Obstetrics & Gynecology:
Endometrial Effects of Bazedoxifene Acetate, a Novel Selective Estrogen Receptor Modulator, in Postmenopausal Women
Ronkin, Sheila MD*; Northington, Robert PhD*; Baracat, Edmund MD, PhD†; Nunes, Márcia G. MD†; Archer, David F. MD‡; Constantine, Ginger MD*; Pickar, James H. MD*
From *Wyeth Research, Collegeville, Pennsylvania; †Federal University of São Paulo, Brazil; and ‡CONRAD Clinical Research Center, Eastern Virginia Medical School, Norfolk, Virginia.
This study was supported by Wyeth Research, Philadelphia, Pennsylvania.
Address reprint requests to: Sheila Ronkin, MD, Senior Director, Women's Health, Clinical Research and Development, Wyeth Research, 500 Arcola Road, Building B5250, Collegeville, PA 19426–3930; e-mail: firstname.lastname@example.org.
Received October 25, 2004. Received in revised form February 24, 2005. Accepted March 3, 2005.
OBJECTIVE: To assess the endometrial effects of bazedoxifene acetate in healthy postmenopausal women.
METHODS: The endometrial effects of bazedoxifene 2.5, 5.0, 10, 20, 30, and 40 mg/d were evaluated in a 2-part, 6-month, double-blind, randomized, active- and placebo-controlled study among a total of 497 healthy postmenopausal women. Conjugated estrogens (0.625 mg)/medroxyprogesterone acetate (2.5 mg) served as the active control. Patients underwent transvaginal ultrasonography to measure double-wall endometrial thickness and endometrial biopsy at baseline and at 6 months of treatment. The incidence of amenorrhea was assessed from self-reported daily diaries.
RESULTS: Bazedoxifene treatment at 2.5–20 mg/d resulted in mean changes from baseline in endometrial thickness that were no different than those seen with placebo treatment. Changes in endometrial thickness for the bazedoxifene 30 and 40 mg groups were significantly smaller than for placebo. The change from baseline in endometrial thickness was significantly and inversely related to dose (P ≤ .001). None of the endometrial biopsy specimens demonstrated endometrial hyperplasia. Subjects in the 2.5–20 mg bazedoxifene groups experienced amenorrhea rates of 57–74%, comparable with the 59% seen in placebo. Over 90% of subjects treated with bazedoxifene 30 or 40 mg/d were amenorrheic at 6 months.
CONCLUSION: Bazedoxifene at dosages up to 40 mg/d was well tolerated and did not stimulate the endometrium. The significant decreases in endometrial thickness and decreased uterine bleeding observed with doses of 30 and 40 mg/d as compared with placebo suggest endometrial antagonism, representing a novel characteristic not previously associated with any selective estrogen receptor modulator.
LEVEL OF EVIDENCE: I
Osteoporosis represents a significant, and growing, worldwide health care concern (International Osteoporosis Foundation. What is osteoporosis, who gets it and why? press release. IOF Press Release 1:2002. Portugal: Lisboa Congress Center). Therapeutic options currently available for osteoporosis prevention and treatment are each associated with particular side effects that limit their clinical application. For example, nitrogen-containing bisphosphonates have been associated with gastrointestinal events,1 and raloxifene increases the incidence of hot flushes in some women.2,3 Given the limitations associated with current therapies, the search for more tolerable, efficacious osteoporosis agents continues.
Ideally, a selective estrogen receptor modulator should act like estrogens on bone, lipids, and central nervous system without stimulating the endometrium or breast. Bazedoxifene acetate, a novel, chemically distinct selective estrogen receptor modulator, was developed using preclinical selection parameters, which included favorable effects on the skeleton and lipid metabolism, demonstrable mammary and uterine safety, and neutral effects on hot flushes.4 Bazedoxifene treatment maintains bone mineral density, preserves normal bone histology, increases bone compressive strength, reduces total cholesterol levels, and does not promote hot flushes at its bone-sparing efficacious dose in animal models.4–6 Further, bazedoxifene displays minimal uterotropic activity and also exhibits sufficient antiuterotropic activity to inhibit 17β-estradiol (E2)- and raloxifene-induced increases in uterine wet weight and histological changes. Bazedoxifene inhibits 17β-E2–induced proliferation in human breast cancer cells (MCF 7 cells).4,5
The purpose of this study was to examine the preliminary efficacy and safety of 6 doses of bazedoxifene in healthy postmenopausal women with increased bone turnover treated for 6 months. This report will focus specifically on the endometrial effects of bazedoxifene because of the concern that currently available selective estrogen receptor modulators have potential for stimulation of the endometrium via estrogen receptor agonist activity. The effects of bazedoxifene on bone metabolism and on other endpoints will be reported separately.
MATERIALS AND METHODS
Postmenopausal women aged 40–65 years were treated in this 6-month, single-center, double-blind, randomized, active- and placebo-controlled study. The local ethics committee approved the study design and each subject provided written informed consent before enrollment. Women were eligible for inclusion if they were generally healthy, postmenopausal (at least 12 months and within 10 years of last natural menstrual period, and a follicle-stimulating hormone level in the postmenopausal range), had a body mass index of 35 kg/m2 or less, and had increased bone turnover (urinary N-terminal cross-linked telopeptides of type I collagen [bone collagen equivalent] > 30 nmol/mol creatinine). Women were excluded if they had known or suspected acute or uncontrolled chronic disease or were taking medication that would confound the study results. Also, women were ineligible for participation if they had a history of endometrial hyperplasia, were found to have hyperplasia on the baseline endometrial biopsy, or had baseline endometrial thickness of 5 mm or more.
All women in the study were instructed to take blinded test article and a calcium supplement (Caltrate 600; Whitehall-Robins, Madison, NJ) daily. Study drugs were sealed in blister cards code-labeled with a package number and protocol number, instructions for once-daily dosing, and storage requirements. Blinding was maintained through the use of treatment packages that were prepared and code-labeled to a randomization schedule generated by the study sponsor. Participants maintained daily diary cards to record study medication taken as well as mastalgia, uterine bleeding/spotting, hot flushes, and other symptoms.
Each subject with an intact uterus underwent evaluation of the endometrium. Transvaginal ultrasonography examinations were performed at screening and at days 84 and 168 to measure endometrial double-wall thickness. A 5-MHz transvaginal transducer was used to measure both endometrial layers in the sagittal plane (anterior to posterior in the long axis) at the area of maximal thickness. Endometrial biopsies were performed after transvaginal ultrasonography at screening and at day 168 of therapy using a Novak curette (or other sampling device of the operator's choice). One pathologist reviewed biopsy slides using standard criteria.7
Uterine bleeding and spotting were summarized from entries recorded on daily diary cards. The incidence of amenorrhea was defined as the number of subjects with no days of bleeding or spotting over the entire treatment period (bleeding reported on the day of endometrial biopsy or the 6 days after biopsy was considered procedure-related and was not counted).
This study was conducted in two parts. Part I studied 4 daily doses of bazedoxifene (2.5 mg, 5 mg, 10 mg, and 20 mg), placebo, and 0.625 mg conjugated estrogens/2.5 mg medroxyprogesterone acetate. Because of favorable results, the trial was extended to study additional doses for part II, which subsequently enrolled women not previously randomized in part I, to 3 daily doses of bazedoxifene (20 mg, 30 mg, and 40 mg) or placebo. The two parts of the study were conducted in serial by the same investigator, at a single site, and under the same protocol. The flow of participants is depicted in Figure 1.
Subjects in part I were initially randomized in blocks of 6; within each block, 2 subjects were randomly assigned to 2.5 mg bazedoxifene, 2 to 5 mg bazedoxifene, 1 to raloxifene, and 1 to placebo. A second randomization table was used for continued enrollment into part I, again in blocks of 6: 4 subjects were randomly assigned to 10 mg bazedoxifene, 1 to raloxifene, and 1 to placebo. A final randomization table was used for completing enrollment into part I, again in blocks of 6: 4 subjects were randomly assigned 20 mg bazedoxifene, 1 to raloxifene, and 1 to placebo. In total, approximately equal numbers of subjects were randomly assigned to each of the 6 treatment groups. For part II of the study, subjects were randomly assigned in blocks of 4, with 1 subject each being randomly assigned to 20 mg bazedoxifene, 30 mg bazedoxifene, 40 mg bazedoxifene, and placebo.
A total of 600 women were randomized to the overall efficacy study and 595 subjects received at least 1 dose of treatment. Of these, a total of 497 subjects were included in the endometrial evaluable population due to having: 1) an intact uterus, 2) baseline transvaginal ultrasonogram and at least 1 postbaseline transvaginal ultrasonogram (day 84 and/or day 168), and 3) at least 1 recorded dose of medication.
Assuming a standard deviation of 1.5 in the measurement of endometrial thickness, a sample size of 50 per group would provide 90% power at the .05 level to declare a difference between groups of 1.0 mm to be statistically significant. The sample sizes per group in this study ranged from 43 to 55 depending on the treatment group and time point.
Data are reported as means and standard errors unless noted otherwise. All tests were 2-sided with statistical significance set a priori at P value of less than .05. Baseline characteristics (mean and standard deviation) were compared among treatment groups using a 1-way analysis of variance procedure for quantitative data or the χ2 test for qualitative data. The Fisher exact test was used to compare the incidence of adverse events and amenorrhea between each treatment group.
For women in the endometrial evaluable population, an analysis of covariance model with treatment as a factor and baseline endometrial thickness as a covariate was used to compare endometrial thickness at days 84 and 168. To assess the relationship between dose and changes in endometrial thickness at day 168, a regression of change from baseline on dose, with baseline endometrial thickness as an additional variable, was done.
Subjects in part I were enrolled from April to October, 1999; subjects in part II were enrolled from July to August of 2000. Baseline characteristics for all subjects in the endometrial evaluable population of parts I and II of the study are shown in Table 1. Overall, there were no differences in demographic characteristics between the treatment groups in part I or between treatment groups in part II. The only significant difference between parts I and II was in years since menopause for women given placebo; women in the placebo group of part I were further from menopause than women in the placebo group of part II.
Tables 2 and 3 show the mean endometrial thickness at baseline, day 84, and day 168, and the mean changes in endometrial thickness from baseline for women in parts I and II who met the criteria for the endometrial evaluable population. In part I of the study, bazedoxifene at 2.5 to 20 mg/d resulted in mean changes from baseline that were not significantly different from the change observed in the placebo group at 84 days and at 168 days. As expected, treatment with conjugated estrogens (0.625 mg)/ medroxyprogesterone acetate (2.5 mg) resulted in a small but significant increase in endometrial thickness compared with placebo (P < .05). Part II of the study found significantly smaller changes in endometrial thickness from baseline for the 30 and 40 mg bazedoxifene treatment groups at day 168 compared with placebo (P < .05).
Mean changes in endometrial thickness at day 168 are also shown in Figure 2. Groups that received 2.5–20 mg bazedoxifene were not different from placebo with regard to mean change in thickness at day 168. At 30 and 40 mg per day, no endometrial stimulation was observed; in fact, a statistically significant decrease in thickness relative to placebo was observed for both the 30- and 40-mg dose (P < .05). Regression analysis found the change from baseline in endometrial thickness was significantly and inversely related to bazedoxifene dose (P < .001), indicating greater endometrial antagonism as the dose of bazedoxifene increased.
None of the endometrial biopsy specimens obtained from subjects treated with placebo, conjugated estrogens (0.625 mg)/medroxyprogesterone (2.5 mg), or bazedoxifene demonstrated endometrial hyperplasia (Table 4). Overall, no significant difference in the incidence of amenorrhea was noted between the 2.5–20-mg bazedoxifene groups and placebo at 6 months (Table 5). However, in part II, the incidence of amenorrhea in the 30-mg group (93.3%) was significantly greater than placebo (79.3%, P = .032), and in the 40-mg treatment group (91.7%) the comparison with placebo approached significance (P = .069).
Among participants in the overall study population, there were a total of 13 withdrawals from the study due to treatment-emergent adverse events. Of the 13 subjects who withdrew, 10 were receiving 1 of the 6 doses of bazedoxifene (constipation, vomiting, taste perversion, abnormal vision, abdominal pain, lung carcinoma, superficial thrombophlebitis, diarrhea, paresthesia, and cholelithiasis), 2 were receiving conjugated estrogens (0.625 mg)/medroxyprogesterone acetate (2.5 mg) (nausea, biliary colic), and 1 was receiving placebo (migraine). There were no withdrawals due to hot flushes, leg cramps, uterine bleeding, or other urogenital complaints.
The most commonly reported treatment-emergent adverse events were abdominal pain, headache, breast pain, and flu syndrome. In part I, breast pain was reported by significantly more participants in the conjugated estrogens (0.625 mg)/medroxyprogesterone acetate (2.5 mg) group than in the placebo group or any of the bazedoxifene groups (P < .05). Furthermore, in part II, breast pain was reported by 25.4% of participants receiving placebo, compared with 13.3%, 11.7%, and 10.0% of patients receiving bazedoxifene at 20 mg, 30 mg, and 40 mg, respectively. Pairwise analysis found the 40-mg bazedoxifene group experienced significantly less breast pain than placebo (P < .05). One possibly related serious adverse event, an episode of supraventricular tachycardia after the concomitant use of a salbutamol inhaler, was reported in a bazedoxifene group.
Bazedoxifene is a novel selective estrogen receptor modulator with an advantageous preclinical profile for the prevention of osteoporosis.4,5 Endometrial stimulation is a concern with estrogen-receptor–based therapies because estrogen receptor activation in this tissue can lead to an increased risk for endometrial carcinoma. This study demonstrates that bazedoxifene at daily doses up to 40 mg was well tolerated and did not stimulate the endometrium. Additionally, bazedoxifene produces statistically significant reductions in markers of bone remodeling without inducing breast pain (Boudes P, Ronkin S, Korner P, Baracat E, Constantine G. Effects of bazedoxifene TSE-424, a novel tissue selective estrogen receptor modulator SERM, on the incidence of breast pain abstract OC39. Osteoporos Int 2003;14 suppl 7:S14; Ronkin S, Baracat E, Roma L, Clarke L, Boudes P, Constantine G, Lindsay R. TSE-424, a novel tissue selective estrogen, reduces biochemical indices of bone metabolism in a dose related fashion abstract P3-145. In: Endocrine Society program and abstracts, 83rd annual meeting 2001, p. 480).
Endometrial effects, or lack thereof, have been a focal point in the development of recent selective estrogen receptor modulators, because differences in their endometrial properties are apparent. Tamoxifen, used in the treatment and prevention of hormone-dependent breast cancer, is known to cause endometrial proliferation in women and to increase the risk of endometrial cancer.8–10 Several selective estrogen receptor modulators such as idoxifene, droloxifene, and levormeloxifene produced dose-related increases in uterine weight, uterine epithelial height, and uterine eosinophilia in the ovariectomized rat model (Adrian MD, Cole HW, Shetler PK, Rowley ER, Magee DE, Pell T, et al. Comparative pharmacology of a series of selective estrogen receptor modulators [abstract]. J Bone Miner Res 1996;11 suppl:S447).11 Clinical trials by and large corroborated preclinical findings; idoxifene12 and levormeloxifene13,14 produced dose-related increases in endometrial thickness as evaluated by transvaginal ultrasonography. Each of these compounds has been halted in clinical development partly on the basis of uterine liabilities.15,16
Preclinical data on the uterine effects of raloxifene have been discordant. In contrast to early data that did not find stimulatory effects of raloxifene in the uterus,17 more recent studies in immature18 and ovariectomized rats19 have shown that raloxifene treatment leads to significant increases in uterine wet weight and associated morphological changes. In clinical studies, overall analysis of small phase 1/2 trials of raloxifene shows no increase in endometrial thickness20–23; however, the MORE trial of over 7,000 women demonstrated that, after 3 years of treatment, the raloxifene group experienced a small but significant increase in endometrial thickness compared to placebo, as measured by transvaginal ultrasonography.24 Further, a significantly greater number of women in MORE treated with raloxifene had endometrial thicknesses greater than 5 mm on at least 1 follow-up ultrasound examination compared with placebo-treated women (P = .02).24
The preclinical data on bazedoxifene have consistently suggested a comparatively favorable uterine profile in contrast to other selective estrogen receptor modulators. Both tamoxifen and raloxifene stimulate complement component 3 promoter activity in vitro (predictive of a compound's in vivo uterine activity) whereas bazedoxifene does not.4 A comparative study of uterine wet weight stimulation in a 3-day immature rat model found that bazedoxifene was the only selective estrogen receptor modulator tested that produced no significant changes in uterine weight; all other selective estrogen receptor modulators, including lasofoxifene and raloxifene, resulted in greater weight increases than those seen with bazedoxifene.4 Similarly, bazedoxifene has been shown to have no effect on uterine weight compared with untreated or control animals in both the mouse xenograft4 and the immature rat models.5 In addition, animal studies have shown that bazedoxifene displays antiestrogenic effects in the uterus by inhibiting both E25 and raloxifene-induced increases in uterine weight.4 The ability to block potential uterotropic effects of raloxifene suggests that bazedoxifene may be a more favorable selective estrogen receptor modulator with regard to uterine activity.
The data from this trial are consistent with favorable preclinical findings. After 6 months of treatment, no endometrial stimulation was observed with any dose of bazedoxifene examined, and at daily doses of 30 mg and 40 mg, treated women showed a statistically significant decrease in endometrial thickness compared to women treated with placebo. Changes in endometrial thickness were inversely related to dose. Amenorrhea data and results from endometrial biopsies further demonstrated that bazedoxifene does not stimulate the endometrium.
The demonstration that the 30 mg and 40 mg bazedoxifene may have antiestrogenic activity in the endometrium is consistent with animal studies5 and is unique for the selective estrogen receptor modulator class of compounds. No other selective estrogen receptor modulator, including raloxifene, has been shown in clinical studies to have estrogen antagonistic activity in the endometrium. There has been some recent interest on the potential combination therapy of a selective estrogen receptor modulator with an estrogen for treatment of postmenopausal women with menopausal symptoms.25 Given its unique antiestrogenic action on the endometrium, adding bazedoxifene to estrogens may represent a novel alternative to current hormone therapies if the selective estrogen receptor modulator and conjugated estrogens combination affords endometrial protection comparable to progestins without potential progestin-associated side effects. Based on preclinical results and the data shown here, a fixed combination of bazedoxifene with estrogens for the treatment of menopausal symptoms warrants further investigation.
This report demonstrates the favorable endometrial effects of bazedoxifene in postmenopausal women and suggests this compound may represent an important advance in selective estrogen receptor modulator development. Investigation of bazedoxifene in phase 3 trials for the prevention and treatment of osteoporosis is currently underway. Investigation of bazedoxifene in combination with conjugated estrogens for the treatment of menopausal symptoms and the prevention of postmenopausal osteoporosis is also currently underway.
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© 2005 The American College of Obstetricians and Gynecologists
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