Bisphosphonates and Risk of Upper Gastrointestinal
Cancer — A Case Control Study Using the General
Practice Research Database (GPRD)
Ellen Wright*, Peter T. Schofield, Paul Seed, Mariam Molokhia
Department of Primary Care and Public Health Sciences, King’s College London, London, United Kingdom
Background: Concerns have been raised as to the safety of bisphosphonates; in particular a possible link between
bisphosphonate use and upper gastrointestinal (GI) cancer. Two published studies using different study populations but
drawn from earlier versions of the same national UK database, reached differing conclusions: one finding no evidence for an
increase in the risk of gastric or oesophageal cancer in bisphosphonate users and one finding a small but significantly
increased risk of oesophageal cancer linked to duration of bisphosphonate use.
Methodology/ Principal Findings: Design-A case control study comparing bisphosphonate prescribing in cases of upper GI
cancer from 1995 to 2007 using UK primary care electronic health records (GPRD).
(approximated to Odds Ratio for rare events) for oesophageal and gastric cancer development in bisphosphonate users
compared to non–users. The odds of being a case of oesophageal cancer, adjusted for smoking status, were significantly
increased in women who had had one or more bisphosphonate prescriptions, odds ratio 1?54 (95% CI 1?27–1?88) compared
to non-users. There was no significant effect on gastric cancer in women, odds ratio adjusted for smoking status, 1.06 (95%
CI 0.83–1.37) and also no apparent risk in men for either oesophageal or gastric cancer, odds ratio adjusted for smoking
status 0.78 (95%CI 0.56–1.09) and 0.87 (95% CI 0.55–1.36) respectively.
Main Outcome Measure-Relative Risk
Conclusions/ Significance: Our results support a small but significant increased risk of oesophageal cancer in women
prescribed bisphosphonates and is based on the largest number of exposed cases to date in the UK.
Citation: Wright E, Schofield PT, Seed P, Molokhia M (2012) Bisphosphonates and Risk of Upper Gastrointestinal Cancer — A Case Control Study Using the
General Practice Research Database (GPRD). PLoS ONE 7(10): e47616. doi:10.1371/journal.pone.0047616
Editor: Georgina L Hold, University of Aberdeen, United Kingdom
Received February 26, 2012; Accepted September 19, 2012; Published October 24, 2012
Copyright: ? 2012 Wright et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: This research is supported by the National Institute for Health Research (NIHR) Biomedical Research Centre at Guy’s and St Thomas’ NHS Foundation
Trust and King’s College London. The GPRD dataset for this study was obtained under the collaborative research licence funded by the Medical Research Council
and the study was approved by the Independent Scientific Advisory Committee of the GPRD (protocol number 09_093R). The funders had no role in study design,
data collection and analysis, decision to publish, or preparation of the manuscript.
Competing Interests: MM has received grants from AstraZeneca and Pfizer and from the Serious Adverse Events Consortium (collaboration of academia &
industry) for studies of adverse drug reactions.This does not alter the authors9 adherence to all the PLOS ONE policies on sharing data and materials.
* E-mail: email@example.com
There has been a 20-fold rise in the prescribing of bisphospho-
nates in general and alendronate in particular in recent years. In
1992 0?2% of women over 40 included in the UK General
Practice Research Database (GPRD) were prescribed a bisphos-
phonate but by 2005 this had risen to 4?1%. At the same time
there has been a parallel reduction in hormone replacement
therapy (HRT) prescribing from 8?2% in 1991 to 7?0% in 2005,
with a 50% fall since 2002, largely driven by concerns over excess
risk of breast cancer (and to a lesser degree ovarian cancer) and
Bisphosphonates and particularly alendronate are well known to
cause both dyspepsia and inflammatory changes such as erosive
oesophagitis, delayed healing, and mucosal abnormalities.
Multinucleated giant cells have been detected in oesophageal
inflammatory exudates. Whether these can undergo malignant
transformation is not known but concerns have been raised as to a
possible link between bisphosphonate use and upper GI
Wysowski, in her report to the US Federal Drug Adminis-
tration (FDA), noted that since the initial marketing of alendronate
in 1995 the FDA had received 23 reports of patients who
developed oesophageal tumours after taking the drug. Typically 2
years elapsed between the time patients started taking the drug
and the onset of oesophageal cancer. In Europe and Japan a
further 31 cases had been reported linking oesophageal cancer and
bisphosphonate use. The FDA reporting did not include any
denominator data. Wysowski suggested distal oesophageal carci-
noma might be associated with bisphosphonate use but recom-
mended more rigorous study approaches with sufficient size,
length of follow up, inclusion of a control group, and control for
confounding variables. In the meantime the authors advised that
the drugs should not be used in patients with Barrett’s oesophagus
(an abnormal change in the cells of the lower portion of the
oesophagus, thought to be due mainly to chronic acid reflux from
the stomach, its main significance is an increased risk of developing
PLOS ONE | www.plosone.org1 October 2012 | Volume 7 | Issue 10 | e47616
adenocarcinoma of the oesophagus). However, Merck (the makers
of alendronate) have not reported any cases of oesophageal cancer
linked to bisphosphonate use in their clinical database of 17,000
Following the FDA reports, rapid communications of studies
using a large national database in Denmark and Medicare
beneficiaries in the US concluded there was no evidence for an
increased risk of oesophageal cancer in bisphosphonate users[5,6].
However, again the follow up period was short (2 years). Because
of the relative rarity of these conditions and the limited number of
patients, the confidence intervals were wide and it was impossible
to conclude whether there could be a clinically important
association. Two published studies using the UK General Practice
Cardwell et al. in a retrospective cohort study found no
evidence of an increase in the combined risk for gastric and
oesophageal cancer in bisphosphonate users compared to non-
users, Hazard Ratio 0?96, (95% CI 0?74–1?49) but again
confidence intervals were wide (i.e. study is also consistent with a
fairly substantial effect). Green et al. carried out a nested case
control study using a sample drawn from the same database and
found an overall increased risk of oesophageal cancer in
bisphosphonate users (Relative Risk 1?30, 95% CI 1?02–1?66).
This increased with more than ten prescriptions or longer than
three years use (RR 1?93). Although these studies appear to give
different results, the relatively wide confidence intervals overlap
substantially, so results could be consistent with a similar
magnitude of risk. In Cardwell’s study a relatively small proportion
of exposed cases were included limiting power and precision.
Dixon and Solomon  have reviewed in detail the conflicting
results of these two studies and concluded similarly that even when
confining the comparison to patients with greater than three years
exposure to bisphosphonates (allowing for induction and latency
periods) the confidence intervals of the relative risks for both
studies included the possibility of a 50% increase in risk. At less
than three years exposure, although neither study found an
increase in relative risk of oesophageal cancer with bisphosphonate
use, Dixon and Solomon point out that the confidence intervals of
both span one and, therefore, one should say that the results are
‘inconclusive’ rather than ‘‘there is no effect’’. The upper limits of
the RR’s of 3 years’ exposure are 1.73 and 1.81 respectively
according to the 95% confidence intervals of the two analyses.
They note ‘‘it is, therefore, plausible in both studies that, despite
the best guess being of ‘no increased risk’, there may be as much as
a 70% increase in baseline risk.’’
Haber et al concluded after reviewing both Green and
Cardwell’s studies and the observational study on the incidence of
oesophageal cancer in patients with Barrett’s oesophagus taking
bisphosphonates by Nugyen, as well as the case reports in
Wysowski’s article, that ‘‘the evidence on the use of bisphospho-
nates and risk of esophageal cancer is weak and conflicting’’.
Our primary aim was to carry out a retrospective case control
study with the greatest possible power using a large UK primary
care database (the GPRD), to determine whether any association
exists between prescribing of alendronate specifically (and
bisphosphonates in general) and the development of upper GI
malignancy. We were particularly concerned to have enough
statistical power to detect a small increase in a rare, but serious
disease and, therefore, chose to do a matched case control study
using all known cases of oesophageal and gastric cancer. Although
this is the third study using data drawn from the GRPD, it uses a
later and significantly larger version of the database and it is
substantially more powerful.
The study population included all adults (men & women)
registered with up to standard GP (General Practitioner) practices
in the UK General Practice Research Database (GPRD) from 1/
1/1995 to 31/12/2007. The GPRD is a primary care database
holding approximately 5 million longitudinal anonymised records
of patients registered with a national health service (NHS) GP.
Only UK general practices with data of approved quality can
contribute to the database. Strict protocols are followed by
practices for data entry. The accuracy and completeness of GPRD
data, particularly with respect to prescribing (almost 100%) and
cancer diagnosis (95%) is high and has been confirmed in
validation studies.[13,14]. The data extraction was performed
from the May 2010 version of the GPRD.
Case and control definition
Cases had a clinical or referral record of incident upper GI
(UGI) malignancy in the study period and their registration
UGI cancer events were identified by the following READ
codes: (See appendix S1 for full list)
B11 + all daughter codes–malignant neoplasm of stomach
B10 + all daughter codes–malignant neoplasm of oesophagus
BB5C–gastrinoma and carcinoma
B105–malignant neoplasm of lower third of oesophagus
For every case, four control patients matched on age (+/22
years) and gender and with no record of UGI cancer were selected
from the database. Observation window matching was used: i.e.
observation of all four controls started before that of the case, and
ended after that of the case. The observation times of the controls
matched exactly those of their matched cases. Control events
outside the observation window of the case were ignored. The
period of follow up was earliest of: death, last medical record,
practice transfer, or end of study period.
Exposure assessment. (bisphosphonate use)
Bisphosphonate use was defined as any patient ever prescribed a
bisphosphonate during the study period. We excluded patients
with prescriptions for bisphosphonates licensed to treat Paget’s
disease or bone metastases (pamidronate, ibandronate) in the
sensitivity analysis as these patients would already be suffering
from cancer or Paget’s disease. Duration of bisphosphonate use
was the time between first and last prescription. We categorized
bisphosphonate use by number of prescriptions issued in the study
period into low (,10 prescriptions) and high (.10 prescriptions).
As covariates and potential confounders we evaluated the
presence of smoking as a major risk factor for UGI cancer.
Smoking was defined as any record of use from 1980. We also
adjusted for alcohol intake, dyspepsia, proton pump inhibitor (PPI)
use, Helicobacter pylori (H. pylori) status and body mass index (BMI)
although previous studies had not shown an effect.
Sample size calculation
Typically for rare diseases case control studies are used to
maximize efficiency and power to provide a valid estimate of risk
or hazard ratio. Using multiple controls per case can increase
power, although the gain in power beyond 4 controls is relatively
small. With 8,000 cases & 32,000 controls, we calculated we would
have 89% power to detect a difference of 2% (50% compared to
52%) in the rate of bisphosphonate use in the two arms. If the rate
Bisphosphonates and Risk of Upper GI Cancer
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of bisphosphonate use was lower, the minimum detectable odds
ratio would be increased; but its clinical importance would be
similar. For example, for 4% use in controls (a more realistic figure
based on recent figures)  and 4?8% use in cases, we would be
able to detect an odds ratio of 1?21 with 88% power. We used a
matched (age and gender) design to reduce confounding.
Taking into account the matched study design we used
conditional logistic regression to calculate unadjusted and adjusted
odds ratios (ORs) and corresponding 95% confidence intervals
(CIs) for the association between bisphosphonate use and UGI
cancer. We adjusted for the main confounder smoking, as well as
alcohol intake, dyspepsia, proton pump inhibitor (PPI) use, H.
pylori status and body mass index (BMI). We tested for the
interaction between gender and bisphosphonate use and risk of
upper GI cancer. We restricted analyses to oesophageal cancer,
gastric cancer and alendronate alone. We carried out sensitivity
analyses as follows: excluding bisphosphonates used to treat bone
metastases; excluding bisphosphonates commenced 6 months or
less before the diagnosis of UGI cancer and excluding cases where
the READ code for UGI cancer was uncertain. All analyses were
conducted using Stata version 11 (Stata Corporation, USA).
We received data on 8,636 cases of UGI cancer where the
cancer diagnosis date was between January 1, 1995, and
December 31, 2007, and 34,544 controls, 4 per case, matched
on age (+/22 years) and sex. We initially analyzed the complete
data set and then looked at the subsets of oesophageal and gastric
cancer cases and controls. Table 1 gives summary descriptive
statistics separately for the cases and controls.
Risk of all bisphosphonates on UGI cancer
We initially investigated the effect of all bisphosphonates on
UGI cancer in both men and women and found an Odds Ratio
(OR) of 1?13 (95% CI 0?99–1?28) for men and women combined
(appendix S2). The OR for the effect of all bisphosphonates on
UGI cancer in women adjusted for smoking status was 1?34 (95%
CI 1?14–1?56) and 0?81 (95% CI 0?62–1?06) for men.
Risk of all bisphosphonates on oesophageal cancer and
When we analysed the effects of all bisphosphonates on
oesophageal cancer only we found an OR of 1?43 (95% CI
1?18–1?72) in women and 0?87 (95% CI 0?65–1?18) in men. The
corresponding results for gastric cancer were OR 1.06 (95% CI
0.83–1.35) in women and OR 0.77 (95% CI 0.50–1.20) in men.
Adjusting the analyses for smoking status did not change the
results significantly. The OR for the effect of all bisphosphonates
on oesophageal cancer adjusted for smoking status was 1?54 (95%
CI 1?27–1?88) for women and 0?78 (95% CI 0?56–1?09) for men
(tables 2 and 3).
Risk of alendronate alone on oesophageal cancer
When we restricted to alendronate alone we found correspond-
ing ORs of 1.37 (95% CI 1.07–1.75) for women and 0.78 (95% CI
0.50–1.22). The OR for alendronate alone on oesophageal cancer
adjusted for smoking status was 1?42 (95% CI 1?10–1?83) for
women and 0?73 (95% CI 0?46–1?17) for men (table 4).
Interaction of bisphosphonate use and oesophageal
cancer risk with gender
We looked at the interaction of bisphosphonate use and
oesophageal cancer risk with gender, which gave an OR of 1?27
(95% CI 1?10–1?47) for women (Table 2) and 0?84 (95% CI 0?66–
1?07) for men (Table 3); in other words there appeared to be an
effect in women but not in men. The interaction between
bisphosphonate use and gender, using the likelihood-ratio test
(LRT) was statistically significant, p=0.0011.
We performed three sensitivity analyses none of which
significantly altered the results (table 5). Firstly we excluded
bisphosphonates licensed to treat bone metastases, as these
patients by definition would already be suffering from cancer.
The corresponding ORs for the effect of all bisphosphonates on
UGI cancer adjusted for smoking status were 1?34 (95% CI 1?14–
1?57) for women and 0?80 (95% CI 0?61–1?05) for men. Secondly
we excluded prescriptions of bisphosphonates commenced six
months or less before the UGI diagnosis date on the grounds that
the time interval was too short for bisphosphonates to be causative.
The subsequent ORs adjusted for smoking status were 1?30 (95%
CI 1?10–1?53) for women and 0?77 (95% CI 0?58–1?04) for men.
Finally we excluded cases where the READ code for UGI cancer
diagnosis was uncertain. The ORs adjusted for smoking in these
cases were 1?34 (95% CI 1?14–1?56) for women and 0?81 (95% CI
0?62–1?06) for men.
Summary of main findings
The results show that female cases of oesophageal cancer were
significantly more likely to have been prescribed a bisphosphonate
than controls. This effect was more pronounced when we looked
at alendronate rather than all bisphosphonates. The risk remained
significant after adjusting for to the effect of smoking. There was
no significant apparent effect in men although the confidence
intervals did not exclude this. There was also no effect on gastric
cancer. Adjusting for covariates – dyspepsia, PPI use, BMI, alcohol
intake and H. pylori status did not alter the result.
Excluding bisphosphonates prescribed for bone metastases;
bisphosphonates commenced 6 months or less before the diagnosis
of upper GI cancer and cases where there was uncertainty
regarding the READ coding of the case did not significantly alter
From the data, 95 out of 4442 female cases of upper GI cancer
annually in the UK could be linked to bisphosphonate use (based
on an OR of 1?34 for bisphosphonates in women for UGI cancer,
4442 new cases of UGI cancer in women in 2007 and 8?43% of
female cases of UGI cancer being prescribed a bisphospho-
How our studies differed from other findings
Solomon et al in their response to Wysowski’s article used
SEER (Surveillance, Epidemiology and End Results) registry data
to compare rates of oesophageal cancer in persons receiving oral
bisphosphonates with those receiving other medications for
osteoporosis and the general incidence rate in the SEER registry.
They did not find a difference but, as they admitted, due to the
rarity of oesophageal cancer, the confidence intervals were very
wide and compatible with an effect as well as no effect.
Nugyen et al performed a nested case-control study
examining bisphosphonate use in oesophageal cancer cases and
controls in patients with Barrett’s oesophagus. The data came
from the National Department of Veterans Affairs database. They
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did not find a significant difference between the groups but the
number of cases and controls were relatively small (116 and 696
respectively) and the number of bisphosphonate users in both
groups was small which the authors admit limits the power to
detect significant differences between the groups.
Abrahamsen and colleagues have reported two cohort studies
using data from national registries in Denmark. The first in
2009, published as a response to Wysowski’s case reports,
looked at 13,678 patients with fractures who had used bisphos-
phonates and compared them with 27,356 controls of the same sex
and similar age and fracture type. They found a reduced incidence
of oesophageal cancer in the bisphosphonate group and no
difference in gastric cancer between the two groups. However, the
follow up period was relatively short (2.2 years) and the total
number of cases identified small (37 and 48 for gastric and
oesophageal cancer respectively). In November 2010 they reported
Table 1. Summary descriptive statistics for cases and controls.
CharacteristicsOES CA CASES’
All UGI CA
All UGI CA
Male3,41213,648 2,0848,3365,496 21,984
Female 1,8147,2561,3265,304 3,140 12,560
Total (male and female) 5,22620,9043,410 13,6408,636 34,544
Mean Age (at time of diagnosis of case) 63?4 63?4 66.5 66.564?7 64?7
Mean age men61?6 61?665.6 65.6 63?1 63?1
Mean age women67?0 67?0 68.1 68.167?5 67?5
Mean years observed in data base6?36?3 5.75.76?16?1
Smoking-any positive record of smoking (%) 2,229 (51.5) 8,437 (45.4) 1,303 (46.5) 5,274 (43.9)3,532 (49.5) 13,711 (44.9)
Dyspepsia–any record up to 12 mths
before cancer diagnosis in cases and
equivalent date in controls (%)
1,169 (22.3) 4,184 (20.0) 827 (24.3)2,910 (21.3) 1,996 (23.1) 7,094 (20.5)
PPI-any use within study window (%)1,100 (21.1) 3,215 (15.4)728 (21.4) 2,073 (15.2)1,828 (21.2)5,288 (15.3)
H. pylori positive–any record121 (2.3)491 (2.4) 128 (3.8)321 (2.4) 249 (2.9) 812 (2.4)
BMI.30 (%) 88 (1.7) 1,621 (7.8)58 (1.8) 948 (6.7)146 (1.7) 2,569 (7.44)
Alcohol intake–any record greater than
recommended limits (%)
620 (11.9) 2,293 (11.0)286 (8.4)1,345 (9.9)906 (10.5) 3,638 (10.5)
Prescribed bisphosphonate-male and
225 (4?3) 749 (3?6) 117 (3.4)478 (3.5)342 (4?0) 1227 (3?6)
Men (%) 54 (1.6)246 (1.8) 24 (1.2)124 (1.5)78 (1.4) 370 (1.7)
Women (%) 171 (7.8) 503 (6.9)93 (7.0)354 (6.7)264 (8.4) 857 (6.8)
Prescribed alendronate (%)119 (2?3) 410 (2?0)72 (2.1)252 (1.9)191 (2?2)662 (1?9)
Men (%)24 (0.7) 122 (0.9)14 (0.7)68 (0.8) 38 (0.7)190 (0.9)
Women (%) 95 (5.2) 288 (4.0)58 (4.4) 184 (3.5) 153 (4.9)472 (3.8)
Prescribed bisphosphonate–xcluding those
used to treat metastases (%)
218 (4?2)726 (3?5) 113 (3.3)461 (3.4)331 (3?8)1,187 (3?5)
Prescribed bisphosphonates-less than 10
prescriptions-mean number per time
observed in database
3?84?0 3.9 3.83?83?9
Prescribed bisphosphonates–more than 10
prescriptions–mean number per time
observed in database
26?5 26?2 23.026.0 25?4 26?1
Table 2. Risk of bisphosphonates on oesophageal and gastric cancer in women.
Odds Ratio (95% CI)
Gastric Cancer Odds
Ratio (95% CI)
All UGI Cancer Odds Ratio
Women taking bisphosphonates 1.43 (1.18–1.72) (171
cases, 503 controls)
1.06 (0.83–1.35) (93 cases,
1?27(1.10–1.47) (264 cases, 857
Adjusted for smoking 1.54 (1.27–1.88)1.06 (0.83–1.37) 1.34 (1.14–1.56)
Adjusted for smoking, alcohol intake, PPI, H. pylori status, dyspepsia
1.43 (1.16–1.75)0.98 (0.76–1.27)1.24 (1.06–1.45)
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a further study, which compared 30,606 alendronate users with
122,424 matched controls. This time they found a lower risk
of gastric cancer in the alendronate group (OR 0.61; 95% CI
0.39–0.97) and no increased risk for oesophageal cancer (OR 0.71;
95% CI 0.43–1.19), however the confidence interval for oesoph-
ageal cancer is quite wide and is compatible with an effect as well
as no effect. They also found that alendronate users were more
likely to have had a recent upper endoscopy.
Vestargaard carried out another cohort study of Danish
patients but with significantly larger numbers. 103,562 patients
using drugs for osteoporosis were compared with 310,683 age and
gender matched controls. They found an excess risk with
alendronate and etidronate for oesophageal cancer (RR 2.32
and 2.00 respectively) which was most pronounced for low doses
and short duration but still present at higher doses and longer
Chen et al have used claims data from the National Health
Insurance Database of Taiwan (NHIRD) to carry out a case
control study comparing alendronate prescriptions in 282 cases of
oesophageal cancer and 2,811 controls. They found 31.2% of the
cases had been prescribed alendronate and 27.1% of the controls
which equated to an adjusted OR of 0.61; 95% CI 0.21–1.75 with
a p-value of 0.36. The confidence interval, as in other studies, is
compatible with a modest effect (e.g. 50% increase or decrease) as
well as no effect.
Ho et al recently published another study from Taiwan
using the same claims database (NHIRD). This was a large case
control study comparing oral bisphosphonate prescribing in
16,204 cases of oesophageal cancer with 64,816 controls. Overall
they found bisphosphonates had been prescribed to 7.8% of the
cases versus 3.6% of the controls, however they then break the
analysis down by frequency of use of bisphosphonates and find a
decreasing trend of ORs from rare to regular users of 3.86 to 2.68
and also with time observed and conclude that there is no effect.
Unfortunately no confidence intervals are reported and the
numbers of frequent and regular bisphosphonate users are very
small overall; the authors rely on the basic error of comparing p-
values between unequal-sized groups rather than carrying out a
valid test. If one looks at the rare user group which has the
largest numbers of cases and controls for the three observation
periods then the OR’s are 3.86, 2.58 and 2,27 for one year, three
years and five years respectively with a p value of 0.001.
This last study illustrates the problem of studies on side effects of
drugs where the outcome is a rare disease (oesophageal cancer,
incidence 9.8:100,000 UK age standardized rate 2008) and
the exposure is also relatively small (average prescribing of
bisphosphonates in the UK 4.1% in 2005).
The two previous studies using this data set (GPRD) followed
different approaches and had substantially smaller numbers of
exposed oesophageal cancer cases (79 Cardwell, 90 Green) than
ours. Their confidence intervals are correspondingly wider, and
indeed overlap. (Cardwell: adjusted HR 1?07 (95% CI 0?77–1?49);
Green: RR1?30 (95% CI 1?02–1?66). In the context of a rare
disease, the tiny numerical difference between Hazard Ratio, Risk
Ratio and Odds Ratio can be ignored. A formal test for a
difference is not possible as the studies draw on the same data.
However, there is a substantial overlap of Cardwell & Green’s
results from 1?02 to 1?49.
In the present study, with 225 exposed oesophageal cancer
cases, over twice as many, the OR for oesophageal cancer, for men
and women adjusted for smoking, is 1?30 (95% CI 1.21–1?39),
which is within the overlap noticed above, but the confidence
interval is much narrower.
Possible mechanisms for association of bisphosphonates with
oesophageal cancer and why this may vary by gender
The mechanism may be via inflammatory changes to the
oesophageal mucosa, well known already as a side effect of
bisphosphonates.[21,22]The apparent lack of an effect in men
may be a) due to the much smaller numbers of men (25% of total)
prescribed bisphosphonates (and hence the difficulty of demon-
strating an effect on a rare disease), however, the significant
interaction test strongly suggests that the difference is real; b) the
observation that the average age of the men prescribed
bisphosphonates (67?8) was less than the women (69?7) and the
incidence of UGI cancer increases significantly with age. When we
reduced the whole sample size to 25% of the original and re-ran
the analysis, the effect in women, although present (OR1.2) was no
longer significant (p=0.2). Women are usually prescribed
Table 3. Risk of bisphosphonates on oesophageal and gastric cancer in men.
Odds Ratio (95% CI)
Gastric Cancer Odds
Ratio (95% I)
All UGI Cancer Odds
Men taking bisphosphonates 0.87 (0.65–1.18) (54 cases,
0.77 (0.50–.20) (24 cases,
0?84 (0.66–1.07) (78 cases,
Adjusted for smoking 0.78 (0.56–1.09)0.87 (0.55–1.36)0.81 (0.62–1.06)
Adjusted for smoking, alcohol intake, PPI, H. pylori, dyspepsia andBMI0.73 (0.53–1.03) 0.77 (0.49–1.21) 0.75 (0.57–0.98)
Table 4. Effect of alendronate on oesophageal cancer for men and women (mean number of observations 19,991.
Odds Ratio P value 95% confidence interval
Women on alendronate (95 cases, 288 controls)1?370?0141?07–1?75
Adjusted for smoking1?420?0071?10–1?83
Men on alendronate (24 cases and 122 controls)0?780?280?50–1?22
Adjusted for smoking0?730?190?46–1?17
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bisphosphonates for osteoporosis occurring idiopathically whereas
men are more likely to be prescribed bisphosphonates for
iatrogenically caused osteoporosis, typically from steroids pre-
scribed for chronic obstructive pulmonary disease, or even
prophylactically if on high dose steroids for more than three
months. Some of the risk factors, apart from prolonged steroid use,
for developing osteoporosis – smoking, heavy alcohol intake,
anorexia/low BMI, and poor nutrition – also are risk factors for
upper GI cancer. Although correcting for these factors in the
analysis did not alter the results it may be that as a group women
with osteoporosis are at higher risk than men of a similar age for
upper GI cancer.
Strengths and limitations
The main strength of our study is that it is based on one of the
most reliable population samples to date and uses electronic
patient records rather administrative claims data (Zhang et al
have described the problems related to using the latter). It is also
based on the largest number of cases giving a relatively precise
confidence interval. We were confident from our sample size
calculations about being able to detect even quite small differences
and that a negative result would be strong evidence against an
adverse effect that was important from a public health perspective.
Limitations of our study are that adherence to bisphosphonates
was not formally measured (but this is a general difficulty with
large anonymised database studies) and although the accuracy of
the GPRD cancer codes is likely to be high they were not formally
validated. Walker has recently published a study on the
accuracy of identification of oesophageal cancer in the GPRD and
concluded that while essentially all cases bearing a code for the
condition had oesophageal cancer the clinical onset might be
significantly earlier than the first code recorded in the GPRD. This
could affect cohort studies with short follow up times but not case
With any retrospective longitudinal study there are also always
limitations due to incomplete data recording; prescriptions issued
not dispensed/taken; missing data; unmeasured confounders etc.
Oesophageal cancer is rare but often fatal and associated with
significant morbidity. Bisphosphonates in general and alendronate
in particular are being recommended, by current osteoporosis
prevention guidelines, to increasing numbers of men and women
in predominantly older age groups. Our data supports a small
increased risk of oesophageal cancer in women prescribed
bisphosphonates. With a rare disease such as this (incidence of
oesophageal cancer in 60–79 age group is 10/100,100) it would
need very large prospective cohort studies, with sufficiently long
follow up to confirm and clarify the size of the association and
none have been published to date, however, Vinogradova et al
have recently published a protocol for a large nested case-control
study using the Qrisk research database (significantly larger than
GPRD) which will look at the association between bisphosphonate
prescribing and the 10 most common primary cancers diagnosed
in patients between 1996 and 2011.
In the presence of an association and with a plausible
mechanism to account for possible causation (irritation of the
gastric and oesophageal mucosa) it would be sensible to exercise
caution in prescribing bisphosphonates to patients with pre-
existing risk factors for upper GI cancer (although unfortunately
many of these are also risk factors for developing osteoporosis) and
to have a lower threshold for investigating such patients, if on
bisphosphonates, should they develop symptoms suggestive of
upper GI cancer.
upper GI malignancy.
List of Read/OXMIS codes as evidence of
for men and women.
Effect of bisphosphonates on UGI cancer
Conceived and designed the experiments: EW PS. Performed the
experiments: EW PS PTS. Analyzed the data: PTS PS. Contributed
reagents/materials/analysis tools: PTS. Wrote the paper: EW. Data
interpretation: MM EW PTS. Revised article critically for important
intellectual content: MM. Original hypothesis and study design: EW.
Literature search: EW. Final manuscript editing: EW. Contributions to
final manuscript: PS PTS.
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