DIFFERENTIAL-EFFECTS OF 1,25-DIHYDROXYVITAMIN D-3-ANALOGS ON OSTEOBLAST-LIKE CELLS AND ON IN-VITRO BONE-RESORPTION

Although numerous studies have shown potent antiproliferative and diff erentiation-inducing effects of 1,25-dihydroxyvitamin D-3 (1,25-(OH)(2 )D-3) and its analogs on cells not directly related to bone metabolism , only few reports focussed on the effects of these analogs on bone. W e compared the action of several recently developed analogs with that of 1,25-(OH)(2)D-3 on human (MG-63) and rat (ROS 17/2.8) osteoblast-li ke cells and on in vitro bone resorption. In MG-63 cells the analogs E B1089 and KH1060 were about 166,000 and 14,000 times more potent than 1,25-(OH)(2)D-3 in stimulating type I procollagen and 100 and 6,000 ti mes more potent in stimulating osteocalcin production, respectively. A lso 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 time s more potently stimulated by EB1089 and KH1060, respectively. In MG-6 3 cells, 1,25-(OH)(2)D-3 and the analogs inhibited cell proliferation, whereas both 1,25-(OH)(2)D-3 and the analogs stimulated the growth of ROS 17/2.8 cells. Differences in potency could neither be explained b y affinity for the vitamin D receptor nor by a differential involvemen t of protein kinase C in the action of the analogs. Together, these da ta show that also in bone the analogs EB1089 and KH1060 are more poten t than 1,25-(OH)(2)D-3 but that the potency of the analogs compared to 1,25-(OH)(2)D-3 is dependent on the biological response. On the basis of these observations it can be concluded that the reported reduced c alcemic effect in vivo is not the result of a decreased responsiveness of bone to these analogs. Lastly, in view of eventual clinical applic ation of 1,25-(OH)(2)D-3-analogs, the observed stimulation of in vitro bone resorption and growth of an osteosarcoma cell line warrant in vi vo studies to further examine these effects.