The mechanism of bone mass increasing action of 24R,25(OH)2D3 and its application on the metabolic bone diseases

本研究揭示了24R，25-二羟基维生素D3增加骨量作用的细胞机制，并提示其在绝经后骨质疏松症治疗中的应用。我们观察到，在大鼠和家兔中，大量给药可大大增加骨量，而不增加血清钙水平。通过断裂测试，发现骨头的机械性能是正常的。骨组织形态测定显示，侵蚀面和破骨细胞数量减少，骨形成也减少。类骨厚度和矿物质附着率均增加。这些数据是本研究项目获得的最重要的结果。然后，我们将该药物应用于小猎犬静脉曲张切除术后骨丢失。24R，25-二羟基维生素D3能很好地保存骨量。组织形态计量学分析显示，在去卵巢的动物中，破骨细胞吸收增加，成骨细胞功能降低，在用该药物治疗的动物中，这两种细胞功能保持与假手术组相同的水平。这些数据清楚地表明，在雌激素缺乏的情况下，给药能够维持骨细胞的功能。目前还不确定这些功能是否是24R，25-二羟基维生素D3所特有的。维生素d的补充是24R，25-二羟维生素D3发挥作用的先决条件，而减少成骨细胞数量和增加成骨细胞骨基质生成的作用都与1,25-二羟维生素D3的作用密切相关。因此，我们可以合理预测24R，25-二羟基维生素D3的骨量增加作用是通过修饰1,25-二羟基维生素D3对骨细胞的作用来发挥的。这项研究很可能为进一步的研究提供依据，通过改变1,25-二羟基维生素D3的化学结构来获得其他增加骨量的物质。

This research demonstrated the cellular mechanism of bone mass increasing action of 24R,25-dihydroxyvitamin D3 and indicated its application for the treatment of postmenopausal osteoporosis. We have observed that the massive administration of the agent greatly cincreases the bone mass without increasing serum calcium level in rats and rabbits. Mechanical properties of the bone were found to be normal by breaking tests. Bone histomorphometry demonstrated that both the eroded surface and the osteoclast number reduced and bone formation also reduced. Both the osteoid thickness and the mineral apposition rate increased. These data are the most important results obtained in this research project. Then, we applied this agent on the postovariectomy bone loss in beagles. The 24R,25-dihydroxyvitamin D3 administration well preserved the bone mass. Histomorphometrical analyses showed an increase of osteoclastic boner esorption and a reduction in osteoblast bunctions in ovariectomized animals, and in animals treated with the agent, both of these cellular functions maintained the same level as in the sham group. These data clearly demonstrated that the agent administration is able to maintain the bone cell functions in estrogen deficient condition. It is uncertain whether these functions are specific for 24R,25-dihydroxyvitamin D3. Vitamin D-repletion is found to be the prerequisite for the action of 24R,25-dihydroxyvitamin D3, and the actions of decreasing the osteoclast number and increasing the bone matrix production in osteoblast are both closely related to the actions of 1,25-dihydroxyvitamin D3. Therefore, it may be rather reasonable to anticipate that the bone mass increasing action of 24R,25-dihydroxy vitamin D3 are exerted through the modification of 1,25-dihydroxyvitamin D3 actions on bone cells. This study may well warrant further studies to obtain other bone mass increasing substances by modifying the chemical structure of 1,25-dihydroxyvitamin D3.