Recombinant human parathyroid hormone (PTH) analogs (1-34) and (1-84) are used as bone anabolic agents in clinical practice. Hitherto, PTH analogs shorter than 28 amino acids have not demonstrated any bone anabolic activity in vivo. Recently, Zealand Pharma A/S has developed a novel, cyclic PTH(1-17) analog, ZP2307, with a high efficacy and potency on the human PTH receptor in vitro. This study characterized the effects of intermittent treatment with ZP2307 on
established osteopenia in adult ovariectomized (OVX) rats. Female Sprague-Dawley rats were ovariectomized at 6 months of age. After 6 weeks without treatment, a reduction in trabecular bone mineral density (Tb.BMD) was confirmed by peripheral quantitative computed tomography (pQCT) in tibial metaphysis of OVX rats. Treatment was started at 7 weeks after the operations and continued once daily for 6 weeks. The osteopenic rats were treated subcutaneously with ZP2307 at 2, 6, 20, 60 and 200 µg/kg/d and with PTH(1-34) at 1.2, 4, 12, 40 and 120 µg/kg/d. Treatment effects were
analyzed by pQCT, bone histomorphometry and biomechanical testing in long bones and lumbar spine. During the treatment period, Tb.BMD decreased in tibial metaphysis of OVX rats treated with vehicle. Treatment with ZP2307
reversed the OVX-induced reduction in Tb.BMD and bone volume (BV/TV) in tibial metaphysis and lumbar vertebra at all doses in a dose-dependent manner. ZP2307 enhanced an OVX-induced increase in bone formation rate (BFR/BS) at 200 µg/kg/d and reversed an OVX-induced increase in the number of osteoclasts (N.Oc/B.Pm) at 2-200 µg/kg/d. As a functional consequence in lumbar vertebra, ZP2307 reversed an OVX-induced reduction in maximal load at 6-200 µg/kg/d and increased modulus at 20-200 µg/kg/d. Furthermore, ZP2307 increased cortical thickness and enhanced endocortical BFR/BS in tibial diaphysis at 60-200 µg/kg/d. Treatment with PTH(1-34) induced similar dose-dependent effects although stronger than ZP2307. ZP2307 exhibited 51% efficacy and 1.4-fold potency in tibial metaphysis and 92% efficacy and 3.4-fold potency in lumbar vertebra compared to PTH(1-34). This study demonstrated that the intermittent treatment with ZP2307, the novel cyclic PTH(1-17) analog, is effective in reversing the established osteopenia in adult
OVX rats to normal conditions. Due to its broad dose response relationship, ZP2307 may have a wider therapeutic window and a better safety/efficacy profile than the PTH analogs used in clinical practice.