ANTIESTROGENS INHIBIT IN-VITRO BONE-RESORPTION STIMULATED BY 1,25-DIHYDROXYVITAMIN-D-3 AND THE VITAMIN-D-3 ANALOGS EB1089 AND KH1060

1,25-Dihydroxyvitamin D-3 (1,25-(OH)(2)D-3) has been shown to inhibit breast cancer cell growth both in vitro and in vivo. A major drawback is that high doses of 1,25-(OH)(2)D-3 are needed which may result in u ndesirable side effects like the development of hypercalcemia and an i ncreased risk of bone metastases due to the stimulation of bone resorp tion by 1,25-(OH)(2)D-3. Several newly developed 1,25-(OH)(2)D-3 analo gs have a reduced calcemic activity, but their direct effects on bone resorption have not yet been examined. Presently, the antiestrogen tam oxifen is the most important endocrine therapy for breast cancer. Rece nt studies have demonstrated the benefit of the combination tamoxifen and 1,25-(OH)(2)D-3/analogs for the inhibition of breast cancer cell g rowth. Besides inhibition of breast cancer growth tamoxifen appeared t o have beneficial effects on bone. The purpose of the present study wa s to investigate the effect of tamoxifen on 1,25-(OH)(2)D-3- and analo gs (EB1089 and KH1060)-stimulated bone resorption in an in vitro model . Bone resorption was stimulated by 1,25(OH)(2)D-3 and analogs in a do se-dependent manner with KH1060 and EB1089 being more potent than 1,25 (OH)(2)D-3 Tamoxifen caused a strong dose-dependent inhibition (70% at 10 mu M) of 1,25-(OH)(2)D-3- and EB1089-stimulated bone resorption. K H1060-stimulated bone resorption was also inhibited by tamoxifen but t o a lesser extent (36%). Also the pure antiestrogen ICI164,384 but not 17 beta-estradiol inhibited 1,25-(OH)(2)D-3-stimulated bone resorptio n. Together, this study demonstrates that tamoxifen considerably reduc es 1,25-(OH)(2)D-3/analogs-stimulated bone resorption and therefore ma y be useful to reduce the risk of bone metastases. This together with the observed beneficial effects on breast cancer cell growth indicates that tamoxifen together with 1,25-(OH)(2)D-3/analogs is an interestin g combination for the treatment of breast cancer. The mechanism of the bone resorption inhibitory action is not yet known but seems to be in dependent of the estrogen pathway.