BONE-SELECTIVE ANALOGS OF HUMAN PTH(1-34) INCREASE BONE-FORMATION IN AN OVARIECTOMIZED RAT MODEL

Intermittent parathyroid hormone (PTH) therapy increases bone mass, Th e purpose of this study was to determine if analogs of human PTH(1-34) (hPTH[1-34]), which differ from the native sequence in their receptor- activating properties, could promote bone formation in an ovariectomiz ed (OVX) osteopenic rat model, We synthesized two hPTH(1-34) analogs w ith single substitutions for serine in the 3-position that in vitro ar e partial agonists in kidney, In the renal cell line OK, maximal cycli c adenosine monophosphate (cAMP) activation by [His(3)]hPTH(1-34) was 50%, and maximal cAMP activation by [Leu(3)]hPTH(1-34) was 20% of that produced by hPTH(1-34). Both analogs were full agonists in UMR-106 ra t osteosarcoma cells and other bone-derived systems, but both had redu ced potency compared with hPTH(1-34). Six-month-old retired breeder Sp rague-Dawley rats were ovariectomized, and five animals underwent sham operation, On day 56 post-OVX, five sham-operated and five pre-PTH tr eatment OVX animals were sacrificed, and the remaining animals were ra ndomized into 10 groups of six animals each, All other animals were in jected with one of the hPTH analogs or hPTH(1-34) at 0, 4, 40, or 400 mu g/kg of body weight (BW)/day and were killed on day 84, Histomorpho metry of the proximal tibia metaphysis and biochemical markers of bone turnover (osteocalcin and pyridinoline cross-links) were the primary endpoints, The cancellous bone volume was significantly lower at day 5 6 post-OVX (pretreatment) and at day 84 post-OVX (post-vehicle treatme nt) than at baseline, None of the compounds significantly increased th e cancellous bone volume, Trabecular number declined after OVX and did not change with hPTH treatment, In contrast, the trabecular thickness declined after OVX but was higher after treatment with 40 mu g/kg of BW/day or 400 mu g/kg of BW/day of hPTH(1-34). In OVX rats, the minera lizing surface,vas higher than baseline at day 56 and fell toward cont rol levels by day 84, All three peptides produced marked dose-related increases in the mineralizing surface and bone formation rates, but th e two analogs were less potent than hPTH(1-34). Likewise, all peptides produced significant dose-related increases in the serum osteocalcin level, The osteoclast surface was not affected by OVX but was decrease d with medium and high doses of hPTH(1-34), Pyridinoline cross-link ex cretion was not significantly affected by treatment with hPTH(1-34) bu t responded with a dose-dependent decrease to treatment with [His(3)]h PTH(1-34), These data suggest that bone selective analogs of hPTH(1-34 ) maintain the ability to induce bone formation but are less potent th an hPTH(1-34).