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24 R，25-二羟维生素D3增加骨量的细胞机制，并为24 R，25-二羟维生素D3治疗绝经后骨质疏松症提供了新的思路。我们已经观察到，大量给予该制剂可大大增加大鼠和家兔的骨量，而不增加血清钙水平。通过断裂试验发现骨的力学性能正常。骨组织形态计量学显示，侵蚀面减少，破骨细胞数量减少，骨形成减少。类骨质厚度和矿物沉积率均增加。这些数据是本研究项目中获得的最重要的成果。然后，我们将该制剂应用于比格犬的卵巢切除术后骨丢失。24 R，25-二羟维生素D3给药能很好地保护骨量。组织形态计量学分析显示，在卵巢切除的动物中，成骨细胞骨吸收增加，成骨细胞结合减少，而在用该药物治疗的动物中，这两种细胞功能均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，药物给药能够维持骨细胞功能。目前还不确定这些功能是否是24 R，25-二羟维生素D3所特有的。维生素D的补充是24 R，25-二羟维生素D3发挥作用的前提，而减少破骨细胞数量和增加成骨细胞中骨基质生成的作用均与1，25-二羟维生素D3的作用密切相关。因此，预期24 R，25-二羟基维生素D3的骨量增加作用是通过改变1，25-二羟基维生素D3对骨细胞的作用而发挥的可能是相当合理的。这项研究很可能保证进一步的研究，以获得其他骨量增加物质通过修改的化学结构的1，25-二羟维生素D3。

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.