REVIEW Open Access

The effect of non-steroidal anti-inflammatory drugs on the osteogenicactivity in osseointegration: a systematicreviewJie Denny Luo1, Catherine Miller2, Tamara Jirjis1, Masoud Nasir1 and Dileep Sharma1*

Abstract

Non-steroidal anti-inflammatory drugs are commonly used in implant dentistry for management of post-operativepain. The objective of this systematic review was to analyse the effect of non-steroidal anti-inflammatory drugs onthe osteogenic activity of osteoblasts with an emphasis on its effect on osseointegration. A systematic literaturesearch for in vitro, animal models, and clinical trials was conducted using Ovid, PubMed, Scopus, and Web ofScience databases. Articles published since the introduction of selective COX-2 inhibitors, between January 1999and July 2018, were selected. The integrated search followed the PRISMA statement with the following key terms:non-steroidal anti-inflammatory drug/s, titanium, osseointegration, and osteoblast. The review is registered atPROSPERO database: CRD42016051448. The titles and abstracts of each research article in the initial search (n = 875)were independently screened by two reviewers. A third independent reviewer reviewed the articles that wereincluded by one but excluded by the other reviewer. This resulted in the cataloguing of 79 full-text manuscriptswhere the articles were assessed for the following criteria: the study investigates the effects of NSAIDs onosteoblasts, explores the COX pathway and its effect on osteogenic activity, and compares the effects of NSAIDs onosteoblasts with a control group. A total of 13 articles have been included for qualitative synthesis. There is a lackof consensus in the literature to explicitly conclude that there is a relationship between the use of post-operativeNSAIDs and failed osseointegration; however, osseointegration does not appear to be negatively affected byNSAIDs in the human clinical studies.

Keywords: Non-steroidal anti-inflammatory drug, Osseointegration, Osteoblast, Dental implant

ReviewIntroductionNon-steroidal anti-inflammatory drugs (NSAIDs) are agroup of drugs with anti-inflammatory, analgesic, and anti-pyretic effects. They are commonly used in dentistry formanagement of dental pain associated with inflammation.NSAIDs exert their effects through the inhibition of thecyclooxygenase (COX) enzyme, therefore interfering withthe synthesis of prostaglandins (PG) and thromboxanes;PGs and thromboxanes are inflammatory mediators thatare responsible for pain. COX has three isoforms: COX-1,

COX-2, and COX-3. COX-1 exhibits characteristics of aconstitutive enzyme, as its activity is associated with theinvolvement of PGs and thromboxanes in controllingnormal physiological functions [1]. COX-2 exhibits charac-teristics of an inducible enzyme in inflammatory cells andis activated in response to pathological stimuli [2]. COX-3is a variant of COX-1, though it shares the characteristicsof both COX-1 and COX-2. The osseointegration processthat is observed after implant insertion can be compared tobone fracture healing through the process of an inflamma-tory response in which the recruitment of osteoprogenitorcells occurs, followed by their downstream differentiationinto osteoblasts that leads to bone deposition on theimplant surface [3, 4]. COX-1 is expressed in normal boneand at the site of bone fracture, whilst COX-2 is

* Correspondence: dileep.sharma@jcu.edu.au1College of Medicine & Dentistry, James Cook University, 14-88 McGregorRoad, Smithfield, QLD 4878, AustraliaFull list of author information is available at the end of the article

International Journal ofImplant Dentistry

© The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, andreproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link tothe Creative Commons license, and indicate if changes were made.

Luo et al. International Journal of Implant Dentistry (2018) 4:30 https://doi.org/10.1186/s40729-018-0141-7

upregulated during inflammation and the initial stages ofbone repair [5]. The effects of NSAIDs on altering bonegrowth, remodelling, and repair are generally not consid-ered when prescribed for post-operative pain managementafter implant placement.Hypoxia occurs locally in bone tissues when pathological

conditions such as implant placement and bone fracturesarise [6, 7]. It has been established, through clinical studiesof bone cultures, that hypoxia is directly responsible fordirecting the synthesis of prostaglandin E (PGE) by osteo-blasts [6]. Therefore, the presence of the COX enzymes inbone healing is of importance [6]. Prostaglandins have thecapacity to influence bone metabolism and can both induceand inhibit tissue repair mechanisms [6]. Local administra-tion of PGE1 has been shown to stimulate bone formation,increase alveolar bone height, and induce formation of newcementum and periodontal ligament adjacent to the site ofdelivery in canine mandibles [8, 9]. Furthermore, PGE2 hasbeen shown to stimulate replication and differentiation ofosteoblasts cultured on smooth titanium surfaces therebyincreasing bone formation around titanium implants [10].Additionally, PGs can also inhibit the formation andgrowth of osteoblasts [6]. Therefore, altered PG levels as aresult of COX inhibition can have a negative impact on therole of PG in bone tissue, potentially causing a shift in pre-cursor cell action towards bone resorption [6].Cyclooxygenases have an important role in the

production of PGs where these enzymes in bone tissuesshow increased activity under the influence ofhypoxia-inducible factors [6, 11]. Therefore, local activityof COX enzymes promotes bone formation and resorp-tion through the production of PGs [12]. Non-selectiveNSAIDs are reported to inhibit the activity of COX-1equally, if not more than COX-2 [2]. Therefore, NSAIDsinhibit the production of PGs at the site of implantplacement or fracture, thereby influencing the bonehealing cascade [13]. There is evidence from animalstudies that indicate that COX-2 inhibitors delay donehealing in diaphyseal fracture models in rats [13]. How-ever, the exact roles of COX-1 and COX-2 in the PGproduction has not been ascertained in humans, andassumptions have been made suggesting a milder ornon-significant inhibitory effect of selective COX-2inhibitors on bone healing when compared to anon-selective COX inhibitor [2, 13]. Furthermore, asystematic review conducted by Marquez-Lara et al.highlighted the great variability regarding the impact ofNSAIDs on bone healing, and that there is no consensusregarding the impact of NSAIDs following orthopaedicprocedures [14]. Therefore, the rationale of the presentsystematic review is to address the gaps in the literatureby identifying if variables such as the dosage, duration ofadministration, and selectivity of post-operative NSAIDsnegatively affect osseointegration.

Material and methodsProtocol and registrationThe systematic review was conducted in accordance withthe Preferred Reporting Items for Systematic Reviews andMeta-Analyses (PRISMA) statement [15]. The review isregistered at PROSPERO database, and the review protocolcan be accessed at http://www.crd.york.ac.uk/PROSPERO/display_record.php?ID=CRD42016051448.The PROSPERO registration number is CRD4201605

1448.

Eligibility criteriaThe review included in vitro, clinical and in vivo studies;animal models. Articles published since the introductionof selective COX-2 inhibitors in 1999 were included [3].Studies published outside this time period, not in the Eng-lish language, non-peer reviewed, and review studies wereexcluded.

Information sourcesAn electronic search into four databases: Ovid, Pubmed,Scopus, and Web of Science was performed to sys-tematically identify the available literature. Articlespublished between January 1, 1999, and July 7, 2018,were considered.

Focus questionThe focus question, used to guide the search strategy,according to the PICO schema is “Will variables such asthe dosage, duration of administration, and selectivity ofpost-operative NSAIDs impair the bone healing aroundtitanium implants?”

Search strategyThe search string comprised the combination of medicalsubject headings (MeSH) and free keywords. The linkagewas conducted using the Boolean operator (AND, OR).The choice of keywords was intended to be broad tomaximise the number of relevant studies considered.The following search strategy was applied to Ovid andPubMed:

1) (anti inflammatory agents, non steroidal[MeSHTerms]) AND osseointegration[MeSH Terms]

2) (anti inflammatory agents, non steroidal[MeSHTerms]) AND osteoblast[MeSH Terms]

3) (anti inflammatory agents, non steroidal[MeSHTerms]) AND dental implants[MeSH Terms]

Furthermore, the following search strategy was appliedto Scopus and Web of Sciences to supplement recordsidentified through Ovid and PubMed:(non steroidal anti inflammatory agent OR non ster-

oidal anti inflammatory agents OR non steroidal anti

Luo et al. International Journal of Implant Dentistry (2018) 4:30 Page 2 of 12

inflammatory drug OR non steroidal anti inflammatorydrugs OR cyclooxygenase inhibition OR COX inhibitionOR ibuprofen OR celecoxib) AND (osseointegration ORosteoblast OR osteoblasts OR titanium implant OR ti-tanium implants OR dental implant OR dental implants)

Study selectionThe titles and abstracts of each research article in the ini-tial search were independently screened by the primary(JDL) and the second reviewer (TJ). A third independentreviewer (MN) reviewed the articles that were included byone but excluded by the other reviewer. The full-textmanuscripts of the articles were catalogued in accordanceto the “Eligibility criteria” section as mentioned above andwere assessed for the following criteria:

� The study explored the COX pathway and its role inosseointegration.

� The effects of NSAIDs on osteoblasts attached totitanium are investigated (in vitro studies).

Data collection processThe full-text manuscripts of included studies were catalo-gued into in vitro, clinical, and in vivo studies. The datafrom the included studies were independently extracted bythe primary (JDL) and the second reviewer (TJ) accordingto the “Data items” section as listed below. Disagreementsor uncertainties were discussed with the third reviewer(MN) until an agreement was reached.

Data itemsThe data collected from the included studies were ar-ranged in the following fields:

� Author (year)—reveals the author/s and year ofpublication

� Sample (size)—describes the sample and sample sizeused in the study

� Treatment group (size)—describes the treatmentsused in study

� Methodology—describes the method of drugdelivery

� Parameter—describes the parameter/s that aremeasured

� Outcome—describes the outcome/s of theexperiments

Quality and risk of bias in individual studiesThe quality and risk of bias assessments were performedindependently by two reviewers (JDL and TJ) during thedata extraction process. Any disagreements or uncertain-ties were discussed with the third reviewer (MN) until anagreement was reached. The quality and bias assessmentfor all studies addressed various bias domains. A Modified

CONSORT checklist of items for reporting in vitro studiesof dental materials outlined by Faggion (Tables 1 and 2)was used to assess quality and risk of bias of included invitro studies [16]. The Cochrane Collaboration’s Tool(Table 3) was used to assess quality and risk of bias ofincluded human clinical studies [17]. A quality assessmentof the methodology of the animal studies (Table 4) hasbeen performed according to items (Table 5) of theARRIVE guidelines [18].

Synthesis of resultsThe relevant data collected for qualitative synthesis aresummarised in three critical analysis tables: in vitrostudies (Table 6), clinical studies (Table 7), and in vivostudies (Table 8).

Statistical analysisNo meta-analyses could be performed due to the hetero-geneity between the studies—different samples, experi-mental groups (drugs and concentrations), study models,and outcome measures.

ResultsStudy selectionThe electronic search in the databases of Web of Science,PubMed, Ovid, and Scopus resulted in the identificationof 875 potential titles and abstracts. After removal of theduplicates, independent screening of the abstracts resultedin the selection of 79 studies for assessment of eligibility.A total of 13 studies were eligible and are included in thesystematic review (Fig. 1).

Exclusion of studiesThe eligibility and study selection criteria as mentionedabove were applied to the 79 full-text articles. A total of66 studies were excluded after a full-text assessment forthe following reasons:

� The study did not explore the role of COX pathwayin osseointegration (n = 26).

� The effects of NSAIDs on osteoblasts were notinvestigated on titanium (n = 24).

� The study was a systematic review (n = 16).

Study characteristicsThe included studies were catalogued into three groupscharacterised by the type of study: in vitro studies(Table 6), clinical studies (Table 7), and in vivo studies(Table 8). The cataloguing provided a clearer under-standing of the effects of NSAIDs in osseointegration invarious study models, ultimately contributing to the sen-sitivity of the systematic review.

Luo et al. International Journal of Implant Dentistry (2018) 4:30 Page 3 of 12

Quality and risk of bias assessmentThe quality and risk of bias assessments of includedstudies are summarised in Tables 1, 2, 3, 4, and 5. Thequality assessment revealed a high risk of bias (for oneor more domain) for most of the included studies. Theincluded in vitro studies had high risk of bias accordingto the Modified CONSORT checklist [16, 19, 20]. Oneclinical study was classified as unclear risk of bias (forone or more domain) according to the Cochrane Collab-oration’s Tool [17, 21]. An in vivo animal study had an

unclear risk of bias according to the ARRIVE guidelines[18, 22].

DiscussionNon-steroidal anti-inflammatory drugs are widely used inclinical dentistry to manage post-operative inflammationand pain. Two systematic reviews have been performed toreview the literature concerning the possible influence ofNSAIDs on the osseointegration of titanium implants: areview conducted by Gomes et al. concluded that osseoin-tegration is impaired in the presence of conventionalNSAIDs, whilst the review conducted by Kalyvas et al.concluded that short-term post-operative NSAIDs do notappear to negatively impact osseointegration [3, 4]. Des-pite these conflicting conclusions regarding post-operativeuse of NSAIDs, both Gomes et al. and Kalyvas et al.agreed that prolonged or long-term use of NSAIDs, par-ticularly in patients with chronic diseases, impairedosseointegration and, therefore, reduced the success ofimplant surgery [3, 4]. The current review extends onthese existing reviews by identifying if dosage, duration ofadministration, and selectivity of post-operative NSAIDsimpair osseointegration.

In vitro studiesThe effects of NSAIDs on the osteogenic activity of oste-oblasts have been extensively studied at the molecularpharmacological level [23]. However, only two studieshave been identified that investigated the effect ofNSAIDs on osteoblasts attached to titanium surfaces(Table 6). In the study conducted by Boyan et al., theirresults demonstrated that a non-selective COX inhibitor(indomethacin, 0.1 μM), a selective COX-1 inhibitor(resveratrol, 1 and 10 μM), and a selective COX-2 in-hibitor (NS-398, 1 and 10 μM) did not have a significanteffect on the number of cells derived from human osteo-sarcomas [20]. Furthermore, Boyan et al. demonstratedthat the NSAIDs reduced prostaglandin E2 (PGE2) pro-duction of cells attached to a rough titanium surface.Their results indicated that both COX-1 and COX-2 areinvolved in the production of osteocalcin, PGE2, andTGF-β1 by osteoblasts [20]. They also demonstrated thatosteoblasts produced increased levels of PGE2 on roughtitanium surfaces and that this was correlated with in-creased alkaline phosphatase activity and osteocalcinproduction [20]. This suggests that PGE2 may have arole in osteoblast proliferation and differentiation on ti-tanium surfaces, and that this favourable effect of PGE2

Table 1 Quality assessment of in vitro studies according to the items of the Modified CONSORT checklist [16]

Study 1 2 3 4 5 6 7 8 9 10 11 12 13 14 Summary assessment

Arpornmaeklong et al. [19] + ? + + – – – – n/a + + – + – High

Boyan et al. [20] + + + + – – – – n/a + + – + – High

Key: (+) = low risk of bias, (?) = unclear risk of bias, (−) = high risk of bias

Table 2 Modified CONSORT checklist of items for reporting invitro studies of dental materials [16]

Item Domain

1 Abstract: structured summary of trial design, methods, results,and conclusions

Introduction

2 Scientific background and explanation of rationale with specificobjectives and/or hypotheses

Methods

3 Intervention: the intervention for each group, including howand when it was administered, with sufficient detail to enablereplication

4 Outcomes: completely defined, pre-specified primary andsecondary measures of outcome, including how and whenthey were assessed

5 Sample size: how sample size was determined

6 Randomisation: method used to generate the random allocationsequence

7 Allocation: mechanism used to implement the random allocationsequence, describing any steps taken to conceal the sequenceuntil intervention was assigned

8 Implementation: who generated the random allocation sequence,who enrolled teeth, and who assigned teeth to intervention

9 Blinding: if done, who was blinded after assignment tointervention and how

10 Statistics: statistical methods used to compare groups for primaryand secondary outcomes

Results

11 For each primary and secondary outcome, results for each group,and the estimated size of the effect and its precision

Discussion

12 Trial limitations, addressing sources of potential bias, imprecision,and, if relevant, multiplicity of analyses

Other information

13 Sources of funding and other support role of funders

14 Where the full trial protocol can be accessed, if available

Luo et al. International Journal of Implant Dentistry (2018) 4:30 Page 4 of 12

was inhibited when a NSAID was present [20]. Arpom-maeklong et al. found that a non-selective COXinhibitor(indomethacin, 0.1 μM) and a selective COX-2 inhibitor(celecoxib, 1.5, 3.0, and 9.0 μM) inhibited the growth ofcell cultures derived from rat calvarias, where the effectwas dose-dependent in the cultures treated with cele-coxib [19]. Furthermore, Arpommaeklong et al. demon-strated that PGE2 levels were significantly lower in thegroups that were treated with a NSAID, and have postu-lated that PGE2, consistent with Boyan et al., may have arole in osteoblast growth and differentiation [19, 20].

Clinical studiesThe clinical evidence demonstrating the effects ofNSAIDs on the osseointegration of titanium dental im-plants is limited with only two clinical trials and oneretrospective study identified in the database searches(Table 7). In the clinical trial conducted by Alissa et al.,the effect of a 7-day post-operative course of ibuprofen(600 mg, taken four times daily) on the marginal bonelevel around dental implants was investigated [21]. Theyfound that there were no statistically significant differ-ences between the treated and placebo groups in themean marginal bone level around dental implants at 3and 6 months after implant placement [21]. In a similarclinical trial conducted by Sakka et al., the effect of a7-day course of ibuprofen (600 mg, taken four timesdaily) on the marginal bone level around dental implantswas also investigated [24]. They found that there wereno significant differences between the ibuprofen andnon-ibuprofen groups, consistent with the findings ofAlissa et al., when comparing the changes in marginalbone level around dental implants [24]. However, a

retrospective study conducted by Winnett et al. postu-lated that the adverse biological events following dentalimplant placement were associated with perioperativeuse of NSAIDs [25]. Winnett et al. reported a total lossof 197 dental implants due to failed osseointegrationfrom patients with failing implant/s (468 implants in 104patients) treated in a postgraduate dental clinic (between1979 and 2012). The patients (n = 60) that used NSAIDsperi-operatively experienced a total of 119 failedimplants, whilst the non-NSAID cohort (n = 44) experi-enced a total of 78 failed implants. Winnett et al. identi-fied that ibuprofen (600 mg, taken four times daily) wasthe most commonly prescribed; however, otherprescribed NSAIDs included Ketorolac, Vioxx, Celebrex,Diflunisal, Meloxicam, and Naproxen [25]. Despite theclinical trials conducted by Alissa et al. and Sakka et al.,both of whom have demonstrated that a 7-daypost-operative course of ibuprofen (600 mg, taken fourtimes daily) did not significantly affect bone levels arounddental implants at 3 and 6 months after placement, thedata gathered by Winnett et al. indicates that NSAIDsmay have detrimental effect on osseointegration [25].

Animal studiesThe influence of NSAIDS on bone healing in animalmodels has been shown to be related to the duration oftreatment and drug selectivity [5]. A total of seven stud-ies were identified that investigated the effect of NSAIDson the osseointegration of titanium implants in animals:mice, rabbits, and rats (Table 8).The duration of treatment is a factor to consider when

using NSAIDs, and a study conducted by Goodman etal. investigated the effect of a selective COX-2 inhibitor

Table 3 Quality and bias assessment of human clinical studies using The Cochrane Collaboration’s Tool [17]

Study Random sequencegeneration

Allocationconcealment

Blinding ofparticipants/personnel

Blinding ofoutcome assessment

Incompleteoutcome data

Selectivereporting

Summaryassessment

Alissa et al. [21] + + + ? + + Unclear

Sakka et al. [24] – – – + + + High

Winnett et al. [25] n/a – – – ? + High

Key: (+) = low risk of bias, (?) = unclear risk of bias, (−) = high risk of bias, n/a= not available

Table 4 Quality assessment of the methodology of the animal studies according to the items of the ARRIVE guidelines [18]

Study 5 6 7 8 9 10 11 12 13 Summary assessment

Cai et al. [22] + ? + + ? ? ? + + Unclear

Chikazu et al. [30] + – + + – – ? + + High

Goodman et al. [29] ? + + + – ? – + + High

Goodman et al. [26] ? + + + – ? – + + High

Pablos et al. [31] + ? + + – – ? + + High

Ribeiro et al. [27] + ? + + – – ? + + High

Ribeiro et al. [28] + ? + + – – ? + + High

Salduz et al. [32] – + + + ? – + + + High

Key: (+) = low risk of bias, (?) = unclear risk of bias, (−) = high risk of bias

Luo et al. International Journal of Implant Dentistry (2018) 4:30 Page 5 of 12

(rofecoxib, 12.5 mg/kg/day) administered for 6 weeks onbone growth in a bone harvest chamber during threedifferent time periods: initial 2 of the 6 weeks, final 2 ofthe 6 weeks, and continuously for 6 weeks [26]. Thebone harvest chamber was a titanium device that wasimplanted into the tibia of rabbits and had an inner re-movable core with canals that allowed for bone ingrowthinto the inner chamber. Their results revealed that rofe-coxib given continuously for 6 weeks significantly re-duced bone ingrowth and osteoblasts per area comparedwith the control (no treatment), whilst rofecoxib givenfor 2 weeks did not appear to interfere with bone in-growth and number of osteoblasts [26]. Furthermore,the studies conducted by Ribeiro et al. investigated the

effect of long-term administration (60 days) of a select-ive COX-2 inhibitor (meloxicam, 3 mg/kg/day) on thebone growth on a titanium implant [27, 28]. Their re-sults also indicated that long-term use of a selectiveCOX-2 NSAID significantly reduces bone-to-implantcontact, bone area, and bone density, ultimately leading tofailed osseointegration [27]. The data gathered in bothstudies suggest that duration of treatment is an importantfactor in the use of selective COX-2 NSAIDs, as short pe-riods of rofecoxib and meloxicam did not adversely affectosseointegration [26, 27].The COX selectivity of NSAIDs and their interference

with prostaglandin synthesis have been shown to inhibitbone healing [23]. Goodman et al. performed afollow-up study where the titanium bone harvest cham-ber was again implanted into the tibia of rabbits and therabbits were treated with water (control), a non-selectiveCOX inhibitor (naproxen, 110 mg/kg/day), or a selectiveCOX-2 inhibitor (rofecoxib, 12.5 mg/kg/day) for a4-week period [29]. Their results again demonstratedthat COX-2 inhibition significantly decreased bone in-growth, where rofecoxib also decreased the number ofosteoblasts per area [29]. Furthermore, the conclusionsby Goodman et al. were supported by the study by Chi-kazu et al. where titanium implants were inserted inwild-type and COX-2-knockout mice [30]. Their resultsrevealed that the expression of COX-2 was induced inbone surrounding the implants in wild-type mice, butnot in COX-2-knockout mice and that the bone-to-implant

Table 5 Items of the ARRIVE Guidelines [18]

Item Domain

5 Ethical statement

6 Study design

7 Experimental procedures

8 Experimental animals

9 Housing and husbandry

10 Sample size

11 Allocating animals to experimentalgroups

12 Experimental outcomes

13 Statistical analysis

Table 6 In vitro studies that investigated the effect of NSAIDs on osteoblasts attached to titanium surfaces

Study (year) Sample Treatment group Methodology Parameter Outcome

Arpornmaeklonget al. (2009) [19]

Mouse calvariacell line (MC3T3-E1)

Indomethacin0.1 μMCelecoxib 1.5 μMCelecoxib 3.0 μMCelecoxib 9.0 μMControl

Incubation in treatmentmedium for 5 days.Investigations wereperformed in threeexperimental phases:static, log, and plateau

The following parameterswere assessed at 1, 3, and5 days: cell attachment, cellgrowth, cell differentiation,secretion of PGE2

Cells were able to grow andattach to titanium surface forall treatment groups.Indomethacin and celecoxibcell growth on days 3 and 5in static phase and on day 3in log phase.Indomethacin and celecoxibcaused a significant decreasePGE2 concentration in staticand plateau but not logphases.

Boyan et al.(2001) [20]

Human osteosarcomacell line (MG63)

Indomethacin0.1 μMResveratrol1 μMResveratrol10 μMNS-398 1 μMNS-398 10 μM

Incubation in treatmentmedium for 5 days.Cells were cultured ontissue culture plastic,smooth titanium, andtwo rough titaniumsurfaces: grit-blasted/acid-etched and titanium-plasma sprayed

The following parameterswere assessed after 5 days:osteocalcin content, PGE2content, and TGF-β1 content.

Indomethacin, resveratrol,and NS-398 had no effecton osteocalcin content.Indomethacin andresveratrol blocked PGE2production. NS-398 had noeffect on PGE2 productionon smooth surfaces butcaused a reduction onrough surfaces.Indomethacin blocked TGF-β1production on roughsurfaces. Resveratrol blockedTGF-β1 on TPS. NS-398 didnot cause TGF-β1 inhibition.

Luo et al. International Journal of Implant Dentistry (2018) 4:30 Page 6 of 12

Table

7Clinicalstud

iesthat

investigated

theeffect

ofNSA

IDson

osseointeg

ratio

n

Stud

y(year)

Sample(size)

Treatm

entgrou

p(size)

Metho

dology

Parameter

Outcome

Alissa

etal.

(2009)

[21]

Eligiblehu

man

patients

(n=61).

Implantsinserted

(n=132).

Ibup

rofen(n=31),im

plants

(n=67).

Placeb

o(n=30),im

plants

(n=65).

Ibup

rofen,600mgq.i.d.for

7days

orally

Post-ope

rativeradiog

raph

icmarginalb

onehe

ight

at3

and6mon

ths

Nostatisticallysign

ificant

differences

inmean

marginalb

onelevelchang

esat

3or

6mon

ths.

Sakkaet

al.

(2013)

[24]

Eligiblehu

man

patients

(n=28).

Implantsinserted

(n=57).

Ibup

rofen(n=14),im

plants

(n=31).

Non

-Ibup

rofen(n=14),

implants(n=26).

Ibup

rofen,600mgq.i.d.for

7days

orally

Post-ope

rativeradiog

raph

icmarginalb

onehe

ight

at3

and6mon

ths

Nostatisticallysign

ificant

differences

inmean

marginalb

onelevelchang

esat

3or

6mon

ths.

Winne

ttet

al.

(2014)

[25]

Patientstreatedbe

tween

1979

and2012

with

failed

andsurgicallyremoved

dentalim

plants

Coh

ortthat

used

post-ope

rative

NSA

IDs(n=60,w

ith119failed

implants).

Coh

ortthat

didno

tuse

post-ope

rativeNSA

IDs(n=44,

with

78failedim

plants).

Ibup

rofenwas

themostcommon

lyprescribed

,600

mgq.i.d.

Other

prescribed

analge

sics

were

ketorolac,vioxx,celebrex,d

iflun

isal,

meloxicam

,paracetam

ol,and

naproxen

.

Radiog

raph

icbo

neloss.

Verticalbo

nehe

ight

ofremaining

implants.

NSA

IDcoho

rtexpe

rienced

moreim

plantfailures

than

theno

n-NSA

IDcoho

rt.

TheNSA

IDcoho

rtexpe

rienced

morecasesof

radiog

raph

icbo

neloss

greaterthan

30%

ofthe

verticalhe

ight

oftheirremaining

implants.

Luo et al. International Journal of Implant Dentistry (2018) 4:30 Page 7 of 12

Table

8In

vivo

stud

iesusinganim

almod

elsthat

investigated

theeffect

ofNSA

IDson

osseointeg

ratio

n

Stud

y(year)

Sample(size)

Treatm

entgrou

p(size)

Metho

dology

Parameter

Outcome

Caiet

al.(2015)[22]

New

Zealandwhite

rabb

its(n=18).

Implantinserted

into

calvaria(n=18).

Con

trol

(n=6)

Diclofenac(n=6)

Parecoxib(n=6)

Treatm

entswere

administeredfor7days:

Diclofenac,2mg/kg/day

orally

Parecoxib,

1.5mg/kg/day

subcutaneo

usinjection

Parametersob

served

atweek4and

12afterim

plantatio

n:Micro-CT:bo

nevolumeratio

,mean

trabecular

thickness,andmean

trabecular

separatio

n.Histomorph

ometric:b

one-to-im

plant

contact.

Nostatisticallysign

ificant

differences

betw

eenthethreeseparate

grou

ps,

norbe

tweenthedifferent

timepo

ints.

Chikazu

etal.(2007)

[30]

9-weekoldmalemice

(n=72).

Implantinserted

infemur

(n=72).

Micewith

theoriginal

C57BL6/129S7hybrid

backgrou

ndwere

gene

ratedand

maintaine

d:Wild-type

(n=36)

COX-2-knockout

(n=36)

Nodrug

was

administered

mRN

Alevelswereob

served

atdays

0,1,2,4,7,and56

afterim

plant

insertion:expressio

nof

COX-2an

dosteocalcinmRN

A.Histomorph

ometric

analysisat

weeks

4and8:bo

ne-to-im

plantcontact.

Expression

ofCOX-2andosteocalcin

mRN

Awas

indu

cedin

bone

surrou

nding

implantsin

wild-typemice,bu

tno

tin

knockout

mice.

Bone

-to-im

plantcontactwas

minim

alin

knockout

mice.

Goo

dman

etal.(2002)

[29]

New

Zealandwhite

rabb

its(n=8).

Titanium

bone

harvest

cham

berinserted

intib

ia(n=8).

Con

trol

Naproxen

Rofecoxib

Treatm

entsadministered:

Con

trol:w

eeks

0–4and9–

12.

Naproxen,110mg/kg:

weeks

5–8orally.

Rofecoxib,

12.5mg/kg:

week13–16orally.

Immun

ohistochem

istryob

served

:total

tissuearea,totalbo

nearea,ratio

ofbo

nearea,and

totaln

umbe

rof

osteob

lastsandosteoclast-like

cells

persectionarea

Naproxenandrofecoxibde

creasedbo

neingrow

thsign

ificantly.

Rofecoxibde

creasedthearea

ofosteob

lasts

perarea

comparedwith

controls,and

naproxen

sodium

didno

treachstatistical

sign

ificance.

Goo

dman

etal.(2005)

[26]

New

Zealandwhite

rabb

its(n=8).

Titanium

bone

harvest

cham

berim

planted

bilaterally

intib

ia(n=16).

Con

trol

Rofecoxib

Treatm

entswere

administeredfor6weeks

each:con

trol-nodrug

;rofe-

coxib(12.5mg/day)forthe

first2weeks

ofa6-week

trial,or

thelast2weeks

orgivencontinuo

uslyforall

6weeks

washo

utpe

riods

Immun

ohistochem

istryob

served

:total

tissuearea,totalbo

nearea,ratio

ofbo

nearea,and

thetotaln

umbe

rof

osteob

lastsandosteoclast-like

cells

persectionarea.

Rofecoxibgivencontinuo

uslyfor6weeks

hadless

bone

ingrow

th,osteo

clast-like

cells

andosteob

lastspe

rarea

compared

tothecontroltreatmen

t.Ro

fecoxibgivenfor2of

a6-weeks

cycle

didno

tinterfe

rewith

theparameters.

Pablos

etal.(2008)[31]

MaleSpragu

e-Daw

ley

rats,3-m

onth-old,w

eigh

ing

250-300g(n=30).

Implantinserted

intib

ia(n=30).

Con

trol

(n=10)

Diclofenac(n=10)

Meloxicam

(n=10)

Diclofenac,1.07

mg/kg

b.i.d.for

5days.

Meloxicam

,0.2mg/kg

daily

for5days.

Histomorph

ometric

analysisat

28days

afterim

plantinsertion:bo

ne-to-im

plant

contact,corticalbo

nearea,and

trabecular

bone

area

with

intheim

plantthreads

Thebo

ne-to-im

plantcontactwas

lower

indiclofen

accomparedwith

the

meloxicam

andcontrol.

Thetrabecular

bone

area

was

greater

indiclofen

accomparedwith

meloxicam

andcontrol.

Ribe

iroet

al.(2006)[27]

MaleWistarrats,age

d10

weeks

(n=31).

Implantinserted

intib

ia(n=31).

Con

trol

(n=14)

Meloxicam

(n=17)

Dailysubcutaneo

usinjections

for60

days:

control,1mL/kg

ofsaline

Meloxicam

,3mg/kg

Histomorph

ometric

analysisat

60days

after

implantinsertion:bo

ne-to-im

plantcontact,

bone

area,and

bone

density

inthecortical

andcancellous

bone

areas

Meloxicam

redu

cedbo

ne-to-im

plant

contact,bo

nearea,and

bone

density

inbo

ththecorticalandcancellous

bone

areas.

Ribe

iroet

al.(2009)[28]

MaleWistarrats,age

d10

weeks

(n=30).

Implantinserted

intib

ia

Con

trol

(n=14)

Meloxicam

(n=16)

Dailysubcutaneo

usinjections

for60

days:

control,1mL/kg

ofsaline

Histomorph

ometric

analysisat

60days

after

implantinsertion:bo

ne-to-im

plantcontact,

bone

area,and

bone

density

inthecortical

Blastin

gim

plantsurface

with

alum

inium

oxidecanincrease

bone

-to-im

plantcontact;

however,itdo

esno

treversethene

gative

Luo et al. International Journal of Implant Dentistry (2018) 4:30 Page 8 of 12

Table

8In

vivo

stud

iesusinganim

almod

elsthat

investigated

theeffect

ofNSA

IDson

osseointeg

ratio

n(Con

tinued)

Stud

y(year)

Sample(size)

Treatm

entgrou

p(size)

Metho

dology

Parameter

Outcome

(n=30).

Meloxicam

,3mg/kg

andcancellous

bone

areas

effectscaused

byaselectiveCOX-2inhibitor

onbo

nehe

alingarou

ndim

plants.

Salduz

etal.(2017)[32]

New

Zealandwhite

rabb

its,

skeletallymatureweigh

ing

3.5–4kg

(n=40).

Titanium

rods

implanted

bilaterally

infemur

(n=80).

Con

trol

Diclofenac

Celecoxib

Treatm

entswere

administeredfor8weeks:

control,regu

larfood

Diclofenac,5mg/kg/day

intram

uscularly

Celecoxib,

3mg/kg/day

orally

Biom

echanicaland

histom

orph

ometric

analysisat

8weeks

afterim

plantinsertion:

interface

failure

load,b

onequ

ality,b

one

implantinterface,hostreactio

n,totalb

one

area,and

bone

-to-im

plantcontactrate

Nosign

ificant

differencein

thebiom

echanical

andhistolog

icalresults

betw

eenthegrou

ps.

Luo et al. International Journal of Implant Dentistry (2018) 4:30 Page 9 of 12

contact was minimal in newly formed bone inCOX-2-knockout mice [30]. The data collected by Good-man et al. and Chikazu et al. postulated that COX-2 mayhave an important role in osseointegration [26, 30]. How-ever, a study conducted by Pablos et al., that investigatedthe effect of a non-selective COX inhibitor (diclofenac,1.07 mg/kg/day) and a selective COX-2 inhibitor (meloxi-cam, 0.2 mg/kg/day) administered for 5 days onperi-implant healing in rats, revealed that diclofenacdelayed peri-implant bone healing and negatively affectedthe bone-to-implant contact, whereas meloxicam had nonegative effect on peri-implant healing [31]. The results ofPablos et al. were inconsistent with the results of the studyconducted by Cai et al. that also investigated the effect ofdiclofenac (2 mg/kg/day) and a selective COX-2 inhibitor(parecoxib, 1.5 mg/kg/day) administered for 7 days on theosseointegration of titanium implants in rabbit calvarias.Their results revealed no statistically significant differencesbetween the experimental groups and the control [22].Furthermore, a recent study conducted by Salduz et al. thatinvestigated the effect of a non-selective COX inhibitor(diclofenac, 5 mg/kg/day) and a selective COX-2 inhibitor(celecoxib, 3 mg/kg/day) administered for 8 weeks on bone

growth and osseointegration on two different alternativetitanium surfaces revealed no statistically significant differ-ences in the biomechanical and histological results betweenthe experimental groups and the control, suggesting thatlong-term use of NSAIDs does not affect osseointegration[32]. The data collected in animal studies regardingduration of treatment and drug selectivity is inconsistent,and there is a lack of consensus on the influence ofNSAIDs on osseointegration in animal models.

LimitationsThe majority of the included studies revealed a high risk ofbias, and conclusions from studies that have a high risk ofbias are sufficient to affect interpretation of data [16–18].Publication and selection bias is apparent in severalincluded studies, as the negative effects of NSAIDs onosseointegration can be expected in the studies thatadministered NSAID at a high concentration and/or for aprolonged period of time. The conclusions of this system-atic review were largely based on animal studies, as thereare very few published in vitro and clinical studies relatingto the effect of NSAIDs on osseointegration. The effects ofNSAIDs on osseointegration in animals cannot be

Fig. 1 PRISMA flow diagram of literature search

Luo et al. International Journal of Implant Dentistry (2018) 4:30 Page 10 of 12

translated to humans due to the vastly differentpharmacokinetics.

ConclusionsThe analgesic and therapeutic effects of NSAIDs areachieved by COX-2 inhibition [4]. It is likely that COXinhibition by NSAIDs is detrimental to the bone healingprocess, given the favourable actions of PG on this process[4]. Osteoblasts have the capacity to produce PGs, wherePGE2 is most abundant, through the COX pathway thoughthe evidence asserting that PGs have a direct role in bonehealing is inconclusive [1, 23]. Furthermore, there is insuffi-cient evidence in the current literature to explicitlyconclude that there is a relationship between the use ofNSAIDs and early implant failure. However, osseointegra-tion does not appear to be negatively affected by NSAIDsin the human clinical studies, which contrasts with theexperimental in vitro and in vivo animal studies. Further-more, there are no human clinical studies that have investi-gated the effect of a selective COX-2 NSAID onosseointegration. Therefore, further research with an em-phasis in human clinical studies comparing the effect of theCOX selectivity of NSAIDs on osseointegration is required.

AbbreviationsCOX: Cyclooxygenase; NSAID/s: Non-steroidal anti-inflammatory drug/s;PG: Prostaglandin; PGE2: Prostaglandin E2

AcknowledgementsThe authors acknowledge and are grateful for the help and preparation ofmanuscript by the supporting research supervisors: Dr. Ernest Jennings andProf. Alan Nimmo.

FundingThe systematic review is funded by James Cook University College ofMedicine and Dentistry as part of a Dentistry Honours Research Project.

Availability of data and materialsA meta-analysis was not conducted for this systematic review. The criticalanalysis tables that support the conclusions of this article are included withinthe article (Tables 6, 7 and 8).

Authors’ contributionsAll the authors have made significant contributions to the systematic review.JDL, TJ, and MN were the primary, second, and third reviewer, respectively.JDL was involved in the primary literature acquisition. JDL, TJ, and MN wereall involved in the interpretation and analysis of data. TJ and MN contributedequally in designing and drafting the tables. JDL drafted the manuscriptwhich was critically revised by DS and CM. DS and CM are the primarysupervisors of the Honours Research Project. All authors read and approvedthe final manuscript.

Ethics approval and consent to participateNot applicable

Consent for publicationNot applicable

Competing interestsJie Denny Luo, Catherine Miller, Tamara Jirjis, Masoud Nasir, and DileepSharma declare that they have no competing interests.

Publisher’s NoteSpringer Nature remains neutral with regard to jurisdictional claims inpublished maps and institutional affiliations.

Author details1College of Medicine & Dentistry, James Cook University, 14-88 McGregorRoad, Smithfield, QLD 4878, Australia. 2College of Public Health, Medical andVeterinary Sciences, James Cook University, 14-88 McGregor Road, Smithfield,QLD 4878, Australia.

Received: 22 May 2018 Accepted: 13 July 2018

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