RS-66271, a C-terminally substituted analog of human parathyroid hormone-related protein (1–34), increases trabecular and cortical bone in ovariectomized, osteopenic rats

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Abstract
It was predicted from the amino acid sequence of the bone anabolic peptides, parathyroid hormone (PTH) (1–34) and PTH related protein (PTHrP) (1–34), that the C-terminal amino acids form an amphipathic α-helix. Therefore, we substituted a model amphipathic α-helical peptide (MAP) sequence in the C-terminal region of hPTHrP(1–34), obtaining RS-66271 ([MAP1–10]]22–31 hPTHrP(1–34)-NH2). The anabolic activities of RS-66271 and hPTHrP(1–34) were evaluated in 3-month-old, ovariectomized (OVX) osteopenic rats. Subcutaneous injection of hPTHrP(1–34) at 80 μg/kg/day partially reversed estrogen depletion trabecular bone loss but was ineffective in the cortex. In contrast, RS-66271 dose-relatedly reversed loss at both sites and, at 80 μg/kg/day, returned both trabecular and cortical bone calcium to the level of sham-operated controls. Histomorphometric analysis showed significantly elevated bone formation rates over vehicle-treated OVX in both trabecular and cortical tibial bone following treatment with RS-66271. Electron microscopy showed an increase in the relative surface area of vertebral trabeculae covered by osteoblasts in animals treated with RS-66271. These studies demonstrate that the C-terminal amino acids of hPTHrP(1–34) can be replaced by a model amphipathic helix and that the new chemical entity has greater anabolic activity than the parent peptide. The results suggest that RS-66271 may be a candidate molecule for the treatment of human osteoporosis.