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Endocrine Care |
Creighton University Medical Center (J.C.G.), Omaha, Nebraska 68131; Jerry L. Pettis VA Medical Center (D.J.B.), Loma Linda, California 92357; Albert Einstein College of Medicine (R.F.), Bronx, New York 10461; and Oregon Osteoporosis Center (M.M.), Portland, Oregon 97213
Address all correspondence and requests for reprints to: J. Christopher Gallagher, M.D., Creighton University Medical Center, St. Joseph’s Hospital, 601 North 30th Street, Suite 6712, Omaha, Nebraska 68131. E-mail: jcg{at}creighton.edu
Abstract
Tibolone, a novel compound with tissue-specific effects, has been found to have antiresorptive properties in bone. To confirm the efficacy of tibolone and determine its minimum effective dose for prevention of bone loss in early postmenopausal women, two randomized, double-blind, placebocontrolled, dose-finding studies were performed.
Seven hundred seventy healthy women postmenopausal within 1–4 yr, with normal bone density for their age, were treated for 2 yr with 0.3, 0.625, 1.25, or 2.5 mg tibolone daily or placebo. All subjects took supplemental calcium carbonate (500 mg daily). Bone mineral density (BMD) of the lumbar spine and right proximal femur was measured by dual-energy x-ray absorptiometry for up to 2 yr.
At each dose level, except the lowest (0.3 mg), tibolone produced a progressive increase in lumbar spine and total hip BMD over the 2-yr treatment period; at 0.3 mg, total hip density was maintained. However, only the doses 1.25 mg and 2.5 mg produced a progressive increase in femoral neck BMD. The differences in mean percent change from baseline in spine and total hip density were significant (P < 0.05) for all tibolone dose groups compared with placebo at all time points. Tibolone was well tolerated, with a similar overall incidence of adverse events compared with placebo. Tibolone 1.25 mg per day is recommended because it shows a positive and statistically significant change in BMD of spine and femoral neck.
DESPITE SUBSTANTIAL STRIDES in the diagnosis and treatment of osteoporosis, the search continues for new therapeutic approaches with potential advantages in efficacy, safety, and compliance. In the United States, hormone replacement therapy (HRT) including E therapy has long been the treatment of choice for preventing peri- and postmenopausal bone loss leading to osteoporosis (1). However, because of undesirable side effects, women tend to use HRT primarily for alleviating climacteric symptoms and often discontinue therapy once they are no longer symptomatic (2). On discontinuation of HRT, progressive bone loss resumes.
Currently, the classes of pharmaceutical agents most commonly used to manage patients with osteoporosis are the bisphosphonates, E, and selective E receptor modulators (SERMs). Bisphosphonates increase bone mineral density (BMD) and reduce fracture risk. Some members of this class may be associated with esophageal irritation and gastrointestinal symptoms and the daily regimen for taking bisphosphonates may be restrictive (3). SERMs, such as raloxifene, exert tissue-specific effects through their interactions with the E receptor. Raloxifene has E agonist effects in bone but, unlike HRT, does not stimulate breast tissue or the endometrium. Raloxifene is associated with a relative risk of venous thrombotic events comparable with that of oral E (4).
Tibolone is a synthetic compound with a unique pharmacological profile of tissue-specific effects in bone, breast tissue, the endometrium, and the cardiovascular system (5, 6, 7). Unlike SERMs, tibolone is thought to exert tissue-specific activity through the enzymatic conversion of steroids in different body tissues to more or less bioactive forms (8). This leads to tissue-specific pharmacological effects. Some of the actions of tibolone may also be mediated through the E receptor. This idea is supported by the observation that anti-E administration counteracts the protective effects of tibolone in maintaining bone mass in rats with ovariectomy-induced osteoporosis (9).
After oral administration, tibolone is rapidly converted into two
estrogenic metabolites (3
-OH and 3ß-OH-metabolites)
(10), which are responsible for its estrogenic effects on
bone, vagina, and climacteric symptoms. A third metabolite, the
4-isomer, has progestogenic and androgenic activities and is
specifically formed in the endometrium (11). In addition,
tibolone has a different effect on breast tissue compared with E; the
incidence of breast tenderness is lower and mammographic density is not
increased (12, 13). These effects may be explained by
tibolone’s inhibition of sulfatase resulting in decreased local E2
levels, and the stimulation of apoptosis as well as inhibition of
proliferation (14, 15).
Clinical trials have shown that tibolone prevents bone loss and maintains skeletal integrity in postmenopausal women (16, 17, 18, 19, 20, 21, 22, 23, 24, 25). These studies generally used a daily oral dose of 2.5 mg tibolone. Some evidence also suggests that 1.25 mg, as well as 2.5 mg, orally per day may be effective in preventing loss of bone mass (20). Until the present time, however, there have been no studies from which to determine the minimum effective dose of tibolone for prevention of early postmenopausal bone loss. We conducted two identical randomized, placebo-controlled, dose-finding studies to identify the lowest dose of tibolone with optimal effect for the prevention of bone loss in women postmenopausal within 1–4 yr, and to evaluate the efficacy and safety of tibolone. The combined results of these two studies are reported here.
Materials and Methods
Study design
Two identically designed randomized, double-blind,
placebocontrolled, dose-finding studies were conducted in the
United States. Twenty-three investigative sites were included in one
study, and 24 sites in the other. Planned total enrollment was 700
postmenopausal women (350 per study). For each study, sample size
estimation was based on the percentage change in BMD of the lumbar
vertebrae. A two-tailed test, with = 0.05 for each pairwise
comparison of interest and power = 0.80, was assumed. Comparisons
of interest were between placebo and each of the tibolone treatment
groups. Assuming a mean difference of 2.0% expected between placebo
and at least one tibolone group in terms of the percentage change from
baseline in lumbar vertebral BMD, and a SD of 3.5%, then
the sample size required for each study was 50 evaluable subjects per
treatment group.
Inclusion criteria
Subjects were recruited from the investigators’ practices,
referrals, and advertisements in local media. Healthy Caucasian or
Asian women 45 yr of age or older, within 80–130% of ideal body
weight, 1 yr or more but 4 yr or less past natural menopause (confirmed
with serum E2 level 
30 pg/ml and serum FSH levels 
40 mIU/ml), and
without osteoporosis (BMD of the lumbar vertebrae was within 2
SD of the age-matched mean) were eligible for enrollment.
The protocol also allowed for up to 25% of subjects enrolled at each
site to be 35 yr of age or older and 1 yr or more but 4 yr or less past
surgical menopause (hysterectomy-oophorectomy).
Exclusion criteria
Reasons for exclusion included smoking more than 10 cigarettes per day; current or previous chronic treatment with any drug affecting bone metabolism (e.g. corticosteroids, loop diuretics, or antacids); treatment with fluoride or bisphosphonates at any time; calcitonin treatment within the preceding 6 months; any form of E or combination Eprogestogen replacement therapy in the preceding 8 wk, for more than 2 wk in the preceding 3 months, or for more than 1 month in the preceding 6 months; or the use of E-containing vaginal cream in the preceding 8 wk. Additional exclusion criteria were the use of vitamin D or vitamin A supplements at doses greater than two times the recommended daily allowances (i.e. 800 IU vitamin D or 10,000 IU vitamin A).
Potential subjects were also excluded if they had any illness known to affect bone metabolism, such as vitamin D deficiency, Paget’s disease, hyperparathyroidism, or uncompensated hyper- or hypothyroidism. Subjects who were euthyroid on thyroid medication could be enrolled. Other exclusion criteria included evidence of nontraumatic vertebral fracture, active or previous thromboembolic or cerebrovascular disorders, serious cardiovascular conditions, severe migraine headaches, insulin-dependent diabetes mellitus, gallbladder disease, decompensated renal or liver disease, or known or suspected endometrial hyperplasia or neoplasia, or cancer of the breast or genital organs. The protocol and subject consent form were approved by the ethical review board for each site, and all subjects provided written informed consent before enrollment.
Treatment
All eligible subjects were randomly assigned to receive one of five treatments: 0.3 mg, 0.625 mg, 1.25 mg, or 2.5 mg tibolone daily, or placebo. Identically appearing tibolone and placebo tablets were used to maintain blinding. Study drug was to be administered for 24 months, with subjects not permitted to continue taking study drug for a longer period of time. Subjects were instructed to take one tablet of study drug orally with water each night at bedtime and one tablet of a calcium supplement (Os-Cal 500; SmithKline Beecham Consumer, Pittsburgh, PA) orally each day with a meal. Ingestion of study medication and the calcium supplement were to be recorded by subjects in their daily diaries. Dosing compliance was calculated as the number of tablets taken (based on the subject’s diary) divided by the number of tablets that should have been taken (based on the extent of exposure) and multiplied by 100.
The use of concomitant medications, with the exception of nutritional supplements approved by the investigator and not excluded specifically by the protocol, was strongly discouraged. Patient use of concomitant medications, including any calcium supplementation beyond the 500 mg administered as part of the study, and any over-the-counter preparations, was recorded and constituted grounds for discontinuing a patient from the study if the medication was prohibited as part of exclusion criteria.
Efficacy evaluations
The efficacy parameters analyzed for both studies are BMD of the lumbar vertebrae (L1–L4) and the total hip region. BMD measurements were performed using dual-energy x-ray absorptiometry (DXA) scans at screening and at the 6-, 12-, 18-, and 24-month patient visits. DXA scanners were Lunar DPX or DPX-L (Lunar Corp., Madison, WI) densitometers in one study, or Hologic QDR-1000, 1000W, 1500, or 2000 (Hologic, Inc. Waltham, MA) densitometers in the other, with final scan analysis and quality assurance performed by the Oregon Osteoporosis Center (Portland, OR). DXA scanner precision was carefully monitored by means of a dedicated Hologic spine phantom for each system, which was to be scanned every day a subject was scanned or at least three times a week. The Oregon Osteoporosis Center examined the Hologic spine phantom data every 3 months for any deviations and, if present, determined the cause of the deviation and instituted corrective measures. Correction factors were applied when system recalibrations or other changes in calibration made such factors necessary to compensate for minor machine drifts. Subjects considered to be at risk of excessive loss of BMD were withdrawn from the study and advised of approved therapies to prevent additional bone loss. These subjects were defined as those with BMD decreasing at a rate more than 7% per year or with BMD more than 2 SD below the age-matched normal level, as shown at the 12-month DXA assessment and confirmed by repeat measurement at the same time point. Subjects whose rate of BMD loss was more than 7% per year, but less than 10% per year could also be withdrawn, depending on their baseline BMD and the judgment of the investigator at the subject’s study center and other medical personnel.
In both studies, biochemical markers of bone metabolism were measured
as secondary efficacy parameters. Serum osteocalcin and serum
bone-specific alkaline phosphatase were assessed as markers of bone
formation or turnover, in addition to urinary cross-linked
N-telopeptides of bone collagen (normalized to creatinine)
as a bone resorption marker. Biochemical markers of bone metabolism
were evaluated at screening and at the 6-, 12-, 18-, and 24-month
patient visits. Serum samples for assays of "formation" markers
were collected in the morning after an overnight (10 h) fast. Urine
samples for assays of "resorption" markers were collected at the
second morning void after an overnight fast.
Osteocalcin was measured by a chemiluminoimmunoassay method, in which osteocalcin and chemiluminescence (acridinium ester)-labeled osteocalcin competitively react with a limited amount of osteocalcin antibody from immunized rabbits. The determination of serum bone-specific alkaline phosphatase was based on selective inhibition of the three common isoenzymes of alkaline phosphatase (bone, liver, and a third group of isoenzymes from intestinal mucosa, placenta, and neoplastic tissue that are sensitive to L-phenylalanine). Urinary cross-linked N-telopeptides were analyzed using a commercially available competitive-inhibition ELISA (Osteomark; Ostex International, Inc., Seattle, WA).
Gynecological and cardiovascular evaluations and results will be reported separately, in subsequent publications.
Metabolic evaluations
Laboratory assessments (standard blood chemistry, hematology, urinalysis, hemostasis parameters, and serum lipid/lipoprotein analyses) were performed at the screening visit and at the 6-, 12-, 18-, and 24-month patient visits. Hemostasis parameters, which were obtained in one of the reported studies, included prothrombin time, activated partial thromboplastin time, fibrinogen, antithrombin III, and plasminogen activity. Routine serum lipid/lipoprotein analyses on fasting samples, including total triglycerides; total cholesterol; high-density lipoprotein (HDL)-, low-density lipoprotein (LDL)-, and very low density lipoprotein (VLDL)-cholesterol; and lipoprotein(a) [Lp(a)] were performed in one study. In the other reported study, comprehensive serum lipid/lipoprotein analyses on fasting samples were done, including total triglycerides and total cholesterol; ß-quantification of HDL-, LDL-, and VLDL-cholesterol; HDL subfractions -2 and -3; apolipoproteins A-1 and B; and Lp(a).
Physical examinations and mammography were performed at the screening visit and the 12- and 24-month visits. Spinal x-rays were obtained at the screening visit and 24-month visit. In addition, subjects recorded the occurrence of vaginal bleeding in a daily diary and submitted the information at each clinic visit.
At the time of each return visit, subjects were questioned about symptoms or adverse events (AEs). All symptoms not present at screening, or that increased in severity or frequency during the study, were recorded as AEs. Any changes in laboratory values or physical examinations that appeared to represent AEs were also recorded.
Statistical analysis
Primary efficacy analyses. Collection and review of data from both studies were performed under blinded conditions. Analyses of BMD were performed at the 6-, 12-, 18-, and 24-month clinic visits, using data from all randomly assigned subjects according to the intent-to-treat (ITT) principle using the last observation carried forward (LOCF) approach. [The ITT group consisted of all subjects from the all subjects treated (AST) group who had at least one postbaseline primary efficacy assessment during the treatment period, regardless of the amount of medication ingested by the subject.] Per protocol, analyses on subjects who complied with all requirements and completed the study were performed to confirm the findings of the ITT analyses. The per protocol analyses consistently agreed with the ITT analyses.
Given that the two studies were conducted with identical treatment groups and a virtually identical design (differing only in the use of Lunar vs. Hologic densitometers and the measurement of certain lipid and hemostasis parameters), data were pooled for analysis after study completion. The percentage change from baseline in BMD was compared between the placebo group and each tibolone treatment group at the 6-, 12-, 18-, and 24-month patient visits for the lumbar spine and the total hip region, based on ANOVA with study center and treatment interaction terms. These results are reported here.
Secondary efficacy analyses. The percentage change from baseline in biochemical markers of bone metabolism (serum osteocalcin, serum bone-specific alkaline phosphatase, and urinary cross-linked N-telopeptides of bone collagen) was analyzed for the 6-, 12- 18- and 24-month visits, using the LOCF approach. A two-way ANOVA with study center and treatment on rank transformed data were performed, because distributions were not normal. Pairwise comparisons were performed between placebo and each of the tibolone groups. These results are also reported as pooled data from the two studies.
Results
Subject disposition
Figure 1
depicts the general
disposition of subjects in the two studies. Of the 1689 women screened
for enrollment, 919 were screening failures, primarily due to E2 or FSH
levels outside the predefined protocol specifications, withdrawal of
consent, or unstable hypothyroidism. A total of 770 subjects were
randomly assigned to treatment with placebo or 0.3, 0.625, 1.25, or 2.5
mg tibolone. Three subjects withdrew from the study between
randomization and start of treatment (baseline dropouts). Of the 767
treated subjects, 656 had at least one postbaseline assessment of the
lumbar spine BMD and comprised the ITT population. A total of 519
subjects completed the 2-yr study treatment period.
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A total of 88 of 767 subjects (11.5%) withdrew prematurely due to AEs. By treatment group, the rates of discontinuation due to AEs were for placebo, 12 of 149 (8.1%); for 0.3 mg, 12 of 153 (7.8%); for 0.625 mg, 16 of 158 (10.1%); for 1.25 mg, 26 of 154 (16.9%); and for 2.5 mg, 22 of 153 (14.4%). For the majority of subjects who discontinued due to AEs, the severity of the AE was mild to moderate. In one of the two studies, the most common AE for which subjects discontinued was weight increase, with 6 patients dropping out for this reason: 2 of 77 (2.6%), 1 of 79 (1.3%), 2 of 78 (2.6%), and 1 of 79 (1.3%) in the placebo, 0.625, 1.25, and 2.5 mg groups, respectively. In the other study, the most common AE for which subjects withdrew was menopausal vaginal bleeding, with 5 subjects discontinuing due to this AE: 1 of 72 (1.4%), 1 of 76 (1.3%), and 3 of 74 (4.1%) in the placebo, 1.25, and 2.5 mg groups, respectively.
Noncompliance with medication was defined as missing more than 20% of the total number of tablets to be taken during the entire treatment period (overall dosing compliance <80%). Of the 767 treated subjects, 749 (97.6%) had an overall compliance with study medication of 80% or more.
Baseline characteristics
Baseline demographic data for the ITT group are presented by
treatment group in Table 1. There were no
clinically meaningful differences among treatment groups or between the
two studies in terms of age, height, body mass index, or number of
years since menopause. Over 97% of subjects were Caucasian. Nearly all
women had an intact uterus; 2.6% (17/656) of subjects were
hysterectomized. Potentially confounding variables such as smoking
(11% of total) and alcohol consumption (19%) were equally distributed
among treatment groups.
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A. In Table 2B, T scores are provided by
region of interest (lumbar spine and total hip) and by study.
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With respect to the lumbar vertebrae, a statistically significant
difference (P < 0.05) in the mean percent change from
baseline BMD was observed for all tibolone dose groups as compared with
placebo at all time points (see Fig. 2).
Within each of the three higher tibolone dose groups (0.625 mg, 1.25
mg, and 2.5 mg), lumbar spine BMD generally increased with increasing
duration of treatment. In contrast, the placebo group showed a
continuing decrease in lumbar spine BMD from baseline throughout the
study period. A highly significant treatment effect was demonstrated in
favor of the 0.625 mg mean increase in BMD (1.1%; P =
0.0001), 1.25 mg (2.0%; P = 0.0001), and 2.5 mg groups
(2.6%; P = 0.0001) compared with placebo (-2.3%) at
yr 2. Although minor lumbar bone loss was evident in the 0.3 mg group
throughout the 2-yr treatment period, the loss was significantly less
(-0.4%; P = 0.0001) than that found in the placebo
group.
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For the total hip region, a significant difference (P
< 0.001) in the mean percent change from baseline for total hip BMD
was found for each tibolone dose group compared with placebo at all
time points, with the exception of the 0.3 mg group at 6 months (see
Fig. 3). In contrast to the placebo
group, total hip BMD was maintained in the 0.3 mg group and increased
in the 0.625 mg, 1.25 mg, and 2.5 mg groups in a dose-related
manner.
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The proximal femoral neck was analyzed separately from the other
regions of the hip. The pooled analysis of these data showed that the
mean percent change from baseline BMD in the proximal femoral neck
increased significantly (P 0.001) for the 1.25 mg
and 2.5 mg doses at all time points, except for the 6-month time point,
compared with placebo. The net gain of bone mass over baseline was also
documented at all time points, except for a small loss at 6 months with
the 1.25 mg dose. As seen in Fig. 4,
a loss in bone mass was not prevented in the 0.3 mg and the 0.625 mg
dose groups for most of the time points.
Biochemical markers
Median baseline values of N-telopeptides of bone
collagen, in pmol/µmol creatinine, were 48 for the placebo group, and
46, 45, 51, and 47 for tibolone in the 0.3 mg, 0.625 mg, 1.25 mg, and
2.5 mg treatment groups, respectively. For LOCF analysis, decreases
(median percent change from baseline) were observed for all doses of
tibolone at all time points. Statistically significant differences
(P < 0.001) for the percent change from baseline
compared with placebo were observed for all tibolone dose groups at all
time points, with the exception of the 6-month time point for the 0.3
mg group (Fig. 5). Medians are presented,
because the data were not normally distributed. In only the two highest
dose groups did the N-telopeptide values return to
premenopausal levels of about 40% suppression from baseline.
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0.001) for the percent change from baseline between the 0.625, 1.25,
and 2.5 mg dose groups and placebo at all time points. In these dose
groups, serum osteocalcin levels decreased (median percent change from
baseline) at all time points (Fig. 6). In
contrast, the placebo group showed increases from baseline. In general,
more marked decreases in serum osteocalcin were observed as the dose of
tibolone increased (-4.8%, -13%, and -25% median change from
baseline at end point for the 0.625, 1.25, and 2.5 mg dose groups,
respectively).
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). In general, the decreases in
bone-specific alkaline phosphatase were similar in patients receiving
the tibolone doses of 1.25 mg and 2.5 mg.
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No significant abnormalities in laboratory safety parameters were observed during the course of the study.
Lipid profiles
The median percent change from baseline in serum lipid/lipoprotein
parameters is presented by treatment group in Table 3. Mean baseline values for these
parameters were comparable across treatment groups, with the exception
of Lp(a), which was higher in the placebo group (105.7 nmol/liter)
compared with the tibolone groups (85.0–90.1 nmol/liter). Total
cholesterol decreased in all tibolone dose groups at both time points,
with no apparent relationship to dose. In contrast, the decrease in
HDL-cholesterol, apolipoprotein A-1, Lp(a), and triglycerides observed
for the tibolone groups seemed to be dose-related. For all tibolone
groups at all time points, except the last visit for the 0.3 mg group,
Lp(a) was statistically significantly decreased compared with placebo
(P < 0.05), with a generally larger decrease in groups
with higher tibolone doses. The decreases in both total cholesterol and
HDL-cholesterol generally were smaller at yr 2 than at yr 1. In
general, serum lipid/lipoprotein changes were maximal after 1 yr of
treatment, and did not show further clinically significant changes
during the second year.
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All doses of tibolone were generally well tolerated over the 2-yr treatment period. There were no cases of deep venous thrombosis or pulmonary embolism in placebo or tibolone groups. The most commonly reported AEs included upper respiratory tract infection (30.2% placebo vs. 26.8% 0.3 mg, 25.9% 0.625 mg, 24% 1.25 mg, and 21.6% 2.5 mg), headache (20.8% placebo vs. 20.9% 0.3 mg, 18.4% 0.625 mg, 19.5% 1.25 mg, and 24.2% 2.5 mg), and back pain (16.1% placebo vs. 13.1% 0.3 mg, 15.8% 0.625 mg, 13.6% 1.25 mg, and 17% 2.5 mg). Additional AEs reported at an incidence 10% or more included arthralgia, accidental injury, influenza-like symptoms, sinusitis, pain, and abdominal pain. There was no apparent dose relationship between tibolone and these AEs.
The incidence of hot flashes was lower in subjects treated with
tibolone (7.2%, 0.3 mg; 7.6%, 0.625 mg; 7.1%, 1.25 mg; 3.3%, 2.5
mg) compared with placebo-treated subjects (11.4%). The fewest hot
flashes were reported with the highest tibolone dose (2.5 mg). The
incidence of weight increase and breast pain did not seem to be related
to the dose of tibolone, and differences were not observed between the
placebo group and the tibolone groups. As shown in Table 4, the incidence of menopausal vaginal
bleeding was greatest in the group receiving the higher dose of
tibolone (2.5 mg). It should be noted that vaginal bleeding was not to
be recorded as an AE unless the subject discontinued from the study or
required further diagnostic evaluation as a result.
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Body weight
At baseline, mean height, weight, and BMI were comparable across treatment groups for each study. The mean body weight change (kg) was not statistically different between treatment groups and placebo [0.72 ± 3.72 (placebo); 1.22 ± 3.61 (0.3 mg); 1.18 ± 3.67 (0.625 mg); 1.58 ± 3.85 (1.25 mg); 0.76 ± 4.54 (2.5 mg)].
Endometrial histology
Endometrial tissue was obtained at baseline, 1 yr, and 2 yr for histological evaluation. Endometrial hyperplasia was diagnosed in 4 subjects: 1 (1 of 146) from the placebo group and 3 (3 of 600) from the tibolone treatment groups (1 receiving 1.25 mg and 2 receiving 2.5 mg tibolone). The two patients receiving 2.5 mg had simple hyperplasia diagnosed at the end of the second year, whereas the subject receiving 1.25 mg had complex hyperplasia diagnosed at the end of the first year. Three (3 of 600) patients receiving tibolone (one from each of the 0.3, 1.25, and 2.5 mg treatment groups) were diagnosed with endometrial adenocarcinoma at the end of the first year, and no cases were diagnosed at the end of the second study year. A retrospective review of baseline biopsies from the three patients identified preexisting carcinoma in each case. A detailed presentation and discussion of these findings will be provided in a separate report.
Vaginal bleeding
The incidence of vaginal bleeding decreased with continued use of tibolone. Based on completer analysis, the cumulative rate of amenorrhea at 1 and 2 yr was, respectively, 99.2% and 99.0% for the placebo group, and for patients treated with tibolone, 97.4% and 97.8% (0.3 mg); 95.8% and 97% (0.625 mg); 93.9% and 98% (1.25 mg); 92.4% and 94% (2.5 mg). A detailed discussion of the gynecological aspects of tibolone will be presented in a separate publication.
Discussion and Conclusion
Our results show that treatment for two years with tibolone at
doses of 0.625–2.5 mg daily increased BMD in the lumbar spine and hip,
and a dose of 0.3 mg maintained hip BMD (Figs. 2
and 3). In comparison,
despite supplementation with 500 mg calcium daily, placebo-treated
subjects lost bone mass (-2.3% and -1.9%, mean change from baseline
at 2 yr) at the lumbar spine and hip, respectively. These findings were
consistent with the measurements of biochemical markers of bone
metabolism, which decreased significantly for tibolone-treated patients
compared with placebo, suggesting a reduced rate of bone
resorption.
Because the propensity to fracture is a direct consequence of both bone mass reduction and increased bone resorption, any effective antiresorptive therapy for osteoporosis must normalize bone resorption and prevent further bone loss, or increase bone mass. In the studies reported here, the decrease in bone resorption in tibolone-treated subjects was dose dependent and sustained throughout the 2-yr treatment period. These results demonstrate that the doses studied are within the therapeutic range for the population under investigation. They are consistent with previously reported positive effects of tibolone on bone mass and strength (19, 20, 21, 22, 23, 24, 25).
Our studies have several design characteristics that limit extrapolation of the results to certain populations. Inclusion criteria limited participants to healthy Caucasian or Asian women (1.7% of ITT patient population) within 1–4 yr of menopause and without evidence of osteoporosis, as the studies were designed to evaluate osteoporosis prevention. Because individuals who meet the clinical definition of osteoporosis tend to demonstrate a greater percentage response to antiresorptive agents compared with those in the normal or osteopenic range, one may observe a greater percent change in BMD when tibolone is investigated in an osteoporotic population as part of a therapeutic study. Caution must, therefore, be exercised in comparing the results of this study with trials investigating other agents, since the patient populations may differ substantially.
Additional studies are needed to determine the effectiveness of tibolone in preventing bone loss in non-Caucasian populations, older patients, patients with established osteoporosis, or patients in poor health. Nevertheless, the results of this study have positive implications in terms of fracture prevention, particularly at the spine and hip, considering the strong association between low BMD and fracture risk (26, 27).
The efficacy results we found with tibolone compare favorably with those of other agents used for the prevention and management of postmenopausal osteoporosis, although comparable data from long-term, double-blind, placebocontrolled trials are limited. In the Postmenopausal Estrogen/Progestin Interventions trial (28), healthy postmenopausal women on E therapy alone or in combination with a progestin for 3 yr demonstrated mean total increases in BMD ranging from 3.5–5.0% in the spine, and 1.7% in the hip. In recently postmenopausal women taking alendronate at 5 mg or 10 mg for 3 yr, or 20 mg for 2 yr followed by placebo for 1 yr, BMD increased 1–4% at the lumbar spine and total hip (29). In healthy postmenopausal women receiving 30–150 mg raloxifene for 2 yr, mean percent increases from baseline in BMD were 1.3–2.2% for the lumbar spine and 1–1.5% for the total hip (30). Another study (31) evaluated risedronate in early postmenopausal women as either a 5 mg daily dose or "cyclic" therapy (5 mg daily for 2 wk of a month, then placebo for the remaining 2 wk). The researchers reported a mean BMD increase from baseline in the lumbar spine of 1.4% for patients receiving risedronate (5 mg daily), and a decrease in BMD from baseline of 1.6% in the risedronate cyclic group.
In the present studies, tibolone demonstrated statistically significant and clinically important efficacy in osteoporosis prevention, compared with placebo, for most doses tested. Although the lower doses had an effect, the 1.25 and 2.5 mg doses of tibolone were more consistent and showed more positive changes in BMD, and had statistically significant differences from placebo at spine, femoral neck, and total hip. The gain in BMD in the proximal femoral neck seen in the 1.25 mg and 2.5 mg groups is a desirable outcome of therapy. The efficacy results found with the 1.25 mg dose were positive, statistically significantly different than placebo at all regions of interest at the 2-yr end point and most other time points, and comparable with those seen with 2.5 mg (although in some cases the 2.5 mg dose showed greater increases in BMD), supporting a recommendation of 1.25 mg as the initial starting dose for the indication of osteoporosis prevention.
All doses of tibolone evaluated in this study (up to 2.5 mg daily) generally were well tolerated. The overall incidence of clinical AEs was as expected, given the population studied and the length of the trial. Furthermore, no clinically significant differences were seen between any tibolone treatment group and the placebo group in the incidence of overall, serious, or drug-related clinical AEs. For most patients who discontinued due to AEs, the AE was mild to moderate. The most common AEs cited as a reason for discontinuation were vaginal bleeding and weight gain. The incidence of vaginal bleeding reported elsewhere for tibolone is significantly lower than that of HRT (32). At the 2.5 mg dose, which has been extensively studied in Europe, tibolone has been found to increase only slightly endometrial thickness (32). Clinical effects on the endometrium are thought to be due to the local conversion of tibolone into its progestogenic metabolite (5).
Vaginal bleeding is a common event seen with the majority of hormonally active agents used to prevent osteoporosis. In the present studies, only seven patients treated with tibolone withdrew prematurely due to vaginal bleeding. The gynecological findings will be presented and discussed in detail in a separate publication.
The results presented here demonstrate that tibolone favorably alters several markers of cardiovascular risk in healthy, postmenopausal women, including total cholesterol, triglycerides, VLDL cholesterol, and Lp(a). Unlike E, tibolone decreased HDL-cholesterol and antithrombin activity in all the treatment groups. Although the decrease in HDL-cholesterol could be perceived as an unfavorable effect, it must be interpreted with respect to the other potentially beneficial changes that were produced on lipid metabolism, such as decreased triglycerides and Lp(a). The positive effects of tibolone on total cholesterol, triglycerides, Lp(a), and antithrombin III activity, all of which have been demonstrated to play a role in cardiovascular disease, have been consistently found in other studies as well (33, 34, 35, 36).
The main objective of the two randomized, double-blind, placebo-controlled, dose-finding studies reported here was to determine the efficacy of tibolone for osteoporosis prevention and to assess its safety during a 2-yr treatment period in healthy women 1–4 yr after menopause. Tibolone was found to be effective for osteoporosis prevention, with 1.25 mg the recommended dose, and to be well tolerated with mild to moderate AEs. The ability of tibolone to provide dose-dependent increases in BMD of the lumbar spine and total hip permit clinicians to individualize antiresorptive therapy for postmenopausal women according to clinical response after an appropriate treatment period, to decrease the possibility of making medication change interpretations based on regression to the mean (37).
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We acknowledge the participation of the following investigators: J. Aloia, M.D. (Mineola, NY); A. Bankhurst, M.D. (Albuquerque, NM); D. Baylink, M.D. (Loma Linda, CA); R. Beyerlein, M.D. (Eugene, OR); M. B. Block, M.D. (Phoenix, AZ); M. A. Bolognese, M.D. (Gaithersburg, MD); S. L. Bonnick, M.D. (Denton, TX); D. Brecher, M.D. (Palm Harbor, FL); W. Brown, M.D. (Pittsburgh, PA); C. H. Chesnut, M.D. (Seattle, WA); L. M. Cohen, M.D. (Sarasota, FL); S. Corson, M.D. (Philadelphia, PA); M. Davidson, M.D. (Chicago, IL); M. Drehobl, M.D. (San Diego, CA); B. L. Drinkwater, Ph.D. (Seattle, WA); F. E. Dunlap, M.D. (Tuscon, AZ); R. D. Emkey, M.D. (West Reading, PA); E. Evans, M.D. (Seattle, WA); R. Freeman, M.D. (Bronx, NY); S. A. Funk, M.D. (Atlanta, GA); J. C. Gallagher, M.D. (Omaha, NE); R. Gottesfeld, M.D. (Denver, CO); M. Greenwald, M.D. (Palm Springs, CA); M. Heuer, M.D. (Gainesville, FL); B. Kessel, M.D. (Boston, MA); R. A. Khairi, M.D. (Indianapolis, IN); M. Kleerekoper, M.D. (Detroit, MI); M. Layton, M.D. (Olympia, WA); R. Levitt, M.D. (Laurel, MD); S. E. Lipton, M.D. (Philadelphia, PA); J. Lucas, M.D. (Fort Lauderdale, FL); M. McClung, M.D. (Portland, OR); M. T. McDermott, M.D. (Austin, TX); N. H. E. Mezitis, M.D. (New York, NY); D. Mishell, M.D. (Los Angeles, CA); L. Nachtigall, M.D. (New York, NY); L. Olansky, M.D. (Oklahoma City, OK); C. Rosen, M.D. (Bangor, ME); P. J. Sulak, M.D. (Temple, TX); S. L. Schwartz, M.D. (San Antonio, TX); L. L. Shane, M.D. (White Plains, NY); S. L. Silverman, M.D. (Beverly Hills, CA); R. Stoltz, M.D. (Evansville, IN); T. Stovall, M.D. (Winston-Salem, NC); S. Swanson, M.D. (Lincoln, NE); M. Vranian, M.D. (Richmond, VA); R. L. Young, M.D. (Houston, TX).
Footnotes
This study was supported by a grant from Organon Inc. (West Orange, NJ).
Abbreviations: AE, Adverse event; AST, all subjects treated; BMD, bone mineral density; DXA, dual-energy x-ray absorptiometry; HDL, high-density lipoprotein; HRT, hormone replacement therapy; ITT, intent-to-treat; LDL, low-density lipoprotein; LOCF, last observation carried forward; Lp(a), lipoprotein(a); SERM, selective E receptor modulataor; VLDL, very low density lipoprotein.
Received March 7, 2001.
Accepted June 6, 2001.
References
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