Annals of Physical and Rehabilitation Medicine 59 (2016) 184–189

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Review

Evidence and recommendations for use of intra-articular injections for

knee osteoarthritis
Christelle Nguyen a,b,*, Marie-Martine Lefèvre-Colau a,c, Serge Poiraudeau a,c,
François Rannou a,b
a
Université Paris Descartes, PRES Sorbonne Paris Cité, Service de Rééducation et de Réadaptation de l’Appareil Locomoteur et des Pathologies du Rachis,
Hôpital Cochin, Assistance Publique – Hôpitaux de Paris, Paris, France
b
Université Paris Descartes, PRES Sorbonne Paris Cité, Laboratoire de Pharmacologie, Toxicologie et Signalisation Cellulaire, INSERM UMR-S 1124,
UFR Biomédicale des Saints Pères, Paris, France
c
Université Paris Descartes, PRES Sorbonne Paris Cité, INSERM UMR-S 1153 et Institut Fédératif de Recherche sur le Handicap, Paris, France

A R T I C L E I N F O A B S T R A C T

Article history: Pharmacological treatments are widely recommended in international guidelines for management of
Received 6 December 2015 osteoarthritis (OA). However, the use of intra-articular (IA) therapies of diverse active drugs remains
Accepted 28 February 2016 controversial. We critically reviewed studies of the efficacy and safety of IA injections of corticosteroids
(CS), hyaluronic acid (HA), platelet-rich plasma (PRP), and botulinum toxin A (BTA) and evidence-based
Keywords: international recommendations for their use in treating knee OA. The process of article selection was
Osteoarthritis unsystematic. Articles were selected on the basis of authors’ expertise, self-knowledge, and reflective
Intra-articular injections
practice. Only studies assessing knee OA were included. IA CS and HA injections were conditionally to
Corticosteroids
Hyaluronic acid
fully recommended for treating knee OA. No recommendations have been formulated for IA PRP or BTA.
Platelet-rich plasma The evidence remains inconsistent and controversial for the use of IA therapies for knee OA. The
Botulinum toxin A characteristics of and selection criteria for the OA population that would likely benefit from these
Evidence-based medicine therapies need to be identified. Accurately phenotyping and selecting patients is mandatory in future
randomized controlled trials. Therefore, efficacy and safety meta-analyses should be performed, as
should qualitative and sensitivity analyses of published trial results.
ß 2016 Elsevier Masson SAS. All rights reserved.

1. Introduction reviews are often inconclusive regarding the benefits of these

Pharmacological treatments, including acetaminophen and
non-steroidal anti-inflammatory drugs, are widely recommended
in national and international guidelines for managing knee
osteoarthritis (OA) in primary care settings [1,2]. However,
patients with knee OA often have comorbidities, which raise
concerns about the risk/benefit ratio of these widely prescribed
drugs [3]. Therefore, intra-articular (IA) therapies might be an
alternative and safe treatment for these patients.
However, the efficacy of IA therapies of diverse active drugs
remains controversial among organizations because of important
differences in the interpretation of evidence. Indeed, recommen-
dations are usually based on the results of systematic reviews and
meta-analysis of randomized controlled trials (RCTs). These
* Corresponding author at: Service de Rééducation et de Réadaptation de
l’Appareil Locomoteur et des Pathologies du Rachis, 27, Rue du Faubourg Saint-
Jacques, 75014 Paris, France. Tel.: +33 1 58 41 29 45; fax: +33 1 58 41 25 38.
E-mail address: christelle.nguyen2@aphp.fr (C. Nguyen).
treatments and are limited by the heterogeneity and quality of the
included studies. Furthermore, concerns have been raised about
the risk/benefit profile of IA drugs.
Here, we review studies of the efficacy and safety of IA
injections of corticosteroids (CS), hyaluronic acid (HA), platelet-
rich plasma (PRP), and botulinum toxin A (BTA) and evidence-
based international recommendations for their use in treating
knee OA.
2. Methods
The process of selecting articles related to knee OA for this
critical narrative review was not systematic. Individual trials,
systematic reviews and meta-analyses included in the latest
American College of Rheumatology (ACR) and Osteoarthritis
Research Society International (OARSI) international guidelines
were searched, as was MEDLINE via PubMed from inception to
December 2015 for additional guidelines, trials, systematic
reviews and meta-analyses. The following MeSH terms were used:

http://dx.doi.org/10.1016/j.rehab.2016.02.008
1877-0657/ß 2016 Elsevier Masson SAS. All rights reserved.
 C. Nguyen et al. / Annals of Physical and Rehabilitation Medicine 59 (2016) 184–189
injection, knee osteoarthritis, corticosteroids, hyaluronic acid,
platelet-rich plasma, and botulinum toxin. Articles were selected
on the basis of authors’ expertise, self-knowledge, and reflective
practice.
3. Results
3.1. CS injection
Although OA is generally considered a degenerative joint
disorder, there is evidence that a low-grade inflammation also
occurs at some phases of the disease [4], which provides sound
rationale for the use of drugs targeting local inflammation. CSs are
potent anti-inflammatory agents that act by a variety of mecha-
nisms on different cellular levels. IA CS has been used for knee OA
for over 50 years [5] and is available in both crystalline and non-
crystalline forms. The crystalline triamcinolone and the non-
crystalline prednisolone and methylprednisolone are used most
frequently. Although the 2012 ACR [1] and 2014 OARSI guidelines
[2] both recommend participation in exercise programs as well as
weight loss (for overweight patients) as first-line treatments for all
patients with symptomatic knee OA, the recommendations largely
differ in the use of IA CS [1,2]. ACR guidelines include a conditional,
weak recommendation for the use of IA CS in patients unrespon-
sive to basic treatment [1]. Conversely, in OARSI guidelines, IA CS is
considered an appropriate treatment, whatever the OA subtype
and comorbidities [2]. This recommendation is based on 2 system-
atic reviews, published before 2010, that supported clinically
significant short-term decreases in pain [6,7]. The quality of
evidence was rated good. However, no effect size for pain was
available [2].
The 2015 update of a 2006 Cochrane review [7] included 14 new
trials, for a total of 27 trials [8]. Studies included were RCTs or
quasi-RCTs, with a control group receiving sham or no interven-
tion. The median prednisolone equivalent dose across all trials was
50 mg, and the median number of CS injections was one. Trials
randomized a median of 76 participants (range 16–205). The meta-
analysis found CS more effective for pain reduction than control
interventions (standardized mean difference [SMD] 0.40, 95% CI
0.58 to 0.22), which corresponds to a difference in pain scores of
1.0 cm on a 10-cm visual analog scale (VAS) [8]. When results were
stratified by length of follow-up, benefits were moderate at 1–2
weeks (SMD 0.48, 95% CI 0.70 to 0.27), small to moderate at 4–
6 weeks (SMD 0.41, 95% CI 0.61 to 0.21), and small at 13 weeks
(SMD 0.22, 95% CI 0.44 to 0.00), with no effect found at
26 weeks (SMD 0.07, 95% CI 0.25 to 0.11) [8]. In addition, CS
injection was more effective for improving function than the
control intervention (SMD 0.33, 95% CI 0.56 to 0.09)
[8]. Adverse events could not be accurately assessed. Little to no
evidence was found for an association with CS dosage, ultrasound
guidance, local anesthetic, crystalline preparation, or type of
control intervention [8]. However, the authors found a moderate to
large degree of between-trial heterogeneity, and most of the
identified trials were considered small, and the quality of evidence
for the major outcomes was graded ‘‘low’’ [8]. Interestingly,
analysis of pain and function stratified by funding source,
independent or not of industry, did not show any differences.
No hierarchy could be clearly established between corticosteroids
in terms of efficacy according to their half-life, onset of action or
duration. Therefore, the choice of the corticoid mainly relies on the
physician’s practice and the availability of the product.
Finally, a systematic review and network meta-analysis of
pharmacological treatment for knee OA that included 129 trials
(32,129 participants) [9] found that for treating OA-related knee
pain at 3 months, the effect size (ES) was superior for IA CS than IA
placebo (ES = 0.32, 95% CI 0.16–0.47), oral placebo (ES = 0.61, 95%
185
CI 0.32–0.89), oral acetaminophen (ES = 0.42, 95% CI 0.12–0.73)
and all other oral treatments [9] and was among the highest of all
the pharmacological treatments assessed.
3.2. HA injection
The clinical benefit of IA HA on knee OA may rely on
2 mechanisms: [1] mechanical viscosupplementation of the joint
(allowing lubrication and shock absorption), and [2] the re-
establishment of joint homeostasis by inducing endogenous HA
production, which continues long after the exogenous injection
has left the joint. However, international guidelines are even more
inconsistent for the use of IA HA than IA CS for knee OA. The
2014 OARSI guidelines recommended IA HA injection with a
degree of uncertainty for knee-only OA and not appropriate for
multiple-joint OA [2]. This recommendation was based on a recent
systematic review demonstrating a small but significant efficacy of
IA HA for knee OA pain by week 4, with a peak at week 8 (reaching
moderate clinical significance) and residual benefit until 24 weeks
[10]. Another review found moderate benefits of IA HA for pain and
physical function in knee OA [11]. A third review comparing IA HA
and IA CS found that IA HA provided greater benefit at 12 and
26 weeks [6]. Conversely, the 2012 ACR guidelines contain no
recommendations regarding the use of IA HA as first-line
treatment. IA HA injections for knee OA were conditionally
recommended only for patients with inadequate response to
initial therapy by the technical expert panel [1].
In a systematic review and network meta-analysis of pharma-
cological treatment for knee OA by Bannuru et al., the ES for IA CS
(ES = 0.63, 95% CI 0.39–0.88) was the highest among all the
pharmacological treatments assessed [9]. In the most recently
updated systematic review and meta-analysis, including only trials
considered to have low risk of bias (adequate randomization and
concealment, and double-blind design), 8 RCTs (2199 randomized
patients) met the inclusion criteria [12]. At 3 months, IA HA
significantly reduced pain intensity (SMD 0.21, 95% CI 0.32 to
0.10) and improved function (SMD 0.12, 95% CI 0.22 to 0.02)
as compared with placebo. The authors concluded that IA HA
provided a moderate but real benefit for patients with knee OA
[12]. Experimental data suggest a differential action by HA
molecular weight (MW). Consistently, some authors found that
HA MW may affect its efficacy and safety, with the highest MW
more efficient than low MW HA [13]. However, the studies
included were heterogeneous, publication bias was high and these
conclusions were not supported by other studies. Another meta-
analysis even suggested more frequent post-injection reactions
with high rather than low MW HA [14]. In clinical practice, HA LW
is most commonly used. In trials with low risk of bias, the number
of IA HA injections varied from 1 injection for 1 cycle to 5 injections
for 4 cycles [12]. However, trials directly comparing different
regimens of injections are lacking, and till date, we lack evidence of
an effect of number of joint injections. One can assume that
increased number of injections might increase the risk for serious
adverse events [11]. Seven of the 8 trials included in this meta-
analysis received industry funding, and the authors of the meta-
analysis disclosed competing interests [12]. However, stratified
analysis by funding source has not been performed.
3.3. PRP injection
IA ‘‘biological therapies’’ have generated intense interest as
possible modifiers of cartilage biology. PRP derived from autolo-
gous blood with a high concentration of activated platelets in a
small volume of plasma, which can release a host of mediators and
growth factors that act during the initial phase of tissue healing
and regeneration. Several growth factors are released, such as
186 C. Nguyen et al. / Annals of Physical and Rehabilitation Medicine 59 (2016) 184–189
insulin growth factor-1 (IGF-1), platelet-derived growth factor
(PDGF), epidermal growth factor (EGF), vascular EGF (VEGF),
transforming growth factor-b (TGF-b), and others [15]. In vitro,
PRP has been shown to have many and complex biological
activities, including cellular proliferation, anti-apoptotic activity,
cartilage regeneration, collagen synthesis, angiogenesis, and
increased vascular permeability [15]. PRP interacts with various
tissues, including cartilage, synovial membrane, synovial fluid, and
subchondral bone [16]. In vivo, in 2 animal models of OA, treatment
with IA PRP was associated with reduced chondrolysis [17,18].
The comparative efficacy and safety profile of IA PRP with other
IA drugs for treating knee OA remains controversial. More than
20 open-label studies have been published and have suggested
short- to mid-term efficacy in improving both pain and function
[19]. The many limitations of these studies included heterogeneity
in selected patients and differences in PRP preparations and
administration regimens [16]. The most recent comprehensive
systematic review of English language, original research RCTs for
level I evidence identified only 6 eligible trials [20]; in 5 studies, IA
PRP was compared to IA HA [21–25] and in one study to IA saline
[26]. Because of the heterogeneity of outcome measures, a meta-
analysis could not be performed, and a best-evidence synthesis
was used instead [20]. Authors of this systematic review concluded
that all but one study [22] showed significant differences in clinical
outcomes between PRP and HA, or PRP and saline, in pain and
function, with mean post-treatment Western Ontario and
McMaster Universities Osteoarthritis Index (WOMAC) scores
significantly better for PRP than HA at 3–6 months and 6–12
months [20]. However, many limitations and biases were noted
among the 6 studies included, with serious concerns about
randomization and blinding procedures; only one of the RCTs
used a double-blind approach [24], and in 2 studies, the
randomization procedure was not reported [21,26]. Furthermore,
the PRP preparation and composition differed and were not
standardized, so results were difficult to compare. In the absence of
an appropriate blinding, a high placebo effect related to the novelty
of the product could not be excluded. Finally, PRP is a blood
product that should be submitted to specific regulation. Therefore,
the long-term effects of IA PRP with this type of product on the
joint (i.e., abnormal cell activation) should be cautiously assessed.
Of note, the authors of this review disclosed potential conflicts of
interest [20].
After February 2015, 3 supplementary RCTs were published:
2 RCTs comparing IA PRP to IA HA [27,28] and 1 RCT comparing, for
the first time, IA PRP to IA CS [29]. The first study randomized
162 patients with different stages of knee OA into 4 groups
receiving 3 doses of IA PRP, 1 dose of IA PRP, 1 dose of IA HA or
1 dose of IA saline (control group). Patients were assessed at
6 months. All groups showed improvement on the EuroQol VAS
and International Knee Documentation Committee scores as
compared with controls. Patients injected with 1 dose of IA PRP
or IA HA did not differ in outcome. In the early OA subgroups
Table 1
International guidelines for the use of intra-articular treatments for knee OA.
ACR 2012 [1]
Corticosteroids Conditional
recommendation
Hyaluronic acid No recommendation
Platelet-rich plasma – –
Botulinum toxin A – –
ACR, American College of Rheumatology; EULAR, European League Against Rheumatism; LOA, level of agreement; LOE, level of evidence; MA, meta-analysis; OARSI,
Osteoarthritis Research Society International; RCT, randomized controlled trial; SOR, strength of recommendation; SR, systematic review.
(Kellgren–Lawrence score I–II), patients who received 3 IA PRP
doses showed better clinical results. Patients with advanced OA
(Kellgren–Lawrence score III–IV) showed no difference among
treatments [28]. The second study randomized 192 knee OA
patients (Kellgren–Lawrence score 0–III) to 2 groups: 3 weekly IA
PRP or IA HA. Patients were assessed at 2, 6, and 12 months. Post-
injection swelling and pain were more frequent with PRP than HA.
Both treatments were effective in improving knee functional status
and reducing symptoms by the International Knee Documentation
Committee (IKDC) subjective score. The 2 groups did not differ at
any follow-up time [27]. Finally, in a double-blind RCT, Forogh
et al. compared, for the first time, a single IA PRP injection to IA CS
in 41 participants with knee OA (Kellgren–Lawrence score II–III), at
2 and 6 months. As compared with IA CS, IA PRP decreased joint
pain more and for longer than IA CS and improved activities of daily
living and quality of life in the short-term [29].
3.4. BTA injection
BTA is a potent neurotoxin produced by the bacterium
Clostridium botulinum [30]. BTA inhibits acetylcholine release into
the synaptic cleft in cholinergic nerve terminals causing muscle
paralysis [31]. In humans, BTA was originally used for its muscle
paralyzing effects in neuromuscular disorders, such as spasticity,
cervical dystonia and blepharospasm [32,33]. However, growing
evidence from RCTs also supports a potent role of IA BTA as a pain
modulator in various types of musculoskeletal conditions
[34,35]. Consistently, preclinical experimental studies of dogs
[36,37] (OA), horses [38] (synovitis) or mice [39,40] with painful
joint conditions confirmed an antinociceptive efficacy of IA BTA.
The exact mechanisms of pain modulation by BTA in OA remain
unclear. Pain in OA involves both nociceptive and neuropathic
complex mechanisms and abnormal excitability in peripheral and
central pain pathways [41–46]. BTA was suggested to suppress the
secretion of neurotransmitters, thus directly decreasing peripheral
sensitization and indirectly decreasing central sensitization
[47,48]. Recent studies also suggest an inhibitory role of BTA on
the release of mediators involved in nociception, such as substance
P, calcitonin gene-related peptide and glutamate [49].
Non-randomized trials and RCTs of BTA in various osteoarti-
cular conditions, including OA, were comprehensively reviewed in
2013 [34]. The author of the review declared no financial
competing interests directly related to the study [34]. In the Boon
et al. study, 60 patients (61–64 years old) with chronic knee pain
(symptom duration 6–10 years) were randomized to 3 groups: IA
BTA 100 U (n = 20), IA BTA 200 U (n = 20), and IA CS (n = 20). At
week 8, the 3 groups showed reduced pain and improved function
as assessed by the WOMAC, with no differences between the
3 groups. Quality of life assessed by the Medical Outcomes Survey
36-Item Short Form was improved only in the IA BTA group for the
pain index [50]. In the Mahowald et al. study, 42 patients with
refractory chronic painful knees (pain duration not provided) were
EULAR 2003 [57] OARSI 2014 [2]
SOR A: category 1 evidence Appropriate, appropriateness score: 7/9
LOE 1B: at least one RCT LOE: SR and MA of RCTs
SOR B: category 2 evidence Uncertain, appropriateness score: 5/9 with
or extrapolated recommendation no comorbidities and 4/9 with comorbidities
from category 1 evidence
LOE 1B: at least one RCT LOE: SR and MA of RCTs
–
–
Table 2
Ongoing registered studies of intra-articular treatments for knee osteoarthritis (OA).

Registration Date Phase RCT Study population Intervention Comparator Primary outcome Status Sponsor

NCT01518257 2012 I/II Yes Painful OA A single 200-U dose of IA BTA A single 2-mL dose of IA saline Pain at 4, 8 and 12 weeks Completed Allergan
NCT00279903 2005 I Yes Painful OA 100 or 200 U of IA BTA 40 mg of IA Pain at 8 weeks Completed Mayo Clinic
KL II/III methylprednisolone
NCT02139319 2014 I Yes Knee OA Single IA injection of BT Single IA injection of placebo AEs up to 6 weeks Completed Q-Med AB
NCT02230956 2014 II Yes Painful OA 1 or 2 IA injections of BTA IA injection of saline Pain at 8 weeks Ongoing Allergan
Not recruiting
NCT02239029 2014 – Yes Painful OA Single IA injection of PRP Single IA injection of saline Pain at 2 weeks, 1, 3 and 6 months Recruiting Yung-Tsan Wu
NCT01381081 2011 III Yes Painful OA Single IA injection of PRP Betamethasone and Pain at 1 month Completed Hospital Universitari Vall
bupivacaine IA injection d’Hebron Research Institute
NCT02039531 2013 III Yes Painful OA One cycle of 3 IA injection of PRGF Single IA injection of HA WOMAC and Lequesne at 6 months Completed Fundacion para la Investigacion
KL II/III every 15 days Biomedica del Hospital
Universitario Principe de Asturias

C. Nguyen et al. / Annals of Physical and Rehabilitation Medicine 59 (2016) 184–189

NCT02142842 2014 I/II No Knee OA IA injection of autologous stromal – AEs up to 6 months Completed University of Science Ho Chi Minh
Grade 2/3 vascular fraction and PRP City
NCT02370420 2015 III Yes Knee OA Single IA injection of PRP Triple IA injections of PRP WOMAC at 3 and 6 weeks, and 3, 6, Recruiting Universidad Autonoma de Nuevo
KL I/II with an interval of 2 weeks 9 and 12 months Leon
NCT01697423 2012 II Yes Painful OA IA PRP IA HA WOMAC at 12 months Recruiting Assistance Publique – Hôpitaux
De Marseille
NCT02468492 2015 0 Yes Knee OA Single IA injection of PRP Single IA injection of saline Biochemical molecular outcomes Ongoing Hunter Holmes Mcguire Veteran
KL II/III at 10 days Not recruiting Affairs Medical Center
NCT01270412 2010 II/III Yes Knee OA Single IA injection of PRGF Single IA injection of HA Pain, function, quality of life and Unknown Meir Medical Center
activity level at 1 and 2 years
NCT02588872 2015 III Yes Painful knee OA 3 weekly IA injections of PRP 3 weekly IA injections of HA IKDC at 6 weeks, 6 months and Completed Rush University Medical Center
1 year
NCT02365142 2014 II Yes Knee OA 3 IA injections of PRP Single IA injection of Pain and KOOS at 1, 3, 6 and Recruiting Clinica Universidad de Navarra,
KL  II 100 million bone-marrow 12 months Universidad de Navarra
mesenchymal stem cells and
3 IA injections of PRGF
NCT02448407 2015 III Yes Painful OA 3 IA injections of PRP 3 IA injections of HA Pain at 28 days, 3 and 6 months Completed Fundación Pública Andaluza para
KL I/II/III la Investigación de Málaga en
Biomedicina y Salud
NCT01782885 2013 III Yes Knee OA 3 IA injections of PRP Acetaminophen (500 mg/8 h) WOMAC at 6, 12 and 24 weeks Completed Hospital Universitario Dr. Jose E.
KL I/II Gonzalez
NCT01926327 2013 III Yes Painful OA Single IA injection of PRP Single IA injection of saline Pain and WOMAC at 3 months, Completed Royan Institute
Grade II cartilage repair at 12 months
NCT01923909 2013 IV Yes Painful OA Single IA injection of PRP Single IA injection of WOMAC and Oxford Knee Score Unknown King Hamad University Hospital,
KL I/II/III Bupivacaine and Depomedrol from 6 weeks to 6 months Bahrain
NCT02211521 2014 III Yes Painful OA Single IA injection of PRP Single IA injection of HA Pain at 6, 12 and 24 weeks Completed Samsung Medical Center
NCT01985633 2013 I/II Yes Knee OA Single IA injection of PRP and Single IA injection of PRP Pain at 6 months Unknown Aditya K Aggarwal
Grade I/II mesenchymal stem cell
suspension
NCT00782197 2008 IV Yes Painful OA 3 IA injections of PRP 3 IA injections of HA WOMAC Lequesne and pain at Completed Biotechnology Institute IMASD
Grade III 6 months
NCT01747018 2012 I/II No Early OA and Single IA injection of PRP – Pain at 6 months Completed The Catholic University of Korea
degenerative
chondropathy
NCT01670578 2012 IV Yes KL  III 3 IA injections of PRP 3 IA injections of HA IKDC at 12 months Completed Istituto Ortopedico Rizzoli
NCT02135367 2014 IV Yes KL  II 3 IA injections of PRP 3 IA injections of HA IKDC at 12 months Recruiting Istituto Ortopedico Rizzoli
NCT02012530 2014 III Yes Painful knee Single IA injection of PRP Single IA injection of HA and KOOS at 3 months Not yet open Shetty-Kim Research Foundation
degenerative anesthetic
cartilage lesions
(Grade 1–3)
Source: https://clinicaltrials.gov/ February 2016.
AEs, adverse events; HA, hyaluronic acid; IA, intra-articular; IKDC, International Knee Documentation Committee score; KL, Kellgren–Lawrence; KOOS, Knee injury and Osteoarthritis Outcome Score; PRGF, plasma rich in growth
factors; PRP, platelet-rich plasma; RCT, randomized controlled trial; WOMAC, Western Ontario and McMaster Universities Osteoarthritis Index.

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188 C. Nguyen et al. / Annals of Physical and Rehabilitation Medicine 59 (2016) 184–189
randomly assigned to IA BTA 100 U (n = 21) or IA saline (n = 21).
At 1 month, the 2 groups were comparable for pain reduction. At
3 months, pain reduction compared to baseline was significant
only for the IA BTA group [51]. In these 2 studies, whether knee
pain was related to knee OA or to another knee condition was not
detailed.
4. Discussion
In our critical review of the latest evidence and evidence-based
guidelines, IA CS and HA injections were conditionally to fully
recommended for treatment of knee OA. No recommendations
have been formulated regarding IA PRP or BTA (Table 1).
In addition to oral treatments, IA HA injections are often used in
daily practice for managing knee OA. The effectiveness of IA HA,
used for more than 20 years, remains debated. HA is now not
recommended by the American Academy of Orthopedic Surgeons
[52] and is conditionally recommended by the ACR [1]. OARSI
recently provided an uncertain recommendation [2]. To help
practitioners in the use of IA HA, a panel of 8 international experts
achieved unanimous agreement in favor of the following 9 of
24 statements: ‘‘(1) IA HA is an effective treatment for mild to
moderate knee OA; (2) IA HA is not an alternative to surgery in
advanced hip OA; (3) IA HA is a well-tolerated treatment of
knee and other joints OA; (4) IA HA should not be used only in
patients who have failed to respond adequately to analgesics and
NSAIDs; (5) IA HA is a ‘positive’ indication but not a ‘lack of
anything better’ indication; (6) the dosing regimen must be
supported by evidence-based medicine; (7) cross-linking is a
proven means for prolonging IA residence time of HA; (8) the best
approach to inject accurately knee joint is the lateral mid-patellar
one; (9) when IA HA injection is performed under fluoroscopy, the
amount of radiopaque contrast agent must be as low as possible to
avoid HA dilution’’ [53].
Despite the long-standing use of IA CS, its effectiveness and
safety remains debated. Authors of the 2015 updated Cochrane
review of IA CS for knee OA concluded that ‘‘it remained unclear
whether there were clinically important benefits one to six weeks
after CS injection in view of the low quality of the included trials,
the large amount of heterogeneity, and the likely presence of
small-study effects, that IA CS should therefore be considered
experimental in knee OA and not be routinely used until
adequately powered and properly designed trials clearly indicate
a short- to mid-term benefit’’. This apparent discrepancy between
practice and evidence could be related to methodological issues
but also to patient selection. Indeed, patients included in RCTs
might not be the same as those clinicians are likely to treat in ‘‘real
life.’’ Obviously, not all knee OA patients could benefit from IA CS.
Most of the RCTs of patients with knee OA support a slightly
better symptomatic effect of IA PRP than IA HA [20], IA CS [29] or IA
saline [26], especially with early disease [28]. However, the designs
of the trials were not always appropriate to demonstrate the
superiority of IA PRP, and results should be interpreted cautiously
in terms of the strong placebo effect of IA injections in knee OA
[9]. In addition, given the large number of mediators and the wide
range of joint biological effects, the accurate mechanism of the
potent chondroprotective properties of PRP remains unclear
[15,16]. The main concerns that preclude the generalizability of
experimental and clinical findings are the high variability in
composition of PRP, with platelet concentrations varying five-fold
across studies, uncontrolled growth factor concentrations among
donors, and different IA administration regimen [15,16]. Finally,
the safety data suggest low frequency of serious adverse events,
including infections and allergic reactions. Post-injection pain may
be more common and more severe with IA PRP than other
injections [16].
Overall, only 2 small RCTs provided inconsistent evidence of the
short-term efficacy of a single IA BTA injection for relieving pain
and improving function and quality of life in patients with chronic
knee pain related to various musculoskeletal conditions, with no
clear superiority over the comparator treatment [50,51]. Although
the rationale for pain modulation by IA BTA in OA is promising, till
date, evidence is lacking to recommend IA BTA for treating
symptomatic knee OA. Therefore, IA BTA is neither included nor
considered in any of the national or international guidelines for
managing OA. In addition, concerns have been recently raised
about the safety of treatment strategies targeting nociceptive
mechanisms in OA, such as anti-nerve growth factor (NGF)
therapies [54]. The syndrome of rapid progression of OA associated
with chondrolysis and bone destruction appears to be a safety
signal associated with increasing doses of anti-NGF antibodies
[54]. The occurrence of rapidly progressive OA might represent a
form of neuropathic arthropathy caused by nerve damage resulting
in the loss of ability to feel pain in the joint combined with reduced
joint proprioception [55]. This kind of adverse event could
theoretically translate to treatments modifying joint pain percep-
tion but has not been specifically assessed for IA BTA. RCTs
specifically assessing the efficacy and safety of IA BTA in
symptomatic knee OA are mandatory. Currently, 4 studies are
registered, and 3 of 4 are completed (ClinicalTrials.gov identifiers:
NCT01518257 [n = 121], NCT00279903 [n = 62], NCT02139319
[n = 22], NCT02230956 [n = 176]). The results of these studies are
not yet available. Ongoing registered studies of IA treatments with
PRP and BTA for knee OA are summarized in Table 2.
Overall, IA injections should be considered part of a multi-
modal approach to the management of OA, combining both non-
pharmacological and pharmacological interventions, as recom-
mended in all the international guidelines.
5. Conclusions
Evidence is rather inconsistent and controversial about IA
therapies for the management of knee OA. The most frequently
used IA drugs, namely CS and HA, are conditionally to fully
recommended. There are no recommendations for the use of PRP
and BTA.
One can question the heterogeneity of the OA patient
phenotypes included in the studies, which may have precluded
the generalizability of the results and may not correspond to
patients who would have been treated in ‘‘real life.’’ Indeed, there is
a gap between practice and recommendations regarding IA
treatments in OA. Efforts should be made to identify the
characteristics of and selection criteria for the OA population
likely to benefit from these therapies. Accurately phenotyping and
selecting patients [56] is mandatory in future RCTs. Therefore,
efficacy and safety meta-analyses should be performed, as should
qualitative and sensitivity analyses of published trials. Finally,
powerful methodological approaches, such as network meta-
analyses, have allowed for comparing available pharmacological
treatments in OA according to their relative efficacy, safety profiles
and relative costs. These approaches may be helpful in formulating
evidence-based algorithms.
Disclosure of interest
The authors declare that they have no competing interest.
References
[1] Hochberg MC, Altman RD, April KT, Benkhalti M, Guyatt G, McGowan J, et al.
American College of Rheumatology 2012 recommendations for the use of
nonpharmacologic and pharmacologic therapies in osteoarthritis of the hand,
hip, and knee. Arthritis Care Res (Hoboken) 2012;64:465–74.
 C. Nguyen et al. / Annals of Physical and Rehabilitation Medicine 59 (2016) 184–189
[2] McAlindon TE, Bannuru RR, Sullivan MC, Arden NK, Berenbaum F, Bierma-
Zeinstra SM, et al. OARSI guidelines for the non-surgical management of knee
osteoarthritis. Osteoarthr Cartil 2014;22:363–88.
[3] Roberts E, Delgado Nunes V, Buckner S, Latchem S, Constanti M, Miller P, et al.
Paracetamol: not as safe as we thought? A systematic literature review of
observational studies. Ann Rheum Dis 2016;75(3):552–9.
[4] Creamer P. Intra-articular corticosteroid injections in osteoarthritis: do they
work and if so, how? Ann Rheum Dis 1997;56:634–6.
[5] Miller JH, White J, Norton TH. The value of intra-articular injections in
osteoarthritis of the knee. J Bone Joint Surg Br 1958;40-B:636–43.
[6] Bannuru RR, Natov NS, Obadan IE, Price LL, Schmid CH, McAlindon TE.
Therapeutic trajectory of hyaluronic acid versus corticosteroids in the treat-
ment of knee osteoarthritis: a systematic review and meta-analysis. Arthritis
Rheum 2009;61:1704–11.
[7] Bellamy N, Campbell J, Robinson V, Gee T, Bourne R, Wells G. Intraarticular
corticosteroid for treatment of osteoarthritis of the knee. Cochrane Database
Syst Rev 2006;CD005328.
[8] Juni P, Hari R, Rutjes AW, Fischer R, Silletta MG, Reichenbach S, et al. Intra-
articular corticosteroid for knee osteoarthritis. Cochrane Database Syst Rev
2015;10:CD005328.
[9] Bannuru RR, Schmid CH, Kent DM, Vaysbrot EE, Wong JB, McAlindon TE.
Comparative effectiveness of pharmacologic interventions for knee osteoar-
thritis: a systematic review and network meta-analysis. Ann Intern Med
2015;162:46–54.
[10] Bannuru RR, Natov NS, Dasi UR, Schmid CH, McAlindon TE. Therapeutic
trajectory following intra-articular hyaluronic acid injection in knee osteoar-
thritis – meta-analysis. Osteoarthr Cartil 2011;19:611–9.
[11] Rutjes AW, Juni P, da Costa BR, Trelle S, Nuesch E, Reichenbach S. Viscosup-
plementation for osteoarthritis of the knee: a systematic review and meta-
analysis. Ann Intern Med 2012;157:180–91.
[12] Richette P, Chevalier X, Ea HK, Eymard F, Henrotin Y, Ornetti P, et al. Hyalu-
ronan for knee osteoarthritis: an updated meta-analysis of trials with low risk
of bias. RMD Open 2015;1:e000071.
[13] Lo GH, LaValley M, McAlindon T, Felson DT. Intra-articular hyaluronic acid in
treatment of knee osteoarthritis: a meta-analysis. JAMA 2003;290:3115–21.
[14] Reichenbach S, Blank S, Rutjes AW, Shang A, King EA, Dieppe PA, et al. Hylan
versus hyaluronic acid for osteoarthritis of the knee: a systematic review and
meta-analysis. Arthritis Rheum 2007;57:1410–8.
[15] Pintan GF, de Oliveira Jr AS, Lenza M, Antonioli E, Ferretti M. Update on
biological therapies for knee injuries: osteoarthritis. Curr Rev Musculoskelet
Med 2014;7:263–9.
[16] Ornetti P, Nourissat G, Berenbaum F, Sellam J, Richette P, Chevalier X. Does
platelet-rich plasma have a role in the treatment of osteoarthritis? Joint Bone
Spine 2016;83(1):31–6.
[17] Kwon DR, Park GY, Lee SU. The effects of intra-articular platelet-rich plasma
injection according to the severity of collagenase-induced knee osteoarthritis
in a rabbit model. Ann Rehabil Med 2012;36:458–65.
[18] Saito M, Takahashi KA, Arai Y, Inoue A, Sakao K, Tonomura H, et al. Intraartic-
ular administration of platelet-rich plasma with biodegradable gelatin hydro-
gel microspheres prevents osteoarthritis progression in the rabbit knee. Clin
Exp Rheumatol 2009;27:201–7.
[19] Zhu Y, Yuan M, Meng HY, Wang AY, Guo QY, Wang Y, et al. Basic science and
clinical application of platelet-rich plasma for cartilage defects and osteoar-
thritis: a review. Osteoarthr Cartil 2013;21:1627–37.
[20] Meheux CJ, McCulloch PC, Lintner DM, Varner KE, Harris JD. Efficacy of intra-
articular platelet-rich plasma injections in knee osteoarthritis: a systematic
review. Arthroscopy 2016;32(3):495–505.
[21] Cerza F, Carni S, Carcangiu A, Di Vavo I, Schiavilla V, Pecora A, et al. Comparison
between hyaluronic acid and platelet-rich plasma, intra-articular infiltration
in the treatment of gonarthrosis. Am J Sports Med 2012;40:2822–7.
[22] Filardo G, Kon E, Di Martino A, Di Matteo B, Merli ML, Cenacchi A, et al. Platelet-
rich plasma vs hyaluronic acid to treat knee degenerative pathology: study
design and preliminary results of a randomized controlled trial. BMC Muscu-
loskelet Disord 2012;13:229.
[23] Raeissadat SA, Rayegani SM, Hassanabadi H, Fathi M, Ghorbani E, Babaee M,
et al. Knee osteoarthritis injection choices: platelet-rich plasma (PRP) versus
hyaluronic acid (a one-year randomized clinical trial). Clin Med Insights
Arthritis Musculoskelet Disord 2015;8:1–8.
[24] Sanchez M, Fiz N, Azofra J, Usabiaga J, Aduriz Recalde E, Garcia Gutierrez A,
et al. A randomized clinical trial evaluating plasma rich in growth factors
(PRGF-Endoret) versus hyaluronic acid in the short-term treatment of symp-
tomatic knee osteoarthritis. Arthroscopy 2012;28:1070–8.
[25] Vaquerizo V, Plasencia MA, Arribas I, Seijas R, Padilla S, Orive G, et al.
Comparison of intra-articular injections of plasma rich in growth factors
(PRGF-Endoret) versus Durolane hyaluronic acid in the treatment of patients
with symptomatic osteoarthritis: a randomized controlled trial. Arthroscopy
2013;29:1635–43.
[26] Patel S, Dhillon MS, Aggarwal S, Marwaha N, Jain A. Treatment with platelet-
rich plasma is more effective than placebo for knee osteoarthritis: a prospec-
tive, double-blind, randomized trial. Am J Sports Med 2013;41:356–64.
[27] Filardo G, Di Matteo B, Di Martino A, Merli ML, Cenacchi A, Fornasari P, et al.
Platelet-rich plasma intra-articular knee injections show no superiority versus
viscosupplementation: a randomized controlled trial. Am J Sports Med
2015;43:1575–82.
[28] Gormeli G, Gormeli CA, Ataoglu B, Colak C, Aslanturk O, Ertem K, Multiple PRP.
injections are more effective than single injections and hyaluronic acid in
189
knees with early osteoarthritis: a randomized, double-blind, placebo-con-
trolled trial. Knee Surg Sports Traumatol Arthrosc 2015 [Epub ahead of print].
[29] Forogh B, Mianehsaz E, Shoaee S, Ahadi T, Raissi GR, Sajadi S. Effect of single
injection of platelet-rich plasma in comparison with corticosteroid on knee
osteoarthritis: a double-blind randomized clinical trial. J Sports Med Phys Fit
2015.
[30] Sugiyama H. Clostridium botulinum neurotoxin. Microbiol Rev 1980;44:
419–48.
[31] Dressler D, Adib Saberi F. Botulinum toxin: mechanisms of action. Eur Neurol
2005;53:3–9.
[32] Balash Y, Giladi N. Efficacy of pharmacological treatment of dystonia: evi-
dence-based review including meta-analysis of the effect of botulinum toxin
and other cure options. Eur J Neurol 2004;11:361–70.
[33] Simpson DM, Blitzer A, Brashear A, Comella C, Dubinsky R, Hallett M, et al.
Assessment: botulinum neurotoxin for the treatment of movement disorders
(an evidence-based review): report of the Therapeutics and Technology
Assessment Subcommittee of the American Academy of Neurology. Neurology
2008;70:1699–706.
[34] Singh JA. Use of botulinum toxin in musculoskeletal pain. F1000Research
2013;2:52.
[35] Sun SF, Hsu CW, Lin HS, Chou YJ, Chen JY, Wang JL. Efficacy of intraarticular
botulinum toxin A and intraarticular hyaluronate plus rehabilitation exercise
in patients with unilateral ankle osteoarthritis: a randomized controlled trial. J
Foot Ankle Res 2014;7:9.
[36] Hadley HS, Wheeler JL, Petersen SW. Effects of intra-articular botulinum toxin
type A (Botox) in dogs with chronic osteoarthritis. Vet Comp Orthop Traumatol
2010;23:254–8.
[37] Heikkila HM, Hielm-Bjorkman AK, Morelius M, Larsen S, Honkavaara J, Innes
JF, et al. Intra-articular botulinum toxin A for the treatment of osteoarthritic
joint pain in dogs: a randomized, double-blinded, placebo-controlled clinical
trial. Vet J 2014;200:162–9.
[38] DePuy T, Howard R, Keegan K, Wilson D, Kramer J, Cook JL, et al. Effects of intra-
articular botulinum toxin type A in an equine model of acute synovitis: a pilot
study. Am J Phys Med Rehabil 2007;86:777–83.
[39] Anderson S, Krug H, Dorman C, McGarraugh P, Frizelle S, Mahowald M.
Analgesic effects of intra-articular botulinum toxin Type B in a murine model
of chronic degenerative knee arthritis pain. J Pain Res 2010;3:161–8.
[40] Mahowald ML, Krug HE, Singh JA, Dykstra D. Intra-articular botulinum toxin
type A: a new approach to treat arthritis joint pain. Toxicon 2009;54:658–67.
[41] Garrett NE, Mapp PI, Cruwys SC, Kidd BL, Blake DR. Role of substance P in
inflammatory arthritis. Ann Rheum Dis 1992;51:1014–8.
[42] Konttinen YT, Kemppinen P, Segerberg M, Hukkanen M, Rees R, Santavirta S,
et al. Peripheral and spinal neural mechanisms in arthritis, with particular
reference to treatment of inflammation and pain. Arthritis Rheum 1994;37:
965–82.
[43] Schaible HG. Peripheral and central mechanisms of pain generation. Handb
Exp Pharmacol 2007;3–28.
[44] Schaible HG, Richter F, Ebersberger A, Boettger MK, Vanegas H, Natura G, et al.
Joint pain. Exp Brain Res 2009;196:153–62.
[45] Schaible HG, Schmelz M, Tegeder I. Pathophysiology and treatment of pain in
joint disease. Adv Drug Deliv Rev 2006;58:323–42.
[46] Welch MJ, Purkiss JR, Foster KA. Sensitivity of embryonic rat dorsal root
ganglia neurons to Clostridium botulinum neurotoxins. Toxicon 2000;38:
245–58.
[47] Arezzo JC. Possible mechanisms for the effects of botulinum toxin on pain. Clin
J Pain 2002;18(6 Suppl.):S125–32.
[48] Freund B, Schwartz M. Temporal relationship of muscle weakness and pain
reduction in subjects treated with botulinum toxin A. J Pain 2003;4:159–65.
[49] Durham PL, Cady R, Cady R. Regulation of calcitonin gene-related peptide
secretion from trigeminal nerve cells by botulinum toxin type A: implications
for migraine therapy. Headache 2004;44:35–42. discussion-3.
[50] Boon AJ, Smith J, Dahm DL, Sorenson EJ, Larson DR, Fitz-Gibbon PD, et al.
Efficacy of intra-articular botulinum toxin type A in painful knee osteoarthri-
tis: a pilot study. PM R 2010;2:268–76.
[51] Mahowald ML, Singh JA, Dykstra D. Long term effects of intra-articular
botulinum toxin A for refractory joint pain. Neurotox Res 2006;9:179–88.
[52] Jevsevar DS, Brown GA, Jones DL, Matzkin EG, Manner PA, Mooar P, et al. The
American Academy of Orthopaedic Surgeons evidence-based guideline on:
treatment of osteoarthritis of the knee, 2nd edition. J Bone Joint Surg Am
2013;95:1885–6.
[53] Henrotin Y, Raman R, Richette P, Bard H, Jerosch J, Conrozier T, et al. Consensus
statement on viscosupplementation with hyaluronic acid for the management
of osteoarthritis. Semin Arthritis Rheum 2015;45:140–9.
[54] Hochberg MC. Serious joint-related adverse events in randomized controlled
trials of anti-nerve growth factor monoclonal antibodies. Osteoarthr Cartil
2015;23(Suppl. 1):S18–21.
[55] Chisholm KA, Gilchrist JM. The Charcot joint: a modern neurologic perspective.
J Clin Neuromuscul Dis 2011;13:1–13.
[56] Maricar N, Callaghan MJ, Felson DT, O’Neill TW. Predictors of response to intra-
articular steroid injections in knee osteoarthritis – a systematic review.
Rheumatology (Oxford) 2013;52:1022–32.
[57] Jordan KM, Arden NK, Doherty M, Bannwarth B, Bijlsma JW, Dieppe P, et al.
EULAR Recommendations 2003: an evidence based approach to the manage-
ment of knee osteoarthritis: Report of a Task Force of the Standing Committee
for International Clinical Studies Including Therapeutic Trials (ESCISIT). Ann
Rheum Dis 2003;62:1145–55.