Marc Darrow MD,JD

Many patients we see, have been researching their options in treating their chronic knee pain. These people come to see us because they are exploring non-surgical alternatives and have investigated various forms of regenerative medicine techniques. This includes the use of their own blood platelets as a healing solution, (more commonly referred to as Platelet Rich Plasma Therapy) or stem cell therapy which we will discuss below in relation to hyaluronic acid injections.

Many of these patients, perhaps including yourself as well, have had prior discussion with doctors about hyaluronic acid injections. These injections can provide a good amount of pain relief, temporarily. But ultimately they do not regenerate tissue and they are only a stop gap measure to delaying inevitable joint replacement.

  • Hyaluronic acid is a naturally occurring substance that is a major component of the protective synovial fluid that surrounds the knee. In its natural form it is also a key component of wound healing. In its processed form used for injection purposes, hyaluronic acid is NOT a key healing component as attested to by suggestions and recommendations that these injections are stop gaps until knee replacement can be performed.

Seven different knee osteoarthritis treatments

A December 2021 study (1) assessed seven different knee osteoarthritis treatments.

  • platelet rich plasma (PRP),
  • corticosteroids,
  • mesenchymal stem cells (MSCs),
  • hyaluronic acid,
  • ozone,
  • administration of nonsteroidal anti-inflammatory drugs,
  • administration of nonsteroidal anti-inflammatory drugs with physical therapy.

These were the researchers conclusions:
The interventions had different effects on the participants suffering from knee osteoarthritis.

In primary outcome (WOMAC at 12 months – WOMAC is the The Western Ontario and McMaster Universities Osteoarthritis Index. It is universally used by health professionals to evaluate the condition of knee osteoarthritis patients), mesenchymal stem cells and PRP were significantly better than the chosen control (placebo) and associated with improvement in knee status.

Corticosteroid improved outcomes but did not perform better than the control.

Ozone injection is the only intervention for which knee pain and/or function got worse at the end of the study compared with the baseline. Ozone injection showed no improvement in pain and function at 12 months.

The results of NSAID alone or with physical exercise (physiotherapy) were not associated with improvement in pain and function compared with the injection of hyaluronic acid. Otherwise, the combination of hyaluronic acid and dexamethasone (steroid) was not associated with improvement in WOMAC at 3 and 6 months compared with the injection of hyaluronic acid alone.

Among all the interventions studied, the results of mesenchymal stem cells (MSCs) and PRP were the most consistent and associated with improvement in pain and articular function on the long-term.

Mesenchymal stem cells (MSCs) had the highest probability to be the best treatment with primary outcome and also associated with improvement in pain and function especially at mid and long term. Moreover, the greatest improvement of pain and function at 12 months compared with baseline were observed in mesenchymal stem cells (MSCs) intervention groups.

Intra-articular corticosteroid, hyaluronic, or PRP injections?

Here is a second 2021 study (2).

“Intra-articular corticosteroid, hyaluronic, or PRP injections can provide short-term to medium-term (4 to 12 weeks) improvement in pain and function as measured by either WOMAC and/or VAS scores (standard pain and functional assessment scores) with minimal incidence of serious adverse events. Out of the above, the evidence behind cortisone for pain relief is most substantiated. There is a scarcity of head-to-head comparisons between each injectable therapy, although there is some emerging evidence that suggest possibly superior pain reduction with hyaluronic over the long-term (6 months to 1 year) compared to hyaluronic. Some trials also tentatively demonstrated superior and sustained pain improvements with PRP over the longer term (6 months to 1 year), although they are limited by their small sample sizes and quality. In addition, current evaluation of PRP is severely limited by the heterogeneity in its preparation and injection techniques between trials, which makes it difficult to make a blanket statement regarding its efficacy.”

In this article we will examine more research and discuss the controversy surrounding how PRP injections are given.

Electrical Dry Needling Plus Corticosteroid Injection

Electrical Dry Needling is the use of electric stimulation in needle form. A 2022 study (20) suggests that patients with knee osteoarthritis may benefit from this treatment. In this study Sixty patients with knee osteoarthritis were randomly assigned to the electrical dry needling plus corticosteroid injection group or corticosteroid injection alone.

The corticosteroid injection group received glucocorticoid injection only once during the trial, and the electrical dry needling plus corticosteroid injection group received glucocorticoid injection combined with 4 sessions of electrical-Electrical Dry Needling.

Results: Electrical Dry Needling therapy at myofascial trigger points combined with corticosteroid injection is more effective at alleviating pain, improving dysfunction, and global change than corticosteroid injection alone for patients with knee osteoarthritis. Electrical Dry Needling may be an essential part of treatment for knee osteoarthritis  rehabilitation.

In our practice we have seen patients who do well with some type of electric stimulation device. Unfortunately for many the results were not long lasting. This is why we do not offer this treatment.

Hyaluronic acid injections “buying time,” until you are ready for knee replacement

  • A study in the journal Public Library of Science one (3agrees with the current beliefs that Hyaluronic Acid Injections are at best, a treatment best used to help delay inevitable total knee replacement. How much so? In this research, the patients of the study were able to delay knee replacement for about 1.5 years on average.
  • A study published in October 2019 in the medical journal Cartilage (4) noted less time between Hyaluronic Acid Injections and knee replacement. They also noted some other findings:
    • Most knee replacement patients did not use hyaluronic acid injections prior to knee replacement. (Researchers put this number at 73.7%)
    • When the patient did receive hyaluronic acid injections, it was associated with an average knee replacement delay of 7 months, though the cause and effect could not be examined. (This means the researchers were not sure the delay was the result of the hyaluronic acid injections.)
  • To some researchers, this delay to knee replacement is so small that they suggest Hyaluronic Acid Injections are a waste of time, money, and resources. Some patients should be encouraged to proceed directly to the knee replacement and not consider the Hyaluronic Acid Injections. The research from the journal American Health and Drug Benefits suggest that patients over the age of 70 should proceed to total knee replacement as opposed to intra-articular injections of steroids or hyaluronic acid  to save on national health care costs.(5)

As many of you know first-hand, Hyaluronic acid injections, commonly known as Euflexxa®, Supartz®, Supartz FX®, Hyalgan®, Synvisc®, HYMOVIS®etc, is an attempt to restore the knee’s synovial fluid’s lubrication properties through viscosupplementation and restoration of  lost hyaluronic acid levels. These injections can not be given over long periods of time as their effect dwindles to the point of providing no benefit. This is outlined in the medical research.

In support of hyaluronic acid injections

We do not offer hyaluronic acid injections in our office based on over twenty years of clinical observation in our patients. This does not mean that hyaluronic acid injections are not beneficial for some, but, as research above and below point out, these benefits are seen as delaying the inevitable knee replacement.

In March 2022 a research team (21) suggested that one injection of hyaluronic acid (Synvisc-One®) would be offers benefit to patients for up to one year. In this study while the researchers noted that intra-articular hyaluronic acid injections have been widely studied with variable and conflicting results fifty patients in their study  saw “Short-term (up to one year) beneficial effects of intra-articular viscosupplementation with hyaluronic acid in early primary knee osteoarthritis (which) can be seen with a decreasing trend in the intensity of pain and an increasing trend in improving the physical functioning and health-related quality of life.”

Comparing PRP and hyaluronic acid in the treatment of knee osteoarthritis

A July 2020 study in the journal Arthroscopy (6) compared the effectiveness and safety of platelet-rich plasma (PRP) and hyaluronic acid in adult knee osteoarthritis patients. In this research Twenty-six randomized controlled trials involving 2430 patients were included. Pain and functioning scores the PRP group were better than the those of the hyaluronic acid group at 3, 6 and 12 months. The PRP group had better pain and functioning scores than the hyaluronic acid group at 6 and 12 months.

Conclusions: For the nonsurgical treatment of knee osteoarthritis, compared with hyaluronic acid , intra-articular injection of PRP could significantly reduce patients’ early pain and improve function. There was no significant difference in adverse events between the two groups. PRP was more effective than hyaluronic acid in the treatment of KOA, and the safety of these two treatment options was comparable.

A March 2019 study (7) wrote: “Intra-articular PRP injections into the knee for symptomatic early stages of knee osteoarthritis are a valid treatment option. The clinical efficacy of Intra-articular PRP is comparable to that of the Intra-articular hyaluronic acid and Intra-articular cortisone forms after 3 months and the long-term efficacy of Intra-articular PRP is superior to Intra-articular hyaluronic acid and Intra-articular cortisone.”

A 2015 study (8)  found that the intra-articular PRP injection was more effective than the hyaluronic acid injections in pain relief and function in early knee osteoarthritis patients.

A March 2020 study (9) looked at knee osteoarthritis in patients who suffer from being overweight or obese. They found that PRP was better than hyaluronic acid  for the treatment of knee osteoarthritis in these patients. in the long-term.

An August 2022 paper (29) examined thirty-three different studies with 7003 patients knee osteoarthritis patients. Five therapeutic treatments were analyzed.

  • Meta-analysis showed that the efficacy of platelet-rich plasma injection was superior to both ozone and hyaluronic acid therapies.
  • Hyaluronic acid+ozone and platelet-rich plasma+hyaluronic acid were both superior to ozone and hyaluronic acid monotherapy.
  • The differences in efficacy between hyaluronic acid and ozone compared with platelet-rich plasma were statistically significant, and the differences in efficacy between the 2 combination therapies (platelet-rich plasma+hyaluronic acid, hyaluronic acid+ozone) and the 3 monotherapies (platelet-rich plasma, ozone, hyaluronic acid) were statistically significant.
  • Platelet-rich plasma+hyaluronic acid, hyaluronic acid+ozone compared with 3 monotherapies (platelet-rich plasma, ozone, hyaluronic acid) were statistically significant, except for the difference in efficacy with platelet-rich plasma, which was not statistically significant, indicating that this platelet-rich plasma+hyaluronic acid and Hyaluronic acid+ozone combination therapy was superior to monotherapy.
  • Also, the efficacy of platelet-rich plasma was better than hyaluronic acid and ozone and the difference was statistically significant, indicating that platelet-rich plasma was more effective than ozone and sodium glass in the treatment of osteoarthritis of the knee in monotherapy.

Comparing PRP to Cortisone and hyaluronic acid injections

A March 2022 review study (22) evaluated the maximum medical improvement and minimal clinically important difference (the minimum scores necessary to suggest a treatment worked) of corticosteroid, hyaluronic acid and PRP  injectables in the treatment of symptomatic knee osteoarthritis. Overall, 79 studies were reviewed discussing 8761 patients.

  • Corticosteroid injections, hyaluronic acid injections, and  platelet rich plasma injections reached their maximum pain control at 4 to 6 weeks after injection, as measured by visual numerical pain scores ( 0 no pain-10 unbearable pain).
  • PRP injections provide continued pain relief at up to one year after injection. Corticosteroids and hyaluronic acid have good efficacy and are suitable for many patients but lack this longevity.

A May 2022 study (26) evaluated the efficacy and safety of Platelet Rich Plasma (PRP) injections in patients affected by knee osteoarthritis.

    • One hundred and fifty-three patients received three consecutive PRP injections and completed follow ups.
    • Results: Statistically significant function increase and pain reduction emerged suggesting PRP injection represents a valid conservative treatment to reduce pain, improve quality of life and functional scores even at midterm of 6 months follow-up.

Controversy as to whether hyaluronic acid injections cause side-effects

There is a controversy surrounding not only the long-term / short-term benefits of hyaluronic acid injections, but also, as to whether or not these injections cause unwanted adverse reactions.

      • Doctors at Bern University Hospital in Sweden suggested in their published research in the Annals of internal medicine (10) that in patients with knee osteoarthritis, viscosupplementation offered a small and clinically irrelevant benefit and an increased risk for serious adverse events.
      • In another larger study in the French medical publication Prescribe International, researchers found that hyaluronic acid injections only provided a small relief to patients with osteoarthritis of the knee, but agreed that hyaluronic acid injections could provoke both local reactions and serious adverse effects.”(11)
      • In the journal Clinical neurology and neurosurgery, doctors recently warned that while Hyaluronic acid injections can provide significant pain relief and improvement in the knee – This may cause excessive loading on the knee joints, which may further accelerate the rate of knee degeneration.(12)

There has been some research to suggest that hyaluronic acid injections do not cause adverse effects, but a May 2019 study challenged this notion.In the journal Drugs & Aging (13) a multi-national team of researchers suggested:

      • “(In reviewing the) available data on studies without any concomitant anti-osteoarthritis medication permitted during clinical trials, hyaluronic acid injections seems not to be associated with any safety issue in the management of osteoarthritis. However, this evidence was associated with only a “low” to “moderate” certainty. A possible association with increased risk of serious adverse effects, particularly when used with concomitant osteoarthritis medications, requires further investigation.”

In brief, the evidence is not good that hyaluronic acid injections are safe and further, they seem to cause worse adverse effects when used in conjunction with other osteoarthritis medications.

How about combining hyaluronic acid and PRP? Research says: PRP and hyaluronic acid combined in no better than PRP alone.

We have a new 2021 review study (14) that looked into “a new trend” of combining hyaluronic acid and PRP in an effort to have a more beneficial synergistic effect. Here are the results:

      • Hyaluronic acid and PRP combination therapy resulted in improved patient report outcomes in all reviewed studies.
      • Of the comparative and randomized studies examined, 2 studies demonstrated that combination therapy was superior to hyaluronic acid alone.
      • However,  combination therapy was not superior to PRP alone.

When hyaluronic acid works best? When it is naturally produced in the body and provides a self-renewing source of joint protection

The reason you may have been recommended to Hyaluronic acid injections is that you have none or very little of your own. Your body, for the most part has stopped producing it or that which your body produces is a weakened, diluted product ravaged by incessant inflammation. Stem cell therapy may be able to reverse this problem and “re-open” Hyaluronic acid production.

      • There is new fascinating research about the inter-relationship between natural hyaluronic acid and stem cell therapy. Here is where we will get into the research and discussions surrounding stem cell therapy’s ability to increase the natural production of hyaluronic acid in osteoarthritic knees.

A paper published in the Journal of orthopaedic research (15) made these observations:

      • First, the researchers investigated whether mesenchymal stem cells in synovial fluid increased in the knee with degenerated cartilage and osteoarthritis.
        • Observation: The number of stem cells found in the synovial fluid of patients with good knees and little of no degenerative problems were “hardly noticed.”
        • Observation: The number of stem cells found in the synovial fluid of patients with degenerative knee disease or injury  increased along with degenerated cartilage and osteoarthritis.

Stem cells “re-hydronate” the synovial fluid with natural hyaluronic acid.

In other words, as there was more knee damage, stem cells were making their way to the damaged knee. Many stem cells found their way to the synovial fluid. There they could help with the production of natural hyaluronic acid and help produce more of the natural and protective fluid.

      • This unique relationship between stem cells and hyaluronic acid was also noted by doctors at the University of Leeds in the UK who suggested a spontaneous healing of cartilage in a newly created  “favorable biochemical and biomechanical (knee) environment.(16)

A January 2019 (17) study in the journal Stem Cell International made similar observations. Here the researchers found that synovial fluid cells taken from patients who did not have knee osteoarthritis, when exposed in a laboratory to the synovial fluid of a patient with knee osteoarthritis, increased its metabolic activity. They started healing. If you would like to explore more information, send in your question or ask us about your candidacy for treatment.

One study suggests: glucocorticoid injections slightly protected people from knee replacement compared to hyaluronic acid injections

A February 2022 report (23) sought to determine whether intraarticular glucocorticoid injections are associated with increased knee osteoarthritis  progression compared to hyaluronic acid  injections. The study noted that hyaluronic acid  injections have been reported to delay osteoarthritis progression and knee replacement.

      • This paper studied 791 participants (980 knees) with knee osteoarthritis, of whom 629 reported glucocorticoid injections use and 162 hyaluronic acid injection use.
      • Hazard of total knee replacement was slightly lower for those receiving intraarticular glucocorticoid injections compared to those receiving hyaluronic acid
      • Conclusion: Intraarticular glucocorticoid injections are not associated with an increased risk of knee osteoarthritis progression compared to hyaluronic acid injection use.

One injection vs one injection vs one injection – the latest research

From November 2021, a team of researchers lead by the Medical Faculty, University of Belgrade compared one injection of Bone Marrow Aspirate Concentrate, one injection of PRP, and one injection of Hyaluronic acid in treating knee osteoarthritis. Here is the summary of their research findings: (18)

“In the last decade, regenerative therapies have become one of the leading disease modifying options for treatment of knee osteoarthritis. Still, there is a lack of trials with a direct comparison of different biological treatments. Our aim was to directly compare clinical outcomes of knee injections of Bone Marrow Aspirate Concentrate (BMAC), Platelet-rich Plasma (PRP), or Hyaluronic acid (HA) in the osteoarthritis treatment.”

Methods: Patients with knee pain and osteoarthritis stage 2, 3, or 4 were randomized to receive a Bone Marrow Aspirate Concentrate injection, a PRP injection, and a Hyaluronic acid injection in the knee.

Results:

      • 111 were treated with Bone Marrow Aspirate Concentrate injection,
      • 30 with Hyaluronic acid injection, and
      • 34 patients with PRP injection.

Conclusions: Bone marrow aspirate concentrate, Platelet Rich Plasma, and Hyaluronic acid injections are safe therapeutic options for knee osteoarthritis and provide positive clinical outcomes after 12 months in comparison with findings preceding the intervention. BMAC could be better in terms of clinical improvements in the treatment of knee osteoarthritis than PRP and Hyaluronic acid up to 12 months. PRP provides better outcomes than Hyaluronic acid during the observation period, but these results are not statistically significant.

One injection of bone marrow stem cells versus one injection of PRP

A January 2022 study (19) compared bone marrow derived stem cell therapy vs. PRP. I want to point out this is one shot vs one shot and the results were compared 12 months later. Typically we do not see patients achieve good results with a one-hot PRP treatment. In this study of one shot versus one shot, bone marrow aspirate concentrate significantly outperformed the PRP injection. This is something we would expect to see. The researchers of this study concluded: “Intra-articular autologous BMAC injections are safe, effective in treating pain, and ameliorate functionality in patients with symptomatic knee osteoarthritis to a greater extent than PRP injections. Intra-articular autologous BMAC therapy is safe and provides more relief to patients with symptomatic knee osteoarthritis compared to PRP therapy.”

More research on different types of stem cell therapy versus PRP Injections

A May 2022 paper (24) compared research outcomes for  platelet-rich plasma (PRP); bone marrow-derived mesenchymal stem cells; adipose-derived mesenchymal stem cells and amniotic-derived mesenchymal stem cells. This comparison complied eighty-two research studies. The researchers had difficulty making solid comparisons because of inconsistencies in preparation of the injection solutions. In general the studied treatments to more fair to good outcomes in most patients.

Research:  Long-term safety and efficacy of adipose-derived mesenchymal stem cell therapy

In a June 2022 study (25), researchers assessed the benefit of adipose-derived mesenchymal stem cell therapy in the treatment of mild to severe knee osteoarthritis. From the study: “A total of 329 study participants with painful knee osteoarthritis undertook stem cell therapy and were followed up for two years. Stem cell therapy was well tolerated and safe. Significant pain and functional improvement were observed in all of the participant groups including those with severe bone-on-bone osteoarthritis.”

A May 2022 paper (27) however, did not offer as convincing evidence for the effectiveness of adipose-derived mesenchymal stem cells for knee osteoarthritis. In examining 15 studies with a total of 463 patients researchers did notice a significant improvement in quality of life among the three dose subgroups (high, medium, and low doses), They also, after three months of follow-up, detected significant pain reduction as measured by the numeric pain rating scale (NPRS), with no significant difference between the low and medium doses. However, after a year, the results were no longer significant. Conclusion: In the present single-arm meta-analysis (retrospective study of smaller sample size), adipose-derived mesenchymal stem cells were associated with significant reductions in pain improvement in quality of life and knee functions in patients with knee osteoarthritis. However, double arm analyses (more specific analysis) did not confirm these positive findings, which may be returned to the small sample size of included patients. Therefore, to introduce ADMSCs into clinical practice and establish guidelines for their use, more randomized controlled clinical trials with large sample sizes and long-term follow-ups are needed.”

Do you have questions? Ask Dr. Darrow

Marc Darrow, MD. JD., discusses the treatment philosophy of the Darrow Stem Cell Institute. Transcript of video

A leading provider of stem cell therapy, platelet rich plasma and prolotherapy
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References:

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3 Altman R, Lim S, Steen RG, Dasa V. Hyaluronic Acid Injections Are Associated with Delay of Total Knee Replacement Surgery in Patients with Knee Osteoarthritis: Evidence from a Large U.S. Health Claims Database. PLoS One. 2015 Dec 22;10(12):e0145776. doi: 10.1371/journal.pone.0145776. eCollection 2015
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