Injection therapy in knee osteoarthritis: cortisol, hyaluronic acid, PRP, or BMAC (mesenchymal stem cell therapy)?

Osteoarthritis (OA) is the most common chronic joint disease and a leading cause of disability. (1) Globally, the number of prevalent OA cases rises exponentially, with knee OA contributing the most to the overall burden. (2) This will lead to substantial healthcare expenditures and an unmet demand for orthopedic surgeons in most OECD countries. (3,4) Cell-based therapies are being utilized more frequently, and the outcomes of bone marrow aspirate concentrate (BMAC) or "stem cell therapy" demonstrate promising short-to mid-term results. With the use of BMAC the "Dilemma of Drink Selection for the Modern Orthopaedic Surgeon" is becoming increasingly complex even for experienced practitioners "What should I inject into the patients with osteoarthritis (OA) of the knee? Platelet-Rich Martini or Vodka Hyaluronic acidate?" (5).Our primary focus in this paper will be on critically comparing various treatment options using published data. Secondly, we will emphasize addressing specific patient needs and share our perspective on personalized medicine for treating knee osteoarthritis. This opinion is informed by over 20 years of experience as the team doctor for the Austrian national soccer team and the Austrian national ski team, applying these insights to the treatment of regular patientsInjection therapy for knee OA is unquestionable, but the question which type of injection is not easy. The currently used Kellgren-Lawrence (KL) classification for OA dates back to the year 1957 and is not of great help in decision making. (6) Today, we have evidence, that BMAC injections even have excellent outcome in patients with severe OA (7) and implants have become so good, that the compound annual growth rate in knee arthroplasty in younger patients exceeds the demand in the elderly since over 15 years.(4) The European Society for Sports Traumatology, Knee Surgery and Arthroscopy (ESSKA) also recommends platelet rich plasma (PRP) in OA grade I-III. (8) Furthermore, the discrepancy between radiological classification and patient reported symptoms is well known.The following key points have to be highlighted in our opinion:• Conservative means (e.g., stretching, insoles, physio, weight reduction, cycling) are the first choice of therapy and accompany every injection therapy. • Mechanical errors, such as patellar malalignment, varus/valgus deviations greater than 6°, and ligament or meniscal injuries, must be surgically corrected first-regardless of age (!) -since they are significant risk factors for knee osteoarthritis.(9-12) • Total knee arthroplasty (TKA) is still the gold standard for severe osteoarthritis, not responding to conservative means, with 95% good and excellent results at 20 years.(13)Undoubted intra-articular corticosteroid injections offer clinically perceivable pain relief and functional improvement higher than the placebo effect only at short-term follow-up in patients affected by knee OA, with benefits losing clinical relevance already after 6 weeks. (14) The effect may vary substantially in different patient groups and "appropriate patient" selection is important.(15) However, it is not possible to predict which patients are most likely to benefit from intra-articular corticosteroid injections (16).Patients receiving co-treatment with oral duloxetine (serotonin reuptake inhibitor) and CS injections experience considerable improvement in pain and knee function compared to those who receive an CS injection alone.( 17)A register study on 15.000 Medicare patients showed, that the patients receiving hyaluronic acid(HA) was associated with a longer time to knee arthroplasty (KA) of 8.7 months (8.3-9.1, P < .001) as compared with patients without HA. Patients with both intra-articular HA and intra-articular CS had an additional 6.3 months (5.5-7.0, P < .001) to KA over those with only IA HA. (18) In a registry study with 182.000 patients it was evident, that with one course of HA, the mean delay time to total knee arthroplasty was 1.4 years (p < 0.0001); patients who received ≥5 courses delayed total knee arthroplasty by 3.6 years (p < 0.0001).( 19) A recent metaanalysis with 943 patients in 10 RCTs showed, that PRP + HA therapy resulted in more pronounced pain and functional improvement in symptomatic KOA patients than HA treatments.(20)One shot of PRP injection decreased joint pain more and longer-term, alleviated the symptoms, and enhanced the activity of daily living and quality of life in comparison with CS.( 21) In a meta-analysis of all studies comparing HA with PRP, intra-articular PRP injection appeared to be more efficacious than HA injection for the treatment of knee OA in terms of short-term functional recovery (IKDC, WOMAC, Lequesne, VAS score) and long-term (pain relief and function improvement). PRP did not increase the risk of adverse events compared to HA. (22) Recent ESSKA guidelines consider PRP injections appropriate in patients aged ≤80 years with knee KL 0-III OA grade after failed conservative non-injective or injective treatments, while they are not considered appropriate as first treatment nor in KL IV OA grade.(8)One metaanalysis of 16 short term studies with 875 patients receiving BMAC showed a significant pain reduction (VAS) from the 3 rd month onwards. (23) Another meta-analysis compared HA, PRP, and BMAC at 6 months and found out, that all led to a significant improvement in function scores when compared with placebo. ( 24) A third meta-analysis of 27 studies and 1042 patients with a mean 13-month follow-up compared PRP, BMAC, and HA for knee OA: This meta-analyses demonstrated significantly better postinjection WOMAC (P < .001), VAS (P < .01), and IKDC scores (P < .001) in patients who received PRP compared with patients who received HA. Similarly, other meta-analyses demonstrated significantly better postinjection WOMAC (P < .001), VAS (P = .03), and IKDC (P < .001) scores in patients who received BMAC compared with patients who received HA, but no significant differences when comparing PRP with BMAC.(25) A further metaanalysis with a mean 14-month follow-up comprising of 15 studies (585 patients), BM-MSC therapy was most effective in improving the VAS and the ROM, while other types of mesenchymal stem cells (MSCs, such as umbilical cord-and adipose tissue-derived mesenchymal stem cells) were more effective in improving functional out-comes, such as Whole-Organ Magnetic Resonance Imaging Score (WORMS) and Western Ontario McMaster Universities Osteoarthritis Index (WOMAC) scores. (26) No further meta-analyses comparing different sources of pluripotent stem cells or comparing cellbased injections with established therapeutic options (HA, CS, PRP) were published to date. However, all these meta-analyses have a follow up of approximately one year. However, we know, that the positive effect of BMAC is becoming statistically and clinically relevant from year two onwards.( 27)Furthermore, a clinical study with 175 patients directly comparing clinical outcomes of knee injections of BMAC, PRP, and HA with a 1-year follow up showed that the BMAC group had the best positive effect regarding IKDC and WOMAC at all time-points of time.(28) However, there is also one single study, describing the effect at one year not superior to corticosteroids. (29) According to our knowledge, there is only one study with a 4-year follow-up regarding BMAC therapy in patients with OA: 35 of 37 knees improved regarding IKDC and WOMAC score from the first to the last follow-up. IKDC increased significantly from 56 ± 12 (range 34-81) to 73 ± 13 (range 45-100), p < 0.001. WOMAC decreased significantly from 40 ± 23 (range 6-96) to 18 ± 18 (range 0-67), p < 0.001. ( 7)Undoubted the evolution in injection therapy from 1964 with CS to PRP and BMAC nowadays is impressive: It is evidence based, that several HA injections can postpone knee arthroplasty by 4 years. ( 19) Note, that PRP can be combined with HA and has an even stronger effect.(20)• CS injections are used in acute patients in our institution: Those, who need immediate care, e.g. days before a tournament / match / private social event. We use Betamethason 1ml.Regarding HA injections, we switched to the one-treatment 60mg HA injection a decade ago instead of the three times 20mg in order to minimize patients' travelling, infection risk and pain.• HA injections are given, when the characteristic onset of "starting pain", or pain experienced during prolonged sitting with a flexed knee (often referred to as the 'cinema sign') occurs.We advice symptomatic patients, that a renewal of an injection after 6-18 months has a better long term effect. (19) We never inject prophylactically in asymptomatic knees.Speaking about PRP we now use a one-treatment 60ml blood withdrawl system, that produces 4ml of PRP. This seems better to us, than the 4 to 5 times repetitive injections of 1-2ml PRP, made out of 15ml, because the risk of infection and pain is minimized. The ESSKA statement on PRP several days ago makes it clearer, when to use PRP:• PRP injections are used, when HA or CS or conservative treatment did not help.Since all metaanalyses on BMAC showed at least equivalent results of BMAC to PRP already one year after the injection and since we know, that the therapeutic effect of BMAC takes two years to occur, it is most likely, that BMAC will outperform the PRP results in the next years. (23,(25)(26)(27).• BMAC injections are therefore used in our institution, when other injections have failed. We see impressive long term effects: 35 of 37 patients benefit from this kind of treatment. (27) These patient groups are best suited: 1. Young patients (< 50 years) who are not jet suitable for knee prosthesis. We know that operating in these patients too early will not result in a "happy patient"(30) Thus, the aim is to gain several years until a prosthesis can be implanted. 2. Old patients (> 80 years) with contraindications for surgery or severe comorbidities. Here the aim is to avoid complications and surgical procedures. 3. "Procrastinating patients" (all ages) with "no time for a knee prosthesis", because they have to "take care about relatives", are "too much engaged in the jobs at the moment" can also be consideres for BMAC injections.Regarding the injection of intra-articular micro fragmented adipose tissue (MF-AT, also known as (mesenchymal) stem cell therapy, stromal vascular fraction (SVF)-therapy), ), such types of injections have also been proposed for the treatment of knee OA. In several recent studies a single intra-articular injection of MF-AT was not superior to PRP -meta-analyses are missing. (31)(32)(33) We would like to emphasize, that our stem cell research study group had great troubles in cultivating fat cells in an experimental setting, whereas we could easily work with bone marrow cells. We therefore do not recommend this kind of fat-tissue derived cell treatment.We also use all the above mentioned injections in patients with rheumatoid arthritis, as an additional option to their basis therapy with similar outcome as compared to degenerative arthritis. However, literature on injection therapy in rheumatoid arthritis with autologous PRP or BMA(C) is sparse and industry fosters small-molecule and biologic therapies, devices and gene therapy. (34) Based on the above mentioned metaanalyses we can estimate that future publications will demonstrate the superior long-term effectiveness of BMAC injections as compared to PRP. (27) Currently fluoroscopic guided subchondral injections (of BMAC) for knee osteoarthritis are discussed and few pilot study studies shows promising results. (35,36) At the moment, a double-blind randomized controlled trial is conducted, comparing bone marrow aspirate concentrate intra-articular injection combined with subchondral injection versus intra-articular injection alone for the treatment of symptomatic knee osteoarthritis. (37) This might be an option for patients with additional bone marrow edema.Single studies also recommended the use of BMA instead of BMAC, which makes the procedure faster and cheaper, but this depends on the methodology of the harvesting procedure, in order to gain a maximum cell yield. (27,38) Maybe this will become an option for the future, when the harvesting procedure of BMA will become standardized.Transferring this evidence into daily clinical praxis, we developed a 1-page handout-sheet, that can help patients and doctors to choose the right injection at the right point of time. (Fig Acute patients, who need immediate care, e.g. days before a tournament or match or a private social event.When the characteristic onset of "starting pain", or pain experienced during prolonged sitting occurs or radiographic signs of arthritis ar present.When HA or CS or conservative treatment did not help (ESSKArecommendation).(1) Young patients: "Too young for prostheses" (2) Old patients with contraindications for surgery (3) Procrastinating patients "no time for a knee prosthesis right now"Effects described in metaanalysesHandout for patients and doctors to choose the appropriate type of injection.CP wrote the first draft. All authors contributed to the work quoted and approved the final draft.

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