6.21002EOR0010.1302/2058-5241.6.

210026
review-article2021

EOR | volume 6 | June 2021

Instructional Lecture: Knee DOI: 10.1302/2058-5241.6.210026
www.efortopenreviews.org

Injections in the osteoarthritic knee: a review of

current treatment options
Gerardo Fusco1,2,4
Francesco M. Gambaro1,2,4
Berardo Di Matteo1,3
Elizaveta Kon1,2

„„ Knee osteoarthritis is a degenerative condition character- Keywords: injection; osteoarthritis; stem cells
ized by progressive cartilage degradation, subchondral
damage, and bone remodelling. Among the approaches Cite this article: EFORT Open Rev 2021;6:501-509.
implemented to achieve symptomatic and functional DOI: 10.1302/2058-5241.6.210026
improvements, injection treatments have gained increas-
ing attention due to the possibility of intra-articular
delivery with reduced side effects compared to systemic
therapies.
Introduction
„„ In addition to well-established treatment options such as Osteoarthritis (OA) is a degenerative disease with a ten-
hyaluronic acid (HA), cortico-steroids (CS) and oxygen- dency to worsen over time, characterized by articular
ozone therapy, many other promising products have cartilage degradation, subchondral damage, and bone
been employed in the last decades such as polydeoxyri- remodelling, most commonly affecting weight-bearing
bonucleotide (PDRN) and biologic agents such as platelet- joints such as the knee and hip. The aim of OA treatment
rich plasma (PRP) and mesenchymal stem cells (MSCs). is to control symptoms until the severity of the condi-
Moreover, ultrasound-guided intra-meniscal injection and tion mandates surgical intervention; an early therapy
X-ray-guided subchondral injection techniques have been may be a vital step for delaying the progression to end-
introduced into clinical practice. stage disease. 1 Symptomatic control can be achieved
„„ Even when not supported by high evidence consensus, through different therapeutic strategies such as lifestyle
intra-articular CS and HA injections have gained precise modifications, exercise therapy, pharmacological thera-
indications for symptomatic relief and clinical improve- pies and injections of various substances.2 Pharmaco-
ment in OA. Biological products are strongly supported logical approaches based for example on non-steroidal
by in vitro evidence but there is still a lack of robust clinical anti-inflammatory drugs (NSAIDs) and paracetamol have
evidence. PRP and MSCs seem to relieve OA symptoms been shown to be effective in controlling pain in OA,3
through a regulation of the joint homeostasis, even if their but due to their systemic administration, they have also
capability to restore articular cartilage is still to be proved been associated with gastrointestinal, cardiovascular and
in vivo. renal adverse events, especially in patients already pre-
„„ Due to increasing interest in the subchondral bone pathol- senting with comorbidities.4 Injections have therefore
ogy, subchondral injections have been developed with gained increasing attention thanks to their more direct
promising results in delaying joint replacement. Neverthe- effect on the target tissues and reduced side effects due to
less, due to their recent development and the heteroge- intra-articular delivery. Among the most frequently used
neity of the injected products (biologic agents or calcium products we include corticosteroids (CS), hyaluronic acid
phosphate), this approach still lacks strong enough evi- (HA), polynucleotides, oxygen-ozone therapy, platelet-
dence to be fully endorsed. rich plasma (PRP) and mesenchymal stem cells (MSCs).
„„ Combined biological treatments, nano-molecular CS and HA are ranked first as the most frequently injected
approaches, monoclonal antibodies and ‘personalized’ substances and their use is supported by a large amount
target therapies are currently under development or under of literature, although some controversial findings have
investigation with the aim of expanding our armamentar- emerged.5 Conversely, there exists a more limited amount
ium against knee OA. of evidence in support of the use of PRP and MSCs, due to
their more recent discovery and introduction as OA treat- found CS injections to be superior to oral NSAIDs, even
ments. Autologous biologic products, according to their if the author suggests a possible bias represented by the
capability of modulating the joint environment by releas- intra-articular (IA) placebo effect.10
ing a series of growth factors and immune-modulatory Despite its beneficial effects, CS knee injections are
molecules, could play a beneficial role in reducing the associated with some known side effects. The latest meta-
local inflammation and promoting cartilage and synovial analysis on the safety of this procedure reported rare and
anabolism.6 In addition, advances in research have not mild side effects such as temporary joint pain, erythema
only brought about new products to be injected but also and itching, but no cases of joint infection.11
novel techniques of injection such as subchondroplasty
and intra-meniscal application. The aim of the present Hyaluronic acid (HA)
narrative review is to summarize the different mechanisms Hyaluronic acid (HA) is a glycosaminoglycan that pro-
of action of the various injectables for knee OA, present- vides joint lubrication and shock absorbency and acts as
ing also their clinical results and potential areas of future the backbone for the proteoglycans of the extracellular
development. matrix. In normal adult knees, HA concentration ranges
from 2.5 to 4.0 mg/ml, whereas in OA it decreases by
Off-the-shelf products 33–50%.12 Besides their different origins and biological
characteristics, viscosupplements currently available are
Corticosteroids (CS) classified based on the molecular weight (MW), method
Intra-articular injection of CS is perhaps the most com- of preparation, and dosage. Currently, no clinical trials
mon conservative approach in the treatment of knee OA. indicate a clear advantage of one product over another,
The rationale behind its use relies on its immunosuppres- even though a higher MW allows optimal binding on
sive activity in the knee joint acting at different levels of cell surfaces. In addition, there is no evidence to support
the inflammatory cascade. In particular, it acts by blocking that HA viscosupplementation affects OA progression. HA
the synthesis of pro-inflammatory signalling molecules, effects may last up to 26 weeks.12 The benefits in terms of
such as interleukin 1 (IL-1), leukotrienes, prostaglandins pain relief and function improvement associated with HA
and catabolic proteins such as metalloproteinases.2 These have been recently rediscussed.13 Osteoarthritis Research
combined actions may be accountable for the pain relief Society International (OARSI) guidelines assigned a level
observed in patients treated with CS. of recommendation 1B/2 to the use of HA in the treatment
Indeed, the latest 2019 Osteoarthritis Research Soci- of knee OA.
ety International (OARSI) guidelines have assigned to Intra-articular HA is particularly recommended for
intra-articular CS injections a recommendation level of 1B long-term treatment, as it is associated with symptom
(‘high consensus’), the same level as for HA. In particular, improvement beyond 12 weeks (i.e. more durable effects
their use is suggested for short-term pain relief compared compared to CS), and has demonstrated a more favoura-
to hyaluronic acid, which instead requires a longer time to ble safety profile than repeated corticosteroids injections.7
provide its more beneficial effects in terms of pain control On the other hand, the American Academy of Orthopaedic
(2–4 weeks).7 Surgeons (AAOS), in light of inconclusive evidence, has
Concerning the indications for CS injections, synovitis neither endorsed nor discouraged HA use. However, the
has been seen as a single predictor of treatment response: real benefits of HA in the early stages of joint degeneration
therefore, patients with an inflammatory phenotype of need to be confirmed by specifically designed studies.
OA, characterized by stiffness, joint swelling and effusion,
are more likely to respond to CS compared to HA.8 Polynucleotides
The latest Cochrane meta-analysis of 27 randomized Polydeoxyribonucleotide (PDRN) is composed by poly-
controlled trials (RCTs) found CS to be more beneficial mers of various chain lengths capable of binding large
in pain reduction (lower visual analogue scale (VAS)) amounts of water molecules, hence capable of reorgan-
and function improvement (measured with the Western izing the cartilage surface.14 Moreover, PDRN in vitro
Ontario and McMaster Universities Osteoarthritis Index experiments have shown enhancement of chondrocyte
(WOMAC) score) than control interventions, but this dif- survivorship if compared to HA exposure, with a reduced
ference was gradually lost after up to 13 weeks of follow- proteoglycans degradation.15
up, at which point no statistical difference was detected. PDRN effects seem to be related to viscoelastic prop-
Nevertheless, the reliability of these results is poor due erties, cell grown induction, collagen and cell migration
to the low methodological quality of the included RCTs, and anti-inflammatory capabilities. Moreover, in animal
hence the quality of evidence in support of CS injections models, not only symptomatic improvement has been
for knee OA was graded as ‘low’.9 Most recent studies reported, but also a decrease of proinflammatory factors,

502
 Injections in the osteoarthritic knee

such as IL-6, tumor necrosis factor-alpha (TNF-α) and high

mobility group box 1 (HMGB-1). Despite the need for fur-
ther studies, PDRN has been shown to reduce cartilage
oligomeric matrix protein (COMP) levels, which them-
selves have recently been investigated as a biomarker of
arthritis.16
PDRN offers mechanical protection towards the dam-
aged cartilage, replacing the synovial fluid and restoring
an ideal microenvironment for matrix production. The
PDRN preparation appears colourless, transparent, viscoe-
lastic and it is provided in pre-filled glass sterile disposable
syringes containing a solution of 2 ml (the concentration
of polynucleotides is 20 mg/ml). PDRN intra-articular treat-
ment has been shown to produce faster improvement of
activities of daily living compared to HA.17 According to
a meta-analysis, intra-articular PDRN injections provided
more significant pain reduction for up to two months
after the procedure and equal functional improvements Fig. 1 Oxygen-ozone preparation before intra-articular
if compared to HA.18 Therefore, the clinical advantages of injection.
PDRN, unlike HA, could be better exploited by extending
the interval between the different injections, thus reduc-
ing the frequency of injections. However, there are still no
large-scale RCTs determining the effect of PDRN injections
on knee OA.

Oxygen-ozone therapy
The rationale behind the use of intra-articular ozone (O3)
therapy arose from the assumption that chronic oxidative
stress plays an important role in OA. Ozone is a molecule
discovered in the mid-19th century consisting of three
atoms of oxygen in a dynamically unstable structure.
Clinical experiences and research have considered O3 as Fig. 2 PRP preparation process. (A) Centrifugation after blood
a powerful anti-inflammatory, immune-modulatory sub- sample collection; (B) final output consisting in this case of
stance. Due to its high reactivity, it may be able to reduce leukocyte-poor PRP.
Note. PRP, platelet-rich plasma.
oxidative stress, stimulate fibroblastic joint repair and may
promote new cartilage growth. It can be safely admin-
istered intra-articularly as an O3-O2 gas mixture (Fig. 1). Biologic products
When dissolved into the synovial fluid, it can generate
reactive oxygen species (ROS) and lipid oxidation prod- Platelet-rich plasma (PRP)
ucts that may inhibit proteolytic enzymes. Indeed, O3 PRP is an autologous blood derivate characterized by
therapy leads to a localized increase in oxygen delivery by a higher platelet concentration than peripheral blood
promoting vasodilation and angiogenesis.19 (Fig. 2). The rationale behind the employment of plate-
Despite controversial results, O3 therapy has shown bet- lets relies on the ability of the latter to release biologically
ter results in terms of pain relief, joint function and quality active proteins that are able to promote tissue healing;
of life compared to placebo or corticosteroids injections. a property that becomes even more relevant when the
The kinematics of O3 effects seem to be slow but lasting. target tissue has low healing potential as cartilage.22 In
In some trials HA treatment was clinically superior to O3 particular, this beneficial effect of PRP on knee homeo-
therapy20 and therefore oxygen-ozone therapy still lacks stasis is exerted by means of a number of growth factors
a large consensus. In terms of safety profile, O3 proved to released by platelets as insulin-like growth factor (IGF),
be a safe procedure with almost zero adverse events: O3 is tissue growth factor (TGF), epidermal growth factor
bacteriostatic, fungicidal, and viricidal, therefore the infec- (EGF), platelet derived growth factor (PDGF), vascular
tion risk is minimal.21 endothelium growth factor (VEGF) and fibroblast growth

503
factor (FGF).23 In particular, PRP effects can be ascribed to segmental characterization, environmental factors, growth
its effect on the Wnt/β-catenin pathway, which is impli- factors, and adequate pool of MSCs.36 In addition, having
cated in OA development.24 The Wnt family of proteins low expression of antigen-presenting molecules, MSCs
plays a central role in inflammation signalling cascades are non-immunogenic;37 moreover, cartilage tissue, due
stimulating the release of catabolic molecules such as to lack of vascular and lymphatic system, is particularly
metalloproteinases, which are responsible for cartilage immune-privileged. That is why the use of allogenic MSCs
degradation and progressive degeneration of all the artic- may be feasible, and preliminary phase I and II studies are
ular tissues. Moreover, the Wnt pathway is significantly demonstrating their long-term efficacy and safety.
involved in Type II collagen degradation and chondro- In clinical practice, MSCs can be used as a cell suspen-
cyte apoptosis.25 The clinical application of PRP injec- sion, after expansion in culture or enzymatic digestion, or
tions for knee OA has been investigated by an increasing they can be concentrated directly in the operating room
number of clinical studies, including many RCTs, that (OR), which is currently the favoured approach due to the
have demonstrated its safety and overall clinical benefits. stringent regulations and higher costs affecting the proce-
Looking at high-quality studies, the majority have shown dures undergoing extensive manipulation in the lab. MSC
that PRP is superior to hyaluronic acid (HA), especially in products differ markedly in composition, and the most
the case of low-grade articular degeneration,26,27 whereas suitable strategy is far from clear, with biological and prac-
in severe OA less satisfactory outcomes have been docu- tical considerations currently guiding the development of
mented, with results quite similar in comparison to vis- treatment strategies. Expanded MSCs allow a more repro-
cosupplementation.26,28 A potential explanation for these ducible treatment but a two-step procedure is needed
contradictory results might be the high variability of PRP with an increase in costs, manipulation-related infection
products. Indeed, PRP formulations may be prepared by risks and invasiveness. Cell expansion transforms MSCs in
different methods resulting in different compositions, advanced-therapy medicinal products (ATMPs), subjected
thus acting as a source of bias in the analysis of clinical to more rigorous regulatory requirements, similar to those
outcomes. This limitation in the ability of clinical studies of conventional drugs. This is why in both the USA and
to investigate the real efficacy of PRP may be overcome by Europe ‘minimally manipulated’ MSCs, such as bone mar-
future studies employing a novel coding system as pro- row aspirate concentrate (BMAC) and adipose-derived
posed by Kon et al.29 An example of PRP’s formulation stromal vascular fraction (SVF) are the most exploited
variability is the amount of leukocytes present.29 In fact, strategies for clinical application.
both leukocyte-rich PRP and leukocyte-poor PRP products
are available. Nevertheless, comparison between these BMAC
two formulations has been performed showing no inter- BMAC is commonly obtained from the iliac crest using
product differences; similarly, no clear evidence exists on needle aspiration and concentration through centrifu-
the ideal number of injections and their timing to maxi- gation (one or multiple) occurring directly in the OR to
mize the clinical results.30 obtain a product for immediate use (Fig. 3). Furthermore,
recent technological developments have provided a con-
Mesenchymal stem cells (MSCs) centration system without the need for centrifugation.
MSC treatment consists of intra-articular injections of stem With regard to clinical outcomes, even if BMAC has been
cells associated to a pool of immune-modulatory and anti- shown to have a positive effect on function and pain,
inflammatory stromal molecules. Many adult tissues are its regenerative effects and superiority compared to vis-
populated by MSCs (adipose tissue, muscles, dermis, peri- cosupplementation and corticosteroids are still to be
osteum, synovial membrane, synovial fluid, etc.),31 but, proved.38,39
in clinical practice, they are usually harvested from either
bone marrow or adipose tissue. Even if many issues are SVF
still to be verified, MSCs, given their capacity to differen- SVF contains 300-fold more MSCs when compared to
tiate in mesenchymal derived tissue such as osteoblasts, BMAC, and is composed of a heterogenous cell popula-
chondrocytes and adipocytes, may have not only an anti- tion: preadipocytes, vascular endothelial cells, smooth
inflammatory, pro-angiogenetic and anti-apoptotic func- muscle cells and pericytes (ASCs), leucocytes, and eryth-
tion, but also a reparative or regenerative role.32,33 Their rocytes.40 Biologically, the maintenance of the stromal
effects are consequences of direct cell–cell interaction and cell niche architecture seems to be a great advantage.41
secretion of factors.34 Similar to PRP, MSCs affect Wnt/β- Indeed, this beneficial aspect is thought to arise from the
catenin expression, thus controlling OA progression.25,35 cross talk between progenitors, resident cells and immune
However, differentiation potential is dependent on several cells, possibly displaying a wound-healing phenotype (i.e.
factors such as architectural extracellular and inter-cellular M2 alternatively activated macrophages). SVF has proved

504
 Injections in the osteoarthritic knee

Fig. 3 BMAC preparation in the OR. (A) Harvesting of bone marrow aspirate; (B) centrifugation; (C) final output rich in MSCs.
Note. BMAC, bone marrow aspirate concentrate; OR, operating room; MSCs, mesenchymal stem cells.

to be a safe treatment with positive clinical consequences Combined therapies

and a radiological and histological improvement com-
pared to BMAC.42,43,44 Another strategy that has been attempted in the conserva-
SVF products differ in terms of preparation methods: tive treatment of knee OA is a combination therapy based
originally SVF was obtained by enzymatic digestion with on a single intra-articular administration of multiple sub-
collagenase and trypsin, but, following safety and regu- stances. Different combinations have been investigated,
latory concerns, minimally manipulative methods were among PRP, MSCs, HA and corticosteroids. A recent meta-
developed,45 exploiting mechanical forces such as centrif- analysis showed that combined IA injections of CS and HA
ugation or microfragmentation in order to obtain a readily were superior to HA alone in the reduction of pain both in
injectable product. Although we still lack clearly defined the short and long-term outcomes.48 Similar results were
protocols to optimize the outcomes, such an approach found in a study comparing PRP and HA against HA and
may pave the way for a simpler application of adipose- PRP alone, where the combined therapy achieved better
derived MSCs in clinical practice by reducing operative clinical outcomes.49,50 Preliminary results on a PRP + MSCs
times and costs.46 combination showed significant reduction of symptoms
up to 12 months after the procedure.51 However, besides
Potential contraindications the preliminary encouraging results, combination therapy
should be proposed with caution, especially when adopt-
The aforementioned biologic products are reaching a
ing biologic products, and further data should be col-
wider number of clinics, who must be aware of some
lected before endorsing its routine application.
potential contraindications for their use. Although no
absolute contraindication exists, there are some condi-
tions warranting caution and that should be considered
Subchondral injections
for correct patient counselling and management. In the
case of PRP, low basal platelet count (< 150,000/mm3), Subchondral injections refer to minimally invasive intra-
the presence of haematological diseases, coagulopathies osseous delivery under fluoroscopic guidance of products
(both congenital or acquired) or chronic anti-aggregant such as PRP, MSCs or as calcium phosphate (CaP) (Fig. 4);
or steroidal therapy may impair or reduce the biologic when the latter is employed the procedure takes the name
efficacy of PRP.47 PRP and MSCs should be also avoided of subchondroplasty.52 The rationale behind this proce-
in cases of recent diagnosis of malignancies, in particu- dure stems from an increasing interest in the role of the
lar hematologic ones: in fact, stem cells have theoretically subchondral bone in OA. The latter is defined as the bony
an increased transformation and tumourigenic potential component lying distal to the calcified cartilage and it is
that suggests avoiding their use in oncological patients. directly linked to it by means of channels, which transport
More debated is the administration of biologic products a high number of tiny branches of vessels and nerves.53
in patients affected by concurrent rheumatic diseases: Indeed, bone marrow lesions (BML), an alteration of the
although in these cases a systemic therapy may be neces- bone marrow visible on T2-weighted magnetic resonance
sary to control the progression of the disease, intra-articular imaging (MRI), is commonly identified in osteoarthritic
injections of PRP or MSCs may still contribute to reduce knees.54 In addition, subchondral sclerosis is generally
local symptoms and improve the joint functional status. recognized as a hallmark of OA.

505
 conflicting results related to both the augmented risk of
OA progression and reduced efficacy when compared to
placebo surgery.59 The first-line management of degen-
erative meniscal lesions without ‘mechanical’ symptoms
is conservative.60 The conservative approach appears
challenging and consists of physiotherapy, NSAIDs, HA
or corticosteroid intra-articular injections, and also the
aforementioned biological products. In recent years there
have been attempts to target selectively the meniscal tis-
sue with intra-meniscal injections. Among them, PRP,
due to its anti-inflammatory and regenerative effects, has
recently been spreading in clinical practice. Guenoun et al
Fig. 4 Intra-osseous placement of the trocars, under performed an ultrasound-guided intra-meniscal, meniscal
fluoroscopic guidance. BMAC was injected into the bone wall and intra-articular injection procedure, demonstrat-
marrow lesions of the medial femoral condyle and tibial plateau.
ing that intra-meniscal PRP treatment is feasible, safe and
Note. BMAC, bone marrow aspirate concentrate.
efficient. A prolonged clinical and functional improve-
ment was observed. Despite promising in vitro results, no
There is an etiopathogenetic hypothesis suggesting MRI healing signs were noted.61 Randomized controlled
that OA may start as subchondral bone pathology, leading studies with a higher number of patients are needed to
to destruction of the overlying articular cartilage. Hence, confirm these encouraging results.
subchondral injections exploit the possibility to fill the Micro-fragmented adipose tissue (MFAT) rich in SVF,
trabecular space within the BML with substances capable once processed, may also be used for intra-meniscal injec-
of ameliorating the bone integrity. Two recent systematic tions; it acts as trophic mediator by secreting a variety of
reviews on the topic55,56 showed that, independently from cytokines and growth factors, inhibiting fibrosis and apop-
the employed substance, the subchondral injection is a tosis, enhancing angiogenesis and stimulating the differ-
safe procedure able to relieve OA-related symptoms. In entiation of tissue-intrinsic reparative or stem cells. Mild
particular, subchondroplasty was able to reduce the rate mechanical forces may preserve the microarchitecture of
of conversion to arthroplasty therefore delaying this pro- the stromal vascular niche, where pericytes are located.
cedure in patients with BML. This is particularly relevant if MFAT may not only work as biological vehicle but also as
we consider that patients with BMLs are nine times more an adipose tissue filler for meniscus regeneration. Malanga
likely to progress to TKA compared to patients without et al demonstrated that MFAT is a safe and potentially effi-
BML within three years.57 cacious treatment option. A clinical improvement in pain,
Nevertheless, the quality of evidence in support of the function, and quality of life measures, with no side effects,
efficacy of this procedure is poor. In addition, in spite of was achieved.62
CaP being the most employed substance in subchondral
injections, there is still no comparative analysis demon-
strating its superiority over PRP and MSCs. Moreover,
Future perspectives
there is still no evidence regarding the quantity of sub- A strong limitation of the injective techniques is still the
stance that should be injected into the subchondral bone. limited longevity of a sufficient drug dose inside the joint
One limitation of this technique may be represented by in order to exert a durable therapeutic effect. To overcome
the fluoroscopic guidance for the intraosseous insertion of this limit, numerous new nano-technological approaches
the cannula: in fact, this imaging technique, as opposed have been developed and are currently under testing.63
to MRI, is not able to perfectly localize the exact position of Indeed, the possibility of employing nano-carriers to keep
the bone marrow lesions. On the other hand, a potential the injected substances inside the knee environment and
strength of subchondroplasty is represented by the ability slowly release their contents over time, may achieve what
of this procedure to address osteoarthritis pathophysiol- most injective strategies have failed so far to obtain: long-
ogy at its core: the affected area of the subchondral bone. lasting symptomatic relief. Another new experimental
approach is represented by gene delivery. The concept
is to deliver intra-articularly viral vectors with cDNAs cod-
Intra-meniscal injections
ing for therapeutic proteins such as TGF-β1, IL-1Ra, inter-
Meniscal degenerative tear and/or meniscal degenera- feron-beta (IFN-β), aiming at a sustained, endogenous
tion are often an early sign of knee OA and could elicit drug delivery system.64
significant pain even in the absence of relevant chon- In addition, new injectable substances have been devel-
dral damage.58 Arthroscopic meniscectomy has shown oped in order to slow down, halt or even to reverse the

506
 Injections in the osteoarthritic knee

destruction of the joint tissues either by promoting cartilage ICMJE Conflict of interest statement
anabolism or inhibiting its catabolism. In the first category BDM reports consultancy for Cartiheal Ltd, outside the submitted work.
we include the recombinant human fibroblast growth fac- EK reports consultancy for Cartiheal Ltd, Fidia Farmaceutici Spa and Greenbone Ortho
tor 18 (rhFGF-18, Sprifermin): it has been investigated both Srl, payment for lectures including service on speakers’ bureaus from Zimmer Biomet,
in vitro and in rat models showing its ability to expand hya- and stock/stock options in Cartiheal Ltd, all outside the submitted work.
line cartilage-producing chondrocytes leading to an over- The other authors declare no conflict of interest relevant to this work.
all increase in cartilage volume.65 However, despite these
encouraging pre-clinical findings, the first RCT assessing Funding statement
its efficacy in humans found no difference between rhFGF- No benefits in any form have been received or will be received from a commercial
18 and a placebo, thus again revealing the challenges of party related directly or indirectly to the subject of this article.
addressing the complex in vivo human joint system.66
Among the cartilage catabolism inhibitors, we should Open access
mention IL-1 receptor antagonist (IL-1Ra): its use as an © 2021 The author(s)
intra-articular injectable was found to be safe in humans This article is distributed under the terms of the Creative Commons Attribution-Non
and effective in reducing cartilage degeneration and syno- Commercial 4.0 International (CC BY-NC 4.0) licence (https://creativecommons.org/
vial inflammation in animal models.67 Moreover, mono- licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribu-
clonal antibodies directed against nerve growth factor tion of the work without further permission provided the original work is attributed.
(NGF) (tanezumab, fulranumab, and fasinumab) have
also been suggested as potentially therapeutic in OA. References
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