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

Molecular analysis of the vaginal response to estrogens in the ovariectomized rat and postmenopausal woman

<p>Abstract</p> <p>Background</p> <p>Vaginal atrophy (VA) is the thinning of the vaginal epithelial lining, typically the result of lowered estrogen levels during menopause. Some of the consequences of VA include increased susceptibility to bacterial infection, pain during sexual intercourse, and vaginal burning or itching. Although estrogen treatment is highly effective, alternative therapies are also desired for women who are not candidates for post-menopausal hormone therapy (HT). The ovariectomized (OVX) rat is widely accepted as an appropriate animal model for many estrogen-dependent responses in humans; however, since reproductive biology can vary significantly between mammalian systems, this study examined how well the OVX rat recapitulates human biology.</p> <p>Methods</p> <p>We analyzed 19 vaginal biopsies from human subjects pre and post 3-month 17β-estradiol treated by expression profiling. Data were compared to transcriptional profiling generated from vaginal samples obtained from ovariectomized rats treated with 17β-estradiol for 6 hrs, 3 days or 5 days. The level of differential expression between pre- vs. post- estrogen treatment was calculated for each of the human and OVX rat datasets. Probe sets corresponding to orthologous rat and human genes were mapped to each other using NCBI Homologene.</p> <p>Results</p> <p>A positive correlation was observed between the rat and human responses to estrogen. Genes belonging to several biological pathways and GO categories were similarly differentially expressed in rat and human. A large number of the coordinately regulated biological processes are already known to be involved in human VA, such as inflammation, epithelial development, and EGF pathway activation.</p> <p>Conclusion</p> <p>At the transcriptional level, there is evidence of significant overlap of the effects of estrogen treatment between the OVX rat and human VA samples.</p

Estrogen receptor transcription and transactivation: Estrogen receptor knockout mice - what their phenotypes reveal about mechanisms of estrogen action

Natural, synthetic and environmental estrogens have numerous effects on the development and physiology of mammals. Estrogen is primarily known for its role in the development and functioning of the female reproductive system. However, roles for estrogen in male fertility, bone, the circulatory system and immune system have been established by clinical observations regarding sex differences in pathologies, as well as observations following menopause or castration. The primary mechanism of estrogen action is via binding and modulation of activity of the estrogen receptors (ERs), which are ligand-dependent nuclear transcription factors. ERs are found in highest levels in female tissues critical to reproduction, including the ovaries, uterus, cervix, mammary glands and pituitary gland. Since other affected tissues have extremely low levels of ER, indirect effects of estrogen, for example induction of pituitary hormones that affect the bone, have been proposed. The development of transgenic mouse models that lack either estrogen or ER have proven to be valuable tools in defining the mechanisms by which estrogen exerts its effects in various systems. The aim of this article is to review the mouse models with disrupted estrogen signaling and describe the associated phenotypes

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

Search for neutral MSSM Higgs bosons decaying to a pair of tau leptons in pp collisions

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Measurement of top quark–antiquark pair production in association with a W or Z boson in pp collisions at √s=8 TeV

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Searches for electroweak production of charginos, neutralinos, and sleptons decaying to leptons and W, Z, and Higgs bosons in pp collisions at 8 TeV

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Measurement of prompt J/ψ pair production in pp collisions at √s = 7 Tev

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Study of hadronic event-shape variables in multijet final states in pp collisions at √s=7 TeV

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