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Alendronate and Naproxen Are Synergistic for Development of Gastric Ulcers
David Y. Graham, MD;
Hoda M. Malaty, MD, PhD
Arch Intern Med. 2001;161:107-110.
ABSTRACT
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Background Both alendronate sodium use and nonsteroidal anti-inflammatory drug
use are associated with gastric ulcers. The aim of this study was to investigate
whether alendronate and naproxen are synergistic as causes of gastric ulcers.
Methods We performed an endoscopist-blind, randomized, crossover, single-center
comparison of 10 mg/d of alendronate sodium, 500 mg of naproxen sodium twice
daily, or the combination taken orally for 10 days in volunteers aged 30 years
or older. Videoendoscopy was used to evaluate the presence and degree of mucosal
damage to the esophagus, stomach, or duodenal bulb before and after each treatment.
There was a 1- to 4-week washout between evaluations.
Results Twenty-six healthy volunteers participated (18 women and 8 men), aged
30 to 50 years. Gastric ulcers were present in 2 subjects receiving alendronate
(8%), in 3 receiving naproxen (12%), and in 10 receiving both (38%) (P<.05 for the combination vs either drug alone).
Conclusions Both alendronate and naproxen can cause gastric ulcers. The combination
appears synergistic. Alendronate should be used with caution in those who
simultaneously require nonsteroidal anti-inflammatory drugs.
INTRODUCTION
ALENDRONATE sodium (Fosamax) is a primary amino-bisphosphonate used
for the treatment of osteoporosis and Paget disease.1
The most common adverse effects associated with alendronate use are abdominal
pain and discomfort. There have been a number of reports of esophageal damage
associated with the amino-bismophonates, alendronate and pamidronate disodium.2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15
In a study of gastrointestinal toxicity in patients treated with 40 mg/d of
alendronate sodium assessed by the same endoscopic techniques used to evaluate
nonsteroidal anti-inflammatory drugs (NSAIDs), alendronate was shown to cause
visible gastric mucosal injury in the majority of those studied.16
The gastric mucosal injury was deemed severe in 55% of those receiving alendronate
(6 of 11), and in 1 patient (8%) an alendronate-associated acute gastric ulcer
was seen. To date, 141 volunteers have been studied following the oral administration
of aldendronate in doses ranging from 5 to 40 mg/d and in durations of from
4 to 28 days (Table 1). Overall,
7% developed gastric ulcers16, 17, 18, 19, 20, 21, 22, 23
(Table 1).
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Table 1. Results of Endoscopic Studies of Bisphosphonates in Relation
to Gastric Ulcer Formation
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NSAIDs are known for their ability to cause gastric mucosal damage and
ulceration.24 The target population for alendronate
treatment and the population most likely to take NSAIDs are similar. Therefore,
the present study was designed to determine whether the combination of alendronate
and an NSAID had an adverse effect on the mucosa of the upper gastrointestinal
tract.
SUBJECTS AND METHODS
The study was an endoscopist-blind, crossover, randomized, single-center
endoscopic study. All volunteers gave informed written consent in accordance
with the guidelines of the Committee on Human Investigation at Baylor College
of Medicine, Houston, Tex, and in accordance with the rules of the Helsinki
Declaration. Subjects were assigned to receive in random order (1) alendronate
sodium, 10 mg once a day; (2) naproxen sodium, 500 mg twice a day; or (3)
the combination of alendronate 10 mg once a day and naproxen 500 mg twice
a day for 14 days. Alendronate was dosed according to the labeling instructions.
Following a normal screening endoscopy, subjects received study medications
from the study coordinator each morning for 14 days and underwent follow-up
endoscopy on the 15th day. At least 1 week elapsed between each arm of the
crossover. Endoscopic evaluations of the gastric mucosa were made prior to
each treatment period, and starting a new drug was delayed until there was
complete healing of any visible lesions.
Entry criteria included subjects with endoscopically normal gastric
and esophageal mucosa. The subjects had to be willing to abstain from alcohol,
caffeine-containing beverages, tobacco, highly spiced foods, and all other
medications, including all over-the-counter products (except oral contraceptives)
from 72 hours prior to each baseline endoscopic examination until the end
of each of the 3 treatment periods. Exclusion criteria included a history
of peptic ulcer, gastroesophageal reflux disease, dysphagia, gastrointestinal
bleeding, gastrointestinal surgery, gastrointestinal dysfunction that could
interfere with drug absorption, and current or recent treatment with any histamine2 receptor antagonists, proton pump inhibitors, misoprostol, sucralfate,
metoclopramide hydrochloride, antacids, vitamins, or laxatives. Subjects were
prohibited from using aspirin or NSAIDs for the 2 weeks prior to entry.
Within 48 hours of enrolling in the study, each subject underwent a
baseline endoscopic evaluation of the gastric mucosa, after having fasted
from 12 midnight the night before. Only subjects who had normal esophageal,
gastric, and duodenal bulb mucosa were allowed to participate. Videoendoscopy
was repeated after 7 and 14 days of treatment. All endoscopic examinations
were performed by the same gastroenterologist (D.Y.G.) who remained blinded
to the treatment given. Scoring was done as the endoscope was advanced. The
esophagus, stomach, and duodenal bulb were scored separately using a standard
scoring system that minimizes trivial damage such as mucosal hemorrhages (Table 2). The endoscopic scoring system
has previously been validated.25, 26
An erosion was defined as a lesion producing a definite discontinuance in
the mucosa but having no depth. An ulcer was defined as any lesion measuring
3 mm or more with depth.
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Table 2. Endoscopic Scoring System for Drug-Induced Mucosal Damage
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The endoscopic scores were compared using the Kruskal-Wallis 1-way analysis
of variance on ranks (the normality test failed) with all multiple pairwise
comparisons being done by the Student-Newman-Keuls method. Categorical data
were analyzed by the  2 statistic. All analyses were done using
SigmaStat 2.03 software (SPSS Inc, Chicago, Ill).
RESULTS
Twenty-six healthy volunteers participated, including 18 women and 8
men ranging in age from 30 to 50 years. Gastric ulcers were present in 8%
receiving alendronate (n = 2), in 12% of those receiving naproxen (n = 3),
and in 38% of those receiving the combination of alendronate and naproxen
(n = 10) (P<.05 for the combination vs either
drug alone). Endoscopic scores for overall gastric mucosal damage are shown
in Table 3. The median endoscopic
score was O for the alendronate-alone arm, between B and C for for the naproxen-alone
arm, and D for the combination arm. The combination regimen resulted in a
significantly higher degree of gastric damage than either drug alone (P<.05). In addition, treatment with naproxen alone was
significantly more injurious than alendronate alone (P<.05).
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Table 3. Endoscopic Scores for Mucosal Damage After 7 and 14 Days of
Drug Therapy
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No esophageal injury was seen in any group. Duodenal injury was mild
but was significantly more common in the alendronate-naproxen group than with
the alendronate-alone group (P<.05).
Naproxen was significantly better tolerated than either alendronate
or the combination of alendronate and naproxen. Side effects were mild and
were reported in only 6 volunteers receiving naproxen compared with 14 receiving
alendronate, and 18 receiving both (P<.05 for
naproxen vs alendronate or alendronate plus naproxen). The side effects reported
for each treatment arm were as follows: for the alendronate group, headache
(6 subjects), loss of appetite/nausea (4 subjects), abdominal pain (3 subjects),
diarrhea (2 subjects); for the naproxen group, headache (2 subjects), loss
of appetite/nausea (5 subjects), abdominal pain (3 subjects), diarrhea (1
subject); and for the the alendronate-naproxen group, headache (2 subjects),
loss of appetite/nausea (8 subjects), abdominal pain (8 subjects), and diarrhea
(2 subjects).
COMMENT
The evidence is now overwhelming that use of alendronate alone can cause
acute gastric ulcers (Table 1).16, 17, 19, 20, 21, 22, 23
This study showed that the combination of alendronate and an NSAID was markedly
more likely to produce severe gastric mucosal damage and symptoms than either
drug given alone. The combination produced ulcers in more than one third of
those studied. Naproxen has both a local effect and a systemic effect on the
stomach. In contrast, alendronate is a topically caustic drug thought to cause
gastric or esophageal mucosal damage by direct contact.7, 16, 20
Why the combination of alendronate and an NSAID appears to be synergistic
is unknown. Because NSAIDs reduce the rate of ulcer healing in the stomach
or duodenum, it is possible that the NSAID slows healing and thus exaggerates
the mucosal injury caused by alendronate. To test this hypothesis, it would
be interesting to study whether NSAIDs also would accentuate the damage caused
by other drugs known to cause topical gastric mucosal injury, such as the
solid-dose forms of potassium.27
The present study showed that subjects taking alendronate and the combination
of alendronate and naproxen experienced side effects more often than those
taking naproxen alone: 18 (69%) of those receiving alendronate plus naproxen
reported side effects and 10 (38%) developed gastric ulceration. These results
are consistent with an interview follow-up study of 813 women who filled prescriptions
for alendronate. New symptoms referable to alendronate were reported by 32.8%,
and 28.7% discontinued the drug, primarily because of gastrointestinal complaints.28 In that study, the risk of patients with an outpatient
visit or hospitalization for an upper gastrointestinal complaint was associated
with concurrent NSAID use and increasing age.28
Studies in animals have shown that following the administration of indomethacin,
alendronate may cause acute mucosal damage similar to that seen with aspirin
or other NSAIDs.29 The data from animal and
human studies suggest that bisphosphonates with primary amino side chains
(primary amino-bisphosphonates), such as alendronate and pamidronate, may
have increased potential to cause gastric damage.2, 8, 13, 29, 30, 31
Risedronate sodium is not a primary amino-bisphosphonate, and studies comparing
the effects of alendronate and risedronate on the gastroduodenal mucosa are
currently in progress. Preliminary results using the doses prescribed for
Paget disease have not reported a major difference in the development of ulcers.32
Both alendronate and NSAIDs can cause gastric ulcers and one would therefore
expect alendronate use to be associated an increase in gastroduodenal complications
of ulcer disease. Yet, prospective studies have not reported an increase in
ulcer complications.33 It is important to note
that if the risk of gastroduodenal complications associated with alendronate
use is about the same order of magnitude as with NSAIDs (eg, 1%-2% per year),
an association could easily be missed unless large epidemiologic studies were
done. At the same time, one should also note that use of potassium chloride,
which also causes acute gastric mucosal damage, appears to be associated with
a low risk of gastroduodenal ulcer complications.27
It remains unclear whether the gastrointestinal risks associated with alendronate
are more akin to that seen with NSAIDs or with potassium. Further studies
are warranted. Whatever the mechanism, until epidemiologic studies clearly
show that alendronate use is not associated with an increased risk of ulcer
complications, it would appear prudent not to prescribe anti-inflammatory
doses of traditional NSAIDs to patients receiving alendronate (and vice versa).
This study did not address the effect of coadministration of a selective cyclo-oxygenase
2 inhibitor instead of a traditional NSAID.
AUTHOR INFORMATION
Accepted for publication July 28, 2000.
From the Department of Medicine, Veterans Affairs Medical Center and
Baylor College of Medicine, Houston, Tex.
Corresponding author and reprints: David Y. Graham, MD, Veterans
Affairs Medical Center (111D), 2002 Holcombe Blvd, Houston, TX 77030.
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