Bisphosphonate use and gastrointestinal tract cancer risk: Meta … · 2019. 4. 29. · Oh YH et al. Bisphosphonate and gastrointestinal tract cancer WJG| 5780 October 28, 2012|Volume

BRIEF ARTICLE

Bisphosphonate use and gastrointestinal tract cancer risk: Meta-analysis of observational studies

Yun Hwan Oh, Chan Yoon, Sang Min Park

World J Gastroenterol 2012 October 28; 18(40): 5779-5788 ISSN 1007-9327 (print) ISSN 2219-2840 (online)

© 2012 Baishideng. All rights reserved.

Online Submissions: http://www.wjgnet.com/esps/[email protected]:10.3748/wjg.v18.i40.5779

5779 October 28, 2012|Volume 18|Issue 40|WJG|www.wjgnet.com

Yun Hwan Oh, Sang Min Park, Department of Family Medi-cine, Seoul National University Hospital, Seoul National Uni-versity College of Medicine, Seoul 110-774, South Korea Chan Yoon, Seoul National University Hospital, Seoul Nation-al University College of Medicine, Seoul 110-774, South Korea Author contributions: Oh YH and Yoon C contributed equally to this work; Yoon C was responsible for the study design, data acquisition, data extraction, data interpretation, statistical analy-sis and conducting the study; Oh YH was responsible for data acquisition, data extraction, data interpretation and conducting the study; and Park SM was responsible for the conception, study design, data interpretation, critical revision and supervis-ing the study. Supported by The Basic Science Research Program through the National Research Foundation of Korea funded by the Min-istry of Education, Science and Technology, No. 2012-0003761Correspondence to: Sang Min Park, MD, MPH, PhD, Depart-ment of Family Medicine, Seoul National University Hospital, Seoul National University College of Medicine, 28 Yeongeon-Dong, Jongno-Gu, Seoul 110-774, South Korea. [email protected] Telephone: +82-2-20723331 Fax: +82-2-20723276Received: April 5, 2012 Revised: August 23, 2012Accepted: August 25, 2012Published online: October 28, 2012

AbstractAIM: To perform a meta-analysis of observational stud-ies to further elucidate the relationship between oral bisphosphonate use and gastrointestinal cancer risk.

METHODS: Systematic literature search was con-ducted in MEDLINE, EMBASE, and the Cochrane Library to identify studies through January 2011. Search terms were “bisphosphonates” or trade names of the drugs, and “observational studies” or “cohort studies” or “case-control studies”. Two evaluators reviewed and se-lected articles on the basis of predetermined selection criteria as followed: (1) observational studies (case-control or cohort studies) on bisphosphonate use; (2) with at least 2 years of follow-up; and (3) reported data

on the incidence of cancer diagnosis. The DerSimonian and Laird random effects model were used to calculate the pooled relative risk (RR) with 95% confidence in-terval (CI). Two-by-two contingency table was used to calculate the outcomes not suitable for meta-analysis. Subgroup meta-analyses were conducted for the type of cancer (esophageal, gastric and colorectal cancers). Sensitivity analyses were performed to examine the ef-fect sizes when only studies with long-term follow-up (mean 5 years; subgroup 3 years) were included.

RESULTS: Of 740 screened articles, 3 cohort studies and 3 case-control studies were included in the analy-ses. At first, 4 cohort studies and 3 case-control studies were selected for the analyses but one cohort study was excluded because the cancer outcomes were not categorized by type of gastrointestinal cancer. More than 124 686 subjects participated in the 3 cohort stud-ies. The mean follow-up time in all of the cohort studies combined was approximately 3.88 years. The 3 case-control studies reported 3070 esophageal cancer cases and 15 417 controls, 2018 gastric cancer cases and 10 007 controls, and 11 574 colorectal cancer cases and 53 955 controls. The percentage of study partici-pants who used bisphosphonate was 2.8% among the cases and 2.9% among the controls. The meta-analysis of all the studies found no significant association be-tween bisphosphonate use and gastrointestinal cancer. Also no statistically significant association was found in a meta-analysis of long-term follow-up studies. There was no negative association between bisphosphonate use and the incidence of esophageal cancer in the over-all analysis (RR 0.96, 95% CI: 0.65-1.42, I 2 = 52.8%, P = 0.076) and no statistically significant association with long-term follow-up (RR 1.74, 95% CI: 0.97-3.10, I 2 = 58.8%, P = 0.119). No negative association was found in the studies reporting the risk of gastric cancer (RR 0.89, 95% CI: 0.71-1.13, I 2 = 0.0%, P = 0.472). In case of colorectal cancer, there was no association between colorectal cancer and bisphosphonate use (RR 0.62, 95% CI: 0.30-1.29, I 2 = 88.0%, P = 0.004) and

Oh YH et al . Bisphosphonate and gastrointestinal tract cancer


also in the analysis with long-term follow-up (RR 0.61, 95% CI: 0.28-1.35, I 2 = 84.6%, P = 0.011).

CONCLUSION: Oral bisphosphonate use had no sig-nificant effect on gastrointestinal cancer risk. However, this finding should be validated in randomized con-trolled trials with long-term follow-up.

© 2012 Baishideng. All rights reserved.

Key words: Bisphosphonate; Gastrointestinal tract can-cer; Esophageal cancer; Gastric cancer; Colorectal can-cer; Meta-analysis

Peer reviewer: Dr. Kok Sun Ho, Department of Colorectal Surgery, Singapore General Hospital, Outram Road, Singapore 169608, Singapore

Oh YH, Yoon C, Park SM. Bisphosphonate use and gastrointes-tinal tract cancer risk: Meta-analysis of observational studies. World J Gastroenterol 2012; 18(40): 5779-5788 Available from: URL: http://www.wjgnet.com/1007-9327/full/v18/i40/5779.htm DOI: http://dx.doi.org/10.3748/wjg.v18.i40.5779

INTRODUCTIONBisphosphonates are commonly used in postmenopausal women with osteoporosis. In vitro and in vivo studies have suggested that bisphosphonate has anticancer proper-ties[1]: promoting apoptosis[2], inhibiting tumor cell adhe-sion and invasion[3], inhibiting angiogenesis[4], altering tumor-associated macrophage function[4], and enhancing immune surveillance[1,5]. However, it was recently re-ported that the Food and Drug Administration received reports of 23 cases of esophageal cancer in the United States and another 31 cases in Europe and Japan, all oc-curring from 1995 through 2008 among patients using oral bisphosphonates[6]. Since then, there have been sev-eral cohort studies and case-control studies to elucidate the association between the use of bisphosphonate and the risk of gastrointestinal tract cancer. However, results of the observational studies are inconsistent[7,8].

As yet, there have been no randomized controlled tri-als demonstrating a causal relationship between bisphos-phonate use and gastrointestinal track cancer. Moreover, no meta-analysis has been performed despite the incon-sistent results of observational studies. Therefore, in the present study, we aimed to investigate the association between the use of oral bisphosphonate and the risk of gastrointestinal cancer via meta-analysis of cohort stud-ies and case-control studies.

MATERIALS AND METHODSStudy selection We conducted a systematic literature search of MED-LINE, 1977 April 2011; EMBASE, 1971 April 2011; and the Cochrane Database of Systematic Reviews in

the Cochrane Library, 1973 April 2011. We identified observational studies of bisphosphonate use whose pri-mary or secondary outcomes included gastrointestinal tract cancer. The search terms were "bisphosphonates" or trade names of the drugs, and "observational studies" or "cohort studies" or "case-control studies" (Table 1). All the searches were restricted to human studies. In ad-dition, a manual review of references from primary and review articles was performed to locate any additional relevant studies. All the potentially relevant articles were independently reviewed by 2 investigators (Oh YH and Yoon C). Disagreements between evaluators were re-solved by discussion or consultation with a third author (Park SM).

The inclusion criteria were: (1) observational studies (case-control or cohort studies) on bisphosphonate use; (2) with at least 2 years of follow-up; and (3) reported data on the incidence of cancer diagnosis.

Data synthesis To compute a pooled relative risk (RR) with 95% con-fidence interval (CI), we used the RRs or odds ratios and 95% CIs that were adjusted for most confounders. Because the incidence of cancer is generally low, we did not distinguish between the various measures of RR. If the outcome measures were unsuitable for meta-analysis, we calculated a crude estimate using a two-by-two con-tingency table.

We also assessed the heterogeneity for each meta-analysis by using the I2 value which measures the per-centage of total variation across that is attributable to heterogeneity rather than chance. High value of I2 index suggests increased heterogeneity. We also calculated P value of Q-test which represents heterogeneity. If which represents heterogeneity. IfIff P value is less than 0.10, it represents there is heterogeneity. 0.10, it represents there is heterogeneity. it represents there is heterogeneity.

Because of the known clinical and methodological heterogeneity of the studies we analyzed, we calculated the pooled RR with 95% CI based on the DerSimonian and Laird random effects model. We used Stata Version 11.0 (Stata Corp., College Station, Texas) for the statisti-cal analysis.

Statistical analysisSubgroup meta-analyses were carried out for the study design (cohort and case-control) and type of cancer. For the cancer subgroup analyses, esophageal, gastric and colorectal cancers were analyzed independently.

We also performed sensitivity analyses to examine the effect sizes when only studies with long-term follow-up (mean 5 years; subgroup 3 years) were included.

RESULTSIdentification of relevant studies Figure 1 is a flow diagram of how we identified the relevant studies. Of the 740 articles identified, 4 cohort studies[7,9-11] and 3 case-control studies[8,12,13] were selected for the analyses. Many of initial 742 articles are not in


our scope. They are mainly about effect of bisphos-phonates, effects of several types of bisphosphonate regimen, other adverse effects of bisphosphonate, such as atrial fibrillation, osteonecrosis of jaw syndrome, and anti-cancerous bisphosphonate use for breast cancer and prostate cancer. We performed review of titles and abstract of the articles, then excluded irrelevant for our study. Thirty articles were remained after overall pro-cess, but 23 of 30 articles included no available data for outcome measures. One cohort study[9] was excluded be-cause the cancer outcomes were not categorized by type of gastrointestinal cancer.

We also contacted Dr. Chris Cardwell to ask the data for the adjusted hazards ratio and 95% CI for gastric cancer only in bisphosphonate users[7].

Characteristics of the studies included in the analyses More than 124 686 subjects participated in the 3 cohort studies[7,10,11] used in our meta-analyses. The mean follow-up time in all of the cohort studies combined was ap-proximately 3.88 years (range: 0.5-13 years). The 3 case-control studies[8,12,13] used in our meta-analyses reported the number of cases and controls: 3070 esophageal

cancer cases and 15 417 controls, 2018 gastric cancer cases and 10 007 controls, and 11 574 colorectal cancer0 007 controls, and 11 574 colorectal cancer 007 controls, and 11 574 colorectal cancer cases and 53 955 controls. The percentage of study par-ticipants who used bisphosphonate was 2.8% among the cases and 2.9% among the controls. Tables 2 and 3 sum-marize the general characteristics of the studies included in our analyses.

The methods of the studies we included were as-sessed on the basis of 5 predetermined quality assess-ment items (Table 4). All of the studies included in our analyses were based on the secure record linkage regard-ing medication use and cancer diagnosis.

Association between bisphosphonate use and the risk of gastrointestinal tract cancer There was no negative association between bisphospho-nate use and the incidence of esophageal cancer in the overall analysis (RR 0.96, 95% CI: 0.65 1.42, I2 = 52.8%,, P = 0.076; Figure 2A). In 2 studies with long-term fol-0.076; Figure 2A). In 2 studies with long-term fol-; Figure 2A). In 2 studies with long-term fol-low-up, there was a tendency for bisphosphonate users to develop esophageal cancer; however, this finding was not statistically significant (RR 1.74, 95% CI: 0.97-3.10, I2 = 58.8%,, P = 0.119�. �o significant association was0.119�. �o significant association was�. �o significant association was

Table 1 Search strategy

Search strategy for MEDLINE Search strategy for EMBASE Search strategy for Cochrane reviews of the Cochrane Library

1. Diphosphonates [MH] OR diphosphonates [ALL] OR diphosphonate [ALL]

1. Bisphosphonates/de 1. Bisphosphonates [ALL]

2. Bisphosphonates [ALL] 2. Diphosphonate/de 2. Diphosphonate [ALL] 3. Alendronate [MH] OR alendronate [ALL] 3. Alendronate/de 3. Alendronate [ALL] 4. Clodronic acid [MH] OR clodronic acid [ALL] OR clodronate [ALL] 4. Clodronate/de 4. Clodronate [ALL] 5. Etidronic acid [MH] OR etidronic acid [ALL] OR etidronate [ALL] 5. Etidronate/de 5. Etidronate [ALL] 6. Ibandronic acid [NM] OR ibandronic acid [ALL] OR ibandronate [ALL] 6. Ibandronate/de 6. Ibandronate [ALL] 7. Minodronate [ALL] OR YM 529 [NM] OR YM 529 [ALL] 7. Minodronate/de 7. Minodronate [ALL] 8. Neridronate [ALL] OR 6-amino-1-hydroxyhexane-1,1-diphosphonate [NM] OR 6-amino-1-hydroxyhexane-1,1-diphosphonate [ALL]

8. Neridronate/de 8. Neridronate [ALL]

9. Olpadronic acid [NM] OR olpadronic acid [ALL] OR olpadronate [ALL] 9. Olpadronate/de 9. Olpadronate [ALL] 10. Pamidronate [NM] OR pamidronate [ALL] 10. Pamidronate/de 10. Pamidronate [ALL] 11. Risedronic acid [NM] OR risedronic acid [ALL] OR risedronate [ALL] 11. Risedronate/de 11. Risedronate [ALL] 12. Tiludronic acid [NM] OR tiludronic acid [ALL] OR tiludronate [ALL] 12. Tiludronate/de 12. Tiludronate [ALL] 13. Zoledronic acid [NM] OR zoledronic acid [ALL] OR zoledronate [ALL] 13. Zoledronate/de 13. Zoledronate [ALL] 14. 1 OR 2 OR 3 OR 4 OR 5 OR 6 OR 7 OR 8 OR 9 OR 10 OR 11 OR 12 OR 13 14. 1 OR 2 OR 3 OR 4 OR 5 OR 6 OR 7

OR 8 OR 9 OR 10 OR 11 OR 12 OR 13 14. 1 OR 2 OR 3 OR 4 OR 5 OR 6 OR 7 OR 8 OR 9 OR 10 OR 11 OR 12 OR 13

15. Observational studies [ALL] 15. Observational studies/de 16. CohORt studies [ALL] 16. CohORt studies/de [ALL] - in all text 17. Case control studies [ALL] OR case-control studies [ALL] 17. Case control studies/de OR case-

control studies/de 18. Case referent studies [ALL] OR case-referent studies [ALL] 18. Case referent studies OR case-

referent studies 19. 15 OR 16 OR 17 OR 18 19. 15 OR 16 OR 17 OR 18 20. 14 OR 19 20. 14 OR 19 21. Humans [MH] 21. [Humans]/lim 22. 20 AND 21 22. [Embase]/lim OR [embase clas-

sic]/lim 23. 20 AND 21 AND 22

Date of search: April 29, 2011 (1973 April 2011); Result: 1709 articles found

Date of search: April 29, 2011 (1977 April 2011);Result: 2129 articles found

Limitation: cochrane database of systematic reviews;Date of search: April 29, 2011 (1971 April 2011); Result: 47 articles found

ALL: All fields; MH: MeSH terms; NM: Supplementary concept/substance name; PT: Publication type; /de: Mapped terms; /lim: Limitation.



foun

d in

the

stud

ies[8

,14] re

port

ing

the

risk

of g

astri

c ca

ncer

(RR

0.89

, 95%

CI:

0.71

-1.1

3, I2

= 0

.0%

,, P =

0.4

72;F

igur

e2B

).0.

472;

Figu

re2B

).; F

igur

e 2B

).Bi

spho

spho

nate

use

rs w

ere

less

like

ly to

rece

ive

a di

agno

sis o

f co

lore

ctal

can

cer;

how

ever

, thi

s find

ing

was

not

stat

istic

ally

sign

ifica

nt in

the

over

all a

naly

sis (R

R 0.

62,

95%

CI:

0.30

-1.2

9, I2

= 8

8.0%

,, P =

0.0

04)o

rin

the

anal

ysis

limite

dto

stud

iesw

ithlo

ng-te

rmfo

llow

-up

(RR

0.61

,95%

CI:

0.28

-1.3

5,0.

004)

orin

the

anal

ysis

limite

dto

stud

iesw

ithlo

ng-te

rmfo

llow

-up

(RR

0.61

,95%

CI:

0.28

-1.3

5,) o

r in

the

anal

ysis

limite

d to

stud

ies w

ith lo

ng-te

rm fo

llow

-up

(RR

0.61

, 95%

CI:

0.28

-1.3

5, I2

= 8

4.6%

,, P =

0.01

1;Fi

gure

2C).

= 0

.011

;Fig

ure

2C).

0.01

1;Fi

gure

2C).

; Fig

ure

2C).

DIS

CU

SSIO

NMa

in fi

ndin

gs

In th

e pr

esen

t stu

dy, w

e ex

amin

ed th

e as

soci

atio

n be

twee

n or

al b

ispho

spho

nate

use

and

the

inci

denc

e of

gas

troin

test

inal

trac

t can

cer b

y an

alyz

ing

the

resu

lts o

f pr

evi-

Tabl

e 2 C

hara

cter

istics

of

coho

rt s

tudi

es (n

= 3

) in

clud

ed in

met

a-an

alys

is r

egar

ding

use

of

bisp

hosp

hona

tes

and

risk

of

canc

er

Ref

.C

ount

ryC

ohor

t fo

rmat

ion

(pop

ulat

ion)

Stud

y pe

riod

Mea

n F/

U

dura

tion

, yr

(ra

nge)

Age

, yr

(m

ean±

SD)

Sex

ratio

(ref

eren

ce

grou

p)

Type

of

canc

erTy

pe o

f dr

ug

(ref

eren

ce g

roup

)R

isk

estim

ate

Adj

ustm

ent

No.

of

canc

er d

evel

opm

ent/

no

. of

stu

dy p

opul

atio

nN

o. o

f to

tal

coho

rt

Bisph

osph

onat

e us

erR

efer

ence

gro

up

Abr

aham

sen

et al

[10]

Den

mar

kPa

tient

s w

ith

frac

ture

who

had

pr

escr

iptio

n fo

r ora

l bi

spho

spho

nate

(n

atio

nal r

egis

ters

)

E:19

95-2

005;

F/

U: -

2005

2.8

(NA

)74

.3 ±

8.8

M: 1

1;

F: 8

9Es

opha

geal

ca

ncer

, ga

stri

c ca

ncer

Any

bi

spho

spho

nate

use

(n

o bi

spho

spho

nate

us

e)

Esop

hage

al o

r ga

stri

c ca

ncer

0.

78 (0

.49-

1.26

); es

opha

geal

can

cer

0.35

(0.1

4-0.

85);

gast

ric

canc

er

1.23

(0.6

8-2.

22)

Age

, sex

, fra

ctur

e ty

pe, C

harl

son

inde

x, n

umbe

r of

con

com

itant

m

edic

atio

n, ti

me

to e

vent

NA

/13

678

NA

/27

356

41 0

34

Solo

mon

et

al[1

1]U

nite

d St

ates

Patie

nts

who

had

pr

escr

iptio

n fo

r ora

l bi

spho

spho

nate

(h

ealth

car

e ut

iliza

tion

reco

rds

of m

edic

are

bene

ficia

ries

)

NA

NA

(NA

)N

AN

AEs

opha

geal

ca

ncer

Any

bi

spho

spho

nate

use

(o

ther

ost

eopo

rosi

s m

edic

atio

ns u

se)

Esop

hage

al c

ance

r 0.

55 (0

.06-

4.72

)N

AIn

cide

nce

rate

26

.7/1

00 0

00In

cide

nce

rate

48

.4/1

00 0

00N

A

Car

dwel

l et

al[7

]U

nite

d K

ingd

omPa

tient

s re

ceiv

ing

pres

crip

tion

for o

ral

bisp

hosp

hona

te

(GPR

D)

E:19

96-2

006;

F/

U: -

2008

4

.5

(0.5

-12.

9)70

.0 ±

11.

4M

: 19;

F:

81

Esop

hage

al

canc

er,

gast

ric

canc

er

Any

bi

spho

spho

nate

us

e (r

egar

dles

s of

bi

spho

spho

nate

us

e)

Gas

tric

can

cer

0.78

(0.5

0-1.

23);

esop

hage

al c

ance

r 1.

07 (0

.77-

1.49

)

Age

, sex

, ge

nera

l pra

ctic

e,

BMI,

ciga

rette

sm

okin

g, a

lcoh

ol

inta

ke, h

orm

one

ther

apy,

NSA

ID

use,

Bar

rett'

s es

opha

gus,

GER

D,

H2

rece

ptor

an

tago

nist

use

, pr

oton

pum

p in

hibi

tor u

se

Esop

hage

al o

r ga

stri

c ca

ncer

11

6/41

826

(g

astr

ic c

ance

r 37

/41

826;

es

opha

geal

can

cer

79/4

1 82

6)

Esop

hage

al o

r ga

stri

c ca

ncer

11

5/41

826

(g

astr

ic c

ance

r43

/41

826;

es

opha

geal

can

cer

72/4

1 82

6)

83 6

52

E: E

nrol

lmen

t; F/

U: F

ollo

w u

p; B

MI:

Body

mas

s in

dex;

GER

D: G

astr

oeso

phag

eal r

eflux

dis

ease

; NSA

ID: N

onst

eroi

dal a

ntiin

flam

mat

ory

drug

s; M

: Mal

e; F

: Fem

ale;

NA

: Not

ava

ilabl

e; G

PRD

:Gen

eral

Prac

tice

Rese

arch

GPR

D: G

ener

al P

ract

ice

Rese

arch

D

atab

ase..



ous o

bser

vatio

nal s

tudi

es. O

ur m

eta-

anal

yses

foun

d no

sign

ifica

nt a

ssoc

iatio

n be

twee

n th

e us

e of

ora

l bisp

hosp

hona

te a

nd th

e ov

eral

l gas

troin

test

inal

can

cer i

ncid

ence

. In

the

stud

y de

sign

subg

roup

met

a-an

alys

is, n

o st

atist

ical

ly si

gnifi

cant

ass

ocia

tion

was

foun

d fo

r the

coh

ort s

tudi

es o

r cas

e-co

ntro

l stu

dies

. The

can

cer t

ype

subg

roup

ana

ly-

sis id

entifi

ed n

o as

soci

atio

n be

twee

n bi

spho

spho

nate

use

and

eso

phag

eal c

ance

r or

gas

tric

canc

er. C

olor

ecta

l can

cer

was

less

like

ly to

be

diag

nose

d in

bisp

hosp

hona

te u

sers

; ho

wev

er, t

his

findi

ng w

as n

ot s

tatis

tical

ly s

igni

fican

t. T

he r

esul

ts o

f th

e se

nsiti

vity

ana

lyse

s of

the

stud

ies

with

mor

e th

an 3

yea

rs o

f or

al b

ispho

spho

nate

use

wer

e sim

ilar

to

thos

e of

the

over

all a

naly

ses.

Acc

ordi

ng to

our

ana

lyse

s, or

al b

ispho

spho

nate

seem

s to

have

littl

e as

soci

atio

n w

ith th

e in

cide

nce

of g

astro

inte

stin

al c

ance

r. It

is w

ell k

now

n th

at th

e us

e of

ora

l bisp

hosp

hona

te in

duce

s gas

troin

test

inal

pro

blem

s, su

ch a

s ero

sive

esop

hagi

tis[1

5]. T

he e

ndos

copi

c an

d hi

stol

ogic

al fi

ndin

gs o

f m

ucos

al

inju

ry o

f th

e es

opha

gus

in p

atie

nts

usin

g or

al b

ispho

spho

nate

s[15-

20] s

ugge

st th

at p

rolo

nged

use

may

incr

ease

the

risk

of e

soph

agea

l can

cer.

Gre

en et

al[8

] ana

lyze

d th

e U

nite

d

Tabl

e 3 C

ase-

cont

rol s

tudi

es (n

= 3

) in

clud

ed in

met

a-an

alys

is r

egar

ding

use

of

bisp

hosp

hona

tes

and

risk

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Kingdom General Practice Research Database and re-ported that bisphosphonate use increases esophageal cancer risk (RR 1.30, 95% CI: 1.02-1.66). The cancer-promoting effect was even greater in patients who used the drug for more than 3 years (RR 2.24, 95% CI: 1.47-3.43). We can infer from this result that bisphos-phonate should be restricted among people with risk factors for esophageal cancer, such as Barrettv's esopha-gus. However, according to the study of Nguyen et al[12], the use of oral bisphosphonate does not increase the risk of esophageal adenocarcinoma in patients with Barrett's esophagus (incidence density ratio 0.92; 95% CI: 0.21-4.15). The risk of esophageal adenocarcinoma in patients with Barrett's esophagus is 30- to 125-fold

greater than the risk in the general population[21]. The carcinogenic effect of oral bisphosphonate, including damage to the esophagus due to the toxicity of the drug itself and the effect of contact between the pill and the esophageal mucosa[15], may expedite the development of esophageal cancer in patients with Barrett's esophagus. However, a correlation between the risk of esophageal adenocarcinoma and use of oral bisphosphonate by pa-tients with Barrett's esophagus is inconsistent with the concept of the so-called Barrett pathway.

Several in vivo and in vitro studies suggest that bispho-sphonate has anticancerous properties[1-5]. Clinical stud-ies also implicate the anticancerous effect of bisphos-phonate in breast cancer[22]. It can be inferred from these

Table 4 Assessment of study quality

Study Quality assessment items

Representativeness Ascertainment of exposure: Secure record or structured interview

Demonstration that outcome

of interest

Assessment of outcome: Independent blind assessment or record linkage was

not present at start of study

Study controls for age, cigarette smoking, BMI status

Cohort studies Steinbuch et al[9] - (female) + + + - (randomized controlled trials) Abrahamsen et al[10] + + - + + (age) Solomon et al[11] - (medicare beneficiaries) + - + - (not reported) Cardwell et al[7] + + + + +++ (age, cigarette smoking, BMI) Case-control studies Green et al[8] + + - + +++ (age, cigarette smoking, BMI) Nguyen et al[12] - (Barrett’s esophagus) + + + + (age) Rennert et al[13] - (female) + + + ++ (age, BMI)

BMI: Body mass index.

Additional studies identified from relevant articles (n = 2)

Identified articles from databases (n = 740): PubMed (n = 331), EMBASE (n = 362), Cochrane Library (n = 47)

Total identified articles (n = 742)

Duplicates (n = 51)

Excluded articles (n = 661) After review of title and/or abstract (not relevant for the study or follow up duration shorter than 2 years)

Articles screened (n = 691)

Full-text articles assessed for eligibility (n = 30)

Articles included in qualitative synthesis (n = 6)

Articles included in quantitative synthesis (meta-analysis) (n = 6); cohort 3, case control 3

Excluded articles (n = 24)No available data for outcome measures

Figure 1 Flow diagram of the identification of the relevant cohort studies and case-control studies.



Study RR (95% CI) Weight

Overall 0.35 (0.14, 0.85) 13.47

Abrahamsen et al [10] 0.55 (0.06, 4.72) 2.97

Solomon et al [11] 1.07 (0.77, 1.49) 36.40

Cardwell et al [7] 1.30 (1.02, 1.66) 41.36

Green et al [8] (esophagus) 0.81 (0.18, 3.72) 5.80

Nguyen et al [12] 0.96 (0.65, 1.42) 100.00

Overall (I 2 = 52.8%, P = 0.076)

Long-term follow up

Cardwell et al [7] 1.23 (0.66, 2.30) 42.39

Green et al [8] (esophagus) 2.24 (1.47, 3.43) 57.61

Overall (I 2 = 58.8%, P = 0.119) 1.74 (0.97, 3.10) 100.00

NOTE: Weights are from random effects analysis

0.2 0.5 1 2 5

A

B

.. ..


Overall

Abrahamsen et al [10] 1.23 (0.68, 2.22) 15.71

Cardwell et al [7] (stomach) 0.78 (0.50, 1.23) 27.14

Green et al [8] (stomach) 0.87 (0.64, 1.19) 57.16

Overall (I 2 = 0.0%, P = 0.472) 0.89 (0.71, 1.13) 100.00

Long-term follow up

Green et al [8] (stomach) 0.54 (0.24, 1.18)


0.2 0.5 1 2 5


Overall 0.87 (0.77, 1.00) 55.19

Green et al [8] (colorectal) 0.41 (0.25, 0.67) 44.81

Rennert et al [13] 0.62 (0.30, 1.29) 100.00

Overall (I 2 = 88.0%, P = 0.004)

Long-term follow up

Green et al [8] (colorectal) 0.88 (0.67, 1.15) 54.82

Rennert et al [13] 0.39 (0.22, 0.68) 45.18

Overall (I 2 = 84.6%, P = 0.011) 0.61 (0.28, 1.35) 100.00


C

0.2 0.5 1 2 5

Figure 2 Association between bisphosphonate use and some cancer risk using the meta-analysis of the random effects model. A: Esophageal cancer risk; B: Gastric cancer risk; C: Colorectal cancer risk.



studies that there is no significant association between the use of oral bisphosphonate and the risk of esopha-geal cancer because bisphosphonate has anticancerous effects. As for procancerous effects, oral bisphosphonate directly irritates the esophageal mucosa and induces erosive esophagitis. On the contrary, bisphosphonate directly and indirectly interferes with cancer cell growth. Our finding about the correlation between the risk of esophageal cancer and oral bisphosphonate use sug-gests that the procancerous and anticancerous effects of bisphosphonate may cancel each other out.

There is also an implication about esophageal cancer within the statistical results in our study. Two observa-tional studies that have great significance in our meta-analyses Caldwell et al[7] and Green et al[8], reported dis-crepant results (Figure 2A). According to the analyses of Dixon et al[23], the time-dependent RRs of esophageal cancer and oral bisphosphonate indicate no significant increased risk for esophageal cancer within 3 years of oral bisphosphonate use. However, when these inves-tigators restricted their analyses to bisphosphonate use for more than 3 years, their results were different[23]. The Caldwell study[7] reported a RR of 1.01 (95% CI: 0.48-2.12); Green et al[8] reported a RR of 2.24 (95% CI: 1.47-3.43). The result of our meta-analysis was a RR of 1.74 (95% CI: 0.97-3.10) for the follow-up longer than 3 years. Our results show no statistical correlation between the long-term oral bisphosphonate use and the risk of esophageal cancer. However, in the study of Caldwell et al[7], the RR increased to 1.23 (95% CI: 0.66-2.3) when the analysis was restricted to a group of patients with a mean bisphosphonate use duration of 6.8 years. These results indicate that there is somewhat an association between prolonged oral bisphosphonate use and risk of esophageal cancer. Both studies used data from the Uinted Kingdom General Practice Research Database. Inconsistency between the 2 studies may be explained by differences in study design and confounding that could not be measured.

As stated previously, oral bisphosphonates induce esophagitis[15] and esophageal cancer that can be devel-oped from reflux esophagitis through the Barrett path-way[19,20], and this is not a one-time process; it takes time. For this reason, recurrent injuries and healing processes induced by prolonged oral bisphosphonate use could be clinically meaningful factors. The long-term effect of oral bisphosphonate could be confirmed by an observa-tional study that focuses on much longer periods of oral bisphosphonate use.

Regarding gastric cancer, our results show no signifi-cant association with oral bisphosphonate use. There is only 1 study that estimates RR dependent on duration of oral bisphosphonate use. Although there is no sta-tistical significance, Green et al[8] found that RR is less for those using oral bisphosphonate longer than 3 years (RR 0.54, 95% CI: 0.24-1.18) than for those using oral bisphosphonate shorter than 3 years (RR 1.03, 95% CI: 0.67-1.59 for less than 1 year; RR 0.89, 95% CI: 0.52-1.53

for 1-3 years). This implies that there is no cumulative effect of oral bisphosphonate on the risk of gastric can-cer. If bisphosphonate has competing procancerous and anticancerous properties, it may not affect the risk of cancer.

We performed a random-effects model analysis of the data on colorectal cancer because of high heteroge-neity (I2 = 88.0%, P = 0.004). According to our meta-analysis, oral bisphosphonate use demonstrates no effect on the risk of colorectal cancer (RR 0.62, 95% CI: 0.30-1.29). The analysis of the long-term use (more than 3 years) revealed that there is no statistically sig-nificant association between oral bisphosphonate use and colorectal cancer (RR 0.61, 95% CI: 0.28-1.35). However, the subgroup analysis shows a significant negative association between oral bisphosphonate use and the incidence of colorectal cancer (RR 0.87, 95% CI: 0.77-1.00; RR 0.41, 95% CI: 0.25-0.67). Therefore, it may be hasty to conclude on the basis of overall meta-analysis that oral bisphosphonate use does not affect colorectal cancer. In the study by Rennert et al[13], cases and controls were matched for age, ethnicity, family history of colorectal cancer, sports activity, vegetable consumption, body mass index (BMI), low-dose aspirin use, statin use, postmenopausal hormone use, calcium supplement use, and vitamin use, all of which can affect the risk of colorectal cancer. However, in Green et al[8], RRs were only adjusted for smoking status, alcohol in-take and BMI. Thus, there were important differences in the study design and quality of methods.

The study by Rennert et al[13] implies that oral bispho-sphonate has a protective effect against colorectal and breast cancers. The anticancerous effects of bisphospho-nate, such as promoting apoptosis[2], inhibiting tumor cell adhesion and invasion[3], inhibiting angiogenesis[4], al-tering tumor-associated macrophage function[4], and en-hancing immune surveillance, as previously mentioned, may have a key role in such a protective effect. One study reported that ibandronate reduces the incidence of colorectal dysplasia in mice with induced ulcerative colitis[24]. In colorectal cancer, different from esophageal cancer, oral bisphosphonate does not directly injure the intestinal mucosa or induce chronic mucosal inflamma-tion and healing processes.

Considering this background, the results of our me-ta-analyses should be interpreted as inconclusive. A well-designed randomized controlled study or prospective cohort study is needed to confirm the preventive effect of oral bisphosphonate against colorectal cancer.

Our study has a few limitations. First, the number of studies we analyzed is small. There have been few studies about the correlation between oral bisphosphonate use and the risk for gastrointestinal cancer. For this reason, each study that reported on colorectal cancer reported a negative association, but the overall meta-analysis showed no statistical significance. Thus, oral bisphos-phonate use is seemingly irrelevant to colorectal cancer. Second, the quality of our study depends on data from



original publications. Our study inevitably inherits some problems from the observational studies, such as selec-tion bias, surveillance bias, and confounding. For exam-ple, more esophageal and gastric abnormalities might be observed in bisphosphonate users simply because they receive more endoscopic exams for abdominal discom-fort caused by oral bisphosphonate.

We discussed the small number of studies regarding bisphosphonate use and development of gastrointes-tinal cancer in our article as a limitation. However, the actual number of overall subjects in our meta-analysis is not too small. In cohort studies, 124 686 subjects with mean follow up of 3.88 years were included in the final analysis. In case of case-control studies, there were 3070 esophageal cancer cases, 2018 gastric cancer cases and 11 574 colorectal cancer cases were included as well. Moreover, the results of two large observational studies were inconsistent. Caldwell et al[7] showed no significant association between bisphosphonate use and esophageal cancer. On the other hand, Green et al[8] had revealed the significant association. The inconsistent results of ob-servational studies suggest the need of further studies as well as a meta-analysis.

Despite the negative results, our study is meaningful since it provides not an ultimate but a reasonable interim conclusion regarding the safety of bisphosphonate use before definite accumulation of long-term observational studies.

In summary, our meta-analyses indicate that there is no significant association between oral bisphosphonate use and the risk of gastrointestinal cancer. Oral bisphos-phonate use has no significant association with the risk of esophageal cancer. There is an increased, though not statistically significant, risk of esophageal cancer in long-term users of oral bisphosphonate. An observational study focused on long-term use of bisphosphonate is needed to confirm this finding. The risk of gastric can-cer is not associated with oral bisphosphonate use. Each study reporting on colorectal cancer indicates a negative association between the risk of colorectal cancer and oral bisphosphonate use, but our meta-analysis showed no statistically significant association. The confidence in-tervals were large (95% CI: 0.30-1.29). Thus, a random-ized controlled trial or prospective cohort study should be performed to confirm the preventive effect of oral bisphosphonate.

COMMENTSBackgroundThere rises concerns about bisphosphonate use after the reports of 23 cases of esophageal cancer in the United States and another 31 cases in Europe and Japan, all occurring from 1995 through 2008 among patients using oral bisphosphonates. Bisphosphonate induced esophagitis, Barrett's esophagus and gastric ulcer can be the precancerous condition. There were observational studies to evaluate the risk between esophageal cancer and bisphosphonate use. But the results were inconsistent. So the overall evaluation of the associa-tion between gastrointestinal cancer and bisphosphonate is required. Research frontiersMeta-analysis was used to evaluate the risk of bisphosphonate for gastrointes-

tinal cancer (esophageal, stomach, and colorectal cancer) in this study.Innovations and breakthroughsThis meta-analysis systemically assessed the relation between bisphosphonate use and gastrointestinal cancer risk, and also showed site specific, long-term follow up results.ApplicationsThe results of meta-analysis in this study show that use of bisphosphonate has no significant association with gastrointestinal cancers. According to the results, bisphosphonate can be used without charge of carcinogen for now. But there should be a far more long-term observational studies to guarantee the long-term safety. TerminologyMeta-analysis is method focused on contrasting and combining results from different studies to show the overall conclusion. It is essential component of a systematic review procedure. Peer reviewThis is a good descriptive study in which authors perform a meta-analysis of observational studies to further elucidate the relationship between oral bisphos-phonate use and gastrointestinal cancer risk. The results are interesting and suggest that oral bisphosphonate use had no significant effect on gastrointesti-nal cancer risk.

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COMMENTS



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S- Editor Gou SX L- Editor A E- Editor Xiong L


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