1,25-Dihydroxyvitamin D3 (1,25-(OH)2D3) 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)2D3 are needed which may result in undesirable side effects like the development of
hypercalcemia and an increased risk of bone
metastases due to the stimulation of
bone resorption by 1,25-(OH)2D3. Several newly developed 1,25-(OH)2D3 analogs have a reduced calcemic activity, but their direct effects on
bone resorption have not yet been examined. Presently, the
antiestrogen tamoxifen is the most important endocrine
therapy for
breast cancer. Recent studies have demonstrated the benefit of the combination
tamoxifen and
1,25-(OH)2D3/analogs for the inhibition of
breast cancer cell growth. Besides inhibition of
breast cancer growth
tamoxifen appeared to have beneficial effects on bone. The purpose of the present study was to investigate the effect of
tamoxifen on 1,25-(OH)2D3- and analogs (
EB1089 and
KH1060)-stimulated
bone resorption in an in vitro model.
Bone resorption was stimulated by 1,25-(OH)2D3 and analogs in a dose-dependent manner with
KH1060 and
EB1089 being more potent and 1,25-(OH)2D3.
Tamoxifen caused a strong dose-dependent inhibition (70%
at 10 microM) of 1,25-(OH)2D3- and EB1089-stimulated
bone resorption. KH1060-stimulated
bone resorption was also inhibited by
tamoxifen but to a lesser extent (36%). Also the pure
antiestrogen ICI164,384 but not
17 beta-estradiol inhibited 1,25-(OH)2D3-stimulated
bone resorption. Together, this study demonstrates that
tamoxifen considerably reduces
1,25-(OH)2D3/analogs-stimulated
bone resorption and therefore may 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)2D3/analogs is an interesting combination for the treatment of
breast cancer. The mechanism of the
bone resorption inhibitory action is not yet known but seems to be independent of the
estrogen pathway.