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Bazedoxifene: An investigational selective estrogen receptor modulator for the treatment and prevention of osteoporosis in postmenopausal women

Article

A new selective estrogen receptor modulator, bazedoxifene acetate, is currently under development in an effort to maximize potential benefits on bone, lipids and breast tissue while minimizing endometrial hyperplasia and other adverse effects.

Key Points

Abstract

Bazedoxifene is a selective estrogen receptor modulator under investigation for the treatment and prevention of osteoporosis in postmenopausal women. In phase 3 trials, bazedoxifene-treated patients with normal to low bone mineral density (BMD) had significantly higher BMD at the lumbar spine and hip, which was similar to patients treated with raloxifene. In patients with osteoporosis, bazedoxifene significantly decreased the risk of vertebral fractures as well as nonvertebral fractures in a subgroup of high-risk patients. The most common adverse events reported in phase 3 trials were headache, infection, arthralgia, pain, hot flushes, back pain, abdominal pain, accidental injury, flu syndrome, and hypertension. Bazedoxifene-treated patients had a high incidence of hot flushes versus placebo, but this was similar to raloxifene-treated patients. Bazedoxifene is unlikely to interact significantly with other drugs due to its metabolism via glucuronidation and currently does not appear to require dose adjustment for renal or hepatic impairment. (Formulary. 2011; 46:159–176.)

Defined as a skeletal, degenerative bone disease, osteoporosis affects an estimated 10 million persons in the United States.1 An additional 34 million US adults are at risk for developing the disease due to osteopenia. Although prevalent in various patient populations, most cases of osteoporosis occur in postmenopausal women, and prevalence increases with age.2 Estrogen deficiency after menopause is a major contributor to the development of osteoporosis and leads to an imbalance between osteoclast and osteoblast activity.2 Accelerated bone loss increases the risk of fractures, most notably those of the hip. Osteoporotic fractures account for substantial healthcare costs, disability, and mortality.1

SERMs are a heterogeneous class of compounds that exert their pharmacologic effects at estrogen receptors (ERα and ERβ ).3 Currently, SERMs that are FDA approved for use include tamoxifen and raloxifene. These compounds differ from each other in their ability to act as either agonists or antagonists in a tissue-specific manner. Tamoxifen, a triphenylethylene derivative, is indicated for the treatment of breast cancer in pre- and postmenopausal women.4 Raloxifene, a benzothiopene derivative, is approved for the prevention and treatment of postmenopausal osteoporosis.5 Although raloxifene's effects on bone and lipids are well established, raloxifene induces both vasomotor symptoms and vaginal atrophy that may lead to treatment discontinuation.3 A new SERM, bazedoxifene acetate, is currently under development in an effort to maximize potential benefits on bone, lipids, and breast tissue while minimizing endometrial hyperplasia and other adverse effects.6,7 Such advancement in drug development may expand first-line treatment options for postmenopausal osteoporosis.

CHEMISTRY AND PHARMACOLOGY

Bazedoxifene acetate (1H-Indol-5-ol, 1-[[4-[2-(hexahydro-1H-azepin-1-yl)ethoxy]phenyl]methyl]2-(4-hydroxyphenyl)-3methyl, WAY-140424) is a nonsteroidal, indole-based estrogen receptor ligand.3,6,8,9 Structurally, bazedoxifene resembles raloxifene, but differs by substitution of an indole ring for the benzothioprine core.8,10 Within the class of SERMs, chemical differences in the location and structure of side chains determine tissue selectivity, pharmacologic action, and lead to a mixed functional activity at the estrogen receptors.3,10 Bazedoxifene binds to both ERα and ERβ with higher affinity toward ERα.6 Compared to raloxifene, bazedoxifene is less selective for ERα (IC50 26nM) and is about 10-fold lower than 17 β-estradiol (IC50 3.2nM).6 Bazedoxifene exerts pharmacologic activity by binding to estrogen receptors in bone tissue as an agonist promoting preservation of bone mineral density (BMD). At breast and uterine tissue, bazedoxifene acts as an antagonist, therefore lacking stimulation and proliferative activity within these tissues.3,6

PHARMACOKINETICS AND PHARMACODYNAMICS

Single- and multiple-dose pharmacokinetic (PK) studies of bazedoxifene have been completed in healthy, postmenopausal women.11–13 After administration of multiple doses of bazedoxifene 5 mg/d, 20 mg/d, or 40 mg/d for 14 days, maximum concentration in serum (Cmax) was 1.6+0.5 ng/mL, 6.4+2.4 ng/mL, and 12.5+5.1 ng/mL, respectively.12 Maximum concentration in serum is reached within 1 to 2 hours of administration. The absolute bioavailability of oral bazedoxifene is approximately 6.2%; this is 3 times the bioavailability compared with other SERMs on the market, including raloxifene.11 Concentration-time profiles of capsule and tablet formulations are similar, suggesting both oral formulations are bioequivalent with respect to the area under the concentration time curve (AUC).11 Bazedoxifene also demonstrates linear pharmacokinetics when dosed from 5 mg to 40 mg daily.12

The elimination half-life of bazedoxifene is approximately 28 hours. Steady-state concentration is achieved 7 days after administration.12 Bazedoxifene is highly protein bound (>99%) and demonstrates a volume of distribution of 248+134 L/kg.12–14 Bazedoxifene exhibits little to no cytochrome P450 activity, which may minimize potential for drug-drug interactions. The major metabolic pathway of bazedoxifene is via glucuronidation.13 Bazedoxifene-5glucuronide is the primary metabolite (40%-95%) responsible for the majority of circulating radioactivity.13 The major route of excretion is via the feces (84.7%) with only a minor amount (0.81%) excreted in the urine.13

CLINICAL TRIALS

The efficacy of bazedoxifene for the treatment and prevention of postmenopausal osteoporosis has been reported in 4 clinical trials (two phase 2 and two phase 3 trials).15–18 In addition to measuring fracture risk and BMD, markers of bone turnover are often evaluated to help understand mechanism of action. Osteocalcin and serum type 1 collagen C-telopeptide (CTX) are markers of bone formation and resorption, respectively, used in bazedoxifene trials. For example, antiresorptive therapies cause a decrease in both markers of bone formation and resorption while the opposite is true of anabolic therapies such as parathyroid hormone.

Phase 2 trials. The first phase 2 trial evaluated the effects of bazedoxifene on markers of bone turnover.15 This trial was prospective, randomized, and double-blind comparing bazedoxifene 5 mg, 10 mg, and 20 mg to raloxifene 60 mg or placebo. A total of 494 healthy postmenopausal women were enrolled and treated for 3 months. Investigators reported a dose-related reduction in bone markers in the bazedoxifene and raloxifene groups versus placebo, with doses as low as 5 mg of bazedoxifene.

The second phase 2 trial evaluated the endometrial effects of bazedoxifene.16 Women aged 40 to 65 years, at least 12 months post menopause, and within 10 years of last natural menstrual period, with a follicle-stimulating hormone level in the postmenopausal range, BMI ≤35 kg/m2 , and increased bone turnover as measured by urinary N-telopeptide were included. Subjects were excluded if they had known or suspected acute or uncontrolled chronic disease, were taking medication that would confound the study, had a history of endometrial hyperplasia, or were found to have hyperplasia or endometrial thickness greater than 5 mm or more at baseline. Subjects were randomly assigned to receive bazedoxifene doses ranging from 2.5 mg to 40 mg or to placebo. A total of 497 subjects were available for the endometrial analysis. Compared to placebo, patients who received bazedoxifene 2.5 mg to 20 mg daily did not have a difference in endometrial thickness at days 84 and 168 and those who were randomly assigned to bazedoxifene 30 mg or 40 mg had a significantly smaller change in endometrial thickness from baseline at day 168 (P<.05). Investigators reported a significant inverse relationship between bazedoxifene dose and endometrial thickness found in this trial.

Phase 3 trials. Two phase 3 trials have been completed to evaluate the efficacy of bazedoxifene in the treatment and prevention of osteoporosis in postmenopausal women.17,18

A total of 1,583 women from 101 centers in Canada, the United States, and Europe were randomly assigned and received at least 1 dose of bazedoxifene 10 mg (n=321), 20 mg (n=322), 40 mg (n=319), raloxifene 60 mg (n=311), or placebo (n=310).17 The mean age of enrolled subjects was 58 years and the majority of subjects were white (94%). The average number of years since last menstrual period ranged from 10.46 to 11.25 and the mean reported BMD in the treatment groups was no lower than -1.24 at any of the measured locations (lumbar spine, total hip, femoral neck, or femoral trochanter). A total of 1,113 subjects completed the trial (70.3%). A total of 470 participants (29.6%) withdrew from the trial with the most common reason being adverse events (54.9% of withdrawals). A similar percentage of participants withdrew from the trial due to any adverse event across the 5 groups (bazedoxifene 10 mg 16.8%, 20 mg 17.1%, 40 mg 18.2%, raloxifene 60 mg 13.8%, placebo 15.5%).17

The trial by Silverman et al was a 3-year, multicenter, double-blind randomized trial comparing once-daily doses of bazedoxifene 20 mg or 40 mg to raloxifene 60 mg or placebo.18 All subjects also received up to 1,200 mg of calcium and 400 to 800 IU of vitamin D orally daily. Women between aged 55 and 85 years and at least 2 years post menopause with osteoporosis, defined as low BMD or radiographically confirmed vertebral fractures, were considered for inclusion with additional criteria applied (Table 1, page 165).18 The primary efficacy outcome was the incidence of new vertebral fractures after 36 months of therapy. Secondary outcomes included the incidence of clinical vertebral fractures and nonvertebral fractures, change in the BMD from baseline in the lumbar spine, total hip, or femoral neck, and serum osteocalcin and CTX levels. Analysis of the primary outcome was in subjects who were randomly assigned, received at least 1 dose of study drug, and underwent vertebral radiography at baseline and at least once during therapy.18

A total of 7,492 subjects were randomly assigned to and received at least 1 dose of bazedoxifene 20 mg (n=1,886), 40 mg (n=1,872), raloxifene 60 mg (n=1,849), or placebo (n=1,885).18 The mean age of enrolled subjects was 66 years and the majority of subjects were of white ethnic origin (87%). The mean number of years since last menstrual period ranged from 19.3 to 19.7. Mean baseline lumbar spine T-scores were -2.4 in all groups and the mean femoral neck T-score ranged from -1.7 to -1.8. A total of 4,991 subjects completed the study (66.6%) with adverse events leading to the most discontinuations (bazedoxifene 20 mg 42.6%, 40 mg 42.0%, raloxifene 60 mg 43.9%, placebo 38.2%).18 A significantly higher percentage of subjects who discontinued therapy due to a new vertebral fracture or loss of BMD ≥7% was found in the placebo group compared to the active treatment groups.18

Among the 6,847 subjects making up the intent-to-treat population, all treatment groups had a significantly lower incidence of a new vertebral fracture after 36 months of treatment versus placebo and there was no significant difference between the groups (Table 2).18 There was no significant difference in the incidence of nonvertebral fractures among the treatment groups. A post-hoc analysis evaluated a subgroup of women (n=1,772) at higher baseline risk of fractures and found that bazedoxifene 20 mg significantly reduced the risk of nonvertebral fractures compared to placebo (hazard ratio [HR], 0.50; CI, 0.28-0.90); although this was not significantly different versus raloxifene or when bazedoxifene 40 mg was compared to placebo or raloxifene. In the subgroup considered to be at lower risk, no significant differences were found in the incidence of nonvertebral fractures between the groups.18

An independent post-hoc re-analysis of the core trial evaluated the risk of vertebral and all clinical fractures in the bazedoxifene 20-mg and 40-mg groups combined versus placebo using multivariate analysis.19,20 Baseline fracture risk was assessed using the computer-based FRAX algorithms and the 10-year probability of having a new fracture was estimated.19–21 Bazedoxifene did not significantly reduce the risk of all clinical fractures (HR, 0.84; CI, 0.67-1.06); however, as the baseline risk for fractures increased, the HR continued to decrease until the baseline risk of 16%, which was the threshold for probability at which treatment had a significant effect.19

The BMD of the lumbar spine and of the total hip were significantly greater in both bazedoxifene groups versus placebo at 36 months in the core trial (Table 2).18 Authors also reported a small but significant difference at each time point between both bazedoxifene doses and raloxifene throughout the study period for both BMD of the lumbar spine (P<.05) and total hip (P<.01). Compared to placebo, patients in the bazedoxifene and raloxifene groups had significantly decreased serum osteocalcin and CTX levels (Table 2).18 The difference between the bazedoxifene and raloxifene groups of both markers was statistically significant (P<.001). Similar to the trial by Miller et al, bazedoxifene had a neutral to favorable effect on the lipid profile (Table 2).17,22 A 2-year extension of the core trial enrolled 4,216 subjects (Table 2).23 The raloxifene arm was discontinued and subjects originally randomly assigned to bazedoxifene 40 mg were blindly transitioned to 20 mg (bazedoxifene 40/20 mg). Similar to the core trial, there was a significant reduction in the risk of new vertebral fractures in the bazedoxifene 20 mg and 40/20 mg groups versus placebo at 5 years and no significant difference in the risk of nonvertebral fractures between groups in the overall population (Table 2).18,23 In a subgroup of high-risk patients, a significant reduction in the risk of nonvertebral fractures (37% reduction) was seen in the bazedoxifene 20-mg group versus placebo (P=.06).23

Investigators pooled the data from African-American women (n=505) randomized to receive bazedoxifene 20 mg, 40 mg, raloxifene 60 mg, or placebo in these two phase 3 trials.24 Results were similar to the original trials, with bazedoxifene 20 mg and 40 mg and raloxifene 60 mg showing significantly greater changes in BMD at the lumbar spine, total hip, femoral neck, and femoral trochanter from baseline versus placebo at 24 months (Table 2).17,18,24

SAFETY AND TOLERABILITY

A total of 9,075 women comprised the safety population in the phase 3 clinical trials and 5-year data were available for 3,146 women.17,18,25 The most common side effects (reported by ≥20% in at least 1 group in 1 trial) in the core phase 3 trials were headache, infection, arthralgia, pain, hot flushes, back pain, abdominal pain, accidental injury, flu syndrome, and hypertension, and were similar to those reported common at 5 years.17,18,25 A higher percentage of women reported hot flushes in the bazedoxifene groups versus placebo, although this was similar to raloxifene-treated patients.17,18 This effect persisted in the 5-year safety data with significantly higher incidence of hot flushes in the bazedoxifene groups (13.0% and 13.4%) versus placebo (6.6%, P<.001).25 Serious adverse events occurred in 9% to 20.3% of bazedoxifene-treated patients in the core trials and ranged from 23.5% to 24.8% in bazedoxifene-treated patients followed for 5 years.17,18,25

Safety parameters of interest in phase 3 trials included cardiovascular and thromboembolic events. In the trial by Miller et al., 3 myocardial infarctions (MIs) occurred in bazedoxifene-treated patients and 1 occurred in a placebo-treated patient.17 In the trial by Silverman et al., the overall incidence of cardiovascular events (coronary occlusion, MI, myocardial ischemia) was not significantly different between groups.18,22 Cerebrovascular adverse events including outcomes such as hemorrhagic or ischemic stroke were rare in both trials.17,18 The rate of stroke per 1,000 women-years was 2.6, 3.1, 2.6, and 3.0 in bazedoxifene 20 mg, 40 mg, raloxifene 60 mg, and placebo groups, respectively.22 Venous thromboembolism (VTE) was rare in bazedoxifene-treated patients in the trial by Miller et al (2 deep vein thromboses [DVTs], 1 pulmonary embolism, and 0 retinal vein thrombosis).17 However, in the trial by Silverman et al, there was a higher incidence of any VTE (primarily DVT) in the bazedoxifene- and raloxifene-treated patients compared to placebo, but no difference compared to each other.18 The rates of VTE and DVT per 1,000 women-years were: 2.8 and 1.7 in bazedoxifene 20 mg, 2.9 and 2.0 in bazedoxifene 40 mg, 2.0 and 1.5 in raloxifene 60 mg, and 1.7 and 0.2 in placebo, respectively.22

To evaluate bazedoxifene's effects on endometrial, ovarian, and breast tissues, several safety analyses of the phase 3 trials have been conducted.8,26,27 Endometrial and ovarian safety analyses of 1,116 and 1,387 subjects, respectively, from the trial by Miller et al were conducted.8 No significant changes were found in endometrial thickness from baseline to 24 months in the bazedoxifene groups. No patients were diagnosed with endometrial hyperplasia and there was no significant difference in the rate of endometrial polyp formation or in reported gynecologic or endometrial adverse events. Authors concluded that safety findings for bazedoxifene and raloxifene in this study were comparable and that bazedoxifene does not seem to stimulate endometrial, ovarian, or breast tissue.8 Endometrial, ovarian, and breast safety was evaluated in a subset of 753 women from the trial by Silverman et al.26 No significant differences were seen in endometrial thickness, ovarian size, number of ovarian cysts, abnormalities of cervical cytology, breast carcinoma, breast cysts, or breast pain between groups. There was a significant difference in the incidence of ovarian carcinoma between groups (bazedoxifene 20 mg 5 cases, 40 mg 0 cases, raloxifene 2 cases, placebo 0 cases, P<.023), although when classified as treatment-emergent, the difference was no longer significant. The raloxifene group had a significantly higher incidence of fibrocystic breast disease (0.8%) compared to bazedoxifene 20 mg (0.3%) or 40 mg (0.2%, P≤.05). A retrospective study of mammography data from a subset of eligible participants (n=444) from the trial by Silverman et al evaluated the change in breast density from baseline to month 24 and found no significant differences between groups.27 The 5-year safety data were overall consistent with the data available after 3 years.18,25 The incidence of breast carcinoma was similar across bazedoxifene and placebo groups and the incidence of breast pain, cysts, or fibrocystic disease was not significantly different.25 A lower incidence of endometrial carcinoma was observed in bazedoxifene-treated patients (0% and 0.2%) versus placebo (0.3%, P=.05). The mean change in endometrial thickness was not significantly different between bazedoxifene and placebo groups. Four cases of ovarian carcinoma occurred, all in the bazedoxifene groups.

DRUG INTERACTIONS

Bazedoxifene is extensively metabolized via glucuronidation and has little to no cytochrome P450-mediated metabolism; therefore the likelihood of significant drug interactions is low.13 Bazedoxifene was studied with ibuprofen for clinically relevant PK interactions because both drugs are metabolized via glucuronidation and may be taken concurrently.28 An open-label, 3-way crossover study in 12 healthy postmenopausal women with single doses of bazedoxifene 20 mg and ibuprofen 600 mg found no significant alterations in PK parameters. Authors concluded the drugs can be taken together safely without the need for dosage adjustment.

DOSING AND ADMINISTRATION

Although not yet FDA approved, bazedoxifene has been studied for the prevention and treatment of osteoporosis in postmenopausal women with doses ranging from 10 mg to 40 mg daily.17,18 It is, however, worth noting that the 10-mg dose was found to be less effective in protecting against bone loss than the 20-mg and 40-mg doses.17 No data were identified to suggest specific administration of bazedoxifene relative to meals or to suggest dose adjustment in patients with renal or hepatic impairment.

FORMULARY CONSIDERATIONS

Bazedoxifene is currently under investigation for the treatment and prevention of osteoporosis in postmenopausal women. In phase 3 trials, bazedoxifene reduced the risk of new vertebral fractures in women with osteoporosis by 37% to 42% compared to placebo, while decreasing the risk of nonvertebral fractures in a post-hoc subgroup analysis of women with higher baseline risk of fractures. Bazedoxifene also led to preservation of BMD in the lumbar spine and areas of the hip compared to placebo. From this data, bazedoxifene appears similar in efficacy to raloxifene in both prevention of fractures and preservation of BMD. Bazedoxifene appears to have a favorable safety profile on lipids, endometrial, ovarian, and breast tissue. Other adverse events such as VTE may occur more frequently than placebo but appear similar to raloxifene, as does the occurrence of hot flushes. Additionally, the dose regimens studied to date are once daily and the propensity for clinically significant drug interactions with bazedoxifene is lower given its primary metabolic pathways.

Dr Sobieraj is senior research scientist, University of Connecticut School of Pharmacy, Storrs, Conn.

Dr Nigro is clinical assistant professor of pharmacy practice, University of Connecticut School of Pharmacy.

Disclosure Information: The authors report no financial disclosures as related to products discussed in this article.

In each issue, the "Focus on" feature reviews a newly approved or investigational drug of interest to pharmacy and therapeutics committee members. The column is coordinated by Robert A. Quercia, MS, RPh, medical editor, Department of Pharmacy Services, University of Connecticut/Hartford Hospital, Evidence-based Practice Center, Hartford, Conn., and adjunct associate professor, University of Connecticut School of Pharmacy, Storrs, Conn; and by Craig I. Coleman, PharmD, associate professor of pharmacy practice, University of Connecticut School of Pharmacy, and director, Pharmacoeconomics and Outcomes Studies Group, Hartford Hospital.

EDITORS' NOTE: The clinical information provided in "Focus on" articles is as current as possible. Due to regularly emerging data on developmental or newly approved drug therapies, articles include information published or presented and available to the author up until the time of the manuscript submission.

REFERENCES

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7. Pinkerton JV, Archer DF, Utian WH, et al. Bazedoxifene effects on the reproductive tract in postmenopausal women at risk for osteoporosis. Menopause. 2009;16:1102–1108.

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11. Patat A, McKeand W, Baird-Bellaire S, Ermer J, LeCoz F. Absolute/relative bioavailability of bazedoxifene acetate in healthy, postmenopausal women (abstract). Clin Pharmacol Ther. 2003;73:P43, PII–54.

12. Ermer J, McKeand W, Sullivan P, Parker V, Orczyk G. Bazedoxifene acetate dose proportionality in healthy, postmenopausal women (abstract). Clin Pharmacol Ther. 2003;73:P46, PII-66.

13. Chandrasekaran A, Ermer J, McKeand W, et al. Bazedoxifene acetate metabolic disposition in healthy, postmenopausal women (abstract). Clin Pharmacol Ther. 2003;73:P47,PII–67.

14. Chandrasekaran A, McKeand WE, Sullivan P, et al. Metabolic disposition of [14C] bazedoxifene in healthy, postmenopausal women. Drug Metab Dispos. 2009;37:1219–1225.

15. Ronkin S, Clarke L, Boudes P, Constantine G. TSE-424, a novel tissue selective estrogen, reduces biochemical indices of bone metabolism in a dose related fashion. J Bone Miner Res. 2001;16:S413.

16. Ronkin S, Northington R, Baracat E, et al. Endometrial effects of bazedoxifene acetate, a novel selective estrogen receptor modulator, in postmenopausal women. Obstet Gynecol. 2005;105:1397–1404.

17. Miller PD, Chines AA, Christiansen C, et al. Effects of bazedoxifene on BMD and bone turnover in postmenopausal women: 2-yr results of a randomized, double-blind, placebo-, and active-controlled study. J Bone Miner Res. 2008;23:525–535.

18. Silverman SL, Christiansen C, Genant HK, et al. Efficacy of bazedoxifene in reducing new vertebral fracture risk in postmenopausal women with osteoporosis: results from a 3-year, randomized, placebo-, and active-controlled clinical trial. J Bone Miner Res. 2008;23:1923–1934.

19. Kanis JA, Johansson H, Oden A, et al. Bazedoxifene reduces vertebral and clinical fractures in postmenopausal women at high risk assessed with FRAX. Bone. 2009;44:1049–1054.

20. McCloskey E, Johansson H, Oden A, Chines A, Kanis J. Assessment of the effect of bazedoxifene on non-vertebral fracture risk [abstract]. Presented at: American Society for Bone and Mineral Research 31st Annual Meeting; September 11-15, 2009; Denver, CO. Abstract FR0376.

21. FRAX. WHO fracture risk assessment tool. Available at: http://www.shef.ac.uk/FRAX/. Accessed April 13, 2011.

22. Christiansen C, Chesnut CH, Adachi JD, et al. Safety of bazedoxifene in a randomized, double-blind, placebo- and active-controlled phase 3 study of postmenopausal women with osteoporosis. BMC Musculoskelet Disord. 2010;11:130.

23. Silverman S, Chines A, Zanchetta JR, et al. Sustained efficacy of bazedoxifene in preventing fractures in postmenopausal women with osteoporosis: results of a 5-year, randomized, placebo-controlled study [abstract]. Presented at: American Society for Bone and Mineral Research 31st Annual Meeting; September 11-15, 2009; Denver, CO. Abstract 1245.

24. Levine AB, Ciesielska M, Chines A. Efficacy and safety of bazedoxifene in postmenopausal African American women [abstract]. Presented at: American Society for Bone and Mineral Research Annual Meeting; October 15-19, 2010; Toronto, ON, Canada. Abstract FR0402.

25. de Villiers TJ, Chines AA, Palacios S, et al. Safety and tolerability of bazedoxifene in postmenopausal women with osteoporosis: results of a 5-year, randomized, placebo-controlled phase 3 trial. Osteoporos Int. 2011;22:567–576.

26. Archer DF, Pinkerton JA, Utian WH, et al. Bazedoxifene, a selective estrogen receptor modulator: effects on the endometrium, ovaries, and breast from a randomized controlled trial in osteoporotic postmenopausal women. Menopause. 2009;16:1109–1115.

27. Harvey JA, Holm MK, Ranganath R, et al. The effects of bazedoxifene on mammographic breast density in postmenopausal women with osteoporosis. Menopause. 2009;16:1193–1196.

28. Baird SJ, McKeand WE, Ermer JC, Patat AA, Garcia-Querglas E. Lack of clinically relevant pharmacokinetic interaction between bazedoxifene and ibuprofen. Clin Pharmacol Ther. 2002;71;P94, WPIII-68.

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