The Journal of Clinical Endocrinology & Metabolism Vol. 86, No. 2 755-760
Copyright © 2001 by The Endocrine Society
Efficacy of Levormeloxifene in the Prevention of Postmenopausal Bone Loss and on the Lipid Profile Compared to Low Dose Hormone Replacement Therapy1
P. Alexandersen,
B. J. Riis,
J. A. Stakkestad,
P. D. Delmas and
C. Christiansen
Center for Clinical and Basic Research (P.A., B.J.R., J.A.S.,
C.C.), 2750 Ballerup, Denmark; Center for Clinical Osteoporosis
Research (J.A.S.), N-5500 Haugesund, Norway; and INSERM,
U-403 (P.D.D.), 69008 Lyon, France
Address all correspondence and requests for reprints to: Dr. Claus Christiansen, Center for Clinical and Basic Research, Ballerup Byvej 222, 2750 Ballerup, Denmark. E-mail: Ldp{at}CCBR.dk
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Abstract
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Three hundred and one healthy women between 45 and 65 yr of age and at
least 1 yr postmenopausal were randomly assigned to 12-month
double-blind therapy with levormeloxifene [1.25 (n = 51), 5, 10,
or 20 mg/day], low dose continuous combined hormone replacement
therapy [HRT; 1 mg 17ß-estradiol and 0.5 mg norethisterone
acetate/day], or placebo (all n = 50). All of the women were also
given a daily supplement of calcium (500 mg). Serum CrossLaps decreased
by about 50% in the levormeloxifene groups, with no dose-response
effect. The group receiving HRT decreased more (>60%), and the
placebo group (500 mg calcium alone) decreased by about 10%. The
pattern was similar for bone alkaline phosphatase, except that the
decreases were smaller, about 30% for the levormeloxifene groups and
50% for the HRT group. Serum osteocalcin also showed highly
significant decreases, of the same magnitude in the levormeloxifene and
HRT groups. Spinal bone mineral density (BMD) decreased by less than
1% in the placebo group and increased by about 2% in the
levormeloxifene groups and by almost 5% in the HRT group
(P < 0.001 for the difference between
levormeloxifene and HRT vs. placebo). BMD of the total
hip and total body changed in the same direction, although differences
between groups were not as pronounced as those for BMD spine. Total
cholesterol decreased by about 13–20% during levormeloxifene therapy,
whereas daily doses of 1 mg estradiol and 0.5 mg norethisterone acetate
produced a decrease of only about 8%. Levormeloxifene decreased low
density lipoprotein cholesterol by about 22–30% compared with about
12% in the low dose HRT group. High density lipoprotein cholesterol
was unchanged in all groups. Endometrial thickness increased both
clinically and statistically significantly in the levormeloxifene
groups independently of the dose; the difference from the placebo and
HRT groups was significant (P < 0.001). There was
no significant difference between the HRT and placebo groups. Other
adverse events of interest include hot flushes, which did not occur
more frequently in the levormeloxifene than the placebo groups, but
occurred significantly less frequently in the HRT group
(P < 0.05). Breast tenderness was much more common
in the HRT group (<0.001) than in all other groups. In conclusion, the
study shows that levormeloxifene, a new selective estrogen receptor
modulator, has positive effects on BMD and bone turnover and apparently
strong estrogenic effects on the serum concentrations of different
cholesterol subfractions. Levormeloxifene at the doses tested had an
estrogen-like effect on endometrium and no effect on hot flushes. The
study was unable to differentiate between the effects of the different
doses of levormeloxifene.
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Introduction
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ESTROGEN (HORMONE) replacement therapy
(HRT) is effective in preventing postmenopausal bone loss and
osteoporotic fracture (1, 2) and in alleviating
climacteric complaints, such as hot flushes and vaginal dryness.
Furthermore, HRT seems to reduce the risk of coronary heart disease by
changing the lipoprotein subfractions in a favorable way
(3). However, due to side-effects such as vaginal bleeding
and breast tenderness, compliance to long-term use of HRT is poor
(4). Compliance is also affected by apprehensions
regarding the risk of breast cancer (5, 6).
In the search for a drug that possesses the beneficial actions of
estrogen on bone mass and the cardiovascular system, but not its
undesirable effects, a number of compounds with both estrogenic and
antiestrogenic effects have been evaluated over the last few years.
Centchroman, an estrogen antagonist widely used in India since 1980 as
an anti-fertility agent, has been shown to prevent bone loss in animal
studies (7). As Centchroman is a racemic mixture,
investigations were undertaken to examine whether the bone-preserving
effect was confined to one of the enantiomers. It was found to reside
in the L-enantiomer of the compound, named levormeloxifene.
Furthermore, Centchroman is being developed for the treatment of
advanced breast cancer (8). The chemical name of
levormeloxifene is
(-)-3,4-trans-7-methoxy-2,2-dimethyl-3-phenyl-4{4-[2(pyrrolidin-1-ye)ethoxyl]phenyl}chromane.
Like raloxifene, levormeloxifene is a selective estrogen receptor
modulator (SERM). Raloxifene is approved for the prevention and
treatment of osteoporosis. Without stimulating the endometrium,
raloxifene increases bone density in postmenopausal women, decreases
bone turnover, lowers serum total and low density lipoprotein (LDL)
cholesterol, and reduces the incidence of fracture and breast cancer in
osteoporotic women (9, 10, 11). According to nonclinical
pharmacology, levormeloxifene seems to possess the same desired
estrogenic effect on the skeleton and cardiovascular system without
inducing endometrial hyperplasia (7, 12, 13).
We present here the results of a phase II, 12-month interim analysis of
a 2-yr multicenter, double-blind, placebocontrolled study of the
effect of levormeloxifene on bone mineral density (BMD), biochemical
bone markers, lipid profile, and endometrial safety in 301
postmenopausal women.
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Subjects and Methods
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Study subjects
The study was conducted in Norway and Denmark. Most of the
participants were recruited with the aid of lists of social security
numbers or registered voters. The participants were selected as a
representative sample of generally healthy women, between 45 and 65 yr
of age, at least 1 yr postmenopausal, and with an intact uterus. The
enrolment criteria were designed to include both women with low BMD and
those with normal BMD. Women were excluded if they had a known or
suspected acute or chronic disease or were taking medication known to
interfere with the results of the study.
Study design
Three hundred and one participants were randomly assigned to a
double blind therapy with levormeloxifene [1.25 (n = 51), 5, 10,
or 20 mg levormeloxifene/day], low dose continuous combined HRT
[17ß-estradiol (1 mg) and norethisterone acetate (NETA; 0.5
mg/day)], or placebo (all n = 50). All of the women were also
given a daily supplement of 500 mg calcium.
After baseline assessment, study visits took place at 6 weeks and 1.5,
3, 6, and 12 months. Biochemical markers of bone turnover and lipids
were measured at each visit. The BMDs of the spine, hip, forearm, and
total body and endometrial thickness were measured every 6 months.
Participants were questioned at each visit about climacteric complaints
(Kuppermann index), concomitant medication, and the occurrence of
adverse events. The women were followed-up without treatment for 12
months, with examinations at 16, 20, and 24 months. Safety variables
were physical examinations and vital signs, gynecological examinations
with transvaginal ultrasound, endometrial biopsy and pap smear, routine
laboratory evaluations, serum lipids, and mammography. All participants
gave their written informed consent, and the study was performed in
accordance with the Declaration of Helsinki and was approved by the
local ethical committee.
Methods
The BMDs of the total body, lumbar spine (L1–L4), hip, and
forearm were measured by dual energy x-ray absorptiometry with a
QDR-2000 or QDR-4500 densitometer (Hologic, Inc., Waltham,
MA). Scan quality was reviewed, without knowledge of group assignment,
at a central facility (Quality Assurance Center, Ballerup, DK),
which provided correction factors to adjust for changes in the
performance of the densitometer over time.
For blood and urine biochemical analysis, samples were taken in the
morning after a fast for at least 8 h. Biochemical markers of bone
turnover included 1) serum C telopeptide (CrossLaps) measured by
enzyme-linked immunosorbent assay (ELISA; s-CrossLaps, Osteometer,
Copenhagen, Denmark) (14), 2) serum bone-specific alkaline
phosphatase measured by ELISA (Alkaphase-B, Metra Biosystems, San Diego, CA) (15), 3) serum
osteocalcin measured by a human two-site immunoradiometric assay
(ELSA-OSTEO, CIS Biointernational, Gif-sur-Yvette, France)
(16), 4) serum procollagen I-C-terminal peptide (PICP)
measured by ELISA (Prolagen-C Kit, Metra Biosystems)
(17), and 5) urinary CrossLaps measured by ELISA
(u-CrossLaps, Osteometer) (18). All samples were analyzed
at a central laboratory (Lyon, France). Serum lipids, including total
cholesterol, LDL cholesterol, high density lipoprotein (HDL)
cholesterol, very low density lipoprotein cholesterol, and
triglycerides, were analyzed at a central laboratory (CRL, Kiel,
Germany). The double layer thickness of the uterine endometrium
was determined by transvaginal ultrasonography (System 3535,
Brüel & Kjär, Naerum, Denmark; and Siemens, Sonoline
S-1–250, Siemens AG, München, Germany).
Statistical analysis
All analysis was performed on an intention to treat basis. The
dataset comprised all women who had at least one follow-up visit after
randomization. For women who were withdrawn from the study before the
12-month visit, the last observation carried forward principle was
applied. Baseline comparability was estimated by ANOVA. As a response
for endometrial thickness, the absolute change in millimeters from
baseline was used, whereas for all other parameters the percent change
from baseline was used. The responses were compared by ANOVA. The
results were checked for interaction of center and age, which had no
influence on the significance level. For comparison of reported adverse
events between group, Fischer’s exact test was used.
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Results
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All 301 participants who entered this trial were Caucasian. Table 1
gives the baseline demographic data per
treatment group. On the average, the total group was 57.9 ± 3.8
(mean ± 1 SD) yr old and had a body weight of
69.7 ± 10.3 kg, a body height of 163 ± 6 cm, and a body
mass index of 26.1 ± 3.6 kg/m2. There were
no significant differences among the 6 treatment groups. The groups
were also comparable for menopausal age (mean ± 1 SD,
105.9 ± 56.0 months), blood pressure, and heart rate. Of the 301
participants, 233 (77.4%) completed all examinations. Sixty-eight
(22.6%) left the study: 46 (15.3%) because of adverse events, 2
(0.7%) for noncompliance, and 20 (6.6%) for other reasons. The
distribution is shown in Table 2. The
most important adverse event (increased endometrial thickness) is
graphically presented in Fig. 1. In the
levormeloxifene groups, endometrial thickness increased significantly
both clinically and statistically. The difference from the placebo and
HRT groups was significant (P < 0.001). There was no
significant difference between the HRT and placebo groups. At the point
of this interim analysis, increased endometrial thickness caused no
discomfort and no dropouts. Other adverse events of interest include
hot flushes, which did not occur more frequently in the levormeloxifene
groups than in the placebo group, but occurred significantly less
frequently in the HRT group (P < 0.05; Table 3). On the other hand, breast tenderness
was much more common in the HRT group (<0.001) compared with all other
groups (Table 3). Bleeding was experienced by 1 person in the placebo
group, by 1–9 subjects in the levormeloxifene groups (not
dose-related; P = 0.24), and by 12 subjects in the HRT
group (P < 0.05). Other adverse events were evenly
distributed among the groups. All data from the 12-month follow-up have
not finally analyzed, but in this period endometrial thickness declined
toward baseline levels in patients who had experienced an increase
during levormeloxifene treatment. Levormeloxifene did not induce
endometrial hyperplasia or any significant endometrial proliferation.
Eight women, all in the levormeloxifene groups, experienced
uterovaginal prolapse in the 12-month follow-up period.
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Figure 1. Mean thickness (millimeters) of the
endometrium, as measured by transvaginal ultrasonography.
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Table 3. Number of participants and percentage of all
included participants with breast tenderness and hot flushes with onset
during treatment
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Figure 2 shows the treatment/time plots
of four of the biochemical markers, i.e. serum CrossLaps (as
marker of bone resorption) and serum osteocalcin, bone alkaline
phosphatase, and PICP (as markers of bone formation). Values are given
as a percentage of the baseline. Bone resorption, as reflected by serum
CrossLaps, decreased by about 50% in the levormeloxifene groups, with
no dose-response effect. The group receiving HRT decreased more
(>60%), and the placebo group (500 mg calcium alone) decreased by
about 10%. The pattern was very similar for bone alkaline phosphatase,
except that the decreases were smaller, about 30% for the
levormeloxifene groups and 50% for the HRT group. The decrease in the
placebo group was between 10–15%. Serum osteocalcin also showed
highly significant decreases, but the responses in the levormeloxifene
and HRT group were the same at 52 weeks. The response of PICP was
comparable, but with much larger interindividual variations. Figure 3 shows a column diagram of the 52 week
values (mean ± 1 SEM) of urinary CrossLaps. Again,
the pattern was the same as those mentioned above, but this marker had
the most pronounced response. Furthermore, Fig. 3 shows the BMD values
(mean ± 1 SEM) at 52 weeks in the spine,
total hip region, and total body. The results were most pronounced in
the spine. BMD decreased by less than 1% in the placebo group and
increased by about 2% in the levormeloxifene groups and by almost 5%
in the HRT group (P < 0.001 for the difference between
levormeloxifene vs. HRT and placebo). BMD in the total hip
and total body changed in the same manner, although the differences
between the groups were not as pronounced as those for BMD spine.
Forearm BMD showed no change that was statistically significantly
different between any of the groups during the study.
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Figure 2. Percentage (mean ± 1 SEM)
of baseline values at the different analysis time points of biochemical
markers of bone resorption [serum CrossLaps (CL)] and bone formation
[serum osteocalcin (OC), bone alkaline phosphatase (B-AP), and PICP]
in four levormeloxifene, one estradiol/NETA, and one placebo group.
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Figure 3. Urinary CrossLaps (U-CL) and BMD in the
spine, hip, and total body presented as the percentage (mean ± 1
SEM) of baseline values at 12 months.
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All six groups were comparable in terms of baseline values of serum
lipids and lipoproteins. Levormeloxifene decreased total cholesterol
and LDL cholesterol more than did low dose HRT. Total cholesterol
decreased by about 13–19% during levormeloxifene therapy, whereas a
daily dose of 1 mg estradiol and 0.5 mg norethisterone acetate produced
a decrease of only slightly more than 8%. Levormeloxifene decreased
LDL cholesterol by about 22–30% compared with a decrease of slightly
more than 11% in the low dose HRT group. HDL cholesterol was unchanged
in the levormeloxifene groups and decreased by 3.74% in the HRT group,
but this did not reach statistical significance. The results are
presented in Table 4. Levels of very low
density lipoprotein cholesterol and triglycerides did not change
significantly.
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Table 4. Serum lipids given as the mean (±1 SD)
baseline (millimoles per L) and 52 weeks (percentage of baseline)
values
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Discussion
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This study was a phase II dose-finding trial of levormeloxifene, a
new SERM with promising preclinical and clinical phase I results. It
was designed as a 2-yr multicenter study with an interim analysis at 12
months.
The main outcome of the trial was that levormeloxifene had an apparent
estrogen-like effect on the endometrium that resulted in the
discontinuation of any further development of the drug. All patients
were followed-up for 12 months without treatment where endometrial
thickness declined. The extent of normalization was dose related. All
women were followed until their endometrium was normal. Levormeloxifene
did not induce endometrial hyperplasia or any significant endometrial
proliferation. The increase in endometrial thickness is thus believed
to be related to focal and general fluid accumulation in the uterus.
This may have caused the uterovaginal prolapse experienced by eight
women, although the etiology is not clear. At the end of the follow-up,
two women had recovered completely, and six had not recovered from the
uterine prolapse. Further analysis of all data from the follow-up may
clarify the nature of the uterine changes caused by levormeloxifene and
the speed of recovery.
Levormeloxifene resulted in a maximum difference from placebo in
spinal, hip, and total body BMD of +2.9%, +1.9%, and +0.9%. These
were not as great as the increases in the HRT group, in which only 1 mg
estradiol and 0.5 mg NETA resulted in increases of 4.3%, 2.2%, and
1.4%, respectively. On the other hand, they were of the same magnitude
as those in the group given 60 mg raloxifene, in which the mean
differences in BMD from the placebo group at 12 months were 2.0%,
2.0%, and 1.5% at the spine, hip, and total body, respectively
(9). The effect might also be compared with that of 5 mg
alendronate, which is approved for the prevention of osteoporosis, in
the same target population as the one in this trial. With alendronate,
the corresponding mean BMD differences from the placebo group at 12
months were 3.8%, 2.2%, and 1.8% for spine, hip, and total body
(19).
When bone turnover increases at the time of the menopause, the levels
of bone resorption and formation determine the resulting bone loss. The
higher the bone turnover, the higher the bone loss, i.e. the
higher the difference between resorption and formation and vice
versa (20, 21). This is illustrated by this study
compared with others. Levormeloxifene produced a maximum decrease of
59% of urinary CrossLaps, whereas low dose HRT decreased it by almost
80%. The corresponding values were about 40% for raloxifene
(9) and 70% for 5 mg alendronate (22).
Whereas daily doses of 1 mg estradiol and 0.5 mg NETA had a greater
estrogenic effect on bone turnover, BMD, hot flushes, and breast
tenderness, this was not the true for serum cholesterol and related
parameters. In fact, the response to levormeloxifene was almost double
that of low dose HRT. NETA was previously regarded as a suboptimal
progestogen, because its androgenic effects were considered to have
negative effects on serum lipoprotein (23). In several
animal and clinical studies, we have, however, provided evidence that
if given in the correct dose for endometrial protection, NETA is more
or less neutral in terms of cardiovascular risk factors and is neither
better nor worse than other progestogens (24, 25, 26).
Furthermore, NETA might have additional positive bone effects in
addition to that of the estrogen itself (27). This
corresponds to the data from the present trial in the sense that the
great bone response is a result of the combined effects of estradiol
and NETA, whereas the relatively smaller effect on lipids is caused by
a relatively low estrogen dose (and a neutral progestogen).
Accordingly, it may further be concluded that the doses of
levormeloxifene used in the present study have a stronger estrogenic
effect on serum lipids than has 1 mg estradiol. Furthermore, the
effects on serum lipids are stronger than that of 60 mg raloxifene,
which decreases total cholesterol by 6.4% and LDL cholesterol by
10.1% over 2 yr (9).
In conclusion, this report presents a SERM with positive effects on the
bone and bone metabolism and with apparently strong estrogenic effects
on the serum concentrations of different cholesterol subfractions. Our
study was not able to differentiate between the effects of the
different doses of levormeloxifene. This indicates that the lowest dose
may be sufficient or even too high. The latter is supported by the
significant increase in endometrial thickness, which led to an
important amount of adverse events and, ultimately, to the termination
of further development of the drug. It is unknown whether this
compound, with its many positive characteristics, could be of value in
doses lower than those used in this trial.
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Footnotes
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1 This work was supported by Novo Nordisk A/S. 
Received June 2, 2000.
Revised August 21, 2000.
Revised October 9, 2000.
Accepted October 10, 2000.
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Abstract
Introduction
