# Safety profile comparison of intra-articular corticosteroids, hyaluronic acid, platelet-rich plasma, and cell-based injections for knee osteoarthritis: A systematic review and meta-analysis by the ESSKA Orthobiologics Initiative

Alessandro Bensa, Andrea Piano, Giacomo Arthur Fumagalli, Laura de Girolamo, Lior Laver, Jérémy Magalon, Mikel Sánchez, Thomas Tischer, Giuseppe Filardo

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## To cite this version:

Alessandro Bensa, Andrea Piano, Giacomo Arthur Fumagalli, Laura de Girolamo, Lior Laver, et al. Safety profile comparison of intra-articular corticosteroids, hyaluronic acid, platelet-rich plasma, and cell-based injections for knee osteoarthritis: A systematic review and meta-analysis by the ESSKA Orthobiologics Initiative. Knee Surgery, Sports Traumatology, Arthroscopy, 2025, 10.1002/ksa.70230. hal-05525558

HAL Id: hal-05525558

https://amu.hal.science/hal-05525558v1

Submitted on 24 Feb 2026

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# Safety profile comparison of intra-articular corticosteroids, hyaluronic acid, platelet-rich plasma, and cell-based injections for knee osteoarthritis: A systematic review and meta-analysis by the ESSKA Orthobiologics Initiative

Alessandro Bensa¹,²

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

Andrea Piano¹

Giacomo Arthur Fumagalli¹

Laura de Girolamo³

Lior Laver⁴,⁵,⁶

Jérémy Magalon⁷,⁸,⁹

Mikel Sánchez¹⁰,¹¹

Thomas Tischer¹²,¹³

Giuseppe Filardo¹,²

## Correspondence

Alessandro Bensa, Service of Orthopaedics and Traumatology, Department of Surgery, EOC, Lugano, Switzerland.

Email: Alessandro.Bensa@eoc.ch

## Abstract

**Purpose:** The aim was to compare the safety profiles of corticosteroids (CS), hyaluronic acid (HA), blood-derived products based on platelet concentrates (for simplicity indicated as PRP - platelet-rich plasma - being PRP the most common product), and cell-based therapies (namely products exploiting the therapeutic function of mesenchymal stromal cells and other cell populations, either expanded or prepared at the point of care) for knee osteoarthritis (OA) injective treatment.

**Methods:** The literature search was conducted on PubMed, Cochrane, and Web of Science according to PRISMA guidelines on clinical studies reporting adverse events of CS, HA, PRP, or cell-based therapies. Number of patients with adverse events and number and type of adverse events were collected for each treatment. A meta-analysis was conducted for each product on the total, non-severe, severe adverse events, and on the infection rate.

**Results:** Out of 848 included studies, 559 reported data on the adverse events in 76,061 patients and were used for the meta-analysis. These studies included 7121 patients treated with CS, 51,146 patients with HA, 11,941 patients with PRP, and 5853 patients with cell-based therapies. The rates of patients reporting at least one adverse event were 11.0% for CS, 10.5% for HA, 8.7% for PRP, and 14.7% for cell-based therapies. The mean number of total adverse events per treated patient was 0.21 for CS, 0.13 for HA, 0.05 for PRP, and 0.19 for cell-based therapies, with a significant difference in each individual comparison (p < 0.001) except for CS versus cell-based therapies. The same trend was observed for non-severe adverse events. The rates of severe adverse events were 1.1% for CS, 0.7% for HA,

For affiliations refer to page 9.

**Abbreviations:** CI, confidence interval; CS, corticosteroids; HA, hyaluronic acid; OA, osteoarthritis; PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analysis; PRP, platelet-rich plasma.

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.

© 2025 The Author(s). *Knee Surgery, Sports Traumatology, Arthroscopy* published by John Wiley & Sons Ltd on behalf of European Society of Sports Traumatology, Knee Surgery and Arthroscopy.

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0.3% for PRP, and 0.5% for cell-based therapies, while infection rates were 0.4% for CS, 0.1% for HA, 0.3% for PRP, and 0.4% for cell-based therapies.

**Conclusion:** CS, HA, PRP, and cell-based therapies for knee OA have different safety profiles. PRP presented the lowest total adverse event rate, followed by HA, cell-based therapies, and CS. The same trend was observed for non-severe adverse events. PRP demonstrated the lowest rate of severe adverse events, followed by cell-based therapies, HA, and CS, while HA showed the lowest infection rate followed by PRP, CS, and cell-based therapies.

**Level of Evidence:** Level IV.

KEYWORDS

adverse events, infection, knee, osteoarthritis, safety

INTRODUCTION

Knee osteoarthritis (OA) is a prevalent and debilitating condition, affecting 23% of individuals over the age of 40 and imposing a substantial burden on patients and healthcare systems worldwide [14, 17]. The clinical manifestations of knee OA, including pain, stiffness, and functional limitations, significantly impair patients' quality of life [1, 13]. When other conservative therapies are no longer effective, intra-articular injection treatments can represent a minimally invasive option to avoid or delay the need for more invasive and more expensive surgical solutions [3, 8, 37].

Injective treatments aim at providing clinical improvement by restoring joint homoeostasis through the direct local administration of therapeutic products [23, 45]. The most commonly used therapeutic options in clinical practice include corticosteroids (CS), hyaluronic acid (HA), blood-derived products based on platelet concentrates (for simplicity indicated as PRP - platelet-rich plasma - being PRP the most common product), and, more recently, cell-based therapies [6, 27, 28]. While the clinical effectiveness of these products has been largely investigated and is still fuelling an ongoing debate on the best option for intra-articular injection, the comparison of their safety profile represents a considerably less discussed subject, despite being a decisive aspect to consider when choosing the optimal option for knee OA management [5]. Even if generally considered safe procedures, especially compared to more invasive surgical strategies, intra-articular injections carry some risks that should be considered in clinical decision-making. Adverse events vary across products, ranging from local reactions such as post-injection pain, swelling, synovitis, and harvest-site complications for autologous cell-based therapies, to more severe adverse events, including joint infection and systemic side effects [44]. However, the evidence on the safety profiles of CS, HA, PRP, and cell-based therapies in the current literature remains scattered, and a comprehensive comparative investigation would

be of clinical relevance by providing patients and physicians with crucial information for the choice of the optimal injective approach for knee OA.

The aim of this systematic review and meta-analysis was to quantify and compare the safety profiles in terms of type, rate, and severity of adverse events of CS, HA, PRP, and cell-based therapies used as intra-articular injective treatments for patients affected by knee OA. The hypothesis was that not all treatments present the same number and type of adverse events when treating knee OA.

MATERIALS AND METHODS

A systematic review of the literature was performed on CS, HA, PRP, and cell-based intra-articular injections for the treatment of knee OA. The literature search was conducted on 25 October 2024 on three electronic databases (PubMed, Cochrane, and Web of Science), with no time limitation and without any filters, using the following string: (inject* OR intra-articular* OR infiltrat*) AND (osteoarthritis OR OA) AND (knee) (Table S1). The study protocol was registered on PROSPERO (ID: CRD42024617662). The preferred reporting items for systematic reviews and meta-analysis (PRISMA) were used [30].

Study selection and data extraction

The article selection and data extraction process were conducted separately by two authors (A.P. and G.A.F.), and any discrepancies between them were resolved by discussion and consensus with a third author (A.B.). The initial title and abstract screenings were made using the following inclusion criteria: clinical studies of any level of evidence (at least six patients), written in the English language, and reporting the adverse events of CS, HA, PRP, or cell-based therapies (both autologous and allogenic) used for the injective treatment of patients affected by knee OA. The exclusion criteria
were: articles written in other languages, literature reviews, in vitro articles, preclinical in vivo studies, case reports, case series with less than six patients, congress abstracts, clinical studies reporting the combined use of CS, HA, PRP, or cell-based therapies without analysing the adverse events of the single product, clinical studies on joints different from the knee, or other diseases different from OA. In the second step, the full texts of the selected articles were screened, with further exclusion according to the previously described criteria. For the included studies, the relevant data were extracted from the articles and then summarised and analysed to the purpose of the present study. In particular, the following data were collected: authors, year of publication, study design, injected product, number of evaluated patients, number of patients with adverse events, and number and type of adverse events, analysing separately non-severe and severe adverse events (as reported by the authors in the included articles), and infections.

## Statistical analysis

The statistical analysis and the forest plots were performed according to Neyeloff et al. using Microsoft Excel. The Random effects DerSimonian and Laird method, based on the Poisson distribution, was used to provide a pooled rate of the adverse events for single patient [19]. The Poisson model was chosen because it is well-suited for rare and independent events and helped to reduce the disproportionate influence of a few studies with multiple events. To analyse the rate of patients with and without adverse events, considering that the outcome was dichotomous and most of the articles showed zero events, the proportions were first transformed via the Freeman-Tukey double arcsine method. This approach minimises variance instability and allows the inclusion of studies with zero events. An inverse-variance weighted random-effects meta-analysis was then performed, and results were back-transformed to provide pooled rates across studies [36]. The comparisons among the groups were based on the analysis of variance [12]. The number needed to harm (NNH) was calculated for each pairwise comparison of the rates of patients reporting at least one adverse event. Potential publication bias was evaluated by visual inspection of funnel plots and formally tested using Egger's regression intercept. A *p*-value < 0.05 was considered significant.

## RESULTS

### Study selection and inclusion

The literature search identified 18,124 records. After removing duplicates and screening titles, abstracts, and full

texts for eligibility, a total of 848 articles were retrieved (Figure 1). Of those, 289 did not mention if they evaluated or not the adverse events: 74 in the CS group (50.7% of CS studies), 105 in the HA group (30.5% of HA studies), 77 in the PRP group (33.9% of PRP studies), and 33 in the cell-based therapies group (25.2% of cell-based therapies studies). Those mentioning the adverse events evaluation were 559 articles on 76,061 patients (mean age 62.3 ± 22.5 years), published between 1959 and 2024, and were included in the analysis (Table S2). Of these, 315 were RCTs, 69 were comparative studies (retrospective or prospective), and 175 were case series. Among the included articles, 87 focused on at least one group of patients treated with CS (7121 patients, mean age 60.6 ± 7.2 years), 284 articles focused on at least one group of patients treated with HA (51,146 patients, mean age 62.5 ± 34.2 years), 179 articles focused on at least one group of patients treated with PRP (11,941 patients, mean age 56.8 ± 6.1 years), and 112 articles focused on at least one group of patients treated with cell-based therapies (5853 patients, mean age 58.9 ± 6.2 years).

Egger's regression test indicated funnel plot asymmetry across all outcomes (*p* < 0.001). Intercept values were 0.27 for total adverse events, 0.20 for non-severe adverse events, 0.19 for severe adverse events, and 0.20 for infections. The analyses were then performed using a Poisson distribution, which confirmed the robustness of the findings. Funnel plots and Egger's test results are reported in Table S3.

### Total adverse events

Data on total adverse events were reported in 514 of the 559 included studies (91.9%) on 53,311 treated patients. Among these studies, 318 (60.4%), involving a total of 39,187 patients, documented at least one adverse event. The percentage of studies reporting at least one adverse event for each product was 55.0% for CS, 67.0% for HA, 53.8% for PRP, and 57.8% for cell-based therapies. The mean number of total adverse events per treated patient were 0.21 (95% confidence interval [CI]: 0.08–0.24) for CS, 0.13 (95% CI: 0.12–0.14) for HA, 0.05 (95% CI: 0.05–0.06) for PRP, and 0.19 (95% CI: 0.16–0.21) for cell-based therapies (Figure 2). The direct comparison between products showed a statistically significant difference in each individual comparison (*p* < 0.001 in all comparisons) except for the CS versus cell-based therapies comparison (Table 1). The rates of patients reporting at least one adverse event were 11.0% (95% CI: 6.2%–17.0%) for CS, 10.5% (95% CI: 8.4%–12.9%) for HA, 8.7% (95% CI: 6.3%–11.5%) for PRP, and 14.7% (95% CI: 8.5%–22.5%) for cell-based therapies (Figure 2). The direct comparison between products showed no statistically significant difference in any individual comparison (Table 1). The NNH analysis results are reported in Table S4.
<figure><img src="image_5.png" /><figcaption>**FIGURE 1** Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flowchart. CS, corticosteroids; HA, hyaluronic acid; PRP, platelet-rich plasma; OA, osteoarthritis.</figcaption></figure>

## Non-severe adverse events

Data on non-severe adverse events, including any adverse event not classified as severe by the authors of the included articles, were reported in 509 of the 559 included studies (91.1%) on 52,591 treated patients. Among these studies, 314 (61.7%), involving a total of 38,955 patients, documented at least one non-severe adverse event. The mean number of non-severe adverse events per treated patient was 0.20 (95% CI: 0.17–0.23) for CS, 0.12 (95% CI: 0.11–0.13) for HA, 0.06 (95% CI: 0.05–0.07) for PRP, and 0.19 (95% CI: 0.16–0.21) for cell-based therapies. The direct comparison between products showed a statistically significant difference in each individual comparison (*p* < 0.001 in all comparisons) except for the CS versus cell-based therapies comparison (Table 1). The rates of patients reporting at least one non-severe adverse event were 10.1% (95% CI: 5.5%–15.8%) for CS, 9.9% (95% CI: 7.9%–12.2%) for HA, 9.0% (95% CI: 6.5%–11.8%) for PRP, and 13.7% (95% CI: 7.8%–20.8%) for cell-based therapies (Figure 2). No statistically significant differences were observed in any of the individual comparisons (Table 1). The NNH analysis results are reported in Table S4.

## Severe adverse events

Data on severe adverse events, including any adverse event classified as severe by the authors of the articles, were reported in 549 of the 559 included studies (98.2%) on 75,113 patients. Among these studies, 50 (9.1%), involving a total of 14,732 patients, documented at least one severe adverse event. The rates of patients reporting at least one severe adverse event were 1.1% (95% CI: 0.7%–1.6%) for CS, 0.7% (95% CI: 0.5%–0.9%) for HA, 0.3% (95% CI: 0.2%–0.4%) for PRP, and 0.5% (95% CI: 0.3%–0.7%) for cell-based therapies (Figure 2). The direct comparison between products revealed a statistically significant difference in the HA versus PRP comparison (*p* = 0.016) and a trend towards significance in the comparison between CS versus PRP (*p* = 0.060). No statistically significant differences were observed in the other pairwise comparisons (Table 1). The NNH analysis results are reported in Table S4.

## Infections

Data on infections were reported in 551 of the 559 included studies (98.6%) on 75,349 patients. Among
Adverse events of intra-articular injectables for knee osteoarthritis

<figure><img src="image_6.png" /><figcaption>**FIGURE 2** Graphical representation of adverse event rates for corticosteroids (CS), hyaluronic acid (HA), platelet-rich plasma (PRP), and cell-based therapies for knee osteoarthritis treatment. The left panel represents the pooled mean number and the 95% confidence interval [CI] of total adverse events per patient, while the right panel represents the pooled rates and the 95% CI of patients reporting at least one adverse event for total adverse events, non-severe adverse events, severe adverse events, and infections.</figcaption></figure>

these studies, eight (1.4%), involving a total of 3926 patients, documented at least one infection. Only three of these studies reported details about the infective complications (one infection each), all associated with HA injections. Two studies reported one septic arthritis each, both caused by *Staphylococcus aureus*. The first one was resolved with antibiotics, the other one with a combination of arthroscopic lavage and antibiotics. The third study reported one severe infection resulting in the withdrawal of the patient from the study. The remaining five studies (37 infections) did not mention the details of the infections. The rates of patients reporting at least one infection across the different products were 0.4% (95% CI: 0.2%–0.5%) for CS, 0.1% (95% CI: 0.1%–0.1%) for HA, 0.3% (95% CI: 0.2%–0.4%) for PRP, and 0.4% (95% CI: 0.2%–0.6%) for cell-based therapies (Figure 2). The direct comparison between products showed a statistically significant difference in CS versus HA and HA versus PRP (p = 0.033 and p = 0.005, respectively), as well as a trend towards significance in the comparison of HA versus cell-based therapies (p = 0.090). No statistically significant differences were observed in the other pairwise comparisons (Table 1). The NNH analysis results are reported in Table S4.

Cell-based therapies subanalyses

Among the 112 studies on cell-based therapies, 20 investigated only allogenic products, 91 only autologous products, and one study included both an

allogenic and an autologous treatment group. The mean number of total adverse events per treated patient was significantly lower in the autologous group (0.16, 95% CI: 0.13–0.18) compared to the allogenic group (0.51, 95% CI: 0.41–0.61), with the difference reaching statistical significance (p < 0.001). Similarly, the rate of patients reporting at least one adverse event was lower in the autologous group (6.4%, 95% CI: 3.8%–9.6%) than in the allogenic group (31.5%, 95% CI: 1.9%–71.8%), although without reaching statistical significance. Breaking down adverse events by specific procedural steps, the total adverse events at the injection site, calculated as the mean number of total adverse events per treated patient, were 0.03 (95% CI: 0.02–0.04) for the autologous group and 0.31 (95% CI: 0.22–0.40) for the allogenic group (p < 0.001). Adverse events related to the tissue harvesting procedure, calculated in the autologous group, occurred at a rate of 0.01 (95% CI: 0.01–0.02).

DISCUSSION

The main finding of this study is that the most common injectable products for knee OA exhibit different safety profiles. PRP presented the lowest rate of both total and non-severe adverse events, followed by HA, cell-based therapies, and CS. PRP also demonstrated the lowest rate of severe adverse events, followed by cell-based therapies, HA, and CS. Conversely, for infections, HA showed the lowest rate, followed by PRP, CS, and cell-based therapies.
<table><caption>TABLE 1 Comparisons between the intra-articular injective approaches analysed with the respective 95% confidence intervals and *p*-values.</caption><thead><tr><th>Comparison</th><th>Mean number of total adverse events</th><th>Mean number of non-severe adverse events</th><th>Total adverse event rate</th><th>Non-severe adverse event rate</th><th>Severe adverse event rate</th><th>Infection rate</th></tr></thead><tbody><tr><td>CS versus HA</td><td>0.21 (0.08–0.24) versus 0.13 (0.12–0.14)</td><td>0.20 (0.17–0.23) versus 0.12 (0.11–0.13)</td><td>11.0% (6.2–17.0) versus 10.5% (8.4–12.9)</td><td>10.1% (5.5–15.8) versus 9.9% (7.9–12.2)</td><td>1.1% (0.7–1.6) versus 0.7% (0.5–0.9)</td><td>0.4% (0.2–0.5) versus 0.1% (0.1–0.1)</td></tr><tr><td>CS versus PRP</td><td>p&lt;0.001</td><td>p&lt;0.001</td><td>NS</td><td>NS</td><td>NS</td><td>p=0.033</td></tr><tr><td>CS versus cells</td><td>0.21 (0.08–0.24) versus 0.05 (0.05–0.06)</td><td>0.20 (0.17–0.23) versus 0.06 (0.05–0.07)</td><td>11.0% (6.2–17.0) versus 8.7% (6.3–11.5)</td><td>10.1% (5.5–15.8) versus 9.0% (6.5–11.8)</td><td>1.1% (0.7–1.6) versus 0.3% (0.2–0.4)</td><td>0.4% (0.2–0.5) versus 0.3% (0.2–0.4)</td></tr><tr><td>CS versus cells</td><td>p&lt;0.001</td><td>p&lt;0.001</td><td>NS</td><td>NS</td><td>p=0.060</td><td>NS</td></tr><tr><td>HA versus PRP</td><td>0.21 (0.08–0.24) versus 0.19 (0.16–0.21)</td><td>0.20 (0.17–0.23) versus 0.19 (0.16–0.21)</td><td>11.0% (6.2–17.0) versus 14.7% (8.5–22.5)</td><td>10.1% (5.5–15.8) versus 13.7% (7.8–20.8)</td><td>1.1% (0.7–1.6) versus 0.5% (0.3–0.7)</td><td>0.4% (0.2–0.5) versus 0.4% (0.2–0.6)</td></tr><tr><td>HA versus cells</td><td>p&lt;0.001</td><td>NS</td><td>NS</td><td>NS</td><td>NS</td><td>NS</td></tr><tr><td>HA versus cells</td><td>0.13 (0.12–0.14) versus 0.19 (0.16–0.21)</td><td>0.12 (0.11–0.13) versus 0.19 (0.16–0.21)</td><td>10.5% (8.4–12.9) versus 14.7% (8.5–22.5)</td><td>9.9% (7.9–12.2) versus 9.0% (6.5–11.8)</td><td>0.7% (0.5–0.9) versus 0.3% (0.2–0.4)</td><td>0.1% (0.1–0.1) versus 0.3% (0.2–0.4)</td></tr><tr><td>PRP versus cells</td><td>p&lt;0.001</td><td>p&lt;0.001</td><td>NS</td><td>NS</td><td>p=0.016</td><td>p=0.005</td></tr><tr><td>PRP versus cells</td><td>0.05 (0.05–0.06) versus 0.19 (0.16–0.21)</td><td>0.06 (0.05–0.07) versus 0.19 (0.16–0.21)</td><td>8.7% (6.3–11.5) versus 14.7% (8.5–22.5)</td><td>9.0% (6.5–11.8) versus 13.7% (7.8–20.8)</td><td>0.3% (0.2–0.4) versus 0.5% (0.3–0.7)</td><td>0.3% (0.2–0.4) versus 0.4% (0.2–0.6)</td></tr><tr><td>PRP versus cells</td><td>p&lt;0.001</td><td>p&lt;0.001</td><td>NS</td><td>NS</td><td>NS</td><td>NS</td></tr></tbody></table>

Abbreviations: CS, corticosteroids; HA, hyaluronic acid; NS, not significant; PRP, platelet-rich plasma.
The comparison of the clinical effectiveness of CS, HA, PRP, and cell-based therapies remains central to the ongoing debate on the optimal intra-articular treatment for knee OA, with numerous studies evaluating their impact on pain relief, functional improvement, and quality of life [7]. However, the safety profile represents a critical factor in the choice of the most appropriate intra-articular treatment for knee OA, with important implications for patient care beyond the mere clinical effectiveness [21]. The present study builds upon the findings of previous meta-analyses by providing an updated and comprehensive literature review on more than 500 studies focusing on the most used intra-articular injective options for knee OA treatment, and by directly comparing their safety profiles, stratifying outcomes into total adverse events, non-severe adverse events, severe adverse events, and infections [18, 20, 39]. This study highlights that a significant proportion of patients suffers from adverse events of various nature, ranging from 8.7% reporting at least one event for PRP, to 10.5% for HA, 11.0% for CS, and 14.7% for cell-based therapies. Moreover, some patients may suffer from more than one event, as underlined by the analysis of the mean number of total adverse events per treated patient, which showed even higher rates of adverse events being 0.21 for CS, 0.13 for HA, 0.05 for PRP, and 0.19 for cell-based therapies. Each injective product carries inherent risks that should be carefully weighed in clinical decision-making, given their different safety profiles. CS, for instance, have been associated with cartilage degradation and an increased risk of infections following repeated administration [26], HA and PRP treatments may cause local pain, swelling, or inflammation [2, 25], while cell-based therapies raise additional safety concerns such as immunogenic reactions related to allogenic sources and donor site complications for autologous ones [40].

The ESSKA Orthobiologics Initiative documented systematically the preclinical evidence on injectable therapies. Overall, positive findings were reported and even disease-modifying effects for most treatments. However, some differences emerged across different products investigating the adverse events. Intra-articular CS injections induced a wide range of results on OA joints in experimental animal models, from disease-modifying and positive effects to the lack of benefit or even negative effects [4, 10, 9, 38]. Placenta/amniotic tissue also reported to carry the risk of some deleterious effects on OA joints and limited evidence prevented from drawing solid conclusions on other cellular sources such as embryonic, synovial, peripheral blood, dental pulp, cartilage, meniscus, and muscle-derived products [43]. The clinical literature showed promise in terms of efficacy of most treatments, but has so far paid limited attention to the safety profile of injectable treatments for knee OA, underscoring the urgent need for a comprehensive analysis to accurately quantify and characterise adverse

events associated with the most used products in clinical practice.

The findings of the present meta-analysis showed that CS had the highest rate of total, non-severe, and severe adverse events, as well as the highest infection rate together with cell-based therapies. Several studies reported post-injection flare-up of pain lasting for a few days, discomfort at the injection site, swelling, skin atrophy, transient hyperglycaemia (particularly in diabetic patients), and asymptomatic hydroxyapatite calcifications [35]. Severe adverse events included joint infection, osteonecrosis, hypothalamic-pituitary-adrenal axis suppression, and cartilage damage with accelerated knee OA progression, which represent a concern especially after repeated administration. This is not surprising given the well-documented cytotoxic and immunosuppressive effects of CS on joint tissues, which may contribute to both tissue damage and increased susceptibility to infections [34, 46].

Compared to CS, HA showed a better safety profile. In fact, HA presented the lowest infection rate among the products investigated, and the second-lowest total adverse event and non-severe adverse event rates, which are mostly related to pain at the injection site, local joint pain and swelling, and local skin reactions [29]. On the other hand, the rate of HA severe adverse events was lower only compared to CS. Severe adverse events can include joint infection and pseudoseptic reactions, which are characterised by joint inflammation and swelling not caused by infection, that can be severe and require further medical treatment [25]. While the HA severe adverse event rate was higher than cell-based therapies and PRP, they can still be considered rare, particularly in terms of joint infection, as confirmed by the present meta-analysis. Overall, HA exhibited a positive safety profile, with the findings of this study showing more favourable results than cell-based therapies and CS.

The product showing the best safety profile is PRP, which presented the lowest rate of total adverse events as well as of non-severe and severe adverse events among the investigated intra-articular options for knee OA management. These results confirm previous literature reports showing that PRP can produce adverse events mostly of brief duration and of mild entity, such as pain at the injection site, swelling, or transient inflammatory responses [11, 41]. However, while there is in vitro evidence on antimicrobial properties of blood-derived products [15, 22, 32, 31], concerns about the risk of post-injection infections have been raised due to their preparation procedure. In fact, PRP therapy generally entails the processes of blood collection, manufacturing, and administration to patients, with several handling steps that pose a risk of contamination, potentially leading to infection [2]. To reduce this risk, the majority of the commercially available systems are closed systems, which may reduce the contamination
risk, although this point remains controversial. If properly handled with strict aseptic protocols according to the manufacturing guidelines and international regulatory frameworks, the risk of PRP contamination resulting in infection remains minimal [42], which is reflected by the results of the present study documenting for PRP the second lowest infection rate among the investigated products after HA. Together with the results on the total, non-severe, and severe adverse event rates, these findings showed overall the most favourable safety profile for PRP among the injectable approaches studied.

Although both fall under the category of orthobiologics, PRP showed a more favourable safety profile compared to cell-based therapies. While the severe adverse events rate was the lowest after PRP, cell-based therapies showed the second-highest rate of total and non-severe adverse events, as well as the highest infection rate together with CS. Even though the wide majority of adverse events were non-severe both in the autologous and allogenic cell-based therapies, the latter presented a significantly higher risk of total adverse events as well as of injection-related adverse events. An aspect possibly playing a role in the adverse events of autologous cell-based therapies could be the harvesting process. In the autologous cell-based therapies, such as adipose-derived and bone-marrow derived point-of-care products, this process is more invasive than blood harvesting, potentially leading to adverse events at the harvest site. The harvesting process is absent not only for the allogenic products, but also for CS and HA, while it is of minimal invasiveness for PRP. However, the results of this study showed that the risk of adverse events associated with the harvesting process was approximately half that of those linked to the injection procedure in autologous cell-based therapies, suggesting a minor impact on the overall safety profile. Most adverse events of intra-articular cell-based therapies injections are of mild entity, including joint or harvest site pain and swelling, but severe ones can include allergic reactions of variable severity, particularly related to products of allogenic origin, and joint infection [33, 40].

The risk-benefit balance of each injective treatment should be considered in relation to patient-specific factors such as age, comorbidities, and disease severity, which may influence both safety and efficacy. For instance, patients with lower Kellgren-Lawrence grades, younger age, and lower BMI are more likely to experience sustained benefit from intra-articular HA or PRP, whereas advanced OA is associated with poorer and shorter responses [18]. Intra-articular CS may provide short-term relief but should be used cautiously in patients with diabetes due to transient hyperglycaemia, while obesity and multimorbidity generally predict reduced clinical efficacy of viscosupplementation [16, 24]. Besides the clinical perspective, the economic implications of each treatment should be

considered as well. CS, while being the least expensive treatment and offering short-term relief, may lead to higher long-term healthcare costs due to their potential for repeated administration and the risk of side effects. On the other hand, HA and PRP may involve higher upfront costs for patients and healthcare systems, particularly with repeated treatments, but seem to provide longer-lasting results. Cell-based therapies come with added burdens depending on the autologous or allogeneic nature of the product, with complex manufacturing processes and potential logistical challenges, which can significantly impact the overall cost. The choice of treatment should take into account both the direct and indirect costs, together with the impact on the patient's recovery and quality of life. In this context, the present results may play an important role in contributing to the most suitable treatment decision, as safety monitoring is a priority for agencies and professional societies, particularly when evaluating the newer orthobiologic products. Moreover, safety data support shared decision-making between clinicians and patients, which is central to evidence-based and patient-centred care. Overall, the results of this meta-analysis showed that cell-based therapies present an overall safety profile less favourable than PRP and HA, but better than CS. The clinical relevance of these findings was confirmed by the NNH analysis, which corroborated the differences emerged among the safety profiles of the investigated products. An important element to be considered in the interpretation is the most recent introduction of cell-based therapies, since in recent years the research context is changing, possibly affecting the reporting and consequently the results of the adverse event analyses of the different approaches. In fact, while for the oldest treatment a significant proportion of studies did not focus on the adverse events (51% for CS), most studies on cell-based treatments (75%) placed their focus on this aspect as well. The possible heterogeneous reporting within the literature analysed is a potential limitation that warrants caution in the interpretation of the documented findings.

This systematic review also presents other limitations that reflect those of the included articles. First, the studies analysed presented a considerable variability of designs, from small case series to well-powered placebo-controlled RCTs. Second, products used in clinical practice have a significant heterogeneity in terms of characteristics, posology, and administration among and within each injective product category, and future studies should address the safety profiles of specific products, as well as the factors that could be implemented to reduce the adverse events risk. Additionally, the lack of adverse event definitions standardisation and the heterogeneity in adverse events severity reporting, with some studies listing all the non-severe and severe adverse events encountered and others mentioning only the number of non-severe and severe adverse events without specifying the nature and type of the adverse events, hindered the possibility
of applying a standardised classifications system. Moreover, the variability in knee OA diagnostic criteria reported by each of the included studies may have introduced further heterogeneity. This considerable variability also prevented from performing subgroup analyses based on OA severity, demographic factors, or injection dosage. Another important limitation is the heterogeneity in adverse event reporting across different decades and treatment types. CS and HA have been investigated for several decades, whereas PRP and cell-based therapies represent more recent approaches. Over time, reporting standards and regulatory requirements for adverse events have evolved, which may have influenced the observed rates. In this light, the higher attention documented in the most recent cell-based studies versus the oldest CS literature shows promise towards producing more data to better study this important aspect for choosing the injectable treatment option. Moreover, the analysis of the mean number of adverse events per patient could be performed only for total and non-severe adverse events, since the application of this type of analysis for rare events such as severe adverse events and infections would have yielded considerably wide confidence intervals with uncertain results. The subanalysis on cell-based therapies included a relatively limited amount of studies with heterogeneous data and was performed only on the total number of adverse events to limit results uncertainty. Another limitation is the evidence of funnel plot asymmetry. Although Egger's test suggested asymmetry across outcomes, this is more plausibly attributable to heterogeneity rather than true publication bias, as the distribution was strongly influenced by the small number of studies reporting multiple events. The additional Poisson modelling further confirmed the robustness of our findings. Despite the limitations, the present systematic review and meta-analysis offered detailed information regarding the most used intra-articular products for knee OA by performing an extensive literature analysis on more than 800 studies and providing quantitative insights from 559 studies on 76,061 patients about a decisive aspect for clinical practice. Treatment safety represents a key factor in clinical decision-making, and the results of the present meta-analysis could serve as a reference point for clinicians to evaluate the most appropriate intra-articular option for each individual patient as well as for researchers to further elucidate the factors contributing to treatment success, ultimately contributing to optimise the management of knee OA.

## CONCLUSIONS

CS, HA, PRP, and cell-based therapies for knee OA injective treatment have different safety profiles. PRP presented the lowest rate of both total and non-severe

adverse events, followed by HA, cell-based therapies, and CS. PRP also demonstrated the lowest rate of severe adverse events, followed by cell-based therapies, HA and CS, while HA showed the lowest infection rate followed by PRP, CS, and cell-based therapies. Overall, PRP exhibited the best safety profile, with HA being the second safest approach, while cell-based therapies and especially CS showed less favourable safety profiles.

## AUTHOR CONTRIBUTIONS

**Alessandro Bensa**: Conceptualisation; data curation; formal analysis; investigation; methodology; supervision; validation; writing—original draft. **Andrea Piano**: Data curation; formal analysis; investigation; methodology; visualisation; writing—original draft. **Giacomo Arthur Fumagalli**: Data curation; formal analysis; investigation. **Laura de Girolamo**: Validation; writing—review and editing. **Lior Laver**: Validation; writing—review and editing. **Jérémy Magalon**: Validation; writing—review and editing. **Mikel Sánchez**: Validation; writing—review and editing. **Thomas Tischer**: Validation; writing—review and editing. **Giuseppe Filardo**: Conceptualisation; investigation; methodology; project administration; resources; supervision; validation; writing—review and editing.

## AFFILIATIONS

## ACKNOWLEDGEMENTS

Open access publishing facilitated by Università della Svizzera italiana, as part of the Wiley - Università della Svizzera italiana agreement via the Consortium Of Swiss Academic Libraries.

## CONFLICT OF INTEREST STATEMENT

The authors declare no conflicts of interest.

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

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

<footnote n="3">³Orthopaedic Biotechnology Laboratory, IRCCS Ospedale Galeazzi Sant'Ambrogio, Milan, Italy</footnote>

<footnote n="4">⁴Department of Orthopaedics, Hillel Yaffe Medical Center (HYMC), Hadera, Israel</footnote>

<footnote n="5">⁵Arthrosport Clinic, Tel-Aviv, Israel</footnote>

<footnote n="6">⁶Rappaport Faculty of Medicine, Technion University Hospital (Israel Institute of Technology), Haifa, Israel</footnote>

<footnote n="7">⁷Cell Therapy Laboratory, Hôpital De La Conception, AP-HM, Marseille, France</footnote>

<footnote n="8">⁸INSERM, NRA, C2VN, Aix Marseille Univ, Marseille, France</footnote>

<footnote n="9">⁹Remedex Network, Marseille, France</footnote>

<footnote n="10">¹⁰Arthroscopic Surgery Unit, MiKS Hospital, Vitoria-Gasteiz, Spain</footnote>

<footnote n="11">¹¹Advanced Biological Therapy Unit, MiKS Hospital, Vitoria-Gasteiz, Spain</footnote>

<footnote n="12">¹²Department of Orthopaedic Surgery, University of Rostock, Rostock, Germany</footnote>

<footnote n="13">¹³Department of Orthopaedic and Trauma Surgery, Malteser Waldkrankenhaus St. Marien, Erlangen, Germany</footnote>
DATA AVAILABILITY STATEMENT

No additional data were generated for this review. The
data are found in the referenced papers.

ETHICS STATEMENT

Not applicable.

ORCID

Alessandro Bensa https://orcid.org/0000-0002-1021-063X

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## SUPPORTING INFORMATION

Additional supporting information can be found online in the Supporting Information section at the end of this article.

**How to cite this article:** Bensa A, Piano A, Fumagalli GA, de Girolamo L, Laver L, Magalon J, et al. Safety profile comparison of intra-articular corticosteroids, hyaluronic acid, platelet-rich plasma and cell-based injections for knee osteoarthritis: a systematic review and meta-analysis by the ESSKA Orthobiologics Initiative. Knee Surg Sports Traumatol Arthrosc. 2025;1–11. https://doi.org/10.1002/ksa.70230