PRP – Rational/Indication Does current clinical evidence support the use of PRP for knee OA For which degrees of knee OA is PRP best indicated? Can PRP be used in severe knee OA (KL4)? Is PRP indicated for the treatment of Patellofemoral OA (PFOA)? Are there specific contraindications for the use of PRP for knee… Continue reading ORthoBIologics InitiaTive (ORBIT) Consensus from ESSKA – Section 1
PRP – Rational/Indication
- Does current clinical evidence support the use of PRP for knee OA
- For which degrees of knee OA is PRP best indicated?
- Can PRP be used in severe knee OA (KL4)?
- Is PRP indicated for the treatment of Patellofemoral OA (PFOA)?
- Are there specific contraindications for the use of PRP for knee OA?
- For what age range is PRP recommended?
- Could PRP for knee OA be used during the inflammatory phase when joint effusion is present (following effusion aspiration)?
- Is a repeated cycle of PRP injections recommended following a previous successful PRP treatment for knee OA upon the re-emergence of symptoms?
- Is there rationale in injecting PRP in asymptomatic early knee OA? (Prevention?)
- Are there advantages of PRP use in comparison to corticosteroids for treating knee OA?
- Is PRP a clinically better injectable option than hyaluronic acid for the treatment of knee OA?
- Does PRP induce disease-modifying effects in knee OA?
- Does current clinical evidence support the use of Autologous Conditioned Serum (ACS) for knee OA?
- Does current clinical evidence support the use of Alpha-2-Macroglobulin (A2M) for knee OA?
1 – Does current clinical evidence support the use of PRP for knee OA?
Grade A – Score 8.0
Orbit Consensus: “Clinical evidence confirms the efficacy of PRP in the treatment of knee osteoarthritis (OA).“
Regen Lab Evidence-based medicine:Twelve clinical studies [1-12], on a total of 816 patients suffering from knee OA treated with Regen PRP, report a significant reduction in pain and improvement in function.
2 – For which degrees of knee OA is PRP best indicated?
Grade A – Score 8.1
Orbit Consensus: “Clinical evidence has shown the effectiveness of PRP in patients for mild to moderate degrees of knee OA (KL ≤ 3). The consensus group concludes that PRP can be indicated mainly in mild and moderate cases of knee OA.”
Regen Lab Evidence-based medicine: Most Regen Lab clinical studies on knee OA were performed on patients with mild to moderate degrees of knee OA (KL 2 to 3).
3 – Can PRP be used in severe knee OA (KL4)?
Grade C – Score 8.1
Orbit Consensus : “ The consensus group agrees that PRP treatment could be considered in selected severe knee OA cases (KL4) .”
Regen Lab Evidence-based medicine:The study from Hegaze et al.  shows positive results (significant pain reduction) also in patients with KL 4 after 2 or 4 Regen PRP injections with a monthly interval.
4 – Is PRP indicated for the treatment of Patellofemoral OA (PFOA)?
Grade C – Score 7.6
Orbit Consensus : “ As PRP has been shown to affect the knee environment in general, the consensus group considers PRP as an option in the presence of PFOA .”
Regen Lab agrees with Orbit consensus
5 – Are there specific contraindications for the use of PRP for knee OA?
Grade D – Score 8
Orbit Consensus : “Besides the generally accepted contraindications for any knee injections, other specific contraindications have been identified for PRP injections for the treatment of knee OA. While the majority of suggested contraindications have not been thoroughly or sufficiently studied, the consensus group chose to recommend caution in the presence of co-existent malignancies or systemic conditions due to possibility of unknown interactions.”
Regen Lab agrees with Orbit consensus
6 – For what age range is PRP recommended?
Grade D – Score 8.4
Orbit Consensus : “ The majority of studies included patients with a mean age between 55 and 65 years of age. The consensus group agrees that a specific age range cannot be recommended, though recognizes that there is evidence of reduced response in older patients. The consensus group suggests that other factors should come into consideration and that the decision should not be based only on chronologic age.”
Regen Lab Evidence-based medicine: In the clinical studies on knee OA patients treated with Regen PRP the mean age value was 62 years. Mean age values ranged from 47.7 to 73 years old. Patients over 80 years old were treated in two studies.[4,8]
7 – Could PRP for knee OA be used during the inflammatory phase when joint effusion is present (following effusion aspiration)?
Grade D – Score 7.9
Orbit Consensus : “Current clinical evidence is lacking regarding the injection of PRP during the inflammatory phase in knee OA, as well as with regards to effusion aspiration prior to PRP injection. While evidence is lacking with regards to the optimal timing of PRP injection for knee OA when effusion is present, the consensus group recognizes that when present, effusion aspiration is likely beneficial in pain improvement and relieving functional limitations. The consensus group recommends effusion aspiration also to avoid the dilution of the PRP following injection.”
Regen Lab agrees with Orbit consensus. Some Regen PRP users recommend, when there is a high-volume effusion, to treat the inflammatory phase first with corticosteroids, and after one month to start the treatment with Regen PRP afterward, on dry knees.
8 – Is a repeated cycle of PRP injections recommended following a previous successful PRP treatment for knee OA upon the re-emergence of symptoms?
Grade D – Score 8.4
Orbit Consensus : “While current evidence regarding repeated cycles of PRP treatment for knee OA is limited, it has been suggested this strategy may have clinical benefit. As evidence suggests a decrease in the effects of PRP for knee OA over time, the consensus group agrees that an additional cycle could be considered upon the re-emergence of symptoms. ”
Regen Lab Evidence-based medicine: The Gobbi et al. study quoted in the Orbit literature summary for this question is a study performed with Regen PRP . This study has shown that annual repetition of Regen PRP injection cycle can improve the results obtained on pain and joint functionality after the first cycle of 3 monthly injections.
9 – Is there rationale in injecting PRP in asymptomatic early knee OA? (Prevention?)
Grade D – Score 8.7
Orbit Consensus : “Currently, there are not enough clinical studies addressing this question, and therefore it cannot be stated that the application of PRP in asymptomatic osteoarthritis prevents its progression. Although preclinical studies suggest a chondroprotective role of PRP, there is no sufficient clinical evidence on the chondroprotective effect of PRP in patients with asymptomatic early stages of OA. Therefore, the consensus group currently does not advocate the use of PRP in asymptomatic early knee OA. ”
Regen Lab agrees with Orbit consensus.
10 – Are there advantages of PRP use in comparison to corticosteroids for treating knee OA?
Grade A – Score 8.7
Orbit Consensus: “ While corticosteroids (CS) are strong anti-inflammatory agents and can provide short term relief in knee OA, they have been shown to have detrimental effects on chondrocytes and can lead to accelerated cartilage degeneration, especially with multiple/repeated injections. PRP injections have been shown to have a longer effect in comparison to the shorter-term effect of CS injections. They also seem to provide a safer use profile with less potential related complications. The consensus group considers PRP injections to be a safer, non-chondro-toxic and more effective treatment option, with longer term clinical improvements compared to CS injections.”
Regen Lab Evidence-based medicine: They are not yet published clinical studies comparing Regen PRP with CS. However, it had been shown in vitro that Regen PRP has inhibitory effects on expression of proinflammatory and proteolytic molecules in human articular chondrocytes [13,14].
11 – Is PRP a clinically better injectable option than hyaluronic acid for the treatment of knee OA?
Grade B – Score 8.1
Orbit Consensus : “ Based on current available evidence, the consensus group supports the use of PRP over HA for knee OA due to overall clinical improvement and expected longer-lasting effects, whilst acknowledging that there are different formulations of the products that may introduce some bias in the conclusions of meta-analyses.”
Regen Lab Evidence-based medicine: A randomized double blind controlled study  has shown that intra-articular injections of Regen PRP can provide clinically significant functional improvement for at least 1 year in patients with mild to moderate osteoarthritis of the knee. In comparison to the controls, placebo (normal saline) or hyaluronic acid injections, only the Regen PRP group reached the minimal clinically important difference in the WOMAC score at every evaluation (15%, 21%, 18%, and 21% at 1, 2, 6, and 12 months, respectively) and the minimal clinically important difference in the IKDC score at 6 months (improvement of 11.6). It is worth noting that in this study only 2 ml of Regen PRP were injected, i.e., only half of the usual volume, in order to have a uniform injection protocol and to maintain the blinding.
12 – Does PRP induce disease-modifying effects in knee OA?
Grade C – Score 8.3
Orbit Consensus : “Preclinical studies (animal models) suggest some disease modifying effects, with positive changes on cartilage tissue and on the synovial membrane. Although few clinical studies have suggested disease modifying potential of PRP on degenerative cartilage, the consensus group recognizes that current clinical evidence regarding the disease modifying effects of PRP in knee OA in humans is insufficient.”
Regen Lab Evidence-based medicine: Regen PRP has been shown to have a protective effect in an animal model of knee osteoarthritis . This animal study established an association between hypervascularity of subchondral bone marrow and articular degradation in OA. Perfusion parameters and MRI T2* values changed as OA progressed. The observed decrease in vascularization and MRI T2* values with Regen PRP therapy reflected the improving effect of Regen PRP on subchondral bone marrow and cartilage in OA knees.
Clinical studies have also shown that Regen PRP injections positively modified the composition of the synovial fluid (SF) of knee OA patients, reduced its volume and its protein concentration. The markers linked with inflammation were decreased while the proteins associated with chelation and anti-aging physiological functions increased significantly. These changes were combined with clinical improvements and reduction of the Lequesne severity index of OA [7,10].
13 – Does current clinical evidence support the use of Autologous Conditioned Serum (ACS) for knee OA?
Grade B – Score 8.8
Orbit Consensus : “ Compared to PRP, ACS is much less well investigated. There is no clear evidence with regards to the role of ACS in OA management. While it may have a role as a possible inflammation modulating agent due to the dominance of IL-1 receptor antagonists in this product, results on the clinical efficacy of this approach are inconsistent. Currently no recommendations can be provided given due to the lack of sufficient evidence. ”
Regen Lab Evidence-based medicine: In comparison to PRP that contains alive and functional platelets that are able to release growth factors and other bioactive molecules on the long term, cf. Atashi et al. in vitro study that showed continuous release of growth factors in a controlled manner for 10 days , ACS contains only the molecules that were released during the preparation process. As growth factors  and anti-inflammatory molecules such as IL-1RA  have short half-life, only a short term benefit can be expected with ACS.
14 – Does current clinical evidence support the use of Alpha-2-Macroglobulin (A2M) for knee OA?
Grade D – Score 8.7
Orbit Consensus : “ since there are no clinical RCT studies regarding the use of A2M for knee OA, currently no recommendations can be provided. ”
Regen Lab agrees with Orbit consensus.
|Grade A||High Scientific Level|
|Grade B||Scientific Presumption|
|Grade C||Low Scientific Level|
|Grade D||Expert Opinion|
These proposals have been submitted to another group of 22 experts (rating group) to validate the recommendations (rating from 1 to 9 -> 9 being a total agreement with the recommendation)
RegenLab’s Scientific team
1. Gobbi, A.; Karnatzikos, G.; Mahajan, V.; Malchira, S. Platelet-rich plasma treatment in symptomatic patients with knee osteoarthritis: preliminary results in a group of active patients. Sports health 2012, 4, 162-172, doi:10.1177/1941738111431801.
2. Napolitano, M.; Matera, S.; Bossio, M.; Crescibene, A.; Costabile, E.; Almolla, J.; Almolla, H.; Togo, F.; Giannuzzi, C.; Guido, G. Autologous platelet gel for tissue regeneration in degenerative disorders of the knee. Blood Transfus 2012, 10, 72-77, doi:10.2450/2011.0026-11.
3. Papalia, R.; Franceschi, F.; Carni, S.; Zampogna, B.; Diaz, L.; Tecame, A.; Maffulli, N.; Denaro, V. Intra-Articular injections for degenerative cartilage lesions of the knee: platelet rich plasma vs hyaluronic acid. Muscles, ligaments and tendons journal 2012, 2, 67.
4. Mangone, G.; Orioli, A.; Pinna, A.; Pasquetti, P. Infiltrative treatment with Platelet Rich Plasma (PRP) in gonarthrosis. Clinical cases in mineral and bone metabolism : the official journal of the Italian Society of Osteoporosis, Mineral Metabolism, and Skeletal Diseases 2014, 11, 67-72.
5. Abate, M.; Verna, S.; Schiavone, C.; Di Gregorio, P.; Salini, V. Efficacy and safety profile of a compound composed of platelet-rich plasma and hyaluronic acid in the treatment for knee osteoarthritis (preliminary results). European journal of orthopaedic surgery & traumatology : orthopedie traumatologie 2015, 25, 1321-1326, doi:10.1007/s00590-015-1693-3.
6. Gobbi, A.; Lad, D.; Karnatzikos, G. The effects of repeated intra-articular PRP injections on clinical outcomes of early osteoarthritis of the knee. Knee Surg Sports Traumatol Arthrosc 2015, 23, 2170-2177, doi:10.1007/s00167-014-2987-4.
7. Chen, C.P.C.; Cheng, C.H.; Hsu, C.C.; Lin, H.C.; Tsai, Y.R.; Chen, J.L. The influence of platelet rich plasma on synovial fluid volumes, protein concentrations, and severity of pain in patients with knee osteoarthritis. Experimental gerontology 2017, 93, 68-72, doi:10.1016/j.exger.2017.04.004.
8. Huang, P.H.; Wang, C.J.; Chou, W.Y.; Wang, J.W.; Ko, J.Y. Short-term clinical results of intra-articular PRP injections for early osteoarthritis of the knee. Int J Surg 2017, 42, 117-122, doi:10.1016/j.ijsu.2017.04.067.
9. Wu, Y.T.; Hsu, K.C.; Li, T.Y.; Chang, C.K.; Chen, L.C. Effects of Platelet-Rich Plasma on Pain and Muscle Strength in Patients With Knee Osteoarthritis. Am J Phys Med Rehabil 2018, 97, 248-254, doi:10.1097/PHM.0000000000000874.
10. Chen, C.P.C.; Chen, J.L.; Hsu, C.C.; Pei, Y.C.; Chang, W.H.; Lu, H.C. Injecting autologous platelet rich plasma solely into the knee joint is not adequate in treating geriatric patients with moderate to severe knee osteoarthritis. Experimental gerontology 2019, 119, 1-6, doi:10.1016/j.exger.2019.01.018.
11. Lin, K.Y.; Yang, C.C.; Hsu, C.J.; Yeh, M.L.; Renn, J.H. Intra-articular Injection of Platelet-Rich Plasma Is Superior to Hyaluronic Acid or Saline Solution in the Treatment of Mild to Moderate Knee Osteoarthritis: A Randomized, Double-Blind, Triple-Parallel, Placebo-Controlled Clinical Trial. Arthroscopy 2019, 35, 106-117, doi:10.1016/j.arthro.2018.06.035.
12. Hegaze, A.H.; Hamdi, A.S.; Alqrache, A.; Hegazy, M. Efficacy of Platelet-Rich Plasma on Pain and Function in the Treatment of Knee Osteoarthritis: A Prospective Cohort Study. Cureus 2021, 13, e13909, doi:10.7759/cureus.13909.
13. Wang, C.C.; Lee, C.H.; Peng, Y.J.; Salter, D.M.; Lee, H.S. Platelet-Rich Plasma Attenuates 30-kDa Fibronectin Fragment-Induced Chemokine and Matrix Metalloproteinase Expression by Meniscocytes and Articular Chondrocytes. The American journal of sports medicine 2015, 43, 2481-2489, doi:10.1177/0363546515597489.
14. Lu, H.T.; Lu, J.W.; Lee, C.H.; Peng, Y.J.; Lee, H.S.; Chu, Y.H.; Ho, Y.J.; Liu, F.C.; Shen, P.H.; Wang, C.C. Attenuative Effects of Platelet-Rich Plasma on 30 kDa Fibronectin Fragment-Induced MMP-13 Expression Associated with TLR2 Signaling in Osteoarthritic Chondrocytes and Synovial Fibroblasts. Journal of clinical medicine 2021, 10, doi:10.3390/jcm10194496.
15. Huang, G.S.; Peng, Y.J.; Hwang, D.W.; Lee, H.S.; Chang, Y.C.; Chiang, S.W.; Hsu, Y.C.; Liu, Y.C.; Lin, M.H.; Wang, C.Y. Assessment of the efficacy of intra-articular platelet rich plasma treatment in an ACLT experimental model by dynamic contrast enhancement MRI of knee subchondral bone marrow and MRI T2( *) measurement of articular cartilage. Osteoarthritis Cartilage 2021, 29, 718-727, doi:10.1016/j.joca.2021.02.001.
16. Atashi, F.; Serre Beinier, V.; Nayernia, Z.; Pittet Cuenod, B.M.; Modarressi Ghavami, S.A. Platelet rich plasma promotes proliferation of adipose derived mesenchymal stem cells via activation of AKT and Smad2 signaling pathways. J Stem Cell Res Ther 2015, 5, 301.
17. Kuroda, Y.; Kawai, T.; Goto, K.; Matsuda, S. Clinical application of injectable growth factor for bone regeneration: a systematic review. Inflammation and Regeneration 2019, 39, 20, doi:10.1186/s41232-019-0109-x.
18. Akash, M.S.; Rehman, K.; Chen, S. IL-1Ra and its delivery strategies: inserting the association in perspective. Pharm Res 2013, 30, 2951-2966, doi:10.1007/s11095-013-1118-0.