Effect of a selective agonist for prostaglandin E receptor subtype EP4 (ONO-4819) on the cortical bone response to mechanical loading.

The influence of a selective agonist for prostaglandin E receptor subtype EP4 (ONO-4819) on the bone response to mechanical loading was evaluated. Six-month-old female Wistar rats were used and assigned to three groups (n = 12/group): Vehicle administration (EP4-V), low-dose ONO-4819 administration (EP4-L, 3 microg/kg BW), and high-dose ONO-4819 administration (EP4-H, 30 microg/kg BW). ONO-4819 was subcutaneously injected in the back twice a day for 3 weeks. Loads on the right tibia at 39.4 N for 36 cycles at 2 Hz were applied in vivo by 4-point bending every other day for 3 weeks. Whole-body bone mineral content showed a significant difference between EP4-V and EP4-H (P < 0.05). Bone mineral density (BMD) of the total and regional tibia (the region with maximal bending at the central diaphysis) was higher in EP4-H than EP4-V, showing a significant effect of loading (P < 0.001) and ONO-4819 (P < 0.05). BMD of the total femur was higher in EP4-H than EP4-V (P < 0.01) and that of the distal femur was higher in EP4-H than EP4-V (P < 0.001). Histomorphometry of the cortical bone showed that loading increased formation surface (FS/BS), mineral appositional rate (MAR), and bone formation rate (BFR/BS) significantly at the lateral periosteal surface (P < 0.001); however, the effect of ONO-4819 was not significant. At the medial periosteal surface, loading increased the three parameters (P < 0.001) and ONO-4819 increased FS/BS (P < 0.001) and MAR (P < 0.05) significantly. At the endocortical surface, the effects of both loading and ONO-4819 were significant on all three parameters (for loading; FS/BS P < 0.01, MAR P < 0.05, BFR/BS P < 0.03, for ONO-4819 all P < 0.001). It was concluded that ONO-4819 increased cortical bone formation in rats and there was an additive effect on the bone response to external loading by 4-point bending.