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C OPYRIGHT 2012 BY T HE J OURNAL OF B ONE AND J OINT S URGERY, I NCORPORATED

The Effect of Nonsteroidal Anti-Inflammatory

Drug Administration on Acute Phase
Fracture-Healing: A Review
Andrew P. Kurmis, BMBS, PhD, Timothy P. Kurmis, BMBS, Justin X. OBrien, BMBS, and Tore Dale n, MD, PhD

Investigation performed at the Department of Orthopaedics, Repatriation General Hospital, Daw Park, South Australia, Australia,

Background: The analgesic efficacy of nonsteroidal anti-inflammatory drugs (NSAIDs) is well established, and these
agents often form an integral part of posttraumatic pain management. However, potentially deleterious effects of resulting
prostaglandin suppression on fracture-healing have been suggested.
Methods: A systematic literature review involving searches of electronic databases and online sources was performed to
identify articles exploring the influence of NSAIDs on fracture-healing.
Results: A structured search approach identified 316 papers as potentially relevant to the topic, and these were
manually reviewed. The majority described small-scale studies that were retrospective or observational in nature, with
limited control of potentially confounding variables, or presented little key information that was not also present in
other studies.
Conclusions: Although increasing evidence from animal studies suggests that cyclooxygenase-2 (COX-2) inhibition
suppresses early fracture-healing, in vivo studies involving human subjects have not provided convincing evidence to
substantiate this concern. We found no robust evidence to attest to a significant and appreciable patient detriment
resulting from the short-term use of NSAIDs following a fracture. The balance of evidence in the available literature
appears to suggest that a short-duration NSAID regimen is a safe and effective supplement to other modes of post-fracture
pain control, without a significantly increased risk of sequelae related to disrupted healing.
Level of Evidence: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.

A
dequate early pain control following a traumatic fracture
is a key priority. Control of acute pain is well recognized
to play an important role in both improving the time
to healing1 and reducing the occurrence of adverse medical
sequelae. Although monotherapeutic approaches, often using
narcotics, remain widely employed2, polytherapeutic approaches
that take advantage of the synergistic utility of agents targeting
different aspects of the pain-modulation pathway have evolved
to become the standard of care in some regions3,4. Nonsteroidal
anti-inflammatory drugs (NSAIDs) are frequently used for their
analgesic and anti-inflammatory properties5, with more than
$7 billion spent annually on such medications in the United
States alone6.
Historically, the use of NSAIDs has been championed in
the management of musculoskeletal injuries, and this has in-
cluded their use following a fracture7,8. NSAIDs provide effec-
tive reduction of both acute pain and regional swelling8 and
decrease requirements for concurrent narcotic administration.
The decreased side effects of short-term NSAID use compared
with opioid use9,10 and the ability of NSAIDs to provide im-
proved analgesia through synergistic effects when used to-
gether with other agents11 have also been shown to decrease the
length of hospital stay12.
However, evidence has emerged that raises concerns about
the role of NSAIDs in routine patient management immediately
following a fracture13. It has been suggested that NSAIDs may

Disclosure: None of the authors received payments or services, either directly or indirectly (i.e., via his or her institution), from a third party in support of
any aspect of this work. None of the authors, or their institution(s), have had any financial relationship, in the thirty-six months prior to submission of this
work, with any entity in the biomedical arena that could be perceived to influence or have the potential to influence what is written in this work. Also, no
author has had any other relationships, or has engaged in any other activities, that could be perceived to influence or have the potential to influence what
is written in this work. The complete Disclosures of Potential Conflicts of Interest submitted by authors are always provided with the online version of the
article.

J Bone Joint Surg Am. 2012;94:815-23 d http://dx.doi.org/10.2106/JBJS.J.01743

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Fig. 1
Flowchart showing the structured database search (completed on October 2, 2010) that formed the basis of the literature review.

actually slow the intrinsic fracture-healing process14 and increase
the likelihood of subsequent delayed union or nonunion
events15. The controversy surrounding NSAID use after a frac-
ture is not a new one, with reports dating from the 1970s having
prompted early debate on the matter16,17. Concerns about the
potential effect of NSAIDs on fracture-healing have moved
many orthopaedic clinicians away from routine administration
of these agents in patients with a fracture5, even though this
increases reliance on other agents such as narcotics that result in
potentially deleterious side effects and morbidity15.
The purpose of this review was to systematically ap-
praise the contemporary literature on the physiologic role of
NSAIDs in influencing fracture-healing pathways and to as-
certain whether sufficient reasonable evidence exists to direct
clinicians regarding the use of NSAIDs in the acute post-fracture
period.
Materials and Methods
T o facilitate review of the defined topic, we performed a structured search of
electronic databases and a real-time search of literature available online.
These searches utilized the PubMed (MEDLINE), CINAHL, and Google
Scholar search engines as well as the Cochrane and BMJ Clinical Evidence
libraries. Two separate full searches were performed by the first author (A.P.K.)
and cross-verified by two of the other authors (T.P.K. and J.X.O.). The initial
search was undertaken on April 4, 2010, and the second (to ensure the con-
temporary nature of the review prior to submission) was performed on Oc-
tober 2, 2010. Sixteen additional studies were identified by repeating the search.
The defined search criteria were replicated precisely in each instance. Author-
defined MeSH and keyword searches were performed with use of Boolean
descriptors (e.g., non-steroidal anti-inflammatory drugs OR NSAIDs AND (which play an essential role in bone repair)28.
fracture-healing), with initial searches limited to English-language materials
for which complete abstracts were available (to assess suitability for full-text
retrieval) (Fig. 1). The searches were not actively limited by the date of original
publication. The abstracts of all 316 articles identified with use of the above-
described criteria were manually reviewed, and full-text articles were obtained
using institutional document retrieval services as appropriate.
The majority of the articles described small-scale studies that were retro-
spective or observational in nature, with limited control of potentially confounding
variables, or presented little key information that was not also present in other
studies. Eighty-three of the 316 articles are cited in the present review.
Source of Funding
No external funding was received for this study.
Results
Mechanism of Anti-Inflammatory Action of NSAIDs
A lthough NSAIDs were introduced to clinical medicine in
1899, it was not until 1971 that British pharmacologist
John Robert Vane18,19 first reported that NSAIDs appeared to act
through the nonselective acetylation, and thus inhibition, of
cyclooxygenase (COX) enzymes19-23. Cyclooxygenases play a
critical role in catalyzing the oxygenation of arachidonic acid to
prostaglandins and leukotrienes, which are important physio-
logic mediators of tissue inflammation and swelling, pain, and
fever (Fig. 2)4,20,21,23-26. Inhibitors of COX activity are therefore
widely utilized for their analgesic, anti-inflammatory, and an-
tipyretic effects5,8,25,26.
Traditionally, cyclooxygenases have been separated into
isoenzymes 1 and 24,25,26 (although the controversial description of
a COX-3 isoenzyme has also been championed27). Although both
recognized forms play roles in physiologic functions, COX-1
is considered ubiquitous and constitutive, whereas COX-2 is
induced in response to inflammatory stimuli4,8,25,26 and has been
the focus of a substantial volume of research20. In addition to its
defined role in the inflammatory cascade, COX-2 is also re-
sponsible for the production by osteoblasts of prostaglandins
Common NSAIDs are subdivided into nonspecific,
preferential, and selective inhibitors on the basis of the
pathways they affect. The newer selective COX-2 inhibi-
tors were designed in an attempt to minimize negative effects
on hemostasis and gastric protection5,14,29, which were largely
attributed to COX-1 inhibition. In early meta-analyses, COX-2
inhibitors appeared to be as effective as traditional NSAIDs for
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Fig. 2
Arachidonic acid degradation pathway and sites of NSAID action. NSAIDs = nonsteroidal anti-inflammatory drugs, COX = cyclooxygenase, PG = prosta-
glandin, TX = thromboxane, LOX = lipooxygenase, HPETE = hydroperoxyeicosatetraenoic acid, HETE = hydroxyeicosatetraenoic acid, and EP1R through
EP4R = prostaglandin-E2 receptors 1 through 4.

analgesia but were better tolerated because they had fewer gas-
trointestinal side effects30. However, the absolute safety of cur-
rently available selective COX inhibitors remains a focus of
scientific debate13.
COX-1 and COX-2
Although both are involved in the arachidonic acid degradation
cascade, COX-1 and COX-2 play decidedly different roles in
the body. Extensive research has demonstrated the effect of
COX-1 modulation on both platelet aggregation and mucosa-
protective prostaglandin production31,32. Under normal in vivo
conditions, the activity of COX-2 has also been demonstrated
to influence two key physiologic areas.
First, COX-2 has been implicated in the production of
endothelial cell-derived prostacyclin, which has demonstrated
anti-thrombogenic activity18 (primarily through luminal
modulation of platelet function) 25,26 . Loss of this protective
intravascular mechanism, especially within the delicate mi-
crocirculation, may explain the increased rate of substantial
cardiovascular morbidity and mortality that resulted in halting
of active trials of COX-2 inhibitors during the past decade.
Suppression of COX-2 may therefore retard angiogenesis at a
microscopic level, which is a process critical for the conversion
of soft to hard osseous callus5.
Second, COX-2 production, upregulated in response to
direct tissue insult, is a critical early inducer required for the
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downstream production of pro-inflammatory prostanoids
which, in turn, play an important early role in the initiation of
self-protective and healing mechanisms. Histological observations
suggest that COX-2 may be an essential component of the en-
dochondral ossification process at the stage of hard callus for-
mation through signaling the production of pro-inflammatory
prostaglandins33. This implies that COX-2 may be a constitu-
tively required component of normal fracture-healing, sup-
porting the premise that agents that modulate COX activity
may directly influence osseous repair14,18.
Since hemostatic and inflammatory processes are essential
components of bone remodeling, COX enzymes likely play
important physiologic roles in fracture-healing29. Preclinical
rodent models have widely been utilized as vehicles for the
controlled demonstration of COX activity on bone, at normal
COX levels as well as supraphysiologic and subphysiologic ones.
For example, the detailed investigations by Zhang et al. in 200234,
which used purebred wild-type (1/1) and knockout (COX-12/2
and COX-22/2) mouse models, demonstrated the essential role
of COX-2 in endochondral and intramembranous bone forma-
tion during skeletal repair. The healing of stabilized tibial fractures
was significantly delayed in COX-22/2 mice compared with both
COX-12/2 and wild-type controls. Subsequent protein assays
showed that the COX-22/2 defect correlated strongly with
reduced expression of cbfa1 and osterix35,36, downstream genes
necessary for bone formation34.
The COX-2 Controversy
Although much heralded at the time of their release, selective
COX-2 inhibitors have fallen sharply out of favor because of
potentially serious adverse event profiles14. The VIGOR study
in 2000 was credited as one of the earliest to identify an in-
creased risk of myocardial infarction and sudden cardiac death
in patients taking the COX-2 inhibitor rofecoxib compared
with the prototypical nonselective COX inhibitor, aspirin37.
This subsequently led to a dramatic decline in use of rofecoxib
because of fears of unjustified potential patient morbidity or
mortality. These findings were largely upheld in 2004 when the
APPROVe trial was discontinued prematurely because of a
statistically significant increase in adverse cardiovascular events
in patients taking rofecoxib compared with an inactive pla-
cebo38. Although many hypotheses exist to explain this obser-
vation, one of the more widely accepted is that the increase in
cardiovascular events due to COX-2 inhibition is related to
prevention of prostacyclin synthesis by endothelial cells, with
subsequent unopposed local thromboxane A2 activity. Sequelae
include unmodulated platelet aggregation and an increased
likelihood of intravascular thrombus formation18. Later in 2004,
rofecoxib was withdrawn from the market by the manufacturer39.
Subsequently, there remained much debate regarding
whether the reported deleterious side effect profile represented
an agent-specific or a class-specific effect of COX-2 inhibitors13.
The 2006 meta-analysis by Caldwell et al. of four trials in-
cluding 4422 patients compared celecoxib to a placebo. This
study also demonstrated an increased risk of myocardial in-
farction with COX-2 inhibitor therapy, consistent with the
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previously suggested class effect30. Secondary analyses by the
same authors, involving meta-analysis of studies including
nearly 13,000 patients, also showed an increased risk of myo-
cardial infarction secondary to celecoxib use (odds ratio, 2.3)
but no increased risk for the composite of stroke, major car-
diovascular events, and death due to cardiovascular causes30. At
odds with these studies, the larger meta-analysis by White et al.
in 200341, which involved stratified outcome analysis of almost
32,000 patients, found the COX-2 inhibitor celecoxib to actu-
ally lower the risk of serious cardiovascular thrombotic events
(including myocardial infarction) compared with paracetamol
(relative risk, 0.9)although there was considerable scepticism
regarding the absolute validity of the post hoc composite anal-
yses performed by these authors.
NSAIDs and Prostaglandins
Prostaglandins are released as an end point of the intrinsic
inflammatory response. They are synthesized by the degra-
dation of arachidonic acid by the COX enzymes 29 (Fig. 2).
NSAIDs either reversibly or irreversibly block the COX path-
way, thereby inhibiting prostaglandin synthesis19-21,23,29,37. The
COX-modulated prostaglandins E2 (PG-E2) and F2a (PG-F2a)
are both known to promote active bone formation and to in-
crease bone mass25,26,42, largely by stimulating production of
osteoclast-activating factor by osteoblasts. Bone fractures stim-
ulate high local prostaglandin production and release5,24,26,43, with
controlled experimental models having shown that local ad-
ministration of exogenous prostaglandins can induce local bone
formation9,25,44. Collectively, evidence points to a contributory
role for prostaglandins at multiple steps along the fracture-
healing and remodeling pathway.
In addition to its hypothesized involvement in osseous
repair, PG-E2 has also been shown to regulate expression of
bone morphogenetic protein-2 (BMP-2) and BMP-7, suggesting
a potential role in the modulation of basal bone metabolism.
Such theoretical and physiologic evidence appears to indicate an
integral and important role for prostaglandins in bone, and thus
a potentially important effect of NSAIDs on fracture-healing.
However, translation of these lines of evidence into demon-
strable and objective evidence of an effect in the setting of an
acute injury (such as quantification of the impact of exogenously
administered NSAIDs on the reparative process after a fracture)
remains lacking8.
Prostaglandins and Bone
Fracture-healing following mechanical injury is an extremely
complex process dependent on the coordinated recruitment and
action of several cell lineages through a cascade of signal path-
ways and biochemical events24,42. Broadly, a variety of biological
changes follow a fracture, starting with disruption of blood
supply, hematoma formation, local hypoxia, and inflamma-
tion43. The production and activation of pro-inflammatory
factors, especially release of cytokines and growth factors16,45,46,
results in increased production of bone-inductive prostaglan-
dins47. Prostaglandins then play an important role in the regu-
lation of osteoblast and osteoclast functioning14,21,48.
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Presumably owing to upstream effects, either directly on
osteoblast proliferation and aggregative migration40,48 or indi-
rectly via effects on progenitor cells, COX inhibitors have been
found to inhibit prostaglandin production by tissue49, poten-
tially undermining the efficacy of intrinsic fracture-healing
mechanisms23,25,29,49. Most contemporary work, reinforced by
gene knockout studies in animals14, suggests that preferential
COX-2 inhibition impairs fracture-healing to a greater extent
compared with nonspecific COX inhibition21,50, owing to the
direct impact on osteoblastic signal induction21,29,50.
PG-E2 is the most abundant and potent prostaglandin
affecting cells of the osteoblastic lineage. It plays many roles in
bone metabolism5,51, and there is increased focal release of this
compound during the first two weeks of fracture callus for-
mation16,33,52. It has been shown to interact with four distinct
PG-E2 receptor subtypes: EP1R, EP3R, EP2R, and EP4R. EP2R
and EP4R appear to stimulate bone formation and bone re-
sorption, respectively. In animal models, systemic high-dose
administration of PG-E2 has been shown to stimulate new
bone formation, with a subsequent increase in mean bone
mass, whereas low doses triggered an increase in osteoclast
recruitment and activity, leading to bone resorption47. Thus,
prostaglandins clearly play an important role in both phases of
bone activity (formation and resorption)21,49,50, and this con-
clusion is also supported by widespread anecdotal clinical ob-
servations. For example, infants born with congenital heart
disease who are given infusions of prostaglandin E2 to maintain
the life-preserving patency of the ductus arteriosus exhibit
striking new periosteal bone formation42. Conversely, NSAIDs
are routinely administered, with good clinical efficacy, to sup-
press heterotopic ossification in certain specific post-surgical
or post-injury settings8,13, such as following hip arthroplasty14,53,54
or direct injury to peripheral muscle bellies55.
Evidence from Animal Studies
A large volume of research to explore the potential impact of
NSAIDs on fracture-healing has been performed with use of
controlled animal cohorts, including rat7,9,15,47,56-59, mouse14,26,
and rabbit models40,60. The fundamental premise on which this
research relies is the plausible extrapolation of findings in the
animal model to those in human beings. However, this key
tenet is not without flaws. To date, the published literature in
this field has overwhelmingly made use of rodent models.
Acknowledged differences in basal hormonal state, quadrupe-
dal long-bone loading patterns, post-fracture treatment com-
pliance, and comorbidity load between animal and human
subjects would undoubtedly contribute to differences in heal-
ing. However, the extent to which these differences affect the
results remains poorly defined.
A number of animal studies using fracture models suggest
that NSAIDs (both nonselective COX inhibitors and selective
COX-2 inhibitors) adversely affect fracture-healing8,45,61,62. NSAIDs
have been reported to delay primary fracture-healing15,63-65 and to
contribute to an increased nonunion rate. As previously men-
tioned, this is most likely secondary to NSAID-induced inhibition
of osteoblast recruitment and differentiation through effects on
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signal transduction pathways48. Investigations have identified two
important determinants of delayed fracture-healing: timing (i.e.,
administration early in the fracture-healing process) and dose-
dependent effects20,46,56,66.
Timing of Administration
In animal models, treatment during the early stages of fracture
repair reduces mechanical properties of the callus at subse-
quent stages of healing (compared with matched controls) and
increase the prevalence of nonunion46,56. Early administration
of NSAIDs has also been reported to be associated with greater
fracture hematoma volume and with delayed clearance and or-
ganization of the hematoma, most likely as a result of COX-1
inhibition. Early NSAID administration has also been reported
to be associated with decreased formation of mineralized callus
(most likely as a result of COX-2 inhibition)16,63-65, delayed callus
maturation as seen histomorphologically40,62, and inhibited ha-
versian remodeling63-65. Although the noted effects of COX-1 in-
hibition on early fracture hematomas and soft callus organization
seem well supported, the specific effects of COX-2 dysregulation
on the fracture-healing process remain less clear and un-
quantified. Collectively, these changes lead to delays in fracture-
healing or to nonunion59. Biomechanically, dose-dependent
reduction in the restoration of maximal tensile strength, elastic
stiffness, and maximal bending moment at the fracture site after
fracture-healing16 have all been described. In rats treated with
NSAIDs during fracture-healing, bone density appeared to be
reduced19, bone stiffness and strength were reduced19,40 and his-
tological evidence of increased fibrous tissue accumulation was
apparent15,68.
In 2005, Goodman et al. studied the effect of short-term
administration of a COX-2 inhibitor after fracture in a rabbit
model69. Their results indicated that bone ingrowth was not
affected by administration of a COX-2-specific agent within the
first two weeks after fracture. In contrast, other studies have
suggested that COX-2 inhibitors administered early after a
fracture (i.e., <7 days from injury)47,57 or for an extended period
(i.e., for 6 weeks) substantially decreased bone ingrowth and
mineralization40,62. Mechanistically, these studies suggest a greater
influence of COX-2 on impaired fracture-healing, especially the
later stages of hard callus formation56,70. The validity of these
pharmacodynamic studies was reinforced by subsequent con-
trolled gene-based investigations, with purebred COX-22/2 mice
demonstrating apparent deficiencies in intrinsic fracture-healing
capacities14. Complicating matters, however, several other inves-
tigations using various models have failed to convincingly dem-
onstrate a significant effect of NSAIDs on fracture-healing8,42,64,71 in
either simulated trauma or osseous fusion models72.
Class Effects and Dosage Considerations
Although it has long been presumed that appreciable delays
in fracture-healing reflect a class effect of NSAIDs, previous
work has also suggested the existence of agent-specific dispar-
ities. For example, despite both indomethacin and ibuprofen
having been clearly shown in animal models to impair fracture-
healing58,62, reversibility of this effect after drug withdrawal was

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demonstrated in studies using indomethacin62 but was not
replicated in comparable studies using ibuprofen62. This finding
may simply reflect a lack of dose equivalency in the head-to-head
comparison of these two agents21.
The influence of the dose per unit of body weight is more
readily appreciated among individual agents. For example, the
landmark early work of Bo et al. in 1976 suggested inhibition
of osseous repair resulted from administration of >2 mg/kg/day
of indomethacin but not lower dosages16. The premise of a
dose-dependent deleterious effect has been supported by other
studies21. Diclofenac40,59, celecoxib25,56,, rofecoxib56,60, parecoxib7,57,
ketorolac7, tenoxicam73, and etodolac47,73 have also been shown to
delay fracture-healing or to result in suboptimal mechanical
properties in separate animal studies using high-dosage regimes.
However, a number of reasonably comparable investigations have
either failed to demonstrate any deleterious effects on fracture-
healing or have reported only nonsignificant suppression9,26,57.
The relatively small cohorts employed in many of the
reported animal studies and methodological disparities among
the studies must be acknowledged and make sound meta-
analyses unreliable. However, the strong collective trend to-
ward demonstration of significant suppression of bone repair
after controlled injury, as well as corresponding differences in
histology, prostaglandin levels, and expression of genes in-
volved in fracture-healing compared with control populations,
add credible weight to the suggestion that COX-2 suppression
may negatively influence fracture-healingin small-animal
models.
Evidence from Human Studies
For many years, NSAIDs have formed a nearly essential part of
the multifaceted approach to pain control in orthopaedics,
both after a traumatic fracture and postoperatively14,21,46,50. By
inhibiting the formation of PG-E2, NSAIDs dampen the in-
trinsic local inflammatory response and also function to de-
sensitize peripheral pain receptors18. Although an increasingly
robust body of evidence supports the role of COX-2 inhibition
in suppressing fracture-healing in animal studies, current evi-
dence of a comparable effect in human subjects is less clear42.
Thus, in many clinical spheres, the opinion regarding use of
NSAIDs following a fracture remains divided, and routine
prescription of NSAIDs in this setting has been termed
controversial74,75. Widely disparate clinical reports exist, and
many of the published findings are unhelpfully inconclusive20.
Previous researchers have recommended cautious use of
NSAIDs after an osseous injury48 but have often failed to pro-
vide convincing data to support this recommendation. Several
studies of long-bone fractures have indicated an increased
prevalence of nonunion in patients treated with NSAIDs76, but
these studies have largely constituted uncontrolled retrospec-
tive analyses74. Whether these results reflect an incidental as-
sociation or true causality is unclear. Previous work has suggested
an association between NSAID use and delayed healing of long-
bone77,78, spinal59,79, and stress fractures44. Much research has also
focused on nonunion following vertebral fusion79, but interpre-
tation of the resulting findings is complicated by questions re-
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garding how well findings in the axial skeleton can be extrapolated
to the appendicular skeleton.
Recent evidence suggests that NSAID administration
within 90 days of injury in an older population12 is significantly
associated with nonunion (relative risk, 3.7; 95% confidence
interval, 2.4 to 5.6)80 and that long-duration oral administra-
tion reduces local bone formation by up to 58% (p < 0.05)81.
However, the validity of retrospective observational studies
suggesting an increased prevalence of long-bone nonunion
after long-term NSAID use has been broadly called into
question82. In 2003, Aspenberg82 raised an important point:
given the remarkable efficacy with which the human body in-
trinsically handles osseous repair, the patients who are most
likely to have required long-duration NSAID therapy after
injury are those with additional barriers to the normal healing
process, such as comorbid load, a high-energy mechanism
of injury, or biomechanical instability at the fracture site.
Aspenberg tendered the viewpoint that such medications were
frequently administered because of analgesia demands associ-
ated with an evolving nonunion rather than being the attrib-
utable cause82. Also, some studies have reported the prevalence
of delayed union and nonunion following long-bone fracture
to be as high as 10% even in the absence of NSAID use, sug-
gesting that many of the reports of a high prevalence of delayed
healing after NSAID use may actually be consistent with such a
baseline frequency of occurrence56.
There are no large, prospective randomized studies that
have explored the effect of short-term and long-term NSAID
use on fracture-repair. However, other studies revealed that the
short-term administration of celecoxib, rofecoxib, or low-dose
ketorolac had no significant deleterious effect on the prevalence
of nonunion79. Collectively, these data appear to support the
safety of a short course of NSAID administration, even in the
immediate post-injury period. It should be made clear, how-
ever, that no clear consensus exists regarding the true safe
interval and duration during which such therapy can be con-
fidently applied12. Also, no clear data exist to appraise long-
duration use.
Discussion
T he role of prostaglandins in basal bone turnover is com-
plex, with previous research having demonstrated their
association with the regulation of most facets of bone growth
and remodeling20,44,51,83. The critical importance of these in-
ductive messengers during the acute post-fracture setting
cannot be overstated. Transcription-level analyses have shown
COX-2 messenger RNA and downstream prostaglandin levels
to be elevated locally after a fracture24, with peaks observed
during the first fourteen days followed by a return to near the
basal expression level at approximately twenty-one days and
complete normalization by forty-two days52. These results
suggest that COX-2 is important in early, or activated, stages of
healing but likely exhibits little effect on the long-term healing
process52.
The ability of exogenous NSAIDs to influence intrinsic
prostaglandin activity is clear and undisputed. However, the
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degree to which such pathway modulation interferes with the
acute phase of fracture-healing in human beings remains
highly controversial. Robust evidence from preclinical labora-
tory investigations and animal studies does demonstrate that
NSAIDs can adversely disrupt fracture-healing10,56,62 at various
discrete stages of the healing and remodeling process, but this
link has not been definitively proven or disproven in human
subjects10,21,45,63.
The authors acknowledge several limitations to the cur-
rent review. Although retrospective literature reviews provide a
synoptic appraisal of the available evidence, they are rarely all-
encompassing and are not entirely without bias. We have at-
tempted to use a structured search to identify the available body
of evidence on this topic and, through a subjective evaluation
that takes into account the limitations of publication, to in-
clude those articles deemed most relevant to the discussion
presented. We acknowledge that this process inevitably leads to
some degree of potential selection bias and to the omission of
some previous works that others may deem relevant for
mention. Although it is well recognized that electronic database
searches may fail to identify a number of works from non-
indexed sources, and the inherent time lag prior to publication
(of both our own work and the works being reviewed) un-
dermines the contemporary standing of the work, we offer that
our review represents the most up-to-date appraisal at the time
of submission.
Most notably, a broad appraisal of the topic area indicates
that large-scale, robust clinical evidence in human subjects
does not exist at this time32, and the extrapolation of experi-
mental animal data to humans is subject to inherent limita-
tions50,62. Suitable clinical trials would likely prove difficult to
undertake because of the need for large, controlled patient
cohorts to detect subtle differences in outcome. Furthermore,
no clear, highly sensitive, and objective means for quantifying
fracture-healing exist in the routine (non-research) clinical
setting, and many other factors are already recognized to in-
fluence the rate of healingincluding smoking status, micro-
vascular disease burden, diabetic status, the amount of energy
transfer at the time of the trauma, and the basal health and
nutritional state75,76. Many of these commonly exist concur-
rently in fracture patients, and separating the influences of
References
1. Gerner P, OConnor JP. Impact of analgesia on bone fracture healing. Anesthe-
siology. 2008;108:349-50.
2. Brown JC, Klein EJ, Lewis CW, Johnston BD, Cummings P. Emergency department
analgesia for fracture pain. Ann Emerg Med. 2003;42:197-205.
3. Kolesnikov YA, Jain S, Wilson R, Pasternak GW. Peripheral morphine analgesia:
synergy with central sites and a target of morphine tolerance. J Pharmacol Exp Ther.
1996;279:502-6.
4. Dorn U, Grethen C, Effenberger H, Berka H, Ramsauer T, Drekonja T.
Indomethacin for prevention of heterotopic ossification after hip arthroplasty.
A randomized comparison between 4 and 8 days of treatment. Acta Orthop
Scand. 1998;69:107-10.
5. Abdul-Hadi O, Parvizi J, Austin MS, Viscusi E, Einhorn T. Nonsteroidal anti-
inflammatory drugs in orthopaedics. J Bone Joint Surg Am. 2009;91:2020-7.
6. Murnaghan JM, Marsh DR. NSAID use following skeletal trauma. Br J Gen Prac.
2003;53:407-8.
E F F E C T O F N O N S T E R O I D A L A N T I - I N F L A M M AT O RY D R U G
A D M I N I S T R AT I O N O N A C U T E P H A S E F R A C T U R E -H E A L I N G
individual factors would likely require complex multivariate
analyses.
In summary, although increasing evidence suggests a
detrimental role of COX-2 inhibition in suppressing early
fracture repair in animal studies, translation of these concerns
to demonstrable and convincing effects in human subjects re-
mains lacking. At present, although theoretical concerns about
the adverse effects of NSAIDs on fracture-healing exist, there is
not enough clinical evidence to deny patients with simple frac-
tures the analgesic benefits of these compounds. Given the sys-
temic action of NSAIDs, several previous authors have also
recommended avoiding their use in high-risk patient groups
with clear preexisting risk factors for poor osseous repair and
low blood flow to the fracture site. Although this premise re-
mains fundamentally sound, at present there is no defensible
evidence to support such sentiments.
Long-term NSAID use after a fracture and NSAID use in
instances of demonstrated or evolving nonunion fall outside
the scope of the current review and cannot, therefore, be ac-
tively supported or discouraged on the basis of the information
presented herein. n
Andrew P. Kurmis, BMBS, PhD
Department of Orthopaedics, Repatriation General Hospital,
Daws Road, Daw Park 5041, South Australia, Australia.
E-mail address: Andrew.Kurmis2@health.sa.gov.au
Timothy P. Kurmis, BMBS
Department of Medical Imaging,
Flinders Medical Centre, Flinders Drive,
Bedford Park 5042, South Australia, Australia
Justin X. OBrien, BMBS
Taylor Laboratory, Department of Anatomy and Cell Biology,
University of Melbourne, Grattan Street,
Parkville 3052, Victoria, Australia
Tore Dalen, MD, PhD
Department of Orthopaedics, Ume University Hospital,
S-901 85 Ume, Sweden
7. Gerstenfeld LC, Thiede M, Seibert K, Mielke C, Phippard D, Svagr B, Cullinane
D, Einhorn TA. Differential inhibition of fracture healing by non-selective and
cyclooxygenase-2 selective non-steroidal anti-inflammatory drugs. J Orthop Res.
2003;21:670-5.
8. Beck A, Salem K, Krischak G, Kinzl L, Bischoff M, Schmelz A. Nonsteroidal
anti-inflammatory drugs (NSAIDs) in the perioperative phase in traumatology
and orthopedics effects on bone healing. Oper Orthop Traumatol. 2005;17:
569-78.
9. Akman S, Gogus A, Sener N, Bilgicx B, Aksoy B, Seckin F. Effect of diclofenac
sodium on union of tibial fractures in rats. Adv Ther. 2002;19:119-25.
10. Koester MC, Spindler KP. Pharmacologic agents in fracture healing. Clin Sports
Med. 2006;25:63-73, viii.
11. Meunier A, Lisander B, Good L. Effects of celecoxib on blood loss, pain, and
recovery of function after total knee replacement: a randomized placebo-controlled
trial. Acta Orthop. 2007;78:661-7.
 822
TH E JO U R NA L O F B O N E & JO I N T SU RG E RY J B J S . O RG
d
V O LU M E 94 -A N U M B E R 9 M AY 2, 2 012
d d
12. Busti AJ, Hooper JS, Amaya CJ, Kazi S. Effects of perioperative antiinflammatory
and immunomodulating therapy on surgical wound healing. Pharmacotherapy.
2005;25:1566-91.
13. Dahners LE, Mullis BH. Effects of nonsteroidal anti-inflammatory drugs on bone
formation and soft-tissue healing. J Am Acad Orthop Surg. 2004;12:139-43.
14. Vuolteenaho K, Moilanen T, Moilanen E. Non-steroidal anti-inflammatory drugs,
cyclooxygenase-2 and the bone healing process. Basic Clin Pharmacol Toxicol.
2008;102:10-4.
15. Brown KM, Saunders MM, Kirsch T, Donahue HJ, Reid JS. Effect of COX-2-
specific inhibition on fracture-healing in the rat femur. J Bone Joint Surg Am.
2004;86:116-23.
16. Bo J, Sudmann E, Marton PF. Effect of indomethacin on fracture healing in rats.
Acta Orthop Scand. 1976;47:588-99.
17. Sudmann E, Hagen T. Indomethacin-induced delayed fracture healing. Arch
Orthop Unfallchir. 1976;85:151-4.
18. Solomon DH. UpToDate. NSAIDs: mechanism of action. http://www.uptodate.
com/patients/content/topic.do?topicKey=;_oo70Z29uZf9D. Accessed 2010
Sep 24.
19. Vane JR. Inhibition of prostaglandin synthesis as a mechanism of action for
aspirin-like drugs. Nat New Biol. 1971;231:232-5.
20. Einhorn TA. Cox-2: Where are we in 2003? The role of cyclooxygenase-2 in bone
repair. Arthritis Res Ther. 2003;5:5-7.
21. Gerstenfeld LC, Einhorn TA. COX inhibitors and their effects on bone healing.
Expert Opin Drug Saf. 2004;3:131-6.
22. Clarke S, Lecky F. Best evidence topic report. Do non-steroidal anti-inflammatory
drugs cause a delay in fracture healing? Emerg Med J. 2005;22:652-3.
23. Krischak GD, Augat P, Blakytny R, Claes L, Kinzl L, Beck A. The non-steroidal
anti-inflammatory drug diclofenac reduces appearance of osteoblasts in bone defect
healing in rats. Arch Orthop Trauma Surg. 2007;127:453-8.
24. Gerstenfeld LC, Thiede M, Seibert K, Mielke C, Phippard D, Svagr B, Cullinane D,
Einhorn TA. Differential inhibition of fracture healing by non-selective and
cyclooxygenase-2 selective non-steroidal anti-inflammatory drugs. J Orthop Res.
2003;21:670-5.
25. Bergenstock M, Min W, Simon AM, Sabatino C, OConnor JP. A comparison
between the effects of acetaminophen and celecoxib on bone fracture healing in
rats. J Orthop Trauma. 2005;19:717-23.
26. Mullis BH, Copland ST, Weinhold PS, Miclau T, Lester GE, Bos GD. Effect of
COX-2 inhibitors and non-steroidal anti-inflammatory drugs on a mouse fracture
model. Injury. 2006;37:827-37.
27. Berenbaum F. COX-3: fact or fancy? Joint Bone Spine. 2004;71:451-3.
28. Raisz LG. Potential impact of selective cyclooxygenase-2 inhibitors on bone
metabolism in health and disease. Am J Med. 2001;110 Suppl. 3A:43S-5S.
29. Nwadinigwe CU, Anyaehie UE. Effects of cyclooxygenase inhibitors on bone and
cartilage metabolisma review. Niger J Med. 2007;16:290-4.
30. Caldwell B, Aldington S, Weatherall M, Shirtcliffe P, Beasley R. Risk of cardio-
vascular events and celecoxib: a systematic review and meta-analysis. J R Soc Med.
2006;99:132-40.
31. Darling RL, Romero JJ, Dial EJ, Akunda JK, Langenbach R, Lichtenberger LM.
The effects of aspirin on gastric mucosal integrity, surface hydrophobicity, and
prostaglandin metabolism in cyclooxygenase knockout mice. Gastroenterology.
2004;127:94-104.
32. Williams A. Should non-steroidal anti-inflammatory drugs be given to ortho-
paedic patients with fractures? Br J Hosp Med (Lond). 2007;68:452.
33. Simon AM, Manigrasso MB, OConnor JP. Cyclo-oxygenase 2 function is es-
sential for bone fracture healing. J Bone Miner Res. 2002;17:963-76.
34. Zhang X, Schwarz EM, Young DA, Puzas JE, Rosier RN, OKeefe RJ.
Cyclooxygenase-2 regulates mesenchymal cell differentiation into the osteo-
blast lineage and is critically involved in bone repair. J Clin Invest. 2002;109:
1405-15.
35. Tu Q, Zhang J, James L, Dickson J, Tang J, Yang P, Chen J. Cbfa1/Runx2-
deficiency delays bone wound healing and locally delivered Cbfa1/Runx2 promotes
bone repair in animal models. Wound Repair Regen. 2007;15:404-12.
36. Baek WY, Lee MA, Jung JW, Kim SY, Akiyama H, de Crombrugghe B, Kim JE.
Positive regulation of adult bone formation by osteoblast-specific transcription factor
osterix. J Bone Miner Res. 2009;24:1055-65.
37. Bombardier C, Laine L, Reicin A, Shapiro D, Burgos-Vargas R, Davis B, Day R,
Ferraz MB, Hawkey CJ, Hochberg MC, Kvien TK, Schnitzer TJ; VIGOR Study Group.
Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients
with rheumatoid arthritis. VIGOR Study Group. N Engl J Med. 2000;343:1520-8.
38. Bresalier RS, Sandler RS, Quan H, Bolognese JA, Oxenius B, Horgan K, Lines C,
Riddell R, Morton D, Lanas A, Konstam MA, Baron JA; Adenomatous Polyp Prevention
on Vioxx (APPROVe) Trial Investigators. Cardiovascular events associated with ro-
fecoxib in a colorectal adenoma chemoprevention trial. N Engl J Med. 2005;352:
1092-102.
39. Thompson CA. MI risk prompts rofecoxib withdrawal. Am J Health Syst Pharm.
2004;61:2234-6, 2238.
E F F E C T O F N O N S T E R O I D A L A N T I - I N F L A M M AT O RY D R U G
A D M I N I S T R AT I O N O N A C U T E P H A S E F R A C T U R E -H E A L I N G
40. Krischak GD, Augat P, Sorg T, Blakytny R, Kinzl L, Claes L, Beck A. Effects of
diclofenac on periosteal callus maturation in osteotomy healing in an animal model.
Arch Orthop Trauma Surg. 2007;127:3-9.
41. White WB, Faich G, Borer JS, Makuch RW. Cardiovascular thrombotic events in
arthritis trials of the cyclooxygenase-2 inhibitor celecoxib. Am J Cardiol. 2003;92:411-8.
42. Pountos I, Georgouli T, Blokhuis TJ, Pape HC, Giannoudis PV. Pharmacological
agents and impairment of fracture healing: what is the evidence? Injury.
2008;39:384-94.
43. Huo MH, Troiano NW, Pelker RR, Gundberg CM, Friedlaender GE. The influence
of ibuprofen on fracture repair: biomechanical, biochemical, histologic, and histo-
morphometric parameters in rats. J Orthop Res. 1991;9:383-90.
44. Li J, Waugh LJ, Hui SL, Burr DB, Warden SJ. Low-intensity pulsed ultrasound and
nonsteroidal anti-inflammatory drugs have opposing effects during stress fracture
repair. J Orthop Res. 2007;25:1559-67.
45. Seidenberg AB, An YH. Is there an inhibitory effect of COX-2 inhibitors on bone
healing? Pharmacol Res. 2004;50:151-6.
46. Simon AM, OConnor JP. Dose and time-dependent effects of cyclooxygenase-2
inhibition on fracture-healing. J Bone Joint Surg Am. 2007;89:500-11.
47. Endo K, Sairyo K, Komatsubara S, Sasa T, Egawa H, Ogawa T, Yonekura D,
Murakami R, Yasui N. Cyclooxygenase-2 inhibitor delays fracture healing in rats. Acta
Orthop. 2005;76:470-4.
48. Kellinsalmi M, Parikka V, Risteli J, Hentunen T, Leskela HV, Lehtonen S,
Selander K, Vaa nanen K, Lehenkari P. Inhibition of cyclooxygenase-2 down-regulates
osteoclast and osteoblast differentiation and favours adipocyte formation in vitro.
Eur J Pharmacol. 2007;572:102-10.
49. H W1odarski K, Galus R. Histological aspects of bone fracture healing. Ortop
Traumatol Rehabil. 2005;7:351-60.
50. Radi ZA, Khan NK. Effects of cyclooxygenase inhibition on bone, tendon, and
ligament healing. Inflamm Res. 2005;54:358-66.
51. Bhandari M, Schemitsch EH. Bone formation following intramedullary femoral
reaming is decreased by indomethacin and antibodies to insulin-like growth factors.
J Orthop Trauma. 2002;16:717-22.
52. Sudmann E, Dregelid E, Bessesen A, Mrland J. Inhibition of fracture healing by
indomethacin in rats. Eur J Clin Invest. 1979;9:333-9.
53. Nilsson OS. Heterotopic ossification. Acta Orthop Scand. 1998;69:103-6.
54. Fijn R, Koorevaar RT, Brouwers JR. Prevention of heterotopic ossification after
total hip replacement with NSAIDs. Pharm World Sci. 2003;25:138-45.
55. Jones P, Lamdin R. Oral cyclo-oxygenase 2 inhibitors versus other oral anal-
gesics for acute soft tissue injury: systematic review and meta-analysis. Clin Drug
Investig. 2010;30:419-37.
56. Murnaghan M, Li G, Marsh DR. Nonsteroidal anti-inflammatory drug-induced
fracture nonunion: an inhibition of angiogenesis? J Bone Joint Surg Am. 2006;88
Suppl. 3:140-7.
57. Dimmen S, Nordsletten L, Engebretsen L, Steen H, Madsen JE. Negative effect
of parecoxib on bone mineral during fracture healing in rats. Acta Orthop.
2008;79:438-44.
58. Engesaeter LB, Sudmann B, Sudmann E. Fracture healing in rats inhibited by
locally administered indomethacin. Acta Orthop Scand. 1992;63:330-3.
59. Beck A, Krischak G, Sorg T, Augat P, Farker K, Merkel U, Kinzl L, Claes L.
Influence of diclofenac (group of nonsteroidal anti-inflammatory drugs) on fracture
healing. Arch Orthop Trauma Surg. 2003;123:327-32.
60. Goodman S, Ma T, Trindade M, Ikenoue T, Matsuura I, Wong N, Fox N, Genovese
M, Regula D, Smith RL. COX-2 selective NSAID decreases bone ingrowth in vivo.
J Orthop Res. 2002;20:1164-9.
61. Goodman SB, Ma T, Genovese M, Lane Smith R. COX-2 selective inhibitors and
bone. Int J Immunopathol Pharmacol. 2003;16:201-5.
62. Altman RD, Latta LL, Keer R, Renfree K, Hornicek FJ, Banovac K. Effect of
nonsteroidal antiinflammatory drugs on fracture healing: a laboratory study in rats.
J Orthop Trauma. 1995;9:392-400.
63. Wheeler P, Batt ME. Do non-steroidal anti-inflammatory drugs adversely affect
stress fracture healing? A short review. Br J Sports Med. 2005;39:65-9.
64. Reikeraas O, Engebretsen L. Effects of ketoralac tromethamine and indo-
methacin on primary and secondary bone healing. An experimental study in rats. Arch
Orthop Trauma Surg. 1998;118:50-2.
65. Sudmann E, Bang G. Indomethacin-induced inhibition of haversian remodelling
in rabbits. Acta Orthop Scand. 1979;50(6 Pt 1):621-7.
66. Giordano V, Giordano M, Knackfuss IG, Apfel MI, Gomes RD. Effect of tenoxicam
on fracture healing in rat tibiae. Injury. 2003;34:85-94.
67. Langford RM, Mehta V. Selective cyclooxygenase inhibition: its role in pain and
anaesthesia. Biomed Pharmacother. 2006;60:323-8.
68. Leonelli SM, Goldberg BA, Safanda J, Bagwe MR, Sethuratnam S, King SJ.
Effects of a cyclooxygenase-2 inhibitor (rofecoxib) on bone healing. Am J Orthop
(Belle Mead NJ). 2006;35:79-84.
69. Goodman SB, Ma T, Mitsunaga L, Miyanishi K, Genovese MC, Smith RL.
Temporal effects of a COX-2-selective NSAID on bone in growth. J Biomed Mater
Res A. 2005;72:279-87.
 823
TH E JO U R NA L O F B O N E & JO I N T SU RG E RY J B J S . O RG
d
V O LU M E 94 -A N U M B E R 9 M AY 2, 2 012
d d
70. Gurgel BC, Ribeiro FV, Silva MA, Nociti FH Jr, Sallum AW, Sallum EA, Toledo S,
Casati MZ. Selective COX-2 inhibitor reduces bone healing in bone defects. Braz Oral
Res. 2005;19:312-6.
71. Karachalios T, Boursinos L, Poultsides L, Khaldi L, Malizos KN. The effects of the
short-term administration of low therapeutic doses of anti-COX-2 agents on the healing
of fractures. An experimental study in rabbits. J Bone Joint Surg Br. 2007;89:1253-60.
72. Long J, Lewis S, Kuklo T, Zhu Y, Riew KD. The effect of cyclooxygenase-2
inhibitors on spinal fusion. J Bone Joint Surg Am. 2002;84:1763-8.
73. Endo K, Sairyo K, Komatsubara S, Sasa T, Egawa H, Yonekura D, Adachi K,
Ogawa T, Murakami R, Yasui N. Cyclooxygenase-2 inhibitor inhibits the fracture
healing. J Physiol Anthropol Appl Human Sci. 2002;21:235-8.
74. Giannoudis PV, MacDonald DA, Matthews SJ, Smith RM, Furlong AJ, De Boer P.
Nonunion of the femoral diaphysis. The influence of reaming and non-steroidal anti-
inflammatory drugs. J Bone Joint Surg Br. 2000;82:655-8.
75. Gaston MS, Simpson AH. Inhibition of fracture healing. J Bone Joint Surg Br.
2007;89:1553-60.
76. Bandolier Extra. NSAIDs, coxibs, smoking and bone. 2004 Mar. http://
www.medicine.ox.ac.uk/bandolier/booth/painpag/wisdom/NSB.pdf. Accessed
2010 Sep 24.
E F F E C T O F N O N S T E R O I D A L A N T I - I N F L A M M AT O RY D R U G
A D M I N I S T R AT I O N O N A C U T E P H A S E F R A C T U R E -H E A L I N G
77. Burd TA, Hughes MS, Anglen JO. Heterotopic ossification prophylaxis with
indomethacin increases the risk of long-bone nonunion. J Bone Joint Surg Br.
2003;85:700-5.
78. Banovac K, Renfree K, Makowski AL, Latta LL, Altman RD. Fracture healing and
mast cells. J Orthop Trauma. 1995;9:482-90.
79. Reuben SS, Ablett D, Kaye R. High dose nonsteroidal anti-inflammatory drugs
compromise spinal fusion. Can J Anaesth. 2005;52:506-12.
80. Bhattacharyya T, Levin R, Vrahas MS, Solomon DH. Nonsteroidal antiinflam-
matory drugs and nonunion of humeral shaft fractures. Arthritis Rheum. 2005;
53:364-7.
81. Ma T, Nelson ER, Mawatari T, Oh KJ, Larsen DM, Smith RL, Goodman SB.
Effects of local infusion of OP-1 on particle-induced and NSAID-induced inhibition of
bone ingrowth in vivo. J Biomed Mater Res A. 2006;79:740-6.
82. Aspenberg P. COX inhibitors and bone healing. Acta Orthop Scand. 2003;74:
230-1.
83. Gerstenfeld LC, Al-Ghawas M, Alkhiary YM, Cullinane DM, Krall EA, Fitch JL,
Webb EG, Thiede MA, Einhorn TA. Selective and nonselective cyclooxygenase-2
inhibitors and experimental fracture-healing. Reversibility of effects after short-term
treatment. J Bone Joint Surg Am. 2007;89:114-25.