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  • Raloxifene is a second generation SERM that

    2019-07-11

    Raloxifene is a second generation SERM that has tissue-specific effects that differ from those of tamoxifen. Raloxifene was marketed for prevention and treatment of osteoporosis in postmenopausal women in the US and Europe. In a phase II randomized double-blind study, tamoxifen and raloxifene were equally effective in preventing breast cancer progression over a 5-year period (Vogel et al., 2006), but unlike tamoxifen, raloxifene did not increase the risk of endometrial cancer. However, raloxifene, just as tamoxifen, had no beneficial effect on climacteric symptoms, particularly hot flushes, and increased the risk of thrombotic events, sharing thereby most of the limitations of tamoxifen (D\'Amelio and Isaia, 2013; Martinkovich, Shah, Planey, and Arnott, 2014). Bazedoxifene (BZA) is a third-generation SERM with Istradefylline structure agonistic effects in bone (Palacios et al., 2015) and lipid metabolism (Kim et al., 2014), and antagonistic activities in the breast and uterus (Komm et al., 2005). BZA was approved in the US for the treatment of postmenopausal osteoporosis. Interestingly, at variance with most SERMs, BZA induces degradation of ERα in some tissues, such as the uterus and the breast, and thus has an additional mechanism to prevent estrogen action on these two sex targets (Lewis-Wambi et al., 2011). In the liver of mice, BZA acts as an antagonist after acute treatment, but displays agonistic effects in the liver following chronic exposure (Buscato et al., 2017). This could contribute to the metabolic protection conferred by BZA in mouse models of obesity and type II diabetes (Kim et al., 2014). In comparison with other SERMs, this underlines the importance of the time- and tissue–specific action of BZA. Finally, in a 3-year randomized study conducted on post-menopausal women, an increased incidence of VTE (primarily deep vein thrombosis) was observed in the BZA treated groups compared to controls (Silverman et al., 2008) (Fig. 1). A new concept called Tissue Selective Estrogen Complex (TSEC) combines SERM with one or more estrogens (Mirkin and Komm, 2013), that is not “a priori” an intuitive molecular combination because it associates agonist and antagonist molecules at the same time. For example, in a randomized, double-blind trial comparing 17β-estradiol/raloxifene with raloxifene alone, the combination effectively relieved vasomotor symptoms, but did not provide protection against endometrial stimulation (Stovall et al., 2007). In contrast, in double-blind clinical trials, BZA in combination with CE led to significant improvements in menopausal symptoms, including hot flushes, vaginal atrophy, quality of life and prevention of bone resorption, with no change in mammographic density (de Villiers et al., 2011; Harvey et al., 2013; Mirkin and Komm, 2013). In addition, in a randomized trial comparing placebo and CE/BZA in a cohort of 2000 women, there was no difference between control and treatment groups regarding the risk of venous thrombosis, although the power of this trial was not sufficient to conclude the safety of this combination on this parameter (Skouby, Pan, Thompson, Komm, and Mirkin, 2015). Although coagulation factors were slightly modified by the treatment in this trial, there was no potentiation of the hepatic effects by the combination compared to each compound given alone (Skouby et al., 2015). Concerning the risk of breast cancer, in vitro studies on breast cancer cells (Chang, Wang, Bodine, Nagpal, and Komm, 2010), and in vivo experimentation on animal models of breast cancer (Peano, Crabtree, Komm, Winneker, and Harris, 2009) showed a protective effect of the CE/BZA combination. In this context, it can be reasonably expected that this association will not increase the risk of breast cancer in women, although this remains to be demonstrated by clinical studies and their follow-up. The combination of BZA with CE is the first estrogen-based, progestin-free, oral MHT treatment approved by the US Food and Drug Administration (FDA) to relieve moderate to severe VMS and prevent bone demineralization in non-hysterectomized postmenopausal women (Komm and Mirkin, 2013). This treatment has been marketed in the US as Duavee® and has also been approved by the European Medicines Agency (EMA) in Europe (Fig. 1).