Current Perspectives on Platelet-Rich Plasma Injections for Knee Osteoarthritis: How to Optimize Clinical Outcomes

Introduction

Osteoarthritis (OA) of the knee is the most common joint disorder in the United States and a major cause of chronic pain and disability worldwide.¹ Characterized by progressive cartilage degeneration, synovial inflammation, and subchondral bone remodeling, knee OA impacts mobility and quality of life.^2,3 Increasing evidence suggests that knee OA is a whole-joint disease involving not only articular cartilage but also the synovium, subchondral bone, menisci, ligaments, and infrapatellar fat pad.⁴ These tissues interact through inflammatory and biomechanical pathways and contribute to disease progression and symptom manifestation.⁵ While definitive treatment for end-stage OA often involves total knee arthroplasty, the focus of early and mid-stage management remains symptom control and preservation of joint function.⁶ Non-surgical treatment options include lifestyle modifications, physical therapy, oral nonsteroidal anti-inflammatory drugs (NSAIDs), and intra-articular injections. Among the injectable therapies, platelet-rich plasma (PRP) has gained increasing attention as a promising biologic option.^7,8

PRP is an autologous blood product obtained by centrifugation, which results in a plasma fraction containing a higher concentration of platelets than baseline. Upon activation, platelets release numerous growth factors from their alpha granules, including transforming growth factor-beta (TGF-β), platelet-derived growth factor (PDGF), insulin-like growth factor-1 (IGF-1), and vascular endothelial growth factor (VEGF).⁹ These factors are involved in modulating inflammation, stimulating chondrocyte activity, and promoting extracellular matrix production.^10,11 In contrast to corticosteroids or hyaluronic acid (HA), which primarily provide symptomatic relief, PRP is believed to exert disease-modifying effects through biologic pathways.^12,13 However, it should be noted that HA also has demonstrated biologic activity, including modulation of cartilage matrix turnover and reduction of inflammatory mediators, rather than acting solely as a viscosupplement.¹³ The proposed advantages of PRP include the suppression of inflammatory cytokines implicated in the OA cascade. Additionally, because PRP is autologous, it minimizes the risk of immunologic reactions or transmission of infectious diseases.¹⁴ A recent systematic review of 27 Level I studies, published in 2023,¹⁰ demonstrated improved clinical outcomes in patients undergoing treatment for knee OA with PRP when compared to HA. Despite multiple Level I studies demonstrating its efficacy, PRP injections for knee OA are not currently covered by insurance, and patients are often required to pay out-of-pocket, typically ranging from $500 to $2000 per injection.^10,15 Furthermore, there are currently no universally accepted guidelines on the optimal number of injections, frequency of treatment, or patient selection criteria for PRP injections in the treatment of knee OA. Recent systematic reviews and meta-analyses have attempted to clarify its role, but significant inconsistency remains among studies due to heterogeneity in PRP preparation methods, leukocyte content, dosing regimens, and outcome reporting, which contributes to ongoing debate regarding true clinical efficacy.^16,17 This narrative review aims to evaluate and synthesize the current body of literature regarding PRP for knee osteoarthritis.

Methods

A literature search was conducted using PubMed, Embase, and Cochrane Library databases for studies published from inception to August 31, 2025. Search terms included “platelet-rich plasma,” “PRP,” “knee osteoarthritis,” and “intra-articular injection.” English-language clinical studies, systematic reviews, and meta-analyses evaluating PRP for the treatment of knee OA were included. Exclusion criteria comprised animal studies, non-knee OA applications, case reports, and studies lacking clinical outcome data. Reference lists of relevant reviews were also screened to identify additional articles.

PRP versus Other Injection Options

Given the increasing incidence of knee OA, intra-articular injectables such as PRP, hyaluronic acid (HA), corticosteroids, and bone marrow aspirate concentrate (BMAC) have become common non-surgical treatment options. However, there remains ambiguity regarding the most effective treatment, and clinical guidelines have yet to establish clear recommendations. The 2019 American College of Rheumatology (ACR) and Arthritis Foundation guidelines conditionally recommend against the use of PRP and HA due to heterogeneity in study quality and lack of standardized protocols, while supporting short-term corticosteroid injections for symptom relief.¹⁸ Similarly, the 2019 EULAR recommendations acknowledge the potential of PRP and other biologics but advise that evidence remains insufficient for formal recommendation.¹⁹ As the evidence base continues to expand, several high-level systematic reviews and meta-analyses have attempted to clarify the comparative efficacy of these modalities.

A systematic review of Level I randomized controlled trials published in 2021²⁰ compared outcomes between PRP and HA for the treatment of knee OA (Table 1). The analysis included 18 studies comprising 811 patients treated with PRP and 797 with HA, with an average follow-up of 11.1 months. PRP was associated with significantly superior improvements in several patient-reported outcomes (PROs), including the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), visual analog scale (VAS) for pain, and Subjective International Knee Documentation Committee (IKDC) scores. Notably, 51.7% of outcome comparisons favored PRP over HA, and a higher proportion of PROs demonstrated significant pre- to post-treatment improvement in PRP recipients (81.0%) versus those who received HA (38.1%).

Table 1 Systematic Reviews of Randomized Controlled Trials That Compared PRP with Other Treatment Modalities for Knee Osteoarthritis

An updated systematic review published in 2023¹⁰ analyzed 27 Level I studies, encompassing 1042 patients treated with PRP, 226 with BMAC, and 1128 with HA. The authors found that both PRP and BMAC were significantly more effective than HA across multiple PROs including WOMAC, VAS, and Subjective IKDC scores. However, no statistically significant difference was observed between PRP and BMAC, suggesting that either biologic may offer comparable benefits in terms of symptomatic relief.

Another meta-analysis published in 2023 by Qiao et al¹² evaluated 35 studies involving 3104 patients, comparing corticosteroids, HA, PRP, and PRP+HA combination therapy against placebo. At 3-month follow-up, PRP and PRP+HA yielded the most favorable WOMAC and VAS scores. While PRP+HA maintained superior VAS outcomes across all time points, by 12 months both PRP and PRP+HA demonstrated the most robust improvements in pain and function, reinforcing the potential of PRP as a stand-alone or adjunct treatment.

A 2025 meta-analysis by Li et al²¹ further validated PRP’s long-term efficacy. This study included 15 double-blind randomized controlled trials comprising 1632 patients with Kellgren-Lawrence grade I–III OA. At 12 months, patients undergoing treatment with PRP demonstrated significantly lower WOMAC pain scores and total scores compared to those receiving HA—both exceeding the minimal clinically important difference (MCID). Additionally, patients treated with PRP had significantly lower VAS pain scores at 12 months and improved Subjective IKDC scores at 1-month post-injection, suggesting a faster and more sustained therapeutic benefit.

Although most of the literature supports PRP as a more effective option for symptomatic relief in knee OA, several limitations persist. Many studies vary in PRP preparation and injection protocols, utilize heterogeneous outcome measures, and lack long-term follow-up data regarding structural progression or time to arthroplasty, which limits definitive conclusions regarding disease modification.

Leukocyte-Rich vs Leukocyte-Poor PRP

Leukocyte-rich PRP (LR-PRP) refers to platelet-rich plasma that contains a higher number of white blood cells, while leukocyte-poor PRP (LP-PRP) has most white blood cells removed, resulting in a preparation that is primarily platelets with minimal immune cells.²² Both LR-PRP and LP-PRP have been utilized for the treatment of knee OA, yet there is limited evidence clearly defining the ideal leukocyte concentration for this indication.²³ LR-PRP contains a higher concentration of white blood cells, particularly neutrophils, which can release pro-inflammatory cytokines and growth factors such as IL-1β and TNF-α that may stimulate a more robust early healing response.²² However, LR-PRP may be detrimental because the elevated levels of pro-inflammatory cytokines and reactive oxygen species released by neutrophils can exacerbate inflammation, theoretically leading to increased pain, joint irritation, and potential degradation of cartilage in osteoarthritic joints.²⁴ However, these theories have yet to bear out in clinical trials.¹⁸

A 2016 meta-analysis²⁵ incorporating 6 randomized controlled trials and three prospective comparative studies (totaling 1055 patients) evaluated the clinical outcomes and adverse event rates associated with LP-PRP, LR-PRP, hyaluronic acid (HA), and placebo treatments for knee OA (Table 2). The analysis demonstrated that LP-PRP led to significantly better WOMAC scores when compared to HA or placebo, while LR-PRP did not show a significant difference. Across all groups, no significant differences in Subjective IKDC scores were observed. Although PRP treatments were associated with more adverse reactions than HA, leukocyte content did not appear to influence the rate of these effects. Adverse events, which were reported in 1.6% of patients, were generally mild and included swelling and pain; less commonly, symptoms such as syncope, dizziness, headache, gastritis, and tachycardia were reported.

Table 2 Studies That Compared Different Aspects of PRP Injections for Knee Osteoarthritis

A subsequent meta-analysis in 2021²⁸ further explored the comparison between LR-PRP and LP-PRP. Among the 32 studies reviewed—most with lower levels of evidence—only one directly compared both PRP types. In total, 1162 knees received LP-PRP and 628 received LR-PRP. Both formulations showed similar improvements in pain and function after 12 months. However, LR-PRP was associated with a higher frequency of adverse reactions.

In 2022, Abbas et al²⁹ conducted a network meta-analysis of 20 RCTs and 3 prospective comparative studies involving 2260 patients with knee OA. Follow-up averaged 9.9 months. The authors found no significant differences between LR-PRP and LP-PRP in terms of PROs or adverse events. That same year, Di Martino et al²² published an RCT comparing 90 patients treated with LR-PRP and 85 with LP-PRP. Again, there were no statistically significant differences between the groups at 12-month follow-up in terms of clinical results or adverse reactions.

In a recent double-blind RCT, Romandini et al³⁰ evaluated 132 patients with Kellgren–Lawrence grade I–III knee osteoarthritis who received either LR-PRP or LP-PRP injections. Over a 12-month follow-up period, both groups demonstrated significant and comparable improvements in pain, function, and overall clinical outcomes, with no differences in treatment failures or adverse events. These findings suggest that the presence of leukocytes in PRP does not significantly influence the efficacy or safety of the injection, supporting the notion that both LR-PRP and LP-PRP can be effectively utilized in the treatment of knee OA.

In summary, current evidence does not favor one PRP formulation over the other for managing knee OA. Further investigation is necessary to better understand how differences in PRP composition and delivery influence joint outcomes. However, despite these comparative analyses, the body of evidence directly evaluating leukocyte concentration as an independent variable remains limited. Variability in PRP preparation methods, leukocyte quantification, and reporting standards makes it challenging to establish definitive conclusions. Consequently, while current data suggest comparable efficacy and safety between LR-PRP and LP-PRP, further high-quality, standardized studies are warranted to clarify the true influence of leukocyte content on clinical outcomes.

Influence of Platelet Concentration on Clinical Outcomes

An important consideration in the clinical application of PRP for knee OA is the variability in platelet concentration achieved with different preparation methods. Since platelets are the primary carriers of growth factors and bioactive molecules, it has been hypothesized that higher concentrations may yield superior therapeutic effects.³⁴ Recent evidence supports this dose–response relationship, suggesting that platelet concentration directly impacts both the magnitude and durability of clinical improvements.³⁵

In a Level III cohort study by Boffa et al,²⁷ the authors analyzed 253 patients with knee OA (Kellgren–Lawrence grade I–III) who received three intra-articular PRP injections and were stratified into high-, medium-, and low-platelet concentration groups. Across all clinical metrics—including Knee Injury and Osteoarthritis Outcome Score (KOOS) subscales (Pain, Symptoms, activities of daily living [ADL], Sport and Recreation) and Subjective IKDC scores—higher platelet concentrations significantly correlated with better outcomes at 2, 6, and 12 months (Table 2). Moreover, the low-platelet group exhibited a notably higher failure rate (15.0%) compared with both the medium- and high-platelet groups (each 3.3%), while adverse event rates were similar across all groups.

A recent meta-analysis¹⁶ of 18 RCTs including 1995 patients with knee OA confirmed that PRP provides clinically relevant improvements in pain and function compared with placebo. Subanalysis based on platelet concentration revealed that high-platelet PRP offered superior pain relief and more durable functional improvement at 3, 6, and 12 months, whereas low-platelet PRP failed to provide clinically meaningful pain reduction, particularly in terms of the MCID for VAS scores. These findings underscore the importance of platelet concentration in determining the efficacy of PRP treatment for knee OA.

Collectively, these findings highlight that higher platelet concentrations in PRP are associated with superior clinical outcomes and lower failure rates, reinforcing the importance of preparation methods that maximize platelet yield. Nevertheless, it is important to note that despite these encouraging findings, the current evidence base directly examining the dose–response relationship of platelet concentration remains limited. Most studies employ heterogeneous preparation protocols and inconsistent reporting standards, which restrict definitive conclusions. This highlights the need for further standardized, high-quality studies to clarify the optimal platelet concentration for clinical efficacy.

Single Injection versus Multi-Dose Therapy

The optimal number of PRP injections for treating knee OA remains a topic of clinical debate. While single-dose protocols offer convenience and reduced cost, multiple-dose regimens may provide enhanced and more sustained therapeutic effects by maintaining a higher concentration of growth factors within the joint over time. To better understand the clinical impact of injection frequency, a recent systematic review and meta-analysis²⁶ compared outcomes between single and multiple PRP injections. This review included 7 RCTs (575 patients, aged 20–80 years, balanced sex distribution) and compared the efficacy of one, two, or three intra-articular PRP injections for knee OA (Table 2).²⁶ At 12-month follow-up, the group receiving three PRP injections reported significantly greater pain reduction—measured by a VAS—than the single-dose group (P < 0.0001), whereas the two-dose regimen did not demonstrate a statistically meaningful difference compared to a single injection. Regarding safety, no notable increase in adverse events was associated with either two-dose (p = 0.28) or three-dose (p = 0.24) protocols compared to a single injection. Reported complications were typically mild and transient. Injection spacing in the multi-dose groups was not specified in most studies, but the interval between injections ranged from 1 to 4 weeks in those studies which did report on injection intervals.

PRP Efficacy by Kellgren-Lawrence Grade

A key consideration in the application of PRP therapy is whether its effectiveness varies based on OA severity. The Kellgren-Lawrence (K-L) grading system is the most widely accepted tool to assess the severity of knee OA, with grades ranging from 0 (no radiographic evidence of OA) to IV (severe joint space narrowing and osteophyte formation).³⁶ Clinicians often use this classification to guide treatment selection and prognosis. However, data regarding the relationship between OA grade and PRP outcomes have shown inconsistent results.

A comprehensive meta-analysis of 31 RCTs, including 2705 knees with follow-up periods ranging from 3 months to 2 years, assessed the efficacy of PRP across different stages of OA.³¹ The studies were grouped by K-L grade into three categories: early OA (grades I–II), mild to moderate OA (grades I–III), and all-stage OA (grades I–IV) (Table 2). The pooled analysis showed that PRP injections significantly improved both pain and function across all K-L stages when compared with control interventions such as HA, corticosteroids, BMAC, prolotherapy, and placebo injections. These findings support the use of PRP as a viable treatment option even in more advanced disease stages, although the greatest benefits were typically observed in those with early to moderate OA. Furthermore, improvements in pain and functional scores were generally sustained throughout the follow-up period, ranging from 3 months up to 2 years, indicating that PRP can provide both short- and long-term benefits for patients across different stages of knee OA.

These findings are further supported by recent prospective studies evaluating outcomes based on radiographic severity. In a study of 100 knees (K-L grades I–IV) undergoing a single injection with LP-PRP, all K-L subgroups demonstrated significant improvements in both VAS and WOMAC scores from baseline to 6-month follow-up, but the greatest improvements were observed in knees with K-L grades I and II.³² Knees with grade IV disease still improved but to a lesser degree. Another prospective cohort study included 105 knees with K-L grades I–III which underwent a series of three LP-PRP injections spaced one month apart.³³ Patients were followed for 24 months and showed sustained improvements in both pain and function (as measured by WOMAC and VAS scores), with no statistically significant differences in outcomes between the K-L I, II, or III groups. This suggests that PRP may provide durable and clinically meaningful benefits even in moderate OA, especially when delivered as a series of injections.

Collectively, the evidence suggests that PRP therapy is effective in improving pain and function across all stages of knee OA, with the greatest benefits observed in early and moderate disease. While advanced OA (K-L IV) may demonstrate a lessened response, knees with K-L grades I–III consistently experience meaningful and sustained clinical improvement. These findings reinforce the utility of PRP as a treatment option across a range of OA severities, particularly when initiated before end-stage disease.

Discussion

Based on the current literature, PRP injections are a safe and effective non-surgical option for managing knee OA in patients with all Kellgren-Lawrence grades.^31,32 While several studies have demonstrated clinically meaningful improvements in pain and function compared with placebo and hyaluronic acid, others have reported modest or non-significant effects, reflecting ongoing heterogeneity in outcomes. Clinicians may consider offering PRP therapy as an initial non-surgical treatment option for patients who are motivated and able to afford these injections, recognizing that responses may vary. A protocol involving three intra-articular PRP injections spaced 1–4 weeks apart has demonstrated superior pain relief and functional improvement compared to a single injection, without a corresponding increase in adverse events.²⁶ Current evidence shows no consistent differences in safety or efficacy between leukocyte-rich and leukocyte-poor PRP for the treatment of knee OA.^29,30

To maximize clinical benefit, PRP treatment should ideally be initiated in the earlier stages of OA.³² However, significant methodological limitations in the existing literature-including variability in PRP preparation and classification, small sample sizes, lack of blinding, and short follow-up durations- continue to limit the strength of current conclusions. Given this variability, standardized protocols regarding dosage, frequency, and composition are needed to improve reproducibility and interpretability of findings. Until such guidelines are established, clinicians are encouraged to use consistent preparation techniques and validated outcome measures to monitor efficacy. In addition, further research should aim to optimize delivery protocols and explore the long-term disease-modifying potential of PRP in knee OA. In particular, more studies are needed on the potential for PRP injections in delaying knee arthroplasty. Collaborative, multicenter randomized controlled trials with uniform methodology will be instrumental in advancing the clinical utility of PRP and integrating it into standardized OA management pathways.

Conclusion

PRP represents a biologically active and increasingly utilized nonoperative treatment option for knee osteoarthritis, particularly in early to moderate stages of disease. Current evidence suggests that PRP provides superior short- to mid-term pain and functional outcomes compared to hyaluronic acid and results comparable to other orthobiologics such as bone marrow aspirate (BMAC). However, significant heterogeneity exists among study protocols, and no single preparation or regimen has demonstrated clear superiority. Overall, PRP appears to be a safe and potentially beneficial adjunct in the management of knee osteoarthritis, though further high-quality randomized trials are needed to establish its long-term efficacy and optimal use parameters.