title: Safety and tolerability of subcutaneous PTHrP(1-36) in healthy human volunteers: a dose escalation study.
abstract: Parathyroid hormone-related protein (PTHrP) is an anabolic skeletal agent in mice, rats and humans. In previous studies, we have demonstrated that PTHrP can be administered to osteoporotic postmenopausal women at a dose of 6.56 microg/kg/day (or approximately 400 microg/day) for 3 months to yield a 4.7% increase in lumbar spine BMD. This regimen was free of hypercalcemia or adverse effects. Moreover, PTHrP appeared to stimulate bone formation selectively, without stimulating bone resorption. This efficacy in the absence of adverse effects, as well as the apparent "pure anabolic" action of PTHrP, prompted us to attempt to define the complete therapeutic window for PTHrP. In this study, we gradually escalated the dose of PTHrP(1-36) from 9 to 28 microg/kg (or approximately 570 microg to 1,946 microg) administered as a single subcutaneous dose to 22 healthy young adult subjects. PTHrP(1-36) was well tolerated even at the highest dose, just under 2.0 mg, some five times higher than we have previously demonstrated to be effective in increasing bone mass, and some 100 times higher than the maximal approved dose of PTH(1-34). Despite the large dose of PTHrP, the highest serum calcium achieved was 10.6 mg/dl, and this was observed in only one subject at the highest dose. The mean serum calcium in subjects receiving the highest dose was 9.6 mg/dl. Only one subject experienced adverse symptoms/signs, and this was at the highest dose. We conclude that subcutaneous PTHrP(1-36) is safe when administered in single doses approaching 2.0 mg. These findings indicate that the therapeutic window for PTHrP(1-36) in humans is wide and permit the design and implementation of longer safety and efficacy trials.
authors.affiliation: Division of Endocrinology, University of Pittsburgh School of Medicine, Falk 580 3601 Fifth Ave., Pittsburgh, PA 15213, USA. horwitz@pitt.edu
authors.forename: Mara J
authors.initials: MJ
authors.lastname: Horwitz
authors.forename: Mary Beth
authors.initials: MB
authors.lastname: Tedesco
authors.forename: Susan M
authors.initials: SM
authors.lastname: Sereika
authors.forename: Adolfo
authors.initials: A
authors.lastname: Garcia-Ocaña
authors.forename: Alessandro
authors.initials: A
authors.lastname: Bisello
authors.forename: Bruce W
authors.initials: BW
authors.lastname: Hollis
authors.forename: Caren
authors.initials: C
authors.lastname: Gundberg
authors.forename: Andrew F
authors.initials: AF
authors.lastname: Stewart
mesh_terms: D000328:Adult; D015415:Biomarkers / Q000032:analysis; D001794:Blood Pressure / Q000502:physiology; D015519:Bone Density / Q000187:drug effects; D050071:Bone Density Conservation Agents / Q000008:administration & dosage* / Q000009:adverse effects; D001862:Bone Resorption / Q000097:blood; D002118:Calcium / Q000097:blood / Q000652:urine; D024042:Collagen Type I / Q000097:blood; D004334:Drug Administration Schedule; D004341:Drug Evaluation / Q000379:methods; D005260:Female; D006339:Heart Rate / Q000502:physiology; D006801:Humans; D007279:Injections, Subcutaneous; D008297:Male; D008875:Middle Aged; D044162:Parathyroid Hormone-Related Protein / Q000008:administration & dosage* / Q000009:adverse effects; D010446:Peptide Fragments / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood; D011347:Procollagen / Q000097:blood
chemical_list: D015415:Biomarkers; D050071:Bone Density Conservation Agents; D024042:Collagen Type I; D044162:Parathyroid Hormone-Related Protein; D010446:Peptide Fragments; D011347:Procollagen; C079957:parathyroid hormone-related peptide (1-36); C047202:procollagen Type I N-terminal peptide; D002118:Calcium