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.