Comparative effectiveness of intra-articular therapies in knee osteoarthritis: a meta-analysis comparing platelet-rich plasma (PRP) with other treatment modalities

Introduction: Knee osteoarthritis (KOA) is a progressive joint disease commonly treated with intra-articular injections, including platelet-rich plasma (PRP), hyaluronic acid (HA), or corticosteroids (CS). This updated meta-analysis aims to enhance the statistical power of the results and provide comprehensive clinical evidence that reflects the most current research. By doing so, the authors aim to suggest a reliable estimate for the development of guidelines, addressing the pressing need for effective and minimally invasive treatment options. Methods: PubMed, Scopus, clinicaltrials.gov, Cochrane Central were searched until March 2023, for randomized controlled trials (RCTs) comparing the effectiveness of intra-articular injectable therapies, including PRP, HA, CS, and placebo, in KOA. Data extraction involved baseline characteristics and outcome measures [Western Ontario and McMaster Universities Arthritis Index (WOMAC) scores, Visual Analog Scale (VAS) pain scores, KOOS, and IKDC scores] at 1, 3, 6 and 12 months. Statistical analysis, including subgroup analysis, assessment of heterogeneity, and publication bias, was conducted using Review Manager. Results: Our meta-analysis of 42 studies involving 3696 patients demonstrated that PRP treatment resulted in significant pain relief compared to HA injections, as evidenced by improved WOMAC pain (MD: −0.74; 95% CI: −1.02 to −0.46; P≤0.00001; I 2=94%) and VAS pain (MD: −0.65; 95% CI: −1.24 to −0.06; P=0.03; I2=97%) outcomes. Similarly, PRP showed greater efficacy in reducing WOMAC pain (MD: −8.06; 95% CI: −13.62 to −2.51: P=0.004; I 2=96%) and VAS pain (MD: −1.11; 95% CI: −1.64 to −0.59; P≤0.0001; I 2=68%) compared to CS injections, with the most significant improvement observed at 6 months. Conclusions: PRP is an effective treatment for KOA. It provides symptomatic relief, has the potential to reduce disease progression, and has sustained effects up to 12 months. PRP offers superior pain relief and functional enhancement compared to CS and HA injections.


Introduction
Osteoarthritis (OA) is a degenerative joint disease involving all joints, while knee osteoarthritis (KOA) is a multi-morbid disability of the knee joint characterized by knee pain, inflammation, and articular degeneration that leads to not only an increase in health care burden but also has a major effect on an individual's quality of life [1] .Advancing age [2] , female sex [3] , obesity, inflammation [4,5] and lower adherence to the HIGHLIGHTS • Knee osteoarthritis is a widespread condition causing pain and reduced quality of life.• Various treatments option exist, including platelet-rich plasma (PRP) therapy, but current guidelines lack clear recommendations due to limited evidence.Mediterranean diet [6] are risk factors in progression of KOA [2][3][4][5] .
PRP is an autologous blood derivative with high growth factors such as transforming growth factor, platelet-derived growth factor, insulin-like growth factor, vascular endothelial growth factor, vascular endothelial growth factor and bioactive proteins, affecting the healing of bone, cartilage, ligament and tendon [7] .Therapies are evolving in markets such as hyaluronic acid (HA), platelet-rich plasma (PRP), ozone gas, saline, corticosteroids (CS) and mesenchymal stem cell therapy [8,9] .HA and intra-articular CS play an anti-inflammatory role in KOA and release pain and inflammation [10,11] .Recent research has also focused on using mesenchymal stem cells (MSCs), derived from sources such as adipose tissue, bone marrow and umbilical cord blood, for treating OA.MSCs show promise in slowing cartilage degradation in OA by regulating the immune response and releasing beneficial compounds [9] .In addition, according to recent evidence, PRP therapy reduces pain and stiffness and delays articular degeneration in patients with mild to moderate KOA [12] .To enhance the quality of life in patients with KOA, it is necessary to compare the effects of various therapies with PRP.Despite an increasing body of literature on the effectiveness of PRP in mild to moderate KOA, current guidelines from the American Academy of Orthopedic Surgeons (AAOS) do not provide a clear recommendation for or against its use due to insufficient scientific evidence [13] .Additionally, a recent position paper by the American Association of Hip And Knee Surgeons (AAHKS) also does not recommend PRP for advanced hip and knee arthritis due to insufficient evidence regarding its efficacy [14] .Although a recent network meta-analysis suggests that platelet-rich plasma therapy may be as effective as or more effective than other intra-articular therapies, the authors were unable to make clinical recommendations for PRP use in KOA due to methodological flaws and limitations in the included studies [15] .Therefore, we conducted an updated systematic review and meta-analysis, incorporating recently published trials, to increase statistical power and strengthen clinical evidence on the efficacy of PRP compared to other intra-articular therapies for KOA.The findings of this analysis can contribute to the formulation of clinical guidelines for the treatment of KOA.

Methods
This meta-analysis conforms to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) 2020 recommendations, Supplemental Digital Content 1, http://links.lww.com/MS9/A332 [16] .The protocol of this systematic review and meta-analysis was registered on PROSPERO.

Literature search and study selection
We conducted an extensive electronic literature search on PubMed/MEDLINE, Scopus, clinicaltrials.gov,Cochrane Central (in the Cochrane Library) and Google Scholar from inception until March 2023 to identify studies that compared the effectiveness of intra-articular injectable therapies with PRP.For literature search, following keywords and MeSH term combinations were used: (Platelet-rich plasma OR platelet-rich growth factors OR platelet-rich fibrin OR platelet concentrates) AND (Interarticular corticosteroid injection OR Triamcinolone injection OR corticosteroid shots OR corticosteroids OR steroids OR hyaluronic acid OR Sodium Hyaluronate OR Vitrax OR billon OR Etamucine OR hyvisc OR Luronit OR Amvisc OR healing OR placebo) AND (Knee osteoarthritis OR patellofemoral arthritis OR kneecap arthritis OR degenerative joint disease OR wear and tear arthritis of knee OR osteoarthritis of the knee) were used.
After the initial search, duplicates were removed, and abstracts were then screened independently by two reviewers.This was followed by full-text eligibility screening, also conducted by two independent reviewers.Any discrepancies on study eligibility were resolved by consultation by a third reviewer.Additionally, reference list of included studies was also searched to identify more studies.

Eligibility criteria
The studies selected were based on a strict eligibility criteria.All Randomized controlled trials (RCTs) comparing the effects of injectable therapies like hyaluronic acid, steroids, placebo, ozone, etc. with PRP on knee osteoarthritis were included.Outcome measures were Western Ontario and McMaster Universities Arthritis Index (WOMAC) scores, Visual Analog Scale (VAS) pain scores, Knee Injury and Osteoarthritis Outcome Score (KOOS), and International Knee Documentation Committee (IKDC).We excluded all types of reviews articles, cross-sectional studies, observational studies, case reports, case series, editorials, commentaries, and animal-based studies, as well as any studies that were not published in the English language.Studies including individuals with recent or imminent knee surgery, or patients who had prosthetic implants, were also eliminated.

Data extraction
Data was extracted on Microsoft Excel.Baseline characteristics extracted were as follows: Author, year of publication, sample size of study population in each intervention group, mean age, sex, and mean BMI of patients in each group, mean baseline WOMAC scores, mean baseline VAS score.To assess the efficacy of PRP treatment versus other injectables, the outcomes measures that were compared were: the mean WOMAC pain, stiffness, function, and total scores at 1 month, 3 months, 6 moths, and 12 months; mean VAS pain scores at 1, 3, 6, and 12 months; mean IKDC scores at 1, 3, 6, and 12 months and KOOS pain scores at 1, 3, 6, and 12 months.Quality assessment of the studies included was carried out by two reviewers using Cochrane risk of bias tool for Randomized Controlled Trials [17] .In addition, A Measurement Tool to Assess systematic Reviews 2 (AMSTAR 2) checklist was used to self-evaluate this meta-analysis (Supplemental Digital Content 2, http://links.lww.com/MS9/A333) [18] .

Statistical analysis
Review Manager-v 5.4.1 was used for the statistical analysis.The included studies' mean differences (MD) were estimated with 95% CIs.To pool the effect sizes across studies, a random effects model was applied.Additionally, we performed a subgroup analysis of different intra-articular treatment modalities including HA, CS and placebo, comparing them with PRP.We hoped to find any changes in treatment effects between different intraarticular therapies by analyzing the subgroups.A P value of less than 0.05 was deemed significant.We used the I 2 statistic to examine heterogeneity and considered it significant if I 2 was greater than 75%.To ensure the robustness of our findings, we conducted a leave-one-out sensitivity analysis when high heterogeneity was observed.This analysis involved iteratively removing one study at a time.we performed sensitivity or leaveone-out analysis.In addition, funnel plots and Egger's test were used to assess publication bias.

Literature search and quality assessment
A comprehensive literature search initially identified a total of 4862 articles.Following removal of duplicates and screening of titles and abstracts, full-text screening was conducted, resulting in the inclusion of 42 randomized controlled trials (RCTs) in the final analysis  . These tials involved a total of 3696 participants, with 1824 in the PRP group, 1269 in the HA group, 437 in the placebo group, and 166 in the CS group.PRP was compared with HA in 28 studies, saline in 10 studies, CS in 6 studies, and ozone in three studies.A detailed literature search is illustrated in the PRISMA flowchart (Fig. 1).SDC 3, Table 1, Supplemental Digital Content 3, http://links.lww.com/MS9/A334 provides a summary of the baseline characteristics of all studies that were included in the analysis.

Quality assessment and publication bias
The quality of the studies was assessed using the Cochrane risk of bias tool for RCTs, and the results indicated low risk of bias in majority of studies, as shown in (SDC 3, Table 2, Supplemental Digital Content 3, http://links.lww.com/MS9/A334).Egger's test revealed a significant publication bias in almost all the outcomes as demonstrated in SDC 3, Table 3, Supplemental Digital Content 3, http://links.lww.com/MS9/A334.Funnel plots for publication bias have been shown in SDC 4, Figures S1-3, Supplemental Digital Content 4, http://links.lww.com/MS9/A335.

WOMAC total
Two studies recorded WOMAC total scores that demonstrated a significant improvement with PRP as compared to CS (MD: − 8.83; 95% CI − 16.77 to − 0.89; P = 0.03; I 2 = 97%).Subgroup analysis of two studies reporting WOMAC total at 6 months did not reveal a significant difference between the two treatment groups.At 3-and 12-months follow-up subgroup analysis could not be performed due to a limited number of studies.(Table 1; SDC 4, Figure S11, Supplemental Digital Content 4, http://links.lww.com/MS9/A335).

Discussion
Current Meta-analysis including 42 trials involving 3696 patients suggests that PRP is an effective treatment for knee osteoarthritis when compared with HA, CS and placebo.The recent evidence based clinical practice guidelines from the AAOS on appropriate use criteria for the management of knee osteoarthritis provided treatment recommendations for specific patient scenarios.In the majority of cases, PRP was rated as "Rarely Appropriate," while intra-articular CS was considered "Appropriate." [14]In an effort to provide symptomatic relief and postpone surgery, intraarticular CS injections are frequently prescribed prior to secondary care referral.While these injections have shown temporary improvement in pain scores among osteoarthritic patients, they are also associated with side effects [61] .Thus, our findings have the potential to provide valuable decision support in favour of PRP for the development of future guidelines.Inflammation plays a significant role in the development and progression of osteoarthritis, contributing to joint symptoms and disease advancement [62] .Anti-inflammatory approaches can effectively counteract this key mechanism of disease progression.Blood derivatives such as PRP have the potential to exert broad influences on the joint environment.PRP can affect synoviocytes, meniscal cells, and mesenchymal stem cells, thereby modulating various cellular activities [63][64][65] .Additionally, the chemo-attractant properties of PRP can attract other beneficial cells to participate in the overall therapeutic effect [63] .This multifaceted action of PRP may result in anabolic effects, down-regulation of joint inflammation, and positive modulation of chondrocyte apoptosis [66] .Consequently, PRP can offer clinical benefits by improving symptoms and function and potentially slowing down the degenerative processes, even though it may not directly regenerate hyaline cartilage [67] .
Our findings align with previous meta-analyses, indicating that PRP outperforms HA, CS, and placebo in terms of efficacy [61,67,68] .Specifically, when compared to CS injections, PRP demonstrates greater efficacy in reducing WOMAC pain and VAS pain outcomes, with the most significant improvement observed at 6 months.A Cochrane review examining the use of CS injections for knee OA supports our results, stating that the effectiveness of the injection diminishes over time, with no sustained effect at 6-month post-injection [61,69] .Additionally, subgroup analysis showed significant improvement with steroids at 3 months, likely due to their quick and symptomatic relief.However, the limited number of studies included in this analysis necessitates further research to validate these findings.Additionally, WOMAC pain, stiffness, and function in the PRP group showed greatest improvement in the 12th month followup.This is supported by previous evidence by Shen et al. [70] .and Filardo et al. [67] .who suggested a sustained effect following PRP injections of up to 12 and even 24 months [61] .
The research findings demonstrate that PRP showed greater improvement in relieving pain in the knee joint compared to CS, as indicated by the significant differences in WOMAC parameters (total, pain) and VAS pain outcomes.Both PRP and corticosteroids have anti-inflammatory properties.However, PRP exerts a more targeted and controlled anti-inflammatory response.It reduces inflammation by modulating the immune response and increasing angiogenesis and re-epithelialization [71] .Whereas corticosteroids broadly suppress the immune system providing only temporary pain relief [72] .Additionally, PRP has the potential to modify the underlying disease process in knee joint conditions, such as osteoarthritis [14] .By promoting tissue repair and regeneration, PRP may slow down the progression of the disease and prevent further joint damage.Corticosteroids do not have disease-modifying properties and primarily address symptom management Significant improvement in pain relief was observed with PRP treatment compared to intra-articular injections of HA for several outcomes such as WOMAC parameters (total, pain, stiffness, function), VAS pain and IKDC.PRP contains a high concentration of growth factors (GF), cytokines, and other bioactive molecules that have regenerative effects on damaged tissues.These substances stimulate tissue repair, reduce inflammation, and promote healing in the knee joint [73] .This regenerative capacity of PRP may lead to more effective pain relief compared to HA.Additionally, subgroup analysis revealed the greatest improvement in function at the 12-month follow for WOMAC scores (total, stiffness and function).The beneficial effects of PRP treatment may persist over a longer duration compared to HA. PRP stimulates tissue healing and regeneration, leading to sustained pain relief and functional improvements.HA, being primarily a lubricant, may provide temporary relief but may not have the same long-term impact as PRP [74] .
Different PRP formulations exist, varying in concentrations of blood cells, plasma, and GFs.The role of leucocytes in PRP remains debated, with conflicting findings regarding their proinflammatory effects [67] .The only available comparative trial showed similar outcomes between leucocyte-rich (LR) and leucocyte-poor (LP) PRP formulations [75] .According to recent metaanalysis results, it was found that three injections of PRP had a significantly greater effect compared to a single injection, and LR-PRP demonstrated higher efficacy than LP-PRP [67] .However, due to the limited available information, additional research is required to further substantiate these findings [14] .It is worth noting that the reporting of PRP composition is often inadequate, and inconsistent definitions further complicate the analysis.Thus, additional high-level studies that compare specific PRP formulations are necessary to draw reliable conclusions [67] .In the management of knee osteoarthritis, the concentration of platelets, the volume of PRP injected, and the treatment protocol can be customized based on the severity and characteristics of the knee osteoarthritis.This individualized approach may contribute to better outcomes compared to the standardized intra-articular treatment.

Limitations
One potential limitation is the presence of high unexplained heterogeneity.This could be attributed to factors such as the method of preparation, centrifugation process, concentration of leucocytes, and dosage of PRP.These variations have the potential to generate distinct biological effects of PRP and HA, leading to varying physiological responses in patients.An author's review provides guidance and recommendations on the key components that should be included in a standardized PRP protocol [76] .There is also substantial heterogeneity among the patients included in the meta-analyses regarding patient age, sex, BMI.Additionally, our selection of studies was limited to those published in the English language, which introduces the possibility of a bias related to language or culture.Lastly, the significant results of Egger's test indicate that publication bias may have influenced our meta-analysis findings.This suggests that studies with positive or statistically significant results are more likely to be published, which could result in an overestimation of the treatment effect.Caution is advised when interpreting our results, and additional studies are required to gain a more thorough and unbiased understanding of the topic.

Conclusions
In conclusion, PRP offers symptomatic relief, potentially slows down disease progression, and has sustained effects up to 12 months.It provides better pain relief and functional improvement than CS and HA injections.PRP's effectiveness is contributed to by its anti-inflammatory and regenerative properties.However, additional research is required to investigate the function of leucocytes in PRP formulations.Individualizing PRP treatment based on disease severity has the potential to improve outcomes.In general, PRP has the potential to influence future knee osteoarthritis treatment guidelines and decision-making.

Figure 2 .
Figure 2. Forest plots for the subgroup analysis of platelet-rich plasma (PRP) versus hyaluronic acid (HA) for the outcomes of Western Ontario and McMaster Universities Arthritis Index total at 1, 3, 6, and 12 months.

Figure 3 .
Figure 3. Forest plots for the subgroup analysis of platelet-rich plasma (PRP) vs hyaluronic acid (HA) for the outcomes of Visual Analog Scale pain at 1, 3, 6, and 12 months.

•
Our meta-analysis found that PRP treatment significantly reduced pain compared to hyaluronic acid (HA) and corticosteroid (CS) injections, as demonstrated by improved Western Ontario and McMaster Universities Arthritis Index and Visual Analog Scale pain scores.•Themost significant improvement observed at 6 months.•PRP effectively treats knee osteoarthritis, providing lasting pain relief, potential disease progression reduction, and superior results compared to CS and HA injections.
a Department of Medicine, Dow University of Health Sciences, b Shaheed Mohtarma Benazir Bhutto Medical College Lyari, c Dow International Medical College, Karachi, d Services Institute of Medical Sciences, e King Edward Medical University, Lahore,

Table 2
VAS pain, IKDC and KOOS scores at one, three, six-and 12-months follow-up stratified by subgroups PRP versus HA, CS or placebo CS, corticosteroid; HA, hyaluronic acid; IKDC, International Knee Documentation Committee; KOOS, Knee Injury and Osteoarthritis Outcome Score; MD, mean difference; PRP, platelet-rich plasma; VAS, Visual Analog Scale.