ANOTHER LOOK

PLATELET-RICH PLASMA AS A TREATMENT FOR OSTEOARTHRITIS OF THE KNEE

Solange VISCHER.., Antoine TURZI.

1 Senior Scientific Advisor, Regen Lab SA, Switzerland ;  2. CEO, Regen Lab SA, Switzerland

Summary

Platelet-rich plasma (PRP) is an autologous biological drug prepared from the patient's own blood and used as a treatment for wound healing and other lesions on the same patient.

It is still considered by many to be an experimental treatment for osteoarthritis, and is therefore not covered by insurance companies.

  • However, a growing number of scientific societies recognize PRP as a safe and effective treatment modality for knee osteoarthritis, based on a large number of studies published on the subject by clinicians worldwide.
  • These clinical studies have been compiled and synthesized in various recent meta-analyses, which are summarized here.
  • These meta-analyses demonstrate the safety, efficacy and superiority of PRP over other methods of treating knee osteoarthritis with intra-articular injections.

Keywords: knee osteoarthritis, platelet-rich plasma, PRP, medical devices, regulations, MDR 2017/745, FDA, MDSAP, ISO13485

 

Regen Kit THT

INTRODUCTION

In the USA, as in the rest of the world, a variety of technologies are used to prepare PRP. Many preparation methods lack standardization and repeatability from patient to patient, and there are even "home-made" processes, as transfusionists did 30 years ago.

However, the devices used to isolate PRP from patient blood fall within the definition of a medical device, and must therefore comply with current regulations.

 

Over the past 20 years, multiple technologies for bedside preparation of PRP have been approved by health authorities in every country.

  • In the European Union, they are governed by Regulation 2017/745 (MDR), which replaces Directive 93/42/EEC (MDD) from 2021.
  • In the United States, devices for the preparation of PRP are regulated by the Food and Drug Administration's (FDA) Center for Biologics Evaluation and Research (CBER). They carry the product code ORG or PMQ (for those intended for wound treatment) and follow section 864.9246 of the Code of Federal Regulation Title 21 (21 CFR 864.9245) for automated blood cell separators.
  • The Centers for Medicare & Medicaid Services (CMS) has decided in 2021 to reimburse PRP treatments for diabetic foot ulcers.
  • For several years, TRICARE has been reimbursed for PRP treatments for military patients with osteoarthritis of the knee.

 

Regen Lab, Switzerland has been ISO13485 certified since 2003 for the manufacture and international marketing of RegenKits.

  • In Europe, RegenKits have already obtained their CE certificate under MDR 2017/745. RegenLab® USA received its first FDA clearance in May 2010 with RegenKit® THT®, which has been part of a family of medical devices manufactured in the USA since November 2021.
  • In compliance with MDSAP ISO-13485, the production of these medical devices follows the highest quality management standards.

 

RegenKit® technology enables rapid, standardized preparation of PRP in a closed-loop system. This PRP (RegenPRP) has demonstrated its safety, reliability and efficacy in over 300 scientific and clinical publications in academic journals.

  • Autologous PRP is a suspension of platelets in plasma, prepared from the patient's own blood and used as a treatment for wound healing and other lesions on the same patient, minimizing the possibility of cross-reactivity and allergic reactions.
  • PRP contains live, functional platelets, making this biological product different from other blood-derived autologous growth factor preparations such as clot extracts.
  • Similarly, frozen/thawed PRP is no longer considered true PRP, as most platelets do not survive this process [...1].
  • RegenKit® technologies produce PRP treatments from fresh, minimally manipulated blood to harness and maximize the patient's natural healing capacity.

 

Recent reviews, such as Li et al. 2022 [2], and meta-analyses, see below, have concluded that platelet-rich plasma is an effective and safe biological approach to treating osteoarthritis, and more specifically osteoarthritis of the knee.

  • These studies show that PRP, compared to the two main intra-articular injectable therapies, corticosteroids (CS) and hyaluronic acid (HA), offers superior pain relief and functional improvement [...3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15].
  • Knee osteoarthritis treatments with CS and HA are currently covered by insurance in the United States. However, although these treatments have been clinically shown to relieve pain, they have no impact on slowing the progression of knee osteoarthritis.

In addition, visco-supplementation with HA offers only a small reduction in pain symptoms compared with placebo [16].

Corticosteroids, on the other hand, are useful in patients with acute exacerbations of pain and joint effusion, but their long-term use has been associated with greater loss of cartilage volume [17].

As a result, a growing number of scientific societies are recognizing PRP as a safe and effective treatment modality for osteoarthritis of the knee.

  • AAOS (American Academy of Orthopaedic Surgeons) acknowledged that PRP demonstrated a significant improvement in patient-reported outcomes compared to placebo [18].
  • ASPN (American Society for Pain and Neuroscience)The STEP guidelines reached a strong consensus regarding the safety and efficacy of intra-articular PRP for the treatment of pain and improvement of joint functionality in patients with osteoarthritis, noting that it was at least as effective, if not more so, than an entire course of HA visco-supplementation [19].
  • The ORBIT consensus of the ESSKA (European Society of Sports Traumatology, Knee Surgery and Arthroscopy)) concluded that there is sufficient preclinical and clinical evidence to support the use of PRP in knee osteoarthritis [20].
  • Likewise, GRIIP (Groupe de recherche international sur les injections de plaquettes) stated that PRP is an effective symptomatic treatment for mild to moderate knee osteoarthritis and may be useful in severe knee osteoarthritis, with a high level of evidence [21].
  • At least 75% experts from the "German Working Group for Clinical Regeneration of fabrics " from the Company German orthopedics and from traumatology (GSOT) have reached a consensus that PRP injection may be useful in patients with mild knee osteoarthritis (Kellgren-Lawrence grade II) [22].
  • The group from work SIOT (Company Italian orthopedics and traumatology) supports the use of PRP injections in symptomatic osteoarthritis of the knee [23].
  • The meta-analysis from Riboh concluded that leukocyte-poor PRP (LP-PRP) was the top-ranked treatment compared to leukocyte-rich PRP (LR-PRP), HA or placebo for both measures of clinical efficacy (Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and Subjective International Knee Documentation Committee (IKDC) scores) [24].
  • After reviewing and summarizing the published literature up to March 2023, Mende et al. 2024 have reached the same conclusion and recommend the use of LP-PRP for Canadian Armed Forces (CAF) personnel with mild to moderate knee osteoarthritis (Kellgren- Lawrence grades 1 to 3) in order to slow the progression of osteoarthritis and prolong the military career of CAF members [25].
  • The U.S. Army also provides intra-articular PRP injections to military personnel and TRICARE [26].
  • Compared to other devices designed to prepare PRP, RegenLab® produce a PRP with a composition standardized.
    • The use of thixotropic separator gels with specific densities enables precise isolation of PRP from other blood components at cellular level.
    • This method of blood fractionation is highly reproducible because it is independent of the operator and the patient.

The resulting PRP, RegenPRP, is a leukocyte-poor PRP in which there is specific depletion of pro-inflammatory neutrophil granulocytes. The platelet recovery rate in RegenPRP is greater than 80 % without specific loss of the largest and densest platelets, which are known to be the richest in growth factors [27].

This standardized PRP has proved effective in many different therapeutic areas.

  • For osteoarthritis of the knee, 18 studies involving a total of 1,057 patients treated with RegenPRP reported a significant reduction in pain and improvement in function [...28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45].
  • In addition, the study by Chen et al. showed that RegenPRP injections positively modify synovial fluid composition, with a decrease in inflammation-related molecules and an increase in proteins associated with chelation and anti-aging physiological functions [31].
  • Russo et al. carried out an economic evaluation of the intra-articular use of RegenPRP therapy in the treatment of knee osteoarthritis compared with hyaluronic acid (HA), which represents the standard intra-articular therapy [46]. Both therapies can reduce pain, improve the patient's quality of life and help the patient delay joint surgery, which represents a high cost to the national healthcare system. A cost-effectiveness analysis was carried out using a decision-tree model. Efficacy outcomes were reported in terms of quality-adjusted life years (QALYs). Costs were reported in euros (€) valued in 2016.

Analyses were carried out for three European countries: Germany, Italy and France.

RegenPRP treatment was more expensive but also more effective than HA. Using a willingness-to-pay threshold of €10,000/QALY, PRP proved cost-effective compared with HA for patients with moderate to severe knee osteoarthritis considering a one-year time horizon.

RegenPRP's main efficacy, in addition to improving quality of life, was that it could delay total knee arthroplasty and reduce the eventual revision of the prosthesis, thus reducing the total costs of knee osteoarthritis and the economic burden on healthcare systems.

RECENT META-ANALYSES ON OSTEOARTHRITIS

  • In 2023, Cao et al. conducted a meta-analysis of randomized controlled trials (RCTs) to quantitatively evaluate the efficacy of PRP, compared to hyaluronic acid, and to identify relevant factors that significantly affect the efficacy of PRP treatment for osteoarthritis [3].
  • A total of 45 RCTs (3829 participants) involving 1,805 participants who received a PRP injection were included in the analysis.
  • Conventional meta-analyses and maximum-effect pharmacodynamic models showed that PRP was significantly more effective than HA for joint pain and functional disorders (additional score decreases of 1.1, 0.5, 4.3 and 1.1 compared to HA treatment at 12 months for WOMAC pain index, stiffness, function and visual analog scale (VAS) pain scores, respectively).
  • Higher baseline symptom scores, older age (≥ 60 years), higher BMI (≥ 30), lower Kellgren-Lawrence grade (≤ 2) and shorter duration of OA (< 6 months) were significantly associated with greater efficacy of PRP treatment. These results suggest that PRP is a more effective treatment for osteoarthritis than the better-known HA treatment.
  • Xiong et al. conducted a meta-analysis in 2023 reviewing relevant RCTs to determine the efficacy and safety of PRP injections for the treatment of osteoarthritis [47]. They included 24 RCTs comprising 1,344 osteoarthritis patients. Their results indicated that PRP injections were effective in improving VAS pain scores. Compared with controls, PRP injections were also effective in improving the Knee Injury and Osteoarthritis Outcome Score (KOOS), including patient pain symptoms, activities of daily living (ADL) and adherence symptomatology.
  • PRP injections proved effective in improving WOMAC scores, including pain, stiffness and functional joint movement, in OA patients compared to the control group.
  • In addition, subgroup analysis showed that leukocyte-poor PRP (LP-PRP) injections were more effective than leukocyte-rich PRP (LR-PRP) in improving pain symptoms in osteoarthritis patients.
  • They concluded that PRP injection therapy can safely and effectively improve functional activity in OA patients and produce positive analgesic effects in OA patients. Moreover, the analgesic effect of LP- PRP was superior to that of LR-PRP.

RECENT META-ANALYSES ON KNEE OSTEOARTHRITIS

 2024

  • Jawanda et al. compared the efficacy of common intra-articular injections used in the treatment of knee osteoarthritis, including corticosteroids (CS), hyaluronic acid (HA), platelet-rich plasma (PRP) and bone marrow aspirate concentrate (BMAC), with a minimum follow-up of 6 months [4].
  • The literature search was carried out using the PRISMA 2020 guidelines in August 2022 in the following databases: PubMed/MEDLINE, Scopus, the Cochrane Database of Controlled Trials and the Cochrane Database of Systematic Reviews. Forty-eight level I to II randomized clinical trials, with a minimum follow-up of 6 months, involving a total of 9,338 knees were included.
  • The most studied intra-articular injection was HA (40.9 %), followed by placebo (26.2 %), PRP (21.5 %), CS (8.8 %) and BMAC (2.5 %). Both HA and PRP led to a significant improvement in pain compared with placebo. HA, PRP and BMAC all led to a significant improvement in functional scores compared with placebo. The area under the cumulative ranking curves (SUCRA) of the interventions revealed that PRP, BMAC and HA were the treatments with the greatest likelihood of improving pain and function, with overall SUCRA scores of 91.54, 76.46 and 53.12 respectively. Overall SUCRA scores for CS and placebo were 15.18 and 13.70.
  • They concluded that, with a follow-up of at least 6 months, PRP demonstrated a significant improvement in pain and function in patients with knee osteoarthritis compared with placebo. In addition, PRP had the highest SUCRA values for these outcomes compared with BMAC, AH and CS.

Khalid et al. compared the efficacy of intra-articular injectable therapies, including PRP, HA, CS and placebo, in knee osteoarthritis.

Data extraction focused on baseline characteristics and outcome measures (WOMAC, EVA, KOOS and IKDC scores at 1, 3, 6 and 12 months [5].

Statistical analysis, including subgroup analysis, assessment of heterogeneity and publication bias, was carried out using Review Manager.

The results showed that their 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 scores (p ≤ 0.00001) and VAS pain scores (p = 0.03).

Similarly, PRP was more effective in reducing WOMAC scores (p = 0.004) and VAS pain scores (p ≤ 0.0001) than CS injections, with the most significant improvement observed at 6 months. They concluded that PRP is an effective treatment for knee osteoarthritis.

It provides symptomatic relief, has the potential to reduce disease progression and has long-lasting effects for up to 12 months.

PRP offers greater pain relief and functional improvement than CS and HA injections.

Oeding et al. conducted an analysis of RCTs comparing PRP with other injections for knee osteoarthritis to assess the statistical power of their findings [6]. This analysis covered the results of 1,993 patients.

Based on random-effects meta-analyses, PRP demonstrated a significantly higher rate of positive outcomes compared to hyaluronic acid (p = 0.002) as well as higher rates of patient-reported symptom relief (p = 0.019), requiring no re-intervention after initial injection treatment (p = 0.002) and achieving the minimum clinically important difference for pain improvement (p = 0.007) compared to all other non-surgical treatments.

They concluded that the statistical significance of the pooled treatment outcome measures used to evaluate PRP for knee osteoarthritis was more robust than about half of all comparable meta-analyses conducted in medicine and healthcare.

 2023

Belk et al. carried out a systematic review and meta-analysis of the literature to identify Level I studies comparing the efficacy and safety of PRP, bone marrow aspirate concentrate (BMAC) and hyaluronic acid injections for the treatment of knee osteoarthritis [7].

Twenty-seven of these Level I studies met the inclusion criteria and included a total of 1042 patients who received one or more intra-articular PRP injections, 226 patients treated with BMAC and 1128 patients treated with HA.

The meta-analysis demonstrated significantly better post-injection WOMAC scores (p < 0.001), VAS pain scores (p < 0.01) and IKDC scores (p < 0.001) in patients who received PRP versus HA.

There were no significant differences in post-injection outcome scores when comparing PRP to BMAC.

They concluded that patients undergoing treatment for knee osteoarthritis with PRP or BMAC can expect to achieve better clinical outcomes compared to patients receiving HA.

Chen et al. compared the efficacy of PRP and HA in the treatment of osteoarthritis [8].

A total of 30 articles involving 2733 patients were included.

The WOMAC and IKDC scores of the PRP groups at the end of the study were better than those of the AH groups, while there was no significant difference in adverse events, satisfaction and VAS between the two groups.

Kim and al. also conducted a meta-analysis of Level I studies [ .9]. A total of 138 studies were reviewed and twenty-one Level 1 RCTs assessed, encompassing a total of 2,086 knees (1,077 treated with PRP and 1009 treated with HA).

PRP showed a significant improvement in VAS pain scores compared with HA at 6 and 12 months.

In terms of function, PRP injections led to significantly better improvement in total WOMAC scores compared with HA at 6 months. There was no significant difference in procedure-related knee pain or swelling between the PRP and HA groups.

They concluded that intra-articular PRP injections improve pain and function in patients with knee osteoarthritis for up to 12 months, and are superior to HA.

The results of this study support the routine clinical use of intra-articular PRP injections for the treatment of knee osteoarthritis, irrespective of the type and frequency of PRP injection.

Li et al. compared the clinical efficacy of multiple injections of platelet-rich plasma (m-PRP) with multiple injections of HA (m-AH) in the treatment of osteoarthritis of the knee [10].

Fourteen RCTs, evaluating 1512 patients, had outcome measures that included postoperative VAS, WOMAC, IKDC or EQ-VAS scores and were included in this systematic review.

Compared with the m-AH intra-articular injection group, the m-PRP intra-articular injection group had better VAS pain scores at 3-month and 12-month follow-ups. In addition, the m-PRP group had better WOMAC scores at 1-month, 3-month, 6-month and 12-month follow-up than the m-AH group.

Finally, the group receiving intra-articular injections of m-PRP had higher IKDC scores at 3-month and 6-month follow-ups compared with the m-AH group.

Qiao et al. carried out a network meta-analysis using the Bayesian random-effects model on 35 studies involving 3,104 participants with knee osteoarthritis [11].

They found that PRP and PRP combined with HA were most effective in improving function and relieving pain at 3, 6 and 12 months compared with corticosteroids, HA and placebo.

In addition, combined PRP and PRP-AH therapies did not result in an increased incidence of treatment-related side events compared with placebo.

Tao et al. compared the efficacy of a single dose of platelet-rich plasma (PRP) with several doses of PRP therapy in the treatment of osteoarthritis of the knee [48].

Pooled analyses of VAS pain scores, WOMAC scores and adverse events were performed.

Seven studies (all RCTs) of high methodological quality involving 575 patients were included. The age of patients included in this study ranged from 20 to 80 years, and the male/female ratio was balanced.

Triple-dose PRP treatment resulted in significantly better VAS pain scores compared with single-dose PRP treatment at 12 months (p < 0.0001), with no significant change observed in VAS scores between double-dose PRP and single-dose PRP at 12 months.

In terms of adverse effects, double-dose and triple-dose treatment showed no significant difference in terms of safety compared with single-dose treatment.

Vilchez-Cavazos et al. conducted a meta-analysis using a random-effects model and the generic inverse variance method to assess whether the use of PRP would be as effective in studies of patients with early-to-moderate knee osteoarthritis as in studies of patients with end-stage osteoarthritis, based on the Kellgren-Lawrence classification [49].

They included 31 clinical trials reporting data from 2705 subjects. The meta-analysis revealed a significant overall improvement in pain and function in favor of PRP.

Sub-analysis of pain and functional improvement showed significant pain relief in studies with Kellgren-Lawrence OA stages 1-3 and 1-4, and significant functional improvement in studies with knee OA stages 1-2, 1-3 and 1-4, in favor of PRP.

Xue et al. compared the efficacy of different intra-articular injections for mild to moderate knee osteoarthritis [12]. They included 16 RCTs with a total of 1,652 patients.

PRP injection therapy had the highest probability of being the best intervention for reducing pain, stiffness and WOMAC functional scores, according to SUCRA.

In the VAS pain score group, PRP outperformed hyaluronic acid and corticosteroids. PRP also outperformed corticosteroids in the WOMAC total score group.

In addition, PRP outperformed other treatments in terms of reducing function, stiffness and WOMAC functional scores.

 2022

Abbas et al. conducted a meta-analysis of studies comparing LP-PRP or LR-PRP [50]. Follow-up periods were 6 and 12 months.

The primary endpoint was the change in WOMAC score from baseline to follow-up.

Secondary endpoints were changes in the WOMAC pain subscale, VAS pain scores and IKDC scores between baseline and follow-up, and the incidence of local adverse events.

Treatment results were analyzed using the mean difference between treatments for continuous outcomes and the odds ratio for binary outcomes, with credibility intervals of 95 %.

Treatment modalities were ranked using the surface area under cumulative ranking probabilities (SUCRA).

Twenty-three studies (20 RCTs and 3 prospective comparative studies) involving a total of 2,260 patients and a mean follow-up period of 9.9 months were evaluated.

They found no significant differences (p < 0.05) in all outcome measures and local adverse events between LP-PRP and LR-PRP.

SUCRA rankings revealed that, for all outcome measures, LP-PRP is preferred to LR- PRP for follow-up periods.

Donovan et al. studied the effects of recurrent intra-articular corticosteroid injections (IACI) at 3 months and beyond in RCTs, comparing IACI with other injectables, placebo or no treatment [...13]. Ten RCTs were included (eight studies of knee osteoarthritis (n = 763) and two studies of trapeziometacarpal osteoarthritis (n = 121)). Patients received between 2 and 8 injections, varying by study.

Studies compared recurrent IACI with hyaluronic acid (HA), platelet-rich plasma (PRP), saline or orgotein with follow-up ranging from 3 to 24 months.

Greater improvements in pain, function and quality of life throughout the 3-24 month follow-up period were noted for comparators than for IACI, with comparators demonstrating an equal or greater effect.

Recurrent IACI showed no benefit in pain or function compared with placebo at 12-24 months.

No serious adverse events were recorded. They concluded that recurrent IACI often provided less (or no more) symptom relief than other injectables (including placebo) at 3 months and beyond.

Other injectable products (HA, PRP) have often led to greater improvements in pain and function up to 24 months after injection.

Rahimzadeh et al. compared the effect of intra-articular injection of PRP and ozone therapy [51]. A meta-analysis was carried out using the latest version of STATA (version 16). A total of 12 studies were evaluated; 6 RCTs carried out on 251 patients treated with ozone therapy versus 235 patients in the control groups, and 6 RCTs on 251 patients treated with PRP versus 230 patients in the control groups.

The mean difference in VAS pain scores between the ozone therapy group and the control group during the first month after injection was -0.02 (p < 0.05).

Mean differences in pain, stiffness and WOMAC physical function score between baseline and after PRP were -3.53 (p = 0.00), -0.60 (p = 0.00) and -5.96 (p = 0.00), respectively.

Their results showed that treating knee osteoarthritis with PRP produces better clinical results for a longer period of 6 to 12 months after injection, while ozone therapy has only short-term results.

Singh et al. evaluated and compared the efficacy of different intra-articular injections used for the treatment of knee osteoarthritis, including HA, CS and PRP, with patient follow-up of at least 6 months [14].

Twenty-three studies were included, in which 4,604 injections were performed (592 with PRP, 2,371 with HA, 521 with CS and 1,120 with placebo). All intra-articular treatments, with the exception of CS, were found to produce statistically significant improvements in results compared with placebo. In terms of improvements in pain and function, PRP was found to have the highest probability of efficacy, followed by HA, CS and placebo.

Wang et al. systematically analyzed RCTs comparing the efficacy of PRP to HA in the treatment of knee osteoarthritis [15]. Studies were included according to PICOS criteria and relevant event data extracted.

The risk of bias was analyzed and a random-effects model was used to calculate the pooled odds ratio and hazard ratio using RevMan software.

A total of 14 studies were included in the meta-analysis, from 2000 to 2021, covering a total of 613 patients.

The meta-analysis had a low risk of publication bias, and they achieved the combined odds ratio of 2.55 (95 CI %: 1.35-4.84) with a t2 value of 1.01, a c2 value of 52.79, an I2 value of 77 %, a Z value of 2.87 and a p value < 0.00001.

The combined hazard ratio was 1.34 (95 CI %: 1.09-1.65) with a t2 value of 0.09, a c2 value of 73.48, an I2 value of 84 %, a Z value of 2.80 and a p value < 0.00001. They concluded that their meta-analysis strongly recommends the use of PRP for the treatment of knee osteoarthritis.

 

 

 

CONCLUSION

Osteoarthritis of the knee is a frequent source of musculoskeletal pain.

As the population ages, osteoarthritis of the knee is expected to become an even more frequent cause of disability, resulting in a growing burden for individuals and a financial burden for our societies and healthcare systems.

Over the past decade, a growing number of studies have evaluated PRP for osteoarthritis of the knee.

Many of these studies and the resulting meta-analyses confirm that PRP is an effective and safe treatment option for knee osteoarthritis.

Medico-economic evaluations also show that, by delaying arthroplasty, PRP reduced the cost total from osteoarthritis from knee and so the load economic on the systems from health.These results are prompting learned societies to gradually incorporate autologous PRP into their recommendations for the management of knee osteoarthritis, on the basis of large volumes of published evidence demonstrating its efficacy, safety and superiority to other covered treatment modalities.

RegenLab's standardized technology, evaluated in numerous clinical trials, facilitates the reproducible production of autologous PRP at the point of intervention, guaranteeing the highest level of quality and safety to deliver these effective and cost-effective treatments to patients suffering from osteoarthritis of the knee.

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