title: Parathyroid hormone-related protein for the treatment of postmenopausal osteoporosis: defining the maximal tolerable dose.
abstract: BACKGROUND
  PTH is the only approved skeletal anabolic agent for the treatment of human osteoporosis. Unlike PTH, which is a mixed anabolic and catabolic agent, PTHrP displays features suggesting that it may be a pure anabolic agent when intermittently administered. The full dose range of PTHrP is unknown.
  
  
  OBJECTIVE
  The primary objective of the study was to define the complete therapeutic window and dose-limiting toxicities of PTHrP. The secondary objective was to determine whether PTHrP retains a pure anabolic profile at the highest usable doses.
  
  
  METHODS
  This was a single-blinded, two-part, dose-escalating clinical trial.
  
  
  METHODS
  The study was conducted in a university academic setting.
  
  
  METHODS
  Participants included 41 healthy postmenopausal women between the ages of 45 and 75 yr.
  
  
  METHODS
  INTERVENTIONs included PTHrP(1-36) or placebo in a dose-escalating design for 3 wk.
  
  
  METHODS
  Safety measures (hypercalcemia, nausea, vomiting, hemodynamics, flushing, miscellaneous) and bone turnover markers were measured.
  
  
  RESULTS
  Intermittent PTHrP was administered safely and without serious adverse events in subjects receiving 500 and 625 microg/d for 3 wk. Subjects receiving 750 microg/d developed mild hypercalcemia. Bone turnover markers suggested that even at the highest doses, daily sc PTHrP may not activate bone resorption, i.e. may be purely anabolic. Interestingly, when hypercalcemia occurred, it may have resulted not from bone resorption but from activation of intestinal calcium absorption by 1,25 dihydroxyvitamin D.
  
  
  CONCLUSIONS
  In doses as high as 750 microg/d, in contrast to PTH, intermittently administered PTHrP appears to act as a pure skeletal anabolic agent. Surprisingly, PTHrP in the high doses studied activates 1,25 dihydroxyvitamin D production. Dosing information obtained herein can be used to design a longer term head-to-head comparative efficacy trial of PTHrP vs. PTH.
authors.affiliation: Division of Endocrinology, Falk 560, University of Pittsburgh School of Medicine, 3601 Fifth Avenue, Pittsburgh Pennsylvania 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: Adolfo
authors.initials: A
authors.lastname: Garcia-Ocaña
authors.forename: Susan M
authors.initials: SM
authors.lastname: Sereika
authors.forename: Linda
authors.initials: L
authors.lastname: Prebehala
authors.forename: Alessandro
authors.initials: A
authors.lastname: Bisello
authors.forename: Bruce W
authors.initials: BW
authors.lastname: Hollis
authors.forename: Caren M
authors.initials: CM
authors.lastname: Gundberg
authors.forename: Andrew F
authors.initials: AF
authors.lastname: Stewart
mesh_terms: D000368:Aged; D001862:Bone Resorption; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D006934:Hypercalcemia / Q000097:blood / Q000139:chemically induced; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D015675:Osteocalcin / Q000097:blood; D010012:Osteogenesis / Q000187:drug effects; D015663:Osteoporosis, Postmenopausal / Q000097:blood / Q000188:drug therapy*; D044162:Parathyroid Hormone-Related Protein / Q000008:administration & dosage* / Q000009:adverse effects*; D016037:Single-Blind Method
chemical_list: D044162:Parathyroid Hormone-Related Protein; D015675:Osteocalcin