Differential effects of 1,25-dihydroxyvitamin D₃-analogs on osteoblast-like cells and onin vitro bone resorption

Although numerous studies have shown potent antiproliferative and differentiation-inducing effects of 1,25-dihydroxyvitamin D₃ (1,25-(OH)₂D₃) and its analogs on cells not directly related to bone metabolism, only few reports focussed on the effects of these analogs on bone. We compared the action of several recently developed analogs with that of 1,25-(OH)₂D₃ on human (MG-63) and rat (ROS 17/2.8) osteoblast-like cells and onin vitro bone resorption. In MG-63 cells the analogs EB1089 and KH1060 were about 166,000 and 14,000 times more potent than 1,25-(OH)₂D₃ in stimulating type I procollagen and 100 and 6,000 times more potent in stimulating osteocalcin production, respectively. Also in ROS 17/2.8 cells EB1089 and KH1060 were most potent in inducing osteocalcin synthesis. In vitro bone resorption was 2.3 and 17.5 times more potently stimulated by EB1089 and KH1060, respectively. In MG-63 cells, 1,25-(OH)₂D₃ and the analogs inhibited cell proliferation, whereas both 1,25-(OH)₂D₃ and the analogs stimulated the growth of ROS 17/2.8 cells. Differences in potency could neither be explained by affinity for the vitamin D receptor nor by a differential involvement of protein kinase C in the action of the analogs. Together, these data show that also in bone the analogs EB1089 and KH1060 are more potent than 1,25-(OH)₂D₃ but that the potency of the analogs compared to 1,25-(OH)₂D₃ is dependent on the biological response. On the basis of these observations it can be concluded that the reported reduced calcemic effectin vivo is not the result of a decreased responsiveness of bone to these analogs. Lastly, in view of eventual clinical application of 1,25-(OH)₂D₃-analogs, the observed stimulation ofin vitro bone resorption and growth of an osteosarcoma cell line warrantin vivo studies to further examine these effects.