New Selective Estrogen Receptor Modulators (SERMs) in Development

Selective estrogen receptor modulators (SERMs) or estrogen agonists/antagonists have shown promise in osteoporosis in that they have the potential to reduce the risk of fracture, and also reduce the risk of breast cancer. SERMs maybe classified according to their core structure, which is typically a variation of the 17 beta-estradiol template and subclassified according to the side chain at the helix 12 affector region. The best known are the triphenylethylenes such as tamoxifen, used in the management of breast cancer. However, the clinical application of this class of SERMs has been limited due to endometrial stimulation. A second class is the benzothiophenes such as raloxifene and arzoxifene, which have skeletal benefit with little, if any, uterine stimulation. Indole-based SERMs such as bazedoxifene have a 2-phenyl ring system that serves as a core binding unit. Other classes include benzopyrans and naphthalenes (eg, lasofoxifene). In this review article, I will discuss raloxifene and three new SERMs—arzoxifene, bazedoxifene, and lasofoxifene—that have been recently studied. I will discuss their effect on bone, breast, and the cardiovascular system, as well as on safety

Safety of bazedoxifene in a randomized, double-blind, placebo- and active-controlled phase 3 study of postmenopausal women with osteoporosis

Background. We report the safety findings from a 3-year phase 3 study (NCT00205777) of bazedoxifene, a novel selective estrogen receptor modulator under development for the prevention and treatment of postmenopausal osteoporosis. Methods. Healthy postmenopausal osteoporotic women (N = 7,492; mean age, 66.4 years) were randomized to daily doses of bazedoxifene 20 or 40 mg, raloxifene 60 mg, or placebo for 3 years. Safety and tolerability were assessed by adverse event (AE) reporting and routine physical, gynecologic, and breast examination. Results. Overall, the incidence of AEs, serious AEs, and discontinuations due to AEs in the bazedoxifene groups was not different from that seen in the placebo group. The incidence of hot flushes and leg cramps was higher with bazedoxifene or raloxifene compared with placebo. The rates of cardiac disorders and cerebrovascular events were low and evenly distributed among groups. Venous thromboembolic events, primarily deep vein thromboses, were more frequently reported in the active treatment groups compared with the placebo group; rates were similar with bazedoxifene and raloxifene. Bazedoxifene showed a neutral effect on the breast and an excellent endometrial safety profile. The incidence of fibrocystic breast disease was lower with bazedoxifene 20 and 40 mg versus raloxifene or placebo. Reductions in total and low-density lipoprotein levels and increases in high-density lipoprotein levels were seen with bazedoxifene versus placebo; similar results were seen with raloxifene. Triglyceride levels were similar among groups. Conclusion. Bazedoxifene showed a favorable safety and tolerability profile in women with postmenopausal osteoporosis. © 2010 Christiansen et al; licensee BioMed Central Ltd.link_to_subscribed_fulltex

Relationships between paranoid thinking, self-esteem and the menstrual cycle.

This study aimed to investigate whether paranoid experiences and levels of self-esteem fluctuate over the menstrual cycle and whether levels of self-esteem are lower when perceived persecution is felt to be deserved. Measures of anxiety, depression, persecution, deservedness and self-esteem were completed on-line by 278 women over their menstrual cycle. Responses were compared at the paramenstrual (3 days before and after menses onset) and mid-cycle phase. At the paramenstrual phase persecution, negative self-esteem, anxiety and depression were higher and positive self-esteem was lower than at mid-cycle. A greater proportion of women experienced persecution as deserved at the paramenstrual phase. This was associated with higher depression and negative self-esteem scores. Increased levels of deservedness significantly strengthened the relationship between persecution and negative, but not positive, self-esteem. These findings suggest that the paramenstrual phase is a time of vulnerability to increased paranoid experiences, an increased likelihood that feelings of persecution will feel deserved and lowered self-esteem. The findings support the view that interpersonal sensitivities may be key to menstrual cycle symptoms and have an impact on relationships. Further, the study illustrated that ideas developed for psychosis could make a valuable contribution to understanding and managing this aspect of menstruation-related distress

Alterations in Epithelial and Mesenchymal Intestinal Gene Expression During Doxorubicin-Induced Mucositis in Mice

In the current study we aimed to gain insight into epithelial-mesenchymal cross-talk and progenitor compartment modulation during doxorubicin (DOX)-induced mucositis in mice. Intestinal segments were collected on various days after DOX treatment. DOX-induced damage at day 1–2 was characterized by increased epithelial proliferation and apoptosis and a decrease in the expression of epithelial differentiation markers. Concurrently, T-cell factor-4 (TCF4) levels increased and the epithelial differentiation enhancing factor, bone morphogenic protein-4 (BMP4), decreased. During severe damage (day 3), BMP4 levels were significantly increased, which inversely correlated with epithelial proliferation. At the same time, the expression of the epithelial differentiation markers was increasing again. At day 7, BMP4 levels were down-regulated, while the levels of the epithelial differentiation markers and TCF4 were normalized again. These data suggest that in response to DOX-induced damage, BMP4 and TCF4 are modulated in such a way that homeostasis of the progenitor compartment is partly preserved

Estrogen receptor transcription and transactivation: Basic aspects of estrogen action

Estrogen signaling has turned out to be much more complex and exciting than previously thought; the paradigm shift in our understanding of estrogen action came in 1996, when the presence of a new estrogen receptor (ER), ERβ, was reported. An intricate interplay between the classical ERα and the novel ERβ is of paramount importance for the final biological effect of estrogen in different target cells

Safety and tolerability of bazedoxifene in postmenopausal women with osteoporosis: results of a 5-year, randomized, placebo-controlled phase 3 trial

Summary: Findings from this 5-year phase 3 study of postmenopausal women with osteoporosis showed that bazedoxifene was associated with an overall favorable safety and tolerability profile, with no evidence of endometrial or breast stimulation. Overall, the results at 5 years were consistent with those seen at 3 years. Introduction: We report safety and tolerability findings from a 5-year randomized, double-blind, phase 3 study of bazedoxifene in postmenopausal women with osteoporosis. Methods: In the core study, healthy postmenopausal women with osteoporosis (N=7,492; mean age, 66.4 years) were randomized to daily doses of bazedoxifene 20 or 40 mg, raloxifene 60 mg, or placebo for 3 years. During the 2-year study extension, the raloxifene 60-mg treatment arm was discontinued after the 3-year database was finalized, and subjects receiving bazedoxifene 40 mg were transitioned in a blinded manner to bazedoxifene 20 mg (bazedoxifene 40-/20-mg group) after 4 years. Safety and tolerability data are reported for subjects in the bazedoxifene 20- and 40-/20-mg and placebo groups; efficacy findings are reported elsewhere. Results: A total of 3,146 subjects in the bazedoxifene 20- and 40-mg and placebo groups were enrolled in the extension study (years 4 and 5). Overall, the 5-year incidence of adverse events (AEs), serious AEs, and discontinuations due to AEs were similar among groups. The incidence of hot flushes and leg cramps was higher with bazedoxifene compared with placebo. Venous thromboembolic events, primarily deep vein thrombosis, were more frequently reported in the bazedoxifene groups compared with the placebo group. Reports of cardiac disorders and cerebrovascular events were few and evenly distributed among groups. Bazedoxifene showed a neutral effect on the breast and endometrium. Conclusion: Bazedoxifene was associated with an overall favorable safety and tolerability profile in postmenopausal women with osteoporosis over 5 years of therapy, consistent with findings at 3 years. © 2010 International Osteoporosis Foundation and National Osteoporosis Foundation