1) could be given in doses that do not alter systemic mineral homeostasis, but increase markers of bone turnover; and 2) is tolerated without adverse effects.

Daily sc PTHrP-(1–36) administration caused no significant changes in serum calcium or phosphorus concentrations, fractional calcium excretion, the tubular maximum for phosphorus, fractional calcium excretion, or plasma 1,25-dihydroxyvitamin D concentrations. Nephrogenous cAMP and endogenous PTH-(1–84) declined. Importantly, markers of bone formation trended upward, as reported in subjects treated with PTH. In marked contrast to findings in PTH-treated subjects, in PTHrP-treated subjects, markers of bone resorption declined in a highly significant fashion.

These observations indicate that PTHrP-(1–36) treatment uncouples bone formation from resorption, in favor of formation. This uncoupling, if it were to continue over the longer term, would predict that PTHrP-(1–36) might be a potent anabolic therapeutic agent for osteoporosis.

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