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-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 s.c. 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 s.c. 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 s.c. 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.
Plotkin
H
H
Department of Endocrinology, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
Gundberg
C
C
Mitnick
M
M
Stewart
A F
AF
D001846:Bone Development / Q000502:physiology*; D016723:Bone Remodeling; D001862:Bone Resorption; D002117:Calcitriol / Q000097:blood; D002118:Calcium / Q000097:blood / Q000652:urine; D000242:Cyclic AMP / Q000378:metabolism; D005260:Female; D005919:Glomerular Filtration Rate; D006801:Humans; D008875:Middle Aged; D010024:Osteoporosis / Q000188:drug therapy*; D010281:Parathyroid Hormone / Q000097:blood; D044162:Parathyroid Hormone-Related Protein; D010446:Peptide Fragments / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use*; D010758:Phosphorus / Q000097:blood; D017698:Postmenopause; D011506:Proteins / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use*
D010281:Parathyroid Hormone; D044162:Parathyroid Hormone-Related Protein; D010446:Peptide Fragments; D011506:Proteins; C079957:parathyroid hormone-related peptide (1-36); D010758:Phosphorus; D000242:Cyclic AMP; D002117:Calcitriol; D002118:Calcium