Bone Mass Response to Discontinuation of Long-term Hormone
Replacement Therapy
Results From the Postmenopausal
Estrogen/Progestin Interventions (PEPI) Safety Follow-up Study
Gail A. Greendale, MD; Mark Espeland, PhD; Stacey Slone, MS; Robert
Marcus, MD; Elizabeth Barrett-Connor, MD; for the PEPI Safety Follow-up Study
(PSFS) Investigators
Background Accelerated bone loss after stopping hormone therapy (HRT) is
postulated to explain the lack of hip-fracture protection conferred by former
HRT use. The abbreviation HRT (traditionally standing for "hormone
replacement therapy") is used herein because of its wide recognition in
the field. However, the pharmacological doses of estrogens and progestins used
are not truly "replacement" in nature.
Objectives To determine whether women lose bone mineral density (BMD) after
stopping HRT; to assess whether their rate of loss is significantly greater
than that of women not undergoing HRT; and to determine whether long-term HRT
is associated with continued gains in BMD.
Methods A total of 495 women who were adherent to assigned treatment in
the 3-year Postmenopausal Estrogen/Progestin Interventions randomized
controlled trial (PEPI-RCT) and who had an additional BMD measurement during
the PEPI Safety Follow-up Study were observed for an average of 3 years during
and 4 years after the PEPI-RCT.
Results Women who stopped HRT after 1 year during the PEPI-RCT had annual
rates of BMD change of -0.54% (hip) and -0.81% (spine) during the following 2
years. Those who underwent HRT for 3 years during the PEPI-RCT and then
discontinued it had annual changes of -1.01% (hip) and -1.04% (spine). Rates of
BMD loss among women who stopped HRT during or after the PEPI-RCT did not
differ significantly from those of women who did not undergo HRT, who lost bone
at a rate of approximately 1% yearly during the first year of the PEPI-RCT and
about half that rate afterward. Women who continued HRT after the PEPI-RCT did
not show additional BMD gains.
Conclusions Our results do not support the hypothesis that bone is lost at an
unusually fast rate after discontinuation of HRT, nor do they suggest that
longer-term HRT leads to additional BMD gain beyond that evident after 3 years.
Arch Intern Med.
2002;162:665-672
POSTMENOPAUSAL hormone therapy (HRT) is a
complex intervention that may have substantial long-term benefits such as
primary prevention of heart disease, osteoporosis, and several other chronic
diseases.1 The
abbreviation HRT (traditionally standing for "hormone replacement
therapy") is used herein because of its wide recognition in the field.
However, the pharmacological doses of estrogens and progestins used are not
truly "replacement" in nature. However, this pharmacological
treatment is not risk free. One of the most feared potential complications of
long-term HRT is breast cancer.2 Although studies of
breast cancer risk related to postmenopausal hormone use have had mixed
outcomes,3 some have shown
that cancer risk increases with longer duration of estrogen use.4, 5
The concern about cumulative risk as a function
of long-term HRT has fueled efforts to maximize potential benefits and minimize
possible risks of this therapy. One optimization strategy would be to limit the
duration of HRT; but this raises the question of when during the postmenopause
period HRT should be provided. If, for example, we wanted to confine HRT use to
10 years, should we recommend that women undergo it early after menopause but
then stop, or would it be advisable to defer HRT until later in the
postmenopause period? Evidence-based answers to these questions are limited and
may be heterogeneous and organ specific. Understanding what happens to bone
when women stop HRT would provide part of the answer to this complex problem.
Cohort studies6, 7 report that former HRT
use (for up to 10 years) confers no hip-fracture protection. Therefore,
starting HRT early in the postmenopause period with subsequent discontinuation
may not be the preferred strategy to prevent hip fracture. In contrast,
numerous studies show that postmenopausal hormone use prevents loss of bone
mineral density (BMD) or increases it slightly.6, 8, 9 Why then do patients
who discontinue HRT (especially after long-term treatment) not accrue sustained
antifracture benefit as a result of former use? An accelerated rate of bone
loss after stopping HRT is a postulated explanation for the lack of
hip-fracture risk reduction in former hormone users.6 However, few studies
directly assess the pattern of BMD loss after stopping HRT.10-13
Much remains to be learned about the skeletal
effects of long-term HRT. Estrogen's antiresorptive action on bone is well
established,14 but unresolved
is whether estrogen causes additional gain in bone mass after the bone
remodeling transient has been closed (transient
is the time during which bone changes from a higher to a lower turnover state
causing gain in bone mass15). Because the length
of the bone remodeling transient is dependent on the bone turnover state, it is
difficult to know how long BMD must be observed to infer that such additional
gains have occurred. However, follow-up beyond 3 years is likely to be beyond
the range of the remodeling transient.15
The Postmenopausal Estrogen/Progestin
Interventions randomized controlled trial (PEPI-RCT) was a 3-year randomized,
placebo-controlled, clinical trial of 4 active HRT regimens; one of its major
outcome measures was BMD.8, 16 The PEPI Safety
Follow-up Study (PSFS) monitored safety end points after the completion of the
trial. As part of the PSFS, participants had BMD testing an average of 4 years
after the PEPI-RCT was completed. We used data from the PEPI-RCT and the PSFS
to address the following questions: (1) Do women lose spinal or hip BMD after
stopping HRT? If so, is the rate of BMD loss greater than that of women not
undergoing HRT? (2) Do patients undergoing long-term HRT continue to accrue spinal
or hip BMD in excess of the levels of BMD achieved by 3 years of use?
SUBJECTS AND METHODS
THE PEPI-RCT
The PEPI-RCT was a randomized, double-masked, placebo-controlled, clinical
trial designed to compare the effects of estrogen, alone or in combination with
1 of 3 progestin regimens, on heart disease risk factors.16 By protocol
requisite, participants were between 45 and 64 years old and were between 1 and
10 years postmenopause. The 4 active PEPI-RCT treatment regimens were as
follows (each included the identical 0.625-mg daily dose of conjugated oral
equine estrogen): (1) unopposed oral conjugated equine estrogen; (2) conjugated
equine estrogen plus 2.5 mg daily of medroxyprogesterone acetate; (3)
conjugated equine estrogen plus 10 mg of cyclical medroxyprogesterone acetate
taken on days 1 through 12 each month; and (4) conjugated equine estrogen plus
200 mg of cyclical micronized progesterone taken on days 1 through 12 each
month. Between December 1989 and February 1991, 7 academic medical centers
enrolled 875 women from the following regions: Baltimore, Md; Iowa City, Iowa;
Los Angeles, Calif; Palo Alto, Calif; San Antonio, Tex; San Diego, Calif; and
Washington, DC. The PEPI-RCT was 3 years in duration; the PEPI-RCT bone
measurements were taken at baseline, 12 months, and 36 months.
THE PSFS
All PEPI-RCT participants were invited to return for the PSFS. This was an
observational study that monitored potential toxicity end points related to
long-term postmenopausal hormone use (ie, mammograms and endometrial histologic
analyses). During the PSFS, women were no longer assigned to randomized
treatments. Rather, if they were taking postmenopausal hormones, these were
privately prescribed. At the termination of the PSFS, a BMD evaluation of the
lumbar spine and hip was offered to all participants. The PSFS BMD was measured
between 3 and 5 years after the participants had completed the PEPI-RCT.
ELIGIBILITY FOR THE PSFS BONE
ANALYSIS
Participants in the present study attended the PSFS BMD visit, completed the
PSFS assessment of hormone therapy use, and were adherent to their assigned
(active or placebo) treatment during each of the intervals of the PEPI-RCT
(baseline to 12 months and 12 months to 36 months). The latter restriction was
applied because the present study is concerned with the effects of long-term
HRT on BMD and with patterns of BMD loss after HRT discontinuation.
THE STUDY SAMPLE
The final PEPI-RCT visit was attended by 847 women (97% of the original 875
PEPI-RCT participants). Among these, treatment adherence to unopposed
conjugated equine estrogen therapy was relatively lower (63%) in women with a
uterus than in those without; this was due to protocol-mandated cessation of
study drug treatment when a woman developed endometrial hyperplasia.16-18 For the other
active and placebo treatments, adherence ranged from 79% to 84% and did not
vary significantly by assignment.17 Because our group
previously found no differences in spine or hip BMD outcomes among active
treatments,8 and for power
considerations, we combined all active treatments into a single analysis group
for the present study. Of the 560 women who came to the PSFS BMD visit, 495
women met the criteria for this analysis, representing 57% of the original
PEPI-RCT sample and 58% of those who attended the final PEPI-RCT visit.
Characteristics of participants in the present analysis and those of women
included in the PEPI-RCT but who did not qualify for the present study are
given in Table 1.
ASSESSMENT AND CODING OF
ESTROGEN AND ESTROGEN/PROGESTIN USE
The PEPI-RCT protocol defined adherence to assigned treatment as having taken
at least 80% of the expected medication, assessed by pill count, during the
interval since the last scheduled BMD measurement (ie, baseline to 12 months
and 12 to 36 months). After the PEPI-RCT, treatment was not randomized; women
were classified as postmenopausal hormone users (yes/no) according to
self-report at the time of their PSFS BMD visit. If at the PSFS BMD visit a
woman reported that she had discontinued taking hormones since the PEPI-RCT, we
did not assess the exact time at which she had stopped taking them. These women
were coded as having stopped HRT at the end of the PEPI-RCT. The PEPI-RCT
debriefing interviews indicated that most women who stopped taking hormones did
so very soon after the trial ended.
We grouped participants into 5 categories of
hormone use over the course of the PEPI-RCT and the PSFS: (1) continuous
hormone users; (2) those who stopped taking hormones after 1 year; (3) those
who stopped taking hormones after 3 years; (4) those who started taking
hormones after the PEPI-RCT; and (5) those who had not used hormones. The
numbers of women with each hormone use pattern are depicted in Figure 1.
BONE DENSITY MEASUREMENTS
The PEPI-RCT BMD protocol has been described in detail.19 Briefly, dual-energy
x-ray absorptiometry scans of the lumbar spine (L2-L4), total hip, and hip
subregions were done at baseline, 12 months, and 36 months using Hologic 1000
QDR instruments (Hologic Inc, Waltham, Mass). Under the BMD quality control
program, a daily Hologic spine phantom scan was taken. To identify morphologic
abnormalities and ensure that all BMD values were within 1% of the standard,
the quality control center reviewed all participant BMD scans. Daily phantom
scans were also reviewed. All unacceptable scans were reanalyzed. Replicate
measures, with repositioning, were performed on each participant at each visit.
At the PSFS BMD visit, the same BMD instruments and quality control methods
were used as in the RCT, but the quality control center had moved from the Mayo
Clinic, Rochester, Minn (Heinz W. Wahner, MD) to Stanford University, Stanford,
Calif (R.M.), for the PSFS. For the present analyses, only spine and total hip
BMDs were considered.
ASSESSMENT AND CODING OF
COVARIATES
Age (years), current smoking status (yes/no), self-reported alcohol intake (
1 drink per day, yes/no),
and intensity-based physical activity level were based on self-report.20, 21 The composite index
of physical activity was constructed by averaging the ordered responses to
activity across 3 domains of home, work, and leisure activity, where 1
indicated light activity; 2, moderate; and 3, heavy. Participants were
classified as relatively slightly active (average response <2), moderately
active (average response 2.0-2.9), and highly active (average response 3). These covariates were
analyzed in a time-varying manner; ie, the values of age, smoking, and physical
activity at each of the BMD measures were used in the analysis.
The following variables were assessed only
during the PEPI-RCT, so their value at the 36-month PEPI-RCT visit was used:
body mass index (BMI; calculated as weight in kilograms divided by the square
of height in meters); education (no college, at least some college, and
postcollege); employment (employed outside the home, homemaker, or other
[retired, unemployed, student, or disabled]); and ethnicity (black, Hispanic,
and other [almost exclusively white]). Total daily calcium intake was based on
a modified version of the food frequency questionnaire developed by Block et al22 from which total
calcium from diet and supplements was calculated.
STATISTICAL ANALYSES
The outcome measure for this study was BMD at the lumbar spine and total hip,
and the major exposure variable was postmenopausal hormone use. Separate
hierarchical linear models23 were fitted to the
longitudinal spine and hip BMD measures using maximum likelihood methods24 in which current HRT
status was included as a time-varying covariate. Post–PEPI-RCT hormone use was
more common in younger women, whites, those with higher educational
backgrounds, and those who adhered to active treatment during the RCT.
Therefore, multivariable models included age, ethnicity, and education as
covariates. Because the PEPI-RCT restricted chronological age and number of
years since menopause, collinearity was created between these 2 variables.25 Therefore,
controlling for age also adjusted for time from menopause. As BMI, physical
activity level, smoking, alcohol use, and calcium intake might be related to
HRT use and to BMD, multivariable models also included these covariates.
Profiles of mean BMD values over time were computed from these models, and
estimates were obtained for levels of BMD and changes in levels of BMD for
women maintaining, initiating, and ceasing hormone use according to different
accumulated exposures to hormones.
RESULTS
Most relevant demographic, anthropometric, and
behavioral characteristics were similar in PEPI-RCT participants who were
included in and excluded from the PSFS bone analysis (Table 1).
Average BMI was 1 kg/m2 lower in PSFS bone study subjects than in
those not included in the present analysis. Table 1
also illustrates that the distributions of PEPI-RCT treatment assignments
differed between those included and those not included in the PSFS bone
analysis. Mean baseline values of lumbar spine and total hip BMD in present
study participants were similar to those in the women who were excluded (Table 1).
The BMD values measured at 36 months were also similar in these groups (data
not shown).
Figure 1
illustrates participants' hormone use during the PEPI-RCT and the PSFS.
Continuous users of postmenopausal hormones for the duration of the PEPI-RCT
and the PSFS follow-up period numbered 247; 35 women stopped active treatment
after 12 months in the PEPI-RCT and persisted in nonuse of hormones during the
PSFS. A group of 87 women ceased HRT when the PEPI-RCT ended, while 68 women
only started using hormones at the end of the PEPI-RCT. Finally, 58 women who
were adherent to placebo during the PEPI-RCT remained without HRT after the
PEPI-RCT terminated.
On average, during the first year of the
PEPI-RCT, women adherent to HRT had statistically significant annual BMD gains
(95% confidence intervals) of 1.41% (1.23%-1.59%) and 3.48% (3.28%-3.68%) at
the hip and spine, respectively (Table 2).
Between 12 and 36 months, continued adherence to active therapy led to further
statistically significant mean increases in BMD: 0.41% (0.21%-0.61%) per year
(hip) and 0.82% (0.62%-1.02%) per year (spine). Persistent HRT use between the
PEPI-RCT and the PSFS did not produce additional BMD increment at the hip. By
contrast, in continuous hormone users, a small but statistically significant
increase in spinal BMD was evident between the end of the PEPI-RCT and the PSFS
BMD measurement (0.32% per year).
Rates of bone loss after HRT discontinuation can
be approximated by examining the annual percentage of BMD lost among women who
stopped HRT after 1 or 3 years of use (Table 2).
Women who stopped HRT after the first 12 months of the PEPI-RCT experienced
statistically significant changes of -0.54% (-1.03% to -0.05%) per year at the
hip and -0.81% (-1.32% to -0.30%) per year at the spine between the 12- and
36-month BMD tests. The 35 women who remained nonusers of hormones after the
PEPI-RCT ended did not manifest further bone loss, with statistically
nonsignificant average annual changes of -0.49% (-1.10% to 0.12%) (hip) and
-0.47% (-1.14% to 0.20%) (spine) per year. Women who stopped HRT after the
PEPI-RCT had significant BMD loss; average rates were -1.01% (-1.40% to -0.62%)
(hip) and -1.04% (-1.45% to -0.63%) (spine) per year.
During the first 12 months of the PEPI-RCT,
women who did not undergo HRT had statistically significant declines in BMD:
-1.02% (-1.35% to -0.69%) at the hip and -1.04% (-1.39 to -0.69%) at the spine.
In these women, bone loss continued at roughly half this rate during the second
2 years of the RCT (Table 2).
After the trial ended, we did not detect statistically significant bone loss in
those who did not undergo HRT.
Figure 2
illustrates the BMD effects of initiating, continuing, or stopping HRT during
the 7 years of RCT and PSFS observation. Continuous hormone users gained a
small amount of spinal BMD but did not experience further hip BMD increases
after the PEPI-RCT. Rates of decline in spine and hip BMD were similar in those
who stopped HRT after 12 months (stopping during the PEPI-RCT) or 36 months
(stopping after the PEPI-RCT). Finally, rates of BMD loss at the spine and hip
in women not undergoing HRT during the first 3 years of the PEPI-RCT were of
similar magnitude to rates of loss evident in women who stopped HRT during or
after the PEPI-RCT.
Models of BMD change over time as a function of
HRT patterns were adjusted for age, education, employment, ethnicity, BMI,
calcium intake, current smoking, alcohol intake, and physical activity (Table 3).
Only 1 difference was apparent compared with unadjusted results: continued
hormone use after the PEPI-RCT did not produce further increases in spine BMD
measured between PEPI-RCT year 3 and PSFS BMD visits.
Self-reported fractures were ascertained at the
PSFS bone visit, but the small number of fractures (n = 69) was too low to
provide adequate statistical power to assess differences among categories of
women undergoing HRT during and after the PEPI-RCT (data not shown).
COMMENT
This study addresses 2 long-standing, unresolved
questions: (1) What are the BMD effects of stopping HRT? and (2) Do long-term
users of estrogen continue to gain bone? Our results indicate that women who stopped
HRT lost bone, but that their rate of loss was not appreciably different from
those women who did not undergo HRT. Our data do not support the existence of
further BMD gains (beyond those seen at 3 years) among women who continued HRT
for approximately 4 additional years after the PEPI-RCT, for a cumulative
average exposure of slightly longer than 7 years.
In a large, comprehensive, cohort study, Cauley
and colleagues6 found that former
users of postmenopausal hormones were not protected from hip fracture
even if they had
previously used hormones for 10 years or more. Values of BMD in current vs
former users of HRT are concordant with these observed hip fracture results.24 Despite past
long-term HRT, average axial and appendicular BMDs in women who quit HRT are
similar to those of untreated women.26
Why is there no apparent fracture reduction or
BMD benefit related to long-term prior HRT? One possibility is that the reason
for hormone discontinuation is associated with greater hip fracture risk or
with a higher rate of bone loss. For example, if HRT were stopped after a
stroke, it would be difficult to disentangle the negative skeletal consequences
of hemiparesis and deconditioning from the effects of stopping HRT (an
illustration of confounding). Although not formally controlling for
comorbidity, studies that have examined the relation between estrogen
cessation, fracture, and BMD were adjusted for physical activity, which is an
imperfect but reasonable proxy for the presence of significantly limiting
illness.
Accelerated (fast) bone loss after
discontinuation of HRT is a second potential reason why former estrogen use
does not prevent hip fracture or substantially preserve BMD.26 However, the
accelerated loss would need to be great enough (ie, faster than the rate of
loss observed in a similar, nontreated, group of postmenopausal women) and/or
persist long enough to bring the BMDs of those women formerly undergoing HRT
down to the level of those who were untreated over similar periods of
observation.
Our data and those of previously published
reports10, 11 do not support the
hypothesis that cessation of HRT leads to a faster rate of bone loss than that
observed in the appropriate reference group of untreated women. In the PEPI-RCT
and the PSFS, the rates of spine and hip bone loss in women during the first 3
years of HRT discontinuation are statistically indistinguishable from the bone
loss rates in untreated women. Similarly, after completion of a 2-year
randomized study of HRT vs placebo, Christiansen and colleagues11 rerandomized
participants to either continue or stop active treatment for another 12 months.
Using forearm bone mineral content as the outcome, these investigators found
that women who stopped HRT lost bone at a rate of roughly 2% per year, the same
as that of the placebo group. These results were corroborated by a 6-year,
open-label extension phase of a 2-year clinical trial performed with women who
had experienced their final menses within the last 2 years (early menopause).13 The authors reported
that the rate of forearm BMD loss among 28 women who had stopped HRT was
similar to that of untreated women, about 2% yearly.13 In contrast, the work
of Lindsay and colleagues10 is widely cited to
support the concept of accelerated bone loss after HRT discontinuation.
However, careful scrutiny of these results casts doubt on that interpretation;
the conclusion rests on selecting the appropriate referent. Lindsay et al
performed an observational study in 14 surgically menopausal women who elected
to stop using HRT after 4 years and 14 women who had never used HRT after
surgery. Follow-up was done 4 years after HRT cessation; the annualized rate of
decline in metacarpal bone mineral content was 2.5% per year in those who
stopped HRT. This rate was virtually identical to the 2.6% per year decline
observed during the first 4 years of observation in the untreated group of
surgically menopausal women.10, 27 Of note, in the
surgically menopausal women who did not take HRT, the rate of bone loss slowed
substantially after the first 4 yearsto
about 0.5% per year.
To date, the PEPI-RCT remains the longest
duration placebo-controlled clinical trial that measured BMD as a function of
randomization to postmenopausal HRT.8 By intention-to-treat
analysis, those assigned to active treatment experienced an approximate gain of
3% in spine BMD and 1.5% in total hip BMD at 1 year. During the next 24 months,
compared with the 1-year values, small but statistically significant increases
in spine BMD (1%) and hip BMD (0.6%) were detected.8 We repeated these
analyses in the present study (the participants in our long-term follow-up were
a subset of the entire trial sample). The additional statistically significant
gains in spine and hip BMD between the 12- and 36-month measurements were
replicated. If we assume that the bone remodeling transient is 1 year, then
both the trial results and the findings of our present subset analysis argue
for a small but measurable increase in BMD after the completion of the
transient phase.
Do those who continue to take hormones for
longer than 3 years gain more bone than is present at 3 years of treatment? In
the PSFS observational study, no statistically significant bone gain (or loss)
was observed at the spine or hip between the 3-year PEPI-RCT BMD and the 7-year
PSFS BMD among women undergoing continuous HRT. This suggests that the BMD
stabilized by 3 years. While cross-sectional analyses have reported higher BMD
values among women undergoing long-term HRT,6, 7, 26 these studies cannot
describe the trajectory of BMD change related to HRT. In one small study,
serial measures of forearm BMD taken over 4 years remained unchanged compared
with baseline in 18 naturally menopausal women treated with daily 17
estradiol and
norethisterone acetate.28
Our study must be interpreted in the context of
its limitations. Importantly, after the trial was over, hormone treatment
choices were not random: younger age, more education, and white race were
positively associated with posttrial HRT continuation.29 Our models were
therefore controlled for these factors, as well as others (BMI, physical
activity, smoking, alcohol use, and calcium intake) that might be associated
with both HRT use and BMD. During the PEPI-RCT, most women who stopped
unopposed estrogen treatment did so because of the development of cystic or
adenomatous endometrial hyperplasia; stopping was required by protocol.17, 18 If there were a
biological linkage between developing endometrial hyperplasia and the response
of bone to estrogen, then results in this endometrial hyperplasia subgroup
would be biased. However, no difference was evident in the pattern of BMD
decline among women who stopped HRT during the PEPI-RCT (principally due to
hyperplasia) and those who stopped it after the trial. Our ascertainment of HRT
use after the PEPI-RCT was by self-report rather than pill count (the method
used during the trial). We did not ask the exact date of HRT cessation in women
who underwent HRT during the PEPI-RCT but stopped treatment after the trial.
Our models assumed that those participants stopped HRT immediately after the
PEPI-RCT. If this assumption was not correct, then unmeasured HRT use in the
"stopped after PEPI group" might be expected to yield a falsely low
estimate of the rate of BMD loss. Of the original randomized sample, 57% were included
in the PSFS bone study, raising the issue of comparability of this subgroup
with the original study sample. The mean BMI of the present study sample was
lower than that of the women who were not in the PSFS bone study. We adjusted
for BMI; further, thinner women would be more likely to demonstrate higher
rates of bone loss. Finally, the PSFS was not randomized. The ideal study
design for evaluating long-term effects of continuous HRT and of
discontinuation of HRT would be a protracted clinical trial with rerandomization
to stopping or continuing HRT after a lengthy initial randomization period.
This 2-phase RCT design is unlikely to be implemented because of ethical
concerns and poor participant acceptance. Thus, despite its limitations, the
PSFS affords reasonable data to approach these important research questions.
In summary, HRT for approximately 7 years did
not provide further BMD benefit beyond that accrued at 3 years. Stopping HRT
did not lead to an accelerated rate of BMD decline. The latter findings argue
against accelerated bone loss as an explanation for the lack of hip fracture
protection afforded by former HRT use. From a clinical perspective, our results
suggest that women who stop HRT may resume bone loss, but that it will not be
at a very rapid rate.
Author/Article Information
From the Division of Geriatrics, University of California at Los Angeles School
of Medicine, Los Angeles (Dr Greendale); the Department of Public Health
Sciences, Wake Forest School of Medicine, Winston-Salem, NC (Dr Espeland and Ms
Slone) the Department of Medicine, Stanford University and the Geriatrics
Research, Education and Clinical Center, Veterans Affairs Medical Center, Palo
Alto (Dr Marcus); and the Department of Family and Preventive Medicine,
University of California at San Diego, San Diego, Calif (Dr Barrett-Connor).
Corresponding author: Gail A. Greendale, MD, University of California at Los
Angeles School of Medicine, 10945 Le Conte Ave, Suite 2339, Los Angeles, CA
90095-1687.
Accepted for publication July 31, 2001.
The PEPI-RCT was supported by cooperative
agreement research grants U01-HL40154, U01-HL40185, UL-HL40195, U01-HL40205,
U01-HL40207, U01-HL40231, U01-HL40232, and U01-HL40273 from the National Heart,
Lung, and Blood Institute, the National Institute of Child Health and Human
Development, the National Institute of Arthritis and Musculoskeletal and Skin
Diseases, the National Institute of Diabetes, Digestive and Kidney Diseases,
and the National Institute on Aging, Bethesda, Md. Packaged medication and
placebos for the PEPI-RCT were provided by Wyeth-Ayerst Laboratories, St
David's, Pa; Schering-Plough Research Institute, Kenilworth, NJ; and The Upjohn
Company (now Pharmacia Corp), Peapack, NJ. The PSFS was funded in whole with
federal funds from the National Heart, Lung, and Blood Institute, National
Institutes of Health, Bethesda, Md, under contracts N01-HV-48132, N01-HV-48133,
N01-HV-48139. Funds to obtain BMD measurements were provided by the National
Institute of Arthritis and Musculoskeletal and Skin Diseases. Dr Greendale was
also supported for this work by the Iris Cantor–University of California at Los
Angeles Women's Center and by grant PHS 282-97-0025 from the University of
California at Los Angeles Center of Excellence in Women's Health.
We thank Valeri Braun for manuscript
preparation.
|
Abridged
List of PSFS Investigators University Centers and
Investigators George Washington University,
Washington, DC Principal Investigator: Vanessa Barnabei, MD, PhD (formerly Valery T. Miller, MD; John
LaRosa, MD) Coinvestigator: Craig Kessler, MD The Johns Hopkins University,
Baltimore, Md Principal Investigator: Trudy Bush, PhD Coinvestigators: Howard Zacur, MD, PhD; David Foster, MD; Roger Sherwin, MD Stanford University,
Stanford, Calif Principal Investigator: Marcia L. Stefanick, PhD (formerly Peter D. Wood, DSc) Coinvestigators: Robert Marcus, MD; Katherine O'Hanlan MD; Melissa Ruyle; Mary
Sheehan, MS University of California, Los
Angeles Principal Investigator: Gail A. Greendale, MD (formerly Howard L. Judd, MD) Coinvestigator: Howard L. Judd, MD University of California, San
Diego Principal Investigator: Elizabeth Barrett-Connor, MD Coinvestigator: Robert Langer, MD The University of Iowa, Iowa
City, Iowa Principal Investigator: Susan R. Johnson, MD (formerly Helmut G. Schrott, MD) The University of Texas
Health Science Center, San Antonio, Tex Principal Investigator: José Trabal, MD (formerly Carl Pauerstein, MD) Coordinating Center: Wake
Forest University School of Medicine, Winston-Salem, NC Principal Investigator: Claudine Legault, PhD (formerly Mark Espeland, PhD; H. Bradley
Wells, PhD) Coinvestigators: George Howard, DrPH; Robert Byington, PhD; Beth A. Reboussin,
PhD; Sally Shumaker, PhD For a complete list of the
original PEPI Investigators, see
JAMA. 1996;276:1389-1396. |
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Edward E.
Rylander, M.D.
Diplomat American
Board of Family Practice.
Diplomat American
Board of Palliative Medicine.