Full text of DOI:10.1359/jbmr.2002.17.6.1057

JOURNAL OF BONE AND MINERAL RESEARCH
Volume 17, Number 6, 2002
©
2002 American Society for Bone and Mineral Research
Daily Oral Pamidronate in Women and Men With
Osteoporosis: A 3-Year Randomized Placebo-Controlled
Clinical Trial With a 2-Year Open Extension
1
1
2
CAROLINE BRUMSEN, SOCRATES E. PAPAPOULOS, PAUL LIPS,
3
1
1
PETRONELLA H.L.M. GEELHOED-DUIJVESTIJN, NEVEEN A.T. HAMDY, JAN OTTO LANDMAN,
4
2
5
6
EUGENE V. MCCLOSKEY, J. COEN NETELENBOS, ERNEST K.J. PAUWELS, JAN C. ROOS,
7
8
ROB M. VALENTIJN, and AEILKO H. ZWINDERMAN
ABSTRACT
The efficacy and safety of oral pamidronate was examined in a double-blind, placebo-controlled trial in women
and men with established osteoporosis. Seventy-eight postmenopausal women and 23 men with at least one
prevalent vertebral fracture were randomized separately to 150 mg/day of pamidronate or placebo for 3 years
followed by 150 mg/day of pamidronate for an additional 2 years. In addition, all patients received 400 U/day
of cholecalciferol and 500 mg/day of elemental calcium. Pamidronate increased significantly bone mineral
density of the lumbar spine (LS-BMD) and of the femoral neck (FN-BMD). The total increase in BMD of the
spine after 5 years of treatment was 14.3%. Lateral spine radiographs were obtained at baseline and after 3
years of treatment. Fractures of previously normal vertebrae occurred in 15 of 45 patients treated with
placebo (33.3%) and in 5 of 46 patients treated with pamidronate (11%). The relative risk was 0.33 (95% CI,
0
.14–0.77). Treatment was well tolerated and there was no difference in gastrointestinal toxicity between
pamidronate and placebo-treated patients. One hundred fifty milligrams daily of pamidronate is an effective
and safe treatment of women and men with established osteoporosis. (J Bone Miner Res 2002;17:1057–1064)
Key words: bisphosphonate, bone mineral density, male osteoporosis, pamidronate, postmenopausal osteo-
porosis, vertebral fractures
INTRODUCTION
nate and risedronate are the only approved treatments
shown in randomized clinical trials to reduce the risk of
ISPHOSPHONATES ARE the most extensively studied ther- vertebral and nonvertebral fractures, including those of the
apies of osteoporosis under controlled conditions. In hip, in calcium- and vitamin D–replete women with post-
addition, the nitrogen-containing bisphosphonates alendro- menopausal osteoporosis.
B
(1–8)
Pamidronate has been used for many years in Leiden as a
model compound to study the action and efficacy of
Dr. Lips serves as a consultant and receives funding from Eli
Lilly and Merck. Dr. Papapoulos receives funding from Eli Lilly,
Alliance for Better Bone Health (Proctor and Gamble), Merck, and
Roche. All other authors have no conflict of interest.
(9–12)
nitrogen-containing bisphosphonates
and was the first
bisphosphonate of this class to be given to patients with
(13,14)
osteoporosis.
Various modes of administration of oral
1
Department of Endocrinology and Metabolic Diseases, Leiden University Medical Center, Leiden, The Netherlands.
Department of Endocrinology, Vrije Universiteit Medical Center, Amsterdam, The Netherlands.
2
3
4
Department of Internal Medicine, Westeinde Hospital, The Hague, The Netherlands.
Centre for Metabolic Bone Diseases (WHO Collaborating Centre for Metabolic Bone Diseases), University of Sheffield Medical
School, Sheffield, United Kingdom.
5
Department of Radiology, Division of Nuclear Medicine, Leiden University Medical Center, Leiden, The Netherlands.
6
Department of Nuclear Medicine, Vrije Universiteit Medical Center, Amsterdam, The Netherlands.
7
Department of Internal Medicine, Rode Kruis Hospital, The Hague, The Netherlands.
8
Department of Medical Statistics, Leiden University Medical Center, Leiden, The Netherlands.
1
057

1
058
BRUMSEN ET AL.
or intravenous pamidronate were shown to prevent bone hospital pharmacy of the Leiden University Medical Center.
loss in patients with postmenopausal, idiopathic and The patients were instructed to take the trial medication on
glucocorticoid-induced osteoporosis in open or controlled an empty stomach at least 30 minutes before breakfast,
(
13–20)
studies.
Early open studies suggested, in addition, that lunch, or dinner with a full glass of water leaving the choice
daily oral pamidronate induces a significant increase in bone of time to the patients. Generally, patients adhered to the
mineral density of the spine (LS-BMD) that is not confined same intake routine during the study. In addition, all pa-
to the first 2 years of therapy, as expected from an antire- tients received cholecalciferol (Devaron; Solvay Pharma,
sorptive agent, but continues for at least 4 years of contin- Weesp, The Netherlands) tablets, 400 IU/day, and calcium
(14,21)
uous treatment.
Recently, this was shown in a con- supplements (Calcium Sandoz Forte; Novartis), 500 mg/
trolled study with alendronate, which progressively day, starting at least 3 months before the beginning of the
increased LS-BMD in women with postmenopausal osteo- trial. Compliance with therapy was tested by tablet count-
(22)
porosis for up to 7 years of treatment. However, there are ing.
no data from controlled studies about the long-term effects
of pamidronate and on its efficacy in fracture prevention.
Study outcomes
In this study, we examined the efficacy and safety of daily
oral pamidronate in women and men with osteoporosis
The primary outcome of the study was the percent change
during 5 years of continuous treatment, the first 3 years of in LS-BMD during the 3-year blinded period. Secondary
which were placebo-controlled.
efficacy measures were changes in BMD of the femoral
neck (FN-BMD), incidence of vertebral fractures after 3
years, changes in stature, and changes in biochemical indi-
ces of bone turnover. Investigators were not blinded to
results of BMD or biochemistry during the trial. However,
MATERIALS AND METHODS
This was a 3-year randomized, double-blind, placebo- assessment of BMD changes at the end of the blinded
controlled, clinical trial conducted in The Netherlands. At treatment was done without knowledge of treatment assign-
the end of the 3-year trial, patients were offered the option ment. In addition, radiological evaluation was performed in
to participate in a 2-year extension during which both a center that did not participate in the trial by personnel
groups received active treatment. Patients were recruited blinded to treatment assignment and other study outcomes.
from those referred to the participating centers for investi- BMD was measured by dual-energy X-ray absorptiometry
gation and treatment of osteoporosis. All patients provided (DXA) at baseline and at yearly intervals by Hologic, Inc.,
informed written consent and the study was approved by the (Waltham, MA, USA) QDR-1000 or Norland Medical Sys-
Ethical Committees of the participating centers.
tems (Fort Atkinson, WI, USA) densitometers that were
Included were women younger than 75 years and at least cross-calibrated during the study. Every patient was mea-
years postmenopausal and men aged between 40 and 75 sured with the same instrument from the beginning to the
5
years with at least one atraumatic radiologically docu- end of the study. At each time point, a double measurement
mented vertebral fracture. Patients had to have a life ex- was performed after repositioning of the patient and the
pectancy of at least 5 years. Excluded were patients with average value was used in the analysis. Scans were analyzed
abnormal liver function; serum creatinine Ͼ140 ␮M; his- in one center. Fractured vertebrae within the region of
tory of any malignant disease; disorders of calcium and interest were excluded from the analysis. Prevalent and
bone metabolism other than osteoporosis; endocrine disor- incident fractures were assessed morphometrically by the
(23)
ders; treatment with antiepileptics or glucocorticoids at a McCloskey-Kanis method
on lateral spine radiographs
dose of Ͼ7 mg/day of prednisolone or equivalent for 1 week taken at baseline and after 3 years of therapy. Briefly,
or longer in the year preceding the trial; or prior treatment prevalent vertebral fractures were characterized by compar-
with bone-acting drugs such as sodium fluoride during the ison of vertebral height ratios with “gender” and “level”-
previous 9 months or any use for Ͼ3 months, bisphospho- specific reference data. The method has high specificity and
nates in the previous 3 years, anabolic steroids or estrogens takes account of common minor variations in vertebral
in the previous 6 months, or calcitonin in the last 3 months shape. Incident vertebral fractures were defined using the
before entry into the study. Peptic ulcer or gastrointestinal same method (point prevalence, i.e., any incident fracture
diseases, other than malabsorption syndromes, were not had to be identified as a prevalent fracture on the follow-up
considered exclusion criteria.
radiographs) together with a required minimum change
from the baseline films. This minimum change was derived
from an analysis of measurement errors undertaken in a
Treatment
Women and men with osteoporosis were randomized random subset of paired radiographs. This analysis sug-
separately per center to receive either 150 mg/day of pam- gested that a new or incident vertebral deformity would
idronate or placebo for 3 years, followed by 150 mg/day of require a reduction in anterior, central, or posterior vertebral
pamidronate for an additional 2 years. Trial medication height of at least 15% and of at least 4.6 mm in absolute
consisted initially of two enteric-coated pellets of 75 mg of height. The stipulation of a minimum change combined
pamidronate or placebo and thereafter of 150 mg of enteric- with the point prevalence method prevents the characteriza-
coated tablets or placebo. Enteric-coated pellets were pro- tion of minor changes in vertebral height ratios as a new
vided by Ciba-Geigy (currently Novartis), Basel, Switzer- fracture. Only fractures of previously normal vertebrae were
land, and enteric-coated tablets were prepared by the counted as incident fractures. The incidence was expressed

ORAL PAMIDRONATE IN OSTEOPOROSIS
1059
as the proportion of patients with new vertebral fractures
after 3 years. Symptomatic fractures occurring during the
trial were confirmed radiologically. Height was measured
by a Harpenden stadiometer. The ratio of urinary hy-
droxyproline to creatinine (OHP/Cr) was used as an index
TABLE 1. BASELINE CHARACTERISTICS OF PATIENTS
RANDOMIZED TO PLACEBO OR PAMIDRONATE (MEAN Ϯ SE)
Characteristics
Placebo
Pamidronate
Sex (M/F)
11/39
12/39
of bone resorption and total serum alkaline phosphatase was Age (years)
used as an index of bone formation.
All
Women
65 Ϯ 1.2
67 Ϯ 1.1
64 Ϯ 1.4
67 Ϯ 1.1
Men
55 Ϯ 2.3
22 Ϯ 1.6
52 Ϯ 2.9
20 Ϯ 1.6
Statistical analysis
Years after menopause
Baseline data are expressed as means Ϯ SEM. All data of Height (cm)
163.8 Ϯ 1.4
64 Ϯ 3.9
163.6 Ϯ 1.5
67 Ϯ 3.8
outcomes, with the exception of changes in height, are Serum 25-hydroxyvitamin
a
expressed as mean percent change from baseline Ϯ SE.
Analyses of efficacy data were by intention-to-treat. Differ-
ences within groups in BMD, height, and biochemical pa-
rameters were tested by two-sided t-tests. Differences be-
tween groups were analyzed using a repeated-measurements
analysis of variance (ANOVA); a value of p Ͻ 0.05 was
considered significant. Difference in incident vertebral frac-
tures between groups was assessed by the Mantel-Haenszel
test.
D (nmol/L)
Serum alkaline
55 Ϯ 2
56 Ϯ 3
phosphatase (U/L)
Urinary OHP/Cr
␮mol/mmol)
17.8 Ϯ 1.1
15.7 Ϯ 1.1
(
2
LS-BMD (g/cm )
LS-BMD (T score)
FN-BMD (g/cm )
FN-BMD (T score)
Number prevalent
vertebral fractures
0.741 Ϯ 0.020 0.755 Ϯ 0.020
Ϫ2.91 Ϯ 0.19 Ϫ2.83 Ϯ 0.17
0.635 Ϯ 0.015 0.641 Ϯ 0.016
Ϫ2.73 Ϯ 0.19
3.1 Ϯ 0.5
2
Ϫ2.70 Ϯ 0.13
2.7 Ϯ 0.5
Safety evaluations
a
All patients were already on 400 U/day of Devaron tablets for
at least 3 months.
Physical examination, standard hematology, and clinical
chemistry were performed every 6 months and all adverse
events were documented. In patients who reported severe
gastrointestinal complaints, endoscopy was performed. Iliac
crest bone biopsy specimens were obtained at baseline and ment groups was significant (p Ͻ 0.001). The increase on
either after 1 year or 2 years of treatment. These results were pamidronate was most prominent in the first year of treat-
(24)
reported previously.
ment but continued during the second and the third year; the
differences between the second and the first year and be-
tween the third and the second year were significant (p Ͻ
0.001 and p Ͻ 0.01, respectively). In the placebo group
LS-BMD, after an initial increase the first year, remained
unchanged during the following 2 years.
RESULTS
Patients
One hundred one patients (78 postmenopausal women
FN-BMD increased significantly after 3 years in
and 23 men) with osteoporosis were randomized to receive pamidronate-treated patients (1.60 Ϯ 0.66%; p Ͻ 0.05) and
placebo or pamidronate. Baseline characteristics of the two in placebo-treated patients there was a small, nonsignificant
groups were similar and are shown in Table 1. Ten patients, decrease (Ϫ0.21 Ϯ 0.68%). The difference between the two
5
patients in each group, were lost to follow-up before the groups was not significant.
end of 3 years. Reasons were loss of interest (n ϭ 4),
Fifty-three patients agreed to participate in the 2-year
Alzheimer’s disease (n ϭ 2), moved out of the area (n ϭ 3), open extension of the study (27 patients from the placebo
and sudden death while on vacation (n ϭ 1). Ninety-one group and 26 patients from the pamidronate group). Base-
patients (90%) completed the 3-year study period and were line characteristics (gender, height, BMD, prevalent frac-
included in the intention-to-treat analysis. At the end of 3 tures, and indices of bone turnover) did not differ between
years, 83/91 patients were still on medication, 43 patients patients who continued the study and patients who did not.
(
33 women and 10 men) were on pamidronate, and 40 Patients included in the extension were slightly younger at
patients (31 women and 9 men) were on placebo. Eight baseline (63.5 vs. 65.6 years). In those patients who had
patients stopped taking the trial medication but continued to received placebo for 3 years, treatment with 150 mg/day of
be followed. Fifty-three patients continued after 3 years, 27 pamidronate for another 2 years induced a significant in-
patients from the placebo group and 26 patients from the crease in LS-BMD by 6.21% (p Ͻ 0.001). Similarly, FN-
pamidronate group.
BMD increased by 3.67% (p Ͻ 0.05). In the patients who
continued taking pamidronate, there were additional small
but significant increases in LS-BMD during the fourth and
fifth year of treatment (2.27% and 2.78%, respectively; p Ͻ
Changes in BMD
Changes in BMD are shown in Fig. 1. LS-BMD increased 0.001, 5 years compared with 3 years). FN-BMD also
by 9.02 Ϯ 1.34% (p Ͻ 0.001) in the pamidronate group and increased slightly (1.32%) but not significantly. Overall
by 3.70 Ϯ 0.93% in the placebo group (p Ͻ 0.01) after 3 continuous administration of pamidronate for 5 years in-
years of treatment. The difference between the two treat- creased LS-BMD and FN-BMD by 14.34 Ϯ 2.24% and

1
060
BRUMSEN ET AL.
FIG. 2. Changes in height during the 3-year placebo-controlled study
with 150 mg/day of oral pamidronate.
0
.77), accounting for a significant reduction (67%) of the
relative risk for new vertebral fractures in patients treated
with pamidronate. There were 5 patients needed to treat
(
NNT) with pamidronate for 3 years to prevent one verte-
bral fracture.
Symptomatic vertebral fractures occurred in 6 patients
treated with placebo and in 3 patients treated with pamidr-
onate. Nonvertebral fractures occurred in 4 patients. Two
patients had a hip fracture: 1 patient in the placebo group, 1
patient in the pamidronate group, and 2 patients had wrist
fractures, one of whom fractured both wrists consecutively.
Both of these patients were treated with placebo. Two
patients on placebo developed multiple symptomatic spinal
FIG. 1. Percent changes in (A) LS-BMD and (B) FN-BMD during 5 fractures and subsequently were treated with pamidronate.
years of treatment with 150 mg daily of oral pamidronate or placebo for Both were analyzed in their original treatment group.
3
years followed by 2 years of 150 mg/day of pamidronate.
Height
There was a progressive decrease in height in both
2
.92 Ϯ 1.32%, respectively. The corresponding increases in
groups, being greater in the placebo-treated patients (Fig. 2),
the patients treated with placebo followed by pamidronate
were 9.81 Ϯ 1.51% and 3.46 Ϯ 1.04%, respectively.
Responses were similar in women and men. During the
although the difference did not reach statistical significance.
Biochemistry
3
-year controlled study the percentage of increase in LS-
BMD in the pamidronate-treated group was higher in
The changes in urinary OHP/Cr are depicted in Fig. 3. In
women (10.13 Ϯ 1.67% vs. 5.98 Ϯ 1.49% in men) but this the pamidronate-treated patients, OHP/Cr, after an initial
was largely because of the lower baseline BMD of the significant decrease, reached a plateau that was sustained
women; compared with placebo, absolute increases were during the whole period of observation. In the placebo-
2
2
0
.047 g/cm in women and 0.040 g/cm in men.
treated patients, there was a small, nonsignificant decrease
in urinary OHP/Cr during the first 3 years. Subsequent
pamidronate therapy for 2 years induced a significant de-
crease in urinary OHP/Cr of a magnitude similar to that
Incident fractures
Assessment of the incidence of vertebral fractures was achieved in patients treated continuously for 5 years. The
done by vertebral morphometry only for the blinded period changes in serum alkaline phosphatase followed the same
of the study on X-rays taken at baseline and after 3 years of pattern (mean decrease of 16%; p Ͻ 0.001).
treatment. Evaluable X-rays were available from 91 pa-
tients: 45 patients from the placebo group and 46 patients
from the pamidronate group. New vertebral deformities
Adverse effects
occurred in 15 patients (33.3%) who received placebo and
Six patients, 3 patients in each treatment group (6%),
in 5 patients (11.0%) who received pamidronate. The rela- stopped treatment during the 3-year blinded period because
tive risk for vertebral fractures was 0.33 (95% CI, 0.14– of gastrointestinal complaints. Three of these patients un-

ORAL PAMIDRONATE IN OSTEOPOROSIS
1061
registration of alendronate in the United States for the
treatment of male osteoporosis. The approved treatment
schedule with alendronate was the same as that for post-
menopausal osteoporosis. We used separate stratification
for women and men but no separate analysis was planned
because of the small numbers. As expected, the overall
response was similar in men and women.
Second, we used a flexible dosing schedule giving the
patients the choice to take the drug at times other than the
morning that may have been inconvenient to some. Gener-
ally, it is advocated that for optimal effect bisphosphonates
should be given in the morning before breakfast because of
their poor intestinal absorption and their interaction with
food, particularly that containing calcium. We show here
that this flexible administration of pamidronate was associ-
ated with increases in spine BMD at least comparable with
those obtained with more rigid administration of other
nitrogen-containing bisphosphonates. Our findings suggest
that for long-term treatment, it may not be necessary to
adhere to a strict dosing timing protocol if the bisphospho-
nate is taken on an empty stomach at least 30 minutes before
FIG. 3. Percent changes in urinary OHP excretion, expressed as
OHP/Cr ratio during 5 years of treatment with 150 mg/day of oral
pamidronate or placebo for 3 years followed by 2 years of 150 mg/day
of pamidronate.
derwent endoscopy because of severe symptoms. Esophagi- a meal. In another study with oral pamidronate, in which the
tis was diagnosed endoscopically in 2 patients on placebo, timing of drug intake was electronically registered, we
one of whom had a known hiatus hernia. One patient on found no difference in BMD responses between patients
pamidronate with epigastric complaints before the trial was who took pamidronate between 6 and 10 a.m. and those who
found to have two duodenal ulcers and esophagitis. In 1 took it between 3 and 7 p.m. (G.L. Leusink, E. de Klerk,
patient treated with pamidronate, a colon carcinoma was J.A. Knottnerus, D. van der Heyde, H.A.P. Pols, and S.E.
diagnosed after 3 years of therapy. No patient reported Papapoulos, unpublished data, 2000). A preliminary report
symptoms suggestive of an acute-phase reaction. No signif- of a study with oral alendronate showed that administration
icant biochemical abnormalities were recorded during the of this bisphosphonate 1 hour before lunch or dinner in-
trial except for a transient increase in serum levels of duced a similar reduction in bone turnover, biochemically
(30)
transaminases and/or ␥-glutamyl transferase activity in 3 assessed, as when given before breakfast. However, cau-
patients. One of these patients was on active treatment and tion is needed before extrapolating these results to
2
patients were on placebo, 1 of whom was found to have all bisphosphonates. Currently, used nitrogen-containing
obstructive cholestatic disease on ultrasound.
bisphosphonates bind calcium with equal affinity that is
independent of their secondary structure, which determines
(31)
their antiresorptive potency. When a relatively high dose
of a bisphosphonate is given, in the case of pamidronate
DISCUSSION
(
150 mg), the presence of a small amount of calcium in the
This study shows that 150 mg/day of oral pamidronate is gastrointestinal tract may have a trivial effect on the amount
an effective and safe treatment for women and men with of the bisphosphonate that fails to be absorbed. However,
osteoporosis. Pamidronate increased LS-BMD progres- the same small amounts of calcium may have more pro-
sively over 5 years and reduced the incidence of new nounced effects when the dose of the bisphosphonate is low,
vertebral fractures by 67% after 3 years. Although the as is the case with the more potent compounds. For exam-
number of patients studied was small and antifracture effi- ple, the currently used doses of alendronate, risedronate and
cacy was not a primary outcome, this is the first study to ibandronate in osteoporosis are 10, 5, and 2.5 mg, respec-
report a significant effect of pamidronate on the incidence of tively. Thus, it may be that in osteoporosis the potential
vertebral fractures under controlled clinical conditions. disadvantage of using a bisphosphonate with a lower anti-
Apart from sample size, several aspects of our study differ- resorptive potency may turn out to represent an advantage in
entiate it from other clinical trials of nitrogen-containing daily practice when oral pharmacokinetics are considered.
bisphosphonates in osteoporosis.
However, this is speculative because no specific studies
First, we included both women and men in the same have addressed this issue, but it represents an intriguing
study. Our early open studies with pamidronate indicated possibility.
that there was no gender difference in the response to the
Third, patients with a high risk of fractures were included
(14,21)
bisphosphonate.
This has been shown repeatedly in in this study, namely, at least one prevalent fracture with a
(13,25–28)
glucocorticoid-induced osteoporosis
was demonstrated also in a specific study of male osteopo- firmed by the high incidence of vertebral fractures in the
and recently mean number of three fractures. The high risk was con-
(29)
rosis by Orwoll et al.
These investigators showed that placebo-treated group (33.3%), which is the highest re-
alendronate was as effective in male osteoporosis as shown ported so far in placebo groups of all bisphosphonate trials
previously in postmenopausal osteoporosis, which led to the with the exception, perhaps, of the first cyclical etidronate

1
062
BRUMSEN ET AL.
(
1,2,6,7,32–35)
trial.
Notwithstanding, this patient selection al- icity thus is dose-dependent, as has been suggested already
(41,42)
lowed the detection of a significant decrease in fracture risk in studies of other bone disorders.
Bone safety exam-
even in a study of this size. Therefore, inclusion of a ined with paired bone biopsy specimens after 1 and 2 years
(24)
high-risk population in a clinical trial in osteoporosis can of therapy has been reported previously.
In summary,
result in a substantial reduction in the necessary number of pamidronate did not adversely affect mineralization of
studied patients when an effective intervention is used. newly formed bone and induced changes that were compat-
However, it is no longer ethical to treat such patients with ible with the primary action of the bisphosphonate on bone
placebo. The high basal fracture risk of the patients studied turnover.
combined with the effectiveness of pamidronate was re-
sponsible for the documented low NNT to prevent a frac- idronate in osteoporosis, its further development for this
ture. indication was pursued only outside Europe and the United
Despite its size, our study met the criteria of a properly States mainly because of few reports of gastrointestinal
Despite early encouraging results with the use of pam-
(36)
(43)
performed clinical trial.
For example, the dropout rate toxicity.
Our data suggest that this may not have been a
was small with 90% of the patients completing the 3-year wise decision. In conclusion, daily oral pamidronate in-
blinded study, all analyses were by intention-to-treat and the creases progressively spine BMD and reduces the incidence
primary and secondary endpoints were predefined in the of new vertebral fractures in women and men with estab-
protocol. Certain issues need further discussion. The in- lished osteoporosis.
crease in spine BMD, the primary endpoint of the study,
followed the predicted and recently established (with alen-
(22,37)
dronate) long-term pattern.
The initial increase in LS-
ACKNOWLEDGMENTS
BMD after 1 year was followed by a progressive gradual
significant increase for 4 consecutive years resulting in an
We thank P. Vermeij for the preparation of pamidronate
overall gain of ϳ14% after 5 years. The mechanism of this and placebo tablets used subsequently in the trial. Initially,
response is not entirely clear and may be caused by im- this study was supported by Ciba-Geigy (currently Novar-
provement of the secondary mineralization of bone as sug- tis).
(38,39)
gested for alendronate in animal and human studies.
A
trend for an increase in mean wall thickness observed in
(24)
bone biopsy specimens of pamidronate-treated patients
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placebo-treated patients showed a significant increase in
spine BMD during the first year but no change thereafter.
Such increases have been observed in most clinical trials in
patients with osteoporosis, although the magnitude of the
increase was greater in our study. Treatment with vitamin D
and calcium may have contributed to that. The changes in
FN-BMD, although significant, are difficult to interpret. For
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years 3 and 5 in patients who originally received placebo
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Oral pamidronate had an excellent safety profile. The
incidence of dropouts caused by gastrointestinal toxicity
was 6% and was distributed equally between the placebo
and active treatment groups. It should be stressed that gas-
trointestinal diseases, except for malabsorption syndromes,
were no exclusion criteria. In addition, of those patients who
underwent endoscopy, two cases of esophagitis were diag-
nosed in the placebo group and one in the pamidronate
group. This favorable safety profile contrasts with our ex-
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Address reprint requests to:
S.E. Papapoulos, M.D.
Department of Endocrinology and Metabolic Diseases,
C4R
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Leiden University Medical Center
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