Six-month daily administration of parathyroid hormone and parathyroid hormone-related protein peptides to adult ovariectomized rats markedly enhancesbone mass and biomechanical properties: A comparison of human parathyroid hormone 1-34, parathyroid hormone-related protein 1-36, and SDZ-parathyroidhormone 893

Daily administration of parathyroid hormone (PTH) and PTH-related protein ( PTHrP) peptides has been shown to increase bone mass and strength in animal s and, for PTH, to increase bone mass in humans, Long-term direct compariso n of multiple members of the PTH/PTHrP family in vivo has not been reported . We therefore selected three PTH/PTHrP molecules for direct comparison in vivo in an adult rat model of postmenopausal osteoporosis: PTH(1-34), PTHrP (1-36), and the PTH analog, SDZ-PTH 893 (Leu(8), Asp(10) Lys(11), Ala(16), Gln(18), Thr(33), Ala(34) human PTH 1-34 [hPTH(1-34)]). A 6-month study was performed in which adult (6-month-old) vehicle-treated ovariectomized (OVX ) and sham OVX rats were compared with OVX rats receiving 40 mu g/kg per da y of either PTH(1-34), PTHrP(1-36), or PTM-SDZ-893. Bone mass, as assessed by ash weight and densitometry, bone histomorphometry, biomechanical proper ties at trabecular and cortical sites, and indices of bone formation marked ly increased in all three PTH/PTHrP peptide-treated groups as compared with controls. In general, this improvement followed a rank order of SDZ-PTH-89 3 > PTH > PTHrP, The adverse effect profile also was greatest with SDZ-PTH- 893; these rats developed moderate hypercalcemia, marked renal calcium accu mulation, and displayed a 13% mortality. These studies show that PTH(1-34), PTHrP(1-36), and PTH-SDZ-893 significantly and progressively increase bone mass and bone strength in this rat model of postmenopausal osteoporosis. T he adverse effect profile correlates in general terms with efficacy. All th ree peptides show promise as skeletal anabolic agents. Further studies in h umans will be required to define optimal efficacy-to-adverse effect ratios and relative efficacy for each peptide in human osteoporosis.