Parathyroid hormone-related protein for the treatment of postmenopausal osteoporosis: defining the maximal tolerable dose.
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.
Horwitz
Mara J
MJ
Division of Endocrinology, Falk 560, University of Pittsburgh School of Medicine, 3601 Fifth Avenue, Pittsburgh Pennsylvania 15213, USA. horwitz@pitt.edu
Tedesco
Mary Beth
MB
Garcia-Ocaña
Adolfo
A
Sereika
Susan M
SM
Prebehala
Linda
L
Bisello
Alessandro
A
Hollis
Bruce W
BW
Gundberg
Caren M
CM
Stewart
Andrew F
AF
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
D044162:Parathyroid Hormone-Related Protein; D015675:Osteocalcin