A nonprostanoid EP4 receptor selective prostaglandin E2 agonist restores bone mass and strength in aged, ovariectomized rats.
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.
Ke
Hua Zhu
HZ
Pfizer Global Research and Development, Groton Laboratories, Groton, Connecticut, USA. hke@amgen.com
Crawford
D Todd
DT
Qi
Hong
H
Simmons
Hollis A
HA
Owen
Thomas A
TA
Paralkar
Vishwas M
VM
Li
Mei
M
Lu
Bihong
B
Grasser
William A
WA
Cameron
Kimberly O
KO
Lefker
Bruce A
BA
DaSilva-Jardine
Paul
P
Scott
Dennis O
DO
Zhang
Qing
Q
Tian
Xiao Yan
XY
Jee
Webster Ss
WS
Brown
Thomas A
TA
Thompson
David D
DD
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
D018078:Receptors, Prostaglandin E; D058309:Receptors, Prostaglandin E, EP4 Subtype; D015232:Dinoprostone