Systemic administration of prostaglandin E2 receptor (EP4) selective agonist increases both bone formation and resorption, and consequently leads to an increase in bone mass. Although previous studies have reported that EP4 agonist enhanced bone remodeling and fracture healing, it was not known if EP4 agonist activates the bone-biomaterial interface. Bioactive titanium prepared by chemical and thermal treatment can bond to living bone and is suitable for use in clinical applications in cementless fixation devices. Therefore, we examined whether the administration of EP4 agonist enhances the bonding strength between bone and bioactive titanium. Bioactive titanium plates were inserted into the tibia bone of rabbits and examined histologically and biomechanically at 4, 8, and 16 weeks. EP4 agonist was administrated systemically every 2 weeks after surgery. A non-administrated control group, a low-dose group (10 microg/kg body weight (BW)), and a high-dose group (100 microg/kg BW) were compared. The bonding strength of bioactive titanium in the EP4 agonist groups was significantly higher than that in the control group at both 4 and 8 weeks, and enhanced bone remodeling and direct bonding around the bioactive titanium plates was observed only in the EP4 agonist groups at 4 weeks. EP4 agonist enhanced bone formation around the bioactive titanium plate, and achieved early direct bone bonding.