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RELATIONSHIP BETWEEN NONSTEROIDAL

ANTI-INFLAMMATORY DRUGS AND


BONE-HEALING AFTER FRACTURE OR
ORTHOPAEDIC SURGERY
Teresa Bigler, DHEd, PA-C Abstract
Inflammation is a complex physiologic response with various theoretical
Emily Weidman-Evans,
effects on the bone-healing process. Retrospective studies show conflicting
PharmD results: some cases demonstrate that prolonged use of nonsteroidal anti-
Daniel Flowers, DPT inflammatory drugs (NSAIDs) leads to healing complications, while others
negate this finding. Prospective studies have shown that NSAIDs offer
quality pain control and possibly show no deleterious effects with early,
short-term use. While some data are concerning regarding NSAID use during
bone-healing, it is difficult to draw conclusions regarding predictive factors.
Based on current studies, NSAIDs should be limited to short-term use.

I
nflammation plays an important subject headings (MeSH) “NSAIDs,”
role in the bone-healing process. “fracture,” and “bone.” Studies written in
Initially, inflammation promotes the English language from January 1960 to
vasodilation that allows necessary October 2016 were considered for this
mediators to reach the site of injury and review article. Fifty clinical trials in humans
begin healing. Inflammatory mediators were performed during that time that met
initiate angiogenesis, which is necessary these criteria. All search results were
to begin bone repair. They also recruit the reviewed, as well as the reference lists of
cells that proliferate into osteoblasts, recent meta-analyses and review articles,
which will lay new healthy bone1,2. and we determined the relevance of each
Interruption of the inflammatory study. Studies involving pediatric patients
process, even for the sake of effective pain were excluded because of differences in the
control, is controversial. This has led some healing process; less inflammation is
authors to question the risk-to-benefit involved in the process in younger
ratio of utilizing nonsteroidal anti- children3. We also excluded studies for
inflammatory drugs (NSAIDs) as first- which the outcomes did not include those
line pain management. The purpose of related specifically to bone-healing or
this review is to describe the relationship fracture-healing, such as pain control or
between bone-healing and inflammation, heterotopic ossification. In total, 14 studies
and to review the available clinical that included only adult subjects who had
literature in order to allow readers to draw received at least 1 dose of an NSAID
a clinical conclusion regarding the safety following either a fracture or orthopaedic
of these medications in patients after a procedure were identified, and bone-
fracture or an orthopaedic procedure. healing outcomes were included (Table I).

Data Search Bone-Healing and Inflammation


An electronic literature search was Bone-healing occurs over 3 phases:
conducted in PubMed using the medical inflammation, repair, and remodeling1.

Disclosure: The authors indicated that no external funding was received for any aspect of this work. The
COPYRIGHT © 2018 BY THE
JOURNAL OF BONE AND JOINT Disclosure of Potential Conflicts of Interest forms are provided with the online version of the article
SURGERY, INCORPORATED (http://links.lww.com/JBJSJOPA/A35).

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| Relationship Between NSAIDs and Bone-Healing After Fracture or Orthopaedic Surgery

TABLE I Study Characteristics and Results


NSAID(s) Used,
Dose, and Follow-up
Study Study Design No. of Subjects Study Outcome Type of Healing Duration Duration Results

Adolphson et al. Randomized 42 (21 exposed Changes in bone Secondary Piroxicam, 20 12 wk No difference in
(1993)13 controlled trial to piroxicam) mineral content, (reduction and mg/day 3 8 wk bone mineral
radial shortening, immobilization content changes,
and dorsal with splint) radial shortening,
angulation after or dorsal angulation
Colles fracture between piroxicam
and placebo
groups
Bhandari et al. Retrospective 192 (44 Time to Both Not specified 12 mo NSAIDs are not a
(2003)14 cohort exposed reoperation after (intramedullary (minimum) predictor of
to NSAIDs) tibial fracture nail, plate, or reoperation after
external multivariate analysis
fixator) controlling for
factors such as
mechanism of
injury, type of
fracture/injury,
antibiotic use,
postoperative
complication, or
type of fixation
Bhattacharyya Retrospective 9,995 (1,032 Humeral shaft Secondary Not specified Up to 365 Use of NSAIDs
et al. (2005)15 cohort exposed to fracture days within 90 days
NSAIDs) nonunions after fracture
increases risk of
nonunion (relative
risk, 3.7 [95% CI,
2.4-5.6]); most
noteworthy at
61-90 days
postfracture
Burd et al. Retrospective 282 (38 Nonunions Primary Indomethacin, Not specified 11 (28.9%) of 38
(2003)16 cohort exposed to occurring in (reduction and 25 mg 33/day 3 (5.3 mo mean patients receiving
indomethacin) patients who internal 6 wk time to indomethacin had a
had concurrent fixation) diagnosis of nonunion (p 5
acetabular and nonunion) 0.004)
long-bone
fractures
Davis and Randomized 98 (50 exposed Functional Secondary Flurbiprofen, 1 yr No cases of
Ackroyd controlled trial to NSAIDs) recovery and 150-300 mg nonunion or
(1988)17 malunion after daily 3 14 days malunion in either
Colles fracture the placebo or
flurbiprofen group
Deguchi et al. Retrospective 73 (27 exposed Fusion rates Primary Not specified 3.8 yr (mean) Those who took
(1998)18 cohort to NSAIDs for (posterior (.3 mo in NSAIDs for 3 mo
3 months after fusion subgroup after surgery had a
surgery) procedure) exposed 55.6% nonfusion
to NSAIDs) rate compared with
a 2.2% rate in those
not taking NSAIDs
(p , 0.001)
Donohue et al. Retrospective 313 (80 Nonunion and Secondary Ketorolac, 1 yr No significant
(2016)24 case-control exposed time to union (rod fixation) 15-30 mg difference in
to ketorolac) intramuscularly nonunion between
every 6 hr 3 those who received
24 hr ketorolac and those
who did not
Giannoudis et al. Retrospective 99 (29 exposed Nonunion after Secondary Not specified Not specified 20 (62.5%) of 32
(2000)19 case-control to NSAIDs) femoral fracture (locked (11.5 mo nonunions had
intramedullary mean time to been exposed to
nailing) diagnosis) NSAIDs (OR, 10.74
[95% CI, 3.55-33.23];
p , 0.001)

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Relationship Between NSAIDs and Bone-Healing After Fracture or Orthopaedic Surgery |

TABLE I (continued)
NSAID(s) Used,
Dose, and Follow-up
Study Study Design No. of Subjects Study Outcome Type of Healing Duration Duration Results

Glassman et al. Retrospective 288 (167 Nonunion after Primary Ketorolac, 60 mg 2-yr minimum 29 (17.4%) of 167
(1998)20 cohort exposed instrumented (pedicle screw- loading dose who received
to NSAIDs) posterior spinal rod constructs) intramuscularly, ketorolac
fusion then 30 mg every developed
6-8 hr as needed nonunion,
(mean no. of compared with 5
doses 5 10) (4.1%) of 121 who
were not exposed
but developed a
nonunion (OR, 4.9
[95% CI, 1.8-16.6];
p , 0.001).
Jeffcoach et al. Retrospective 1,901 (231 Nonunion, Treatment 92.7% of subjects Not specified 17 (7.4%) of 231 who
(2014)25 cohort exposed malunion, and procedure not received either received NSAIDs
to NSAIDs) infection after specified ketorolac (60 mg) experienced a
long-bone or ibuprofen complication
fracture (600 mg) (mean (nonunion,
number of malunion, and/or
doses 5 2 for infection) (OR, 2.17
each, and all [95% CI, 1.15-4.10];
doses p 5 0.016); these all
administered occurred in subjects
with 24-48 hr of receiving either
admission/ ketorolac or
operation) ibuprofen
Lumawig et al. Retrospective 273 (254 Fusion rates and Primary Diclofenac Up to 2 yr All 4 nonunions and
(2009)21 cohort exposed to diclofenac intake (posterior 25-300 mg 25 (61.0%) of 41
NSAIDs) lumbar daily or delayed unions that
interbody .300 mg daily, occurred did so in
fusion 3 14 days those taking high-
procedure) dose diclofenac (p ,
0.001); time to union
correlated to the
amount of
diclofenac sodium
intake (r 5 0.271;
p , 0.001)
Park et al. Retrospective 88 (30 exposed Incomplete and Primary Ketorolac 120 mg At least 1 yr 5 (16.7%) of 30 who
(2005)22 cohort to NSAIDs) nonunion after (pedicle screws over 3 days via received ketorolac
posterolateral and rod patient- had an incomplete
spinal fusion system) controlled or nonunion,
analgesia compared with 2
(3.4%) of 58 who did
not receive
ketorolac (p , 0.05;
OR, 5.64; no CI
reported).
Pradhan et al. Retrospective 405 (228 Nonunion after Primary (screw Ketorolac 30 mg 24-mo No significant
(2008)23 cohort exposed to primary lumbar fixation) intravenously minimum difference in
NSAIDs) posterolateral every 6 hr 3 nonfusion between
intertransverse 48 hours (total those who received
process fusion 240 mg) ketorolac and those
who did not
Sagi et al. Randomized 98 (72 Nonunion of Primary Indomethacin 1 yr 8 (62%) of 13 in
(2014)26 controlled trial exposed to acetabular (reduction and 75 mg 3 3 indomethacin 6-wk
indomethacin) fractures; also fixation days, 7 days, grouphadanonunion
rates of through or 6 wk compared with 4
heterotopic posterior (19%) of 21 in the
ossification approach) placebo group (p 5
0.012); no increase in
risk in those in the
3-day and 7-day
indomethacin groups

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| Relationship Between NSAIDs and Bone-Healing After Fracture or Orthopaedic Surgery

Within these 3 phases, bone-healing inflammatory response with


progresses along 2 continua: primary hematoma formation; however, after
and secondary. Primary bone-healing this point, they progress along 2
occurs when the fracture is reduced separate paths. In primary healing, the
(i.e., placing bone ends and any relative lack of movement results in
fragments back into the anatomic intramembranous bone formation
position) and then directly fixated by and vascularization1. This process is
artificial means in order to keep the slower than secondary bone-healing
bone ends congruent with minimal and is not associated with a major
movement1,4,5. An example of this influx of inflammatory cells.
would be open reduction and internal Secondary healing is more
fixation with compression plates and dependent on inflammatory processes
screws1 (Fig. 1). Secondary bone- because it requires the deposit of
healing, where the fracture is reduced granulation and callus tissue1. A soft
and indirectly fixated via callus consisting mostly of
immobilization in order to prevent cartilaginous and granulation tissue
displacement, allows some movement forms due to micromotion at the
to occur at the fracture site1,4,5. This fracture site and inflammation. Once
motion at the fracture site, which the callus edges meet, angiogenesis Fig. 2
occurs as a result of the approximated begins. The increased blood supply to A radiograph demonstrating secondary
bone ends not being overcompressed, the soft callus transforms cartilaginous bone-healing, which is more dependent
will lead to differences in healing. “bracing” into definitive structure, on the inflammatory process.
Secondary bone-healing includes the which matures into a hard “bony”
use of casts, external fixation, and callus. Mesenchymal stem cells Clinical Effects of NSAIDs on Bone-
intramedullary nailing1 (Fig. 2). (MSCs), also recruited by Healing
Primary and secondary bone- inflammatory mediators, mature into Achieving the appropriate amount
healing both depend on an initial osteoblasts, contributing to the and duration of inflammation is
development of new healthy bone. important, especially in light of the
Eventually, maturation and need for pain control after fracture or
remodeling will take place under all orthopaedic surgery. NSAIDs
healing conditions, with changes generally are considered the first
potentially occurring over the lifetime “step” on the World Health
of the patient1. The goal is to achieve a Organization’s (WHO’s) “analgesic
fully loadable, functional bone. Bone ladder.”6 By inhibiting cyclooxygenase
will typically heal within 6 to 8 weeks (COX) enzymes, NSAIDs block the
after injury, with radiographic signs of production of proinflammatory
callus formation at about 4 weeks. prostaglandins3. The role of
Nonunion is defined as a fracture that prostaglandins is well established in
has not healed at 9 months after inflammatory processes, such as the
injury1,5. Up until 9 months, the recruitment of MSCs and the initiation
fracture-healing is said to be “delayed.” of angiogenesis, as well as with bone
Just as inflammation is imperative formation itself7. Both in vitro and
for a healthy, normal healing cascade, it animal studies suggest that it is the
must also be noted that long-term inducible COX-2 enzyme that is
inflammatory processes can cause responsible for the majority of these
substantial damage. Systemic diseases prostaglandins7; thus, inhibiting this
associated with chronic inflammation, enzyme will theoretically be more
such as rheumatoid arthritis and detrimental to bone-healing during
diabetes mellitus, among others, have the stages that are dependent on
been shown to impair fracture- inflammation. While the exact
healing1. In addition, excessive mechanism is not clearly understood,
inflammation at the site of the healing many potential mechanisms have been
Fig. 1 fracture, such as that seen with localized investigated. One theory that has been
A radiograph demonstrating primary infection, can cause additional damage postulated, but not studied in depth,
bone-healing. to healing bone. involves the effect of NSAIDs

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Relationship Between NSAIDs and Bone-Healing After Fracture or Orthopaedic Surgery |

(COX-independent) on various 2010, Dodwell et al. compiled and methodologic quality than those
kinase-signaling pathways8. Pountos analyzed 11 case-control or cohort involving spinal surgery. When high-
et al. suggested that NSAIDs inhibit studies that were conducted between quality studies involving spinal
MSC proliferation and differentiation, 1996 and December 2008, in which surgery were analyzed based on the
but in vitro models did not support this nonunion after spinal fusion or length of NSAID exposure, the 3 that
theory8. However, in vitro models fracture was an outcome and included prolonged (2 weeks) or
showed that NSAIDs did inhibit the administration of an NSAID was a undefined NSAID use demonstrated a
chondrogenic potential of MSCs. This variable12. (Table I summarizes the significant increase in nonunion (OR,
differentiation takes place during the results of the individual trials13-23 9.1; 95% CI, 2.4 to 33.6), suggesting
first week of bone-healing and is analyzed by Dodwell et al., as well as that the length of therapy is an
associated with a high production of the other studies included in this important variable in determining the
prostaglandin E2 (PGE-2). However, review article24-26.) These studies were relationship between NSAIDs and
while the increase in COX-1 was found assessed by 2 reviewers for nonunion.
to be substantial, there was little methodologic quality using the Another large retrospective
increase in COX-2 during this phase. Newcastle-Ottawa Scale, and included cohort study that has been published
The degree of COX selectivity of 12,051 subjects, 2,067 of whom were since the meta-analysis of Dodwell
NSAIDs was associated with the exposed to NSAIDs. The analysis et al. included 1,901 subjects with
inhibition of chondrogenic potential, showed a significantly elevated risk of fracture of a long bone (femur, tibia, or
with the less COX-2-selective NSAIDs nonunion with NSAID use (7.3% humerus) between October 2009 and
causing more inhibition than the more versus 1.5%; odds ratio [OR], 3.0; 95% September 201125. Of the 231 who
COX-2-selective drugs. Therefore, the confidence interval [CI], 1.6 to 5.6). were administered NSAIDs during
timing of NSAID administration and However, additional subanalysis their hospitalization, 14 (6.1%) had a
its COX selectivity may impact the revealed that this difference was only nonunion or infection, which was
degree of interference with bone- present in the 4 studies that took place higher than the overall rate of 3.2%.
healing. Table II lists the currently with patients with long-bone fractures Seven of the complications in those
available NSAIDs and their relative (OR, 4.4; 95% CI, 2.5 to 7.8); in the 7 who had been administered NSAIDs
selectivity for COX-29-11. studies with patients who had were nonunions, and 7 were
undergone spinal fusions, there was no infections. Other factors identified as
Retrospective Studies increased risk of nonunion (OR, 2.2; being related to healing complications
Retrospective studies in humans have 95% CI, 0.8 to 6.3). Of note, 3 of these 4 included tobacco use, injury severity,
produced conflicting results regarding studies utilized secondary healing the presence of an open fracture, and
the relationship between bone-healing methods. Notably, the long-bone the type of injury (e.g., fall injury or
complications and NSAID use. In studies were deemed to be of lower motor vehicle collision). Once these
variables were adjusted for, logistic
regression analysis still showed a
TABLE II COX-2 Selectivity of NSAIDs9-11 significant increase in healing
complications (nonunion or infection)
COX-2 Selectivity Range associated with NSAID use (OR, 2.17;
(by COX-1:COX-2 IC-50 ratio)* NSAID
95% CI, 1.15 to 4.10; p 5 0.016). The
Nonselective (#1) Ketoprofen reported number of doses of NSAIDs
Ibuprofen given ranged from 1 to 9, and doses all
Naproxen fell within the normal range, which
Ketorolac would qualify as short-term usage. The
Low selectivity (1-10) Indomethacin
type of procedure used for fixation in
Piroxicam
this study was not specified.
Etodolac
A small retrospective cohort
Flurbiprofen
study published in 2016 demonstrated
different results from those in the
Moderate selectivity (10-50) Meloxicam
above analysis and study. Donohue
Diclofenac
et al. showed no relationship between
High selectivity (.50) Celecoxib
NSAID use and rates of nonunion after
Etoricoxib
rod fixation (secondary healing) of
*IC-50 5 half minimum inhibitory concentration. A higher number represents femoral or tibial fractures24. In their
greater selectivity for COX-2. study, 80 subjects who received
ketorolac within 24 hours after their

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| Relationship Between NSAIDs and Bone-Healing After Fracture or Orthopaedic Surgery

surgical procedure were compared at Another randomized double- with the placebo group.) Interestingly,
the time of follow-up with the 233 who blind study of 42 postmenopausal the rate of heterotopic ossification also
did not receive ketorolac, and it was subjects with similar Colles fractures was increased in the indomethacin-
found that only 6 (7.5%) of those investigated the effects of an 8-week only group, but was decreased in the 7-
receiving the NSAID sustained a course of piroxicam versus a placebo day indomethacin group (p 5 0.006).
nonunion, whereas 28 (12%) of those on measures of osteopenia, function This led the authors to conclude that
who did not receive the NSAID had the (grip strength, range of motion), and short-term (1 week) dosing of
same complication. The authors also bone-healing13. Again, all subjects also indomethacin is beneficial following
reported the average doses of the received as-needed acetaminophen for acetabular fracture and surgery
patients receiving ketorolac who had pain control. Bone-healing was because it reduces heterotopic
healed versus those who had measured by the degree of radial ossification and does not increase the
developed a nonunion (85 mg and shortening and dorsal angulation at 10 rate of nonunion. However, these
50 mg, respectively; p 5 0.27), days and at 4, 8, and 12 weeks after study results must be interpreted with
negating the suggestion of a dose- fracture. Based on a visual analog scale caution; the small number of initial
dependent effect in this small trial. (VAS), pain control in the piroxicam subjects, the high withdrawal rate
group was significantly better than in (19% to 43%), and the low rate of
Prospective Studies the placebo group at 10 days and 4 compliance (with only 63% of subjects
The authors of several weeks (2.1 versus 3.1 and 1.0 versus in the indomethacin-only group
studies12,24,25,27 recommended that 2.5, respectively; p , 0.05 for both). showing an indomethacin
more prospective research be There was no overall difference in concentration in their blood at the 6-
conducted to determine the effects of measures of fracture-healing, leading week follow-up) all point to the
NSAIDs on bone-healing because to the conclusion that piroxicam potential for substantial selection bias.
retrospective analyses cannot offered superior pain control than the
determine cause and effect, but simply placebo plus acetaminophen, with no Implications for Pain Management
highlight potential relationships. difference in measures of bone-healing While the safety of the patient is of
Similar to the retrospective data, the or function. (Both of the studies utmost concern, there is still the
few randomized controlled trials that involving Colles fractures were obvious need for acute pain relief
have been completed are of varying included in the previously referenced during the time immediately after
quality and duration, with different meta-analysis.) injury or surgery that must be
outcomes, making comparisons More recently, Sagi et al. addressed, as well as continued pain
between them difficult. undertook a randomized controlled relief as needed. Based on current
In a 1988 randomized double- study to determine if the practice of standards for pain control—which are
blind trial of 100 subjects with a Colles utilizing NSAIDs to prevent bone usually a modification of the WHO’s
fracture (a fracture of the distal part of growth outside of the skeleton 1986 “analgesic ladder”—NSAIDs and
the radius commonly seen in patients (heterotopic ossification) after nonopioid analgesics such as
with osteoporosis), participants were acetabular open reduction and fixation acetaminophen are first-line
given either 84 flurbiprofen (50-mg) increased the rate of nonunion after treatment for mild pain, with “step-
pills or a matched placebo, along with surgery26. Ninety-eight subjects were up” therapy recommended to weak,
acetaminophen for as-needed use17 (if divided into 4 groups, each to be and then strong, opioids if pain relief is
the subjects were taking the maximum treated for 6 weeks according to the not achieved6. However, there are
daily dose of 300 mg of flurbiprofen, following protocols: (1) placebo; (2) several concerns related to safety with
this equated to a 14-day supply)28. indomethacin for 3 days, then placebo; this approach. With NSAIDs, the
While the primary outcome of the (3) indomethacin for 7 days, then potential for delay in bone-healing
study addressed osteoporotic changes placebo; and (4) indomethacin for 6 already has been outlined. There is also
and functional recovery, the rate of weeks. The primary outcome of this a question of efficacy. In 2 small
nonunion at 1 year postfracture was a study was the rate of nonunion, with prospective studies, NSAIDs have
secondary outcome17. In this study, follow-up occurring at 6 weeks, 3 been shown to offer substantial pain
there were no cases of nonunion in months, 6 months, and 1 year relief when compared with a placebo
either the flurbiprofen or placebo postsurgery. Eight (62%) of those in plus acetaminophen in patients with a
group, leading to the authors’ the indomethacin-only group had a Colles fracture, with no change in
conclusion that flurbiprofen offered fracture nonunion, compared with nonunion rate13,17, but most studies
substantial improvement in pain only 4 (19%) in the placebo-only group cited previously did not evaluate pain
control in the first 1 to 8 days of (p 5 0.012). (The rates of nonunion in relief. There are studies suggesting that
treatment and did not increase the rate the other 2 groups were not the administration of an NSAID
of fracture nonunion. significantly different when compared immediately postoperatively in those

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Relationship Between NSAIDs and Bone-Healing After Fracture or Orthopaedic Surgery |

undergoing spinal surgery reduces In addition, nonpharmacologic bone-healing, multimodal pain


pain and the need for opioid methodologies must be explored, management should always be
analgesics2. Another study showed the including rehabilitation. Furthermore, utilized, including appropriate use of
NSAIDs ketorolac, diclofenac, and the Centers for Disease Control and opioids, nonpharmacologic methods,
etoricoxib all to be equally useful at Prevention (CDC), in guidelines and exploration of nontraditional drug
relieving pain after ankle fracture, with released in early 2016, discusses that classes to control the long-term pain
a 70% to 75% reported reduction in exercise should be one of the that can accompany a fracture.
pain in the first 24 hours (2 doses)29. nonpharmacologic therapies pursued
However, the etiology of bone pain is to aid in reducing chronic pain37. NOTE:
varied, with possibly less contribution Although it is beyond the scope of this The authors thank Dr. Thomas Gates,
from inflammation than other types of paper, others have shown that not only Associate Professor of Radiology, for the
pain30, thus rendering NSAIDs pain can be ameliorated via images.
potentially less useful in the long term. nonsurgical means—physical therapy
Teresa Bigler, DHEd, PA-C1
While opioids are fully can aid in improving fracture-healing Emily Weidman-Evans, PharmD1
established as efficacious in relieving via mechanotransduction (i.e., Daniel Flowers, DPT1
pain at appropriate doses, there is the improving cellular processes via 1
Louisiana State University Health Sciences
concern of their abuse or misuse2,30. physical stimulation)38. Center Shreveport, Shreveport, Louisiana
Furthermore, it is hypothesized that,
because of various mechanisms, Conclusions ORCID iD for T. Bigler:
fracture pain in particular can become Many researchers and investigators 0000-0001-8369-6901
chronic in nature and require longer- conclude that the risk of NSAID
term pain management techniques. therapy outweighs the benefits. It must References
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| Relationship Between NSAIDs and Bone-Healing After Fracture or Orthopaedic Surgery

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