1. A Randomized Controlled Trial of Four Doses
of Transdermal Estradiol for Preventing
Postmenopausal Bone Loss
S. R. WEISS, MD, H. ELLMAN, MD, AND M. DOLKER, PhD, FOR THE TRANSDERMAL
ESTRADIOL INVESTIGATOR GROUP
Objective: To determine the effects of four doses of a 7-day
transdermal 17P-estradiol (E2) delivery system, including
0.025 mg/day, on bone loss in postmenopausal women.
Methorls: This was a multicenter, double-masked, ran-
domized, placebo-controlled study of the effects of transder-
ma1 E2 at doses of 0.025, 0.05, 0.06, and 0.1 mg/day for the
prevention of postmenopausal osteoporosis. Efficacy was
evaluated from bone mineral density of lumbar vertebrae
L2-L4, radius, proximal femur, and total hip measured with
dual-energy x-ray absorptiometry. Serum osteocalcin and
urinary pyridinoline and deoxypyridinoline concentrations
were measured.
Results: At 24 months, E2 doses of 0.025, 0.05, 0.06, and
0.1 mg/day resulted in mean increases in bone mineral
density of the lumbar spine of 2.37%, 4.09%, 3.28%, and
4.70%, respectively, and increased bone mineral density of
the total hip by 0.26%, 2.85%, 3.05%, and 2.03%, respectively.
All increases were statistically significantly greater than
placebo, which decreased bone mineral density by 2.49% at
the spine and 2.04% at the hip. Consistent and significant
improvements in biochemical markers of bone turnover also
were noted at various intervals in all treatment groups. The
most frequent adverse events were local reactions from the
transdermal drug-delivery system, effects of estrogen, and
menopausal symptoms.
Conclusion: Transdennal E2 at doses of 0.025, 0.05, 0.06,
and 0.1 mg/day effectively prevented bone loss in postmeno-
From the Sun Diego Endocrine and Medical Clinic, San Diego,
California; and the Department ofClinicalR & D, Female Health Cure,
Berlex Laboratories, Wayne, New jersey.
The Transdermal Estradiol Investigator Group includes Richard Bath,
MD, and ]ea?lne Blevins, Cincinnati, OH; Sidnq Funk, MD, and Stacy
Beasley, RN, Atlanta, GA; Russell Graham, MD, and Wendy Centers-
Cornell, RN, Altamonte Springs, FL; Daniel Henry, MD, Dorotkeu
Bennett, RN, and ]oni Joiner, Salt Lake Cif!y, UT; John P. Lenikan, MD,
and Emily Kellman, Tacoma, WA; Ernie RiJer, MD, Cristy Anderson,
RN, and Kelly Vesse/ey, Phoenix, AZ; John Sckoenberger, Lisa Morello,
RN, and Diane Madey, RN, Redwood City, CA; Douglas Schumacher,
MD, nnd Mary Elsinger, Columbus, OH; Barbara Solfes, MD, Janet
Cahill, andJulie Ckledowski, Chicago, IL; and Stuart Weiss, MD, Denny
Cricksman, and Eileen Evangelista-Hooker, San Diego, CA.
330 0029-7844/99/520.00
PII SOO29-7844(99)00313-O
pausal women. (Obstet Gynecol 1999;94:330-6. 0 1999 by
The American College of Obstetricians and Gynecologists.)
Estrogen deficiency after menopause causes an increase
in the rate of bone loss and a corresponding increase in
the risk of fractures.’ Immediately after menopause,
bone mass decreases by 34% per year, and even after
age 65, bone mass can continue to decrease at a rate of
0.5-l% per year.2,” Increased bone turnover is associ-
ated with increased bone loss and risk of fractures.“r5
Estrogen replacement therapy (ERT) reduces the rate
of bone loss, maintains bone mass, and reduces the risk
of hip fracture associated with reductions in bone mass
after the menopause. ‘~3 Bone mineral density increased
5-10% over 2 years and the fracture rate decreased by
50% with the use of antiresorptive drugs such as
estr0gen.i
It is generally accepted that oral estrogen at a dose of
1 mg of estradiol (EZ) or 0.625 mg of equine estrogen is
needed to prevent postmenopausal bone 10~s.~~~’How-
ever, recent studies have indicated that lower doses of
estrogen may be effective for maintaining bone
mass.‘2,13 This study was done to investigate the effi-
cacy of four doses of a 7-day transdermal 17/3-E2
delivery system, including a dose of 0.025 mg/day, for
the prevention of bone loss in postmenopausal women.
The safety and efficacy of this product in the treatment
of vasomotor symptoms have been reported previous-
ly.*”
Financial Disclosure
This study was supported by grants from Berlex Laboratories,
Wayne, New Jersey, to participating investigators. Authors Ell-
man and Dolker are full-time employees of Berlex Laboratories.
Obstetrics & Gynecology

2. Materials & Methods
We conducted a multicenter, double-masked, random-
ized, placebo-controlled study at ten centers in the
United States. The study protocol was approved by an
appropriate institutional review board. Each participant
gave written informed consent before entry. Because
subjects assigned to active treatment were to receive
unopposed estrogen for 2 years, only women without
uteri were eligible. Women who had undergone hyster-
ectomies without oophorectomies were required to be
at least 45 years old and have ovarian failure, as
evidenced by vasomotor symptoms for at least 1-5
years before enrollment. Women who had also under-
gone oophorectomies had to be at least 40 years old and
4 weeks to 5 years postoophorectomy. All women were
required to have a serum E2 concentration of at most 20
pg/mL, an FSH level of at least 50 U/L, and fasting
serum concentrations of cholesterol of at most 300
mg/dL, triglycerides of at most 300 mg/dL, and glu-
cose of at most 140 mg/dL. Baseline bone mineral
density of L2-L4 measured by dual-energy x-ray ab-
sorptiometry (Lunar Corporation, Madison, WI or Ho-
logic Inc., Waltham, MA) had to be at least 0.09 g/cm*
(Lunar) or at least 0.086 g/cm’ (Hologic).
Exclusion criteria included known or suspected bone
disease, hypo- or hypercalcemia, vitamin D deficiency,
bone fracture within 6 months, immobilization for 2 or
more of the preceding 6 months, hot flashes requiring
hormone therapy, or a history of skin irritation caused
by transdermal drug-delivery systems. Women also
were excluded if they had ever received bisphospho-
nates, fluoride, or calcitonin; were receiving chronic
treatment with corticosteroids or agents that affect bone
metabolism; had had recent ERT or treatment with
lipid-lowering drugs; or had participated in another
clinical trial within 3 months.
Eligible women were assigned randomly in a ratio of
3:2:2:2:2 to receive placebo or one of four doses of a
17/3-E2 transdermal system (Climara; Berlex Laborato-
ries, Wayne, NJ): 0.025,0.05, 0.06, and 0.1 mg/day of E2
delivered in patches of 6.5, 12.5,15, and 25 cm’, respec-
tively. The block size at each center was 11 (ie, 3 + 2 +
2 + 2 + 2). Each subject wore two patches (an active and
a different-sized inactive patch for the study groups;
two different-sized inactive patches for the placebo
group). One of a class of Latin square designs masked
the assignment of four different patch sizes to the 11
combinations of patch pairs worn in each block. A
permuted-blocks randomization for the five treatment
groups was centrally computed independently for each
investigative site, and the drug was packaged and
shipped to each site accordingly. A seeded pseudoran-
dom number generator was programmed with SAS
software (SAS, Inc., Cary, NC). Subjects were sequen-
tially assigned random numbers at each site. Personnel
conducting the study remained masked to the treat-
ment assignments until after the database was locked.
Subjects applied both patches to the anterior trunk and
replaced them weekly. Treatment was continued for 26
4-week cycles. Calcium supplementation was provided
to achieve a total daily calcium intake of 1500 mg.
Baseline examinations included complete histories,
physical examinations including pelvic examinations,
and general laboratory tests including hematology,
blood chemistry, liver function tests, lipid profile, E2,
FSH, and TSH. Serum osteocalcin and urinary concen-
trations of pyridinoline and deoxypyridinoline cross-
links were measured in second morning voided speci-
mens. Subjects wore placebo patches for 1 week to
assess tolerance of the transdermal system.
Bone mineral density was measured at four anatomic
sites (lumbar spine, nondominant radius, ipsilateral
total hip, and femoral neck), and study medication was
dispensed. Participants returned for nine follow-up
assessments at approximately 3-month intervals. Bone
mineral density measurements were repeated at 6, 12,
18, and 24 months. Bone mineral density data were
analyzed at a single quality-assurance center, which
also provided technical training to all investigative sites
and standardization of all equipment used. At these
same time points, assays of serum osteocalcin15 and
urinary concentrations of pyridinoline and deoxypyr-
idinoline crosslinks (Pyrilinks-D; Metra Biosciences,
Mountain View, CA)16,r7 were performed in a central
laboratory, and physical and pelvic examinations, vital
signs, and laboratory tests were repeated. Mammo-
grams were done at baseline and at l- or 2-year inter-
vals, depending on age.
The primary efficacy variable was the percentage
change from baseline in spine bone mineral density in
the anteroposterior view of lumbar vertebrae L2-L4.
Secondary efficacy variables were the percentage
changes from baseline in bone mineral density of the
midshaft of the radius, the proximal femur, and the
total hip. The percentage change from baseline in serum
osteocalcin and the change and percentage change in
urinary deoxypyridinoline-creatinine and pyridinoline-
creatinine ratios were determined. Safety evaluations
were based on physical examinations, mammography,
fracture incidence, vital signs, weight, and laboratory
tests. Adverse experiences and study investigators’ ob-
servations of abnormalities or changes in physical or
biochemical characteristics were recorded.
Efficacy was determined in the intent-to-treat popu-
lation, defined as all randomized subjects who took at
least one dose of study medication. An analysis using
data from the last observation carried forward was
VOL. 94, NO. 3, SEPTEMBER 1999 Weiss et al Low-Dose Transdermal Estradiol 331

3. Table 1. Baseline Characteristics
Transdermal &radio1 dose (mg/d)
~_.
Placebo 0.025 0.05 0.06 0.10
Characteristic (n = 46) (n = 32) 01 = 31) (,I = 31) (n = 35)
Age (Y) 51.5 ? 4.3 51.9 r 3.Y 50.Y t 5.4 50.3 ?I 4.9 51.3 2 5.8
Weight (lb) 163.2 t 3Y.7 162.3 2 31.7 167.4 t 37.7 158.4 + 25.0 165.4 -t 33.6
Race
White 38 (83%) 26 (81%) 24 (77%) 26 (84%) 32 (9 1%)
Black 3 (7X) 5 (16%) 2 (6%) 0 2 (6%)
Hispanic 2 (4%) 0 3 (10%) 4 (13%) 0
Other 3 (7%) 1 (3%) 2 (6%) 1 (3%) 1 (3%)
Data are presented as mean r standard deviation or II (‘X)
done also to minimize bias that may result should
responders tend to stay in the study and nonresponders
tend to drop out. Analysis of continuous variables was
done using two-way analysis of variance with treat-
ment, center, and treatment-by-center interaction as
covariates. Pairwise comparisons were performed using
least-square-means testing of active-dose groups versus
placebo. Paired t tests were used to compare visit and
baseline means within each group. When required,
nonparametric analyses were done with these same
linear models to compare overall and pairwise differ-
ences in treatment, using ranks of the original data.
Treatment and center effects were retained additively in
the model after demonstrating negligible treatment-by-
center effects. Although the statistical error rate was
preset at a! = 0.05, for between-group analyses of
efficacy, P values were adjusted by Hochberg method”
of multiple comparisons before being considered signif-
icant.
The primary objective was to compare the response to
treatment of each dose with placebo. For this analysis,
sample size was calculated to be 176 subjects based
upon detecting a difference of 4% (k-3% standard devi-
ation) in the percentage change in bone mineral density
between placebo and active treatment, which corre-
sponds to (Y= 0.0022 with a power of 60%. The study
was not large enough to show efficacy differences
between treatment groups, nor could it reliably detect
infrequent side effects. A treatment dose was consid-
ered effective if that dose resulted in a mean change in
bone mineral density that was not less than zero. The
fraction of subjects who did not lose bone at each dose
was calculated and compared using the extended Coch-
ran-Mantel-Haenszel test. This overall test was fol-
lowed by pairwise comparisons between placebo and
each active dose using Cochran-Mantel-Haenszel tests.
The P values from these methods for proportions were
corrected by the Hochberg method.r8
Results
A total of 175 women were enrolled, and 97 (55%)
completed 2 years of treatment. Seventy-eight women
did not complete the study; one withdrew for lack of
efficacy (vasomotor symptoms), four (2.3%) had proto-
col deviations, 19 (10.9%) withdrew consent, 20 (11.4%)
had adverse events, and 34 (19.4%) were lost to fol-
low-up or relocated or withdrew for other reasons.
There were no significant differences in baseline demo-
graphic or clinical characteristics among the groups
(Table 1).
All four treatment groups showed increases from
baseline in mean bone mineral density of the lumbar
spine (P < .05 versus placebo at all time points; Figure
1). The mean percentage change in bone mineral den-
sity at month 24 ranged from +2.37% in the group
treated with the 0.025-mg dose to +4.70% with the
O.lO-mg dose, compared with -2.49% in the placebo
group. Using data from the last observation carried
forward to 24 months, the differences between active
treatment and placebo in the mean change in lumbar
spine bone mineral density ranged from 4.65% to 7.53%
(Table 2).
Mean bone mineral density of the total hip increased
from baseline in all four treatment groups (P < .05
versus placebo at all time points; Figure 2). The mean
percentage change in bone mineral density at month 24
ranged from +0.26% with the 0.025-mg dose to +2.03%
with the O.lO-mg dose, compared with -2.04% in the
placebo group. At the 24-month assessment, the differ-
ences in the means for hip bone mineral density com-
pared with placebo were 2.31%, 4.07%, 4.27%, and
3.65% for the 0.025-, 0.05-, 0.06-, and O.lO-mg doses,
respectively (Table 2). The mean percentage changes
from baseline in bone mineral density of the radius and
femoral neck compared with placebo were not statisti-
cally significant except at 18 and 24 months in the
O.lO-mg dose group.
332 Weiss et al Low-Dose Transdermal Estradiol Obstetrics f? Gynecology

4. --(I Placebo --(I Placebo
-o- 0.025 mg/day
+- 0.05 mglday
F-
+ 0.06 mglday * *
”
-w- 0.1 mglday
(u4
.&
$3
m”
;2
8)’
s
50 ----------__
8
C -1
([I
r” -2
- I
0 A IL l’s 2b
Month of Treatment
Figure 1. Mean percentage change from baseline for bone mineral
density of the lumbar spine with active treatment and placebo. *P < .05
versus placebo.
Bone mineral density was maintained at the lumbar
spine and in the total hip in most women at all doses
and time points. The proportions of women who did
not lose bone at 24 months were 90% in the lumbar
spine (Table 3) and 76% in the hip at the O.lO-mg dose
(Table 4). Although between-dose comparisons were
not done, a trend analysis found a significant (P < .05)
dose-response effect for bone mineral density of the
lumbar spine and total hip at 6, 12, 18, and 24 months;
for the radius at 6, 18, and 24 months; for the femoral
neck at 18 and 24 months; and for the total hip at 6, 12,
18, and 24 months.
Serum osteocalcin levels decreased from baseline at
all time points in all treatment groups but increased in
the placebo group. The mean percentage change from
baseline in serum osteocalcin was statistically signifi-
cantly greater than for placebo at 12,18, and 24 months
in all treatment groups except for the O-05-mg and
Table 2. Mean Change From Baseline Relative to Placebo in
Bone Mineral Density of the Spine and Total Hip
Spine (LZ-L4) Total hip
Dose (ma/d) 12 mo 24 mo 12 mo 24 mo
0.025 3.75 4.65 2.13 2.31
0.05 4.97 6.07 3.49 4.07
0.06 4.17 5.78 2.62 4.27
0.10 5.14 7.53 2.53 3.65
Data are presented as percentages.
41
+ 0.025 mglday
-A- 0.05 mglday
+ 0.06 mgiday
E
z 3-
-C 0.1 mglday *
3
m
E2
zk ‘-
s
6 0-I *
E
!z -l-
a”
5 -2-
$
- I
0 6 lh lE!
--1
24
Month of Treatment
Figure 2. Mean percentage change from baseline for bone mineral
density of the total hip with active treatment and placebo. *P < .05
versus placebo.
0.06-mg doses at 24 months (Figure 3). The mean
percentage change in urinary deoxypyridinoline/
creatinine ranged from -12.3% to -22.1% in the four
treatment groups at 24 months. These differences were
not statistically significant compared with placebo be-
cause of a -8.0% change in the placebo group. The
results were similar for urinary pyridinoline/creatinine.
Of the 175 subjects enrolled, 97 (55.4%) reported one
Table 3. Number of Subjects With No Loss of Lumbar
Spine Bone Mineral Density
Dose
(mg/d)
Visit
6mo 12 mo 18 mo 24 mo
Placebo lo/34 (29%) lo/26 (38%) 10/22 (45%) 6/21 (29%)
0.025 18/25 (72%) 13/20 (65%) 13/17 (76%) 11/16 (69%)
P’ ,003’ ,042 ,034 .010+
0.05 20/23 (87%) 20/21 (95%) 16/18 (89%) 17/18 (94%)
P* 1.001’ <.001* .003” <.001+
0.06 18/24 (75%) 20/24 (83%) 17/22 (77%) 17/20 (85%)
P* ,001’ .001* ,047 ,001’
0.10 23/27 (85%) 21/24 (88%) 21/23 (91%) 19/21 (90%)
P* <.001+ .001* .OOlS .001+
Overall <.OOl’ <.OOl’ ,002’ <.OOl¶
P”
* P value for comparison of each dose against placebo. P values were
adjusted by the method of Hochberg.‘*
+Pl < ,042.
* P2 < ,021.
5 P3 < ,014.
“Overall P value (‘P < .05) was obtained from an extended
Cochran-Mantel-Haenszel statistic adjusting for site.
VOL. 94,N0. 3,SEPTEMBER 1999 Weiss et al Low-Dose Transdermal Estradiol 333

5. Table 4. Number of Subjects With No Loss of Total Hip
Bone Mineral Density
Visit
Dose (mg/d) 6mo 12 mo 18 mo 24 mo
Discussion
Placebo
0.025
PI
0.05
lJ*
0.06
P*
0.10
P*
Overall
P”
12/34 (35%)
13/23 (57%)
,116
18/24 (75%)
.004*
17/23 (74%)
.013*
17/24 (71%)
.011*
.OOS’
9/26 (35%) 3/22 (14%) S/21 (38%)
12/18 (67%) 11/16 (69%) 9/14 (64%)
,103 .002+ ,106
19/22 (86%) 16/18 (89%) 14/18 (78%)
.OOl§ .001+ ,067
14/22 (64%) 17/21 (81%) 17/20 (85%)
,058 <.001+ ,011
15/22 (68%) 17/22 (77%) 16/21(76%)
,030 .001+ ,050
,008’ <.OOl’n ,025’
* P value for comparison of each dose against placebo. P values were
adjusted by the method of Hochberg.‘*
+Pl < ,041.
* P2 < ,021.
5 P4 < ,011.
IiOverall P value (‘P < .05) was obtained from an extended
Cochran-Mantel-Haenszel statistic adjusting for site.
or more adverse events during the 2-year treatment.
Overall, 20 women (11.4%) withdrew from the study
because of adverse events. The most common causes
were application-site reactions in six (3.4%), emotional
lability in three (1.7%), breast pain in three (1.7%), hot
flashes in four (2.3%), headache in two (l.l%), and
depression in two (1.1%). The incidence of adverse
events with active treatment was comparable to or
lower than that with placebo. There were no spontane-
ous fractures, but four women experienced traumatic
fractures during the study, one each in the placebo,
0.025-mg, 0.06-mg, and O.lO-mg groups. There were no
clinically relevant or statistically significant changes in
routine laboratory results, diastolic blood pressure,
heart rate, or body weight.
This study reaffirms the efficacy of transdermal delivery
of E2 for preventing postmenopausal bone loss” and
confirms recent reports of decreased bone turnover at
doses as low as 0.025 mg/day.12 Compared with pla-
cebo, there were significant increases in lumbar spine
bone mineral density at 6 months, which were main-
tained or extended among women who were followed
to 24 months. Similar efficacy was seen for maintenance
of bone mineral density in the total hip. Consistent
decreases in serum osteocalcin and urinary deoxy-
pyridinoline/creatinine, indicative of decreased bone
turnover, supported the positive bone mineral density
findings.
The most widely prescribed doses of estrogen
(0.625 mg of conjugated estrogen, 0.05 mg of E2 trans-
dermally, and 1 mg of E2 orally) have been believed to
be at or near the minimum effective dose for preventing
postmenopausal bone loss. However, 0.5 mg of E2
administered orally showed preservation of bone min-
eral density at the lumbar spine at 18 months, although
at 24 months the results were not significantly different
from placebo. 2oThe small sample and low precision of
measurement in that study probably are responsible for
this result. More recently, 0.3 mg of esterified estrogens
was shown to preserve bone mineral density.13 Our
current study has demonstrated in a 2-year prospective
design that doses of transdermal E2 as low as
0.025 mg/day prevent osteoporosis in postmenopausal
women.
The finding of beneficial effects on bone mineral
Placebo
kzl0.025 mg/day
0
0.05 mg/day
•zl 0.06 mg/day Figure 3. Mean percentage change
from baseline in serum osteocalcin
0.1 mg/day levels with active treatment and pla-
cebo. ‘P < .05 versus placebo.
3
m 20
E
g 10
%
s 0
6
E -10
$
t
a
-20
s -30
5
-40-l
6 12 18
Month of Treatment
334 Weiss et al Low-Dose Transdermal Estradiol
*
24
Obstetrics 0 Gynecology

6. density with a 6.5-cm* patch delivering E2 at 0.025
mg/day contrasts with the results of some older studies
that showed no benefit of low estrogen doses for
preventing postmenopausal bone 10~s.‘~~”These differ-
ences may relate to the lower sensitivity of older
instrumentation, which thus required larger popula-
tions to demonstrate efficacy. The most recent report
showing no benefit from low-dose estrogen was a
case-control study, the results of which may be limited
by confounding bias and low statistical power in sub-
group analyses.’ More recent studies have shown effi-
cacy of low doses of estrogen.
The magnitude of changes in bone mineral density in
our study are consistent with those reported in a
double-masked, randomized, placebo-controlled study
of oral esterified estrogens at doses as low as
0.3 mg/day.13 The effects of the 0.025-mg/day dose on
bone mineral density can also be compared with recent
findings using the selective estrogen-receptor modula-
tor raloxifene? Results at 24 months with the 0.025-
mg/day dose (+2.31% relative to placebo) are similar to
those obtained with 60 mg/day of raloxifene (+2.4%
versus placebo) for total hip bone mineral density and
are almost double that of raloxifene relative to placebo
for the lumbar spine (+4.65% versus +2.4% with ralox-
ifene) .
Mean bone mineral density values at the spine and
hip with the 0.025-mg dose were somewhat lower at 24
months than at 18 months. Although the differences
were not statistically significant, this observation may
have clinical implications. Nevertheless, most women
had preservation of bone mass at the hip and spine at 18
and 24 months. Longer studies will be needed to
determine whether these findings are the result of
intrasubject variability or evidence that resumption of
age-related bone loss, albeit at a slower rate, can be seen
as early as 2 years after the start of ERT.
The positive effects of ERT on signs and symptoms of
postmenopausal estrogen deficiency, and the long-term
effects of reducing morbidity and mortality from car-
diovascular disease and osteoporotic fractures, are well
known.22-24 However, most postmenopausal women do
not initiate ERT, and of those who do, most discontinue
therapy within 6 months, depriving themselves of po-
tential long-term benefits.25 Among the reasons cited
for not starting or for discontinuing ERT are the risk of
cancer, adverse events, and continued cyclic bleeding.26
The challenge is to overcome the objections of women
to continuing long-term therapy with ERT. A low-dose
transdermal E2 delivery system that prevents bone loss
is an important option that may address the problem of
long-term compliance by reducing dose-related adverse
events. It remains to be shown that low-dose transder-
ma1 estrogen therapy also conveys the presumptive
cardiovascular protection of higher-dose therapy.
The potential clinical implications of our results are
that women may be offered higher doses of transdermal
E2 early after surgical menopause to control symptoms
and to provide initial protection against the cardiovas-
cular and metabolic effects of estrogen deficiency. As
symptoms decrease, the dose can be reduced progres-
sively and substantially to maintain symptomatic relief
while still providing protection against osteoporotic
bone loss.
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Address reprint requests to:
H. Ellman, MD
Female Health Care, Clinical R 6 D
Berlex Laboratories
340 Changebridge Road
Monfville, NJ 07045-1000
E-mail: herman_ellman@berlex.com
Received November 13, 1998.
Received in revisedform February 25, 1999.
Accepted March 4, 1999.
Copyright 0 1999 by The American College of Obstetricians and
Gynecologists. Published by Elsevier Science Inc.
336 Weiss et al Low-Dose Transdermal Estradiol Obstetrics 0 Gynecology