Bone Formation May Be Uncoupled from Resorption, as Demonstrated by a New Class of hPTHrP-(1-34) Analogues in Both Rapid and Slow Turnover Models of Osteopenia

I. Introduction ........................................................................... 152

II. Design of Model α-Helical Peptide (MAP) Analogs ............ 153

III. In Vivo Effects of the MAP Analogs ...................................... 155 A. Studies in Rats ............................................................... 155 B. Studies in Ovariectomized Monkeys............................ 158 C. Studies in Corticosteroid-Treated Rabbits ................... 159

IV. Implications of the Observed Effects of MAP Peptides in Osteopenia Versus Normal Bone Mass Situations ............... 167

References ......................................................................................... 168

The association between parathyroid hormone, PTH, (as glandular extracts) and anabolic activity in bone has an extensive history, being first noted, although without comment, in 1929 by Fuller Albright.1 The connection was more formally made three years later by Selye.2 There was desultory interest in the phenomenon3,4 until the 1980s and the demonstration that the desired activity resides in the N-terminal 34 amino acid sequence of the 84 amino acid hormone.5,6 The availability of synthetic PTH-(1-34) enabled clinical trials for treatment of osteopenia,7-10 and this in turn sparked a resurgence in animal experimentation.11-13 Overlapping this time, an intriguing story of a ubiquitously expressed PTH-related peptide (PTHrP) family has emerged.14 Although the alternatively spliced, full-size, expressed hormone family ranges from 139-173 amino acids, it now appears that, again, the N-terminal 34 amino acid sequence is a highaffinity agonist at one of the identified PTH receptors (PTH-1R)15,16 and possesses all the bone activity of PTH-(1-34).6,17,18 Clinical pharmacology studies are now being reported with fragments of PTHrP; PTHrP-(1-34) seems less potent than PTH-(1-34), perhaps because of increased metabolic lability.19 However, hPTHrP-(1-36), which may be the endogenously secreted sequence, is reported to be equipotent to PTH-(1-34).20