Department of Pharmacology and

Toxicolog
Biostatistics and Biological
Standardization

CAIRO UNIVERSITY

FACULTY OF PHARMACY

Alendronate induced injury

of the upper gastrointestinal tract
Student Numbers (207-213)
Day (Tuesday)
Time (2.5-4.5) - Lab (A)
Date (12/4/2016)

A randomized controlled trial to

assess alendronate-associated injury
of the upper gastrointestinal tract
AUTHERS:
J. K. MARSHALL*, K. D. RAINSFORD, C. JAMES* &
R. H. HUNT*

Content
introduction
Method
result
Discussion

Introduction

Alendronate
Oral bisphosphonates

inhibit
osteoclast-mediated bone resorption and are
recommended for the treatment of
postmenopausal osteoporosis and
Paget's disease.

Alendronate and
gastrointestinal intolerance ?
Case reports
endoscopic

Prospective

(post-marketing experience)

studies

esophageal ulceration and stricture

gastric erosion and

ulceration

Animal data :
suggest that mucosal damage from alendronate is
likely the result of local irritation rather than any
systemic effect.
Indeed, the systemic administration:
not associated with gastric injury
the bioavailability of oral alendronate is extremely
low.

Ex vivo :
alendronat induced gastric mucosal injury was
associated with luminal release of prostaglandin E2
(PGE2), consistent with a response to local irritation

AIM
A randomized controlled trial was undertaken

to assess :
endoscopic

damage of GIT
changes in gastric mucosal
PGE2 levels in human

METHODS

METHODS
Patients
76Healthy volunteers between the ages of 40 and 60 years .
Have no history of peptic ulcer or taking any medication

induce ulcer .
laboratory tests were performed to exclude presence of

ulcers (rapid urease test ,blood tests,) .

Oesophago-gastroduodenoscopy screening tests performed

to ensure entity of GIT .

mucosal biopsies were taken from antral & gastric body to

determine mucosal PGE2 concentration .

study design

Group C

lactose placebo
o.d

26

Group B

alendronate
10 mg o.d

Group A

acetylsalicylic
acid 650 mg o.d

25
25

Endoscopic evaluation
On day 14

of the treatment period, each

subject
underwent a second oesophagogastroduodenoscopy
by the same endoscopist 2 h after ingestion of
the final dose .

PGE2 assay
Single biopsies were taken from the

gastric antrum and body and

immediately frozen in liquid nitrogen
for later measurement of mucosal
PGE2 concentration

Statistical analysis
Mucosal damage score at day 14

endoscopy and The mean change in

gastric mucosal PGE2 concentration
from baseline to day 14 , was
compared among the treatment
groups using the Kruskal Wallis
analysis of variance (ANOVA) .

Result

RESULTS
Study population

A total of 87 healthy volunteers were screened

with
baseline endoscopy, but 11 were excluded
because of erosions in the oesophagus ,
stomach, or duodenum.
76 volunteers

12 have
Helicobact
er pylori

SMOKER 9

(range 40-60 years)

FEMALE 39

Male 37

Baseline characteristics of treatment groups

Number
Age range
Male : Female
smoker
H. pylori-positive

Placebo

Alendronate

(acetylsalicylic acid)

25

25

26

(40-62)

(40-54)

(40-60)

8 : 17

12 : 13

10 : 16

1
4

4
6

4
2

Endoscopic changes
After 14 days of treatment, visible damage to the

upper
gastrointestinal tract (at least one erosion or ulcer at
any site) .

Placebo
Alendronat
( acetylsalicylic
Number of
subjects
Gastric ulcers
developed

13 of 25
(48.0%)
---

acid)

17 of 25
(68.0%)
2

24 of 26 subjects
(92.3%)
5

Both participants who developed ulcers on

alendronate were negative for H. pylori by rapid

urease testing.

One subject prescribed acetylsalicylic

acid
also developed a duodenal ulcer.
No participant developed clinical
evidence of gastrointestinal bleeding
or perforation.


The mucosal
damage score of
subjects given
acetylsalicylic acid
was significantly
worse than placebo
at all three gastric
sites, as well as in
the duodenum

The mucosal
damage score
of subject given
alendronate in
the gastric body
was significantly
worse than
among those
.given placebo

 The mean mucosal damage score in the

oesophagus
did not differ significantly among treatment
groups
ASA
nine
out of 26

Alendronate

Placebo

a single
5 out of 25
erosion in 6out of
25
two erosions in
one subject

PGE2 levels
Mucosal PGE2 levels (ng/mg protein) were
measured in
both the pre-treatment and post-treatment
specimens of
66 subjects: 21 randomized to placebo, 24
randomized
to acetylsalicylic acid, and 21 randomized to
alendronate.

the mean change in log10[PGE2]

(ng/mg protein)
The mean change in log10[PGE2] did not
differ significantly among treatment
groups, the values being 0.07 for placebo
, 0.80 for acetylsalicylic acid , and 0.62
A secondary analysis was performed after the
for alendronate respectively

exclusion
of subjects who were smokers at the time of
eligibility assessment. Among the remaining 58
subjects

0.36 after treatment with

placebo
1.10 after treatment with
acetylsalicylic acid
1.22 after treatment with

After treatment with alendronate the

difference between alendronate and ASA
.was (P=0.04)

After the exclusion of participants infected with H. pylori

the differences remained non-significant.

Discussion

DISCUSSION
Trial confirm other reports of significant
injury of the gastric mucosa following
treatment with alendronate.
But this did not appear to be related to
significant changes in PGE2 concentration
. in the gastric mucosa

Alendronate was associated with higher mucosal

damage scores than placebo in the gastric body and
with gastric ulcers (8.0%).

The precise mechanism by which alendronate might

cause gastric mucosal injury remains unknown.
But published animal data suggest that alendronate
directly irritates the oesophageal mucosa at acidic pH
and compromises the hydrophobic mucosal
phospholipid barrier in the stomach.

Clinical studies support a topicalcorrosive mechanism

of injury Thus:

1- The dosing instructions are designed to

reduce damage by minimizing
stasis in the esophagus.
2- Newer bisphosphonates have used
cellulose film coatings to accelerate
oesophageal and gastric transit.

 In the stomach, our study did not

demonstrate any significant difference in

gastric mucosal prostaglandin levels
among the treatment groups.
but did suggest a trend to higher

mucosalPGE2 concentration with

alendronate, compared with both placebo
and acetylsalicylic acid.

Smoking was prohibited during the study

period
as smoking may affect PGE2 synthesis and
repeated the analysis with smokers excluded.
The increase in PGE2 concentrations on
alendronate relative to acetylsalicylic acid is
achieved due to drug.
According to hypothesis that alendronate acts
as a topical irritant and induces appropriate
activation of cyclooxygenase.

STUDIES
Month randomized endoscopy study :
No difference in mucosal damage was detected between
alendronate (10 mg/day) and placebo.18 It is possible
that longer treatment allows mucosal adaptation and
alters the severity.
Randomized placebo-controlled study of fracture
rates on alendronate observed no increase in
gastrointestinal adverse events after 3.8 years However,
this study initiated treatment dose (5 mg/day), Excluded
patients with prior upper gastrointestinal disease and
was not designed to monitor gastrointestinal events as a
primary end-point.

:RESULT
The two subjects developed gastric ulcers
whilst
taking alendronate in this study:
Had no other risk factor for ulcer disease.
Neither was infected with H. pylori , and
neither used NSAIDs during the treatment
period or the 30 days prior to randomization.
Thus, it is highly probable that these
ulcers were a direct consequence of
Alendronate therapy.

 The potential interaction of bisphosphonates

with NSAIDs is not well understood but is

clinically important:
In rabbits :
alendronate increases the incidence and size
of indomethacin-induced gastric ulcers and
impairs their healing
Aminobisphosphonates impair healing of
aspirin-induced gastric ulcers in humans.
Randomized crossover design endoscopy
study alendronate and naproxen were highly
synergistic in their association with gastric
ulceration.

Caution if alendronate and NSAIDs are

prescribed concomitantly

The association of alendronate with gastric

injury in this study, and the high frequency of
gastrointestinal adverse events suggest the
frequency, severity, and complications of
amino bisphosphonate-associated mucosal
injury require careful re-evaluation.

Out come
(for community pharmacist)

Alendronates should be taken with at 250 ml

water or more and avoid lying down for at

least30 min after ingestion.

Thank you