Uterine bleeding is a common reason why women discontinue menopausal hormone therapy (HT). This systematic review compared bleeding profiles reported in studies for continuous-combined HT approved in North America and Europe for moderate to severe vasomotor symptoms in postmenopausal women with a uterus. Non-head-to-head studies showed that uterine bleeding varies by formulation and administration route, with oral having a better bleeding profile than transdermal formulations. Cumulative amenorrhea over a year ranged from 18 to 61% with oral HT and from 9 to 27% with transdermal HT, as reported for continuous-combined HT containing 17 beta-estradiol (E2)/progesterone (P4) (56%), E2/norethisterone acetate (NETA) (49%), E2/drospirenone (45%), conjugated equine estrogens/medroxyprogesterone acetate (18-54%), ethinyl estradiol/NETA (31-61%), E2/levonorgestrel patch (16%), and E2/NETA patch (9-27%). Amenorrhea rates and the mean number of bleeding/spotting days improved over time. The oral E2/P4 combination was amongst those with lower bleeding rates and may be an appropriate alternative for millions of women seeking bioidentical HT and/or those who have bleeding concerns with other HT.

Risa Kagan,1,2 Steven R Goldstein,3 James H Pickar,4 Barry S Komm5 1Department of Obstetrics, Gynecology and Reproductive Sciences, University of California, San Francisco, 2East Bay Physicians Medical Group, Berkeley, CA, 3Department of Obstetrics and Gynecology, New York University School of Medicine, 4Department of Obstetrics and Gynecology, Columbia University Medical Center, New York, NY, 5Global Medical Affairs, Pfizer Inc., Collegeville, PA, USA Abstract: Menopausal symptoms (eg, hot flushes and vaginal symptoms) are common, often bothersome, and can adversely impact women’s sexual functioning, relationships, and quality of life. Estrogen–progestin therapy was previously considered the standard care for hormone therapy (HT) for managing these symptoms in nonhysterectomized women, but has a number of safety and tolerability concerns (eg, breast cancer, stroke, pulmonary embolism, breast pain/tenderness, and vaginal bleeding) and its use has declined dramatically in the past decade since the release of the Women’s Health Initiative trial results. Conjugated estrogens paired with bazedoxifene (CE/BZA) represent a newer progestin-free alternative to traditional HT for nonhysterectomized women. CE/BZA has demonstrated efficacy in reducing the frequency and severity of vasomotor symptoms and preventing loss of bone mineral density in postmenopausal women. CE/BZA provides an acceptable level of protection against endometrial hyperplasia and does not increase mammographic breast density. Compared with traditional estrogen–progestin therapy, it is associated with lower rates of breast pain/tenderness and vaginal bleeding. Patient-reported outcomes indicate that CE/BZA improves menopause-specific quality of life, sleep, some measures of sexual function (especially ease of lubrication), and treatment satisfaction. This review looks at the rationale for selection and combination of CE with BZA at the dose ratio in the approved product and provides a detailed look at the efficacy, safety, tolerability, and patient-reported outcomes from the five Phase III trials. Patient considerations in the choice between CE/BZA and traditional HT (eg, tolerability, individual symptoms, and preferences for route of administration) are also considered. Keywords: menopause, conjugated estrogens/bazedoxifene, hormone therapy, hot flashes, osteoporosis, safety

Abstract Objective To evaluate the bioavailability and safety of a novel vaginal capsule containing solubilized bioidentical 17β-estradiol for vulvar and vaginal atrophy and compare its pharmacokinetics with that of an approved vaginal estradiol tablet in healthy postmenopausal women. Methods Two randomized, single-dose, two-way cross-over, relative bioavailability trials compared the pharmacokinetics of a solubilized vaginal estradiol softgel capsule (TX-004HR, test) with that of a vaginal estradiol tablet (Vagifem®, reference) in postmenopausal women (aged 40–65 years) at 10-μg and 25-μg doses. In each study, women were randomly assigned to receive a single dose of the test capsule or reference tablet, followed by a single dose of the alternate drug after a 14-day washout. Results Thirty-five women completed the 10-μg study and 36 completed the 25-μg study. Significantly lower systemic levels of estradiol, estrone, and estrone sulfate at both doses of the test product were observed compared with equivalent doses of the reference product, with lower AUC0-24 and Cmax and earlier tmax. No adverse events were reported in either trial. Conclusion TX-004HR, a novel estradiol vaginal softgel capsule, exhibited significantly lower systemic exposure than equivalent doses of an approved vaginal estradiol tablet at both 10-μg and 25-μg doses. Both doses of each product were safe and well-tolerated.

Conflict of interest in scientific publications has become a topic of critical importance. A primary focus has been the relationship between authors, journals and the pharmaceutical industry. That focus must be expanded to include government funding organizations. There are significant benefits to authors and investigators in participating in government-funded research, and to journals in publishing it. There are substantial risks to patients in not considering the potential for conflict of interest.

ABSTRACT Postmenopausal women with vasomotor and vaginal symptoms are commonly treated with estrogens or combined estrogen/progestin therapy (hormone therapy). However, hormone therapy is associated with some safety and tolerability concerns and its benefit/risk profile may vary for women based on their time since menopause. The tissue selective estrogen complex (TSEC) pairs a selective estrogen receptor modulator with one or more estrogens, with the goal of relieving menopausal symptoms and preserving bone mineral density without stimulating the breast or endometrium. Bazedoxifene/conjugated estrogens (BZA/CE) is the first TSEC in clinical development. BZA 20 mg/CE 0.45 and 0.625 mg have been shown in phase-3 clinical trials to significantly improve hot flushes and vulvar/vaginal atrophy measures in symptomatic postmenopausal women and to prevent bone loss in postmenopausal women at risk for osteoporosis while ensuring endometrial safety. These doses of BZA/CE have also demonstrated significant improvements in quality-of-life scores, sleep parameters, and treatment satisfaction compared with placebo. BZA 20 mg/CE 0.45 and 0.625 mg showed high cumulative rates of amenorrhea and low rates of breast pain, similar to those with placebo. The favorable treatment effects seen with BZA/CE were generally consistent in women < 5 or ≥ 5 years since menopause. Based on its demonstrated efficacy and safety in women both closer to or further from menopause, BZA/CE may be an appropriate alternative to hormone therapy for the treatment of menopausal symptoms and the prevention of osteoporosis.

Objective To assess effects of desvenlafaxine (administered as desvenlafaxine succinate) on secondary outcomes of mood, climacteric symptoms, and treatment satisfaction in postmenopausal women with moderate to severe menopausal vasomotor symptoms (VMS).Methods A 12-week, multicenter, double-blind, placebo-controlled trial was conducted in postmenopausal women with >= 50 moderate to severe hot flushes per week. Participants were randomly assigned to desvenlafaxine 100 mg/day, desvenlafaxine 150 mg/day, or placebo. Secondary outcome efficacy variables included Profile of Mood States (POMS), Greene Climacteric Scale (GCS), and Menopausal Symptoms Treatment Satisfaction Questionnaire (MS-TSQ) scores. Change from baseline in POMS total mood disturbance (TMD) score and subdomain scores were evaluated using analysis of covariance, adjusting for treatment and study site as factors and baseline score. GCS total and subdomain scores were analyzed similarly. Treatment satisfaction was analyzed using the row mean score test.Results A total of 458 women were enrolled. At week 12, desvenlafaxine 100 mg/day significantly improved POMS TMD scores (p < 0.001) and four of six POMS subdomains compared with placebo (all p <= 0.005). Women taking desvenlafaxine 100 mg/day experienced significantly greater improvement in GCS total scores (p < 0.001) and five of six subdomains (all p <= 0.029) compared with placebo. Treatment with desvenlafaxine 100 mg/day resulted in significantly greater treatment satisfaction overall and in six of seven additional MS-TSQ items (all p <= 0.042). Desvenlafaxine 150-mg/day results were similar.Conclusions Desvenlafaxine treatment improved mood and climacteric symptoms in postmenopausal women with moderate to severe VMS compared with placebo, and more women were satisfied with desvenlafaxine treatment than with placebo.

A new analysis from the Women's Health Initiative included data on breast cancer incidence over a 11-year period from the randomized trial of conjugated equine estrogens (CEE) plus medroxyprogesterone acetate (MPA) and a subsequent observational follow-up. The conclusions were that CEE/MPA use was associated with an increase in both breast cancer incidence and mortality. We have concerns over the validity of their statistical analyses, as adjustments for baseline characteristics or for multiple comparisons demonstrate no significant differences in incidence between those allocated to CEE/MPA or placebo. We suspect that the apparent increase in mortality is the result of surveillance and detection bias rather than a true cause and effect. Even if such an effect were true, mortality from breast cancer would still be a very rare event. We also question the clinical relevance and applicability of their findings. The data over the 11 years show no increased risk of breast cancer with CEE/MPA in women who had not previously used hormone replacement therapy (HRT), and the vast majority of women on HRT would not be prior users at initiation. It should be remembered that women using CEE alone showed a signifi cant decrease in breast cancer risk in the WHI trial and follow-up. Even if combined estrogen -progestogen HRT did cause an increase in breast cancer risk, and this is not proven, the magnitude of that risk is small, and less than that risk seen with many lifestyle factors. HRT is a benefit, not a risk, for those women requiring it.

Barrington claims that the women’s health initiative (WHI) trial had impeccable standards.1 We recently highlighted some of its shortcomings relating to hormone replacement therapy (HRT).2 The data and safety monitoring board used a global index of health which was modified on three occasions, including once after formal monitoring had started. Although the oestrogen-progestogen arm of the studies was stopped after a designated safety boundary was breached, the oestrogen alone arm was stopped by staff of the National Heart, Lung and Blood Institute …

This article reviews publications dating back more than a century describing investigations of the endometrium, including those examining the relationship between endometrial hyperplasia and carcinoma, the influence of estrogens on the endometrium, and strategies for protecting the endometrium from unopposed estrogen stimulation. Endometrial hyperplasia and carcinoma studies date from before 1900. The influence of endogenous estrogens on the endometrium became evident with observations of endometrial hyperplasia and/or carcinoma in women with estrogen-secreting tumors or polycystic ovarian disease. Later, observational studies and randomized, controlled trials suggested a relationship between unopposed estrogens and endometrial cancer and hyperplasia. The first, and to date only, effective clinical strategy for protecting the endometrium from unopposed estrogen stimulation has been the use of progestins. A new approach for endometrial protection in menopausal therapy is the pairing of a selective estrogen receptor modulator (SERM) with estrogen(s), also known as a tissue selective estrogen complex (TSEC). Effective protection of the endometrium as well as treatment of menopausal symptoms and prevention of osteoporosis would be key elements for a clinically useful TSEC.

This article reviews publications dating back more than a century describing investigations of the endometrium, including those examining the relationship between endometrial hyperplasia and carcinoma, the influence of estrogens on the endometrium, and strategies for protecting the endometrium from unopposed estrogen stimulation. Endometrial hyperplasia and carcinoma studies date from before 1900. The influence of endogenous estrogens on the endometrium became evident with observations of endometrial hyperplasia and/or carcinoma in women with estrogen-secreting tumors or polycystic ovarian disease. Later, observational studies and randomized, controlled trials suggested a relationship between unopposed estrogens and endometrial cancer and hyperplasia. The first, and to date only, effective clinical strategy for protecting the endometrium from unopposed estrogen stimulation has been the use of progestins. A new approach for endometrial protection in menopausal therapy is the pairing of a selective estrogen receptor modulator (SERM) with estrogen(s), also known as a tissue selective estrogen complex (TSEC). Effective protection of the endometrium as well as treatment of menopausal symptoms and prevention of osteoporosis would be key elements for a clinically useful TSEC.

The first member of the TSEC class of menopausal therapy (pairing of a selective estrogen receptor modulator with estrogens) in clinical development pairs CE with BZA, a new selective estrogen receptor modulator with a unique endometrial profile. The effect of this combination on BMD was evaluated in 2 of the Selective estrogens Menopause And Response to Therapy (SMART) trials. Osteoporosis substudies of 2 randomized double-blind, placebo-controlled, multicenter, phase III trials—SMART-1 and SMART-4. SMART-1 trial randomized postmenopausal women (40–75 years) to 2 years of daily therapy with 6 doses of a TSEC comprised of BZA 10, 20, or 40 mg paired with CE 0.45 or 0.625 mg; raloxifene 60 mg (RLX); or placebo. Endpoints included the rate of endometrial hyperplasia and lumbar spine and hip BMD assessed by dual energy x-ray absorptiometry. SMART-4 trial, the first to compare BZA/CE with hormone therapy, randomized postmenopausal women (aged 40–64 years) to 2 years of daily therapy with 2 doses of a TSEC (BZA 20 mg/CE 0.45 or BZA 20 mg/CE 0.625 mg); hormone therapy (CE 0.45/medroxyprogesterone acetate 1.5 mg); or placebo. The primary endpoints were the rate of endometrial hyperplasia and prevention of osteoporosis at 1 year. SMART-1 osteoporosis substudy enrolled 2315 women (861 women ≤5 years postmenopause and 1454 women >5 years postmenopause). Among women ≤5 years postmenopause, the mean increase from baseline in lumber spine BMD at 2 years was significantly greater with all TSECs (range, 1.15%-2.61%) compared to RLX (0.15%; P<0.05) or placebo (−1.92%; P<0.001). Among women >5 years postmenopause, the increase from baseline in lumbar spine BMD at 2 years was significantly greater with TSECs containing BZA 10 and 20mg (range, 1.57%–2.42%) than with RLX (0.73%; P<0.05); all TSECs were significantly greater than placebo (−1.51%; P<0.001). Similar results were observed for hip BMD. Results will be also presented for the SMART-4 trial osteoporosis substudy, which enrolled >500 postmenopausal women (<5 years postmenopausal). BZA/CE, the first TSEC, significantly improves lumbar spine and hip BMD in postmenopausal women. Together with its favorable endometrial safety profile and efficacy for vasomotor symptoms (reported elsewhere), the clinical profile of BZA/CE may change the way women and physicians approach menopausal symptoms.

A TSEC partners a selective estrogen receptor modulator with estrogens to achieve clinical results based on their blended tissue-selective activity profile. The first TSEC pairs BZA with CE; we report results from the Selective estrogens Menopause And Response to Therapy (SMART) trials that evaluated its effect on the endometrium. Randomized, double-blind, placebo (PBO)-controlled, multicenter, phase III trials—SMART-1 and SMART-4. SMART-1: randomized 3397 postmenopausal women to 2 years of daily therapy with 6 doses of a TSEC containing BZA 10, 20 or 40 mg with CE 0.45 or 0.625 mg; raloxifene (RLX) 60 mg; or PBO. Primary endpoint was rate of endometrial hyperplasia at 1 year; incidence of endometrial hyperplasia at 2 years was secondary. Bleeding was recorded in a daily diary and cumulative amenorrhea rate was calculated and compared between groups. SMART-4: the first 24-month study to compare a TSEC with hormone therapy. Postmenopausal women (N = 1083) were randomized to 2 years of daily therapy with 2 doses of a TSEC containing BZA 20 mg/CE 0.45 or 0.625 mg; CE 0.45/medroxyprogesterone acetate 1.5 mg; or PBO. Primary endpoint was also the rate of endometrial hyperplasia at 1 year. Transvaginal ultrasounds and endometrial biopsies were obtained during both trials. SMART-1: the TSEC doses containing BZA 20 or 40 mg paired with CE 0.45 or 0.625 mg were associated with hyperplasia rates (<1.0%) that did not differ from PBO (Table 1) or RLX at 1 and 2 years; amenorrhea rates were not significantly different from PBO. Results from the SMART-4 trial will also be presented. TableEndometrial hyperplasia at 1 YearTreatment groupIncidence (%)1-sided 95% CICE 0.45 mg with: BZA 40 mg0.00(0.00–1.19)∗ BZA 20 mg0.00(0.00–1.09)∗ BZA 10 mg0.94(0.26–2.41)CE 0.625 mg with BZA 40 mg0.00(0.00–0.96) BZA 20 mg0.32(0.02–1.50) BZA 10 mg3.81(2.27–5.99) RLX 60 mg0.00(0.00–1.00) PBO0.00(0.00–0.96)∗1-sided 97.5% CI per stepwise procedure, to adjust for simultaneous comparisons (CE 0.45 mg combined with BZA 40 mg and BZA 20 mg). Open table in a new tab ∗1-sided 97.5% CI per stepwise procedure, to adjust for simultaneous comparisons (CE 0.45 mg combined with BZA 40 mg and BZA 20 mg). Rates of endometrial hyperplasia and amenorrhea were similar to PBO when pairing ≥20 mg BZA with CE. BZA/CE represents a new paradigm for menopausal therapies with endometrial protection without needing a progestagen.

Objectives: A progestin used for hormone therapy should provide endometrial protection and an acceptable bleeding profile. This study investigated the effects of TMG, a novel, selective, norpregnane progestin, combined with CE on endometrial hyperplasia and bleeding. Design: A randomized, double-blind, placebo-controlled, multicenter trial in 1,655 healthy, nonhysterectomized postmenopausal women (40–65 years old), who received 1 of 5 oral regimens of continuous combined or sequential CE/TMG or placebo for 1 year (13 28-day cycles) was conducted with a 1-year (13 28-day cycles) osteoporosis substudy extension. Materials and Methods: The two continuous combined regimens were CE 0.625 plus TMG 0.0625 or 0.125 mg. The two sequential regimens were CE 0.625 on days 1–28 plus TMG 0.125 or 0.250 mg on days 17–28. Placebo was taken daily on days 1–28. Endometrial biopsies were collected at baseline and at cycles 6, 13, and 26. Two pathologists read the biopsies and, if they disagreed on whether hyperplasia was present, a third pathologist was consulted. For the consensus analysis, endometrial hyperplasia was recorded when 2 pathologists made this diagnosis. Individual pairwise comparisons of each CE/TMG group to CE 0.625 alone (data from previous trials) were made using Fisher’s exact test. Daily diary cards were used to collect information on vaginal bleeding. Irregular bleeding patterns were analyzed separately for the continuous combined and sequential regimens. Results: The consensus rate of endometrial hyperplasia at the end of 13 cycles of treatment was <0.5% for all CE/TMG groups, which was significantly (P<0.001) lower than the 8–20% incidence for the CE 0.625 mg-alone groups from previous studies. Amenorrhea patterns by cycle were similar for both continuous combined CE/TMG treatment groups. At cycle 13, the cumulative amenorrhea rates for CE 0.625/TMG 0.0625 and CE 0.625/TMG 0.125 groups were 85% and 86%, respectively. Withdrawal bleeding following cyclic progestin discontinuation was similar for the two sequential groups, with 78% and 75% of women at cycle 8, and 71% and 70% of women at cycle 13, experiencing withdrawal bleeding with CE 0.625 /TMG 0.125 and CE 0.625 /TMG 0.250, respectively. For both sequential CE/TMG treatment groups, irregular bleeding occurred in 5–10% of cycles, with a mean of 2–4 days of bleeding per cycle. There was no significant difference in the irregular bleeding patterns between these two groups. All CE/TMG treatments had adverse event profiles similar to those of other postmenopausal hormone therapy products. Conclusions: All CE/TMG treatments provide protection against endometrial stimulation by unopposed CE 0.625 mg while exhibiting an acceptable bleeding profile. CE/TMG offers additional options for postmenopausal women in need of hormone therapy. Supported by: Wyeth Research.

OBJECTIVE:To determine the endometrial safety of 2 years of treatment with lower doses of continuous combined conjugated equine estrogens (CEE) and medroxyprogesterone acetate (MPA).DESIGN:Randomized, double-blind, placebo-controlled, multicenter metabolic and osteoporosis substudy of the Women's Health, Osteoporosis, Progestin, Estrogen (Women's HOPE) study.SETTING:Nineteen study centers across the United States.PATIENT(S):Healthy, postmenopausal women (n = 822) with an intact uterus were recruited.INTERVENTION(S):Patients received CEE 0.625, CEE 0.625/MPA 2.5, CEE 0.45, CEE 0.45/MPA 2.5, CEE 0.45/MPA 1.5, CEE 0.3, CEE 0.3/MPA 1.5 (all doses mg/day), or placebo for 2 years. Endometrial biopsies were evaluated at baseline and years 0.5, 1, 1.5, and 2 using a centralized protocol.MAIN OUTCOME MEASURE(S):Efficacy of lower doses of CEE/MPA in reducing the incidence of endometrial hyperplasia rates associated with unopposed estrogen (E).RESULT(S):No cases of endometrial hyperplasia were seen in the four CEE/MPA groups. For the CEE-alone groups, a dose-related increase in incidence rates from 3.17% (CEE 0.3 mg) to 27.27% (CEE 0.625 mg) was seen at 2 years. The number of cases increased from year 1 to year 2. For the CEE-alone groups, the incidence rates and types of hyperplasia diagnosed varied among the pathologists.CONCLUSION(S):Two years of treatment with lower doses of CEE/MPA provided endometrial protection comparable to that seen with commonly prescribed doses. These regimens should be considered for postmenopausal women who are candidates for hormone therapy.

Recent literature has consistently supported the use of postmenopausal estrogens for treatment of moderate-to-severe vasomotor symptoms and for prevention of osteoporosis. Although assessment of quality of life is complex, symptom relief has often been shown to translate into improvements in quality of life measures for women. Recent studies have reported a small increase in breast cancer with long-term hormone therapy, as well as a small increase in cardiovascular events and dementia when therapy is started in a population that is, on average, 13 years post-menopause. Ongoing investigations into different formulations and dosing options, as well as genetic factors that might influence the response to therapy, should provide valuable information.

Objectives: The importance of preventing fracture is well recognized. TMG is a novel, selective, norpregnane progestin developed for use in hormone therapy. The objective of this study was to examine the efficacy of continuous combined and sequential regimens of CE/TMG on BMD.Design: A randomized, double-blind, placebo-controlled, multicenter trial in 1,655 healthy, nonhysterectomized postmenopausal women (40–65 years old) who received 1 of 5 oral regimens of continuous combined or sequential CE/TMG or placebo for 1 year (13 28-day cycles) was conducted with a 1-year (13 28-day cycles) osteoporosis substudy extension.Materials and Methods: The two continuous combined regimens were CE 0.625 plus TMG 0.0625 or 0.125 mg. The two sequential regimens were CE 0.625 on days 1–28 plus TMG 0.125 or 0.250 mg on days 17–28. Placebo was taken daily on days 1–28. BMD of the lumbar spine and proximal femur (femoral neck and femoral trochanter) was measured by dual-energy X-ray absorptiometry (DXA) at baseline and at cycles 6, 13 (1 year), and 26 (2 years). The percentage change in BMD from baseline at 2 years was evaluated by analysis of covariance, with years since menopause and weight as covariates, and treatment group and study site as factors. All subjects randomized to treatment who recorded at least one dose of the study drug and received baseline and at least one BMD measurement post-baseline, were included in the intent-to-treat analysis.Results: The mean age of the 578 women who participated in the osteoporosis substudy was 51.8 years. At the end of 2 years, BMD was significantly increased (P<0.001) in all CE/TMG groups at the lumbar spine, femoral neck, and femoral trochanter compared with placebo. The lumbar spine BMD increase compared with placebo was 4.7%–5.1% for all CE/TMG groups. Similar findings were noted for the femoral trochanter BMD, with increases of 4.2%–5.5%, and at the femoral neck, with increases in BMD of 3.0%–4.0%, compared with placebo. The BMD in the placebo group significantly worsened (P<0.001) by 2.1%, 2.0%, and 2.4% for the lumbar spine, femoral neck, and femoral trochanter, respectively. All the BMD measurements increased significantly from baseline (P<0.001) after 2 years for the CE/TMG groups, except the femoral neck BMD for the two sequential CE/TMG groups, in which the increases were not significant.Conclusions: CE/TMG treatment for 2 years in early postmenopausal women increases spine and proximal femur BMD compared with placebo. These results support the use of CE/TMG as a valuable option for preventing bone loss in postmenopausal women.Supported by: Wyeth Research. Objectives: The importance of preventing fracture is well recognized. TMG is a novel, selective, norpregnane progestin developed for use in hormone therapy. The objective of this study was to examine the efficacy of continuous combined and sequential regimens of CE/TMG on BMD. Design: A randomized, double-blind, placebo-controlled, multicenter trial in 1,655 healthy, nonhysterectomized postmenopausal women (40–65 years old) who received 1 of 5 oral regimens of continuous combined or sequential CE/TMG or placebo for 1 year (13 28-day cycles) was conducted with a 1-year (13 28-day cycles) osteoporosis substudy extension. Materials and Methods: The two continuous combined regimens were CE 0.625 plus TMG 0.0625 or 0.125 mg. The two sequential regimens were CE 0.625 on days 1–28 plus TMG 0.125 or 0.250 mg on days 17–28. Placebo was taken daily on days 1–28. BMD of the lumbar spine and proximal femur (femoral neck and femoral trochanter) was measured by dual-energy X-ray absorptiometry (DXA) at baseline and at cycles 6, 13 (1 year), and 26 (2 years). The percentage change in BMD from baseline at 2 years was evaluated by analysis of covariance, with years since menopause and weight as covariates, and treatment group and study site as factors. All subjects randomized to treatment who recorded at least one dose of the study drug and received baseline and at least one BMD measurement post-baseline, were included in the intent-to-treat analysis. Results: The mean age of the 578 women who participated in the osteoporosis substudy was 51.8 years. At the end of 2 years, BMD was significantly increased (P<0.001) in all CE/TMG groups at the lumbar spine, femoral neck, and femoral trochanter compared with placebo. The lumbar spine BMD increase compared with placebo was 4.7%–5.1% for all CE/TMG groups. Similar findings were noted for the femoral trochanter BMD, with increases of 4.2%–5.5%, and at the femoral neck, with increases in BMD of 3.0%–4.0%, compared with placebo. The BMD in the placebo group significantly worsened (P<0.001) by 2.1%, 2.0%, and 2.4% for the lumbar spine, femoral neck, and femoral trochanter, respectively. All the BMD measurements increased significantly from baseline (P<0.001) after 2 years for the CE/TMG groups, except the femoral neck BMD for the two sequential CE/TMG groups, in which the increases were not significant. Conclusions: CE/TMG treatment for 2 years in early postmenopausal women increases spine and proximal femur BMD compared with placebo. These results support the use of CE/TMG as a valuable option for preventing bone loss in postmenopausal women. Supported by: Wyeth Research.