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 OSTEOPOROSIS

PTH administration increases bone mass in rodents and in humans. PTH-r elated protein (PTHrP) binds to and signals via the skeletal PTH recep tor. Administration of PTHrP on a once daily basis increases bone mine ral content in rats. In humans, PTHrP-(1-36) is equipotent to PTH-(1-3 4) and is active when administered sc. These findings suggest that PTH rP might have therapeutic benefit in the treatment of osteoporosis. In this study, 13 postmenopausal estrogen-deficient women received a sin gle daily sc dose of PTHrP-(1-36) for a 14-day period to determine whe ther PTHrP-(1-36) 1) could be given in doses that do not alter systemi c mineral homeostasis, but increase markers of bone turnover; and 2) i s tolerated without adverse effects. Daily sc PTHrP-(1-36) administrat ion caused no significant changes in serum calcium or phosphorus conce ntrations, fractional calcium excretion, the tubular maximum for phosp horus, fractional calcium excretion, or plasma 1,25-dihydroxyvitamin D concentrations. Nephrogenous cAMP and endogenous PTH-(1-84) declined. Importantly, markers of hone formation trended upward, as reported in subjects treated with PTH. In marked contrast to findings in PTH-trea ted subjects, in PTPFrP-treated subjects, markers of bone resorption d eclined in a highly significant fashion. These observations indicate t hat PTHrP-(1-36) treatment uncouples bone formation from resorption, i n favor of formation. This uncoupling, if it were to continue over the longer term, would predict that PTHrP-(1-36) might be a potent anabol ic therapeutic agent for osteoporosis.