title: A nonprostanoid EP4 receptor selective prostaglandin E2 agonist restores bone mass and strength in aged, ovariectomized rats.
abstract: CP432 is a newly discovered, nonprostanoid EP4 receptor selective prostaglandin E2 agonist. CP432 stimulates trabecular and cortical bone formation and restores bone mass and bone strength in aged ovariectomized rats with established osteopenia.
  
  
  BACKGROUND
  The purpose of this study was to determine whether a newly discovered, nonprostanoid EP4 receptor selective prostaglandin E2 (PGE2) agonist, CP432, could produce bone anabolic effects in aged, ovariectomized (OVX) rats with established osteopenia.
  
  
  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.
authors.affiliation: Pfizer Global Research and Development, Groton Laboratories, Groton, Connecticut, USA. hke@amgen.com
authors.forename: Hua Zhu
authors.initials: HZ
authors.lastname: Ke
authors.forename: D Todd
authors.initials: DT
authors.lastname: Crawford
authors.forename: Hong
authors.initials: H
authors.lastname: Qi
authors.forename: Hollis A
authors.initials: HA
authors.lastname: Simmons
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Owen
authors.forename: Vishwas M
authors.initials: VM
authors.lastname: Paralkar
authors.forename: Mei
authors.initials: M
authors.lastname: Li
authors.forename: Bihong
authors.initials: B
authors.lastname: Lu
authors.forename: William A
authors.initials: WA
authors.lastname: Grasser
authors.forename: Kimberly O
authors.initials: KO
authors.lastname: Cameron
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Lefker
authors.forename: Paul
authors.initials: P
authors.lastname: DaSilva-Jardine
authors.forename: Dennis O
authors.initials: DO
authors.lastname: Scott
authors.forename: Qing
authors.initials: Q
authors.lastname: Zhang
authors.forename: Xiao Yan
authors.initials: XY
authors.lastname: Tian
authors.forename: Webster Ss
authors.initials: WS
authors.lastname: Jee
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Brown
authors.forename: David D
authors.initials: DD
authors.lastname: Thompson
mesh_terms: D000375:Aging / Q000502:physiology*; D000818:Animals; D001835:Body Weight; D015519:Bone Density / Q000187:drug effects* / Q000502:physiology; D001851:Bone Diseases, Metabolic / Q000188:drug therapy*; D015232:Dinoprostone / Q000819:agonists*; D004195:Disease Models, Animal; D005260:Female; D005269:Femur / Q000033:anatomy & histology; D008159:Lumbar Vertebrae / Q000033:anatomy & histology; D015394:Molecular Structure; D009929:Organ Size / Q000187:drug effects; D010012:Osteogenesis / Q000187:drug effects*; D010052:Ovariectomy; D051381:Rats; D017207:Rats, Sprague-Dawley; D018078:Receptors, Prostaglandin E / Q000819:agonists* / Q000378:metabolism*; D058309:Receptors, Prostaglandin E, EP4 Subtype; D013379:Substrate Specificity; D013977:Tibia / Q000033:anatomy & histology
chemical_list: D018078:Receptors, Prostaglandin E; D058309:Receptors, Prostaglandin E, EP4 Subtype; D015232:Dinoprostone