Research and reviews of Hyaluronic injections for Knee Osteoarthritis

Ross A. Hauser, MD., Danielle R. Steilen-Matias, MMS, PA-C. 

Hyaluronic injections for Knee Osteoarthritis: Good or bad?

It should be noted that we see many patients who have tried hyaluronic acid injections. These injections have worked for these people in the short term. These patients are now in our office because the short-term has not transpired to the long-term and now a different treatment approach needs to be undertaken.

The idea behind hyaluronic acid injections is to protect the knee by reintroducing lost or diminished hyaluronic acid in the knee’s synovial fluid or “providing a cushion.” 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.

In our office we also find patients calling Viscosupplementation “rooster comb injections,” “rooster shots,” “chicken shots,” as well as by trade names Euflexxa ®, Supartz ® Supartz FX ®, Synvisc-One ®, Synvisc ®, Hyalgan ®, Orthovisc ®, et al. All these products offer subtle differences in their treatment goals including the number of injections – however, none of them offer a permanent solution. 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.” (1)

This should be enough for anyone considering Hyaluronic Acid Injections to seek alternatives. However many people do not understand that there are alternatives, especially if their doctor does not tell them there are.

Alternatives to Hyaluronic Acid Injections – Just get a knee replacement?

You are going to see in the research below that surgeons are writing that patients should not waste time and money with hyaluronic acid injections. The best alternative to these injections is knee replacement surgery. While we agree that there are better options than hyaluronic acid injections, we differ with the surgeons, we recommend a comprehensive regenerative medicine injection program which we will discuss below.

But I don’t want a knee replacement. Is Hyaluronic Acid Injections or knee replacement really my only two options?

Doctors in Germany, writing in the medical journal The Orthopedist, (2) give a good summary of the patient with knee pain heading into “conservative” treatments.

  • In an effort to delay major surgery, patients with knee instability and osteoarthritis are offered a variety of non-surgical 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.

The German doctors were uncertain if hyaluronic acid had any benefit. The doctors in the research below were more certain.

Two studies are in conflict over the benefits of Hyaluronic Acid Injections

One study suggests that Hyaluronic Acid is a waste of time, money, and resources.

  • The first study, led by the University of California Los Angeles (UCLA) agrees with the current beliefs that Hyaluronic Acid Injections are a treatment best used to help delay an inevitable total knee replacement. (3)
  • The second study suggests that Hyaluronic Acid Injections that delay inevitable knee replacement are 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 suggests 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. (4)

In the first study from UCLA 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
  • For patients who only had one course of Hyaluronic Acid Injections, the meantime 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.

A July 2018 study in the American Journal of Orthopedics (5) recognized that for some people: “Total knee replacement is a significant procedure with potential risk for serious complications and high costs. Alternative lower risk therapies that can delay or (prevent) total knee replacement are valuable to those who are poor candidates for surgery or wish to avoid total knee replacement as long as possible.” Are Hyaluronic Acid Injections the answer? Here is what the study concluded: “Repeated courses of treatment with Hyaluronic Acid are safe and are associated with the delay of total knee replacement for up to 3 years.” So again, we have a three-year delay after repeated courses of Hyaluronic Acid injections supported in the research. But what about the study that says “Hyaluronic Acid Injections that delay inevitable knee replacement are a waste of time, money, and resources.”

This research appearing in the publication American Health and Drug Benefits has this to say about Hyaluronic Acid Injections

  • “(the study) findings indicate that members without significant comorbid conditions who underwent knee or hip replacement procedures 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.

A May 2022 paper from the Department of Orthopaedic Surgery, Cleveland Clinic Foundation, published in The Journal of bone and joint surgery. American volume (35), questioned how doctors use hyaluronic acid in treating knee osteoarthritis patients. The authors write: “The utilization of hyaluronic acid for the management of knee osteoarthritis remains controversial, and more information is needed regarding how its utilization and financial burden have changed over recent years. The purpose of our analysis was to evaluate changes in overall utilization and health-care costs associated with hyaluronic acid injections among Medicare beneficiaries . . . ”

The authors assessed Medicare patient files from 2012 to 2018 . What they found was total hyaluronic acid utilization increased significantly during the years 2012 through 2018. Although orthopaedic surgeons themselves did not show significant changes in total utilization rates in the injections they were providing,  the average number of services per orthopaedic surgeon increased significantly. This according to the paper (reflected) “a substantial growth in the number of advanced practice providers providing injections, there was a significant increase in utilization and associated costs among physician assistants and nurse practitioners.

The authors concluded: “Despite the 2013 American Academy of Orthopaedic Surgeons clinical practice guideline recommending against the clinical utility of these injections, hyaluronic acid services continued to be widely implemented among Medicare beneficiaries.”

Research supporting the use of hyaluronic acid (Synvisc-One®)

A March 2022 study in the Journal of clinical orthopaedics and trauma (34) supported the use of hyaluronic acid (Synvisc-One®) use. They wrote: “The intra-articular injection with hyaluronic acid, corticosteroids and Platelet rich plasma are some of the popular modalities which are increasingly being employed as a stop-gap strategy before considering any surgical intervention for osteoarthritis management. Among these, the intra-articular hyaluronic acid has been widely studied with variable and conflicting results.”

In assessing conflicting results, the researchers of this study found in fifty patients recruited and followed for 52 weeks post injection of hyaluronic acid (Synvisc-One®) that short-term (up to one year) beneficial effects of intra-articular viscosupplementation with hyaluronic acid in early primary knee osteoarthritis 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.

Are Hyaluronic injections low-value health care? Using Medicare Data to Understand Low-Value Health Care: The Case of Intra-articular Hyaluronic Acid Injections.

In the Canadian Medical Association Journal(6) a study led by Austrian researchers found that “according to the currently available evidence, intra-articular hyaluronic acid has not been proven clinically effective and may be associated with a greater risk of adverse events.”

A research letter in the Journal of the American Medical Association Internal Medicine, (7) with the title: Are Hyaluronic injections low-value health care? Using Medicare Data to Understand Low-Value Health Care: The Case of Intra-articular Hyaluronic Acid Injections, 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.”

Side-Effects and Reactions

A recent study compiled 89 studies on hyaluronic acidThis 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. (8)

In this systematic review of 89 randomized medical trials that were 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 in the Annals of Internal Medicine.

A 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 injections patients saw more knee replacements than even cortisone injection patients

In February 2022 researchers at the University of Washington and the University of Chicago published a paper in the Journal of the American Academy of Orthopaedic Surgeons (33) where the effectiveness of corticosteroid and hyaluronic acid injections in the management of knee osteoarthritis was considered questionable.

These are the summary highlights of that paper:

  • Patients between 50 to 70 years old with a knee-related diagnosis of pain, effusion, or osteoarthritis were identified.
  • Patients who received intra-articular injections were grouped by the type and number of injection(s) received.
  • The subsequent rates of total knee replacement were compared between patients who underwent corticosteroid injections, hyaluronic injections, and a benchmarking cohort of patients with osteoarthritis and no history of knee injections in the medical record.

The 10-year conversion to total knee replacement was highest in the hyaluronic injections group (31.6%), followed by the corticosteroid cohort (24.0%) and the non-injection cohort (7.3%). If intra-articular knee injections are indicated for the nonsurgical management of knee osteoarthritis, the results of this study support cortisone over hyaluronic injections.

Then why is your doctor still recommending this treatment?

Let’s look at a well-cited editorial from 2016 published in the journal Clinical Orthopaedics and Related Research. (9) Here are the summary learning points presented by Seth S. Leopold, MD:

  • Surgeons who follow the evidence should relegate injectable viscosupplements (hyaluronic acid products) to the list of abandoned treatments.”
  • “Several comprehensive analyses agree that they either are minimally effective or ineffective. They probably are safe, though their use carries some risk. To the degree that they are not effective, it is hard to make a case for their value.”
  • “Well-done reviews and meta-analyses recommending against the use of this treatment have appeared in The New England Journal of Medicine and Annals of Internal Medicine; The Osteoarthritis Research Society International’s guidelines for the non-surgical management of knee osteoarthritis listed viscosupplementation among the treatments of “uncertain appropriateness.”
  • “The American Academy of Orthopaedic Surgeons released a clinical practice guideline in 2013 based on an analysis of the best available research, which concluded, “We cannot recommend using hyaluronic acid for patients with symptomatic osteoarthritis of the knee”

So why is this treatment being recommended?

According to Dr. Leopold:

  • “One reason might be that surgeons have relatively few effective nonsurgical alternatives that help patients with their joint pain, and—being members of a helping profession—we find this frustrating. However, our lack of effective nonsurgical treatments cannot justify the use of an ineffective one, and it must not be used to justify surgery unless surgery is indicated.”
  • Another reason that viscosupplementation remains in common use is a common perception that it works. There may be many explanations for this perception, but it seems most likely to be the result of transfer bias—the satisfied patients return, and the dissatisfied ones move on to get further care elsewhere, leaving the surgeon feeling more effective than (s)he should.”

Does adding more synovial type fluid in a knee swollen with synovial fluid really help?

A paradox of knee injection treatment may be found in the idea that if you have pain is caused by fluid retention and water build up in your knee, injecting more of the same type of fluid can help reduce this pain. This is the paradox of viscosupplementation. Many people find great relief from their knee pain when they have their knees drained and the fluid removed. Here more fluid is being added. This is why there is a debate over the long-term effectiveness of hyaluronic acid injections for knee osteoarthritis.

A January 2021 study in the medical journal Rheumatology (10) explains it. What the researchers in this study set out to do was to determine whether ultrasound-detected synovitis affects the therapeutic efficacy of hyaluronic acid injection for treating knee osteoarthritis.

  • The 137 patients in this study received hyaluronic acid injection two times at 2-week intervals.
  • Initially, all the patients were helped. However, the patients who had ultrasound detected suprapatellar effusion (knee swelling) had greatly reduced benefits from the injections.

Hyaluronic Acid Injections cause accelerated knee degeneration. Injections may be rushing you towards knee replacement.

In a study published in the journal Clinical Neurology and Neurosurgery, (11) doctors revealed that “Hyaluronic Acid Injections can provide significant pain relief and improvement in activity of daily living function for patients with knee osteoarthritis. However, the reduction in pain and the increase in knee adduction moment may last up to 6 months. This may cause excessive loading on the knee joints, which may further accelerate the rate of knee degeneration. As a result, longer study time is needed to determine whether the observed kinetic findings in this study are associated with detrimental outcomes on the knee joints.”

But I don’t want a knee replacement

Throughout our website, we offer realistic options to not only knee surgery but other treatments that you may have already tried and found less than effective. These treatments are considered regenerative medicine treatments and involve Prolotherapy, Platelet Rich Plasma, and sometimes stem cell therapy or bone marrow aspirate concentrate treatment.

Now while you are here exploring Hyaluronic Acid Injections we are going to briefly summarize these treatments and link you over to more detailed articles covering the research on these treatments.

Researchers ask: “Is Intra-Articular Injection of Synvisc Associated with a Delay to Knee Arthroplasty in Patients with Knee Osteoarthritis?”

As demonstrated in this article, there is a debate over the effectiveness of hyaluronic acid injections. An October 2019 paper published in the medical journal Cartilage (12) had researchers asking do hyaluronic acid injections or Synvisc delay knee replacement? If the patient received more hyaluronic acid injections did this further delay the need for knee replacement? What did they find? They could not tell. This they could tell:

  • 141,305 patients in this study had a knee replacement.
  • From the time the patient was diagnosed with advanced osteoarthritis until they actually had a knee replacement was 1.2 years.
  • The patients who were given hyaluronic acid injections had significantly longer delay, by seven months before they had a knee replacement.
  • Synvisc patients did better by almost two months longer delay than hyaluronic acid injections.
  • Conclusions:
    • Most knee arthritis patients did not get hyaluronic acid injections (73.7%) the reasons may be the same as those outlined above, some doctors do not think they are worth it.
    • Patients who did receive hyaluronic acid injections were associated with delays to knee replacement.

Then what could they not tell? Seems straightforward enough, there was a delay to knee replacement. The researchers wrote that the delay “cause and effect could not be examined.” It is not clear if the delay was because of the hyaluronic acid injections although the more injections the longer the delay.

So again, were people continuing with the injections because they delayed the knee replacement, or did the injections just prolong the delay for something the patients should have had in the first place, as outlined in the research above.

Non-steroid anti-inflammatory drugs (NSAIDs) vs intra-articular hyaluronic acid injection vs extracorporeal shockwave therapy (ESWT)

A January 2022 study in the journal Biomedicine (32) compared the effectiveness of oral NSAIDs, hyaluronic acid injection, and extracorporeal shockwave therapy for early osteoarthritis of the knee. Forty-five patients with early knee osteoarthritis were randomized into three groups.

  • NSAIDs group received celecoxib 200 mg daily for 3 weeks.
  • The hyaluronic acid injection group received intra-articular injection of hyaluronic acid injection once a week for 3 weeks.
  • ESWT group received ESWT for 3 sessions at the bi-weekly intervals.

All patients were followed up for one year. All three groups showed significant improvement in pain and functional scores.

  • ESWT group had better pain relief than NSAIDs and hyaluronic acid injection groups.
  • ESWT group had better therapeutic effects in the functional scores than NSAIDs and hyaluronic acid injection groups.
  • The results demonstrated that ESWT was an effective and alternative therapy than hyaluronic acid injection and NSAIDs for early osteoarthritis of the knees.

Comparing injection treatments

Prolotherapy Knee Injection Sites

In this next section, we will discuss some options for hyaluronic acid injections. We have a detailed article that offers more knee injection comparisons among various treatments including:

  • Cortisone injections
  • Hyaluronic acid injections or Viscosupplementation
  • Platelet Rich Plasma Therapy
  • Stem Cell Therapy
  • Amniotic, Cord Blood, and Placenta Tissue injections
  • Prolotherapy
  • Botox® injections into the knee
  • Ozone therapy

That article can be found here on our website: What are the different types of knee injections for bone on bone knees.

Study: A comparison between Prolotherapy, Botox, Physical Therapy and Hyaluronic Acid Injections

Here we have a September 2020 study published in the International Journal of Rehabilitation Research. (13) In it, researchers compared the effectiveness of four treatments in the management of knee osteoarthritis.

  • In total, 120 patients with knee osteoarthritis, all over the age of 50 years of age were randomly allocated to four groups.
  • The test results were based on pain and functional scoring systems.
  • Exercise recommendations were prescribed daily for all participants throughout the study.
    • For physical therapy (group 1), participants received superficial heat, transcutaneous electrical nerve stimulation, and pulsed ultrasound.
    • Botox: Researchers administered a single intra-articular injection of botulinum neurotoxin type A (group 2)
    • Hyaluronic acid: Researchers administered three injections of hyaluronic acid (group 3)
    • Prolotherapy: Researchers administered 20% dextrose (group 4) to patients in the corresponding groups.


  • There was a statistically significant difference (effectiveness) between the groups in pain and function.
  • Pairwise between- and within-group comparisons showed that botulinum neurotoxin and dextrose prolotherapy were the most effective, and hyaluronic acid was the least efficient treatment for controlling pain and recovering function in patients.
  • Intra-articular injection of botulinum toxin type A or dextrose prolotherapy is an effective first-line treatment. In the next place stands physical therapy particularly if the patient is not willing to continue regular exercise programs. Our study was not very supportive of intra-articular injection of hyaluronic acid as an effective treatment of knee osteoarthritis.

A January 2021 study in the journal Arthroscopy (14) also compared the effectiveness and safety of PRP and hyaluronic acid. In this research 2430 knee osteoarthritis, the patient’s results were documented. What these researchers found was that in 26 previously published studies, the cumulative results in 2430 patients revealed that pain and function scores in patients receiving PRP group were superior to those of the hyaluronic acid group when compared at three, six, and twelve months.

Prolotherapy for knee osteoarthritis

In our article The evidence for Prolotherapy Injections for knee osteoarthritis and as an option to knee surgery, we describe Prolotherapy as a remarkable treatment in its simplicity. Simple in the fact that these are dextrose (simple sugar) injections. The treatment can help many patients avoid joint replacement.

In this video, Danielle R. Steilen-Matias, MMS, PA-C, of Caring Medical demonstrates how we treat a patient with a primary complaint of knee osteoarthritis.

  • The person in this video is being treated for knee osteoarthritis as the primary complaint. The treatment takes a few minutes. The person in this video is not sedated and tolerates the treatment very well. For some patients, we do provide IV or oral medications to lessen treatment anxiety and pain.
  • The first injection is given to the knee joint. The Prolotherapy solution is given here to stimulate repair of the knee cartilage, meniscal tissue, and the ACL as well.
  • The injections continue over the medial joint line making sure that all the tendons and ligaments such as the medial collateral ligament are treated.
  • This patient-reported the greatest amount of pain along the medial joint line. This is why a greater concentration of injections is given here.
  • The injections continue on the lateral side of the knee, treating the lateral joint line all the tendon and ligament attachments there such as the LCL or lateral collateral ligament.

Prolotherapy has been shown to be an effective and safe treatment for many patients. On our Prolotherapy research page, we present the studies.

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.

Caring Medical doctors investigated Prolotherapy in patients with unresolved knee pain at a charity clinic in rural Illinois. Eighty patients, representing a total of 119 knees, were treated every three months with Prolotherapy. On average, 15 months following their last Prolotherapy session, patients were contacted and asked numerous questions in regard to their levels of pain and a variety of physical and psychological symptoms, as well as activities of daily living, before and after their last Prolotherapy treatment. The results of this study showed that patients had:

  • A statistically significant decline in their level of pain, stiffness, crunching sensation, and improvement in their range of motion with Prolotherapy.
  • More than 82% showed improvements in walking ability, medication usage, athletic ability, anxiety, depression, and overall disability with Prolotherapy.
  • Ninety-six percent of patients felt Prolotherapy improved their life overall. (15)

Platelet Rich Plasma injections comparison

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 in many studies documented below.

In our article Platelet Rich Plasma for Knee Osteoarthritis: When it works, when it does not, we point to more research on when the treatment can be successful and when the treatment may not help you.

Research comparing PRP injections, cortisone injections, and hyaluronic acid injections 

Doctors wrote in a January 2019 study (16) that PRP injections, cortisone injections, and hyaluronic acid injections are considered equally effective at relieving patient symptoms at three months, at 6, 9, and 12 months the PRP injections delivered significantly better results.

A July 2020 study (17) published in the Journal of Pain Research also suggested that PRP injections provided better results for patients than hyaluronic acid injections. The study’s conclusions were: Besides significantly higher satisfaction belonging to the (PRP) group, there was a statistically significant improvement in pain and function scores at 12 months compared to hyaluronic acid injections.

In research published in the Medical Science Monitor: International Medical Journal of Experimental and Clinical Research, PRP was shown to provide significant healing of the meniscus (18as well as out out-perform hyaluronic acid in patients with knee joint cartilage degeneration. Similar results were documented in the journal Archives of Physical Medicine and Rehabilitation. (19)

In the medical journal Arthroscopy, researchers noted: “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.”(20)

Here is a summary of further research findings:

  • Dutch doctors writing in the British Journal of Sports Medicine wrote: Platelet Rich Plasma injections for knee osteoarthritis were more effective at reducing pain and increasing range of movement than hyaluronic acid injections. (21)
  • In the medical journal Clinical Medicine Insights, doctors wrote: 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. (22)
  • Research in the journal Knee Surgery, Sports Traumatology, Arthroscopy documented that in the 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. (23)
  • In the Journal of Arthroplasty, Dutch researchers found no clinical outcome significance in comparing Hyaluronic Acid and Placebo. (24)
  • Doctors in Italy wrote in the European Journal of Orthopaedic Surgery & Traumatology that combining platelet-rich plasma and hyaluronic acid has the same efficacy of platelet-rich plasma only, administered in higher volume. (25)
  • Doctors at the University of California at Davis report that PRP contributes to articular cartilage lubrication. (26)
  • Doctors writing in the World Journal of Orthopedics found “hyaluronic acid injections might have efficacy and might provide pain reduction in mild osteoarthritis of the knee up to 24 weeks. But for hyaluronic acid injections, 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. “(27)

Combining PRP and hyaluronic acid

A team of Italian researchers examined the role of a combined hyaluronic acid and PRP treatment in a March 2021 published study. (28)

In this study, clinical outcomes of patients suffering from mild or moderate knee osteoarthritis (stage II and stage III) were treated with Leukocyte (immune white blood cells) – and platelet-rich plasma or PRP + hyaluronic acid intra-articular injections. Outcomes were observed 3 months and 1 year after the injective treatment.

A significant improvement of pain score was present in both groups, the Leukocyte PRP group, and the PRP + hyaluronic acid. Pain reduction was effective after 3 months and improved after 1 year. The group treated with PRP + hyaluronic acid showed a significant improvement in knee mobility and function scores. In both groups, however, the improvement in Knee injury and Osteoarthritis Outcome Score (KOOS), a self-reported measure of functional ability and knee-related quality of life, did not reach significance.

What does this mean? The researchers concluded: “In our point of view, we encourage the use of PRP injections as a simple, safe, and minimally invasive treatment approach. Our comparison of PRP + hyaluronic acid and Leukocyte-PRP suggests that PRP + hyaluronic acid could possibly determine better functional and mobility outcomes. However, our work could not be sufficient to definitively suggest a therapeutic choice: Further evidence is needed.”

What is Leukocyte- and platelet-rich plasma (L-PRP) treatment? What is its connection to hyaluronic acid?

The researchers of this study cited previous papers where outcomes demonstrated that L-PRP stimulates chondrocytic secretion (the cells that make collagen and secrete a “binding” fluid to help them adhere to lesions. Within this fluid is naturally produced hyaluronic acid.) The challenge with Leukocyte- and platelet-rich plasma is that as an immune system cell the Leukocyte can provide benefit in being an anti-inflammatory and bring down inflammation BUT it comes at a price, if the Leukocytes bring down inflammation it may counteract the benefit of the pro-inflammatory response Platelet Rich Plasma. Some suggested that PRP could reduce inflammatory cytokine production. Therefore according to these researchers: “The absence of a strong stimulating effect for the production of hyaluronic acid and the benefits of a viscosupplementation effect led to the idea of combining PRP + hyaluronic acid.”

A December 2020 study in the medical journal Arthroscopy (29) compared using hyaluronic acid injections with combined PRP treatment versus using hyaluronic acid injections alone.

The researchers of this study compared four previous studies, (total of 377 patients – 193 patients received PRP and hyaluronic acid injections, 184 patients received hyaluronic acid injections alone.)

  • People with grade I to grade IV knee osteoarthritis were included.
  • Symptomatic patients with knee osteoarthritis who were injected with a combination of PRP and HA demonstrated greater improvement in pain and function compared with patients who received hyaluronic acid injections only, as assessed by 3-, 6-, and 12-month pain and physical function scores.

This was not the first study to suggest combining the two treatments, and while some people do have success with this treatment, it is still seen only as a means to delay an inevitable knee replacement. This was suggested by researchers in a July 2016 study: (30)

“Our study is strongly suggestive that the combination of hyaluronic acid and PRP to be more effective compared to hyaluronic acid alone. Hence, we suggest a combination of intra-articular hyaluronic acid and PRP injection as an optional treatment modality in the treatment of grade III and IV knee osteoarthritis in terms of functional outcome and pain control for up to 6 months of duration when surgical treatment is not an option.”

Combination therapy with PRP combined with hyaluronic acid improves Patient-Reported Outcomes and is superior to hyaluronic acid alone but is not superior to PRP alone

An April 2021 review study comes to us from the Department of Physical Medicine and Rehabilitation, Sports Medicine Research Institute, The Ohio State University. It was published in The American Journal of Sports Medicine. (31) In this study, the researchers examined the effectiveness of the combined hyaluronic acid and PRP injection. Here are the learning summary points:

  • “Platelet-rich plasma and hyaluronic acid are injectable treatments for knee osteoarthritis. The focus of previous studies has compared their efficacy against each other as monotherapy. However, a new trend of combining these 2 injections has emerged in an attempt to have a synergistic effect.
  • A systematic review was performed a total of 431 articles were screened, 12 (of the papers were) reviewed in full, and 8 included (of the papers were) in the final analysis: 2 case series, 3 comparatives, and 3 randomized studies.
    • What the researchers did was to assess the best possible comparative understanding of the PRP alone, hyaluronic acid alone, and PRP and hyaluronic acid combined treatments.
    • The people in their review studies were assessed nine months after treatment
  • The researchers found combination therapy resulted in improved patient-reported outcomes. However, the combination therapy was no better than the PRP alone. The researchers wrote: Combination therapy with PRP combined with hyaluronic acid improves Patient-Reported Outcomes and is superior to hyaluronic acid alone but is not superior to PRP alone.”

In this October 2023 study (36) published in the journal Cureus researchers also compared outcomes in combining hyaluronic acid and PRP therapy versus using PRP therapy alone in treating knee osteoarthritis patients. They write: “Based on the most up-to-date evidence, the dual approach of PRP and hyaluronic acid therapy yields outcomes similar to PRP therapy alone in the short term, up to 12 months.” They also suggested that “when considering longer-term results, particularly in the 24-month follow-up, dual therapy holds the potential to produce superior outcomes compared to PRP alone therapy.”

We do not combine these two treatments at our center. The treatments we do combine as mentioned above are PRP and Prolotherapy treatments. PRP to address the more advanced conditions in the knee, Prolotherapy to address knee instability and weakness due to knee ligament weakness and laxity.


Summary and contact us. Can we help you?

We hope you found this article informative and it helped answer many of the questions you may have surrounding your knee problems and knee instability.  If you would like to get more information specific to your challenges please email us: Get help and information from our Caring Medical staff

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This article was updated June 6, 2022




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