Systematic Review Article

OPEN

The effect of NSAIDs on postfracture bone

healing: a meta-analysis of randomized controlled
trials
Humaid Al Farii, MD, MRCS (Ir)∗, Leila Farahdel, MD, Abbey Frazer, MD, Ali Salimi, MD,
Mitchell Bernstein, MD, FRCSC

Abstract
Objectives: To determine whether nonsteroidal anti-inflammatory drugs (NSAIDs) have an adverse effect on bone healing by
evaluating all available human randomized controlled trials (RCTs) on this subject.
Data Sources: A comprehensive search of electronic databases (PubMed, MEDLINE, and Cross-References) until October 2018
comparing the occurrence of nonunion in patients who received NSAIDs to the control group through RCTs.
Study Selection: Inclusion criteria were English-only studies, and the type of studies was restricted to RCTs.
Data Extraction: Two authors independently extracted data from the selected studies, and the data collected were compared to
verify agreement.
Data Synthesis: Nonunion was the main outcome evaluated in each study. Regression analysis was used to estimate the relative
risk comparing the duration and the type of NSAIDs by calculating the odds ratio (OR) for dichotomous variables. Studies were
weighed by the inverse of the variance of the outcome, and a fixed-effects model was used for all analyses.
Conclusions: Six RCTs (609 patients) were included. The risk of nonunion was higher in the patients who were given NSAIDs after
the fracture with an OR of 3.47. However, once the studies were categorized into the duration of treatment with NSAIDs, those who
received NSAIDs for a short period (<2 weeks) did not show any significant risk of nonunion compared to those who received NSAIDs
for a long period (>4 weeks). Indomethacin was associated with a significant higher nonunion rate and OR ranging from 1.66 to 9.03
compared with other NSAIDs that did not show a significant nonunion risk.
Keywords: fracture, nonunion, NSAIDs

1. Introduction combination of a complex and sequential set of events that

depends on the stability of the fracture.[1,2]
Tissue damage triggers the processes of coagulation, inflamma-
There are many factors that influence the healing process,
tion, and healing. The healing process for soft tissue around bone
including environmental factors, drugs, and physiological
is defined by regeneration and repair that matures into scar tissue,
changes. One of these factors is the use of NSAIDs, which is
whereas the bone tissue itself has a unique ability to regenerate
commonly used in patients as an anti-inflammatory as well as an
shape, strength, and preinjury function. Fracture healing is a
analgesic. NSAIDs effect on bone healing has been studied for
many years, with results showing debatable effects on bone
healing.
Source of Funding: nil. There have been multiple studies published evaluating the
We disclose that the authors of this study have no commercial or financial benefits and consequences of NSAIDs in bone healing of both
association with regards to this project and, therefore, have no affiliation that may animal and human tissue in vitro and in vivo. The studies that
pose a conflict of interest with the manuscript enclosed. We had full access to all showed that NSAIDs have a significant effect on bone healing are
the data in the study and take responsibility for the integrity and accuracy of the
data, as well as the decision to submit for publication. categorized by mechanism of action of NSAIDs in Table 1.[3–34]
There were no external funding sources for this study.
There have been multiple studies published evaluating the
benefits and consequences of NSAIDs in bone healing of both
The authors have no conflicts of interest to disclose.
animal and human tissue to clinical RCTs. Subsequently, there
Division of Orthopaedic Surgery, McGill University, Montreal, Canada
∗
are animal studies that showed NSAIDs do not have a significant
Corresponding author. Address: McGill University, Montreal, QC, Canada;.
effect on bone healing, which are listed in Table 2.[35–49] In
e-mail address: Humaid44@[Link] (H. A. Farii).
conjunction to several RCTs, there has been meta-analysis of
Copyright © 2021 The Authors. Published by Wolters Kluwer Health, Inc. on
behalf of the Orthopaedic Trauma Association.
strong animal studies, yet the effect of NSAIDs on bone healing is
This is an open access article distributed under the Creative Commons controversial and many surgeons avoid these medications
Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and because of the concern of the possible delay in healing.[13,50–52]
reproduction in any medium, provided the original work is properly cited. The purpose of a meta-analysis of only randomized control
OTA (2021) e092 human trials is to provide a greater understanding of the true
Received: 20 May 2020 / Received in final form: 18 July 2020 / Accepted: 12 effect of NSAIDs on human bone healing, and the risk of
August 2020 nonunion. Secondary outcome measures, duration of NSAIDs
Published online 22 March 2021 use, and type of NSAIDs will also be included to determine its
[Link] effect on healing complications.

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Table 1
Animal studies which showed effect on bone healing with the use of NSAIDs.
Drug classification NSAID Duration References
Acetic acid derivatives Indomethacin Long duration Bo et al (1976)[3]
Sudmann et al (1979)[4]
Allen et al (1980)[5]
Tornkvist et. al (1984)[6]
Sato et al (1986)[7]
Keller et al (1989)[8]
Hogevold et al (1992)[9]
Engesaeter et al (1992)[10]
Altman et al (1995)[11]
Dimar et al (1996)[13]
Long et al (2002)[14]
Riew et al (2003)[15]
Persson et al (2005)[16]
Karachalios et al (2007)[17]
Indomethacin Short duration Reikeraas et al (1998)[12]
Ketorolac Long duration Ho et al (1998)[18]
Gerstenfeld et al (2007)[19]
Diclofenac Long duration Beck et al (2003)[20]
Sen et al (2007)[21]
Bissinger et al (2016)[22]
Etodolac Short duration Endo et al (2005)[23]
Enolic acid derivatives Tenoxicam Short duration Giordano et al (2003)[24]
Sen et al (2007)[21]
Meloxicam Long duration Ribeiro et al (2006)[25]
Karachalios et al (2007)[17]
Propionic acid derivatives Ibuprofen Long duration Tornkvist et. al (1984)[6]
Obeid et al (1992)[26]
Leonelli et al (2006)[27]
O’Connor et al (2009)[28]
Naproxen Long duration Goodman et al (2006)[29]
Kaygusuz et al (2006)[30]
Salicylates Aspirin Long duration Allen et al (1980)[5]
Selective COX-2 inhibitors Parecoxib Long duration Gernstenfeld et al (2003)[31]
Rofecoxib Long duration Goodman et al (2006)[29]
Leonelli et al (2006)[27]
Murnaghan et al (2006)[32]
Karachalios et al (2007)[17]
O’Connor et al (2009)[28]
Celecoxib Short duration Bergenstock et al (2005)[33]
Simon and O’Connor (2007)[34]
Long et al (2002)[14]
Celecoxib Long duration Simon and O’Connor (2007)[34]
Valdecoxib Long duration Gerstenfeld et al (2007)[19]
COX-2 = cyclooxygenase-2.

2. Material and methods technique. Gender and age group were not limited. Neither the
This meta-analysis was conducted following the Preferred type of NSAIDs nor the duration postoperatively was used as a
Reporting Items for Systemic Reviews and Meta-Analyses restriction to the study. The type of study was restricted to human
Statement. The study was deemed exempt from Institutional RCTs only. The summary of the study flow is provided in
Review Board and Animal Use Committee Review. Informed Figure 1.
consent was not applicable in our study. A comprehensive meta- Two reviewers reviewed each title independently and only
analysis of the available clinical evidence was performed, with relevant abstracts were included after the screen, which included
regards to NSAIDs exposure and nonunion risk in humans. 10 studies. From these studies, 3 were excluded. One was a study
Studies were excluded if long bone fractures were not studied, on regenerative periodontal treatment for which the healing
such as dental and spine. process is different from bone healing and was, therefore,
A literature search was conducted through PubMed and excluded.
Medline databases and restricted to English literature. The search The data extraction from each study includes year of
terms used were “anti-inflammatory agents,” “fracture,” “heal- publication, randomization method, patient, and treatment
ing,” with expanded search terms with Boolean operators being characteristics. The studies were evaluated specifically for
used. The period of search included any studies until October publication bias using a funnel plot. RevMan software (version
2018. Manual searching of studies was also done through review 5.3, The Cochrane Collaboration) was used for the analysis.
articles and other relevant material, through the snowballing Treatment effects were estimated by calculating the OR with

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Table 2
Animal studies which showed no effect on bone healing with the use of NSAIDs.
Drug classification NSAIDs Duration References
Acetic acid derivatives Indomethacin Elves et al (1982)[35]
Sudmann et al (1982)[36]
Boiskin et al (1988)[37]
Mbugua et al (1989)[38]
Keller et al (1990)[39]
Brown et al (2004)[40]
Ketorolac Long duration Mullis et al (2006)[41]
Ketorolac Short duration Fracon et al (2010)[42]
Diclofenac Long duration Tiseo et al (2006)[43]
Enolic acid derivatives Meloxicam Long duration Van de Heide et al (2008)[44]
Propionic acid derivatives Ibuprofen Long duration Tornkvist et al (1980)[45]
Huo et al (1991)[46]
Mullis et al (2006)[41]
Ketoprophen Long duration Urrutia et al (2007)[47]
Van de Heide et al (2008)[44]
Selective COX-2 inhibitors Celecoxib Long duration Brown et al (2004)[40]
Mullis et al (2006)[41]
Rofecoxib Long duration Mullis et al (2006)[41]
Tiseo et al (2006)[43]
Hak et al (2011)[48]
Etoricoxib Short duration Fracon et al (2010)[42]
Sulfonanilides Nimesulide Short duration Teofilo et al (2011)[49]
COX-2 = cyclooxygenase-2.

Figure 1. Flow chart illustrating the review process.

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Table 3
Summary of human RCTs on NSAIDs effect on bone healing, used in this meta-analysis.
Bone type and Length of Nonunion
Study No. management NSAID exposure Dose diagnosis Conclusion
Adolphson 42 Displaced Colles fracture Piroxicam 8 weeks 20 mg /d Xray No difference in radial shortening
et al (1993)[53] Closed reduction RD: Paracetamol Small but no significant
reduction in osteopenia in the
piroxicam group after 8 weeks
Brattwall 100 Elective hallux valgus surgery COX-2 inhibitors 7 days Etoricoxib 120 mg CT scan + Clinical None of the CT scans showed
et al (2010)[54] RD: paracetamol, for 4 days then evaluation limited bone healing
oxycodone 90 mg for 3 days
Burd et al 112 Prophylaxis post acetabular Indomethacin 6 weeks 25 mg TID X-ray Risk of nonunion significant for
(2003)[55] fracture ORIF + long bone indomethacin to control, 5.32
fracture to 1
Davis et al 100 Colles’ fractures Flurbiprofen 14 days 50 mg x 3–6 daily X-ray No significant difference with
(1988)[56] RD∗: paracetamol placebo for anatomic position
Drendel et al 336 Simple Arm fracture in Ibuprofen Variable Avg. 4 doses Telephone follow-up No association between
(2009)[57] pediatrics (radius, ulna, or <2 weeks of 10 mg/kg and file review refracture or nonunion
humerus) No direct endpoint related to
bone healing
Sagi et al 98 Acute acetabular fracture Indomethacin 3 days to 75 mg daily CT scan Tx 1 week of indomethacin may
(2014)[58] treated operatively 6 weeks be beneficial for healing,
without increase of nonunion
Tx 6 weeks of indomethacin
increases the incidence of
nonunion
No. = number of patients, ORIF = open reduction internal fixation, RD = rescue drug; Tx, treatment.

95% confidence interval (CI) for dichotomous variables. Studies studies were considered for final analysis (Table 3).[53–58] The
were weighed by the inverse of the variance of the outcome, and a data from these 6 studies were extracted for analysis.
fixed-effects model was used for all analyses.
3.1. Study characteristics and quality
3. Results
From all of the studies that were included, there were 609 patients
A total of 384 studies were initially screened, where 10 studies included where 290 were exposed to an NSAID compared to 319
were considered for inclusion. From those, 2 were excluded control patients. Included in these studies are Adolphson et al and
because they discussed pain management post spinal fusions, and Drendel et al, which had no events of nonunion in either arms of
a third study on healing of enamel matrix, was excluded because the studies.[53,57] Based on the Cochrane handbook for meta-
the healing process differs from long bones. Additionally, the analysis, the standard practice for the calculations of OR and risk
study that included the results from Study to Prospectively ratio is to exclude the studies where there are no events in the
Evaluate Reamed Intramedullary Nails in Patients with Tibial treatment group and in the control.[59] In the calculation table, it
Fractures trial described qualitative results; however, it did not can be seen that the studies are included; however, they do not
provide quantitative information on their conclusions on have weight attributed to the total analysis on the 6 studies, as
NSAIDs use for bone healing. A total of 6 randomized control described in Figure 2. From these studies, 3 considered long bone

Figure 2. Odds ratios of risk of nonunion post fracture healing, NSAIDs vs non-NSAIDs use.

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Figure 3. Funnel plot of the studies included in the meta-analysis.

fractures, Colles fracture,[53,56] or simple arm fractures (radius, exposed to NSAIDs and 12 were not. The 4 studies resulted in an
ulna, or humerus), 2 studies considered acetabular frac- OR of 3.47, with a 95% CI of 1.68 to 7.13. The significance level
tures,[55,58] and 1 studied elective hallux valgus surgery.[54] is P = .001, as described in Figure 2. This indicates that there is
Each study was an RCT comparing NSAIDs with a control. an increased risk of nonunion with NSAIDs exposure which is
Adolphson et al studied piroxicam 20 mg per day, Brattwall et al significant.
studied COX-2 inhibitors etoricoxib (120 mg for 4 days then 90
mg for 3 days) or tramadol (200 mg for 7 days),[53,54] Davis and
3.3. Effect of NSAIDs for short duration compared to long
Ackroyd[56] studied flurbiprofen 150 to 300 mg daily for 2 weeks,
duration on bone healing
Drendel et al[57] studied ibuprofen, whereas Burd et al and Sagi
et al studied indomethacin from 3 days to 6 weeks.[55,58] A subgroup analysis was performed classifying the duration of
The diagnosis of nonunion was made through either X-ray of NSAIDs administration, with a short duration defined as less than
the fracture and CT scan or telephone follow-up and file review. 2 weeks and a long duration defined at more than 2 weeks. Short
From the studies included, the ORs were well distributed in terms duration studies included 2 studies,[54,57,58] with the OR of 1.56,
of publication bias (Fig. 3). 95% CI between 0.48 and 5.10, and P value of 0.484, as described
A power analysis on the selected studies and the subgroups was in Figure 4, whereas the 4 studies included in the long duration,
conducted to understand the limitation from having a limited including 1 study, Sagi et al, which quantified both short and long
number of cases per study and its significance. The power refers duration,[53,55,56,58], had an OR of 5.27, 95% CI between 2.34 and
to the probability that the test will find a statistically significant 11.88 and the P value of less than .0001, as described in Figure 5.
difference when such a difference exists. To calculate this, a type I This indicates that although short use of NSAIDs has no significant
error level (alpha) of 0.05 was used. A type II error (beta) of 0.2 effect on bone healing, long duration of more than 2 weeks has a
was used that corresponds to a power of 0.8. Based on a high significant higher rate of nonunions.
heterogeneity group, with a minimum power of 0.8, ideally it
would need 5 RCTs of 50 patients in each group, 10 RCTs of 30
3.4. Effect of indomethacin NSAIDs compared to
patients in each group, or 15 RCTs of 20 patients in each group.
other NSAIDs on bone healing
In the case of this meta-analysis, there are 4 RCTs with an
average of 43 patients per group. Using these values, with an A subgroup analysis was performed classifying the NSAIDs with
effect size of 0.5, this is considered to have a power of 100%, the exception of indomethacin. From the studies, 4 studies
which means for large differences, this is a significant meta- administered NSAIDs that were not indomethacin.[53,54,56,57]
analysis. However, with the effect size of 0.2, the power is 74.6%, The OR was found to be 2.58 with 95% CI 0.65 to 10.30, the P
which is less than 80%, which means for small differences, this value of .18, therefore, it is not significant, as described in
number of studies is not sufficient to find significance. Figure 6. This means that NSAIDs that did not include
indomethacin did not have a significant effect on nonunion,
compared to studies that included only indomethacin as
3.2. General effect of NSAIDs on bone healing and
NSAIDs,[55,58] had an OR of 3.87 with 95% CI 1.66 to 9.03,
formation of nonunion
and a P value of .002, as described in Figure 7. This means that
From those studies, there were 48 nonunion (36 for NSAIDs vs indomethacin used as an NSAID has a significant effect on
12 for non) , defined as a bone that fails to heal, of which 36 were healing leading to nonunions.

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Figure 4. Odds ratios of risk of nonunion postfracture healing, NSAIDs vs non-NSAIDs short-term use (less than 2 weeks).

Figure 5. Odds ratio of risk of nonunion post fracture healing, NSAIDs compared to control long term use (greater than 2 weeks).

4. Discussion prostaglandins under normal physiological conditions, whereas

NSAIDs are commonly used as part of pain management COX-2 is synthesized under an inflammatory state and induces
postfracture. The negative effect of NSAIDs is mostly related to the release of prostaglandins. NSAIDs decrease the activity of
the inhibition of cyclooxygenase (COX) enzyme activity and the COX isoenzymes that decrease the synthesis of prostanoids.
prostanoid pathway. There are 2 forms of COX enzymes that Research by Simon et al states that COX-2 is necessary for
have been isolated. COX-1 takes part in the synthesis of normal endochondral ossification during fracture healing.[60]

Figure 6. Odds ratio of risk of nonunion post fracture healing, NSAIDs not including indomethacin compared to no NSAIDs.

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Figure 7. Odds ratio of nonunion with indomethacin use compared to no NSAIDs.

NSAIDs are generally classified by chemical structure or for both short and long durations, finding that short duration did
mechanism of action. Some of the commonly used classes are not show a significant difference, whereas long duration did.
salicylates, propionic acid derivatives, acetic acid derivates, enolic These studies were subcategorized to have a better under-
acid derivatives, and selective COX-2 inhibitors. It can be standing of the type and duration of NSAIDs that had an
understood that there is a difference in effect on bone healing with influence on bone healing. After classifying the duration of the
the NSAIDs due to the variation of the mechanism of action of NSAIDs, it was found that short duration (less than 2 weeks) had
NSAIDs. an OR of 1.56 and was not significantly different, whereas long
There have been about 50 animal studies that were published duration NSAIDs use had an OR of 5.27 and was significantly
on the effect of NSAIDs showing a variety of results. These different compared to control. This means that short use of
studies are described in Tables 1 and 2. The animal studies NSAIDs as a means of pain management might not have a
included NSAIDs from different classes of NSAIDs. Animal significant effect on risk of nonunion formation. In contrast, long
studies investigated various NSAIDs during short-term and long- duration does have a significant increased risk of nonunion. This
term use while looking at end point factors including mechanical is an important factor that can influence the clinical management
properties of bone, histological grade, and radiological appear- of patients.
ance. From these studies, most had greater support that NSAIDs A second subgroup that was studied was the type of NSAIDs
delay or prevent bone healing, whereas others denied that effect. used in the RCTs. Indomethacin, an acetic acid derivative, is a
However, the question remains if this is true in humans. A nonselective COX inhibitor. The studies that did not include
thorough meta-analysis of human studies done by Wheatly indomethacin had an OR for nonunion of 2.58, which was not
et al,[61] which included pediatric and adult bone healing and was significant, whereas the studies that included only indomethacin
not limited to RCT studies, showed that NSAIDs exposure had an OR of 3.87, which was significant. This may be a good
increased delayed union or nonunion. However, there is no indicator as to which NSAIDs to prescribe in order to decrease
significance in the pediatric population, or with low-dose or the risk of nonunion.
short-duration use.
The purpose of this meta-analysis was to analyze RCTs that
5. Limitations
studied the use of NSAIDs in bone healing. This meta-analysis of
6 RCTs evaluated 609 patients, of whom 290 were exposed to an The present meta-analysis does have its limitations. The studies
NSAID compared to 310 control patients. From these studies, that were included were limited to only 6 RCTs, which limit the
subcategories were further studied. When comparing all the analysis that is possible to have a better understanding of NSAIDs
included studies, there was a significant increased risk of on bone healing. Among these studies, the primary outcome of
nonunions when exposed to NSAIDs with an OR of 3.47. nonunion was not standardized in terms of outcome measure-
Adolphson et al studied piroxicam for 8 weeks and found that ment, some used X-ray or CT scan, whereas others used clinical
none of the patients had nonunions, similar to control. Similarly, evaluation for healing. For this reason, extraction of the data was
Drendel et al studied ibuprofen compared to acetaminophen, limited to what was made available. Additionally, this meta-
where both groups did not have any nonunions; however, the analysis did not consider the heterogeneity of the population and
main purpose of the study was not to investigate bone healing, the targeted fracture sites that were chosen for the study. This
and, therefore, there was no strong evidence. Since these studies would require a greater availability of studies. The studies that
have zero events, the OR cannot be statistically calculated. were included in the meta-analysis included various fracture
Brattwall et al[54] conducted an RCT that studied COX-2 types. For example, Adolphson, Davis, and Drendel included
inhibitors for a short time and found no significant difference of Colles and pediatric fractures of the upper extremities. Such
nonunions compared to control. Burd et al[55] conducted an RCT fractures are uncommon to have nonunion; therefore, to equate
that studied indomethacin for long duration and found a the risk of nonunion of these fractures to, for example, long bones
significant formation of nonunion. In contrast, Davis et al studied in adults would underestimate the number of possible nonunions.
flurbiprofen for long duration and found no significant difference Additionally, the elective surgeries of hallus valgus described in
in bone healing.[56] Lastly, Sagi et al[58] also studied indomethacin Brattwal have a different healing potential compared to the high

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