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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
Arch Intern Med. 2002;162:665-672.
ABSTRACT
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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.
INTRODUCTION
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.
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Table 1. Characteristics at the Final PEPI-RCT Visit and Bone Mineral
Density at Enrollment in PEPI of Women in the Present Analyses vs Those Who
Did Not Participate*
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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.
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Figure 1. The numbers of women undergoing
each pattern of hormone therapy. PEPI-RCT indicates the Postmenopausal Estrogen/Progestin
Interventions randomized controlled trial. Mean ± SD duration of use
in years is indicated in parentheses.
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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).
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Table 2. Mean Unadjusted Annualized Percentage Changes in Bone Mineral
Density (BMD) of the Hip and Spine by Time of BMD Measurement and Postmenopausal
Hormone Replacement Therapy in Women Enrolled in PEPI-RCT and PSFS*
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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.
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Figure 2. Bone mineral density (BMD) effects
of initiating, continuing, or stopping hormone therapy (HRT) during the 7
years of the Postmenopausal Estrogen/Progestin Interventions randomized controlled
trial (PEPI-RCT) and the PEPI Safety Follow-up Study. Data are mean ±
SE.
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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.
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Table 3. Mean Adjusted Annualized Percentage Changes in Bone Mineral
Density (BMD) of the Hip and Spine by Time of BMD Measurement and Postmenopausal
Hormone Replacement Therapy in Women Enrolled in PEPI-RCT and PSFS*
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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 years—to 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 INFORMATION
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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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.
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).
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