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Keywords:

  • Women's Health Initiative;
  • estrogen;
  • hormone therapy;
  • fracture;
  • BMD;
  • postmenopause;
  • clinical trial

Abstract

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

Further analyses from the Women's Health Initiative estrogen trial shows that CEE reduced fracture risk. The fracture reduction at the hip did not differ appreciably among risk strata. These data do not support overall benefit over risk, even in women at highest risk for fracture.

Introduction: The Women's Health Initiative provided evidence that conjugated equine estrogen (CEE) can significantly reduce fracture risk in postmenopausal women. Additional analysis of the effects of CEE on BMD and fracture are presented.

Materials and Methods: Postmenopausal women 50–79 years of age with hysterectomy were randomized to CEE 0.625 mg daily (n = 5310) or placebo (n = 5429) and followed for an average 7.1 years. Fracture incidence was assessed by semiannual questionnaire and verified by adjudication of radiology reports. BMD was measured in a subset of women (N = 938) at baseline and years 1, 3, and 6. A global index was used to examine whether the balance of risks and benefits differed by baseline fracture risk.

Results: CEE reduced the risk of hip (hazard ratio [HR], 0.65; 95% CI, 0.45–0.94), clinical vertebral (HR, 0.64; 95% CI, 0.44–0.93), wrist/lower arm (HR, 0.58; 95% CI, 0.47–0.72), and total fracture (HR, 0.71; 95% CI, 0.64–0.80). This effect did not differ among strata according to age, oophorectomy status, past hormone use, race/ethnicity, fall frequency, physical activity, or fracture history. Total fracture reduction was less in women at the lowest predicted fracture risk in both absolute and relative terms (HR, 0.86; 95% CI, 0.68–1.08). CEE also provided modest but consistent positive effects on BMD. The HRs of the global index for CEE were relatively balanced across tertiles of summary fracture risk (lowest risk: HR, 0.81; 95% CI, 0.62–1.05; mid risk: HR, 1.09; 95% CI, 0.92–1.30; highest risk: HR, 1.04; 95% CI, 0.88–1.23; interaction, p = 0.42).

Conclusions: CEE reduces the risk of fracture and increases BMD in hysterectomized postmenopausal women. Even among the women with the highest risk for fractures, when considering the effects of estrogen on other important health outcomes, a summary of the burden of monitored effects does not indicate a significant net benefit.


INTRODUCTION

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

Osteoporosis disproportionately affects older women, with 4 of 10 older white women suffering a fracture of the hip, spine, or wrist after age 50.(1) The Healthy People 2010 objectives established a national target to reduce by 20% both the proportion of adults with osteoporosis and the proportion of adults who are hospitalized for vertebral fractures associated with osteoporosis during the current decade (2000–2010).(2) This ambitious goal makes understanding as much as possible about effective strategies for fracture prevention a national priority. The Women's Health Initiative (WHI) Hormone Trials have provided compelling evidence that estrogen, with or without progestin, reduces the risk of hip and other fractures in women ≥50 years of age.(3–5) However, increased risks of cardiovascular events and dementia for both hormone regimens and increased risk of breast cancer for combined hormone therapy have resulted in cautious recommendations about the use of hormone therapy for treatment of osteoporosis or fracture prevention.

Preliminary findings of the WHI Estrogen-alone trial, which was terminated prematurely in February 2004 because of increased stroke risk in the absence of coronary heart disease prevention, showed significant reductions in hip, spine, and total fracture of 39%, 38%, and 30%, respectively, among women assigned to conjugated equine estrogen (CEE) compared with placebo.(5) The main purpose of this article is to present additional and updated analysis of effects on fracture risk and BMD using all verified cases through February 29, 2004. This article also examines whether the effect of CEE on fracture risk was modified according to baseline risk factors or by a summary score for underlying fracture risk.

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: WHI INVESTIGATORS

Details of the WHI design, recruitment procedures, and baseline characteristics of the women in the hormone trials have been previously reported.(6,7) The WHI randomized clinical trial of estrogen-alone is one of two WHI Hormone Trials. The results of the WHI randomized trial of estrogen plus progestin on fracture in 16,608 nonhysterectomized postmenopausal women has been published.(4) The WHI Estrogen-alone trial included 10,739 postmenopausal women with prior hysterectomy, 50–79 years of age at randomization, who were enrolled at 40 clinical centers from across the United States beginning in December of 1993.(5) Eligible subjects were randomized to either CEE 0.625 mg/day (N = 5310) or matching placebo (N = 5429) using a permuted block algorithm stratified by clinical center and age. The CEE (Premarin) and matching placebo were supplied by Wyeth (Radnor, PA, USA). Subjects were followed for an average of 7.1 ± 1.6 (SD) years. The WHI trial design allowed women the opportunity to participate in one or more of the WHI clinical trials. Subjects in the Estrogen-alone trial could also enroll in two additional randomized trials: a dietary modification trial (DM) and a trial of calcium plus vitamin D (CaD) supplement compared with placebo.

The protocol and consent forms were approved by institutional review boards at participating institutions, and all women provided written informed consent. Close-out of the estrogen-alone clinical trial was originally planned for October 2004 through March 2005; early study termination (February 2004) resulted in a follow-up time ∼1 year shorter than planned. At the time of close-out, vital status was known for 94.8% of randomized participants as previously described.(5) This report includes all hip fractures (which were centrally adjudicated) and all other fractures (which were locally adjudicated) occurring through February 29, 2004 and adjudicated as of December 15, 2004.

Risk factors for osteoporosis

Baseline risk factors for fractures were assessed in a standardized manner by questionnaire, interview, and clinical examination as previously described.(7,8) Body mass index (BMI) was calculated as weight in kilograms (measured on a balance beam scale) divided by the square of height in meters (measured on a fixed stadiometer). Age, number of pregnancies, years since menopause, age at hysterectomy, oophorectomy status, race, fall frequency, fracture history, family history of fracture, smoking, alcohol consumption, thiazide diuretic use, past hormone use, and physical activity were obtained by questionnaire. Average daily calcium intake was the sum of dietary calcium intake as assessed using a modification of the Block food frequency questionnaire(9) and reported use of calcium supplements in the previous 2 weeks obtained through an interviewer-administered medication survey. Past use of tamoxifen or current hormone therapy use were exclusion criteria, although women on hormone therapy at recruitment could undergo a 3-month washout period and then enroll. Initiation of hormone therapy, selective estrogen receptor modulators (SERMS), or tamoxifen while on trial required discontinuation of study medication. Initiation of bisphosphonates and calcitonin was permitted: 950 subjects (9.2% total: 10.2% placebo and 8.2% CEE subjects) reported bisphosphonate use at some point during the trial.

DXA was performed in only a subset of subjects from the three bone density clinics (N = 938); therefore, strata of osteoporosis risk for the entire WHI estrogen-alone cohort were defined by a summary fracture risk score that did not include BMD. As previously described, the method developed by Black(10) and modified by Cauley et al.(4) for the analyses of the WHI Estrogen plus Progestin trial used clinical risk factors to predict hip fracture. However, because several demographic and osteoporosis risk factors differed in prevalence in the Estrogen-alone trial in comparison with the Estrogen plus Progestin trial, the summary risk score for the Estrogen-alone trial was calculated using tertile cut points from the placebo group of the Estrogen-alone trial. Of the 20 risk factors included by Black, the fracture summary risk score used in this analysis included all except those not available in the WHI trial for all participants (BMD at the hip, use of arms to stand from a chair, “4 or fewer hours on feet per day” and height at age 25 years). The score calculated from placebo-treated participants in the Estrogen-alone trial was found to have moderate predictive power for hip fracture, with an area under the receiver operating characteristic curve of 0.82 (95% CI, 0.78–0.87). The score predicted an annualized increased risk for hip fractures ranging from 2 per 10,000 (risk score of 0–3) to 53 per 10,000 (summary risk score > 6) in the Estrogen-alone trial placebo women. The score for total fracture was predictive of risk (137 per 10,000 with a risk score 0–3 to 283 per 10,000 with a summary risk score > 6).

The subset of women who underwent DXA of the lumbar spine (L2–L4), total hip, and total body (QDR 2000, 2000+, or 4500W; Hologic, Bedford, MA, USA) were from 3 of the 40 clinical centers (Pittsburgh, PA; Birmingham, AL; and Tucson/Phoenix, AZ) and were chosen to provide maximal racial diversity, and as such, were not representative of the Estrogen-alone trial cohort as a whole. BMD was measured at baseline and years 1, 3, and 6 using standard protocols for positioning and analysis by technologists certified by the University of California San Francisco bone densitometry reading center.(11) SD from the mean (T score) using NHANES III young white female reference values at the total hip and Hologic reference values for all other sites measured were determined at baseline and categorized for severity using WHO definitions.(12) Percent change in BMD from baseline was calculated for each site measured for years 1, 3, and 6. To characterize interscanner variability from the clinical centers, three cross-calibration phantoms (Hologic spine, hip, and linearity) were sent to the BMD sites. These precision phantoms were measured in array mode five times once each day for 5 consecutive days. Spine, hip, and linearity phantoms were in close agreement (maximal interscanner variability: 1.5% for spine, 4.8% for hip, and 1.7% for linearity).

Outcomes

Reports of hip, clinical vertebral, wrist/lower arm, and other osteoporotic fractures (excluding chest/sternum, ribs, skull/face, fingers, toes, and cervical vertebrate) were ascertained by semiannual questionnaire. All reported fractures were confirmed by review of the radiology reports by centrally trained local adjudicators who were blinded to treatment assignment. Hip fractures underwent a second central adjudication. The agreement between central and local adjudication for hip fracture was 94%.

To summarize important aspects of health benefits versus risk in the main WHI study, a global index was created that was defined for each woman as the time-to-first event for a monitored trial outcome (coronary heart disease, invasive breast cancer, stroke, pulmonary embolus, colorectal cancer, hip fracture, or death from other causes).(6) The global index of these outcomes played a supportive role in trial monitoring as a summary measure of overall balance of risks and benefits. In this paper, we present analyses of the global index for the Estrogen-alone trial to determine if the global index varied by the fracture risk summary score.

Statistical analyses

Primary analyses used time-to-event methods based on the intent-to-treat principle. Fracture incidence rates were compared using hazards ratios (HRs), nominal 95% CIs, and Wald statistic p values from Cox proportional hazards models stratified by age, prior fracture history, and randomization status in the DM trial. Poisson regression models were used to determine 95% CI for annualized rates of site-specific and total fractures. Adjustment for randomization status in the CaD trial was made by inclusion of time-dependent covariates for CaD treatment assignment. Approximately 60% of the participants in the Estrogen-alone trial were also enrolled in the CaD trial. Kaplan-Meier plots describe event rates over time.

Over the 7.1 years of the trial, 57.5% (57.3% of CEE and 57.7% of placebo) of study subjects became nonadherent to study medication (defined as taking <80% of study pills per protocol) at some point during follow-up. Sensitivity analyses were conducted to estimate the influence of reduced adherence on fracture outcomes. A second sensitivity analysis was done to censor subjects who began bisphosphonate therapy during trial, with censoring on the date of first reported use.

Potential differential effects across subgroups by important osteoporosis fracture risk factors for both hip and total fractures was assessed by Cox proportional hazards analyses with formal tests for interaction between each risk factor and treatment assignment. Continuous variables for each risk factor were used when possible. For categorical variables (ethnicity, oophorectomy status, parental history of fracture, smoking status, and history of fracture), interaction was determined across strata. Because of the low prevalence of hip fractures in nonwhite participants, race/ethnicity stratification was limited to total fractures. A total of 37 subgroup interactions were examined, and nominal p values are presented in the tables. Parity, weight, and physical activity (data not shown) were also examined and found to have no interaction with CEE. Given the large number of interactions examined, approximately two tests of interaction would be expected to be statistically significant at the 0.05 level by chance alone.

Absolute differences and percentage change in BMD of the lumbar spine, total hip, and total body from baseline to years 1, 3, and 6 were calculated for the BMD subgroup. Linear regression was used to compare rates of change in BMD separately at each time-point in women randomized to CEE versus placebo, after adjustments for clinic center and race/ethnicity. To assess the CEE effect on fracture according to baseline BMD, the interaction of T score as a continuous variable with total fractures was examined.

Last, the balance of risk and benefit (global index) was assessed across tertiles of the summary fracture risk score.

RESULTS

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

Baseline characteristics were similar in women randomized to CEE (N = 5310) compared with placebo (N = 5429; Table 1). Detailed discussions of these characteristics have been previously reported.(5,7) In general, women in the Estrogen-alone trial were characterized by factors associated with low risk for hip fracture. The average age was 63.6 ± 7.3 years. Slightly >75% of women were white. Although the average BMI was 30.1 ± 6.1 kg/m2, ∼20% of women had a BMI < 25 kg/m2 and 152 (1.4%) had a BMI < 20.0 kg/m2. Approximately 10% of the women were current cigarette smokers at randomization. Baseline total calcium intake averaged 970 mg daily. Bisphosphonate and calcitonin use at baseline was low (<2%). More than one half reported no previous postmenopausal hormone therapy exposure. Differences in fall frequency were not clinically meaningful.

Table Table 1.. Baseline Variables by Randomization Assignment*
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In the subgroup of 938 women having BMD measurements, baseline values were similar by treatment assignment. A total of 38.7% of women had low BMD at the total hip (T score between −1.0 and −2.5) and 5.7% met the criteria for osteoporosis (T score ≤ −2.5). Other than a greater proportion of women from ethnic and racial minority groups, reflecting the planned enhanced representation of racial and ethnic minority women in the BMD cohort, there were no meaningful differences in characteristics or risk factors between women in the trial as a whole and those in the BMD subgroup.

Clinical osteoporosis fracture outcomes and subgroup analyses

A total of 1301 fractures occurred during the 7.1 years of follow-up; 540 fractures among women assigned to CEE and 761 among women assigned to placebo. This included 46 hip fractures in the CEE treatment group and 73 hip fractures in the placebo group. There were also 130 lower arm/wrist fractures in the CEE group and 227 in the placebo group and 43 clinical vertebral fractures in the CEE group and 69 in placebo-treated subjects. Overall annualized fracture rates per 10,000 person-years in the CEE and placebo-treated subjects, respectively, were as follows: hip fracture, 12 (95% CI, 9, 16) and 19 (95% CI, 15, 24); lower arm/wrist, 35 (95% CI, 29, 41) and 59 (95% CI, 52, 67); clinical vertebral, 11 (95% CI, 8, 15) and 18 (95% CI, 14, 23); total fractures, 144 (95% CI, 132, 156) and 197 (95% CI, 183, 211). Although consistent with the original report of the WHI Estrogen-alone trial, the incident fractures differ modestly from those published in the 2004 WHI Estrogen-alone trial report(5) because these analyses include additional fracture outcomes that had occurred through close-out of the estrogen-alone intervention in February 29, 2004, that were adjudicated by December 15, 2004.

Hip fracture

A 35% statistically significant reduction in risk of hip fracture was observed (HR = 0.65; 95% CI, 0.45–0.94). The Kaplan-Meier estimates of cumulative hazards for hip fracture indicate that the curves began to diverge between groups after year 3 and increased over time (Fig. 1). To evaluate whether subgroups of women were at different hazards for hip fracture with CEE, the interaction of biologically plausible clinical variables and risk factors was analyzed (Table 2). In subgroup analyses, there was a significant interaction of years after menopause with CEE (p = 0.05), with a greater reduction in hip fracture in women >20 years after menopause. However, the role of time since menopause can be difficult to ascertain in women who have had a hysterectomy, and analyses with oophorectomy status and years since estrogen exposure did not show a similar interaction.

Table Table 2.. Hazard Ratios of Hip Fracture by Randomization Assignment and Stratification*
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Figure Figure 1. Kaplan Meier estimates of cumulative hazards for fracture. HR, hazard ratio; n CI, nominal confidence internal. (A) Hip fracture. (B) Clinical vertebral fracture. (C) Lower arm/wrist fracture. (D) Total fracture.

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In the WHI estrogen-alone trial, only 1.4% of participants had a BMI < 20 kg/m2, and thus, too few participants were in this stratum to make comparison with low BMI meaningful. In women with BMI < 25 kg/m2, CEE decreased the risk of hip fracture by 59% (HR = 0.41; 95% CI, 0.22–0.76). However, the interaction between BMI and hip fracture did not reach statistical significance (p = 0.13). No evidence of interaction was found after stratification for age, oophorectomy status, past use of hormone therapy, smoking, fall frequency, total calcium intake at baseline, parental history of fracture, or prior personal history of fracture (Table 2).

Total fracture

There was a significant 29% reduction in the risk of total fracture with CEE compared with placebo (HR = 0.71; 95% CI, 0.64–0.80). The Kaplan-Meier estimates for total fractures indicated that the curves began to diverge ∼3 years after randomization and increased over time, suggesting continuing benefit on total fractures through the period of observation (Fig. 1). The reduction in risk was similar across strata of individual variables examined except for age, cigarette smoking, and a trend toward an interaction with years since menopause. CEE was associated with reduced risk of total fracture in older subjects (interaction p = 0.03) and in subjects with no current or past cigarette smoking (interaction p = 0.04) with a nonsignificant trend for years since menopause (interaction p = 0.06; Table 3).

Table Table 3.. Hazard Ratios of Total Fractures by Randomization Assignment and Stratification*
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Summary fracture risk score

To determine if CEE had equivalent effects at different levels of risk for osteoporotic fracture, a summary fracture risk score was calculated, and the interaction of CEE with this risk score was analyzed for both hip and total fractures. For hip fracture, there seemed to be a modest suggestion of greater protection with CEE in the two highest risk score groups, although the interaction was not significant (interaction p = 0.08). For total fracture, there was a significant interaction with greater protection with CEE in those in the highest risk score groups (interaction p = 0.04).

In the subgroup of women predicted to be at high risk for fracture (risk scores > 6), CEE decreased the relative risk for hip fracture by 45% (Table 2). The reduction of total fractures with CEE was significant in individuals at moderate and high risk for fracture (HR, 0.68; 95% CI, 0.56–0.82 for summary risk score 4–6 and HR, 0.66; 95% CI, 0.54–0.80 for summary risk score > 6) with no benefit seen in women at low risk (HR, 0.86; 95% CI, 0.68–1.08; Table 3).

Other fracture and sensitivity analyses

CEE was also associated with decreased risk of fractures of the lower arm/wrist (HR = 0.58; 95% CI, 0.47–0.72) and clinical vertebrae (HR = 0.64; 95% CI, 0.44–0.93; Fig. 1). Interaction by subgroups was similar to that of hip fractures, with no significant interactions seen (data not shown).

After censoring data from women 6 months after their adherence fell below 80%, the HR for hip fractures was 0.42 (95% CI, 0.21–0.84) and for total fractures was 0.70 (95% CI, 0.60–0.80). Analyses censoring subjects at the date of first reported bisphosphonate use did not appreciably change the findings (HR for hip fracture, 0.65; 95% CI, 0.44–0.94; HR for total fractures, 0.74; 95% CI, 0.66–0.83).

BMD

A small but consistent positive effect of CEE compared with placebo was seen for BMD at the spine, hip, and total body (Fig. 2). Over 6 years, women receiving CEE had progressive gains in BMD (+7.1%) at the lumbar spine compared with +1.9% gains in the women receiving placebo. The 5.1% difference between groups was statistically significant (p < 0.0001). Total hip BMD increased by 1.8% in women receiving CEE, whereas those receiving placebo lost 1.9% (p < 0.0001). The small losses noted at the total hip from years 3 to 6 were proportional in CEE and placebo groups. There were also small gains in total body BMD with CEE. Sensitivity analyses, including only women remaining 80% adherent throughout the trial, showed similar patterns as in the intent-to-treat analyses over 6 years of follow-up (data not shown).

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Figure Figure 2. Mean percent change in BMD during 6 years of follow-up at (A) the lumbar spine, (B) total hip, and (C) whole body. All results were significant at p < 0.0001 between CEE and placebo at years 1, 3, and 6.

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There was a 22% nonsignificant reduction in total fractures in the BMD subgroup (49 fractures in CEE and 64 fractures in placebo; HR, 0.77; 95% CI, 0.53–1.12). There was no statistically significant reduction in total fracture with CEE in women who had hip T scores consistent with low bone mass (T score between −1.0 and −2.5; HR, 0.83; 95% CI, 0.49–1.40), osteoporosis (T score ≤ −2.5; HR, 0.83; 95% CI, 0.17–3.91), or normal bone mass (HR, 0.99; 95% CI, 0.53–1.84). When the relationship between baseline total hip T score and CEE on risk for total fracture was examined, no significant interaction was noted (interaction p = 0.17).

Global index and fracture risk

In the Estrogen-alone trial, the global index of health risks and benefits was balanced overall.(10) To assess whether women at the greatest benefit for osteoporosis fracture reduction would have a more favorable balance of risks and benefits, the overall risk (global index) of CEE compared with placebo by stratum of the fracture summary risk factor score were examined. The interaction between fracture risk and global index was not significant (p = 0.42); HRs for the global index were 0.81 (95% CI, 0.62–1.05) among women in the lowest tertile of fracture risk, 1.09 (95% CI, 0.92–1.30) for those in the middle tertile, and 1.04 (95% CI, 0.88–1.23) for those at highest risk. These data suggest that even in women at the highest risk for fracture, the global index was balanced, with no evidence of overall benefit or risk noted.

DISCUSSION

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

This randomized clinical trial showed that CEE given to hysterectomized women after menopause significantly reduced incident fractures at the hip, spine, and wrist and total fractures. Use of CEE was also associated with a significant increase in BMD persisting for 6 years of follow-up. This is the first clinical trial of estrogen alone to show fracture protection in a cohort of postmenopausal women not specifically selected for study because of their underlying high risk for fracture. The increases in BMD were greatest at the spine, with positive effects also noted at the hip and total body. The relative fracture reduction was similar at the hip, wrist, and vertebrae and for total fractures. These results are consistent with previous observational reports(13–16) and meta-analyses(17–19) that suggested that unopposed estrogen therapy reduces bone loss and fractures in postmenopausal women. In addition, these findings are consistent with the findings in the WHI estrogen plus progestin trial previously reported.(4)

The effect of CEE on hip and total fractures was remarkably consistent, almost irrespective of individual characteristics contributing to risk for osteoporosis or fractures including age, ethnicity, personal history of falls, calcium intake, personal and family history of fracture, and past use of hormone therapy. There was only a trend toward a weaker effect of CEE in women who smoked than in never or past smokers. However, these analyses should be interpreted cautiously, because, with the large number of interactions examined, we would predict at least two interactions at a 0.05 level by chance alone. The consistency of response across all other strata of women is very similar to the results published for the estrogen plus progestin clinical trial.(4)

CEE also seemed to have less effect in reducing hip and total fracture in women who were overweight or obese, although the interaction of BMI and CEE on hip and total fracture was not significant. Previous studies have suggested that postmenopausal women with low BMI are at higher risk for fracture and have lower circulating estradiol.(20) One hypothesis for this interaction might be that estrogen therapy exerts its greatest effect in women with the lowest endogenous estrogen levels.

There is considerable interest in examining the efficacy of estrogen in reducing fractures in women at intermediate and low risk of fracture. Within the BMD subgroup of the estrogen-alone trial, there was no significant modification of CEE effect on total fractures by baseline T score. However, the small number of fractures in the BMD subgroup and the small percentage of participants with BMD T scores ≤ −2.5 resulted in reduced power for analysis, and subsequently, wide CIs. Thus, to overcome the power limitations in these analyses, we calculated a summary fracture risk score for all estrogen-alone participants in an attempt to characterize and stratify by baseline fracture risk. The effect of CEE on reducing total fractures was weaker in women at the lowest risk of fracture using the composite risk score compared with women at greater risk. There was also a consistent trend supporting this relationship when hip fracture was examined. Thus, women with the greatest risk of fracture achieve both a greater relative and absolute fracture risk reduction with CEE. The greater efficacy of therapy in women at higher risk for fracture has been previously reported with use of bisphosphonates(21,22) and supports the concept that antiresorptive interventions are efficacious in reducing fractures in women at increased risk for fracture but may have less clinical benefit in women at low risk. This differs from the analyses in the WHI estrogen plus progestin trial(5) and data with SERMS,23 where the efficacy was similar in women at high, medium, and low risk of fractures.

There is also significant interest in comparing the results from the WHI Estrogen-alone trial and the Estrogen plus Progestin trial to determine whether the effect of postmenopausal estrogen therapy for hip and total fracture reduction is similar regardless of the addition of a progestin. Unadjusted ratios of the estrogen-alone(5) to estrogen plus progestin(3) HRs from Cox regression analysis stratified on cohort and baseline age are 0.90 (95% CI, 0.53–1.55) and 0.92 (95% CI, 0.79–1.07) for hip and total fracture, respectively, showing no difference in fracture risk between trials. This consistency of response for fracture risk reduction between the two trials occurred despite differences in demographic characteristics between the subjects in the two trials. Despite the fact that women in the Estrogen-alone trial had characteristics that are generally associated with poorer health (i.e., higher BMI) and a greater representation of ethnic and racial minority women who are at lower risk for fracture, overall fracture reduction was similar in the estrogen alone and estrogen plus progestin trials.

Women receiving CEE had consistent positive effects on BMD at the lumbar spine and total body. The differences in BMD observed between CEE and placebo are consistent with results from a meta-analysis of hormone therapy for postmenopausal osteoporosis.(17) At the total hip, after an initial increase in BMD from baseline to year 3, there was a decrease in BMD from year 3 to year 6 in subjects randomized to CEE and placebo, although the relative higher hip BMD with CEE was still maintained. The explanation of this loss in BMD is unknown, but it cannot be explained by a cohort effect of those who completed all BMD time-points because the trend is similar when censoring women who did not complete the year 6 DXA (data not shown).

The overall balance of benefits and risks of estrogen therapy was the primary focus of the Estrogen-alone trial. The prespecified global index was developed to summarize the time-to-first-event for each woman among the monitored outcomes. It is limited to potentially life-threatening events and does not include all potential health benefits and risks but it can be used as an assessment of the monitored balance of risks and benefits over an average of ∼7 years of CEE exposure. Overall, CEE has been shown to have a balance of risks and benefits as defined by the global index.(5) We were interested in determining if women at the greatest risk for fracture (who might benefit by the greatest absolute fracture reduction) had a favorable global index. In the subgroup analyses, there was a greater reduction in fractures for CEE in women predicted to be at the highest risk for fracture. However, we found that regardless of baseline fracture risk (as defined by fracture risk category), the overall global index did not differ significantly, suggesting that, regardless of baseline fracture risk, there was no overall benefit of taking estrogen therapy. Thus, even among the women with the highest risk for total fractures, the global index failed to indicate a significant net benefit, and conversely, in women with the lowest risk for fracture benefit, there was no significant net risk. Therefore, although estrogen alone significantly reduces the risk of fracture in hysterectomized postmenopausal women, the global index as defined in WHI does not support its general use for fracture prevention.

Acknowledgements

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

The WHI Steering Committee gratefully acknowledges the dedicated efforts of investigators and staff at the WHI Clinical Centers, the WHI Clinical Coordinating Center, and the NHLBI program office (listing available at http://www.whi.org). Most importantly, we want to recognize the WHI participants for their extraordinary commitment to the WHI Hormone study. The Women's Health Initiative study is funded by the National Heart, Lung and Blood Institute, U.S. Department of Health and Human Services. The active study drug and placebo were supplied by Wyeth (Radnor, PA).

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. REFERENCES
  9. APPENDIX: WHI INVESTIGATORS
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  • 4
    Cauley JA, Robbins J, Chen Z, Cummings SR, Jackson RD, LaCroix AZ, LeBoff M, Lewis CE, McGowan J, Neuner J, Pettinger M, Stefanick ML, Wactawski-Wende J, Watts NB 2003 Effects of estrogen plus progestin on risk of fracture and bone mineral density: The Women's Health Initiative randomized trial. JAMA 290: 17291738.
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APPENDIX: WHI INVESTIGATORS

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

Program Office—National Heart, Lung, and Blood Institute, Bethesda, MD, USA: Barbara Alving, Jacques Rossouw, Linda Pottern, Shari Ludlam, Joan McGowan, Nancy Geller, and Leslie Ford.

Clinical Coordinating Center—Fred Hutchinson Cancer Research Center, Seattle, WA, USA: Ross Prentice, Garnet Anderson, Andrea LaCroix, Ruth Patterson, Anne McTiernan, Barbara Cochrane, Julie Hunt, Lesley Tinker, Charles Kooperberg, Martin McIntosh, CY Wang, Chu Chen, Deborah Bowen, Alan Kristal, Janet Stanford, Nicole Urban, Noel Weiss, and Emily White; Wake Forest University School of Medicine, Winston Salem, NC, USA: Sally Shumaker, Ronald Prineas, and Michelle Naughton; Medical Research Laboratories, Highland Heights, KY, USA: Evan Stein and Peter Laskarzewski; San Francisco Coordinating Center, San Francisco, CA, USA: Steven R Cummings, Michael Nevitt, and Lisa Palermo; University of Minnesota, Minneapolis, MN, USA: Lisa Harnack; Fisher BioServices, Rockville, MD, USA: Frank Cammarata and Steve Lindenfelser; University of Washington, Seattle, WA, USA: Bruce Psaty and Susan Heckbert.

Clinical Centers—Albert Einstein College of Medicine, Bronx, NY, USA: Sylvia Wassertheil-Smoller, William Frishman, Judith Wylie-Rosett, David Barad, and Ruth Freeman; Baylor College of Medicine, Houston, TX, USA: Jennifer Hays, Ronald Young, Jill Anderson, Sandy Lithgow, and Paul Bray; Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA: JoAnn Manson, J Michael Gaziano, Claudia Chae, Kathryn Rexrode, and Caren Solomon; Brown University, Providence, RI, USA: Annlouise R Assaf, Carol Wheeler, Charles Eaton, and Michelle Cyr; Emory University, Atlanta, GA, USA: Lawrence Phillips, Margaret Pedersen, Ora Strickland, Margaret Huber, and Vivian Porter; Fred Hutchinson Cancer Research Center, Seattle, WA, USA: Shirley AA Beresford, Vicky M Taylor, Nancy F Woods, Maureen Henderson, and Robyn Andersen; George Washington University, Washington, DC, USA: Judith Hsia, Nancy Gaba, and Joao Ascensao; Harbor-UCLA Research and Education Institute, Torrance, CA, USA: Rowan Chlebowski, Robert Detrano, Anita Nelson, and Michele Geller; Kaiser Permanente Center for Health Research, Portland, OR, USA: Evelyn Whitlock, Patricia Elmer, Victor Stevens, and Njeri Karanja; Kaiser Permanente Division of Research, Oakland, CA, USA: Bette Caan, Stephen Sidney, Geri Bailey, and Jane Hirata; Medical College of Wisconsin, Milwaukee, WI, USA: Jane Morley Kotchen, Vanessa Barnabei, Theodore A Kotchen, Mary Ann C Gilligan, and Joan Neuner; MedStar Research Institute/Howard University, Washington, DC, USA: Barbara V Howard, Lucile Adams-Campbell, Lawrence Lessin, Monique Rainford, and Gabriel Uwaifo; Northwestern University, Chicago/Evanston, IL, USA: Linda Van Horn, Philip Greenland, Janardan Khandekar, Kiang Liu, and Carol Rosenberg; Rush University Medical Center, Chicago, IL, USA: Henry Black, Lynda Powell, Ellen Mason, and Martha Gulati; Stanford Prevention Research Center, Stanford, CA, USA: Marcia L Stefanick, Mark A Hlatky, Bertha Chen, Randall S Stafford, and Sally Mackey; State University of New York at Stony Brook, Stony Brook, NY, USA: Dorothy Lane, Iris Granek, William Lawson, Gabriel San Roman, and Catherine Messina; The Ohio State University, Columbus, OH, USA: Rebecca Jackson, Randall Harris, Electra Paskett, W Jerry Mysiw, and Michael Blumenfeld; University of Alabama at Birmingham, Birmingham, AL, USA: Cora E Lewis, Albert Oberman, James M Shikany, Monika Safford, and Mona Fouad; University of Arizona, Tucson/Phoenix, AZ, USA: Tamsen Bassford, Cyndi Thomson, Marcia Ko, Ana Maria Lopez, and Cheryl Ritenbaugh; University at Buffalo, Buffalo, NY, USA: Jean Wactawski-Wende, Maurizio Trevisan, Ellen Smit, Susan Graham, and June Chang; University of California at Davis, Sacramento, CA, USA: John Robbins and S Yasmeen; University of California at Irvine, Irvine, CA, USA: F Allan Hubbell, Gail Frank, Nathan Wong, Nancy Greep, and Bradley Monk; University of California at Los Angeles, Los Angeles, CA, USA: Howard Judd, David Heber, and Robert Elashoff; University of California at San Diego, LaJolla/Chula Vista, CA, USA: Robert D Langer, Michael H Criqui, Gregory T Talavera, Cedric F Garland, and Matthew A Allison; University of Cincinnati, Cincinnati, OH, USA: Margery Gass and Suzanne Wernke; University of Florida, Gainesville/Jacksonville, FL, USA: Marian Limacher, Michael Perri, Andrew Kaunitz, R Stan Williams, and Yvonne Brinson; University of Hawaii, Honolulu, HI, USA: J David Curb, Helen Petrovitch, Beatriz Rodriguez, Kamal Masaki, and Santosh Sharma; University of Iowa, Iowa City/Davenport, IA, USA: Robert Wallace, James Torner, Susan Johnson, Linda Snetselaar, and Jennifer Robinson; University of Massachusetts/Fallon Clinic, Worcester, MA, USA: Judith Ockene, Milagros Rosal, Ira Ockene, Robert Yood, and Patricia Aronson; University of Medicine and Dentistry of New Jersey, Newark, NJ, USA: Norman Lasser, Baljinder Singh, Vera Lasser, John Kostis, and Peter McGovern; University of Miami, Miami, FL, USA: Mary Jo O'Sullivan, Linda Parker, Timothy DeSantis, Diann Fernandez, and Pat Caralis; University of Minnesota, Minneapolis, MN, USA: Karen L Margolis, Richard H Grimm, Mary F Perron, Cynthia Bjerk, and Sarah Kempainen; University of Nevada, Reno, NV, USA: Robert Brunner, William Graettinger, Vicki Oujevolk, and Michael Bloch; University of North Carolina, Chapel Hill, NC, USA: Gerardo Heiss, Pamela Haines, David Ontjes, Carla Sueta, and Ellen Wells; University of Pittsburgh, Pittsburgh, PA, USA: Lewis Kuller, Jane Cauley, and N Carole Milas; University of Tennessee Health Science Center, Memphis, TN, USA: Karen C Johnson, Suzanne Satterfield, Raymond W Ke, Stephanie Connelly, and Fran Tylavsky; University of Texas Health Science Center, San Antonio, TX, USA: Robert Brzyski, Robert Schenken, Jose Trabal, Mercedes Rodriguez-Sifuentes, and Charles Mouton; University of Wisconsin, Madison, WI, USA: Gloria E Sarto, Douglas Laube, Patrick McBride, Julie Mares-Perlman, and Barbara Loevinger; Wake Forest University School of Medicine, Winston-Salem, NC, USA: Denise Bonds, Greg Burke, Robin Crouse, Mara Vitolins, and Scott Washburn; Wayne State University School of Medicine/Hutzel Hospital, Detroit, MI, USA: Susan Hendrix, Michael Simon, and Gene McNeeley.

Former Principal Investigators and Project Officers: Baylor College of Medicine, John Foreyt; Emory University, Dallas Hall, Sally McNagny, and Nelson Watts; George Washington University, Valery Miller; Kaiser (Oakland), Robert Hiatt; Kaiser (Portland), Barbara Valanis; National Cancer Institute, Carolyn Clifford; University of Arizona, Thomas Moon; University of California, Irvine, Frank Meyskens Jr; University of Cincinnati, James Liu; University of Miami, Marianna Baum; University of Nevada, Sandra Daugherty; University of North Carolina, Chapel Hill, David Sheps and Barbara Hulka; University of Tennessee, Memphis, William Applegate; University of Wisconsin, Catherine Allen.

Data and Safety Monitoring Board: Janet Wittes (Chair), Eugene Braunwald, Margaret Chesney, Harvey Cohen, Elizabeth Barrett-Connor, David DeMets, Leo Dunn, Johanna Dwyer, Robert P Heaney, Daniel Marson, Victor Vogel, LeRoy Walters, Kristine Yaffe, and Salim Yusuf.