Mechanisms involved in the inhibition of osteoclast generation by the benzothiophene SERM LY117018.

Selective estrogen receptor modulators are compounds that act via estrogen receptors in different tissues to mediate either estrogenic or estrogen antagonistic effects in osteoporosis patients. The aim of this study was to assess the effect of the selective estrogen receptor modulator LY117018, a raloxifene analogue, on osteoclastogenesis in vitro. In primary murine bone marrow cultures osteoclasts, defined as TRAP-positive multinucleated cells, were induced by 10(-8) M 1,25-dihydroxyvitamin D(3). LY117018 at concentrations between 10(-12) M and 10(-9) M significantly reduced the number of osteoclasts. At higher concentrations no effect of LY117018 on osteoclast generation was observed. LY117018 enhanced alkaline phosphatase activity of mouse calvaria osteoblasts at a concentration of 10(-14) to 10(-7) M, but had no influence on the proliferation and transcription of RANKL and osteoprotegerin. In order to study the effect of the compound on the production of cytokines that can stimulate bone resorption, spleen cells were incubated with LY117018. Data from four-color flow cytometric analysis indicate a significantly decreased frequency of tumor necrosis factor-α positive CD8(+) cells after treatment with LY117018. These findings suggest that LY117018 can significantly inhibit the generation of osteoclasts and stimulate osteogenic differentiation in vitro. Suppression of tumor necrosis factor-α production by LY117018 may contribute to its anti-osteoclastogenic effect.