Search for the new target points of bisphosphonates in bone cells: Their inhibitory actions on bone resorption and the stimulatory actions on bone formation

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Bisphosphonates have been found as an analogue compound of pyrophosphates. They have a strong affinity for binding bone and show a strong inhibitory action on bone resorption. Recently their actions for osteoclast function have been clarified, but our previous studies indicate that other actions of bisphosphonate might be related with the pharmacological effects on bone tis-sue. We focused to find the new targets of the drug and performed the present research. In vivo studies demonstrated that the decrease of bone mineral density induced by the low-calcium feeding in rats was inhibited by the treatments of bisphosphonate. At the same time, bisphos-phonate significantly stimulated the mineral apposition rate of bone formation surface. In in vitro study, the mineralized nodule formation was increased by bisphosphonate in bone marrow cell culture and this effect might be accompanied with the progress of osteoblast differentiation. The-se results indicated that the action of bisphosphonates on bone tissues is the combined effects of the inhibitory actions on bone resorption and the stimulatory actions on bone formation. In addition, bisphosphonate blocked the bone resorption induced by the inoculation of Walker256/s mammary carcinoma cells in rats. Because the bone resorption in this carcinoma bearing rats is due to the inhibition of the estrogen synthesis induced by the LH-RH system, the present inhibi-tory effects of bisphosphonate on the experimental rats indicated the usefulness of the drug for the treatment of this type of disease From these results, the new targets points of bisphospho-nates both on the osteoclasts and osteoblasts are clarified and these targets of bisphosphonates are important to understand the actions of the drug on bone tissues.