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Original Studies |
Department of Rheumatology & Bone Disease (P.J.M., E.C., I.T., C.H., P.D.D.) Pavillon F, Edouard Herriot Hospital, 69437 Lyon, France; and Procter and Gamble Pharmaceuticals (R.B.), European Research and Development, Staines, Middx, TW 18 3AZ United Kingdom
Address all correspondence and requests for reprints to: Professeur P. J. Meunier, M.D, Hôpital Edouard Herriot, Pavillon F (Rhumatologie & Pathologie Osseuse), 69437 Lyon cedex 3, France.
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Abstract |
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Thirty-seven women participated in a 1-yr open-label follow-up study. Twelve months after treatment withdrawal, spinal BMD in the former etidronate group decreased by 1.43% and serum osteocalcin and urinary crossLaps returned to pretreatment values.
In conclusion, cyclical etidronate is an effective therapy for the prevention of both trabecular and cortical bone loss in the early menopause and has a good safety profile.
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Caucasian women, ambulatory and active, weighing between 45 and
90 kg and within 15% of their normal body mass index; with natural
menopause between 6 and 60 months prior to study and a normal bone
mineral density (BMD) (± 2 SD of the expected value for
their age group, i.e. a z-score between +2 and -2) were
recruited by a single centre. Postmenopausal status was confirmed by
serum values of estradiol (
30 pg/mL and FSH 
15 mU/mL). Exclusion
criteria were: any disease known to affect bone metabolism; bilateral
oophorectomy or hysterectomy; prolonged treatment with calcitonin,
vitamin D (at doses exceeding 400 U/day), elemental calcium (at doses
exceeding 500 mg/day), corticosteroids, or anabolic steroids, within
the past 6 months; treatment with estrogens and/or progestagens within
the past year. Women previously treated with any BR or a therapeutic
dose of fluoride were excluded. All prestudy measurements were obtained
over a 3-month period. For each eligible subject the dietary calcium
intake was assessed from a 7-day survey of food. All subjects provided
written informed consent to participate in the study which was approved
by the ethics committee (Comité d’Ethique de l’Université
Claude Bernard et des Hospices Civils de Lyon).
Subjects were seen every 3 months. At each visit, the BMD and serum and urinary samples were obtained. Each subject’s height, body weight, pulse and blood pressure were measured; pain and mobility were rated and history of fractures recorded.
Study design
This was a double-blind, placebo-controlled study. Twenty seven women were randomized to a cyclical dosing regimen of oral doses of etidronate (400 mg/day for 2 weeks) followed by elemental calcium (500 mg/day for 11 weeks) and 27 women to placebo for 2 weeks followed by calcium (500 mg/day for 11 weeks), repeated for a total duration of 104 weeks (24 months). The follow-up was an open label study in which women who had completed the 2-yr study received calcium 500 mg/day of elemental for 12 months duration.
All test materials were supplied by Procter & Gamble Pharmaceuticals; etidronate and its placebo were identical in appearance. [Eti-dronate tablets, contained 400 mg of etidronate. Placebo for etidronate comprised: lactose 0.480 g, sodium chloride 0.025 g, and magnesium stearate 0.005 g]. Supplemental calcium was prescribed by the physician as a marketed product. Etidronate or placebo for etidronate was given at a dose of 400 mg/day for days 1–14 (inclusive) of each treatment cycle on an empty stomach, i.e. 2 h before meals. The tablets were taken with water, coffee, tea or juice but not with milk. On days 15–91 (inclusive), 500 mg/day of elemental calcium was taken orally with a meal. Compliance was assessed by pill count. Subjects were defined as compliant if they took at least 80% of etidronate or its placebo over the treatment period.
Bone densitometry
The bone mineral density (BMD) of the lumbar spine (including L1–L4), the trochanter, Ward’s triangle and the femoral neck was determined at each study visit by Hologic X-ray 1000 QDR dual X-ray absorptiometry (serial number S/N 118). The coefficient of variation for the lumbar spine was 1% and for the hip 1.3% (15).
Serum and urine chemistry
Blood and urinary samples were taken after a 12 h fast. Serum chemistry included intact parathyroid hormone (CIBA Corning Diagnostic, Medfield, MA), osteocalcin (ELISA-OSTEO, CIS Bio-International), calcium (Arsenazo III, colorimetric method), phosphorus (Biotrol, colorimetric method) and alkaline phosphatase (Boehringer-Mannheim automated analysis). Serum FSH and estradiol were measured by RIA (Bio-Merieux) only at baseline. Urine specimens were collected as a 2-h second morning void; urinary hydroxyproline was determined by Prockop’s colorimetric method; crossLaps/creatinine was assessed by ELISA (CIS-Bio International) (16, 17).
To determine safety the following parameters were measured at baseline, 12 and 24 months using standard techniques: creatinine, glutamic oxaloacetic transaminase, glutamic pyruvate transaminase, gamma glutamyl transpeptidase and a routine hematological profile.
X-rays
Lateral and antero/posterior incidence x-rays of the thoracic and lumbar spine were taken at baseline and at 24 months for longitudinal comparison.
Adverse events (AEs)
AEs defined as any undesirable clinical experience occurring to a patient during a study whether or not related to the investigational drug, were assessed at each visit from the time the patient received the first dose of the study drug. All pertinent data, including; incidence, predisposing factors, temporal connection etc., were carefully considered in attempt to establish a cause-effect relationship.
Statistical analysis
Descriptive statistics were used to assess the comparability of the treatment groups at baseline. All results are expressed as the mean ± SEM and where appropriate 95% C.I. are reported. For data not normally distributed the median and lower and upper quartile are used. All analyses were performed on the intent-to-treat population (all subjects who were randomized to treatment). The primary efficacy endpoint was a between group comparison in the mean percent change from baseline in lumbar spine BMD at 24 months assessed by ANOVA. A repeated measures ANOVA on percent changes in spine BMD was carried out to determine a statistically significant effect of time, treatment group or interaction between those factors. Secondary efficacy endpoints were: percent change from baseline at 24 months in femoral neck, trochanter, Ward’s triangle BMD, serum osteocalcin (S-Oc) and urinary crossLaps/creatinine (ucL/Cz). All tests were two-sided and performed at the 5% level of significance. Changes from baseline in each group were assessed for significance using Student paired t-test. For data not normally distributed, the Wilcoxon’s test was applied. No adjustments were made for multiple comparisons. All analyses used SAS software (6.10 version, SAS Institute, Cary, NC).
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Results |
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Thirty-seven women entered the follow-up study (16 from the former placebo group and 21 from the former etidronate group). Thirty five subjects completed. Two subjects withdrew (1 in the placebo group because of distaste of calcium and 1 subject in the former etidronate group decided to commence hormone replacement therapy.
The mean demographic and baseline BMD data are shown in Table 1
. The two groups were comparable with respect to all
demographic and baseline data. Although the mean dietary calcium intake
seems to be lower in the etidronate group, the difference was not
statistically significant. The percentage of smokers was the same in
both groups (3/27). The levels of regular physical activity in the two
groups also were comparable: approximately 42% of subjects did not
exercise, 44% exercised occasionally and the remaining 15% exercised
daily (data not shown). Table 2 presents the baseline
demographics and BMD for the patients who entered the follow-up
study.
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Changes in lumbar spine BMD.
Percent changes from baseline in
the mean lumbar spine BMD are illustrated in Fig. 1. In
the placebo group there were no significant changes during the first
year and at the 24-month visit, BMD was significantly decreased from
baseline (P < 0.05). The mean percent change was
-2.34% (95% C.I., -3.92, -0.77). In the etidronate group, the mean
percent change in BMD at month 24 was 0.58% which was not
statistically different from baseline. The mean treatment difference
was +2.93% (95% C.I., 0.63, 5.22) and was statistically significant
(P < 0.02).
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Changes in femoral neck BMD.
As shown in Fig. 2A in the placebo group, there was a statistically
significant decrease from baseline of approximately -2.0% at month 24
(P = 0.007). In the etidronate group BMD increased in
the first year and remained above pretreatment values thereafter. At
month 24 the treatment difference between groups was 2.02% (C.l. 0.27,
3.78, P < 0.03). Six months after treatment
withdrawal, the mean treatment difference between groups was 2.50%,
(C.l. -0.10, +5.10) and at twelve months was 2.93% (C.l. -0.14,
6.00). The treatment difference was not statistically significant at
either time-point.
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no significant
changes were observed in the placebo group over time but there was a
definite downward trend. In contrast, in the etidronate group BMD was
maintained above pretreatment values through the 24 months. At the
24-month time-point, the mean treatment difference was 1.44% (C.l.
-0.47, 3.34) and was not statistically significant. Six months after treatment withdrawal the median between the former etidronate group and placebo was 2.22% (C.l. +0.21, 4.20, P < 0.04). Twelve months after treatment withdrawal, the median treatment difference was 4.38% (C.l. +2.37, 6.43) which was highly significant (P = 0.004).
Effects on biochemical indices
Urinary markers of bone resorption.
As shown in Fig. 3, there was a general decrease in the etidronate group
for the mean percent change from baseline in Cross-Laps/creatinine. At
the 24 month time-point, there was a statistically significant
treatment difference (P = 0.0134, Wilcoxon rank sum
test).
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There were no statistically significant differences between the treatment groups at any time point for fasting urinary hydroxyproline/creatinine and calcium/creatinine excretion (data not shown).
Changes in markers of bone formation.
Figure 4
depicts mean percent changes in serum osteocalcin. The values of
osteocalcin were in general lower in the etidronate group than in the
placebo group. However, there was no statistically significant
difference at 24 months. Six months after treatment withdrawal, the
mean percent change from baseline was -1.09% in the former etidronate
group and 5.9% in the former placebo group. At twelve months, the mean
percent change from baseline was 6.1% in the former etidronate group
and 6.95% in the former placebo group. The mean treatment differences
were not statistically significant.
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Changes in serum calcium phosphorus, and parathyroid hormone
(PTH).
There were no significant differences in serum calcium and
phosphorus between groups at any of the time points (data not shown).
Figure 5 illustrates changes in serum PTH. Although PTH
values demonstrated a tendency to be higher in subjects receiving
active treatment, starting from month 3, no significant differences
between treatment groups were observed with the exception of one time
point (6 months after treatment withdrawal) when the mean value in the
former etidronate group was significantly greater than that in placebo
(P = 0.031).
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There were no statistically significant differences between the former etidronate and placebo groups with respect to primary and secondary efficacy endpoints except for urinary cross/Laps/creatinine, a measure of bone resorption, which was significantly lower in the former etidronate group (data not shown).
Figure 6, A and B, illustrates the mean percent changes
from end of treatment (month 24) in spine and femoral neck BMD in the
subjects who entered the follow-up. Percent changes were assessed both
at 6 and 12 months after treatment discontinuation. For the lumbar
spine BMD, the mean percent change from end of treatment (24 months) in
the former etidronate group was -1.17% and -1.43% at 6 and 12
months; in the placebo group the changes were -0.98% and -1.56%.
These changes are not significant. At 12 month the mean treatment
difference between the former etidronate and placebo groups was only
0.13% (P > 0.05). For femoral neck BMD mean
percentage changes in the former placebo group were -1.15% and
-0.87% at 6 and 12 months respectively. In the former etidronate
these changes were -0.82% and -0.35%. The treatment difference
between the groups was 0.52% which was not statistically significant.
Figure 6C illustrates the changes in serum osteocalcin. The mean
percentage change in the former etidronate group was +19.2% and
+28.7% at 6 and 12 month respectively. These changes were 4.2% and
7.7% in the placebo. There were no significant differences between
groups. There was a statistically significant increase at 12 months in
S-Oc in the former etidronate group (P < 0.01 paired
t test).
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illustrates the changes in urinary crossLaps/creatinine
(ucL/Cr). The mean percent changes from month 24 in the former
etidronate group were +16.7% and +48.2% at 6 and 12 months,
respectively; in the placebo these changes were -11.3% and +5.2%.
The two groups were statistically significant at 12 months
(P < 0.03 Wilcoxon rank sum test). Adverse events (AEs)
Etidronate generally was very well tolerated. Only two subjects
(in the placebo group) discontinued the study because of AEs during the
first 24 months of study. In addition one patient (former placebo)
withdrew because of AE during the follow-up year. Table 3 shows the AEs most frequently reported in the first 2
yr of study. The majority of AEs reported were mild in severity and the
incidence was comparable between groups. No severe gastrointestinal AEs
were reported. Mild abdominal pain occurred in five subjects (one in
the placebo group, and four in the etidronate group). All five subjects
had a prestudy history of gastro-intestinal problems. The investigator
reported that each of these five subjects experienced intolerance to
the calcium supplement. Serious AEs were relatively more frequent in
the placebo group. In the follow-up year two subjects in the former
placebo group were hospitalized.
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Three subjects in the placebo group and two in etidronate experienced traumatic nonvertebral fractures.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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In keeping with the inhibitory effect of etidronate on bone turnover biochemical markers of bone resorption and formation were suppressed to normal premenopausal levels. The results are similar to those obtained with estrogen or BPs. Urinary crossLaps/creatinine excretion, a specific marker of bone resorption was suppressed, the median percentage change from baseline in crossLaps/creatinine excretion was -36% at 1 yr and no further reduction was observed at 2 yr (-32%). We did not find a reduction in urinary hydroxyproline excretion which can be explained by the fact that this marker has poor specificity and high variability. In addition, urinary calcium did not differ between the two groups; which may be explained by the fact that this parameter reflects both dietary calcium intake and bone resorption. Interestingly, serum osteocalcin, a biochemical marker of bone formation, was significantly decreased during the first year but by the 24 month visit, osteocalcin values had returned to normal. This finding is of interest because it indicates that the inhibition of bone formation is not long-lasting, hence cyclical therapy does not impair the ability of the remodelling system to repair microdamage. Alternatively the data may indicate relative lack of response in the second year. Further data would be needed to confirm this hypothesis.
One of the issues associated with bisphosphonate therapy is the long-term residence of these compounds in bone. It has been speculated that the continuous presence of bisphosphonates may cause excessive suppression of bone turnover ("frozen bone") thereby compromising bone quality. Therefore the objective of the follow-up was to determine the duration of cyclical etidronate effects on BMD and markers of bone turnover in this subject population. The results of the follow-up show that the rate of bone loss (estimated from the mean percent change from month 24 in vertebral BMD) in the two groups of subjects 1 yr after treatment withdrawal was very similar (1.4% in the etidronate group and 1.69% in the placebo group). This also was confirmed by the absolute changes in lumbar spine BMD which were respectively -0.015 g/cm2 decrease in the etidronate group vs. -0.014 g/cm2 in the placebo group suggesting no carry-over effect of therapy. Similar results were obtained for the femoral neck and trochanter BMD. The changes in biochemical markers during the off-treatment period suggest that there is reactivation of bone turnover. Both serum osteocalcin and urinary crossLaps which showed negative changes during active therapy returned toward baseline after treatment withdrawal suggesting that the effects of etidronate subside over time. Similar to our results, Mortsen et al. (1995) (33) reported that withdrawal of risedronate for 1 yr after continuous administration of 5 mg/day for 2 yr to early postmenopausal women was associated with a significant decrease in BMD. It is interesting to note that, whereas the response of the biochemical markers upon treatment discontinuation has been constant for all the BPs studied, the changes in BMD have been quite different. Rossini et al. (1994) (34) reported that spinal and hip BMD did not decrease 6 and 12 months after withdrawal of alendronate (20 mg/day for 6 months) while in agreement with our results all indices of bone turnover attained the pretreatment values within 9 months. Although their study population included postmenopausal women with spinal BMD more than 2 SD below adult mean peak it is unlikely that this explains the difference. In this respect, Ravn et al. (1996) (35) demonstrated that BMD and biochemical markers of bone turnover returned to normal after discontinuation of ibandronate in women at least 10 yr postmenopausal with low radial BMD. It is possible that the different BPs may have different effects on BMD but this is only an hypothesis which would require more in depth investigation.
Our results indicate that although bone loss resumed at the same rate as in the placebo group a beneficial effect of treatment was maintained 1 yr after discontinuation of active therapy given that the mean treatment differences in BMD (estimated from percent change from pretreatment) were 2.8%, 2.9% and 4.4% for lumbar spine, femoral neck and trochanter, respectively. It cannot be determined from these data whether an intermittent therapy would be preferable to a continuous therapy. Certainly given the prompt response of trabecular bone loss, to preserve the architecture and avoid the negative consequences of disruption of the trabecular network (36), continuous administration of cyclical etidronate beyond two yr should be recommended. On the other hand the cyclical regimen would be preferable if reducing overall drug exposure is the preferred option.
The safety profile of cyclical etidronate in the treatment of "established" osteoporosis has been documented recently in a large retrospective postmarketing surveillance study including more than 7000 patients treated with cyclical eti-dronate in the UK (37) as well as in a double-blind placebo-controlled study of 5 yr duration (11). But for a pharmacological intervention to be accepted for "prevention" in healthy individuals rather than for "treatment", a very high safety margin is required. The BPs usually have a good safety profile because of the pharmacokinetic properties of these compounds. Etidronate administration was generally very well tolerated. The majority of AEs reported were of a mild severity and not drug-related. Two subjects discontinued the study because of adverse events, both in the placebo group; three other subjects were withdrawn because of protocol violations. The most frequently reported AEs were asthenia, flu syndrome, pain, and gastrointestinal events (mostly nausea, diarrhea, flatulence, abdominal pain). None of the gastrointestinal AEs was classified as severe. Only two subjects in the etidronate group experienced moderate GI events which resolved, at variance with the findings of esophagitis that have been reported after the administration of amino-BPs (38, 39). Serious AEs were reported for 2 subjects in the etidronate group vs. 6 in placebo and occurred for causes not related to the study drug. There were no changes in stature in either group, suggesting no occurrence of vertebral deformities. We found no clinical or radiological evidence of osteomalacia. No bone biopsy was taken in this normal population for histomorphometric analysis after tetracycline double labeling but in studies on the use of intermittent cyclical therapy with etidronate in the treatment of established vertebral osteoporosis, no generalized mineralization defect has been found after 2 yr of treatment (40) and after 7 yr (41) suggesting that chronic administration of cyclical etidronate is safe when vitamin D supplementation is adequate. There is one report of mineralization defect with etidronate in early postmenopausal women (32) treated for 4 yr. However, no vitamin D levels were reported and baseline measurements of mineralization indices are difficult to interpret.
In conclusion, the results of our study indicate that cyclical etidronate therapy effectively prevented vertebral and femoral bone loss in women in the first 5 yr after menopause. Hence cyclical intermittent therapy with etidronate and calcium should be considered as a safe and effective treatment for the prevention of postmenopausal bone loss in those women who cannot, or are not willing to take estrogen.
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Footnotes |
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Received January 14, 1997.
Revised April 7, 1997.
Accepted April 15, 1997.
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References |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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