Bone Mass Response to Discontinuation of Long-term Hormone Replacement
Therapy

Results From the Postmenopausal Estrogen/Progestin Interventions (PEPI)
Safety Follow-up Study

Author Information
<http://archinte.ama-assn.org/issues/v162n6/rfull/#aainfo>   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
IOI00536
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
<http://archinte.ama-assn.org/issues/v162n6/rfull/#r1>  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
<http://archinte.ama-assn.org/issues/v162n6/rfull/#r2>  Although studies of
breast cancer risk related to postmenopausal hormone use have had mixed
outcomes, 3 <http://archinte.ama-assn.org/issues/v162n6/rfull/#r3>  some
have shown that cancer risk increases with longer duration of estrogen use.
4 <http://archinte.ama-assn.org/issues/v162n6/rfull/#r4> , 5
<http://archinte.ama-assn.org/issues/v162n6/rfull/#r5>
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 studies 6 <http://archinte.ama-assn.org/issues/v162n6/rfull/#r6> , 7
<http://archinte.ama-assn.org/issues/v162n6/rfull/#r7>  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
<http://archinte.ama-assn.org/issues/v162n6/rfull/#r6> , 8
<http://archinte.ama-assn.org/issues/v162n6/rfull/#r8> , 9
<http://archinte.ama-assn.org/issues/v162n6/rfull/#r9>  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
<http://archinte.ama-assn.org/issues/v162n6/rfull/#r6>  However, few studies
directly assess the pattern of BMD loss after stopping HRT. 10-13
<http://archinte.ama-assn.org/issues/v162n6/rfull/#r10>
Much remains to be learned about the skeletal effects of long-term HRT.
Estrogen's antiresorptive action on bone is well established, 14
<http://archinte.ama-assn.org/issues/v162n6/rfull/#r14>  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
mass 15 <http://archinte.ama-assn.org/issues/v162n6/rfull/#r15> ). 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
<http://archinte.ama-assn.org/issues/v162n6/rfull/#r15>
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
<http://archinte.ama-assn.org/issues/v162n6/rfull/#r8> , 16
<http://archinte.ama-assn.org/issues/v162n6/rfull/#r16>  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
<http://archinte.ama-assn.org/issues/v162n6/rfull/#r16>  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 <http://archinte.ama-assn.org/issues/v162n6/rfull/#r16>  For the other
active and placebo treatments, adherence ranged from 79% to 84% and did not
vary significantly by assignment. 17
<http://archinte.ama-assn.org/issues/v162n6/rfull/#r17>  Because our group
previously found no differences in spine or hip BMD outcomes among active
treatments, 8 <http://archinte.ama-assn.org/issues/v162n6/rfull/#r8>  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
<http://archinte.ama-assn.org/issues/v162n6/fig_tab/ioi00536_t1.html> .
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
<http://archinte.ama-assn.org/issues/v162n6/fig_tab/ioi00536_f1.html> .
BONE DENSITY MEASUREMENTS

The PEPI-RCT BMD protocol has been described in detail. 19
<http://archinte.ama-assn.org/issues/v162n6/rfull/#r19>  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
<http://archinte.ama-assn.org/issues/v162n6/rfull/#r20> , 21
<http://archinte.ama-assn.org/issues/v162n6/rfull/#r21>  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
al 22 <http://archinte.ama-assn.org/issues/v162n6/rfull/#r22>  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 models 23
<http://archinte.ama-assn.org/issues/v162n6/rfull/#r23>  were fitted to the
longitudinal spine and hip BMD measures using maximum likelihood methods 24
<http://archinte.ama-assn.org/issues/v162n6/rfull/#r24>  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 <http://archinte.ama-assn.org/issues/v162n6/rfull/#r25>  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
<http://archinte.ama-assn.org/issues/v162n6/fig_tab/ioi00536_t1.html> ).
Average BMI was 1 kg/m2 lower in PSFS bone study subjects than in those not
included in the present analysis. Table 1
<http://archinte.ama-assn.org/issues/v162n6/fig_tab/ioi00536_t1.html>  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
<http://archinte.ama-assn.org/issues/v162n6/fig_tab/ioi00536_t1.html> ). The
BMD values measured at 36 months were also similar in these groups (data not
shown).
Figure 1
<http://archinte.ama-assn.org/issues/v162n6/fig_tab/ioi00536_f1.html>
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
<http://archinte.ama-assn.org/issues/v162n6/fig_tab/ioi00536_t2.html> ).
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
<http://archinte.ama-assn.org/issues/v162n6/fig_tab/ioi00536_t2.html> ).
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
<http://archinte.ama-assn.org/issues/v162n6/fig_tab/ioi00536_t2.html> ).
After the trial ended, we did not detect statistically significant bone loss
in those who did not undergo HRT.
Figure 2
<http://archinte.ama-assn.org/issues/v162n6/fig_tab/ioi00536_f2.html>
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
<http://archinte.ama-assn.org/issues/v162n6/fig_tab/ioi00536_t3.html> ).
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 colleagues 6
<http://archinte.ama-assn.org/issues/v162n6/rfull/#r6>  found that former
users of postmenopausal hormones were not protected from hip fractureeven 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 <http://archinte.ama-assn.org/issues/v162n6/rfull/#r24>
Despite past long-term HRT, average axial and appendicular BMDs in women who
quit HRT are similar to those of untreated women. 26
<http://archinte.ama-assn.org/issues/v162n6/rfull/#r26>
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
<http://archinte.ama-assn.org/issues/v162n6/rfull/#r26>  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 reports 10
<http://archinte.ama-assn.org/issues/v162n6/rfull/#r10> , 11
<http://archinte.ama-assn.org/issues/v162n6/rfull/#r11>  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 colleagues 11
<http://archinte.ama-assn.org/issues/v162n6/rfull/#r11>  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
<http://archinte.ama-assn.org/issues/v162n6/rfull/#r13>  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
<http://archinte.ama-assn.org/issues/v162n6/rfull/#r13>  In contrast, the
work of Lindsay and colleagues 10
<http://archinte.ama-assn.org/issues/v162n6/rfull/#r10>  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
<http://archinte.ama-assn.org/issues/v162n6/rfull/#r10> , 27
<http://archinte.ama-assn.org/issues/v162n6/rfull/#r27>  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 <http://archinte.ama-assn.org/issues/v162n6/rfull/#r8>
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 <http://archinte.ama-assn.org/issues/v162n6/rfull/#r8>  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
<http://archinte.ama-assn.org/issues/v162n6/rfull/#r6> , 7
<http://archinte.ama-assn.org/issues/v162n6/rfull/#r7> , 26
<http://archinte.ama-assn.org/issues/v162n6/rfull/#r26>  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
17beta estradiol and norethisterone acetate. 28
<http://archinte.ama-assn.org/issues/v162n6/rfull/#r28>
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
<http://archinte.ama-assn.org/issues/v162n6/rfull/#r29>  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
<http://archinte.ama-assn.org/issues/v162n6/rfull/#r17> , 18
<http://archinte.ama-assn.org/issues/v162n6/rfull/#r18>  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.