Effects of a prostaglandin EP4 agonist, ONO-4819, and risedronate on trabecular microstructure and bone strength in mature ovariectomized rats

The effects of a prostaglandin EP4 agonist, ONO-4819, and risedronate, a representative anti-resorptive drug, on trabecular microarchitecture and biomechanical properties were investigated in mature estrogen-deficient rats; and effects which affected microstructural components that contributed to the improvement of bone strength were also determined. Thirty-three-week-old OVX rats were treated with various doses of ONO-4819, risedronate, or their combination for 11 weeks. Bone mineral density (BMD), trabecular microstructure, and biomechanical strength were determined at the proximal tibia by peripheral quantitative CT, micro CT, and finite element analysis, respectively. Bone histomorphometry was performed at the same site. The results of trabecular structure analysis indicated that whereas risedronate functioned mainly in maintaining trabecular connectivity, ONO-4819 converted the fragile rod-like trabeculae caused by estrogen deficiency to a plate-like structure. In addition, ONO-4819 is one of the few drugs that are capable of increasing trabecular thickness. When the 2 drugs were combined, the beneficial effects of each drug on the trabecular microarchitecture were maintained, resulting in their additive effects on bone strength. The results of bone histomorphometry suggest that ONO-4819 caused an increase in the rate of bone formation by stimulating the differentiation/recruitment of osteoblasts as well as their mineralizing function. ONO-4819 did not stimulate bone resorption, but rather exerted an anti-resorptive function within a certain dose range. ONO-4819 and risedronate increased BMD and improved trabecular structure and biomechanical strength in an additive and independent manner. Thus, EP4 agonist ONO-4819 in combination with risedronate may be an effective treatment for osteoporosis. (c) 2006 Elsevier Inc. All rights reserved.