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A Nonprostanoid EP4 Receptor Selective Prostaglandin E 2 Agonist Restores Bone Mass and Strength in Aged, Ovariectomized Rats
Author(s) -
Ke Hua Zhu,
Crawford D Todd,
Qi Hong,
Simmons Hollis A,
Owen Thomas A,
Paralkar Vishwas M,
Li Mei,
Lu Bihong,
Grasser William A,
Cameron Kimberly O,
Lefker Bruce A,
DaSilvaJardine Paul,
Scott Dennis O,
Zhang Qing,
Tian Xiao Yan,
Jee Webster SS,
Brown Thomas A,
Thompson David D
Publication year - 2006
Publication title -
journal of bone and mineral research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.882
H-Index - 241
eISSN - 1523-4681
pISSN - 0884-0431
DOI - 10.1359/jbmr.051110
Subject(s) - ovariectomized rat , endocrinology , medicine , osteopenia , cortical bone , osteoclast , chemistry , agonist , bone resorption , osteoporosis , bone mineral , receptor , estrogen , anatomy
CP432 is a newly discovered, nonprostanoid EP4 receptor selective prostaglandin E 2 agonist. CP432 stimulates trabecular and cortical bone formation and restores bone mass and bone strength in aged ovariectomized rats with established osteopenia. Introduction: The purpose of this study was to determine whether a newly discovered, nonprostanoid EP4 receptor selective prostaglandin E 2 (PGE 2 ) agonist, CP432, could produce bone anabolic effects in aged, ovariectomized (OVX) rats with established osteopenia. Materials and Methods: CP432 at 0.3, 1, or 3 mg/kg/day was given for 6 weeks by subcutaneous injection to 12‐month‐old rats that had been OVX for 8.5 months. The effects on bone mass, bone formation, bone resorption, and bone strength were determined. Results: Total femoral BMD increased significantly in OVX rats treated with CP432 at all doses. CP432 completely restored trabecular bone volume of the third lumbar vertebral body accompanied with a dose‐dependent decrease in osteoclast number and osteoclast surface and a dose‐dependent increase in mineralizing surface, mineral apposition rate, and bone formation rate‐tissue reference in OVX rats. CP432 at 1 and 3 mg/kg/day significantly increased total tissue area, cortical bone area, and periosteal and endocortical bone formation in the tibial shafts compared with both sham and OVX controls. CP432 at all doses significantly and dose‐dependently increased ultimate strength in the fifth lumber vertebral body compared with both sham and OVX controls. At 1 and 3 mg/kg/day, CP432 significantly increased maximal load in a three‐point bending test of femoral shaft compared with both sham and OVX controls. Conclusions: CP432 completely restored trabecular and cortical bone mass and strength in established osteopenic, aged OVX rats by stimulating bone formation and inhibiting bone resorption on trabecular and cortical surfaces.