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

JBJS JOPA 2018; 6(2): e14 • http://dx.doi.org/10.2106/JBJS.JOPA.17.00036 1

 | 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)

2 JBJS JOPA 2018; 6(2): e14 • http://dx.doi.org/10.2106/JBJS.JOPA.17.00036

 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
progresses along 2 continua: primary
and secondary. Primary bone-healing
occurs when the fracture is reduced
(i.e., placing bone ends and any
fragments back into the anatomic
position) and then directly fixated by
artificial means in order to keep the
bone ends congruent with minimal
movement1,4,5. An example of this
would be open reduction and internal
fixation with compression plates and
screws1 (Fig. 1). Secondary bone-
healing, where the fracture is reduced
and indirectly fixated via
immobilization in order to prevent
displacement, allows some movement
to occur at the fracture site1,4,5. This
motion at the fracture site, which
occurs as a result of the approximated
bone ends not being overcompressed,
will lead to differences in healing.
Secondary bone-healing includes the
use of casts, external fixation, and
intramedullary nailing1 (Fig. 2).
Primary and secondary bone-
healing both depend on an initial
Fig. 1
A radiograph demonstrating primary
bone-healing.
4 JBJS JOPA 2018; 6(2): e14
inflammatory response with
hematoma formation; however, after
this point, they progress along 2
separate paths. In primary healing, the
relative lack of movement results in
intramembranous bone formation
and vascularization1. This process is
slower than secondary bone-healing
and is not associated with a major
influx of inflammatory cells.
Secondary healing is more
dependent on inflammatory processes
because it requires the deposit of
granulation and callus tissue1. A soft
callus consisting mostly of
cartilaginous and granulation tissue
forms due to micromotion at the
fracture site and inflammation. Once
the callus edges meet, angiogenesis
begins. The increased blood supply to
the soft callus transforms cartilaginous
“bracing” into definitive structure,
which matures into a hard “bony”
callus. Mesenchymal stem cells
(MSCs), also recruited by
inflammatory mediators, mature into
osteoblasts, contributing to the
development of new healthy bone.
Eventually, maturation and
remodeling will take place under all
healing conditions, with changes
potentially occurring over the lifetime
of the patient1. The goal is to achieve a
fully loadable, functional bone. Bone
will typically heal within 6 to 8 weeks
after injury, with radiographic signs of
callus formation at about 4 weeks.
Nonunion is defined as a fracture that
has not healed at 9 months after
injury1,5. Up until 9 months, the
fracture-healing is said to be “delayed.”
Just as inflammation is imperative
for a healthy, normal healing cascade, it
must also be noted that long-term
inflammatory processes can cause
substantial damage. Systemic diseases
associated with chronic inflammation,
such as rheumatoid arthritis and
diabetes mellitus, among others, have
been shown to impair fracture-
healing1. In addition, excessive
inflammation at the site of the healing
fracture, such as that seen with localized
infection, can cause additional damage
to healing bone.
• http://dx.doi.org/10.2106/JBJS.JOPA.17.00036
Fig. 2
A radiograph demonstrating secondary
bone-healing, which is more dependent
on the inflammatory process.
Clinical Effects of NSAIDs on Bone-
Healing
Achieving the appropriate amount
and duration of inflammation is
important, especially in light of the
need for pain control after fracture or
orthopaedic surgery. NSAIDs
generally are considered the first
“step” on the World Health
Organization’s (WHO’s) “analgesic
ladder.”6 By inhibiting cyclooxygenase
(COX) enzymes, NSAIDs block the
production of proinflammatory
prostaglandins3. The role of
prostaglandins is well established in
inflammatory processes, such as the
recruitment of MSCs and the initiation
of angiogenesis, as well as with bone
formation itself7. Both in vitro and
animal studies suggest that it is the
inducible COX-2 enzyme that is
responsible for the majority of these
prostaglandins7; thus, inhibiting this
enzyme will theoretically be more
detrimental to bone-healing during
the stages that are dependent on
inflammation. While the exact
mechanism is not clearly understood,
many potential mechanisms have been
investigated. One theory that has been
postulated, but not studied in depth,
involves the effect of NSAIDs
 Relationship Between NSAIDs and Bone-Healing After Fracture or Orthopaedic Surgery
(COX-independent) on various
kinase-signaling pathways8. Pountos
et al. suggested that NSAIDs inhibit
MSC proliferation and differentiation,
but in vitro models did not support this
theory8. However, in vitro models
showed that NSAIDs did inhibit the
chondrogenic potential of MSCs. This
differentiation takes place during the
first week of bone-healing and is
associated with a high production of
prostaglandin E2 (PGE-2). However,
while the increase in COX-1 was found
to be substantial, there was little
increase in COX-2 during this phase.
The degree of COX selectivity of
NSAIDs was associated with the
inhibition of chondrogenic potential,
with the less COX-2-selective NSAIDs
causing more inhibition than the more
COX-2-selective drugs. Therefore, the
timing of NSAID administration and
its COX selectivity may impact the
degree of interference with bone-
healing. Table II lists the currently
available NSAIDs and their relative
selectivity for COX-29-11.
Retrospective Studies
Retrospective studies in humans have
produced conflicting results regarding
the relationship between bone-healing
complications and NSAID use. In
TABLE II COX-2 Selectivity of NSAIDs9-11
COX-2 Selectivity Range
(by COX-1:COX-2 IC-50 ratio)*
Nonselective (#1)
Low selectivity (1-10)
Moderate selectivity (10-50)
High selectivity (.50)
*IC-50 5 half minimum inhibitory concentration. A higher number represents
greater selectivity for COX-2.
JBJS JOPA 2018; 6(2): e14 • http://dx.doi.org/10.2106/JBJS.JOPA.17.00036
2010, Dodwell et al. compiled and
analyzed 11 case-control or cohort
studies that were conducted between
1996 and December 2008, in which
nonunion after spinal fusion or
fracture was an outcome and
administration of an NSAID was a
variable12. (Table I summarizes the
results of the individual trials13-23
analyzed by Dodwell et al., as well as
the other studies included in this
review article24-26.) These studies were
assessed by 2 reviewers for
methodologic quality using the
Newcastle-Ottawa Scale, and included
12,051 subjects, 2,067 of whom were
exposed to NSAIDs. The analysis
showed a significantly elevated risk of
nonunion with NSAID use (7.3%
versus 1.5%; odds ratio [OR], 3.0; 95%
confidence interval [CI], 1.6 to 5.6).
However, additional subanalysis
revealed that this difference was only
present in the 4 studies that took place
with patients with long-bone fractures
(OR, 4.4; 95% CI, 2.5 to 7.8); in the 7
studies with patients who had
undergone spinal fusions, there was no
increased risk of nonunion (OR, 2.2;
95% CI, 0.8 to 6.3). Of note, 3 of these 4
studies utilized secondary healing
methods. Notably, the long-bone
studies were deemed to be of lower
NSAID
Ketoprofen
Ibuprofen
Naproxen
Ketorolac
Indomethacin
Piroxicam
Etodolac
Flurbiprofen
Meloxicam
Diclofenac
Celecoxib
Etoricoxib
|
methodologic quality than those
involving spinal surgery. When high-
quality studies involving spinal
surgery were analyzed based on the
length of NSAID exposure, the 3 that
included prolonged (2 weeks) or
undefined NSAID use demonstrated a
significant increase in nonunion (OR,
9.1; 95% CI, 2.4 to 33.6), suggesting
that the length of therapy is an
important variable in determining the
relationship between NSAIDs and
nonunion.
Another large retrospective
cohort study that has been published
since the meta-analysis of Dodwell
et al. included 1,901 subjects with
fracture of a long bone (femur, tibia, or
humerus) between October 2009 and
September 201125. Of the 231 who
were administered NSAIDs during
their hospitalization, 14 (6.1%) had a
nonunion or infection, which was
higher than the overall rate of 3.2%.
Seven of the complications in those
who had been administered NSAIDs
were nonunions, and 7 were
infections. Other factors identified as
being related to healing complications
included tobacco use, injury severity,
the presence of an open fracture, and
the type of injury (e.g., fall injury or
motor vehicle collision). Once these
variables were adjusted for, logistic
regression analysis still showed a
significant increase in healing
complications (nonunion or infection)
associated with NSAID use (OR, 2.17;
95% CI, 1.15 to 4.10; p 5 0.016). The
reported number of doses of NSAIDs
given ranged from 1 to 9, and doses all
fell within the normal range, which
would qualify as short-term usage. The
type of procedure used for fixation in
this study was not specified.
A small retrospective cohort
study published in 2016 demonstrated
different results from those in the
above analysis and study. Donohue
et al. showed no relationship between
NSAID use and rates of nonunion after
rod fixation (secondary healing) of
femoral or tibial fractures24. In their
study, 80 subjects who received
ketorolac within 24 hours after their
5
 | Relationship Between NSAIDs and Bone-Healing After Fracture or Orthopaedic Surgery
surgical procedure were compared at
the time of follow-up with the 233 who
did not receive ketorolac, and it was
found that only 6 (7.5%) of those
receiving the NSAID sustained a
nonunion, whereas 28 (12%) of those
who did not receive the NSAID had the
same complication. The authors also
reported the average doses of the
patients receiving ketorolac who had
healed versus those who had
developed a nonunion (85 mg and
50 mg, respectively; p 5 0.27),
negating the suggestion of a dose-
dependent effect in this small trial.
Prospective Studies
The authors of several
studies12,24,25,27 recommended that
more prospective research be
conducted to determine the effects of
NSAIDs on bone-healing because
retrospective analyses cannot
determine cause and effect, but simply
highlight potential relationships.
Similar to the retrospective data, the
few randomized controlled trials that
have been completed are of varying
quality and duration, with different
outcomes, making comparisons
between them difficult.
In a 1988 randomized double-
blind trial of 100 subjects with a Colles
fracture (a fracture of the distal part of
the radius commonly seen in patients
with osteoporosis), participants were
given either 84 flurbiprofen (50-mg)
pills or a matched placebo, along with
acetaminophen for as-needed use17 (if
the subjects were taking the maximum
daily dose of 300 mg of flurbiprofen,
this equated to a 14-day supply)28.
While the primary outcome of the
study addressed osteoporotic changes
and functional recovery, the rate of
nonunion at 1 year postfracture was a
secondary outcome17. In this study,
there were no cases of nonunion in
either the flurbiprofen or placebo
group, leading to the authors’
conclusion that flurbiprofen offered
substantial improvement in pain
control in the first 1 to 8 days of
treatment and did not increase the rate
of fracture nonunion.
6 JBJS JOPA 2018; 6(2): e14
Another randomized double-
blind study of 42 postmenopausal
subjects with similar Colles fractures
investigated the effects of an 8-week
course of piroxicam versus a placebo
on measures of osteopenia, function
(grip strength, range of motion), and
bone-healing13. Again, all subjects also
received as-needed acetaminophen for
pain control. Bone-healing was
measured by the degree of radial
shortening and dorsal angulation at 10
days and at 4, 8, and 12 weeks after
fracture. Based on a visual analog scale
(VAS), pain control in the piroxicam
group was significantly better than in
the placebo group at 10 days and 4
weeks (2.1 versus 3.1 and 1.0 versus
2.5, respectively; p , 0.05 for both).
There was no overall difference in
measures of fracture-healing, leading
to the conclusion that piroxicam
offered superior pain control than the
placebo plus acetaminophen, with no
difference in measures of bone-healing
or function. (Both of the studies
involving Colles fractures were
included in the previously referenced
meta-analysis.)
More recently, Sagi et al.
undertook a randomized controlled
study to determine if the practice of
utilizing NSAIDs to prevent bone
growth outside of the skeleton
(heterotopic ossification) after
acetabular open reduction and fixation
increased the rate of nonunion after
surgery26. Ninety-eight subjects were
divided into 4 groups, each to be
treated for 6 weeks according to the
following protocols: (1) placebo; (2)
indomethacin for 3 days, then placebo;
(3) indomethacin for 7 days, then
placebo; and (4) indomethacin for 6
weeks. The primary outcome of this
study was the rate of nonunion, with
follow-up occurring at 6 weeks, 3
months, 6 months, and 1 year
postsurgery. Eight (62%) of those in
the indomethacin-only group had a
fracture nonunion, compared with
only 4 (19%) in the placebo-only group
(p 5 0.012). (The rates of nonunion in
the other 2 groups were not
significantly different when compared
• http://dx.doi.org/10.2106/JBJS.JOPA.17.00036
with the placebo group.) Interestingly,
the rate of heterotopic ossification also
was increased in the indomethacin-
only group, but was decreased in the 7-
day indomethacin group (p 5 0.006).
This led the authors to conclude that
short-term (1 week) dosing of
indomethacin is beneficial following
acetabular fracture and surgery
because it reduces heterotopic
ossification and does not increase the
rate of nonunion. However, these
study results must be interpreted with
caution; the small number of initial
subjects, the high withdrawal rate
(19% to 43%), and the low rate of
compliance (with only 63% of subjects
in the indomethacin-only group
showing an indomethacin
concentration in their blood at the 6-
week follow-up) all point to the
potential for substantial selection bias.
Implications for Pain Management
While the safety of the patient is of
utmost concern, there is still the
obvious need for acute pain relief
during the time immediately after
injury or surgery that must be
addressed, as well as continued pain
relief as needed. Based on current
standards for pain control—which are
usually a modification of the WHO’s
1986 “analgesic ladder”—NSAIDs and
nonopioid analgesics such as
acetaminophen are first-line
treatment for mild pain, with “step-
up” therapy recommended to weak,
and then strong, opioids if pain relief is
not achieved6. However, there are
several concerns related to safety with
this approach. With NSAIDs, the
potential for delay in bone-healing
already has been outlined. There is also
a question of efficacy. In 2 small
prospective studies, NSAIDs have
been shown to offer substantial pain
relief when compared with a placebo
plus acetaminophen in patients with a
Colles fracture, with no change in
nonunion rate13,17, but most studies
cited previously did not evaluate pain
relief. There are studies suggesting that
the administration of an NSAID
immediately postoperatively in those
 Relationship Between NSAIDs and Bone-Healing After Fracture or Orthopaedic Surgery
undergoing spinal surgery reduces
pain and the need for opioid
analgesics2. Another study showed the
NSAIDs ketorolac, diclofenac, and
etoricoxib all to be equally useful at
relieving pain after ankle fracture, with
a 70% to 75% reported reduction in
pain in the first 24 hours (2 doses)29.
However, the etiology of bone pain is
varied, with possibly less contribution
from inflammation than other types of
pain30, thus rendering NSAIDs
potentially less useful in the long term.
While opioids are fully
established as efficacious in relieving
pain at appropriate doses, there is the
concern of their abuse or misuse2,30.
Furthermore, it is hypothesized that,
because of various mechanisms,
fracture pain in particular can become
chronic in nature and require longer-
term pain management techniques.
This is supported by registry data from
Sweden, which showed that 14% and
36% of patients with tibial and femoral
fractures, respectively, continued to
require opioids for pain relief 12
months after their initial injuries31,32.
Similarly, 25% of patients undergoing
spinal surgery and 20% of orthopaedic
surgery and trauma patients still
required opioids 3 months after
surgery33,34. It is important to note,
however, that there was no indication
of dose escalation among any of these
subjects, which denotes a decided lack
of tolerance or misuse, but rather a
continued need for pain
management31,32,34.
Based on the safety concerns
surrounding both NSAIDs and
opioids, it has been recommended that
patients use these options at the lowest
possible dose for the shortest duration
possible35,36. The varied etiologies of
bone pain, as well as the potential for
the development of chronic pain, point
to the possibilities of other options
being effective, such as regional
anesthesia during surgical procedures,
gabapentin or pregabalin for
neuropathic pain, or bisphosphonates,
which have been used for other
conditions that are associated with
bone pain and high bone turnover2,27.
JBJS JOPA 2018; 6(2): e14 • http://dx.doi.org/10.2106/JBJS.JOPA.17.00036
In addition, nonpharmacologic
methodologies must be explored,
including rehabilitation. Furthermore,
the Centers for Disease Control and
Prevention (CDC), in guidelines
released in early 2016, discusses that
exercise should be one of the
nonpharmacologic therapies pursued
to aid in reducing chronic pain37.
Although it is beyond the scope of this
paper, others have shown that not only
pain can be ameliorated via
nonsurgical means—physical therapy
can aid in improving fracture-healing
via mechanotransduction (i.e.,
improving cellular processes via
physical stimulation)38.
Conclusions
Many researchers and investigators
conclude that the risk of NSAID
therapy outweighs the benefits. It must
be stated that these are general
guidelines based on judgments made
without high levels of evidence, as
shown by the analysis by Marquez-
Lara et al., which demonstrated great
variability in the quality and
interpretation of existing studies39.
Therefore, authors will use language
such as “not generally indicated”40 and
“probable harmful effects”35 without
giving definitive recommendations.
Given the necessity of the initial
inflammatory conditions and
angiogenesis during bone repair,
particularly in secondary bone-
healing, the decision to use or avoid
NSAIDs can be critical.
The evidence suggests a possible
relationship between NSAID use and
impaired bone-healing, but
determining specific risks and benefits
proves difficult. Based on this review of
available information, we recommend
that NSAIDs be used cautiously at the
lowest dose and for the shortest
duration necessary for adequate pain
control, especially when secondary
healing is taking place. Avoidance of
NSAIDs that are selective for the COX-
2 enzyme may be prudent in theory,
although the current clinical literature
does not necessarily support this.
Because of the potential risk of delayed
|
bone-healing, multimodal pain
management should always be
utilized, including appropriate use of
opioids, nonpharmacologic methods,
and exploration of nontraditional drug
classes to control the long-term pain
that can accompany a fracture.
NOTE:
The authors thank Dr. Thomas Gates,
Associate Professor of Radiology, for the
images.
Teresa Bigler, DHEd, PA-C1
Emily Weidman-Evans, PharmD1
Daniel Flowers, DPT1
1
Louisiana State University Health Sciences
Center Shreveport, Shreveport, Louisiana
ORCID iD for T. Bigler:
0000-0001-8369-6901
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