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Original Studies |
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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Introduction |
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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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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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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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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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. Levels of very low
density lipoprotein cholesterol and triglycerides did not change
significantly.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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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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Received June 2, 2000.
Revised August 21, 2000.
Revised October 9, 2000.
Accepted October 10, 2000.
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