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Keywords:

  • osteoporosis;
  • prevention;
  • bazedoxifene;
  • selective estrogen receptor modulator;
  • BMD

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. REFERENCES
  9. APPENDIX

Osteoporosis is an increasingly common health concern in postmenopausal women. In a 2-yr phase III study, bazedoxifene prevented bone loss, reduced bone turnover, and was well tolerated in early postmenopausal women with normal or low BMD.

Introduction: Bazedoxifene is a novel selective estrogen receptor modulator that has increased BMD and bone strength in experimental models, without stimulating breast or uterus. This 24-mo, randomized, double-blind study assessed the efficacy and safety of three doses of bazedoxifene compared with placebo and raloxifene in the prevention of postmenopausal osteoporosis.

Materials and Methods: Healthy postmenopausal women with a BMD T-score at the lumbar spine or femoral neck between –1.0 and −2.5 or clinical risk factors for osteoporosis were randomly assigned to one of five groups: bazedoxifene 10, 20, or 40 mg/d, placebo, or raloxifene 60 mg/d. All women received elemental calcium. Efficacy outcomes included changes from baseline through 24 mo in BMD of the lumbar spine, hip, femoral neck, and femoral trochanter and biomarkers of bone metabolism.

Results: The intent-to-treat population included 1434 women (mean age, 58 yr; mean time from last menstrual period, 11 yr). All doses of bazedoxifene and raloxifene prevented bone loss, whereas in the placebo group, there was significant loss of BMD at all skeletal sites. Mean differences in percent change in lumbar spine BMD from baseline to 24 mo relative to placebo were 1.08 ± 0.28%, 1.41 ± 0.28%, 1.49 ± 0.28%, and 1.49 ± 0.28% for 10, 20, and 40 mg bazedoxifene and 60 mg raloxifene, respectively (p < 0.001 for all comparisons). Comparable BMD responses were observed at other body sites. Significant and comparable decreases in serum osteocalcin and C-telopeptide levels from baseline and relative to placebo with active treatment were observed as early as 3 mo and were sustained through study conclusion (p < 0.001). Overall incidences of adverse events, serious adverse events, and discontinuations caused by adverse events were similar between groups. The most common adverse events included headache, infection, arthralgia, pain, hot flush, and back pain.

Conclusions: Treatment with bazedoxifene prevented bone loss and reduced bone turnover equally as well as raloxifene and was generally well tolerated in postmenopausal women with normal/low BMD.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. REFERENCES
  9. APPENDIX

Osteoporosis is a common, chronic, and progressive disorder characterized by low bone mass, diminished bone strength, and microarchitectural deterioration of bone tissue that results in skeletal fragility and susceptibility to fracture.[1, 2] Low bone mass (osteopenia) and osteoporosis currently affect an estimated 44 million Americans ≥50 yr of age in the United States, with the prevalence expected to increase steadily as the U.S. population continues to age.[3] Postmenopausal women are particularly vulnerable, because they are disproportionately afflicted with osteoporosis[3] and are at increased risk for osteoporosis-related fracture, disability, and mortality.[4-7] Approximately 70–90% of hip, spine, and forearm fractures occurring among white women who are 45–84 yr of age are related to osteoporosis.[4] The current direct cost of treating osteoporotic fractures is estimated to be $10–15 billion annually, primarily because of inpatient care.[1] Indirect costs associated with lost wages and productivity for patients and caregivers are difficult to measure but likely add billions of dollars to the total cost of fracture care.[8] Given health care inflation and projected increases in fracture incidence, osteoporosis-related direct and indirect costs are expected to double or triple over the next few decades.[8, 9]

Remarkable progress has been made in understanding the fundamental role of estrogen in maintaining bone homeostasis and the complex mechanisms by which estrogen deficiency contributes to bone loss.[10-12] Declining estrogen levels may be a principal cause of early and late phases of postmenopausal bone loss, albeit through different mechanisms.[12] Early accelerated bone loss, starting at menopause and persisting for ∼4–8 yr, stems from an increased rate of bone remodeling and an imbalance between bone resorption and formation, which are induced by estrogen deprivation through changes in osteoclast and osteoblast production, working lifespans, and apoptosis.[10, 12] The secondary hyperparathyroidism that mediates the slow phase of bone loss in later menopause has been attributed in part to the loss of estrogen actions on extraskeletal calcium metabolism.[12] In addition to the association with bone loss, reduced estrogen levels have been shown to be associated with increased fracture risk in older women.[13] In the National Osteoporosis Risk Assessment study, fracture risk reduction associated with estrogen use was lost almost immediately after estrogen discontinuation.[14]

Pharmacologic therapy is currently recommended in women with postmenopausal osteoporosis (i.e., prior fracture or BMD T-score < −2.5), women with osteopenia and clinical risk factors for fractures, and women in whom nonpharmacological approaches have failed to prevent bone loss or fracture.[15-17] The efficacy of several pharmacological options for osteoporosis has been established: the bisphosphonates alendronate, risedronate, and ibandronate and the selective estrogen receptor modulator (SERM) raloxifene are approved in the United States for the prevention and treatment of postmenopausal osteoporosis (raloxifene has also been approved for breast cancer risk reduction); systemic estrogen products have received government approval for osteoporosis prevention but not treatment; PTH (teriparatide) and calcitonin are approved for the treatment of women with postmenopausal osteoporosis, but not prevention; and strontium ranelate, although widely approved abroad, is not currently approved for prevention or treatment of osteoporosis in the United States.[16, 17] Although often effective, currently available therapies may not be appropriate for all women, primarily because of safety and tolerability concerns, stimulating the continued search for additional osteoporosis agents.

Bazedoxifene acetate is a novel, chemically distinct SERM that was developed using stringent preclinical screening parameters, including requirements for favorable effects on the skeleton and lipid metabolism and demonstrable breast and uterine safety.[18] In animal models, bazedoxifene treatment was shown to maintain or increase BMD, preserve normal histological bone quality, improve bone compressive strength, and reduce total cholesterol levels.[19, 20] Moreover, bazedoxifene did not stimulate proliferation and inhibited 17β-estradiol–induced proliferation in the MCF-7 breast tissue cell line. It exhibited little or no uterotropic activity in an immature rat model and sufficient anti-uterotropic activity to reduce 17β-estradiol− and raloxifene-stimulated increases in uterine wet weight and raloxifene-stimulated endometrial luminal epithelial and myometrial cell hypertrophy on histological examination.[19, 20] In phase II, randomized, double-blind, controlled studies in healthy postmenopausal women, bazedoxifene administered at daily doses up to 40 mg had a safety profile similar to placebo, did not stimulate the endometrium,[21] and produced statistically significant reductions in markers of bone remodeling without increasing the incidence of breast pain.[22, 23]

The objective of this study was to evaluate the safety and efficacy of 10, 20, and 40 mg/d bazedoxifene compared with placebo and 60 mg/d raloxifene in preventing bone loss in relatively young, healthy postmenopausal women.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. REFERENCES
  9. APPENDIX

Study design and population

This 2-yr, phase III, multicenter, double-blind, randomized, placebo- and raloxifene-controlled trial was conducted at 101 sites in Canada, Europe, and the United States. Enrolled subjects were generally healthy women ≥45 yr of age who were at least 1 yr postmenopausal (i.e., completed their last natural menstrual cycle or underwent bilateral oophorectomy, with or without hysterectomy, at least 1 yr before screening). Women were stratified into two strata based on time since menopause: (1) women who were 1–5 yr postmenopause and (2) those who were >5 yr postmenopause. Women who were postmenopausal between 1 and 5 yr had to have at least one of the following risk factors for osteoporosis to be enrolled: lumbar spine or femoral neck BMD T-scores between −1.0 and −2.5 as measured by DXA, a family history of fracture, bilateral oophorectomy, current history of smoking, small-boned and/or thin frame (weight < 58 kg), inadequate intake of calcium, and little or no weight-bearing exercise. Women in the latter stratum who previously received hormone replacement therapy but had discontinued treatment for ≥6 mo or women who were surgically postmenopausal for <5 yr were required to have accompanying serum follicle-stimulating hormone (FSH) levels ≥40 IU/liter and estradiol levels ≤73.4 pM (20 pg/ml). Women who were postmenopausal for >5 yr had to have the following inclusion criteria: lumbar spine or femoral neck BMD T-scores between −1.0 and −2.5 in addition to one of the following risk factors: a family history of fracture, bilateral oophorectomy, menopause occurring at ≥40 yr of age, current history of smoking, small-boned and/or thin frame (weight < 58 kg), inadequate intake of calcium, and little or no weight-bearing exercise.

Women were excluded at screening if they had other forms of bone disease, conditions that could invalidate BMD testing, at least one osteoporotic vertebral fracture shown on thoracolumbar radiographs, history of or active nontraumatic venous thromboembolic event, endometrial hyperplasia based on biopsy or endometrial thickness of >5 mm on transvaginal ultrasound, abnormal vaginal bleeding, history of malignancy within the previous 10 yr, abnormal laboratory tests including abnormal liver function tests or elevated fasting total cholesterol or triglyceride levels (≥310 or ≥300 mg/dl, respectively), and abnormal physical findings including body mass index (BMI) >32.2 kg/m2 or elevations in blood pressure. Subjects were also ineligible if they received treatment with any of the following medications: a bisphosphonate within 2 yr of screening; PTH, a SERM, or an estrogen-, androgen-, or progestin-containing medication within 6 mo of screening; calcitonin or systemic fluoride for >1 mo within 6 mo of screening; a systemic corticosteroid (equivalent to ≥10 mg of prednisone for >10 days) within 6 mo of screening; and any investigational drug within 60 days of randomization.

All subjects provided written informed consent before enrollment in the study. The study was conducted in accordance with the ethical principles from the Declaration of Helsinki and any amendments that were in place when the study was conducted. The study protocol and an informed consent form were submitted to the independent ethics committee or institutional review board at each institution for review and written approval.

Treatment, randomization, and blinding

Women were randomly assigned to receive one of five treatments: bazedoxifene 10, 20, or 40 mg/d, raloxifene 60 mg/d, or placebo. Study participants were instructed to take one capsule daily of the study drug, at approximately the same time each day, along with a daily supplement of 600 mg of elemental calcium in the form of calcium carbonate (Caltrate 600; Whitehall-Robins, Madison, NJ, USA).

Participants were allocated to their treatment groups using a computerized randomization/enrollment system, which assigned unique randomization and package numbers. Study drugs were packaged and code-labeled with package numbers, protocol numbers, and storage requirements. Blinding was maintained through the use of the treatment packages, which were code-labeled to the randomization schedule generated by the study sponsor. Participants maintained daily dairy cards to record the amount of study drug taken and timing of administration.

Efficacy and safety endpoints and measurements

The primary efficacy endpoint was the percentage change from baseline in BMD of the lumbar spine (L1−L4) after 24 mo of therapy. Secondary efficacy endpoints included percentage change from baseline in BMD of total hip, femoral neck, and femoral trochanter after 24 mo of therapy. Other secondary endpoints were changes in biochemical markers of bone resorption (serum type 1 collagen C-telopeptide [CTX]) and bone formation (serum osteocalcin) and lipid parameters. In all participants, BMD of the lumbar spine and other skeletal sites was measured using either a Hologic or GE Lunar DXA scanner. A quality control program was implemented that included interscanner cross-calibration, intrascanner longitudinal monitoring of calibration, and assessments of machine equivalence of scanners that may have been replaced during the course of the study. DXA was performed at screening and months 6, 12, 18, and 24. All DXA scans were assessed at a central analysis facility. Two DXA scans were performed at both the lumbar spine and hip at screening and month 24 or at the time of subject withdrawal from the study if >3 mo had elapsed since the last measurement. Samples for the assessment of serum osteocalcin and CTX were collected at baseline and months 3, 6, 9, 12, 18, and 24 and assessed by a central laboratory (Synarc, Lyon, France). Serum markers of lipid metabolism, including total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides, were measured at baseline and months 3, 6, 12, 18, and 24 and analyzed at a central laboratory (Covance).

Safety and tolerability were evaluated by the recording of all adverse events at each visit and by regular physical examinations and clinical laboratory determinations. Adverse events were classified using the U.S. Food and Drug Administration's Coding Symbols for Thesaurus of Adverse Reaction Terms (COSTART). The presence of vertebral fractures was assessed by thoracolumbar spine radiographs, which were obtained at screening and at 24 mo and in women withdrawing from the study if >12 mo had elapsed since their last assessment, and were read in a central facility. Routine safety laboratory values were obtained serially and assessed by a central laboratory (Covance). Other safety monitoring included gynecologic, pelvic, and breast examinations, mammograms, cervical cytology smears, and endometrial biopsies. Findings of the latter analyses will be reported elsewhere.

Statistical methods

The plan for data analysis, developed before study unblinding, prespecified all statistical analyses. Efficacy data analyses were performed on the intent-to-treat (ITT) population, which included all women who were randomly assigned to a treatment group; had at least one screening assessment; had recorded at least one dose of study medication; and had at least one on-therapy BMD assessment. Safety analyses included subjects who had received at least one dose of study drug.

The study had a power of 90% (α = 0.05; SD = 4.0%) to detect a dose response, with 45 subjects enrolled in each group, assuming a reduction of 1% from baseline in BMD in the placebo group and a minimum difference of three percentage points from placebo in any of the bazedoxifene groups. BMD efficacy endpoints were assessed using an analysis of covariance (ANCOVA) of the ITT population. The ANCOVA was performed using the percentage change from baseline as the dependent variable; the treatment, skeletal site, and years since menopause as main effects and baseline BMD as covariate. A last-observation-carried-forward (LOCF) approach was used to conduct the analysis, with on-therapy values carried forward. Corrected BMD values, based on evaluable vertebrae, machine equivalency tests, cross-calibration tests, and longitudinal adjustments, were used in place of raw BMD values. For the primary efficacy analysis, dose response was studied in the bazedoxifene and placebo groups using a closed-test procedure. Bazedoxifene treatments found to be significantly different from placebo using the closed-test procedure were compared with raloxifene.

Bone marker efficacy outcomes were analyzed using ANCOVA on ranked data, with the ranked percentage change from baseline as dependent variable, treatment as factor, and baseline as covariate. The percentage change for markers of lipid metabolism was analyzed using ANCOVA, with the percentage change from baseline as dependent variable, treatment as factor, and baseline as covariate. Analyses for LDL-C, HDL-C, LDL-C/HDL-C ratio, and triglycerides used ANCOVA on ranked data. If the overall tests for differences among treatment groups were significant at the 0.05 level for secondary BMD, bone marker, and lipid metabolism outcomes, pairwise comparisons between groups were performed using t-tests, based on the adjusted means and the pooled error terms obtained from the ANCOVA.

The number and percentage of women experiencing adverse events, including treatment-emergent adverse events, and withdrawing from the study because of adverse events were summarized and compared across treatment groups using the Fisher exact test and between groups using pairwise comparisons. For continuous safety data for physical examinations and laboratory parameters, changes from baseline were evaluated using ANCOVA, with the baseline value as a covariate and treatment as a factor; for categorical data, the Fisher exact test was used for comparison. For the latter comparisons, the nominal two-sided significance level was 5%.

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. REFERENCES
  9. APPENDIX

A total of 1583 women were randomly assigned to a treatment group, were given study drug, and were included in the safety analyses (Fig. 1). Of these randomized women, 1434 women were evaluable for BMD analyses of the lumbar spine and 1430 women were evaluable for BMD analyses of the total hip, femoral neck, and femoral trochanter. Four hundred seventy women (29.7%) discontinued treatment in the study. The most common reason for discontinuation in each group was adverse events, which occurred with similar frequency in the bazedoxifene, raloxifene, and placebo groups. The mean age of the population was 57.6 ± 6.5 yr; nearly all (94%) subjects were white. Demographic and baseline characteristics, including BMD values, were similar among all groups (Table 1).

Table Table 1.. Demographic and Baseline Characteristics for Evaluable Subjects in the ITTxs*
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Figure FIG. 1.. Subject disposition.

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BMD

After 24 mo of treatment, lumbar spine BMD was significantly (p < 0.001) greater in all bazedoxifene treatment groups than in the placebo group (Fig. 2A). All bazedoxifene doses resulted in a significant treatment effect compared with placebo within the first 6 mo of therapy, which was sustained through the end of the study. Mean differences (±SD) in the percent change from baseline to 24 mo in lumbar spine BMD for bazedoxifene 10, 20, and 40 mg relative to placebo were 1.08 ± 0.28, 1.41 ± 0.28, and 1.49 ± 0.28, respectively (p < 0.001). Women receiving bazedoxifene 40 mg experienced a significant increase from baseline in lumbar spine BMD at 6 and 12 mo (p < 0.05) and no significant change at 18 and 24 mo. Lumbar spine BMD was not significantly changed from baseline with bazedoxifene 10 and 20 mg during the study, whereas it was significantly decreased from baseline with placebo at all time points (p < 0.001). The differences in response between the bazedoxifene doses were not statistically significant. Changes in lumbar spine BMD in women receiving bazedoxifene were found to be similar to those in women receiving raloxifene at 6 mo and through the end of treatment.

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Figure FIG. 2.. (A) Median percent change from baseline in BMD of the lumbar spine (corrected L1–L4; p < 0.001) vs. placebo for all bazedoxifene (BZA) groups at each time point. (B) Median percent change from baseline in total hip BMD (p < 0.001) vs. placebo for all bazedoxifene (BZA) groups at each time point.

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All bazedoxifene treatment groups had significantly (p < 0.001) greater BMD of the total hip in comparison with the placebo group at 6, 12, 18, and 24 mo (Fig. 2B). Differences in the percent change from baseline to 24 mo observed in total hip BMD with bazedoxifene 10, 20, and 40 mg versus placebo were 1.29 ± 0.21, 1.75 ± 0.21, and 1.60 ± 0.21, respectively (p < 0.001). BMD of the total hip was significantly (p < 0.01) increased at 6 mo in all women receiving bazedoxifene compared with baseline and at 12 and 18 mo in those receiving bazedoxifene 20 and 40 mg (p < 0.05). All active treatment groups preserved BMD of the total hip at 24 mo. Women in the placebo group experienced significant decreases (p < 0.001) from baseline in BMD of the total hip throughout the study. No significant differences in total hip BMD were observed between the bazedoxifene treatment groups. Bazedoxifene treatment was equally as effective as raloxifene in increasing BMD of the total hip at all time points.

Compared with placebo, treatment with bazedoxifene 20 and 40 mg also resulted in significantly greater BMD of the femoral neck (p < 0.01) and femoral trochanter (p < 0.001). Significant increases from baseline in both femoral neck and trochanter BMD were observed in the bazedoxifene 20 and 40 mg treatment groups at most study time points; significant (p < 0.01) decreases from baseline in these measures were seen in the placebo group throughout the study. Femoral neck BMD was significantly (p < 0.05) greater with bazedoxifene 20 and 40 mg than with bazedoxifene 10 mg from month 12 to study end; there was a significant reduction from baseline in femoral neck BMD at 24 mo in the bazedoxifene 10 mg group. Femoral trochanter BMD was not significantly different between any bazedoxifene treatment groups. Treatment with bazedoxifene 20 and 40 mg was also equally as effective as raloxifene in improving femoral neck BMD through the study end. Women in all bazedoxifene groups had comparable changes in femoral trochanter BMD to those in women in the raloxifene group at all time points.

Serum bone markers

Women in the bazedoxifene and raloxifene groups showed significant (p < 0.001) reductions in serum osteocalcin and CTX compared with women in the placebo group throughout the study (Figs. 3A and 3B). At month 24, treatment with bazedoxifene 10, 20, and 40 mg significantly reduced median serum osteocalcin levels from baseline by 21%, 22%, and 22%, respectively (p < 0.001, all bazedoxifene doses versus baseline and placebo) compared with 6% and 27% reductions from baseline with placebo and raloxifene, respectively (p < 0.001, placebo and raloxifene versus baseline). Bazedoxifene 10, 20, and 40 mg decreased serum CTX levels by 25%, 24%, and 22%, respectively, at 24 mo (p < 0.001, all bazedoxifene doses versus baseline and placebo), whereas placebo and raloxifene decreased this bone marker by 13% and 32%, respectively (p < 0.001, placebo and raloxifene versus baseline).

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Figure FIG. 3.. (A) Median percent change from baseline in osteocalcin levels (p < 0.001), all bazedoxifene and raloxifene treatment groups vs. baseline at all time points; placebo vs. baseline at 24 mo; and all bazedoxifene treatment groups vs. placebo at all time points. (B) Median percent change from baseline in CTX levels (p < 0.001), all bazedoxifene and raloxifene treatment groups vs. baseline at all time points; placebo vs. baseline at 24 mo; and all bazedoxifene treatment groups vs. placebo at all time points. Nonparametric ANCOVA.

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Lipid metabolism

Serum concentrations of total cholesterol decreased significantly in the bazedoxifene 10 and 40 mg groups, and LDL-C decreased significantly in each of the bazedoxifene groups compared with the placebo group at 24 mo (Table 2). Serum concentrations of HDL-C increased significantly with bazedoxifene 10 and 20 mg relative to placebo at 24 mo. Significant increases from baseline in median concentrations of triglycerides were observed among women receiving bazedoxifene 20 mg, bazedoxifene 40 mg, and placebo, with no significant difference found among the groups (Table 2). In this study, the number of subjects who developed the adverse event of hypertriglyceridemia was low (0.3–1.6%) and was similarly distributed among all groups. No cases of pancreatitis were reported as a result of hypertriglyceridemia. Treatment with raloxifene 60 mg resulted in a significant reduction in the total cholesterol and LDL-C relative to placebo at 24 mo (Table 2).

Table Table 2.. Changes From Baseline in Serum Lipid Concentrations at 24 mo
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Adverse events

After 2 yr of treatment, all doses of bazedoxifene were generally well tolerated and exhibited a safety profile generally similar to that of placebo. An overall summary of the safety profile is provided in Table 3. The incidence of adverse events, treatment-emergent adverse events, serious adverse events, and discontinuations because of adverse events were similar among all treatment groups. The most common treatment-emergent adverse events were headache, infection, arthralgia, pain, hot flushes, and back pain, which were reported by ≥20% of the women in at least one treatment group. The percentage of women who reported either worsening of preexisting hot flushes or who developed any new hot flush during the course of the study was significantly higher in the bazedoxifene groups than in the placebo group, and similar to that observed in the raloxifene group (Table 3). The number of subjects withdrawing because of the adverse event of hot flushes was low and similar among all groups. The incidence of leg cramps was similar across treatment groups. Four deaths were reported during the study and two deaths were reported after withdrawal or completion of the study. Five of these deaths (accidental injury, arrhythmia, cerebral hemorrhage, hypertension, and lymphoma) were not considered related to the administration of test article. One death in the bazedoxifene 40 mg group, a subject who experienced a pulmonary embolism during a prolonged air flight 30 days after study completion, was considered by the investigator to be possibly related to treatment.

Table Table 3.. Overall Summary of Safety Profile
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Cardiovascular and thromboembolic events, hot flushes, and leg cramps were considered adverse events of special interest. No safety concerns related to the cardiovascular system were observed in the bazedoxifene treatment groups. The number of venous thromboembolic events was low and similarly distributed between treatment groups. During the 24-mo study period, eight women showed fractures (bazedoxifene 10 mg, n = 1; bazedoxifene 20 mg, n = 3; raloxifene 60 mg, n = 1; placebo, n = 3).

No cases of confirmed endometrial hyperplasia or endometrial cancer were detected in any of the bazedoxifene groups; one subject in the placebo group developed endometrial cancer. Endometrial thickness assessed by transvaginal ultrasound remained stable in women treated with bazedoxifene over the course of the study, and mean change from baseline did not differ in the bazedoxifene-treated groups compared with the placebo group. No significant differences were observed between treatment groups in the incidence of endometrial polyp formation at 24 mo. The number of cases of breast cancer was low and evenly distributed among the groups (bazedoxifene 10 mg, n = 1; bazedoxifene 20 mg, n = 2; bazedoxifene 40 mg, n = 0; raloxifene 60 mg, n = 1; placebo, n = 2). The incidence of breast pain was also low and not significantly different between treatment groups.

DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. REFERENCES
  9. APPENDIX

This study was initiated to evaluate the efficacy and safety of various bazedoxifene dose regimens in comparison with that of placebo and raloxifene in preventing bone loss in healthy postmenopausal women with normal/low BMD. The 2-yr results showed a significant protective effect on the skeleton, as shown by increasing BMD at multiple skeletal sites and reduced rate of bone turnover. Bazedoxifene 20 and 40 mg were associated with a significant increase in BMD relative to placebo observed after 6 mo of treatment and preserved through 24 mo. The BMD and bone turnover marker effects of bazedoxifene were comparable to those of raloxifene. The percentage changes in BMD from baseline in the bazedoxifene 20 and 40 mg treatment groups were significant compared with the placebo group at all time points assessed. Although a clear dose response was not observed with bazedoxifene 20 and 40 mg, these doses were consistently more effective in protecting against bone loss than the 10 mg dose, particularly at the site rich in cortical bone, the femoral neck. Bazedoxifene 20 and 40 mg treatment provided comparable skeletal protection to that observed with raloxifene 60 mg.

The observation of a comparable BMD effect in women treated with bazedoxifene as in those treated with raloxifene is not surprising. In previously conducted, prospective, randomized, controlled trials comparing raloxifene 60 mg with placebo in healthy postmenopausal women with normal BMD or osteopenia, raloxifene therapy increased BMD from baseline from 1% to 2%.[24, 25] Although the effects of bazedoxifene and raloxifene on BMD seem to be similar, BMD is a surrogate endpoint for fracture and is a relatively poor predictor of the antifracture efficacy of antiresorptive agents.[26] A recent 3-yr study in postmenopausal women with osteoporosis showed a 42% reduction in the incidence of new vertebral fractures with bazedoxifene 20 mg treatment, which was similar to that with raloxifene.[27] Of interest, a posthoc analysis in the same study in a subgroup of women with high fracture risk found a lower incidence of nonvertebral fractures with bazedoxifene 20 mg compared with placebo or raloxifene. The latter observation suggests potential differences between the SERMs, which require further evaluation.[27]

The primary effect of bazedoxifene treatment on BMD observed in this study was preservation of bone mass, which is consistent with a response in a population of young postmenopausal women with normal BMD or mild spinal osteopenia. On the other hand, calcium supplementation in the placebo group did not prevent bone loss, indicating that calcium supplementation alone is ineffective in preserving bone mass early after menopause.

Increases in BMD observed with SERMs have been more modest than those observed with bisphosphonates when evaluated in the osteoporosis prevention setting.[28] However, reductions in vertebral fracture rates seem to be similar with SERM and bisphosphonate treatment in non–head-to-head comparison trials,[29-31] suggesting that the magnitude of BMD increase may be an inadequate predictor of fracture reduction and that other factors not captured by BMD may also play an important role in improving bone strength beyond changes in BMD.[32] A number of studies, depending on their statistical methodology, have suggested that changes in BMD explain a relatively small fraction of the antifracture efficacy with antiresorptive treatments.[33, 34] Increased BMD with raloxifene treatment accounted for only 4% of the treatment's effect on the incidence of vertebral fractures.[35] The range of BMD changes to risk reduction in the individual bisphosphonate analyses is from 16% to 28%,[36, 37] although a greater proportion of the contribution of increasing BMD to risk reduction has been suggested in two separate meta-analyses examining these interactions.[36, 38] Although increasing BMD with antiresorptive agents does contribute some component to fracture risk reduction, it is clear that there are also many non-BMD factors that independently contribute to risk reduction.[39] Preservation or improvement in the material properties of bone and/or bone microarchitecture could translate into increased bone strength and resistance to fracture, which cannot be fully captured by changes in BMD.[40] Reduction in bone turnover, which has been shown to be significantly associated with fracture risk reduction during antiresorptive therapy, could also play a significant role independent of BMD.[33, 41, 42]

Favorable changes were observed with bazedoxifene treatment in serum concentrations of total cholesterol, LDL-C, and HDL-C relative to placebo. Triglyceride levels were significantly increased in the BZA 20 and 40 mg groups and the placebo group; no significant differences were found between these groups. Baseline mean triglyceride levels were normal in this population of relatively healthy young postmenopausal women, and although increased, these levels remained well within the normal range during treatment with bazedoxifene. Whether the observed changes in lipid profile with bazedoxifene treatment have any clinical relevance remains to be determined.

Bazedoxifene also showed an acceptable safety and tolerability profile in this population of healthy postmenopausal women who were at risk for osteoporosis-related fracture, which was consistent overall with that shown for raloxifene.[43, 44] Incidences of adverse events, serious adverse events, and withdrawals because of adverse events were similar among all treatment groups. No statistically significant differences were observed among the treatment groups for cardiovascular events. Myocardial infarction and hemorrhagic or ischemic strokes were reported in <1% of the women evaluated. The incidence of hot flushes was greater in the active treatment groups than in the placebo group, whereas the incidence of leg cramps was similar across all groups. These events were mild to moderate in severity and did not lead to withdrawal from the study in a large number of subjects. Hot flushes occurred with similar frequency in the bazedoxifene and raloxifene groups. An increased incidence of hot flushes and leg cramps has also been reported in clinical trials of raloxifene.[29, 45] Bazedoxifene was also not associated with stimulation of endometrial tissue or adverse breast effects. No clinically relevant changes in laboratory parameters were observed in the active treatment or placebo groups. Incident fractures occurred with similar frequency across treatment groups during the study.

In this population of relatively young postmenopausal women with normal or low BMD, treatment with bazedoxifene prevented bone loss, increased BMD, reduced bone turnover, and was generally well tolerated. These findings suggest that bazedoxifene is a promising SERM that may become an important therapeutic option for the prevention of postmenopausal osteoporosis.

Acknowledgements

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. REFERENCES
  9. APPENDIX

The authors thank Monika Ciesielska, Wyeth Research, for statistical analysis and Donna McGuire for assistance in manuscript preparation. This study was supported by Wyeth Research, Collegeville, PA, USA.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. REFERENCES
  9. APPENDIX
  • 1
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APPENDIX

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. REFERENCES
  9. APPENDIX

In addition to Drs Miller, Christiansen, Hoeck, Kendler, Lewiecki, Woodson, and Delmas, the following were also principal investigators—Belgium: Piet Geusens, Biomedical Research Institute, Diepenbeck. Canada: François Bissonnette, CHUM-Hopital St-Luc Centre de Recherche, Montreal, Quebec; Denis Callaghan, Hamilton, Ontario; Michel Fortier, Centre Medical Berger, Quebec; Jean-Pascal Ouellet, Q&T Recherche, Quebec; Chui Kin Yuen, Manitoba Clinic, Manitoba. Czech Republic: Karel Buchta, Ginekologicka Ordinace, Ostrava; Olga Hlavackova, Gynekologicka Ordinace, Pisek; Ales Skrivanek, Gynekologicka Ordinace, Olomouc; Lubos Tempir, Gynekologicka Ordinace, Prerov. Denmark: Peter Alexandersen, Center for Clinical and Basic Research, Sal Vejle; Yu Bagger, Center for Clinical and Basic Research, Ballerup. France: Claude-Laurent Benhamou, Hopital Porte-Madelaine, Orleans; Marie-Christine De Vernejoul, Hopital Lariboisère, Paris; Partice Fardellone, CHU Hopital Nord, Amiens Cedex; Georges Werhya, CHU Nancy Brabois, Vandoeuvre les Nancy. Germany: Martina Doeren, Klinikum Benjamin Franklin, Berlin; Hans-Peter Kruse, Universitatsklinikum Hamburg-Eppendorf, Hamburg; Ludwig Schonberg, Gynakologische Praxis, Rheine. Great Britain: Farook Al-Azzawi, Leicester Royal Infirmary, Leicester; Morag Horne, Synexus Limited, Reading; DW Purdie, Center for Metabolic Bone Disease, Kingston Upon Hull; Mansur Salman, Synexus Limited, Birmingham. Italy: Silvano Adami, Dipartimento di Reumatologia Ospedale, Verona; Maurizio Bevilacqua, Ospedal Luigi Sacco, Milano; Domenico De Aloysio, Universita degli Studi di Bologna, Bologna; Fiorenzo De Cicco Nardone, Universita Catolica del Sacro Curo, Rome; Andrea R Genazzani, Universita degli Studi di Pisa, Pisa; Ranoccio Nuti, Instituto di Clinica Medica, Siena. Netherlands: Jan JC Jonker, Andro Medical Research, Rotterdam; Dyonne vanDuren, Menox BV, Nijmegen; Adrian Wadham, Pharma Bio-Research, Zuidlaren. Norway: Johan Halse, Betania Spesialistsenter, Oslo; Erik Ofjord, Center for Clinical Trials, Bergen; Arne Skag, Center for Clinical Trials, Hamar. Romania: Constantin Dumitrache, Institute of Endocrinology, Bucharest; Emilian Ranetti, Spitalul Clinic de Urgenta Militar, Bucarest. Switzerland: Kurt Lippuner, Einheit fur Osteoporose Departement DURN Inselspital, Bern; Rene Rizzoli, Hopitaux Universitaires de Genève, Geneve. United States: Jeffrey Baker, Rosemark Women's Care Specialists, Idaho Falls, ID; Davis Baldwin, LifeSpan Research, Palo Alto, CA; Jenecsis Castro-Skoglund, Research Associates of Central Illinois, Peoria, IL; Charles H Chesnut, III, University of Washington, Seattle, WA; Robert Downs, Jr, MCV Women's Health Clinic, Richmond, VA; Travis Ellison, Radiant Research, Greer, SC; Ronald Emkey, Radiant Research, Wyomissing, PA; H Frank Farmer, Radiant Research, Daytona Beach, FL; Darrell Fiske, Radiant Research, Stuart, FL; Roy Fleischmann, Radiant Research, Dallas, TX; Roan L Flenniken, Highland Clinic, APMC, Shreveport, LA; Janet Funk, Radiant Research, Tucson, AZ; Sidney Funk, Radiant Research, Atlanta, GA; Harry Geisberg, Radiant Research, Anderson, SC; Richard Hedrick, Winston-Salem, NC; Joseph G Herrmann, Radiant Research, St Louis, MO; Joseph Hume, University of Kansas Medical Center, Kansas City, KS; William Jennings, Protocare Trials San Antonio Center for Clinical Research, San Antonio, TX; Michael Keller, OsNet San Diego Arthritis and Osteoporosis Medical Clinic, San Diego, CA; Howard Knapp, Deaconess Billings Clinic Research, Billings, MT; Norman Koval, Center for Rheumatology and Bone Research, Wheaton, MD; Robert Lang, Northeast Clinical Research, Hamden, CT; Wayne Larson, Radiant Research, Lakewood, WA; Samuel Lederman, Radiant Research, Lake Worth, FL; Barry Lubin, Hampton Roads Center for Clinical Research, Norfolk, VA; Norman Lunde, Twin Cities Clinical Research, Arden Hills, MN; Dennis McCluskey, Radiant Research, Mogadore, OH; Frederick Murphy, Altoona Center for Clinical Research, North Duncansville, PA; Michael Noss, Radiant Research, Cincinnati, OH; Ruth Nurnberg, National Clinical Research, Richmond, VA; JoAnn Pinkerton, The Women's Health Place, Charlottesville, VA; Bryan Pogue, Radiant Research, Boise, ID; Michele Reynolds, Radiant Research, Dallas, TX; Jeffrey Rosen, Clinical Research of South Florida, Coral Gables, FL; Suzanne Satterfield, University of Tennessee, Germantown, TN; Philippe Saxe, Arthritis Associates of South Florida, Delray Beach, FL; Thomas Schnitzer, Northwestern Center for Clinical Research, Chicago, IL; Donald Schumacher, Center for Nutrition and Preventive Medicine, Charlotte, NC; Douglass Schumacher, Radiant Research, Columbus, OH; Anthony Scialli, Georgetown University, Washington DC; Lawrence Sherman, Radiant Research, San Diego, CA; Stuart Silverman, Osteoporosis Medical Center, Beverly Hills, CA; James Simon, Women's Health Research Center, Laurel, MD; Michael Spiegel, Clinical Research of CT/NY, Danbury, CT; Craig Sweet, Specialist in Medical Research, Fort Myers, FL; Jerome Targovnik, Radiant Research, Scottsdale, AZ; John Tesser, Protocare Trials, Phoenix, AZ; Richard Wasnich, Radiant Research, Honolulu, HI; Richard Weinstein, Diablo Clinical Research, Walnut Creek, CA; Lisa Wright, Radiant Research, Birmingham, AL; Douglas Young, Northern California Research Corp., Fair Oaks, CA.