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      Endometrial safety of ospemifene: results of the phase 2/3 clinical development program

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          Abstract

          Objective

          This study aims to assess the endometrial safety of ospemifene based on phase 2/3 clinical trials of postmenopausal women with up to 52 weeks of exposure to ospemifene 60 mg/day versus placebo.

          Methods

          Endometrial safety was evaluated in a development program of six randomized, double-blind, placebo-controlled, parallel-group studies of postmenopausal women aged between 40 and 80 years who had vulvar and vaginal atrophy. Participants were randomized 1:1 to ospemifene 60 mg/day or placebo in one 6-week trial and three 12-week trials; one of the 12-week trials had a 40-week extension study. In a separate 52-week trial, women were randomized 6:1 to ospemifene 60 mg/day or placebo. Endometrial safety was assessed by endometrial histology (biopsy), transvaginal ultrasound, and gynecologic examination.

          Results

          In these trials, 1,242 women who received ospemifene 60 mg/day and 924 women who received placebo were evaluable for safety. Endometrial hyperplasia occurred in less than 1% of women treated with ospemifene; no endometrial cancer was reported. The mean (SD) increase in endometrial thickness among women treated with ospemifene was 0.51 (1.54) mm at 12 weeks, 0.56 (1.61) mm at 6 months, and 0.81 (1.54) mm at 12 months. Women who received placebo had a mean (SD) increase of 0.07 (1.23) mm at 12 months.

          Conclusions

          These clinical trial data indicate that up to 52 weeks of treatment with oral ospemifene 60 mg/day was safe for the endometrium. There was no increase in the incidence of endometrial cancer or hyperplasia among postmenopausal women treated with ospemifene compared with placebo.

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          Most cited references 21

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          Selective estrogen-receptor modulators -- mechanisms of action and application to clinical practice.

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            The effect of raloxifene on risk of breast cancer in postmenopausal women: results from the MORE randomized trial. Multiple Outcomes of Raloxifene Evaluation.

            Raloxifene hydrochloride is a selective estrogen receptor modulator that has antiestrogenic effects on breast and endometrial tissue and estrogenic effects on bone, lipid metabolism, and blood clotting. To determine whether women taking raloxifene have a lower risk of invasive breast cancer. The Multiple Outcomes of Raloxifene Evaluation (MORE), a multicenter, randomized, double-blind trial, in which women taking raloxifene or placebo were followed up for a median of 40 months (SD, 3 years), from 1994 through 1998, at 180 clinical centers composed of community settings and medical practices in 25 countries, mainly in the United States and Europe. A total of 7705 postmenopausal women, younger than 81 (mean age, 66.5) years, with osteoporosis, defined by the presence of vertebral fractures or a femoral neck or spine T-score of at least 2.5 SDs below the mean for young healthy women. Almost all participants (96%) were white. Women who had a history of breast cancer or who were taking estrogen were excluded. Raloxifene, 60 mg, 2 tablets daily; or raloxifene, 60 mg, 1 tablet daily and 1 placebo tablet; or 2 placebo tablets. New cases of breast cancer, confirmed by histopathology. Transvaginal ultrasonography was used to assess the endometrial effects of raloxifene in 1781 women. Deep vein thrombosis or pulmonary embolism were determined by chart review. Thirteen cases of breast cancer were confirmed among the 5129 women assigned to raloxifene vs 27 among the 2576 women assigned to placebo (relative risk [RR], 0.24; 95% confidence interval [CI], 0.13-0.44; P<.001). To prevent 1 case of breast cancer, 126 women would need to be treated. Raloxifene decreased the risk of estrogen receptor-positive breast cancer by 90% (RR, 0.10; 95% CI, 0.04-0.24), but not estrogen receptor-negative invasive breast cancer (RR, 0.88; 95% CI, 0.26-3.0). Raloxifene increased the risk of venous thromboembolic disease (RR, 3.1; 95% CI, 1.5-6.2), but did not increase the risk of endometrial cancer (RR, 0.8; 95% CI, 0.2-2.7). Among postmenopausal women with osteoporosis, the risk of invasive breast cancer was decreased by 76% during 3 years of treatment with raloxifene.
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              Increased risk of endometrial carcinoma among users of conjugated estrogens.

               H K Ziel,  W Finkle (1975)
              The possibility that the use of conjugated estrogens increases the risk of endometrial carcinoma was investigated in patients and a twofold age-matched control series from the same population. Conjugated estrogens (principally sodium estrone sulfate) use was recorded for 57 per cent of 94 patients with endometrial carcinoma, and for 15 per cent of controls. The corresponding point estimate of the (instantaneous) risk ratio was 7.6 with a one-sided 95 per cent lower confidence limit of 4.7. The risk-ratio estimate increased with duration of exposure: from 5.6 for 1 to 4.9 years exposure to 13.9 for seven or more years. The estimated proportion of cases related to conjugated estrogens, the etiologic fraction, was 50 per cent with a one-sided 95 per cent lower confidence limit of 41 per cent. These data suggest that conjugated estrogens have an etiologic role in endometrial carcinoma.
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                Author and article information

                Journal
                Menopause
                Menopause
                GME
                Menopause (New York, N.y.)
                Lippincott-Raven Publishers
                1072-3714
                1530-0374
                January 2015
                15 January 2015
                : 22
                : 1
                : 36-43
                Affiliations
                From the 1EndoRheum Consultants, Malvern, PA; 2New York University School of Medicine, New York, NY; and 3Jones Institute for Reproductive Medicine, Eastern Virginia Medical Center, Norfolk, VA.
                Author notes
                Address correspondence to: Ginger D. Constantine, MD, EndoRheum Consultants, 212 Mine Rd, Malvern, PA 19355. E-mail: endorheum@ 123456gmail.com
                Article
                GME14049 00009
                10.1097/GME.0000000000000275
                4274342
                24977459
                © 2014 by The North American Menopause Society

                This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivitives 3.0 License, where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially. http://creativecommons.org/licenses/by-nc-nd/3.0.

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