Two cycles of plasma rich in growth factors (PRGF-Endoret) intra-articular injections improve stiffness and activities of daily living but not pain compared to one cycle on patients with symptomatic knee osteoarthritis

Abstract

Purpose

To assess the clinical efficacy and safety of a treatment based on one cycle versus two cycles of intra-articular injections of plasma rich in growth factors (PRGF-Endoret) on patients with knee osteoarthritis (OA).

Methods

Ninety patients with knee OA were included and evaluated. A total of 48 patients received one cycle (OC group) (3 injections on a weekly basis), while 42 patients received two cycles of PRGF-Endoret (TC group) spaced 6 months between them. Patients were evaluated with LEQUESNE and WOMAC scores before treatment and after 48 weeks. Safety assessment was also performed.

Results

A significant reduction of all assessed outcome measures was shown for both groups at 48 weeks compared with baseline values (P < 0.001). Patients of TCs group showed a significantly higher reduction (P < 0.05) in WOMAC stiffness subscales. Regarding LEQUESNE INDEX, a significantly higher reduction was observed in the TC group in all subscales except in pain score. In the maximum walking distance subscale (MCD), the improvement rate was 31.8% higher for the TCs group compared with the OC group (P < 0.01). In addition, the TC group showed a significant improvement in LEQUESNE activities of daily living (ADV) and global subscales of 14.7 and 11.8% (P < 0.05) higher, respectively, than the OC group.

Conclusions

Treatment with two cycles of PRGF did not show a significantly higher pain reduction compared with one cycle treatment. However, two cycles of PRGF showed a significant improvement in WOMAC stiffness, LEQUESNE MCD, LEQUESNE ADV and LEQUESNE global subscales. Therefore, patients treated with two cycles present an improvement in quality of life.

Level of evidence

II.

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References

  1. 1.

    Anitua E, Sanchez M, Nurden AT, Zalduendo MM, de la Fuente M, Azofra J, Andia I (2007) Platelet-released growth factors enhance the secretion of hyaluronic acid and induce hepatocyte growth factor production by synovial fibroblasts from arthritic patients. Rheumatology (Oxford) 46:1769–1772

    Article  CAS  Google Scholar 

  2. 2.

    Anitua E, Zalduendo M, Troya M, Padilla S, Orive G (2015) Leukocyte inclusion within a platelet rich plasma-derived fibrin scaffold stimulates a more pro-inflammatory environment and alters fibrin properties. PLoS ONE 10:e0121713

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  3. 3.

    Anitua E, Zalduendo MM, Prado R, Alkhraisat MH, Orive G (2015) Morphogen and proinflammatory cytokine release kinetics from PRGF-Endoret fibrin scaffolds: evaluation of the effect of leukocyte inclusion. J Biomed Mater Res A 103:1011–1020

    Article  PubMed  CAS  Google Scholar 

  4. 4.

    Bellamy N (1988) Validation study of WOMAC: a health status instrument for measuring clinically-important patient-relevant outcomes following total hip or knee arthroplasty in osteoarthritis. J Orthop Rheumatol 1:95–108

    Google Scholar 

  5. 5.

    Bendinelli P, Matteucci E, Dogliotti G, Corsi MM, Banfi G, Maroni P, Desiderio MA (2010) Molecular basis of anti-inflammatory action of platelet-rich plasma on human chondrocytes: mechanisms of NF-kappaB inhibition via HGF. J Cell Physiol 225:757–766

    Article  PubMed  CAS  Google Scholar 

  6. 6.

    Brandt KD, Radin EL, Dieppe PA, van de Putte L (2006) Yet more evidence that osteoarthritis is not a cartilage disease. Ann Rheum Dis 65:1261–1264

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  7. 7.

    Castaneda S, Roman-Blas JA, Largo R, Herrero-Beaumont G (2012) Subchondral bone as a key target for osteoarthritis treatment. Biochem Pharmacol 83:315–323

    Article  PubMed  CAS  Google Scholar 

  8. 8.

    Coudriet GM, He J, Trucco M, Mars WM, Piganelli JD (2010) Hepatocyte growth factor modulates interleukin-6 production in bone marrow derived macrophages: implications for inflammatory mediated diseases. PLoS ONE 5:e15384

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  9. 9.

    Descalzi F, Ulivi V, Cancedda R, Piscitelli F, Luongo L, Guida F, Gatta L, Maione S, Di Marzo V (2013) Platelet-rich plasma exerts antinociceptive activity by a peripheral endocannabinoid-related mechanism. Tissue Eng Part A 19:2120–2129

    Article  PubMed  CAS  Google Scholar 

  10. 10.

    Dray A, Read SJ (2007) Arthritis and pain. Future targets to control osteoarthritis pain. Arthritis Res Ther 9:212

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  11. 11.

    Elsaid KA, Jay GD, Warman ML, Rhee DK, Chichester CO (2005) Association of articular cartilage degradation and loss of boundary-lubricating ability of synovial fluid following injury and inflammatory arthritis. Arthritis Rheum 52:1746–1755

    Article  PubMed  CAS  Google Scholar 

  12. 12.

    Fahy N, de Vries-van Melle ML, Lehmann J, Wei W, Grotenhuis N, Farrell E, van der Kraan PM, Murphy JM, Bastiaansen-Jenniskens YM, van Osch GJ (2014) Human osteoarthritic synovium impacts chondrogenic differentiation of mesenchymal stem cells via macrophage polarisation state. Osteoarthr Cartil 22:1167–1175

    Article  PubMed  CAS  Google Scholar 

  13. 13.

    Felson DT (2006) Clinical practice. Osteoarthritis of the knee. N Engl J Med 354:841–848

    Article  PubMed  CAS  Google Scholar 

  14. 14.

    Felson DT (2009) Developments in the clinical understanding of osteoarthritis. Arthritis Res Ther 11:203

    Article  PubMed  PubMed Central  Google Scholar 

  15. 15.

    Fernandez-Tajes J, Soto-Hermida A, Vazquez-Mosquera ME, Cortes-Pereira E, Mosquera A, Fernandez-Moreno M, Oreiro N, Fernandez-Lopez C, Fernandez JL, Rego-Perez I, Blanco FJ (2014) Genome-wide DNA methylation analysis of articular chondrocytes reveals a cluster of osteoarthritic patients. Ann Rheum Dis 73:668–677

    Article  PubMed  CAS  Google Scholar 

  16. 16.

    Filardo G, Kon E, Pereira Ruiz MT, Vaccaro F, Guitaldi R, Di Martino A, Cenacchi A, Fornasari PM, Marcacci M (2012) Platelet-rich plasma intra-articular injections for cartilage degeneration and osteoarthritis: single- versus double-spinning approach. Knee Surg Sports Traumatol Arthrosc 20:2082–2091

    Article  PubMed  Google Scholar 

  17. 17.

    Filardo G, Kon E, Roffi A, Di Matteo B, Merli ML, Marcacci M (2015) Platelet-rich plasma: why intra-articular? A systematic review of preclinical studies and clinical evidence on PRP for joint degeneration. Knee Surg Sports Traumatol Arthrosc 23:2459–2474

    Article  PubMed  CAS  Google Scholar 

  18. 18.

    Gobbi A, Lad D, Karnatzikos G (2015) The effects of repeated intra-articular PRP injections on clinical outcomes of early osteoarthritis of the knee. Knee Surg Sports Traumatol Arthrosc 23:2170–2177

    Article  PubMed  Google Scholar 

  19. 19.

    Gormeli G, Gormeli CA, Ataoglu B, Colak C, Aslanturk O, Ertem K (2015) Multiple PRP injections are more effective than single injections and hyaluronic acid in knees with early osteoarthritis: a randomized, double-blind, placebo-controlled trial. Knee Surg Sports Traumatol Arthrosc. doi:10.1007/s00167-015-3705-6

    PubMed  Article  Google Scholar 

  20. 20.

    Joos H, Wildner A, Hogrefe C, Reichel H, Brenner RE (2013) Interleukin-1 beta and tumor necrosis factor alpha inhibit migration activity of chondrogenic progenitor cells from non-fibrillated osteoarthritic cartilage. Arthritis Res Ther 15:R119

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  21. 21.

    Kapoor M, Martel-Pelletier J, Lajeunesse D, Pelletier JP, Fahmi H (2011) Role of proinflammatory cytokines in the pathophysiology of osteoarthritis. Nat Rev Rheumatol 7:33–42

    Article  PubMed  CAS  Google Scholar 

  22. 22.

    Laudy AB, Bakker EW, Rekers M, Moen MH (2015) Efficacy of platelet-rich plasma injections in osteoarthritis of the knee: a systematic review and meta-analysis. Br J Sports Med 49:657–672

    Article  PubMed  Google Scholar 

  23. 23.

    Leong DJ, Li YH, Gu XI, Sun L, Zhou Z, Nasser P, Laudier DM, Iqbal J, Majeska RJ, Schaffler MB, Goldring MB, Cardoso L, Zaidi M, Sun HB (2011) Physiological loading of joints prevents cartilage degradation through CITED2. Faseb J 25:182–191

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. 24.

    Lequesne MG, Mery C, Samson M, Gerard P (1987) Indexes of severity for osteoarthritis of the hip and knee. Validation-value in comparison with other assessment tests. Scand J Rheumatol Suppl 65:85–89

    Article  PubMed  CAS  Google Scholar 

  25. 25.

    Little CB, Hunter DJ (2013) Post-traumatic osteoarthritis: from mouse models to clinical trials. Nat Rev Rheumatol 9:485–497

    Article  PubMed  CAS  Google Scholar 

  26. 26.

    Ludwig TE, McAllister JR, Lun V, Wiley JP, Schmidt TA (2012) Diminished cartilage-lubricating ability of human osteoarthritic synovial fluid deficient in proteoglycan 4: Restoration through proteoglycan 4 supplementation. Arthritis Rheum 64:3963–3971

    Article  PubMed  CAS  Google Scholar 

  27. 27.

    Malfait AM, Schnitzer TJ (2013) Towards a mechanism-based approach to pain management in osteoarthritis. Nat Rev Rheumatol 9:654–664

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  28. 28.

    Martel-Pelletier J, Wildi LM, Pelletier JP (2012) Future therapeutics for osteoarthritis. Bone 51:297–311

    Article  PubMed  CAS  Google Scholar 

  29. 29.

    Meheux CJ, McCulloch PC, Lintner DM, Varner KE, Harris JD (2016) Efficacy of intra-articular platelet-rich plasma injections in knee osteoarthritis: a systematic review. Arthroscopy 32:495–505

    Article  PubMed  Google Scholar 

  30. 30.

    Montaseri A, Busch F, Mobasheri A, Buhrmann C, Aldinger C, Rad JS, Shakibaei M (2011) IGF-1 and PDGF-bb suppress IL-1beta-induced cartilage degradation through down-regulation of NF-kappaB signaling: involvement of Src/PI-3 K/AKT pathway. PLoS ONE 6:e28663

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. 31.

    Oatis CA, Wolff EF, Lockard MA, Michener LA, Robbins SJ (2013) Correlations among measures of knee stiffness, gait performance and complaints in individuals with knee osteoarthritis. Clin Biomech (Bristol, Avon) 28:306–311

    Article  Google Scholar 

  32. 32.

    Pelletier JP, Martel-Pelletier J, Abramson SB (2001) Osteoarthritis, an inflammatory disease: potential implication for the selection of new therapeutic targets. Arthritis Rheum 44:1237–1247

    Article  PubMed  CAS  Google Scholar 

  33. 33.

    Richardson D, Pearson RG, Kurian N, Latif L, Garle MJ, Barrett DA, Kendall DA, Scammell BE, Reeve AJ, Chapman V (2008) Characterisation of the cannabinoid receptor system in synovial tissue and fluid in patients with osteoarthritis and rheumatoid arthritis. Arthritis Res Ther 10:R43

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  34. 34.

    Sakata R, McNary SM, Miyatake K, Lee CA, Van den Bogaerde JM, Marder RA, Reddi AH (2015) Stimulation of the superficial zone protein and lubrication in the articular cartilage by human platelet-rich plasma. Am J Sports Med 43:1467–1473

    Article  PubMed  PubMed Central  Google Scholar 

  35. 35.

    Sanchez-Adams J, Leddy HA, McNulty AL, O’Conor CJ, Guilak F (2014) The mechanobiology of articular cartilage: bearing the burden of osteoarthritis. Curr Rheumatol Rep 16:451

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  36. 36.

    Sanchez M, Anitua E, Azofra J, Aguirre JJ, Andia I (2008) Intra-articular injection of an autologous preparation rich in growth factors for the treatment of knee OA: a retrospective cohort study. Clin Exp Rheumatol 26:910–913

    PubMed  CAS  Google Scholar 

  37. 37.

    Sanchez M, Fiz N, Azofra J, Usabiaga J, Aduriz Recalde E, Garcia Gutierrez A, Albillos J, Garate R, Aguirre JJ, Padilla S, Orive G, Anitua E (2012) A randomized clinical trial evaluating plasma rich in growth factors (PRGF-Endoret) versus hyaluronic acid in the short-term treatment of symptomatic knee osteoarthritis. Arthroscopy 28:1070–1078

    Article  PubMed  Google Scholar 

  38. 38.

    Scanzello CR, Goldring SR (2012) The role of synovitis in osteoarthritis pathogenesis. Bone 51:249–257

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  39. 39.

    Thakur M, Dickenson AH, Baron R (2014) Osteoarthritis pain: nociceptive or neuropathic? Nat Rev Rheumatol 10:374–380

    Article  PubMed  Google Scholar 

  40. 40.

    van Buul GM, Koevoet WL, Kops N, Bos PK, Verhaar JA, Weinans H, Bernsen MR, van Osch GJ (2011) Platelet-rich plasma releasate inhibits inflammatory processes in osteoarthritic chondrocytes. Am J Sports Med 39:2362–2370

    Article  PubMed  Google Scholar 

  41. 41.

    Vaquerizo V, Plasencia MA, Arribas I, Seijas R, Padilla S, Orive G, Anitua E (2013) Comparison of intra-articular injections of plasma rich in growth factors (PRGF-Endoret) versus Durolane hyaluronic acid in the treatment of patients with symptomatic osteoarthritis: a randomized controlled trial. Arthroscopy 29:1635–1643

    Article  PubMed  Google Scholar 

  42. 42.

    Waller KA, Zhang LX, Elsaid KA, Fleming BC, Warman ML, Jay GD (2013) Role of lubricin and boundary lubrication in the prevention of chondrocyte apoptosis. Proc Natl Acad Sci USA 110:5852–5857

    Article  PubMed  CAS  Google Scholar 

  43. 43.

    Wang-Saegusa A, Cugat R, Ares O, Seijas R, Cusco X, Garcia-Balletbo M (2011) Infiltration of plasma rich in growth factors for osteoarthritis of the knee short-term effects on function and quality of life. Arch Orthop Trauma Surg 131:311–317

    Article  PubMed  Google Scholar 

  44. 44.

    Wu CC, Chen WH, Zao B, Lai PL, Lin TC, Lo HY, Shieh YH, Wu CH, Deng WP (2011) Regenerative potentials of platelet-rich plasma enhanced by collagen in retrieving pro-inflammatory cytokine-inhibited chondrogenesis. Biomaterials 32:5847–5854

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

We would like to thank Verónica Moreno and Esther Montes for their contribution to the paper. Authors wish to thank BTI Biotechnology Institute for their active contribution.

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Correspondence to Víctor Vaquerizo or Gorka Orive.

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Conflict of interest

Vaquerizo V. and Aguirre JJ. declares that have no conflict of interest. Anitua E. is the Scientific Director and GO, SP and LB are scientists at BTI Biotechnology Institute, a dental implant company that investigates in the fields of oral implantology and PRGF-Endoret technology.

Funding

This work was supported by the Biomedical Research Foundation of Principe de Asturias University Hospital.

Ethical approval

This study was performed in accordance with current law regulatory rules, and the international guidelines for Good Clinical Practice. The study protocol was previously reviewed and approved by the institutional review board (EC11-026).

Informed consent

Informed consent was obtained from all individual participants included in the study.

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Vaquerizo, V., Padilla, S., Aguirre, J.J. et al. Two cycles of plasma rich in growth factors (PRGF-Endoret) intra-articular injections improve stiffness and activities of daily living but not pain compared to one cycle on patients with symptomatic knee osteoarthritis. Knee Surg Sports Traumatol Arthrosc 26, 2615–2621 (2018). https://doi.org/10.1007/s00167-017-4565-z

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Keywords

  • PRGF
  • Osteoarthritis
  • Regeneration
  • Growth factors
  • Pain