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# Corticosteroid injections for the treatment of osteoarthritis present a wide spectrum of effects ranging from detrimental to disease-modifying: A systematic review of preclinical evidence by the ESSKA Orthobiologic Initiative

Alessandro Bensa, Manuela Salerno, Angelo Boffa, Laura de Girolamo, Lior Laver, Jérémy Magalon, Mikel Sánchez, Thomas Tischer, Giuseppe Filardo

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Alessandro Bensa, Manuela Salerno, Angelo Boffa, Laura de Girolamo, Lior Laver, et al. Corticosteroid injections for the treatment of osteoarthritis present a wide spectrum of effects ranging from detrimental to disease-modifying: A systematic review of preclinical evidence by the ESSKA Orthobiologic Initiative. Knee Surgery, Sports Traumatology, Arthroscopy, 2024, 32 (11), pp.2725-2745. 10.1002/ksa.12242. hal-04965646

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# Corticosteroid injections for the treatment of osteoarthritis present a wide spectrum of effects ranging from detrimental to disease-modifying: A systematic review of preclinical evidence by the ESSKA Orthobiologic Initiative

Alessandro Bensa<fnref n="1" />,<fnref n="2" />

Manuela Salerno<fnref n="3" />

<figure><img src="image_3.png" /></figure>

Angelo Boffa<fnref n="3" />

Laura de Girolamo<fnref n="4" />

Lior Laver<fnref n="5" />,<fnref n="6" />,<fnref n="7" />

Jérémy Magalon<fnref n="8" />,<fnref n="9" />,<fnref n="10" />

Mikel Sánchez<fnref n="11" />,<fnref n="12" />

Thomas Tischer¹³,¹⁴

Giuseppe Filardo<fnref n="1" />,<fnref n="2" />,<fnref n="3" />

## Abstract

**Purpose:** Aim of this systematic review of preclinical evidence was to determine the effects of intra-articular corticosteroid (CS) injections in joints affected by osteoarthritis (OA).

**Methods:** A systematic review was performed on animal studies evaluating intra-articular CS injections for OA joints. The search was performed on PubMed, Cochrane, and Web of Science databases. A synthesis of the results was performed investigating CS effects by evaluating studies comparing CS with control groups. Morphological, histological, immuno-histochemistry evaluations, clinical outcomes, biomarkers and imaging results were evaluated. The risk of bias was assessed according to the Systematic Review Centre for Laboratory Animal Experimentation's tool.

**Results:** Thirty-two articles analysing CS effects in OA animal models were included (1079 joints), 18 studies on small and 14 on large animals. CS injections showed overall positive effects in at least one of the outcomes in 68% of the studies, while 16% reported a deleterious effect. CS improved cartilage and synovial outcomes in 68% and 60% of the studies, but detrimental effects were documented in 11% and 20% of the studies, respectively. Clinical parameters evaluated in terms of pain, lameness or joint swelling improved in 63% of the studies but deteriorated in 13%. Evidence is limited on imaging and biomarkers results, as well as on the best CS type, dose, formulation and injection protocol. The risk of bias assessment revealed a 28% low and an 18% high risk of bias.

**Abbreviations:** CBPI, Canine Brief Pain Inventory; CMI, clinical metrology instruments; CS, corticosteroids; ECM, extracellular matrix; FRβ, folate receptor β; GNPs, gold nanoparticles; HA, hyaluronic acid; HVAS, Hudson Visual Analogue Scale; LLLT, low-level laser therapy; LOAD, liverpool osteoarthritis in dogs; micro-CT, microcomputed tomography; OA, osteoarthritis; PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-analysis; PRP, platelet-rich plasma; SF, synovial fluid; SPECT/CT, single-photon emission tomography/computed tomography; SYRCLE, Systematic Review Centre for Laboratory Animal Experimentation; β-NGF, β-nerve growth factor.

This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

© 2024 The Authors. *Knee Surgery, Sports Traumatology, Arthroscopy* published by John Wiley & Sons Ltd on behalf of European Society of Sports Traumatology, Knee Surgery and Arthroscopy.

<footnote n="1">¹Service of Orthopaedics and Traumatology, Department of Surgery, EOC, Lugano, Switzerland</footnote>

<footnote n="2">²Università della Svizzera Italiana, Faculty of Biomedical Sciences, Lugano, Switzerland</footnote>

<footnote n="3">³Applied and Translational Research (ATR) Center, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy</footnote>

<footnote n="4">⁴Orthopaedic Biotechnology Laboratory, IRCCS Istituto Ortopedico Galeazzi, Milan, Italy</footnote>

<footnote n="5">⁵Department of Orthopaedics, Hillel Yaffe Medical Center (HYMC), Hadera, Israel</footnote>

<footnote n="6">⁶Arthroscopy Clinic, Tel-Aviv, Israel</footnote>

<footnote n="7">⁷Rappaport Faculty of Medicine, Technion University Hospital (Israel Institute of Technology), Haifa, Israel</footnote>

<footnote n="8">⁸Cell Therapy Laboratory, Hôpital De La Conception, AP-HM, Marseille, France</footnote>

<footnote n="9">⁹INSERM, NRA, C2VN, Aix Marseille Univ, Marseille, France</footnote>

<footnote n="10">¹⁰Regenerative Medicine Department of Excellence, Marseille, France</footnote>

<footnote n="11">¹¹Arthroscopic Surgery Unit, Hospital Vithas Vitoria, Vitoria-Gasteiz, Spain</footnote>

<footnote n="12">¹²Advanced Biological Therapy Unit, Hospital Vithas Vitoria, Vitoria-Gasteiz, Spain</footnote>
¹³Department of Orthopaedic Surgery,
University of Rostock, Rostock, Germany

¹⁴Department of Orthopaedic and Trauma
Surgery, Malteser Waldkrankenhaus St.
Marien, Erlangen, Germany

Correspondence

Manuela Salerno, Applied and Translational
Research (ATR) Center, IRCCS Istituto
Ortopedico Rizzoli, Via di Barbiano 1/10,
Bologna 40136, Italy.
Email: manuela.salerno@ior.it

Funding information

None

**Conclusion:** Intra-articular CS injections induced a wide range of results on OA joints in experimental animal models, from disease-modifying and positive effects on pain and joint function at short-term evaluation to the lack of benefit or even negative effects. This underlines the need to identify more specific indications and treatment modalities to avoid possible detrimental effects while maximising the anti-inflammatory properties and the benefits of intra-articular CS in OA joints.

**Level of Evidence:** Level II.

KEYWORDS

corticosteroids, disease-modifying, injection, cartilage, osteoarthritis

INTRODUCTION

Osteoarthritis (OA) is the most common degenerative joint disease, characterised by progressive deterioration and loss of articular cartilage with concomitant structural and functional modifications in the entire joint [18, 34, 38, 43, 47, 49]. This process is due to a complex interaction of genetic, metabolic, biochemical and biomechanical factors leading to inflammation and degeneration [63]. Several treatments with disease-modifying potential have been recently proposed and investigated, but none was able to demonstrate the ability to revert OA progression [58]. Thus, while the need for disease-modifying strategies capable of altering OA evolution remains unfulfilled, treatments aimed at pain relief and symptomatic improvement remain largely used in clinical practice [51].

Intra-articular corticosteroids (CS) injections have been used for decades in the treatment of symptomatic OA, relying on their anti-inflammatory and immunomodulatory effects to suppress joint inflammatory processes. CS act directly on nuclear steroid receptors, interrupting the inflammatory and immune cascade at several levels reducing pro-inflammatory and pain mediators [27]. Accordingly, intra-articular CS injections aim to provide pain relief, functional benefits and quality-of-life improvement [17, 60]. Several clinical studies demonstrated the efficacy of CS injections in patients affected by OA, so that they have been included in the recommendations of major international societies' guidelines [7, 36]. Despite the longstanding and widespread worldwide use of intra-articular CS injections, concerns for resulting detrimental effects have been risen and opposed to the potential benefits derived from the anti-inflammatory modulation of the joint environment [27, 45, 53], making their use much debated as well in consideration of the doubtful clinical relevance and of the lower benefits compared to other injectable options like platelet-rich plasma (PRP) [9, 26]. In this light, it could be hypothesised that the harmful effects of CS injections might jeopardise their benefits. In this regard, animal models represent an important resource for

exploring and understanding the end results at the joint tissue level of intra-articular CS injections.

The aim of this systematic review of preclinical evidence was to determine the effects of intra-articular CS injections in joints affected by cartilage degeneration and OA.

MATERIALS AND METHODS

Literature search and article selection

A systematic review of the literature was performed on the use of intra-articular CS injections for the treatment of OA in preclinical animal models. A literature search was conducted on three electronic databases (PubMed, Cochrane and Web of Science) on 16 November 2023, with no time limitation and without any filters, using the following string: (steroid* or corticosteroid* or glucocorticoid* or cortisone or hydrocortisone or prednisolone or prednisone or methylprednisolone or triamcinolone or dexamethasone or betamethasone or fludrocortisone or deoxycorticosterone) and (inject* or intra-articular* or infiltrat*).

According to the Preferred Reporting Items for Systematic Reviews and Meta-analysis guidelines [41], the article selection and data extraction process were conducted separately by two authors (A.Be. and M.Sal). After the removal of duplicates, the initial title and abstract screenings were made using the following inclusion criteria: studies written in the English language and with no time limitation, on intra-articular CS injections for the treatment of OA in preclinical animal models with a control group. Exclusion criteria were noncomparative studies, articles written in other languages, absence of control group, systematic reviews, meta-analyses, narrative reviews, expert opinions, in vitro studies. In the second step, the full texts of the selected articles were screened, as well as the reference lists of the selected articles with further exclusions according to the previously described criteria. The screening process is detailed in Figure 1. Two investigators independently reviewed each article (A.Be.
<figure><img src="image_4.png" /><figcaption>**FIGURE 1** Preferred Reporting Items for Systematic Reviews and Meta-analysis flowchart of the study selection process. CS, corticosteroids; OA, osteoarthritis.</figcaption></figure>

and M.Sal), and any discrepancies between them were resolved by discussion and consensus with a third author (A.Bo.).

## Data extraction and quality assessment

For the included studies, relevant data were extracted from article texts, tables and figures, and then summarised and analysed for the purpose of the present work. In particular, the following data were collected for each study: authors, year of publication, country, type of animal, number of animals, sex, age, weight, joint treated, OA model, treatment groups, CS type and dose, number of injections, injection timing, type of control, additional procedures, follow-up time, morphological, histological and immunohistochemistry evaluations, clinical outcomes, biomarkers, imaging results, other outcomes (if present) and adverse events. A synthesis of the obtained results was performed investigating both detrimental and disease-modifying effects of intra-articular CS injections, intended as evidence of objective elements of effects on OA processes going beyond the mere symptomatic improvement. This was achieved by evaluating the

studies that compared animals treated with CS and placebo or no treatment. Moreover, other results were analysed with regard to the benefits provided by different CS types, doses, formulations or injection schedules, as well as the effects versus other injectable treatments. The risk of bias of the included studies was assessed according to the Systematic Review Centre for Laboratory Animal Experimentation's tool [29]. This tool, based on the Cochrane Collaboration RoB Tool [28], contains 10 items related to the types of bias: selection bias, performance bias, detection bias, attrition bias, reporting bias and other biases. All items could be judged as 'yes' (low risk of bias), 'no' (high risk of bias) and 'unclear' (unclear risk of bias). Two reviewers (A.Be. and M.Sal) independently evaluated the studies, and discrepancies were resolved through discussion and consensus with a third author (A.Bo.).

## RESULTS

### Study selection and analysis

The initial search identified 5741 articles; the study selection process led to 32 articles included in the
Papers over the years

<figure><img src="image_5.png" /><figcaption>**FIGURE 2** Number of animal studies on intra-articular corticosteroid injections to address osteoarthritis.</figcaption></figure>

qualitative data synthesis (Figure 1). Since the first report in 1970, the publication trend increased over time, with more than half of the studies published in the last decade (Figure 2). A total of 1079 joints were assessed, with 18 studies (56%) focusing on small animals (10 on rodents such as guinea pig, mouse and rat, and eight on rabbits) and 14 studies (44%) on large animals (eight on dogs, five on horses and one on sheep). The evaluated joints were knee in 21 studies, carpal or tarsal joints in five studies, hip in four studies, and temporo-mandibular joint in two studies. The timing of the first injection after OA induction ranged from the day of the procedure to 6 weeks after. The follow-up evaluation of the included studies ranged from 1 day to 50 weeks after CS injection. More protocol details and characteristics of the included studies are reported in Tables 1–3.

## CS effects on OA joints

Nineteen studies (14 on small animals and five on large animals) investigated the effects of intra-articular CS injections in comparison to OA controls (saline/vehicle-only injections or untreated joints) at the joint tissue level. Overall, 13 studies (68.4%) reported better results in animals treated with intra-articular CS injections in at least one of the following outcomes: macroscopic, histological and/or immunohistochemical findings, while three studies (15.8%) revealed no difference and three studies (15.8%) showed detrimental effects compared to OA controls. In detail, six out of seven studies (85.7%) documented overall better results in terms of macroscopic evaluation (gross morphological scores), 12 out of 18 studies (66.7%) reported overall better histological results (three studies with negative results, 16.7%) and four out of five studies (80.0%) evaluations revealed overall better results at immunohistochemical assessment. The comparison of small and large animal models showed overall positive disease-modifying effects in 9/14

<table><caption>**TABLE 1** Characteristics of the included studies.</caption><thead><tr><th>Article</th><th>Animal model</th><th>Joint</th><th>OA model</th><th>Treatment groups (evaluated joints)</th><th>CS type</th><th>CS dose</th><th>N. of injections</th><th>Final follow-up (weeks)</th><th>Final results</th></tr></thead><tbody><tr><td>Dos Santos Haupenthal et al. [22]</td><td>50 Rats</td><td>Knee</td><td>Medial meniscectomy</td><td>CS (n = 10)<br>Gold<br>nanoparticles (n = 10)<br>CS + gold<br>nanoparticles (n = 10)<br>OA controls (n = 10)<br>Healthy controls (n = 10)</td><td>Triamcinolone acetonide</td><td>0.63–0.83 mg, 2.5 mg/kg</td><td>2</td><td>13</td><td>Triamcinolone acetonide significantly increased anti-inflammatory cytokines compared to OA alone, reduced oxidants and oxidative damage markers and was associated with a superior number of chondrocytes.</td></tr><tr><td>Everett et al. [23]</td><td>19 Horses</td><td>Carpal or tarsal</td><td>Naturally occurring</td><td>CS (n = 6)<br>Bone marrow mononuclear cells (n = 7)<br>Saline (n = 6)</td><td>Triamcinolone acetonide</td><td>4 mg, 2 mg/mL</td><td>1</td><td>3</td><td>There were no significant improvements in lameness or joint circumference in the saline- or triamcinolone-treated groups.</td></tr></tbody></table>
<table><caption>TABLE 1 (Continued)</caption><thead><tr><th>Article</th><th>Animal model</th><th>Joint</th><th>OA model</th><th>Treatment groups (evaluated joints)</th><th>CS type</th><th>CS dose</th><th>N. of injections</th><th>Final follow-up (weeks)</th><th>Final results</th></tr></thead><tbody><tr><td>Alves et al. [3]</td><td>15 Dogs</td><td>Hip</td><td>Naturally occurring</td><td>CS (n = 5)<br>Blood cell<br>secretome (n = 5)<br>CS + blood cell<br>secretome (n = 5)</td><td>Triamcinolone<br>acetonide</td><td>20 mg, 40 mg/mL</td><td>1</td><td>26</td><td>The intra-articular administration of blood cell secretome improved the clinical signs and scores of several clinical metrology instruments in dogs with hip OA, particularly when combined with triamcinolone.</td></tr><tr><td>Alves et al. [6]</td><td>20 Dogs</td><td>Hip</td><td>Naturally occurring</td><td>TA (n = 10)<br>MPA (n = 10)</td><td>Triamcinolone<br>acetonide<br>Methylprednisolone<br>acetate</td><td>20 mg, 40 mg/mL<br>40 mg, 40 mg/mL</td><td>1</td><td>26</td><td>Intra-articular CS may be a treatment option for some dogs with naturally occurring OA, being particularly useful in terms of reducing pain and return to function, with an added cost-effectiveness compared to other therapeutic options.</td></tr><tr><td>Ferrao Blanco et al. [25]</td><td>36 Mice</td><td>Knee</td><td>Collagenase injection</td><td>CS (n = 12)<br>Saline (n = 12)<br>Healthy<br>controls + saline (n = 12)</td><td>Triamcinolone<br>acetonide</td><td>25 µg, 4.16 mg/mL</td><td>1</td><td>8</td><td>Intra-articular injection of triamcinolone acetonide increases long-term synovial macrophage numbers and osteophytosis. Our findings suggest that triamcinolone acetonide accentuates the progression of OA-associated features when applied to an acutely inflamed knee.</td></tr><tr><td>Ishaq et al. [31]</td><td>24 Rats</td><td>Knee</td><td>Medial meniscectomy + ACL resection</td><td>CS (n = 8)<br>Hyaluronic acid (n = 8)<br>Saline (n = 8)</td><td>Triamcinolone</td><td>0.1 mg, 1.4 mg/mL</td><td>4</td><td>7</td><td>Comparison of control group with treatment groups proved chondroprotective effects of hyaluronic acid and triamcinolone.</td></tr></tbody></table>

(Continues)
<table><caption>TABLE 1 (Continued)</caption><thead><tr><th>Article</th><th>Animal model</th><th>Joint</th><th>OA model</th><th>Treatment groups (evaluated joints)</th><th>CS type</th><th>CS dose</th><th>N. of injections</th><th>Final follow-up (weeks)</th><th>Final results</th></tr></thead><tbody><tr><td>Alves et al. [5]</td><td>40 Dogs</td><td>Hip</td><td>Naturally occurring</td><td>CS (n = 20)<br>Saline (n = 20)</td><td>Triamcinolone hexacetonide</td><td>20 mg, 20 mg/mL</td><td>1</td><td>26</td><td>Triamcinolone hexacetonide recorded significant improvements in weight-bearing and in with the considered clinical metrology instruments, particularly pain scores. Lower thermographic values were registered in the triamcinolone hexacetonide group up to the last evaluation day.</td></tr><tr><td>Çağlar et al. [14]</td><td>40 Rats</td><td>Knee</td><td>Monosodium iodoacetate injection</td><td>CS (n = 10)<br>Hyaluronic acid (n = 10)<br>Astaxanthin (n = 10)<br>Astaxanthin + hyaluronic acid (n = 10)</td><td>Triamcinolone acetonide</td><td>0.6 mg, 2 mg/mL</td><td>1</td><td>8</td><td>Intra-articular astaxanthin therapy can be a good alternative to CS and hyaluronic acid currently used in intra-articular therapy to treat OA.</td></tr><tr><td>de Clifford et al. [19]</td><td>31 Horses</td><td>Middle carpal joint</td><td>Naturally occurring</td><td>CS (n = 14)<br>Polyacrylamide hydrogel (n = 13)<br>Hyaluronic acid (n = 12)</td><td>Triamcinolone acetonide</td><td>12 mg, 6 mg/mL</td><td>1</td><td>6</td><td>Treatment with 2.5% polyacrylamide hydrogel led to statistically superior results compared to triamcinolone acetonide and hyaluronic acid.</td></tr><tr><td>Alves et al. [4]</td><td>30 Dogs</td><td>Hip</td><td>Naturally occurring</td><td>CS (n = 10)<br>Hyaluronic acid (n = 10)<br>CS + hyaluronic acid (n = 10)</td><td>Triamcinolone acetonide</td><td>20 mg, 40 mg/mL</td><td>1</td><td>26</td><td>Intra-articular injection with triamcinolone acetonide and hyaluronic acid may be a treatment option for dogs with naturally occurring OA, particularly when simultaneously used.</td></tr></tbody></table>
<table><caption>TABLE 1 (Continued)</caption><thead><tr><th>Article</th><th>Animal model</th><th>Joint</th><th>OA model</th><th>Treatment groups (evaluated joints)</th><th>CS type</th><th>CS dose</th><th>N. of injections</th><th>Final follow-up (weeks)</th><th>Final results</th></tr></thead><tbody><tr><td>Tschon et al. [66]</td><td>80 Rats</td><td>Knee</td><td>Monosodium iodoacetate injection</td><td>CS (n = 16)<br>Hyaluronic acid (n = 16)<br>Hyaluronic acid + CS<br>2.0 mg/mL (n = 16)<br>Hyaluronic acid + CS<br>4.5 mg/mL (n = 16)<br>Saline (n = 16)</td><td>Triamcinolone acetonide</td><td>2 mg, 40 mg/mL</td><td>1</td><td>3</td><td>Triamcinolone acetonide limited the local articular cartilage deterioration in knee OA with an improvement of the physical structure of articular cartilage, gait parameters, sensitivity to local pain and a reduction of the synovial inflammation.</td></tr><tr><td>Abubakr et al. [1]</td><td>60 Rats</td><td>Temporomandibular joint</td><td>Monosodium iodoacetate injection</td><td>CS (n = 20)<br>Low-level laser therapy (n = 20)<br>OA controls (n = 20)</td><td>Dexamethasone</td><td>0.22–0.24 mg, 1.2 mg/kg</td><td>1</td><td>4</td><td>CS treatment had a protective effect on the articular cartilage in models of OA. Caspase-3 values decreased in both of the treated groups. Dexamethasone had an antiapoptotic effect and improved imaging results.</td></tr><tr><td>Barton et al. [8]</td><td>21 Sheep</td><td>Knee</td><td>Partial ACL resection</td><td>CS (n = 5)<br>OA controls (n = 11)<br>Healthy controls (n = 5)</td><td>Methylprednisolone acetate</td><td>80 mg, 80 mg/mL</td><td>4</td><td>40</td><td>Multiple repeated methylprednisolone acetate injections were not appropriate to mitigate injury-related damage in a partial ACL transection ovine model as significant proteoglycan loss was observed in methylprednisolone acetate-treated knees.</td></tr><tr><td>Pawar et al. [52]</td><td>15 Rabbits</td><td>Knee</td><td>Monosodium iodoacetate injection</td><td>Corticosteroids (n = 5)<br>Oxaceprol (n = 5)<br>Saline (n = 5)</td><td>NR</td><td>20 mg, 20 mg/mL</td><td>4</td><td>4</td><td>CS and oxaceprol showed promising results in reducing swelling in comparison to control osteoarthritic rabbits and showing analgesic actions both in scoring of wire walking and hot plate methods.</td></tr></tbody></table>

(Continues)
<table><caption>TABLE 1 (Continued)</caption><thead><tr><th>Article</th><th>Animal model</th><th>Joint</th><th>OA model</th><th>Treatment groups (evaluated joints)</th><th>CS type</th><th>CS dose</th><th>N. of injections</th><th>Final follow-up (weeks)</th><th>Final results</th></tr></thead><tbody><tr><td>Chapman et al. [15]</td><td>36 Mice</td><td>Knee</td><td>Medial meniscectomy</td><td>Mesenchymal stem cells (n = 10)<br>CS (n = 8)<br>Vehicle (n = 10)<br>Sham-operated + vehicle (n = 8)</td><td>Triamcinolone acetonide</td><td>0.2 mg, 10 mg/mL</td><td>1</td><td>6</td><td>Triamcinolone acetonide had a rapid inhibitory effect on meniscectomy-induced weight-bearing asymmetry at 17 and 21 days postmodel induction, compared to control.</td></tr><tr><td>de Grauw et al. [20]</td><td>80 Horses</td><td>Carpal and tarsal joints</td><td>Naturally occurring</td><td>CS (n = 41)<br>CS + hyaluronic acid (n = 39)</td><td>Triamcinolone acetonide</td><td>12 mg, 10 mg/mL</td><td>1</td><td>13</td><td>The combination of triamcinolone acetonide with hyaluronic acid was associated with a lower short-term clinical success rate and a similar medium-term outcome compared with triamcinolone acetonide.</td></tr><tr><td>Kaluzynski et al. [33]</td><td>40 Rabbits</td><td>Temporomandibular joint</td><td>Papain injection</td><td>CS (n = 10)<br>Hyaluronic acid (n = 10)<br>Pioglitazone (n = 10)<br>OA control (n = 10)</td><td>Methylprednisolone acetate</td><td>2 mg, 20 mg/mL</td><td>4</td><td>5</td><td>No obvious influence of methylprednisolone on the improvement of the condition of cartilage was found, but the anabolic processes and cell proliferation were clearly visible.<br>Pioglitazone and hyaluronic acid showed anti-degenerative properties compared to methylprednisolone in an animal model.</td></tr><tr><td>Kroin et al. [37]</td><td>NR Mice</td><td>Knee</td><td>Partial medial meniscectomy</td><td>CS powder (n = NR)<br>CS suspension (n = NR)<br>CS suspension + hyaluronic acid (n = NR)<br>Hyaluronic acid (n = NR)<br>Saline (n = NR)</td><td>Triamcinolone acetonide</td><td>40 µg, 8 mg/mL<br>40 µg, 10 mg/mL<br>100 µg, 20 mg/mL</td><td>1</td><td>5</td><td>Intra-articular triamcinolone acetonide in a sustained-release formulation of viscous 5% hyaluronic acid will produce a long-term attenuation of mechanical allodynia in the OA knees of mice.</td></tr></tbody></table>
<table><caption>TABLE 1 (Continued)</caption><thead><tr><th>Article</th><th>Animal model</th><th>Joint</th><th>OA model</th><th>Treatment groups (evaluated joints)</th><th>CS type</th><th>CS dose</th><th>N. of injections</th><th>Final follow-up (weeks)</th><th>Final results</th></tr></thead><tbody><tr><td>Siebelt et al. [61]</td><td>40 Rats</td><td>Knee</td><td>Papain injection + running</td><td>CS (n = 20)<br/>OA control (n = 20)</td><td>Triamcinolone acetonide</td><td>7 µg, 1.43 mg/mL</td><td>11</td><td>12</td><td>Triamcinolone acetonide injections potently induce a CD163 + - and FRβ + - activated macrophage with anti-inflammatory characteristics such as reduced IL-10 production in vitro and lack of osteophytosis in vivo.</td></tr><tr><td>Huebner et al. [30]</td><td>18 Rabbits</td><td>Knee</td><td>Intra-articular drilling</td><td>CS (n = 6)<br/>OA controls (n = 6)<br/>Healthy controls (n = 6)</td><td>Dexamethasone</td><td>~2 mg, 5 mg/mL</td><td>9</td><td>3</td><td>Dexamethasone decreased joint inflammation and joint tissue degradation and was chondroprotective in this unique model of post-traumatic OA.</td></tr><tr><td>Albano et al. [2]</td><td>44 Rabbits</td><td>Knee</td><td>ACL resection</td><td>CS (n = 11)<br/>Hyaluronic acid (n = 11)<br/>Branched hyaluronic acid (n = 11)<br/>Saline (n = 11)</td><td>Betamethasone</td><td>Betamethasone dipropionate<br/>0.25 mg + betamethasone disodium phosphate 0.1 mg</td><td>3</td><td>12</td><td>Statistical difference with regard to prevention of chondral lesions, between the placebo group and CS group. CS have protective effect on the chondral bone.</td></tr><tr><td>Labens et al. [39]</td><td>51 Horses</td><td>Tarsal joints</td><td>Naturally occurring</td><td>MPA (n = 38)<br/>TA (n = 4)<br/>MPA + hyaluronic acid (n = 17)<br/>OA control (n = 3)</td><td>Methylprednisolone acetate<br/>Triamcinolone acetonide</td><td>20–120 mg<br/>5–20 mg</td><td>1–2</td><td>50</td><td>The intra-articular treatment of horses with OA of the distal tarsal joints with methylprednisolone acetate or triamcinolone acetonide (with or without hyaluronic acid) may lead to an improvement in lameness. No difference between methylprednisolone acetate and triamcinolone acetonide.</td></tr></tbody></table>

(Continues)
<table><caption>TABLE 1 (Continued)</caption><thead><tr><th>Article</th><th>Animal model</th><th>Joint</th><th>OA model</th><th>Treatment groups (evaluated joints)</th><th>CS type</th><th>CS dose</th><th>N. of injections</th><th>Final follow-up (weeks)</th><th>Final results</th></tr></thead><tbody><tr><td>Karakurum et al. [35]</td><td>24 Rabbits</td><td>Knee</td><td>ACL resection</td><td>CS (n = 7)<br>Hyaluronic acid (n = 7)<br>CS then hyaluronic acid x 2 (n = 7)<br>OA control (n = 3)</td><td>Methylprednisolone acetate</td><td>15 mg</td><td>3</td><td>7</td><td>The results showed that the combination of cortisone and hyaluronan is the most effective in the treatment of cartilage degeneration in the course of the OA.</td></tr><tr><td>Pelletier et al. [53]</td><td>30 Dogs</td><td>Knee</td><td>ACL resection</td><td>CS x 1 (n = 7)<br>CS x 2 (n = 7)<br>CS x 3 (n = 8)<br>OA control (n = 8)</td><td>Triamcinolone hexacetonide</td><td>5 mg, 20 mg/mL</td><td>1–3</td><td>12</td><td>This study provides novel data showing the protective effect of CS injections on OA cartilage lesions not only under prophylactic but also under therapeutic conditions.</td></tr><tr><td>Pelletier et al. [56]</td><td>20 Dogs</td><td>Knee</td><td>ACL resection</td><td>CS (n = 8)<br>OA controls (n = 7)<br>Healthy controls (n = 5)</td><td>Methylprednisolone acetate</td><td>20 mg, 40 mg/mL</td><td>2</td><td>8</td><td>These findings provide additional evidence for the protective effect of CS injections on OA lesions, and indicate that the effect of this drug may be mediated through the suppression of stromelysin synthesis.</td></tr><tr><td>Pelletier and Martel-Pelletier [55]</td><td>18 Dogs</td><td>Knee</td><td>ACL resection</td><td>CS (n = 5)<br>Oral tiaprofenic acid (n = 7)<br>OA controls (n = 6)</td><td>Triamcinolone hexacetonide</td><td>5 mg, 20 mg/mL</td><td>3</td><td>8</td><td>Our data confirm the effectiveness of prophylactic treatment with CS in preventing the progression of OA lesions in the dog model.</td></tr><tr><td>Pelletier and Martel-Pelletier [54]</td><td>39 Dogs</td><td>Knee</td><td>ACL resection</td><td>Oral prednisone (n = 6)<br>CS (n = 6)<br>OA controls (n = 12)<br>Healthy controls (n = 11)<br>Healthy + CS (n = 4)</td><td>Triamcinolone hexacetonide</td><td>5 mg, 20 mg/mL</td><td>2</td><td>8</td><td>Intra-articular CS had no deleterious effects on normal articular cartilage. These results indicate that glucocorticoids administered orally or intra-articularly are effective against the development of OA lesions in this model.</td></tr></tbody></table>
<table><caption>TABLE 1 (Continued)</caption><thead><tr><th>Article</th><th>Animal model</th><th>Joint</th><th>OA model</th><th>Treatment groups (evaluated joints)</th><th>CS type</th><th>CS dose</th><th>N. of injections</th><th>Final follow-up (weeks)</th><th>Final results</th></tr></thead><tbody><tr><td>Olijoeho et al. [50]</td><td>46 Rabbits</td><td>Knee</td><td>Immobilisation in extension</td><td>CS (n = 5), Aprotinin (n = 6), Arteparon (n = 6), OA controls (n = 16), Healthy + CS (n = 5), Healthy + aprotinin (n = 4), Healthy + arteparon (n = 4)</td><td>Triamcinolone acetonide</td><td>0.3 mg, 10 mg/mL</td><td>12</td><td>12</td><td>All drugs increased the contents of acidic glycosaminoglycans in the chondrocytes.</td></tr><tr><td>Williams and Brandt [72]</td><td>43 Guinea pigs</td><td>Knee</td><td>Monosodium iodoacetate injection</td><td>CS 0.4 (n = 6), CS 0.04 (n = 5), Healthy + CS 0.4 (n = 6), Healthy + CS 0.04 (n = 5), Vehicle (carboxymethyl cellulose sodium) (n = 5), OA control (n = 6), Healthy controls (n = 10)</td><td>Triamcinolone hexacetonide</td><td>0.23 mg, 0.4 mg/kg 20 µg, 0.04 mg/kg</td><td>1</td><td>3</td><td>Triamcinolone hexacetonide produced a marked, dose-dependent protective effect in this model of chemically induced articular cartilage damage.</td></tr><tr><td>Butler et al. [13]</td><td>NR Rabbits</td><td>Knee</td><td>Partial lateral meniscectomy</td><td>CS (n = NR) Carbenoxolone sodium (n = NR) Algestone acetonide (n = NR) GPA 2163 (n = NR) Pentosan polysulfate (n = NR) Tranexamic acid (n = NR) Aprotinin (n = NR) Orgotein (n = NR) Pirprofen (n = NR) Phenylbutazone (n = NR) Vehicle (n = NR)</td><td>Triamcinolone hexacetonide</td><td>1 mg, 20 mg/mL</td><td>1</td><td>1</td><td>Triamcinolone hexacetonide exhibited significant antiosteoarthritic activity.</td></tr><tr><td>Marcelon et al. [44]</td><td>34 Rabbits</td><td>Knee</td><td>Papain injection</td><td>CS (n = NR) Indomethacin (n = NR) Lysine acetylsalicylate (n = NR) Catalase (n = NR) OA control (n = 16)</td><td>Methylprednisolone acetate</td><td>0.17 mg</td><td>2</td><td>1</td><td>The corticoid potentiated the action of papain (fall in glycosaminoglycan content and synthesis).</td></tr></tbody></table>

(Continues)
<table><caption>TABLE 1 (Continued)</caption><thead><tr><th>Article</th><th>Animal model</th><th>Joint</th><th>OA model</th><th>Treatment groups (evaluated joints)</th><th>CS type</th><th>CS dose</th><th>N. of injections</th><th>Final follow-up (weeks)</th><th>Final results</th></tr></thead><tbody><tr><td>Van Pelt et al. [68]</td><td>13 Horses</td><td>Tarsal joints</td><td>Naturally occurring</td><td>CS (n = 11)<br>Healthy controls (n = 5)</td><td>Betamethasone</td><td>Betamethasone disodium phosphate 3 mg/mL + betamethasone acetate 12 mg/mL</td><td>1–5</td><td>27</td><td>The betamethasone preparation was well tolerated and proved to be beneficial as a temporary, palliative, repeatable local adjunct in the management of noninflammatory joint diseases in horses.</td></tr></tbody></table>

Abbreviations: ACL, anterior cruciate ligament; CS, corticosteroids; MPA, methylprednisolone acetate; OA, osteoarthritis; TA, triamcinolone acetonide.

<table><caption>TABLE 2 Synthesis of protocol details of the included studies.</caption><tbody><tr><td colspan="2">OA induction</td></tr><tr><td>Surgical (anterior cruciate ligament transection and/or meniscectomy or intra-articular drilling)</td><td>13 studies</td></tr><tr><td>Chemical (intra-articular injection of mono-iodoacetate, papain or collagenase)</td><td>9 studies</td></tr><tr><td>Spontaneous</td><td>9 studies</td></tr><tr><td>Mechanical (immobilisation in extension)</td><td>1 study</td></tr><tr><td colspan="2">Type of CS</td></tr><tr><td>Triamcinolone acetonide</td><td>13 studies</td></tr><tr><td>Methylprednisolone acetate</td><td>7 studies</td></tr><tr><td>Triamcinolone hexacetonide</td><td>6 studies</td></tr><tr><td>Dexamethasone</td><td>2 studies</td></tr><tr><td>Betamethasone</td><td>2 studies</td></tr><tr><td>Triamcinolone (not specified in which form)</td><td>1 study</td></tr><tr><td>Triamcinolone acetonide vs methylprednisolone acetate</td><td>2 studies</td></tr><tr><td>Triamcinolone hexacetonide (different doses)</td><td>1 study</td></tr><tr><td>Triamcinolone hexacetonide (1, 2 or 3 injections)</td><td>1 study</td></tr><tr><td>Not reported</td><td>1 study</td></tr><tr><td colspan="2">Number of injections</td></tr><tr><td>1</td><td>18 studies</td></tr><tr><td>2</td><td>7 studies</td></tr><tr><td>3</td><td>4 studies</td></tr><tr><td>4</td><td>4 studies</td></tr><tr><td>5</td><td>1 study</td></tr><tr><td>9</td><td>1 study</td></tr><tr><td>11</td><td>1 study</td></tr><tr><td>12</td><td>1 study</td></tr></tbody></table>

Abbreviations: CS, corticosteroids; OA, osteoarthritis.

(64.3%) and 4/5 (80.0%) of the studies, respectively. A more detailed analysis is reported in the following paragraphs and in Figure 3.

## CS effects at the cartilage level

A total of 19 studies investigated the effects at the cartilage level. Among these, 13 studies (68.4%) reported positive results, four studies (21.1%) revealed no difference and 2 studies (10.5%) showed detrimental effects compared to OA controls. In detail, the macroscopic evaluation in 6/7 studies showed less articular degeneration both at femoral and tibial level, as well as less osteophytes
<table><caption>TABLE 3 Dose of administered corticosteroids for small and large animal models.</caption><thead><tr><td>Dose of corticosteroid (mg)</td><td>Small animal models</td><td>Large animal models</td></tr></thead><tbody><tr><td>Triamcinolone acetonide</td><td>0.025–2</td><td>4–20</td></tr><tr><td>Methylprednisolone acetate</td><td>0.17–15</td><td>20–120</td></tr><tr><td>Triamcinolone hexacetonide</td><td>0.02–1</td><td>5–20</td></tr><tr><td>Dexamethasone</td><td>0.22–2</td><td>/</td></tr><tr><td>Betamethasone dipropionate</td><td>0.25 (one study only)</td><td>/</td></tr><tr><td>Betamethasone disodium phosphate</td><td>0.1 (one study only)</td><td>4.5–30 (one study only)</td></tr><tr><td>Betamethasone acetate</td><td>/</td><td>18–120 (one study only)</td></tr></tbody></table>

<figure><img src="image_6.png" /><figcaption>FIGURE 3 Disease-modifying effects on osteoarthritis (OA) joints induced by intra-articular corticosteroids. The bar chart shows the percentage of studies that met the specific effects. Positive effects (green) versus no effects (orange) versus negative effects (red) in imaging findings (n = 3), clinical results (n = 8), biomarker evaluation (n = 4), macroscopic results (n = 7), histological results (n = 18) and immunohistochemical results (n = 5). IHC, immunohistochemistry.</figcaption></figure>

formation compared to OA controls [2, 13, 53, 55, 54, 56], while one study described no difference in terms of gross cartilage damage [8]. Histological analysis documented a greater cartilage thickness and histological scores, with abundant extracellular matrix (ECM), better collagen, proteoglycan and glycosaminoglycan content, as well as reduced severity of cartilage structural changes in 12/18 studies (66.7%) [1, 13, 22, 30, 31, 52, 53, 55, 54, 56, 66, 72], while no better effects on cartilage alterations were reported in four studies [15, 25, 33, 61] and two studies described detrimental effects on the proteoglycan content compared to OA controls [8, 44]. Immunohistochemical evaluations revealed overall positive effects, including the promotion of chondrogenic markers expression (type II collagen and aggrecan) and the reduction of matrix metalloproteinase 1 (MMP-1), interleukin (IL)-1β, c-Fos and c-Myc staining [53, 56, 66].

## CS effects at the synovial membrane level

Five studies investigated the effects on the synovial membrane [15, 25, 52, 61, 66]. Among these, three studies reported positive results, one study revealed no difference and one study showed detrimental effects compared to OA controls. Histological analysis (three studies) documented a greater reduction in synovitis as measured by Krenn score in one study [66], while one study described similar levels of synovial inflammation [15], and one study reported negative results with an increased long-term synovial macrophages number compared to OA controls [25]. One study analysed in vitro synovial macrophages cultures showing a reduction of CD80 expression and an increase of CD163 expression, suggesting that CS could stimulate macrophages towards an activated M2 phenotype [61]. Only one study addressed immunohistochemical outcomes showing reduced leucocyte
infiltration evaluated by 3,3'-diaminobenzidine stain compared to OA controls [52].

## CS effects on OA biomarker profile

Four studies investigated indirect disease-modifying effects through the measurement of serum or synovial fluid (SF) biomarkers related to cartilage metabolism or inflammation [5, 15, 23, 35]. One study documented greater reduction in CRP and IL-1 in the SF of CS-injected joints compared to saline controls [5]. The other studies described no differences in terms of serum IL-10 and β-nerve growth factor (β-NGF) expression and malondialdehyde levels [15, 35], as well as in SF growth factors, anti- and pro-inflammatory cytokines and chemokines quantification (FGF-2, GM-CSF, IL-1β, IL-6, MCP-1, IL-10, TNF-α, SDF-1, IGF-1, IL-1ra) [23].

## Clinical effects

Eight studies quantitatively evaluated the effects on clinical parameters compared to OA controls [5, 15, 23, 31, 37, 52, 61, 66]. Among these, five studies documented better clinical outcomes in terms of pain threshold (evaluated using the hot plate and wire walking methods), lameness, joint swelling, weight-bearing asymmetry, joint flexibility evaluated by goniometry, gait score, pedometer parameters, Hudson Visual Analogue Scale (HVAS), Canine Brief Pain Inventory (CBPI), Canine Orthopaedic Index, Liverpool Osteoarthritis in Dogs and clinical metrology instruments [5, 15, 31, 37, 52], while two studies described no difference of clinical results in terms of lameness, joint circumference, local pain sensitivity and paw area [23, 66] and one study reported greater body weight loss at 6 and 12 weeks after injection compared to OA controls [61].

## Imaging analysis

Three studies performed imaging analyses to detect the effects on the injected joints [5, 25, 61]. Among these, one study reported positive results and two studies revealed no difference compared to OA controls. In detail, a microcomputed tomography (micro-CT) analysis was performed in two studies, reporting no difference in preserving the microstructural changes in subchondral bone induced by the OA process (evaluated in terms of subchondral plate thickness and porosity and trabecular bone volume fraction) nor in osteophytes formation measured by quantification of ectopic bone formation [25, 61]. One of these studies also performed folate receptor β-targeted

single-photon emission tomography/CT to quantitatively measure macrophages activation showing reduced activation in CS-treated joints at 6 and 12 weeks after the injection [61]. One study performed a digital thermography analysis of the treated joints showing lower mean and maximal values compared to OA controls [5].

## Comparison of CS types, doses, formulations and protocols

Five studies compared the effects of different CS types, doses, formulations or injective protocols [6, 37, 39, 53, 72]. In detail, two studies compared triamcinolone acetonide and methylprednisolone acetate injection in dog and horse OA models, respectively, both reporting similar clinical results of the two compounds on clinical outcomes evaluated in terms of lameness, CBPI and HVAS [6, 39]. One study compared two different doses of triamcinolone hexacetonide (0.4 and 0.04 mg/kg) on knee OA induced in a guinea pig model showing a positive dose-dependent effect on articular surface integrity, chondrocytes and pericellular proteoglycans loss and osteophytes reduction [72]. One study examined different formulations of triamcinolone acetonide showing similar effects of both the fast-release powder and the slower-release suspension on pain withdrawal threshold in a mouse model of knee OA [37]. One study investigated different injection schedules in a canine model of knee OA comparing a 3-injection (at the time of OA induction, after 4 and 8 weeks), with a two-injection (at weeks 4 and 8 after OA induction) and a single-injection protocol (8 weeks after OA induction), suggesting a positive correlation between the number of injections and the extent of the benefits observed in terms of osteophytes reduction, severity of histological cartilage lesions and immunohistochemical outcomes (evaluated using MMP-1, c-Fos and c-Myc staining) [53].

## Comparison with other injectable products and effects of injectable combined treatments

Twenty-one studies compared the disease-modifying effect of CS with injectable or other products. The analysis of these studies showed considerable variability in terms of products compared with CS. Specific details of the studies addressing this aspect are reported in Table 4. Eight studies evaluated the synergistic effects of CS when used in combination with other injectable products. The analysis of these studies showed considerable variability in terms of products combined with CS. Specific details of the studies addressing this aspect are reported in Table 5.
<table><caption>TABLE 4 CS comparison with other injectable products.</caption><thead><tr><td>Product comparison</td><td>Number of studies</td><td>Results</td></tr></thead><tbody><tr><td>HA</td><td>7</td><td>Two studies documented better results of CS in terms of gait parameters, cartilage histology, synovial inflammation and IHC features [14, 66]. Four studies reported similar results of CS in terms of gross morphology, clinical outcomes and biomarker evaluation [2, 4, 19, 35]. One study described worse pathological changes of cartilage histology compared to HA [33].</td></tr><tr><td>BMSCs</td><td>2</td><td>One study documented higher inhibition of weight-bearing asymmetry in animals treated with CS, while no significant differences were found in terms of chondropathy score, synovitis score and levels of pain-related cytokines [15]. One study described similar clinical results and SF biomarkers evaluation [23].</td></tr><tr><td>Blood cell secretome</td><td>1</td><td>Blood cell secretome had better results than triamcinolone acetonide [3].</td></tr><tr><td>Polyacrylamide hydrogel</td><td>1</td><td>CS produced superior clinical benefits in terms of lameness and joint effusion reduction compared to polyacrylamide hydrogel [19].</td></tr><tr><td>Astaxanthin and combination of astaxanthin and HA</td><td>1</td><td>Better gait and histological outcomes for astaxanthin and a combination of astaxanthin and HA compared to triamcinolone acetonide [14].</td></tr><tr><td>Aprotinin, arteparon (composite GAG polysulphate)</td><td>1</td><td>Aprotinin, arteparon (composite GAG polysulphate) and triamcinolone acetonide increased the contents of acidic GAGs in the chondrocytes, while only arteparon had a favourable effect on the integrity of the articular surface [50].</td></tr><tr><td>Oxaceprol</td><td>1</td><td>Similar outcomes in terms of pain reduction and cartilage histology and IHC outcomes [52].</td></tr><tr><td>Indomethacin, acetylsalicylic acid and catalase</td><td>1</td><td>Only acetylsalicylic acid and catalase reduced the fall in histological GAG content generated by papain injection for OA induction [44].</td></tr><tr><td>LLLT</td><td>1</td><td>Similar results in terms of proteoglycan synthesis, while LLLT showed superior antiapoptotic effects evaluated with quantitative real-time polymerase chain reaction for caspase-3 expression [1].</td></tr><tr><td>GNPs</td><td>1</td><td>Similar results in terms of inflammatory cytokines reduction, while GNPs displayed greater antioxidant properties as demonstrated by oxidative damage markers analysis [22].</td></tr><tr><td>Ten intra-articular drugs (including steroidal and nonsteroidal drugs and protease inhibitors)</td><td>1</td><td>Only triamcinolone hexacetonide and tranexamic acid reduced the histological severity of OA at cartilage level [13].</td></tr><tr><td>Oral products</td><td>3</td><td>One study reported worse cartilage histology results compared to oral pioglitazone [33]. One study showed superior osteophytes reduction but similar effect on cartilage gross and histological lesions compared to oral tiaprofenic acid [55]. One study described greater reduction of size and severity of cartilage lesions compared to oral prednisone [54].</td></tr></tbody></table>

Abbreviations: BMSCs, bone marrow mesenchymal stem cell; CS, corticosteroids; GAG, glycosaminoglycans; GNP, gold nanoparticle; HA, hyaluronic acid; IHC, immunohistochemical; LLLT, low-level laser therapy; OA, osteoarthritis; SF, synovial fluid.

Risk of bias assessment

Risk of bias assessment of all included studies is illustrated in Figure 4. There was an 84% agreement between the two authors involved in the evaluation of the risk of bias. Half of the items (54%) were rated as

unclear, while low and high risk of bias were observed in 28% and 18%, respectively. The evaluation of risk of bias over time showed a trend towards improving the quality of the included studies, with low-risk items reported in 38% versus 63% in the most recent half of the papers versus the older ones.
<table><caption>TABLE 5 Effects of injectable combined treatments.</caption><thead><tr><td>Products combination</td><td>Number of studies</td><td>Results</td></tr></thead><tbody><tr><td>Low dosages of triamcinolone acetonide (2.0 and 4.5 mg/mL) with HA</td><td>1</td><td>Dose-dependent synergistic effect, with the combination of HA and 2.0 mg/mL triamcinolone acetonide improving local pain sensitivity and gait parameters and the combination of HA and 4.5 mg/mL triamcinolone acetonide adding benefits also in terms of cartilage histological and IHC outcomes as well as in synovial inflammation reduction compared to HA alone [66].</td></tr><tr><td>Triamcinolone acetonide with HA</td><td>4</td><td>Three studies reported similar clinical outcomes in terms of lameness, pain withdrawal threshold, CBPI and HVAS [4, 37, 39]. One study reported better results 3 weeks after the injection with triamcinolone acetonide alone in terms of lameness and joint effusion [20].</td></tr><tr><td>Three injections of methylprednisolone acetate with a single injection of the same CS followed by two injections of HA</td><td>1</td><td>Better biomarker results for the CS-HA combination in terms of serum malondialdehyde levels [35].</td></tr><tr><td>Triamcinolone acetonide and GNPs vs. GNPs alone</td><td>1</td><td>Synergistic effect, with the combination of triamcinolone acetonide and GNPs showing greater benefits in terms of cytokines levels and chondrocytes number, while producing similar effects on oxidants production and oxidative damage markers compared to GNPs alone [22].</td></tr><tr><td>Blood cell secretome and triamcinolone acetonide</td><td>1</td><td>Synergistic effect, with better clinical results of the combination compared to triamcinolone acetonide alone [3].</td></tr></tbody></table>

Abbreviations: CBPI, Canine Brief Pain Inventory; CS, corticosteroids; GNP, gold nanoparticles; HA, hyaluronic acid; HVAS, Hudson Visual Analogue Scale.

<figure><img src="image_7.png" /><figcaption>FIGURE 4 Systematic Review Centre for Laboratory Animal Experimentation's risk of bias tool assessment of the included studies. The bar chart shows the percentage of all studies that met each quality item, scored as 'Low risk', 'High risk' or 'Unclear'.</figcaption></figure>

DISCUSSION

The main finding of this systematic review of preclinical studies is that intra-articular CS injections can induce a wide range of effects on OA joints. While some negative effects were documented, disease-modifying

effects were observed in at least one of the related outcomes in two-thirds of the studies, reducing the progression of cartilage damage and synovial inflammation with benefits observed at macroscopic, histological and immunohistochemical levels and positive effects in terms of clinical findings.
Intra-articular CS are routinely used in the treatment of symptomatic knee OA, with several clinical studies supporting the effectiveness of this approach in producing short-term pain relief and functional improvement in OA patients [21, 32, 46, 48, 59, 62], although with controversial findings on the objective effects on the joint tissues. Several in vitro studies analysed the effects of CS on chondrocytes and cartilage tissue reporting conflicting results. Some studies showed beneficial effects on human chondrocyte cultures, offering a protection from the ECM degradation via downregulation of catabolic molecules, such as MMPs or via upregulation of ECM proteins like aggrecan, type II collagen and fibronectin [16, 69, 70]. On the other hand, other studies suggested detrimental effects of CS on chondrocytes, inducing apoptosis and reducing cell viability and ECM synthesis [24, 64, 65, 67]. Other authors reported opposite effects on human chondrocytes cultures correlating with the time of exposure of cells to CS [42]. Since controversies of in vitro studies may arise from the experimental models used, often not able to replicate the complexity of the articular joint environment, in vivo preclinical studies have been performed to investigate intra-articular CS effects.

This systematic review assessed the effects of intra-articular CS injections in OA joints in animal studies to provide objective information on both risks and benefits of one of the most common injective procedures for the management of OA. Despite the recent growing interest towards other intra-articular products showing similar or even better clinical outcomes and longer effect duration, this systematic review showed that the research on intra-articular CS injections continues to be active, with an increasing trend in publications of preclinical animal studies on this topic observed over the years. At cartilage and synovial level, intra-articular CS injections showed a beneficial effect in the majority of the studies at macroscopic and immunohistochemical evaluations, while histological outcomes were more conflicting, with some studies reporting detrimental results compared to OA controls. The discrepancy between histological and immunohistochemical findings could be attributed to the different timing of the changes induced by OA induction and/or CS treatment, which varied greatly across the studied OA models.

Overall, these results suggest that intra-articular CS injections have the potential to exert important disease-modulating and possibly disease-modifying effects, but they may also carry the risk of detrimental effects on OA joints. This represents an important difference with other injectable options for OA management. Previous ESSKA ORBIT systematic reviews showed that either adipose tissue- and bone marrow-derived cell-based injectable therapies, as well as PRP, which have been shown to provide improvement and potentially induce

disease modification, do not present such risk in animal OA models, as no detrimental effects were described for any of these products in any of the outcomes analysed [11, 12, 57].

The heterogeneous and sometimes conflicting results of CS may be due to the reported time- and dose-dependent effect on articular cartilage, with beneficial effects occurring at low doses and short durations of use and detrimental effects at high doses and longer durations [71]. The potentially chondrotoxic effect of intra-articular CS has been reported also in humans. In a saline-controlled, double-blind RCT on 140 knee OA patients receiving an intra-articular injection of 40 mg of triamcinolone acetonide every 3 months for 2 years, McAlindon et al. performed a magnetic resonance imaging evaluation revealing a significantly greater cartilage volume loss in patients treated with CS injections compared to saline controls [45]. Similarly, a study from the OA Initiative of Zeng et al. confirmed that repeated intra-articular CS administrations are associated with an increased risk of knee OA progression in terms of Kellgren–Lawrence grade and joint space narrowing compared to controls [73]. This aspect is reflected in the current systematic review, as the majority of the studies reporting similar or worse outcomes at either cartilage or synovial level compared to OA controls performed multiple CS injections.

CS effects on cartilage and synovial membrane can be studied via analysis of the changes in serum and SF biomarkers. Biomarkers can reflect dynamic quantitative changes in joint remodelling and, therefore, disease progression or response to a specific treatment [10]. Nevertheless, only four of the animal studies included in this systematic review performed biomarkers evaluation, reporting conflicting results on SF growth factors and anti- and pro-inflammatory cytokines and chemokines quantification and no difference in serum IL-10 and β-NGF expression and malondialdehyde levels in CS-treated joints compared to OA controls. The limited evidence available prevents drawing solid conclusions on the effect of CS on the biomarkers profile in OA joints. Imaging evaluations were also performed in a minority of studies with inconsistent results, showing positive effects after CS injections only in one-third of the studies and otherwise no differences with OA controls. Finally, other aspects addressed by this systematic review were not supported by solid evidence, like the effects of intra-articular CS in relation to the doses, formulations, injective protocols, synergistic effects with other injectable products and in comparison to other injective therapies. While providing some interesting preliminary indications, this analysis did not result in sufficient information to draw strong conclusions, with the findings collected on these particular aspects being scarce and often controversial.
This systematic review has several limitations that reflect those of the included studies. These studies focused on different animal species and OA models (ranging from small to large animals), with different follow-ups and different CS types, doses and injection protocols and outcomes were evaluated with several approaches. Moreover, the animal models presented the use of different strategies to induce the OA environment, which provoked different joint inflammatory milieus and, therefore, potentially different interaction and response to treatment. Unfortunately, the number of studies did not allow performing subanalyses based on the heterogeneous parameters, which could have influenced the observed outcomes. This heterogeneity clearly represents the complexity of this field and explains the difficulties in the literature analysis, challenging study comparisons and the understanding of some contradictory results. The wide heterogeneity and the differences between human spontaneous OA and experimental animal models of OA, as well as the different joint lifespan between some animal species and humans make it difficult to directly translate these findings to the clinical setting. However, findings as objective as those reported in animals are difficult to reproduce in humans due to various ethical and practical concerns, and only a few clinical studies attempted to evaluate the effects on the OA joints following intra-articular injection of CS.

The fact that the spectrum of documented effects of intra-articular CS injections was wide, ranging from detrimental to positive, underpins the need to identify suitable indications and treatment modalities to avoid the possible detrimental effects while maximising the benefits of intra-articular CS in OA joints, especially considering the presence of orthobiologic approaches providing benefits without showing the risk of detrimental effects [40]. In this light, this systematic review on the preclinical effects of CS is of clinical relevance and warrants caution towards the use of CS in the clinical practice, where the chronic OA symptomatology predisposes repeated injections with their possible deleterious effects. Further clinical studies are required to translate the observed findings into indications on how to more safely apply this treatment in humans, elucidating the outcomes of different types of CS, doses and injection protocols in order to give more suitable treatment indications and optimise the management of OA in the clinical practice.

## CONCLUSION

Intra-articular CS injections induced a wide range of results on OA joints in experimental animal models, from disease-modifying and positive clinical effects at short-term evaluation to the lack of benefit or even negative effects. This underlines the need to identify

more specific indications and treatment modalities to avoid possible detrimental effects while maximising the anti-inflammatory properties and the benefits of intra-articular CS in OA joints.

## AUTHOR CONTRIBUTIONS

**Giuseppe Filardo**: Conceptualisation; writing—review and editing; supervision. **Manuela Salerno**: Methodology; writing—original draft preparation; writing—review and editing. **Mikel Sánchez**: Writing—review and editing. **Alessandro Bensa**: Conceptualization; methodology; data curation; writing—original draft preparation. **Angelo Boffa**: Methodology; data curation; writing—review and editing. **Laura de Girolamo**: Writing—review and editing. **Lior Laver**: Writing—review and editing. **Jérémy Magalon**: Writing—review and editing. **Thomas Tischer**: Writing—review and editing. All authors have read and agreed to the published version of the manuscript.

## ACKNOWLEDGEMENTS

The authors have no funding to report. Open access funding provided by BIBLIOSAN.

## CONFLICT OF INTEREST STATEMENT

Jérémy Magalon is a co-founder of Remedex and received honoraria from Fidia Pharmaceuticals, Horiba, Arthrex Horus Pharma and Macopharma. Laura de Girolamo is scientific consultant for Lipogems S.p.A and received Institutional Research Grant from Fidia Pharmaceuticals. The remaining authors declare no conflict of interest.

## ETHICS STATEMENT

The authors have nothing to report.

## ORCID

Manuela Salerno http://orcid.org/0000-0003-4830-0988

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**How to cite this article:** Bensa, A., Salerno, M., Boffa, A., de Girolamo, L., Laver, L., Magalon, J. et al. (2024) Corticosteroid injections for the treatment of osteoarthritis present a wide spectrum of effects ranging from detrimental to disease-modifying: a systematic review of preclinical evidence by the ESSKA Orthobiologic Initiative. *Knee Surgery, Sports Traumatology, Arthroscopy*, **32**, 2725–2745.
https://doi.org/10.1002/ksa.12242