Knee Osteoarthritis | Research on cortisone, hyaluronic acid, stem cell therapy, PRP, and Prolotherapy

  • New research suggests Hyaluronic Acid Injections may cause accelerated knee degeneration.
  • Research makes direct comparisons of Hyaluronic Acid Injections to alternatives which include stem cell therapy, PRP or Platelet Rich Plasma Therapy, and Prolotherapy.

In an effort to delay major surgery, patients with knee instability and osteoarthritis are offered a variety of nonsurgical options such as weight loss, exercise, physiotherapy, bracing, orthoses, nonsteroidal anti-inflammatory drugs (NSAIDs) and intra-articular viscosupplementation or corticosteroid injection.

In general, the goals of these therapeutic options are to decrease pain and improve function. Some of these treatments  may also have a disease-modifying effect by altering the mechanical environment of the knee. In the case of hyaluronic acid the therapeutic effects and procedure remain uncertain.1

As we will see below hyaluronic acid injections are a treatment to delay knee replacement, they do not prevent it. This is why doctors and patients are seeking other options.

The idea behind hyaluronic acid injections is to protect the knee by reintroducing lost or diminished hyaluronic acid in the knee’s synovial fluid. The synovial fluid is a thick gel-like liquid that helps cushion the knee and acts to absorb the daily impact of walking and running and stair climbing our knees are subjected to.

The treatment of Hyaluronic Acid Injections is also called Viscosupplementation – supplementing the “viscosity” or the thick, sticky, gel like properties of the synovial fluid.

This is what the American Academy of Orthopaedic Surgeons posted on their website:

“The theory is that adding hyaluronic acid to the arthritic joint will facilitate movement and reduce pain.

The most recent research, however, has not found viscosupplementation to be effective at significantly reducing pain or improving function.

Although some patients report pain relief with the procedure, some people are not helped by the injections.”

Two studies are in conflict over Hyaluronic Acid Injections and total Knee Replacement.

  • The first study agrees with the current beliefs that Hyaluronic Acid Injections are to delay total knee replacement.
  • The second study suggests that Hyaluronic Acid Injections that delay inevitable knee replacement is a waste of time, money, and resources. Some patients should proceed directly to the knee replacement. 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.

In the first study on the benefits of delaying surgery with Hyaluronic Acid Injections doctors found:

  • Patients who did not receive Hyaluronic Acid Injections went on to knee replacement  by 114 days post-diagnosis of knee osteoarthritis
  • Patients who only had  one course of Hyaluronic Acid Injections, the mean time to Knee Replacement was 1.4 years – a delay of about 1 year
  • Patients who received more than 5 courses of Hyaluronic Acid Injections courses delayed Knee Replacement by 3.6 years.2

Now from the second study: What is the point of delaying?

Given the dramatic increase in total knee and hip replacement procedures among the US population aged 45 years and older, there is a need to compare the downstream healthcare utilization and costs between patients who undergo joint replacement and those who receive injections as a low-cost alternative.

Medicare members over the age of 45 who were diagnosed with osteoarthritis were identified for this study. Data were compared for patients who underwent primary knee or hip replacement surgery between July 1, 2007, and June 30, 2012, and those receiving injection of pain-relief medication during the same period.

  • The overall results showed a greater decrease in healthcare utilization and costs for the members with joint replacement than for those receiving steroid or viscosupplementation injection.

“Our findings indicate that members without significant comorbid conditions who underwent knee or hip replacement procedure had a greater decrease in osteoarthritis-related healthcare resource utilization and costs after they recovered from surgery, compared with presurgery, and compared with the members who received Hyaluronic Acid Injections and cortisone.

These results are consistent with the American Academy of Orthopaedic Surgeons’ recent  change in evidence-based guidelines for viscosupplementation for symptomatic osteoarthritis pain of the knee, from “inconclusive” to “recommend against.”

A review of 14 studies that assessed outcomes of Hyaluronic Acid Injections demonstrated that the overall effect was not clinically meaningful.3

Hyaluronic Acid Injections

So the, research is ongoing in an attempt to find a definitive answer as to the true role of hyaluronic acid in osteoarthritis and meniscal injuries.

  • There are some who think Hyaluronic Acid Injections are a fantastic treatment because there are studies documenting short-term relief offered by these injections.4-5 
  • However other studies are stacking up against hyaluronic acid injection treatment, documenting a lack of clinical effectiveness, as well as a greater risk of adverse events with its use.6 
  • In agreement with the above research, other studies are showing that hyaluronic acid injections are just the option for knee pain for many patients. One study states plainly “hyaluronic acid injections might have efficacy and might provide pain reduction in mild osteoarthritis of knee up to 24 weeks. But for hyaluronic acid injections, the cost-effectiveness is an important concern that patients must be informed about the efficacy of these preparations. Although more high-quality evidence is needed, recent studies indicate that  platelet rich plasma injections are promising for relieving pain, improving knee function and quality of life, especially in younger patients, and in mild osteoarthritis cases. “7

It is generally agreed Synvisc is used to postpone what is thought of as the inevitable…knee replacement surgery.

Comparing Platelet Rich Plasma, Prolotherapy injections and hyaluronic acid injections

Comprehensive Prolotherapy utilizes various ingredients in the injections to induce inflammation in the joint in order to mimic an injury and bring rebuilding immune cells and healing factors to the area to repair and rebuild the injured and degenerated soft tissue of the knee.

The improvements with Prolotherapy met the expectations of the patients in over 96% of the knees to the point where surgery was not needed. Prolotherapy improved knee pain and function regardless of the type or location of the meniscal tear or degeneration.”8

  • In other research PRP was shown to provide significant healing of the meniscus 9 as well as out out-perform hyaluronic acid in patients with knee joint cartilage degeneration.10

Platelet Rich Plasma Therapy is a “blood injection” taken from the patient’s own blood and “reduced” down to plasma that is heavy with platelets. Blood plasma platelets hold and encourage many healing growth factors that stimulate healing in degenerated tissues. PRP has also been shown to be superior to hyaluronic acid injections.

Plasma rich in growth factors showed superior short-term results when compared with hyaluronic acid in a randomized controlled trial, in alleviating symptoms of mild to moderate osteoarthritis of the knee.”11

Here is a summary of further research findings:

  • PRP injection is more effective  than hyaluronic acid injections in reducing symptoms and improving quality of life and is a therapeutic option in select patients with knee osteoarthritis who have not responded to conventional treatment.13
  • In short-term patient outcomes of one year or less PRP injection improved functional outcomes when compared to hyaluronic acid and placebo, reducing symptoms and improving function and quality of life. This research suggests that PRP has the potential to be the treatment of choice in patients with mild-to-moderate Osteoarthritis of the knee who have not responded to conventional treatment.14
  • Researchers found no clinical outcome significance in comparing Hyaluronic Acid and Placebo.15
  • Doctors report that combining platelet-rich plasma and hyaluronic acid has the same efficacy of platelet-rich plasma only, administered in higher volume.16
  • Doctors at the University of California at Davis report that PRP contributes to articular cartilage lubrication. PRP provides lubrication.22


Hyaluronic Acid Injections MAY CAUSE accelerated knee degeneration

Doctors revealed that while Hyaluronic Acid Injections injections can provide significant pain relief and improvement in activity of daily living function for patients with knee osteoarthritis, the reduction in pain WITHOUT SUPPORTIVE REPAIR can increase in knee adduction movement and cause excessive loading on the knee joints, which may further accelerate the rate of knee degeneration.17

Are Hyaluronic injections low-value health care?

Using Medicare Data to Understand Low-Value Health Care: The Case of Intra-articular Hyaluronic Acid Injections.

This research letter (the title above) backed that up with “based on high-quality evidence that hyaluronic acid injections were not associated with clinically meaningful improvement in symptoms compared with placebo injections.”18

A more recent study compiled close to 90 studies on hyaluronic acid.16 This study found that hyaluronic acid supplementation to the knee produced minimal to non-existent results when it came to pain and function in knee osteoarthritis patients.

Side-Effects and Reactions

In a systematic review of 89 randomized medical trials that was summarized in the medical publication Medscape, doctors compared hyaluronic acid injections to a sham or to non-intervention patients. There were a total of 12,667 patients where the primary measure was pain intensity and the secondary measure was physical functioning.

“Viscosupplementation, the intra-articular injection of hyaluronic acid, produced “minimal or nonexistent” effects on pain and function in patients with knee osteoarthritis but did increase the risks for serious adverse events and local adverse reactions, according to a systematic review and meta-analysis published online June 12, 2012 in the Annals of Internal Medicine.

Flare-up in the injected knee within 24 to 72 hours of injection was the primary safety outcome. Secondary safety outcomes were serious adverse events, withdrawals or dropouts because of adverse events, adverse events overall, effusions at the injected knee, any local adverse event in the injected knee, and dropouts and withdrawals overall (regardless of reason).”

That means thousands of patients in numerous studies received minimal results in pain relief and non-existent results in function.

Hyaluronic Acid Injections Alternatives

Again we read that there are many options with unproven long-term effectiveness, but with an ability to delay the surgery. At least we agree that delaying surgery is a good goal. Preventing it is even better.

In research published in the Journal of Prolotherapy, doctors identified many of the problems with the above listed stopgap treatments and why we do not employ their use in our practice.

“although steroid injections and nonsteroidal anti-inflammatory drugs (NSAIDs) have been shown to be effective in decreasing inflammation and pain of ligament injuries for up to six to eight weeks, the properties of ligament healing are inhibited. For this reason, their use is cautioned in athletes (and patients) who have ligament injuries. As such, NSAIDs are no longer recommended for chronic soft tissue (ligament) injuries, and for acute ligament injuries should be used for the shortest period of time, if used at all. Regenerative medicine techniques, such as Prolotherapy, have been shown in case series and clinical studies, to resolve ligament injuries of the spine and peripheral joints.”19 In “Ligament Injury and Healing: A Review of Current Clinical Diagnostics and Therapeutics” research supports the view that the long-term consequence of non-healed ligament injury is osteoarthritis.20

So is it any wonder why the treatments mentioned above including hyaluronic acid do not last? The situation of osteoarthritis can only be remedied when the problem of ligament laxity is addressed. None of those above treatments address this problem. Comprehensive Prolotherapy does.

In a remarkable piece of research, doctors found that if you want to increase your hyaluronic acid in knees naturally – stem cells maybe the answer.

When the researchers introduced bone marrow derived stem cells into knees, the stem cells started “talking” to the cartilage cells – when the hyaluronan (Hyaluronic Acid) heard this “cross-talk” they started the production of molecules – this is the phenomena of “signalling.”21

In other words the stem cells started the repair by alerting the cartilage cells that “we need more cartilage,” the hyaluronan heard it and said, “if they are making more cartilage, we need more Hyaluronic Acid”. A curative environment is being rallied.


References for this article

1. Diehl P, Gerdesmeyer L, Schauwecker J, Kreuz PC, Gollwitzer H, Tischer T. Conservative therapy of osteoarthritis. Orthopade. 2013 Feb 1. [Epub ahead of print]
2. 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.
3. Pasquale MK, Louder AM, Cheung RY, Reiners AT, Mardekian J, Sanchez RJ, Goli V. Healthcare Utilization and Costs of Knee or Hip Replacements versus Pain-Relief Injections. Am Health Drug Benefits. 2015 Oct;8(7):384-94.
4.Hashemi SM, et al. Intra-aticular hyaluronic acid injections vs. dextrose prolotherapy in the treatment of osteoarthritic knee pain. TUMJ. May 2012; 70(2): 119-125.
5.Gadek A, Miśkowiec K, Wordliczek J, Liszka H. Effectiveness and safety of intra-articular use of hyaluronic acid (Suplasyn) in the treatment of knee osteoarthritis. Przegl Lek. 2011;68(6):307-10.
6. Arrich J, Piribauer F, Mad P, Schmid D, Klaushofer K, Müllner M. Intra-articular hyaluronic acid for the treatment of osteoarthritis of the knee: systematic review and meta-analysis. CMAJ. 2005 Apr 12;172(8):1039-43.
7. Ayhan E, Kesmezacar H, Akgun I. Intraarticular injections for knee osteoarthritis. World J Orthop. 2014 Jul 18;5(3):351-61. doi: 10.5312/wjo.v5.i3.351. eCollection 2014.
8. Hauser R, Phillips HJ, Maddela HS. The Case for utilizing prolotherapy as first-line treatment for meniscal pathology: a retrospective study shows prolotherapy is effective in the treatment of MRI-documented meniscal tears and degeneration. Journal of Prolotherapy. 2010;2(3):416-437.
9. Wei LC, Gao SG, Xu M, Jiang W, Tian J, Lei GH. A novel hypothesis: The application of platelet-rich plasma can promote the clinical healing of white-white meniscal tears. Med Sci Monit. 2012 Aug;18(8):HY47-50.
10. Chang KV, Hung CY, Aliwarga F, Wang TG, Han DS, Chen WS. Comparative Effectiveness of Platelet-Rich Plasma Injections for Treating Knee Joint Cartilage Degenerative Pathology: A Systematic Review and Meta-Analysis. Arch Phys Med Rehabil. 2013 Nov 27. pii: S0003-9993(13)01212-4. doi: 10.1016/j.apmr.2013.11.006.
11. Sánchez M, Fiz N, Azofra J, et al. 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. 2012 Aug;28(8):1070-8.
12. Laudy AB, Bakker EW, Rekers M, Moen MH. Br J Sports Med. 2014 Nov 21. pii: bjsports-2014-094036. doi: 10.1136/bjsports-2014-094036. [Epub ahead of print] Efficacy of platelet-rich plasma injections in osteoarthritis of the knee: a systematic review and meta-analysis.
13. Raeissadat SA, Rayegani SM, Hassanabadi H, Fathi M, Ghorbani E, Babaee M, Azma K. Knee Osteoarthritis Injection Choices: Platelet- Rich Plasma (PRP) Versus Hyaluronic Acid (A one-year randomized clinical trial). Clin Med Insights Arthritis Musculoskelet Disord. 2015 Jan 7;8:1-8. doi: 10.4137/CMAMD.S17894. eCollection 2015.
14. Kanchanatawan W et al. Short-term outcomes of platelet-rich plasma injection for treatment of osteoarthritis of the knee. Knee Surg Sports Traumatol Arthrosc. 2015 Sep 19. [Epub ahead of print]
15. van der Weegen W, Wullems JA, Bos E, Noten H, van Drumpt RA. No Difference Between Intra-Articular Injection of Hyaluronic Acid and Placebo for Mild to Moderate Knee Osteoarthritis: A Randomized, Controlled, Double-Blind Trial. J Arthroplasty. 2014 Dec 13. pii: S0883-5403(14)00943-7. doi: 10.1016/j.arth.2014.12.012. [Epub ahead of print]
16. 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) Eur J Orthop Surg Traumatol. 2015 Sep 24. [Epub ahead of print]
17. Tang AC, Tang SF, Hong WH, Chen HC. Kinetics features changes before and after intra-articular hyaluronic acid injections in patients with knee osteoarthritis. Clin Neurol Neurosurg. 2015 Feb;129 Suppl 1:S21-6. doi: 10.1016/S0303-8467(15)30007-X.
18. Schmajuk G, Bozic KJ, Yazdany J. Using Medicare Data to Understand Low-Value Health Care: The Case of Intra-articular Hyaluronic Acid Injections.JAMA Intern Med. 2014 Oct 1;174(10):1702-4. doi: 10.1001/jamainternmed.2014.3926.
19. Hauser RA. Ligament injury and healing: an overview of current clinical concepts. Journal of Prolotherapy. 2011;3(4):836-846.
20. Hauser RA., et al. Prolotherapy research: Ligament Injury and Healing: A Review of Current Clinical Diagnostics and Therapeutics. The Open Rehabilitation Journal, 2013, 6, 1-20.
21 Antonioli E, Piccinato CA, Nader HB, Cohen M, Goldberg AC, Ferretti M. Modulation of Hyaluronan Synthesis by the Interaction between Mesenchymal Stem Cells and Osteoarthritic Chondrocytes. Stem Cells International. 2015;2015:640218. doi:10.1155/2015/640218.
22. Sakata R, Reddi AH. Platelet-Rich Plasma Modulates Actions on Articular Cartilage Lubrication and Regeneration. Tissue Eng Part B Rev. 2016 Oct;22(5):408-419. Epub 2016 Jun 27.Tissue Eng Part B Rev. 2016 Oct;22(5):408-419. Epub 2016 Jun 27.

2 thoughts on “Knee Osteoarthritis | Research on cortisone, hyaluronic acid, stem cell therapy, PRP, and Prolotherapy

  1. I am interested in PRP on my hip flexor joint–will it work in this location?
    Also in the cervical spine area. I had prolotherapy in the cervical area in 2006, but was unable to continue, due to a move to another state.

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