Background: Polymethylmethacrylate (PMMA) is a potent stimulant of inflammatory response. This study investigated the role of Prostaglandin E2 (PGE2), Platelet activating factor (PAF) and histamine and their specific antagonists in bone changes. Materials: 120 white-male-wistar rats were divided into ten groups. Using sterile technique, a 2mm drill hole was made in the tibia 1cm distal to the knee joint bilaterally. The left tibia was filled with Simplex particulate cement polymer (PMMA) and the right tibia was used as control. The first nine groups respectively received terfenadine 1mg/kg, 10mg/kg and 25mg/kg, alprazolam 0.08mg/kg, 0.32mg/kg and 0.64mg/kg, and naproxen 1mg/kg, 5mg/kg and 25mg/kg; however, the tenth group received no drug and served as control. The animals were killed after 16 weeks and implant areas were harvested aseptically and studied by one pathologist. Results: Our study revealed that the cellular reaction in the left side was statistically more than the right one in all cases (p< 0.05). Also, a significant decrease in histiocytes and giant cells was seen just in those groups that had received 10mg/kg and 25mg/kg of terfenadine, 0.32mg/kg and 0.64mg/kg of alprazolam and 5mg/kg and 25mg/kg of naproxen (P< 0.05) while administration of 1mg/kg naproxen resulted in significant decrease only in giant cells (P< 0.05) but not in histiocytes. Discussion: Previous studies have suggested that particulate debris, PGE2 production and inflammatory response are associated with arthroplasty loosening. This experiment has demonstrated that the increased cellular reaction by the membrane surrounding particulate cement polymer can be suppressed by administration of PGE2, PAF and histamine specific inhibitors. The use of these agents may be indicated in retarding the bone loss associated with early prosthetic loosening