MORE VIDEOS

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

If you are reading this article, there is a very strong chance that one of three things is happening to you.

• You are waiting for a knee replacement or arthroscopic knee surgery and the pain and malfunction of your knee are getting to be a bit much. Now you find yourself being offered more injections and treatments that did not help you in the past but are now being offered as treatments to hold you over until you can get the surgery.
• Or, you are already getting one type of injection treatment and that is not working so you are looking at other injections as options as you would like to avoid surgery.
• Or, you are getting cortisone injections and you are concerned with the long-term effects because you are now into multiple doses.

This article represents an accumulation of all the material presented on this website and summarized. Because the subject “injections for bone on bone knees” is broad, we invite you to research further at these pages, more specific to the type of treatment you are looking for:

For a more detailed discussion please see our articles:

• Alternatives to cortisone shots.
• Why stem cell therapy did not work for your knee pain
• Prolotherapy knee osteoarthritis research: An option to knee surgery
• Platelet Rich Plasma for Knee Osteoarthritis: When it works, when it does not

“What is the best injection for knee pain?”

Many times someone will reach out to us and ask the simple question: “What is the best injection for knee pain?” The answer is, “the one that works for you.”

In this article we will explore:

• Cortisone injections
  • Cortisone Knee Injections: In the past, your doctor may have recommended against the use of cortisone because it was clear to him or her that there was knee surgery in your future.
  • Cortisone is no longer considered the miracle cure for knee pain and should be used sparingly if at all.
  • You need to lose weight so the cortisone injection will work better.
  • RESEARCH: Corticosteroid knee injections provided no significant pain relief after two years. Researchers say: Do not give cortisone for knee osteoarthritis.
  • Although surgery and cortisone are common, randomized trials have failed to produce evidence for the effectiveness of surgery or cortisone injection or how much they do work.
  • Cortisone can make bone on bone worse by thinning out the meniscus. But one injection appears okay.
  • Cortisone injections before knee surgery lead to greater post-surgical infection risk.
  • The cortisone knee injection debate goes on.
  • Cortisone injections five years later, did they make knees worse? Not sure. Maybe no.
  • Electrical Stimulation Combined with Corticosteroid Injection.
• Hyaluronic acid injections or Viscosupplementation for Knee Osteoarthritis: What to expect when getting gel injections in the knee.
  • Over the years we have seen many patients who have been on the “gel shots.”
  • The debate over Hyaluronic Acid Injections and knee injections. One study suggests that Hyaluronic Acid is a waste of time, money, and resources another study says it works okay.
  • Do Hyaluronic Acid Injections Work for Knee Osteoarthritis?
  • “Repeated courses of treatment with Hyaluronic Acid are safe and are associated with the delay of total knee replacement for up to 3 years.”
  • Research: Multiple intra-articular hyaluronic acid injections can delay the need for total knee replacement for one and a half years.
  • Are Hyaluronic injections low-value health care? Using Medicare Data to Understand Low-Value Health Care: The Case of Intra-articular Hyaluronic Acid Injections.
  • One injection is just as good as a series of Hyaluronic Acid Injections.
  • You can delay knee replacement realistically for about 11 months with hyaluronic acid injections.
• Platelet Rich Plasma Therapy
  • Growth and healing factors in PRP. This is what makes PRP work.
  • PRP is not a single shot miracle cure. The effectiveness of PRP is in how many times the treatment is given.
  • Cortisone is a one-shot treatment, PRP should not be given the same way. This is when PRP does not work.
  • Research: The Platelet-Rich Plasma group showed the lowest radiographic (knee osteoarthritis) progression at 52 weeks of follow-up.
  • Is PRP controversial? Yes. Is it effective? Also yes.
  • “The efficacy of (PRP) intra-articular injections as a nonoperative modality for treating symptomatic knee osteoarthritis-related pain while maintaining function has become a subject of increasing interest.”
  • A brief understanding of the differences between PRP and PRGF.
  • When PRP doesn’t work, it is usually not the solution used during treatment, but how the treatment itself is given.
  • Simply put, PRP methods vary by practitioner. Research consistently points to PRP ineffectiveness as being caused by the way the treatment is given and poor patient selection.
  • “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.”
  • In two groups of patients, one group gets PRP and the other group gets cortisone. How did this comparison work out?
  • Study 2: Two groups of patients, one group gets PRP the other group gets cortisone. How did this comparison work out?
  • “Patients undergoing treatment for knee osteoarthritis with PRP can be expected to experience improved clinical outcomes when compared with hyaluronic acid.”
  • Ten patients underwent intra-articular PRP injection and 10 others received the hyaluronic acid injection.
  • Research comparing PRP injections, cortisone injections, and hyaluronic acid injections.
• Types of stem cell injections for knee osteoarthritis.
  • We estimate that 1 in 10 patients who we see in our clinic have already received some type of stem cell therapy in another office. They are in our clinic because the treatment they have received has failed to meet the patient’s expectations.
  • Bone Marrow Aspirate Concentrate or bone marrow concentrate type stem cell therapy.
  • Where do the bone marrow stem cells come from?
  • Mayo Clinic and Yale University studies on your own bone marrow stem cells.
  • “The current literature demonstrates the potential benefits of utilizing concentrated bone marrow aspirate for the repair of cartilaginous lesions, bony defects, and tendon injuries”
  • Successful, safe, and encouraging results of bone marrow-derived mesenchymal stem cells.
  • Caring Medical Research – one marrow-derived mesenchymal stem cell case study.
  • Lipoaspiration, Adipose-derived stem cells, Microfragmented Fat, or Lipogems type stem cell therapy.
  • Direct injection of fat stem cells.
  • Research comparing PRP, Bone Marrow, and Adipose-Derived Stem Cells.
  • One injection of bone marrow aspirate concentrate stem cells versus one injection of PRP.
  • Comparing Seven different knee osteoarthritis treatments.
  • Amniotic, Cord Blood, and Placenta Tissue injections
• Prolotherapy
  • How do Prolotherapy injections work for knee pain?
  • Research: Prolotherapy treatments for patients with knee osteoarthritis showed significant improvement in scores for pain, function, and range of motion.
  • Comparison research: hyaluronic acid and Prolotherapy injections.
  • Combining an injection of hyaluronic acid and dextrose (Prolotherapy).
  • Prolotherapy for knee osteoarthritis video.
• Botox® injections for knee pain.
  • Comparing Botox® to other knee injection treatments.
  • Study: A comparison between Prolotherapy, Botox, Physical Therapy, and Hyaluronic Acid Injections
• Acupuncture
• Dry Needling
• Comparison of Ozone Therapy, Cortisone, Hyaluronic Acid Injections, and Dextrose Prolotherapy injections.
• Another comparison of Ozone, PRP, and Hyaluronic Acid.

Every one of these injection treatments has success stories behind them. Every one of these treatments has less than successful stories behind them. For some people, these injections could not prevent knee replacement.

Cortisone Knee Injections: In the past, your doctor may have recommended against the use of cortisone because it was clear to him or her that there was knee surgery in your future.

The caption of this image reads” “articular cartilage deterioration as evidenced by fibrillation (fraying, splitting, and erosion of cartilage), fissures (cracks), and flaking. Cortisone is known to cause this condition.

In the past, your doctor may have recommended against the use of cortisone because it was clear to him or her that there was a knee surgery in your future. The concern is if you get cortisone injections into your knee prior to surgery, you will have a greater risk of complications after the surgery. There is a lot of debate around this subject. Some doctors say avoid the cortisone, other doctors are saying it is okay to get one shot to hold you over until you can get surgery or maybe the cortisone will reduce your inflammation enough after the first shot that you will have some degree of pain relief and comfort for a few months, a year, maybe longer.

We are going to start with cortisone because cortisone was the injection of choice. Much has changed.

Cortisone is no longer considered the miracle cure for knee pain and should be used sparingly if at all. Side effects such as increases in blood glucose levels a reduction in immune function, and an increased risk of infections

Cortisone causes joint damage. There is no longer the debate on that subject. The debate now is how to use cortisone injections if at all.

In a January 2021 paper from doctors at Northwestern University McGaw Medical Center, Rutgers School of Medicine, and Boston College, a current guideline was given for the use of cortisone: The paper appeared in the journal Pain Physician (1) and included the following observations.

• Corticosteroids provide moderate short-term benefits for reducing pain and improving joint function
• The beneficial effects generally last several weeks but do not have long-term effectiveness.
• In addition to its limited short-term effectiveness, there are multiple potential adverse effects including toxicity (or erosion) to articular cartilage and numerous systemic side effects such as increases in blood glucose levels, a reduction in immune function, and an increased risk of infections.

The one thing that has become the general consensus is: Cortisone is no longer considered the miracle cure for knee pain and should be used sparingly if at all.

You are sitting in the orthopedist’s office: The discussion turns to cortisone

If you have been to your orthopedist recently and are planning treatment options or surgical options you may have been given a paper handout or webpage to visit or verbal advice on what to expect if you are getting a cortisone injection into your knee.

You may have been told:

The cortisone injection is to help you now, it is not a permanent solution.

• It is to hold you over until a more effective plan can be introduced.

Physical therapy may be an option instead of the cortisone injection

• You may then be suggested to physical therapy or continued physical therapy. As we will see below, research suggests that physical therapy would work better than cortisone. But while that may be true for some, it is likely that you are at the cortisone or repeated cortisone injection stage because physical therapy has not worked for you. So you have been to physical therapy and it has not helped you. That is why you are getting the cortisone shot. In fact, you may have tried, yoga, stretching, exercise, and massage for knee pain, and these treatments just didn’t help.

You need to lose weight and exercise so the cortisone injection will work better

• You may also have been told to lose weight if weight is an issue. Many people believe that they cannot lose weight because of the physical limitations that their knee is causing them. They simply cannot exercise. We have a number of articles on weight loss and its beneficial effect on knee pain. You can explore them here:
  • Research: Knee replacement does not help many people lose weight
  • What is the best anti-inflammatory medicine? It may be weight loss: Obesity, inflammation, and joint pain
  • Your bad diet and weight is destroying your knees and will send you to a nursing home
• It should be noted that surgeons writing in The Journal of the American Academy of Orthopaedic Surgeons (2) published findings in which they suggested:
  • “Patients receiving intra-articular corticosteroid injections had improved pain and function. Clinicians should expect less improvement in patients with obesity and/or advanced arthritis. Clinical benefits of intra-articular injections in these patients are less predictable.” It then may have been suggested to you that your cortisone injection would perhaps work better if you lost weight as well. It should also be noted that the surgeons cast a wary eye on giving cortisone injections to overweight or obese patients and those with advanced osteoarthritis.

Corticosteroid knee injections provided no significant pain relief after two years. Researchers say: Do not give cortisone for knee osteoarthritis.

In 2017, doctors from Tufts Medical Center in Boston asked, “What are the effects of intra-articular injection of 40 mg of triamcinolone acetonide (a synthetic corticosteroid medication) every 3 months on the progression of cartilage loss and knee pain in patients with osteoarthritis?” Writing in the Journal of the American Medical Association, (JAMA) (3) they published their answer:

“Among patients with symptomatic knee osteoarthritis, 2 years of intra-articular triamcinolone, compared with intra-articular saline, resulted in significantly greater cartilage volume loss and no significant difference in knee pain. These findings do not support this treatment for patients with symptomatic knee osteoarthritis.“

Although surgery and cortisone are common, randomized trials have failed to produce evidence for the effectiveness of surgery or cortisone injection or how much they do work.

Moving forward on that research, a February 2020 review study with the title “Medical Reversals in Family Practice: A Review,” (4) published in the journal Current Therapeutic Research, Clinical and Experimental offered these points:

• “Despite inconsistent recommendations for more invasive treatments, hundreds of thousands in the United States are treated with corticosteroid injections and surgery. Although these practices are common, randomized trials have failed to produce evidence for their effectiveness.”
• Because corticosteroids have an anti-inflammatory effect and because osteoarthritis is an inflammatory condition, intra-articular corticosteroids have has been used for several decades, and as many as 95% of rheumatologists use them for osteoarthritis; however, in a randomized trial of patients with symptomatic knee osteoarthritis, in which 140 patients were treated with an injection of either triamcinolone or saline every 12 weeks for 2 years, there were no differences in pain between patients treated with triamcinolone or saline. Further, patients assigned to the triamcinolone treatment had a greater loss in cartilage thickness. (This is the study cited above).
• Many patients are likely better off with a less-is-more approach of low-impact physical activity and strength training exercises than cortisone or surgery.

Cortisone can make bone on bone worse by thinning out the meniscus. But one injection appears okay

One of the reasons that you are considering a knee replacement or are thinking about getting a cortisone injection is because you have been told you have a bone-on-bone knee. So the idea that cortisone may make this worse by thinning out your meniscus is concerning doctors.

In August of 2020 in the journal Scientific Reports (5) doctors expressed concerns about damaging the meniscus tissue with cortisone injections. It should be noted that this research’s main findings were that it was okay to get one cortisone injection. For many people, one injection would be considered safe. Here are the learning points of that research:

• Although intra-articular corticosteroid injections are commonly used for the treatment of knee osteoarthritis, there is controversy regarding possible side effects on the knee joint structure.
• In this study, the effects of intra-articular corticosteroid injections on worsening the knee structure and creating greater pain were examined.
• Findings: No significant effect of the intra-articular corticosteroid injections were found on the rate of cartilage loss nor on any other knee structural changes or patient-reported pain scores. In conclusion, a single intra-articular corticosteroid injection for the treatment of osteoarthritis-related knee pain was shown to be safe with no negative impact on structural changes, but there was a transient meniscal thickness reduction, a phenomenon for which the clinical relevance is at present unknown.

Cortisone injections before knee surgery lead to greater post-surgical infection risk.

In August 2021, research led by the Department of Orthopaedics, University of Colorado School of Medicine and published in the Orthopaedic Journal of Sports Medicine (6) suggested that “patients undergoing knee arthroscopy who receive an intra-articular corticosteroid injection during the perioperative period can be expected to experience significantly higher postoperative infection rates when compared with patients not receiving an injection. Furthermore, patients receiving a corticosteroid injection pre- or intraoperatively may experience significantly higher rates of postoperative infection when compared with patients receiving an injection postoperatively.”

The cortisone knee injection debate goes on

A December 2020 (7) study published in the medical journal Rheumatology gives this overview assessment of the debate surrounding the use of cortisone for a bone-on-bone knee. Here are the summary learning points:

• “Existing data indicate that intra-articular corticosteroids in knee osteoarthritis provide short-term pain relief and functional improvement which may last from one to several weeks.
• At present, synovitis (inflammation) is the most important predictor of treatment response, and also a target for anti-inflammatory treatment for intra-articular corticosteroids.”
  • Our explanatory note: If you have a lot of knee swelling, cortisone may be of benefit. Please see our article treating chronic knee swelling.

Returning to the research study:

• “(A) subgroup of patients with the inflammatory phenotype (simply people with pain and other characteristics attributed to knee swelling) with clinical features of pain, stiffness, joint swelling, and effusion are expected to be more responsive than other phenotypes (those people who do not have chronic knee swelling) who do not display clinical manifestations of inflammation.”
  • Our explanatory note: If you do not have chronic knee swelling, cortisone may not be an answer for you.

Returning to the research study: In some people swelling comes and goes, it is hard to suggest who cortisone would be successful for among these people.

• From the study: “Nonetheless, identification of responder from non-responder patients is challenging because the inflammatory presentation of knee osteoarthritis is temporal and is not present at all stages of the knee osteoarthritis process. At present, patients with significant disability or advanced knee osteoarthritis who are non-responsive to standard the­rapy are considered for treatment with intra-articular corticosteroids. The inefficiency of intra-articular corticosteroids in these patients is predictable because, in these subgroups, synovitis alone is not the cause of pain, but structural changes, mechanical and anatomical factors, and even extraarticular factors are also responsible, thus sup­pression of synovial inflammation by using intra-articular corticosteroids is likely to provide short-term pain relief or no therapeutic benefit.
  • Our explanatory note: Simply the study authors are saying when cortisone will likely not work.
  • Cortisone may not work in people whose inflammation comes and goes on its own because the inflammation is a response to a problem and not THE problem. THE problem is the knee joint degenerative condition. Cortisone cannot repair this type of damage.

Returning to the research study: The more suitable cortisone patient is:

• “In particular, patients who are expected to be respondent to intra-articular corticosteroids needs to be selected among the population of knee osteoarthritis patients who have synovial inflammation with minimal or moderate anatomical abnormalities.
• Suppression of inflammatory process at early stages of knee osteoarthritis in addition to pain relief and functional improvement may prevent progression of structural changes. Given the anti-inflammatory and chondroprotective properties of corticosteroids, the goals of future clinical trials should not be limited to short-term pain relief, but also prevention of osteoarthritis progression by identification of patients who not only have synovitis but they are also at higher risk of disease progression.”

We do not offer cortisone injections at our center. In approaching three decades of helping people with knee pain this is a treatment that we did not find beneficial. In 2009, our research team wrote in the Journal of Prolotherapy: “It is (our) opinion that there is no doubt that the rise of osteoarthritis, as well as the number of hip and knee replacements, is a direct result of the injection of corticosteroids into these joints.”(8)

The evidence then was a summary of the effects of cortisone on articular cartilage which included:

• a decrease in protein and matrix synthesis (the nutrient and healing bed that cells grow in),
• mutation of (cartilage) cell shape
• growth of new cartilage inhibited,
• cartilage destruction risk and enhancement
• cartilage surface deterioration including edema, pitting, shredding, ulceration and erosions, etc, etc.

Image-guided corticosteroid injections in the treatment of patients with knee and hip osteoarthritis

A December 2022 paper in the journal Skeletal radiology (9)  comes from a team of authors at Massachusetts General Hospital, Harvard Medical School, NYU Langone Health and Hospital Do Coracao, Sao Paulo, Brazil. In this paper the researchers reviewed previously published studies on the use of image-guided corticosteroid injections in the treatment of patients with knee and hip osteoarthritis. Among this papers reviews were that on 12 knee osteoarthritis outcome studies. The researchers observed cortisone “knee injections were found either to have little or no impact or were similar or inferior to comparison injections (intra-articular hyaluronic acid, PRP, NSAIDs, normal saline, adductor canal blocks). ” The researchers concluded that the research found overall negative outcomes for the knee (injections).

A December 2022 from the University of Bristol in the United Kingdom published in the journal Osteoarthritis and cartilage (10) investigated the effects of recurrent cortisone injections at three months and beyond in patients treated for knee osteoarthritis. Patients received between two and eight injections. They were also compared to patients receiving hyaluronic acid, platelet-rich plasma, or placebo. These are the findings:

• Recurrent recurrent cortisone injections demonstrated no benefits in pain or function over placebo at 12-24 months.
• Recurrent recurrent cortisone injections results were not as good for symptom relief compared with other injectables (including placebo) at 3 months and beyond. Other injectables (hyaluronic acid, platelet-rich plasma) often yielded greater improvements in pain and function up to 24 months post-injection.

Cortisone injections five years later, did they make knees worse? Not sure. Maybe no.

When it comes to corticosteroid injections numerous research studies, as documented here, will be in contradiction of each other. Let’s look at a March 2022 paper in the journal Arthritis & Rheumatology. (11) Here the researchers write:

• Recent findings found intra-articular corticosteroid injections to cause harmful effects on knees with osteoarthritis.
• This research sought to assess in a real-life setting the risk of knee osteoarthritis progression in patients who received intra-articular corticosteroid injections over a 5-year follow-up.

Among the 564 patients with knee osteoarthritis included in this study, 51 (9.0%) and 99 (17.5%) received intra-articular corticosteroids or intra-articular hyaluronan injections, respectively, and 414 (63.1%) did not receive any injection during follow-up.

• Compared with untreated knees, those treated with intra-articular corticosteroid injections had a similar risk of incident needing a total knee replacement or osteoarthritis worsening. Intra-articular hyaluronan injections had no effect on the risk of total knee replacement or osteoarthritis worsening.

Conclusions: In this study, intra-articular corticosteroid injections for symptomatic knee osteoarthritis did not significantly increase the 5-year risk of incident total knee replacement or cause radiographic worsening osteoarthritis on MRI. These findings should be interpreted cautiously and replicated in other cohorts.

In other words – the researchers suggest that they found no significant side effects but they remind others to interpret these findings cautiously.

Electrical Stimulation Combined with Corticosteroid Injection

Electrical Dry Needling is electric stimulation in needle form. A 2022 study (12) in the Archives of Physical Medicine and Rehabilitation added electric stimulation, in needle form, to a group of knee osteoarthritis patients’ treatment. In this study, sixty patients with knee osteoarthritis were divided into two groups, one with electrical dry needling plus corticosteroid injection group or corticosteroid injection alone.

The corticosteroid injection group received one glucocorticoid injection during the study and the electrical dry needling plus corticosteroid injection group received a glucocorticoid injection combined with four 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.” Over the years we have seen patients who initially did very well with some type of electric stimulation therapy. Unfortunately for many the results were not long-lasting and for this and other clinical observations we do not offer this treatment for knee pain.

---

Hyaluronic acid injections or Viscosupplementation for Knee Osteoarthritis: What to expect when getting gel injections in the knee

Much like cortisone, it is very likely that this knee injection treatment has been explained to you already by your orthopedist. It is a conservative care plan to help you try to manage along until you can get a knee surgery scheduled or you are trying to do everything you can to avoid the knee surgery.

Also like cortisone, you may have already had viscosupplementation and the effects and benefits have now worn off and you need to treat your knee differently. For some people, they may not even be reading this sentence because they have moved down the article to other treatments because this one is no longer an option for them.

What are Hyaluronic acid injections or Viscosupplementation?

The explanation that you may have been given is that hyaluronic acid injections will provide a gel-like cushion in your knee, getting between the shin and thigh bones to alleviate your bone-on-bone situation. The injections increase the volume of the protective synovial fluid in the knee.

• The treatment is therefore referred to as Viscosupplementation – because you are supplementing the “viscosity” or the thick, sticky, gel-like properties of the synovial fluid. Hyaluronic acid is naturally occurring in the synovial fluid of the knee.

Over the years we have seen many patients who have been on the “gel shots.”

Over the years we have seen many patients who have been on the “gel shots.” Many people do get very good results with the treatment. They are, however, designed as short-term treatments to help put off or delay knee replacement surgery.

The debate over Hyaluronic Acid Injections and knee injections. One study suggests that Hyaluronic Acid is a waste of time, money, and resources another study says it works okay

We do see many patients who have tried hyaluronic acid injections. For some, they did have a degree of success, and the injections provided short-term pain relief.  Many of these people are now in our office because the short-term has not transpired to the long-term and now they are on the path to knee replacement.

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. People will also recognize these injection treatments as 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:

“Although some patients report relief of arthritis symptoms with viscosupplementation, the procedure has never been shown to reverse the arthritic process or re-grow cartilage. The effectiveness of viscosupplementation in treating arthritis is not clear. It has been proposed that viscosupplementation is most effective if the arthritis is in its early stages (mild to moderate), but more research is needed to support this. Research in viscosupplementation and its long-term effects continues.”

We have two studies here: The first says Hyaluronic Acid Injections are okay. The second says Hyaluronic Acid Injections are a waste.

• 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. (13)
• 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. (14)

Do Hyaluronic Acid Injections Work for Knee Osteoarthritis?

---

“Repeated courses of treatment with Hyaluronic Acid are safe and are associated with the delay of total knee replacement for up to 3 years.”

A July 2018 study in the American Journal of Orthopedics (15) 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?”

Research: Multiple intra-articular hyaluronic acid injections can delay the need for total knee replacement for one and a half years.

A 2021 paper published in the Journal of Long-Term Effects of Medical Implants (16) explored the effect of single versus multiple rounds of intra-articular hyaluronic acid in delaying the need for total knee arthroplasty in patients with knee osteoarthritis, and if additional benefits were seen when used in conjunction with other multimodal treatment options. The other treatments were knee braces and cortisone injections. The researchers found that “treatment of knee osteoarthritis should consider the use of multimodal therapy instead of focusing on individual treatment options. Additionally, the use of repeated courses of intra-articular hyaluronic acid should be considered for the prolonged benefit for patients with symptomatic knee osteoarthritis.”

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

A research letter in the Journal of the American Medical Association Internal Medicine, (17) 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.”

This statement paper is from 2014, let’s see if we can advance the research forward towards 2021.

The first stop is February 2016 and the journal Clinical Orthopaedics and Related Research. (18) It is an editorial from Seth S. Leopold, MD. Here are the quoted learning points:

• “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 (viscosupplements) value.”
• “I (Dr. Leopold) know there are many proponents of these treatments in the orthopaedic community; however, the observations about viscosupplementation’s inefficacy are not mine alone. Well-done reviews and meta-analyses recommending against the use of this treatment have appeared in The New England Journal of Medicine and the Annals of Internal Medicine; The Osteoarthritis Research Society International’s (OARSI) guidelines for the non-surgical management of knee osteoarthritis listed viscosupplementation among the treatments of “uncertain appropriateness. . . “

Then why is your doctor still recommending this Hyaluronic Acid injection?

Let’s let Dr. Leopold continue:

“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. Some patients will have pain that persists despite well-tested nonsurgical treatments, but not enough to warrant major joint surgery; others may not fit the biopsychosocial profile that supports a decision to perform elective arthroplasty. The answer to this is not to use a treatment like viscosupplementation that studies suggest is ineffective, nor to take a chance on surgery when it seems ill-considered to do so, but rather to explain to patients that there are some problems for which we have no effective treatments, and to help those patients adjust and adapt.”

One injection just as good as a series of Hyaluronic Acid Injections

The next stop will be a March 2019 study in the journal Current Therapeutic Research. (19)

The question being asked here is maybe more than one injection would make the treatment more effective. In fact, the question is how this paper opens: “Viscosupplementation of the synovial fluid with intra-articular hyaluronic acid is a well-known symptomatic treatment of knee osteoarthritis. The question arises whether a mono-injection (ie, single injection) could be as efficient as multi-injection (ie, 3–5 injections) regimens.”

Here is how this paper concluded: In the symptomatic treatment of knee osteoarthritis with intra-articular hyaluronic acid, the results of mono-injections (one injection) demonstrate (similar effectiveness) to the multi-injections and also when compared to a placebo injection.

Conclusion: Results of this meta-analysis suggest that the effects of a single injection of hyaluronic acid produce results similar to multi-injections of intra-articular hyaluronic acid in terms of pain relief in the treatment of knee osteoarthritis.

You can delay knee replacement realistically for about 11 months with hyaluronic acid injections

In September 2020, a study in the journal American Health and Drug Benefits,(20) assessed the value of intra-articular hyaluronic acid injections monetarily. This is a way to determine the effectiveness of the treatment. This is what the study said:

Although limiting hyaluronic acid use may reduce knee osteoarthritis-related costs, in this study hyaluronic acid injection only comprised a small fraction of the overall costs related to knee osteoarthritis. Among patients who had a knee replacement, those who received treatment with hyaluronic acid had surgery delayed by an average of 10.7 months.

Comparative study

In March 2023, doctors at the University of Colorado School of Medicine and Houston Methodist Hospital, Department of Orthopedics & Sports Medicine published a systematically review of previously published research in order to compare the effectiveness and safety of platelet-rich plasma (PRP), bone marrow aspirate concentrate (BMAC), and hyaluronic acid (HA) injections for the treatment of knee osteoarthritis.(21)

Twenty-seven studies were included in this review. The patient breakdown was as follows:

• 1,042 patients received PRP injections. These patients were on average about 57.7 years old.
• 226 patients received bone marrow aspirate concentration injections, average age 57.0 years.
• 1,128 patients received with hyaluronic acid injections average age 59.0 years.

Results:

• Non-network meta-analyses demonstrated significantly better post-injection pain, function and disability scores in PRP patients when compared to hyaluronic acid patients.
• Similarly, network meta-analyses demonstrated significantly better post-injection pain, function and disability scores in bone marrow aspirate concentration injection patients when compared to hyaluronic acid patients.
• There were no significant differences in post-injection outcome scores when comparing PRP to bone marrow aspirate concentration injection patients.

Conclusion:

• Patients undergoing treatment for knee osteoarthritis with PRP or bone marrow aspirate concentration can be expected to experience improved clinical outcomes when compared to hyaluronic acid patients.

Platelet-Rich Plasma (PRP)

This is one of the injections that you may have been researching because it is somewhat off the traditional conservative care options path and you stumbled upon PRP online. You may have even asked your orthopedist about “PRP” injections and you were told: “They do not work, they are not covered by insurance.”

That is probably enough to chase anyone away. Except for one thing. There is a lot of research that when administered correctly by a doctor experienced in the treatment, PRP works pretty well. So just like the debate about cortisone and the debate about Hyaluronic Acid Injections, there is a debate about PRP injections.

• PRP treatment takes your blood, your blood is drawn as if you were taking a blood test, and then the blood is spun in a centrifuge.
• Your blood platelets contain growth and healing factors. When concentrated through simple centrifuging, your blood plasma becomes “rich” in healing factors, thus the name Platelet RICH plasma. The PRP then is injected into and around your knee.
• The procedure and preparation of therapeutic doses of growth factors consist of an autologous blood collection (blood from the patient), plasma separation (blood is centrifuged), and application of the plasma rich in growth factors (injecting the plasma into the knee.) In our office, patients are generally seen every 4-6 weeks. Typically three to six visits are necessary per area.

Growth and healing factors in PRP. This is what makes PRP work

A paper in the journal Clinical Cases in Mineral and Bone Metabolism (22) describes the growth, healing, and repair factors found in platelet-rich plasma. These are the healing factors and what they do:

• PDGF (Platelet-derived Growth Factor) initiates connective tissue healing through the promotion of collagen and protein synthesis.
  • The primary effect of PDGF seems to be its mitogenic activity on mesoderm-derived cells such as fibroblasts (which produce collagen, a building block of new cartilage),
  • Vascular muscle cells (new blood vessels to bring healing factors to the injury).
  • Glial cells (protects nerves) and chondrocytes (the stuff cartilage is made of – see our article on Extracellular Matrix).
  • The most important specific activity of PDGF is the creation of cartilage.
• VEGF (Vascular Endothelial Growth Factor) is the major regulator of vasculogenesis and angiogenesis and plays an important role in tissue regeneration. It does so by creating new highways of blood vessels for the healing factors to get to the site of the injury.
• Transforming Growth Factor (TGF) including TGF-b1 stimulates chondrocyte (Cartilage growth) and decreases the catabolic activity (the breakdown of cartilage). There is also research to suggest that TGF-bi stimulates stem cell activity in the injured area.

So the concept is here. These healing growth factors in your blood are taken and “spun,” to separate out a platelet-rich plasma solution filled with these healing and growth factors, and then the solution is injected into your knee.

PRP is not a single shot miracle cure. The effectiveness of PRP is in how many times the treatment is given.

PRP is not a single shot miracle cure. While for the rare patient a single shot may work for them, we have seen in our clinical experience, that PRP not to be as effective as a stand-alone, single-shot treatment. When someone contacts our center with a question about PRP, they understand the concept and that it should have helped them. But it did not. Why?

PRP does not work for every patient. The two main reasons are that some knees are indeed “too far gone.” What is typically too far gone? A knee that does not bend anymore or there is significant structural changes like bone spurs that have fused the knee.

The second reason is that they did not allow the treatment a chance to work. Many people think they are supposed to get immediate relief. That is not how PRP works.

Cortisone is a one-shot treatment, PRP should not be given the same way. This is when PRP does not work.

People get confused with PRP treatment because they think it is “just like cortisone, only safer.” PRP is NOT just like cortisone. Cortisone has an immediate pain-reducing effect for many people, not all, because it is reducing pain brought on by chronic inflammation. Nothing is being healed. PRP brings healing through inflammation. When tissue is repaired, the inflammation goes away. Please read below for a direct comparison of cortisone injection and PRP and the PRP time frame of healing. You will see cortisone is short-term, and PRP is long-term. Cortisone will eventually suppress the body’s natural healing mechanism and send you to knee replacement. PRP will rebuild and repair tissue in the knee and help you avoid a knee replacement or arthroscopic surgery.

Researchers at Queens University in Belfast published a June 2021 paper in the journal BioMed Central Musculoskeletal Disorders (23) in which they compared PRP to cortisone. Here are the observations of care and the findings:

• Intra-articular corticosteroid injections are the mainstay of treatment for symptomatic management in knee osteoarthritis.
• Intra-articular platelet-rich plasma (PRP) injections are a promising alternative, but no systematic reviews to date have compared them to the current standard of care, that is Intra-articular corticosteroid injections
• This study investigated the effect of Intra-articular platelet-rich plasma (PRP) injections versus Intra-articular corticosteroid injections for the symptomatic management of knee osteoarthritis.

Results: “Intra-articular platelet-rich plasma (PRP) injections produce superior outcomes when compared with Intra-articular corticosteroid injections for symptomatic management of knee osteoarthritis, including improved pain management, less joint stiffness, and better participation in exercise/sporting activity at 12 months follow-up. Giving Intra-articular platelet-rich plasma (PRP) injections, with injections separated by a week, appears more effective than one Intra-articular platelet-rich plasma (PRP) injection.”

“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.”

A May 2022 paper published in the Journal of clinical medicine (24) evaluated the Platelet Rich Plasma (PRP) injections for safety and effectiveness in patients affected by knee osteoarthritis. The researchers noted that PRP has shown promising results in achieving pain reduction and better function in these patients.

In this study, one hundred and fifty-three patients from 40-81 years old received three consecutive PRP injections. The patients were then followed up to determine if the treatment helped them. The patients were evaluated before PRP injection, at one month, three months and six months after the treatment.

Results: A statistically significant functional ability and pain reduction was seen during the course of the study. While MRI demonstrated non-statistically significant improvement in cartilage thickness for both tibial plate and femoral plate and no radiographic changes could be seen in any patients.

Conclusions: “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.”

The Platelet-Rich Plasma group showed the lowest radiographic (knee osteoarthritis) progression at 52 weeks of follow-up.

An April 2022 study published in the journal Clinical Rehabilitation (25) compared a single platelet-rich plasma injection, a single triamcinolone hexacetonide, and a single saline solution injection in patients with knee osteoarthritis. After assessing various pain and function questionnaires among the patients, the researchers found: The Triamcinolone Hexacetonide injection was superior for a percentage of improvement in pain and stiffness. The Platelet-Rich Plasma group and Triamcinolone Hexacetonide group were superior to the Saline group in function. The Platelet-Rich Plasma group showed the lowest radiographic progression at 52 weeks of follow-up. ”

In this video, Ross Hauser, MD explains how one injection of PRP will likely not work

A transcript summary is below the video

We will often get emails from people who had previous PRP therapy without the desired healing effects. We explain to these people that their treatment probably did not work because the single PRP injection did not resolve knee instability. The PRP may have tried to create a patch in the meniscus or cartilage to help with a bone-on-bone situation but the instability and the wear and tear grinding down the meniscus and cartilage remain.

When a person has a ligament injury or instability, the knee becomes hypermobile causing degenerative wear and tear on the meniscus and knee cartilage. In other words, the cells of the meniscus and cartilage are being crushed to death. When you inject PRP cells into the knee, without addressing the knee instability, (treating the ligaments,) the injected PRP cells will also be subjected to the crushing hypermobile action of the knee. The single injection PRP treatment will not work for many people. The knee instability needs to be addressed with comprehensive Prolotherapy around the joint. Prolotherapy is the companion injection of simple dextrose. This is explained in detail below.

Is PRP controversial? Yes. Is it effective? Also yes.

When it works. Below are many citations and references showing the effectiveness of PRP. 

A January 2023 paper in the journal Methods in molecular biology (26) summarizes these controversies: “The use of platelet-rich plasma (PRP) has been supported by encouraging data from in vitro and preclinical in vivo studies, both in terms of safety and efficacy. This led to the wide use of PRP injections in the clinical practice, with promising results especially as a minimally invasive treatment for cartilage degeneration and osteoarthritis. While many controversies remain on the best PRP formulation, the overall available clinical studies support the benefits of PRP, with functional improvement and reduction of pain-related symptoms up to 12 months, especially in young patients and early osteoarthritis stages.

PRP injections in the knee can alleviate pain symptoms three days after injection.

A January 2022 paper published in the Journal of Healthcare Engineering (27) evaluated the effect of PRP intraarticular injections in knee osteoarthritis patients suffering from Stage I, Stage II, and Stage III knee osteoarthritis. All 250 patients were treated. A total of 250 patients were treated every week with one injection for three weeks. At our center, this is typically not the way we offer treatment as outlined throughout this article. When assessing pain and disability scores the researchers found that pain and disability scores in the PRP group three days after the first injection, one month, and then three months after the first injection showed significant improvement. The researchers here concluded: that PRP is effective in the treatment of knee osteoarthritis. The pain symptoms can be alleviated at 3 days after injection.”

While an October 2020 study in The Journal of International Medical Research (28) still acknowledges that “the clinical efficacy of platelet-rich plasma (PRP) in the treatment of osteoarthritis remains controversial,” their examination of five clinical trials including 320 patients found: “intra-articular injection of PRP is an effective treatment for osteoarthritis that can reduce post-operative pain, improve locomotor function, and increase patient satisfaction.”

This is a June 2020 study from the journal Clinical Rheumatology, (29) Here researchers suggested that “Intra-articular PRP injection provided better effects than other injections for osteoarthritis patients, especially in knee osteoarthritis patients, in terms of pain reduction and function improvement at short-term follow-up. (At 1, 2, 3, 6, 12 months).

In a study published in the American medical journal Arthroscopy, (30) medical university researchers suggested that PRP injections were more effective in the treatment of knee osteoarthritis, in terms of pain relief and self-reported function improvement at three, six, and twelve months follow-up, compared with other injection treatments. We are going to show the comparative research below.

“The efficacy of (PRP) intra-articular injections as a nonoperative modality for treating symptomatic knee osteoarthritis-related pain while maintaining function has become a subject of increasing interest.”

An August 2021 paper from the Department of Orthopaedic Surgery, Rush University Medical Center published in  The American Journal of Sports Medicine (31) compared the effectiveness of PRP against other knee injections in “younger patients and those without severe degenerative changes.” The reason? is that “the efficacy of intra-articular injections as a nonoperative modality for treating symptomatic knee osteoarthritis-related pain while maintaining function has become a subject of increasing interest.”

In this study the following treatments were compared:

• Hyaluronic acid.
• Corticosteroids.
• Platelet-rich plasma (PRP).
• and plasma rich in growth factors (PRGF).

A brief understanding of the differences between PRP and PRGF

Studies have shown favor for the use of plasma rich in growth factors (PRGF) in surgical healing. The difference in the injections is that in plasma rich in growth factors (PRGF) red and white blood cells are removed leaving only the growth factors. The benefit of this is that in wound healing, removing the red and white blood cells will help reduce inflammation. This is why this treatment is more favored in surgical repair. As regenerative medicine outside of surgery relies on controlled inflammation, PRP is seen as a better choice in many situations where there is knee pain.

Here are the highlights of this study:

• All injection treatments except corticosteroids were found to result in a statistically significant improvement in outcomes when compared with placebo.
• PRP demonstrated a clinically meaningful difference in function-related improvement when compared with corticosteroids and placebo due to large effect sizes.
• Studies evaluating outcomes of plasma rich in growth factors (PRGF) reported significant improvement when compared with placebo due to large effect sizes, whereas a potential clinically significant difference was detected in the same comparison parameters in pain evaluation.

Conclusion: “PRP yielded improved outcomes when compared with plasma rich in growth factors (PRGF), Hyaluronic acid, Corticosteroids, and placebo for the treatment of symptomatic knee osteoarthritis at a minimum six-month follow-up.”

When PRP doesn’t work, it is usually not the solution used during treatment, but how the treatment itself is given.

In the Journal of Knee Surgery, (32) doctors at the Division of Sports Medicine, Department of Orthopedics, at Rush University Medical Center in Chicago wrote:

• Traditionally, treatment options (for older and obese patients with osteoarthritis) have included lifestyle modifications, pain management, and corticosteroid injections, with joint replacement reserved for those who have exhausted nonsurgical measures.
• More recently, hyaluronic acid micronized dehydrated human amniotic/chorionic membrane tissue, and platelet-rich plasma (PRP) injections have started to gain traction.
• PRP has been shown to have both anti-inflammatory effects through (human) growth factors and stimulatory effects on mesenchymal stem cells and fibroblasts (the stuff that helps make collagen/cartilage).
• Multiple studies have indicated that PRP is superior to hyaluronic acid and corticosteroids in terms of improving patient-reported pain and functionality scores.
• Unfortunately, there are many variations in PRP preparation, and lack of standardization is a factor.

Simply put, PRP methods vary by practitioner. Research consistently points to PRP ineffectiveness as being caused by the way the treatment is given and poor patient selection.

In a December 2018 paper titled: “Clinical Update: Why PRP Should Be Your First Choice for Injection Therapy in Treating Osteoarthritis of the Knee,” researchers wrote in the journal Current Reviews in Musculoskeletal Medicine:(33)

“Moving forward, it is imperative that future clinical research be conducted in a more standardized manner, ensuring that reproducible methodology is available and minimizing study-to-study variability. This includes PRP preparation methods (centrifugation times and speeds, harvest methodology, systems being used); PRP composition (platelet concentrations, activation agents, white blood cell concentrations, growth factor, and cytokine concentrations); PRP injection protocols (single versus multiple injections); sufficient clinical follow-up (a minimum of 6 months); and strict inclusion/exclusion criteria.”

In two groups of patients, one group gets PRP and the other group gets cortisone. How did this comparison work out?

In this study from The Journal of Sports Medicine and Physical Fitness, (34) a comparison is made between the effects of a one-time injection of PRP and corticosteroid (a cortisone shot) for the patients suffering from osteoarthritis.

• Patients suffering from Grade II or Grade III  knee osteoarthritis were randomly divided into two groups: intraarticular injection of PRP and cortisone.
• Forty-one participants (48 knees) were involved in the research (66.7% women, with an average age of 61).

Compared to the group treated with corticosteroids, PRP showed significant results for:

• pain relief
• being symptom-free
• activities of daily living and quality of life

This study demonstrated that 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 short-term duration in comparison with the corticosteroid.

Study 2: Two groups of patients, one group gets PRP the other group gets cortisone. How did this comparison work out?

In an October 2020 study (35) also comparing PRP and corticosteroid, similar findings were recorded. PRP results were better over time and the lack of side effects should be considered if debating between one treatment or the other.

• In this study, the researchers found PRP had  “more significant values for improvement in comparison with corticosteroids, especially in the long-term (180 days).”
• Both PRP and corticosteroid improved the functional and pain status in 30 and 180 days, but patients who had the PRP treatment showed a greater pain improvement.

Alpha-2-macroglobulin, corticosteroid and PRP for knee osteoarthritis

A July 2020 paper from doctors at NYU Langone Health, NYU Hospital for Joint Diseases, published in the Orthopaedic journal of sports medicine (36) found “Alpha-2-macroglobulin (A2M) not significantly better than regular PRP for knee arthritis symptoms.”

Alpha-2-macroglobulin is a protein found in the blood that when separated out from the blood plasma and reinjected into the knee, would provide protective properties against cartilage breakdown by acting as an anti-inflammatory. In concept the Alpha-2-macroglobulin counteracts the pro-inflammatory proteins that cause inflammation and tissue breakdown. The researchers of this study noted: “Little clinical data exists on the use of injectable macromolecules (A2M) for the treatment of osteoarthritis of the knee. . . To date, no studies exist evaluating the effectiveness of A2M with other intra-articular injectables.”

The purpose of this study, therefore was to compare the clinical effectiveness of intra-articular injection of A2M against both platelet-rich plasma (PRP) and corticosteroids.

• Seventy-five patients with symptomatic knee osteoarthritis with Kellgren-Lawrence grade 2 or 3 were divided into three groups, each would receive one injection of the three treatments and then they would be evaluated 12 weeks later..
  • One group was given PRP,
  • One group was given A2M, and
  • One group was given corticosteroids.

This study suggested Alpha 2 Macroglobulin showed similar effectiveness to corticosteroids in the treatment of knee osteoarthritis. “Both A2M and corticosteroids appear to show marginally better effectiveness than PRP injection, however the differences are small and did not reach statistical significance in most outcome measures.”

Autologous protein solution (APS) injections

An April 2023 study in the journal Scientific reports (37) suggests that Autologous protein solution (APS) injections may help patients with milder forms of knee osteoarthritis. In 12-month follow-up of patients receiving Autologous protein solution (APS) injections, 148 knees showed (67%) showed significant improvement. People with stage 2 or Kellgren-Lawrence (KL) grade 2 (mild) osteoarthritis showed best improvement when compared with more advanced stage 4 knee osteoarthritis.

Earlier a September 2020 paper in The American journal of sports medicine (38) from a team of European researchers suggested: “Intra-articular use of Autologous protein solution (APS) for mild to moderate knee osteoarthritis was safe, and significant pain improvement was documented three years after a single injection. Patients with better cartilage status seem to respond better than patients with more cartilage loss.” Again patients with milder osteoarthritis responded better than more severe osteoarthritis patients.

“Patients undergoing treatment for knee osteoarthritis with PRP can be expected to experience improved clinical outcomes when compared with hyaluronic acid.”

There is a lot of research comparing PRP to hyaluronic acid. Here are some of the papers:

An April 2020 study led by the Department of Orthopedics, University of Colorado School of Medicine, published in The American Journal of Sports Medicine (39) suggested: “Patients undergoing treatment for knee osteoarthritis with PRP can be expected to experience improved clinical outcomes when compared with hyaluronic acid.”

Doctors writing in the September 2019 issue of the World Journal of Orthopedics (40) offered these findings in assessing PRP versus hyaluronic acid injections over four, eight, and twelve-week follow-ups after treatments.

• The effectiveness of PRP treatment in patients with knee osteoarthritis was significantly greater than in the hyaluronic acid group. In addition, two injections of PRP were more effective at each follow-up than a single injection.

In February 2020, a multi-national team of researchers published findings in the European Journal of Orthopaedic Surgery & Traumatology (41) comparing intra-articular knee injection of PRP and hyaluronic acid and investigating clinical outcomes and pain at both 6 and 12 months.

• Here researchers examined 1,248 cases; 636 PRP, and 612 hyaluronic acids. The results of this systematic review and meta-analysis suggest that PRP is superior to hyaluronic acid for symptomatic knee pain at 6 and 12 months.

Ten patients underwent intra-articular PRP injection and 10 others received the hyaluronic acid injection.

A September 2021 study published in The Archives of Bone and Joint Surgery (42) was designed to compare the effectiveness of intra-articular injection of PRP with hyaluronic acid on mild to moderate knee osteoarthritis.

How the study was conducted:

• Ten patients underwent intra-articular PRP injection and 10 others received hyaluronic acid injections.
• At baseline (pre-injection) visits and one, three, six, and 12 months post-injection, clinical assessments were performed using standardized patient self-reporting scores for pain, function, and disability.
• Physical examinations of the knee, including crepitation and range of motion (ROM) were performed at each visit.

Results:

• The PRP treatment was ascertained to be safe and caused no adverse effects. Significant improvements in the majority of patients were seen in pain and function.
• The hyaluronic acid injection, however, caused only one month’s significant improvement in the majority of patient-reported outcomes.
• In the majority of visits, the extent of improvements in pain and function were significantly greater in PRP recipients, compared to hyaluronic acid recipients.
• The ROM in both groups slightly increased after interventions.
• The frequency of coarse crepitation, which was detected in 100% of the patients in both groups at the baseline visit, decreased significantly to fine crepitation at the first follow-up visit in 80% and 40% of the PRP and hyaluronic acid recipients, respectively.

Published Conclusion: “Intra-articular injection of PRP or hyaluronic acid alleviates symptoms and pain and improves functionality and physical examinations in patients with knee osteoarthritis. However, PRP therapy produces greater and longer-lasting improvements in most of the outcome parameters compared to hyaluronic acid.”

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

Doctors wrote in a January 2019 study (43) 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 (44) 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 (45) as 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. (46)

An August 2021 paper in the Orthopaedic Journal of Sports Medicine (47) suggests however that corticosteroid and hyaluronic acid injections are favored for different knee problems, while PRP currently has insufficient evidence to make a conclusive recommendation for or against its use.

An August 2022 paper in the journal Medicine (48)  did a retro analysis of previously published research in which they explored the data of over seven thousand knee osteoarthritis patients. The data revealed the outcomes of five different treatments:

• Platelet-rich plasma injection which showed superority to both ozone and hyaluronic acid therapies.
• Hyaluronic acid + ozone therapy which was superior to ozone and hyaluronic acid monotherapy
• Platelet-rich plasma + hyaluronic acid which was superior to ozone and hyaluronic acid monotherapy.

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.

Stem Cell Therapy

This is one of the treatments that is considered very promising and equally very controversial. This is also a treatment that may suffer from an over-expectation of what this treatment can do and a misunderstanding of what this treatment cannot do.

If you have a bone on bone knee, stem cell therapy will not grow a new meniscus out of thin air.

As we say to many patients, if you have a bone on bone knee, stem cell therapy will not grow a new meniscus out of thin air. Stem cell therapy can grow new cartilage as a method to patch cartilage and meniscus defects but is not a “miracle” one-shot cure that will rebuild your knee to “good as new.” Some people may get benefit from the one-time shot, others will not. As we will point out in this article and links to our other articles, there is too much being made of young versus old stem cells. We may be getting ahead of ourselves here so let’s start with a basic understanding.

There are different types of stem cell therapy. You have:

• Bone Marrow Aspirate Concentrate or bone marrow concentrate type stem cell therapy
• Lipoaspiration, Adipose-derived stem cells, Microfragmented Fat, or Lipogems type stem cell therapy
• Afterbirth material stem cell therapy which would be umbilical cord blood, amniotic and placenta products, Wharton’s jelly, and Exosomes

At our center, we use stem cell therapy, but not all of these are listed above. We also use stem cell therapy on a few patients, but not every patient.

We estimate that 1 in 10 patients who we see in our clinic have already received some type of stem cell therapy in another office. They are in our clinic because the treatment they have received has failed to meet the patient’s expectations. Simply, One injection stem cell “treatments” are not sustainable pain relief.

People with knee osteoarthritis pain, probably like yourself, go to the orthopedist and hear over and over about their eventual need for a knee replacement. You may have been given a much more critical, “we should schedule this knee replacement now,” recommendation because it took you a long time to walk from the reception area to the examination room, and all along the way you may have been reaching and lunging for chairs, walls, and counters to use as support and your doctor saw you do it.

You would like to avoid the knee replacement for various reasons, all equally important to you. In your research, you have come upon stem cell therapy. You read through some websites that suggest this simple, possibly one-time injection, will make all your pain go away. This is unrealistic thinking as this is almost never the case. The reason it is almost never the case is that stem cell therapy, even when most effective, requires a comprehensive approach to treatment that includes multiple treatments or the use of Prolotherapy injections into the knee’s supportive ligaments.

• Please see this article: Why stem cell therapy did not work for your knee pain. Here we discuss that:
  • Degenerative knee disease does not happen overnight.
  • Healing degenerative knee disease with stem cell therapy cannot be expected to repair decades of wear and tear as a one-time injection treatment.

In the video below, Ross Hauser, MD explains the 5 myths we see concerning Stem Cell Therapy. The biggest one is that people believe that one stem cell injection will make all their pains go away. For most this is not true. It is not true for the same reasons outlined above, a single injection will not be comprehensive enough to reverse years and possibly decades’ worth of damage affecting the entire knee structure. This one-shot thinking leads to an unrealistic expectation of pain relief and joint regeneration.

Comparative research

A May 2022 in The Journal of Arthroplasty (49) compared research outcome findings for platelet-rich plasma (PRP); bone marrow-derived mesenchymal stem cells; adipose-derived mesenchymal stem cells and amniotic-derived mesenchymal stem cells. Eighty-two previously reported studies were included: There were 51 studies on PRP; 15 studies on bone marrow-derived mesenchymal stem cells, 11 studies on adipose-derived mesenchymal stem cells and five studies on amniotic-derived mesenchymal stem cells.

Results: What they researchers found was of the previously published PRP studies most outcomes found patient satisfaction as “fair” to “good.” The problem was inconsistency due to variable cell preparations and formulations. The limited number of studies were included for bone marrow-derived mesenchymal stem cells, adipose-derived mesenchymal stem cells, and amniotic-derived mesenchymal stem cells, all with similar findings to PRP and the same inconsistencies and uncertain efficacy for use in knee osteoarthritis.

Bone Marrow Aspirate Concentrate or bone marrow concentrate type stem cell therapy

Using stem cells taken from a patient’s bone marrow is becoming a therapy of interest due to the potential of these mesenchymal stem cells to differentiate into other types of cells such as bone and cartilage. This is not a new revolutionary treatment, this treatment has been studied and applied for many years. It is a difficult treatment for some doctors to give. You do need experience in all aspects of the treatment to give the patient the best chance at achieving their healing goals.

Bone Marrow is the liquid spongy-type tissue found in the hallow (interior) of bones. It is primarily a fatty tissue that houses stem cells that are responsible for the formation of other cells. These mesenchymal stem cells (MSC), also called marrow stromal cells, can differentiate (change) into a variety of cell types including osteoblasts (bone cells), chondrocytes (cartilage cells), myocytes (muscle cells), adipocytes (fat), fibroblasts (ligament and tendon) and others when reintroduced into the body by injection. Bone marrow also contains hematopoietic stem cells that give rise to the white and red blood cells and platelets.

Where do the bone marrow stem cells come from?

The bone marrow aspirate is taken from the iliac crest of the pelvic bone. It is a simple, easily tolerated procedure and is demonstrated in this video below:

In clinical observations at Caring Medical, the benefit is seen in injecting bone marrow directly after extracting it.

The theory is that the number of stem cells is not as important as how long they live in their natural environment. In other words, when the bone marrow is directly injected, the source of stem cells is fresh and has great potential for healing. We also believe that the body knows best – it can use these immature cells to regenerate all injured tissues in the joint.

In December 2020 Doctors at Loughborough University in the United Kingdom wrote in the journal Knee surgery, sports traumatology, arthroscopy (50) “ . . . clinical applications of intra-articular injections of bone marrow-MSCs are steadily increasing (for patients suffering from knee osteoarthritis), with most studies demonstrating a decrease in poor cartilage index, improvements in pain, function and Quality of Life (QoL); with moderate-to-high level evidence regarding safety for therapeutic administration. However, low confidence in clinical efficacy remains due to a plethora of heterogenous methodologies utilised, resulting in challenging study comparisons. . . Overall, the benefits of intra-articular injections of BM-MSCs were deemed to outweigh the adverse effects; thus, this treatment be considered as a future therapy strategy.”

Mayo Clinic and Yale University studies on your own bone marrow stem cells

Doctors at the Mayo Clinic and Yale University published their research on the benefits of Bone Marrow Aspirate Concentrate for Knee Osteoarthritis in the American Journal of Sports Medicine. Here is the summary of that research:(51)

• In their single-blind, placebo-controlled trial, 25 patients with bilateral knee osteoarthritis were randomized to receive Bone marrow aspirate concentrate in one knee and saline placebo in the other. Early results show that Bone marrow aspirate concentrate is safe to use and is a reliable and viable (stem cell) cellular product. Study patients experienced a similar significant relief of pain in both bone marrow aspirate concentrate- and saline-treated arthritic knees.

“The current literature demonstrates the potential benefits of utilizing concentrated bone marrow aspirate for the repair of cartilaginous lesions, bony defects, and tendon injuries”

Doctors in New Jersey at the Department of Orthopedic Surgery, Jersey City Medical Center published their findings in support of this research, in the World Journal of Orthopedics, here is what the paper said:

• “The current literature demonstrates the potential benefits of utilizing concentrated bone marrow aspirate for the repair of cartilaginous lesions, bony defects, and tendon injuries in the clinical setting. The studies have demonstrated using concentrated bone marrow aspirate as an adjunctive procedure can result in cartilage healing similar to that of native hyaline tissue, faster time to bony union, and a lower rate of tendon re-rupture.”(52)

A June 2018 study in the journal Arthritis and Musculoskeletal Disorders (53) presents the short-term progress of 15 patients (20 knees) with knee osteoarthritis through four bone marrow concentrate treatments.

• Patients underwent four bone marrow concentrate treatments on average 14 days after 1st treatment, 21 days after the second treatment, and 33 days after the third treatment. The last follow-up was conducted on an average of 86 days after the first treatment.

Patients experienced statistically significant improvements in active pain and functionality scores after the first treatment.

• On average, patients experienced:
  • an 84.31% decrease in resting pain,
  • a 61.95% decrease in active pain,
  • and a 55.68% increase in functionality score at the final follow-up.
• Patients also reported a mean 67% total overall improvement at the study conclusion. Outcomes at the final follow-up after the fourth treatment were statistically significant compared to outcomes at baseline, after the first treatment, after the second treatment, and after the third treatment.

Successful, safe, and encouraging results of bone marrow-derived mesenchymal stem cells

A January 2020 (54) study published in the journal Knee Surgery, Sports Traumatology, Arthroscopy found:

“Pre-clinical studies have demonstrated (intra-articular injections of bone marrow-derived mesenchymal stem cells are) successful, safe, and (with) encouraging results for articular cartilage repair and regeneration. This is concluded to be due to the multilineage differential potential, immunosuppressive and self-renewal capabilities of bone marrow-derived mesenchymal stem cells, which have shown to augment pain and improve functional outcomes.”

Caring Medical Research – Case studies

Our research team has published research on patient outcomes and case studies using bone marrow aspirate. Here is a sample of those outcomes. Again, we must remind you that this treatment does not work for everyone. Unfortunately, if you are reading this article you are probably very attuned to medical treatments that do not work.

In the medical journal Clinical Medicine Insights Arthritis and Musculoskeletal Disorders, (55) our Caring Medical research team published our findings on seven patients. The patients who were treated for knee pain are featured below:

Patient case  – Knee pain: A 69-year-old man

A 69-year-old male came into our office with pain in both knees, with his right knee significantly more painful. Pain resulted in frequent sleep interruption and limitation of exercise.

The patient had received Prolotherapy (another injection treatment explained below) at another office in the previous two years but felt that the treatment has reached its maximum ability to heal.

The patient was diagnosed with osteoarthritis and received five bone marrow/dextrose treatments (a combination of bone marrow and Prolotherapy injections) in each knee at two-month intervals.

• Two months after the final treatment, the patient reported that he was completely free of pain or stiffness in both knees, had regained full range of motion, no longer suffered sleep interruption, and was no longer limited in exercise or daily life activities.

Patient case  – Knee pain – A 56-year-old woman

A 56-year-old female came into our office with pain in both knees and her right hip. She reported the knee pain started 3 years prior. The pain was severe in the right knee, with frequent crepitus and instability, and had forced the patient to discontinue running. MRI with a previous physician had shown cartilage degeneration. Right hip pain had been intermittent for 16 years, but instability and continuous pain began six months before her first office visit.

The patient received bone marrow/dextrose treatments for six visits at 8–10 week intervals.

• The patient reported modest (20%–35%) overall improvement following these treatments. At the final two visits, both knees and right hip were treated with bone marrow Prolotherapy injection. During the treatment period, the left hip was also treated for pain resulting from a flexor injury incurred following visit 1.
• Two months after visit 6, the patient reported 65%–95% overall improvement for the three joints. She is able to walk for two hours, no longer has disturbed sleep, and has been able to resume bicycle exercise with minimal discomfort.

Patient case  – Knee pain – A 56-year-old man

A 56-year-old male came into our office with pain in both knees. The patient is a former competitive weightlifter who continues to do strength training exercises. He complained of instability in both knees during exercise, as well as sleep interruption.

The patient received 29 bilateral dextrose Prolotherapy treatments over five years.

At the final Prolotherapy visit, sleep interruption was still present, pain intensity was 4/10, and pain frequency was 100%.

Four months later, the patient was treated with platelet-rich plasma. Three months after plasma treatment, the patient began a series of three bone marrow stem cell injection treatments (without dextrose Prolotherapy) at 2–3 month intervals.

At the time of the second bone marrow stem cell injection treatment, stability was improved. At the time of the third treatment, pain intensity was 2/10, and pain frequency was 30%. Sleep was no longer affected. These gains were maintained for nine months.

Patient case  – Knee pain – A 69-year-old woman

A 69-year-old female came into our office with pain in both knees. She had been previously diagnosed with osteoarthritis, had arthroscopic surgery to both knees eight years earlier, and medial meniscus repair in both knees 15 years earlier.

The patient reported pain occurred climbing or descending stairs and standing or walking for two hours. Pain interrupted sleep and limited participation in racquet sports and golf.

The patient received six treatments on both knees with dextrose Prolotherapy over a ten-month period.

• After the first month of this period, the patient reported uninterrupted sleep, pain intensity of 2/10, resumption of limited golf, and an overall improvement of 50%–55%.

One year after the final Prolotherapy, pain intensity had returned to 4/10 with a frequency of 20%, and sleep interruption had resumed. At this time, the patient received the first of two bone marrow stem cell injection/dextrose treatments, five months apart.

• At the time of the second treatment, pain intensity was 1/10 with a frequency of 20%, sleep interruption was reduced by half, and patient-reported overall improvement was 90%.
• Eight months following the final bone marrow stem cell injection/dextrose treatment, the patient reported being free of pain and able to resume full participation in all of her usual athletic activities.

Lipoaspiration, Adipose-derived stem cells, Microfragmented Fat, or Lipogems type stem cell therapy

Lipoaspirate or Adipose-derived stem cell therapy is a regenerative injection treatment that stimulates the repair of osteoarthritic cartilage and bone through the use of liposuction aspirates (fat stem cells).

Liopgems is better understood as an FDA-approved device that may make it easier for your doctor to inject adipose stem cells.

• In the Lipogem procedure, lipoaspirate or liposuction is done into the “love handles,” or fatty areas of the abdomen. One of the drawbacks we have seen with lipoaspiration is that it is very difficult and challenging to do in a person who has very little body fat. The procedure can be painful and discomforting to the patient.
• The adipose or fat tissue is then cleaned or processed in a “kit,” which makes the injection more tolerable to the patient in the form of a “micro fragmented fat,” perhaps one way to describe this would be a less chunky injection solution.

There is a lot of controversy surrounding the use of adipose-derived stem cells. This is a treatment that we rarely employ we will use it in selected cases where we would have a good expectation that this is the best option for the patient. The reason we don’t go first to this treatment is that we believe we can achieve similar results with much less invasive treatments.

While bone marrow has historically been used as a source of stem cells, adipose (fat)-derived stem cells have been shown to have:

• nearly identical fibroblast-like morphology and colonization (simply the ability of collagen-producing cells to multiple and repair cartilage and soft tissue damage),
• immune phenotype (the immune system’s response to a specific injury. For example, you send cartilage cells to repair cartilage, you send bone cells to repair bone).

Researchers have suggested the benefits of Adipose stem cells, here are the take-home points of that research published in the journal Stem Cell Reviews (56):

• Adipose stem cells are an attractive and abundant stem cell source with therapeutic applicability in diverse fields for the repair and regeneration of acute and chronically damaged tissues.
• Importantly, unlike the human bone marrow stromal/stem cells that are present at low frequency in the bone marrow, ASCs can be retrieved in high numbers from either liposuction aspirates or subcutaneous adipose tissue fragments.
• In the laboratory, Adipose stem cells display properties similar to that observed in bone marrow stromal/stem cells including the ability to undergo at least osteogenic (bone repair mode) and chondrogenic (cartilage repair mode).

Direct injection of fat stem cells 

In reviewing the cumulative research of both animal and human studies, doctors at the Rizzoli Orthopaedic Institute in Italy, published in the journal Stem Cell International, (57) found the injection of adipose-derived mesenchymal stem cells was first, safe and effective, and that secondly, several aspects favor the use of freshly harvested adipose-derived mesenchymal stem cell instead of expanded or cultured adipose-derived mesenchymal stem cell.

Let’s explore this research a little further. The researchers looked at 11 clinical studies. In these studies, the application of fat stem cells into the knee was performed in many different ways including during arthroscopic knee procedures. This is what they found:

• Ten out of the 11 clinical studies reported the use of non-expanded autologous adipose-derived stem cells.
• Adipose tissue was obtained by liposuction from the abdominal area or buttocks in all cases, except for two studies where infrapatellar fad pad (knee) tissue was harvested during knee arthroscopy.
  • However, in the studies where infrapatellar fad pad tissue was used, those studies’ authors concluded that more adipose-derived stem cells can be obtained from the buttocks than from infrapatellar fad pad, with the same differentiation potential in both sources.
• All three of these clinical papers described adipose-derived stem cells injected in varying volumes (3–5 cc) of autologous PRP, stimulated or activated with calcium chloride.
• Three studies used hyaluronic acid as a carrier instead and one of them also added dexamethasone (an anti-inflammatory) to the stem cell-PRP-hyaluronic acid mixture.
• After a single injection of adipose-derived stem cells, a variable number (usually 2) of PRP-only intra-articular injections were used in most of the studies.
• In four of these studies, cells were injected following arthroscopic lavage and debridement.

All clinical studies showed that adipose-derived stem cells improve pain and functional scores at a follow-up of between 3 and 36 months.

In three studies MRI analysis was performed, which revealed improved features, including increased cartilage thickness.

A June 2022 study lead by Charles Sturt University in Australia and published in the journal Regenerative medicine (58) offered a large two-year perspective study on the long-term safety and effectiveness of adipose-derived mesenchymal stem cell therapy in the treatment of knee osteoarthritis.

In this study 329 patients with with knee osteoarthritis underwent intra-articular adipose-derived mesenchymal stem cell therapy. The patients were then followed up for 24 months and were separated based on severity of their knee osoteoarthritis.

The published results of this study were:

• “Treatment was well tolerated with no related serious adverse events.
• All participant groups reported clinically and statistically significant pain improvement.
• Clinical outcome was not influenced by patients’ age or BMI (obese, overweight, normal weight, underweight).”
• Conclusion: adipose-derived mesenchymal stem cell therapy is an effective, safe and long-lasting treatment option for knee osteoarthritis with the potential to delay total joint replacement.

Five year follow up on adipose-derived (AD) MSCs reported in the medical literature

In May 2022, doctors in south Korea writing in the journal Stem Cells Translational Medicine (59) wrote: “Although successful short-term results of the intra-articular injection of mesenchymal stem cells (MSCs) for the conservative treatment of knee osteoarthritis have been reported, the mid-term results of the injection of adipose-derived (AD) MSCs remains unknown.” To add to the research on mid-term results, or in this case five year out study, the researchers assessed eleven patients with knee osteoarthritis who received a single intra-articular injection of autologous high-dose adipose-derived mesenchymal stem cells. The reserarchers found: “A single intra-articular injection of autologous, high-dose ADMSCs provided safe and clinical improvement without radiologic aggravation for five years. Furthermore, structural changes in the osteoarthritic knee showed significant improvement up to three years, suggesting a possible option for disease-modifying outpatient treatment for patients with knee osteoarthritis.”

Comparing adipose-derived stem cells (ADSCs), PRP, and arthroscopic surgery

An October 2022 paper in the Journal of tissue engineering and regenerative medicine (60) offered a comparison of four treatments: The 1st: adipose-derived stem cells (ADSCs). The 2nd platelet-rich plasma (PRP). The third adipose-derived stem cells (ADSCs) + PRP, the 4th: Arthroscopy. The researchers found that taking all the results into account, therapies with adipose-derived stem cells (ADSCs) and  adipose-derived stem cells (ADSCs) by themselves are safe and effective over 6 months for the improvement of pain, functional capacity and joint inflammation in volunteers with osteoarthritis. It is also considered that the use of adipose-derived stem cells (ADSCs) + PRP, particularly, is a promising alternative to help manage this disease, due to the better results presented among the four propose interventions.

In this video, Ross Hauser, MD demonstrates the procedure. The video jumps directly to the treatment at 1:13

Research comparing PRP, Bone Marrow, and Adipose-Derived Stem Cells. Results: They all worked well.

A July 2020 study published in the journal Clinical Medicine Insights Arthritis and Musculoskeletal Disorders, (61) compared Platelet-Rich Plasma (PRP), bone marrow aspirate concentrate, and adipose-derived mesenchymal stem cell (MSC) injections in the treatment of osteoarthritis of the knee using functional scores.

• Methods: A total of 89 patients with painful knee osteoarthritis were included in this study.
• Patients were assigned to one of the 3 treatments according to the severity of osteoarthritis as indicated by symptoms and radiography to PRP (stage I osteoarthritis), bone marrow aspirate concentrate (stage II osteoarthritis), or adipose-derived MSC (stage III osteoarthritis).
• Clinical assessment was performed using standard scoring systems, Surveys were completed at preoperative, and at 90, 180, and 265 days post-treatment.

Results: They all worked well.

• In a general statement, the PRP worked just as well in stage 1 knee osteoarthritis patients as the bone marrow aspirate worked in the stage 2 knee osteoarthritis patients and the adipose-derived stem cells worked for the stage 3 knee osteoarthritis patients. To quote the researchers: “Our findings support previous reports and encourage further research on the use of these cost-effective treatments for osteoarthritis of the knee.”

This is also a validation of our policy of not going straight to stem cell therapy in some of our patients. PRP or Prolotherapy, which is discussed below can provide equally good results without the added expense.

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

A December 2022 study (62) published in the journal BioMed Central Musculoskeletal Disorders compared a one-shot single treatment bone marrow-derived stem cell injection vs. a one-shot single treatment PRP injection. Then the patients were monitored for 12 months to assess the effectiveness of the one-shot treatment for their knee pain and function. The researchers wrote: “Investigational cell therapies injected intra-articularly, such as bone marrow aspirate concentrate (BMAC) and platelet-rich plasma (PRP), have shown safety and therapeutic potency providing patients with pain relief. In the current retrospective comparative study, (the researchers) investigated the differences in pain and functional improvements in patients with symptomatic knee osteoarthritis receiving intra-articular injections of bone marrow aspirate concentrate BMAC vs PRP.

Pain and functionality scores were measured at baseline and at different time points post-injection over 12 months, using 3 self-administered, clinically validated questionnaires to assess pain intensity, functionality, and knee-related quality of life.

The bone marrow aspirate concentrate BMAC group showed significant improvement in pain intensity, functionality, and knee-related quality of life scores between baseline and 12 months. In contrast, the PRP group did not see significant improvement in all scores. The bone marrow aspirate concentrate BMAC, in comparison to PRP, had significant improvement in outcomes. . . Intra-articular autologous bone marrow aspirate concentrates 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.

Platelet-rich plasma or bone-marrow aspirate concentrate injections have better outcomes than patients who receive hyaluronic acid

A March 2023 review paper in the journal Arthroscopy (63) examined previously published literature  to compare the efficacy and safety of platelet-rich plasma (PRP), bone marrow aspirate concentrate, and hyaluronic acid injections for the treatment of knee osteoarthritis. In this review of:

• 1,042 patients (average age 57.7 years old, follow up 13.5 months after treatment) undergoing intra-articular injection(s) with PRP,
• 226 patients with bone marrow aspirate concentrate (average age 57, average follow-up 17.5 months), and
• 1,128 patients with hyaluronic acid injections (average age 59.0 years, average follow-up 14.4 months),

Results showed:

• PRP patients showed significantly better function and pain scores on standard evaluations compared with patients who received hyaluronic acid injections.
• Similarly, bone marrow aspirate concentrate patients showed significantly better function and pain scores on standard evaluations compared with patients who received hyaluronic acid injections.
• There were no significant differences in post-injection outcome scores when comparing PRP with BMAC.

Seven different knee osteoarthritis treatments

A team of researchers from France and Belgium published a November 2021 study (64) in the medical journal Medicine. In it, the researchers evaluated recent clinical trials on seven different non-surgical knee osteoarthritis treatments. What they were looking for is which of these treatments appeared to work the best.

The seven treatments were:

• Platelet Rich Plasma injection (PRP),
• Corticosteroid injection,
• mesenchymal stem cells (MSCs) injection,
• hyaluronic acid injection,
• ozone treatment,
• nonsteroidal anti-inflammatory drugs,
• nonsteroidal anti-inflammatory drugs combined with physical therapy.

What the researchers found was varying and different effects of these treatments in the research study on participants suffering from knee osteoarthritis.

• In the primary outcome (pain and functional scoring at 12 months after treatment), mesenchymal stem cells and PRP were significantly better than the chosen control and associated with improvement in knee status.
• Corticosteroid injection 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.
• NSAID alone or with physical exercise (physiotherapy) was not associated with improvement in pain and function compared with the injection of hyaluronic acid.
• The combination of hyaluronic acid and dexamethasone was not associated with improvement at 3 and 6 months compared with the injection of hyaluronic acid alone.

Comparing different injections plus physical therapy

A March 2023 network meta-analysis study (a study that compares more than three types of treatments) in the International journal of molecular sciences (65)  looked to compare:

• autologous conditioned serum (Autologous conditioned serum is a treatment made from your blood. Interkeukin-1 Receptor Antagonist Protein, a anti-inflammatory cytokine, in pulled from the blood and injected to act as an anti-inflammatory),
• botulinum neurotoxin type A,
• corticosteroids,
• dextrose prolotherapy,
• hyaluronic acid,
• mesenchymal stem cells (MSC),
• ozone,
• platelet-rich plasma,
• plasma rich in growth factor,
• and stromal vascular fraction of adipose tissue.

Among the ten identified injection and physical therapy regimens:

• Prolotherapy plus physical therapy was the most optimal treatment for pain reduction and function restoration, whereas mesenchymal stem cells (MSC) plus physical therapy was the most effective for enhancing walking capability recovery. More severe knee osteoarthritis was associated with greater changes in pain (the worse the osteoarthritis the more pain relief) and better walking capabilities scores.

Amniotic, Cord Blood, and Placenta Tissue knee injections

There is a great amount of misinformation surrounding “amniotic stem cell therapy,” and “umbilical cord blood stem cell therapy.” We have never offered these treatments.

The primary reason we do not offer these products is that we did not find them to be more effective or economically viable to the patient than the utilization of the patient’s own stem cells (which we rarely offer) and because we find simple dextrose Prolotherapy and Platelet Rich Plasma (PRP) to be effective treatments which, in our observations, yield similar if not better results.

• The first thing that should be pointed out about amniotic/placenta stem cell therapy and umbilical cord blood stem cell therapy is that there are many doctors and researchers who suggest that there are NO stem cells in the treatment.
• If there are no stem cells, why are they called stem cell therapy? That’s a good question.
  • Many “stem cell” companies buy amniotic/placenta tissue and cord blood from tissue banks. The tissue and the cord blood are the “leftovers,” or the afterbirth material.
  • The tissue banks get the afterbirth materials from hospitals that collect the material for laboratories doing scientific research or for companies who can make medical products out of them.
  • It should be pointed out that no one is waiting at the blessed birth event to collect the afterbirth to send it directly to your doctor for immediate injection into your knee. As mentioned, afterbirth material is generally collected in the hospitals’ maternity ward. There may be consent forms and the mother signs that allow their afterbirth material to be used for medical needs and scientific research. Therefore they become “donor mothers.”
  • The “stem cell” companies buy this material and must process the amniotic and placenta membranes and umbilical cord blood and fluid for preservation and to remove disease and other unwanted hazards.
  • Some claim that the processing destroys all the living cells, some say there are abundant living cells. As of this moment, no one can prove without reasonable doubt that there are living stem cells in this therapy.
  • The “healing” factors of amniotic tissue treatment are the growth factors found in the remnant of the extracellular matrix of the amniotic tissue and well as remnant natural hyaluronic acid.

Amniotic “stem cells” marketed in many chiropractic offices are, in reality, micronized amniotic fluid. The micronization process takes amniotic fluid, freeze-dries it, and then processes it. The process kills the stem cells. NO live stem cells are present. However, growth factor remnants remain.

Many people attend webinars and seminars on the benefits of amniotic/placenta, and umbilical cord stem cell therapy. These seminars are often conducted by a chiropractor whose presentation includes a segment on how the attendees of the seminar have joint pain because their own stem cells are too few, too weak, too feeble, and too old to repair the damage.

The great irony of this argument is if you have been told that your own stem cells are too few, too weak, too feeble, and too old, how does the amniotic tissue then work if it has no new stem cells in it?

• The entire concept of how “amniotic stem cell therapy,” works is that it relies on the remnant growth factors not donated living stem cells. The remnant growth factors in the donated amniotic tissue stimulate your own stem cells to work.

For amniotic tissue treatment to work, it must work at the expense of debunking its own marketing claim that your stem cells are too few, too weak, too feeble, and too old to work.

Initial comparison:

• Adipose (fat) stem cells contain live growth factors and live stem cells.
• Bone marrow stem cells contain live growth factors and live stem cells.
• Platelet-rich plasma (PRP) contains live growth factors.
• Micronized amniotic fluid and afterbirth products contain processed growth factor material.

Amniotic-derived tissue product vs cortisone

In July 2022, Emory University researchers wrote in the journal Regenerative Medicine (66), of their study to discuss preliminary data from a clinical trial comparing a single injection of an amniotic-derived tissue product (dehydrated cell and protein concentrate) to corticosteroid for the treatment of knee osteoarthritis. Fifty-one patients were enrolled at the time of analysis (27 amniotic-derived tissue product , 24 corticosteroid). Both groups demonstrated improvement in pain and function 6 months after treatment. There was a larger improvement in the amniotic-derived tissue product group, but this did not reach a level of statistical significance. There were limited data beyond 6 months, but this trended toward a continued improvement in the amniotic-derived tissue product group.

Acupuncture

The most recent research on the use of acupuncture for knee osteoarthritis is mixed. People have reported good results with it.

A January 2022 paper published in the Journal of bodywork and movement therapies (67)  did not find acupuncture worked better than other treatments in groups of patients with knee osteoarthritis. The researchers wrote: “At short-term, there was low to very low evidence and there were statistically significant differences in pain intensity and knee function in favor of acupuncture versus control interventions in patients with knee osteoarthritis. However, these differences were not clinically important. (The findings did not warrant a recommendation to use acupuncture). For the acupuncture versus sham (acupuncture), in the short-term, no differences clinical neither statistically significant to favor of acupuncture in pain intensity and knee function.” The acupuncture did not work any better than the fake acupuncture.

Another study recommended its use.

In this April 2022 study published in the journal BioMed research international (68) “Acupuncture has beneficial effect on pain relief and improves function activities, and this treatment can be recommended as a beneficial alternative therapy in patients with knee osteoarthritis, particularly for chronic patients and those currently undergoing long-term pain and help them increasing quality of life.” With this recommendation comes the suggestion that more research is needed but (other) available studies suggested that “acupuncture was superior to sham acupuncture in reduce pain and function.”

How do Prolotherapy injections work for knee pain?

In this section, we will discuss Prolotherapy knee osteoarthritis injections. Prolotherapy is a remarkable treatment in its simplicity. The treatment can help many patients avoid joint replacement. But it is not a miracle cure. The research and evidence for how Prolotherapy may help you are presented here and intermingled with our own 28+ years of empirical observation of patient benefit.

A June 2022 paper in the journal Clinical Rehabilitation (69) describes the controversies and benefits of Prolotherapy injections. In examining previously published data, the researchers found: “Compared with placebo injection and noninvasive control therapy, dextrose Prolotherapy had favorable effects on pain, global function, and quality of life during the overall follow-up.” The researchers then concluded: “Dextrose Prolotherapy may have dose-dependent (the number of treatments) and time-dependent effects on pain reduction and function recovery, respectively, in patients with knee osteoarthritis. Due to remarkable heterogeneity and the risk of biases across the included trials, the study results should be cautiously interpreted.”

In 2016, our Caring Medical research team published our study, “A Systematic Review of Dextrose Prolotherapy for Chronic Musculoskeletal Pain” in the journal Clinical Medicine Insights Arthritis and Musculoskeletal Disorders. (70) In this review, we examined the research in the use of dextrose Prolotherapy for the treatment of tendinopathies, knee and finger joint osteoarthritis, and spinal/pelvic pain due to ligament dysfunction. In our section on knee pain, we referred to a study by Dr. Fariba Eslamian and Dr. Bahman Amouzandeh of Tabriz University of Medical Sciences. This is what they published in the journal Therapeutic Advances in Musculoskeletal Disease. (71)

“Prolotherapy has been reported as a useful method in the treatment of chronic musculoskeletal and joint diseases. It is proposed that Prolotherapy causes mild inflammation and cell stress in the weakened ligament or tendon area, releases cytokines and growth factors and induces a new healing cascade in that area, which leads to activation of fibroblasts, generation of collagen precursors, and strengthening of the connective tissue.”

• • In simpler terms, Prolotherapy injections cause a controlled inflammation to occur by mimicking an injury response. It tricks the cells into thinking a new wound has occurred. This stresses the cells to cause and calls for the release of growth and repair factors to initiate healing. These factors are found in the initial inflammatory response and include:
    • fibroblasts – a collagen and cartilage builder
    • chondrocytes – A chondrocyte is a cell that makes cartilage. In the human body, the chondrocyte is the only cell type in cartilage. Your entire cartilage is a wall of chondrocytes.
    • osteocytes – bone makers
• “These cells then excrete extracellular matrix, which enhances the stability of the joints by tightening and strengthening the ligaments, tendons, and joint stabilizing structures.”
  • We have a fascinating article The Extracellular matrix (ECM) | How comprehensive Prolotherapy repairs cartilage on this website if you would like to research that more.

Simply put, that is how Prolotherapy works. It rebuilds damaged soft tissue.

Recent research:

We have extensive research in our explained article: Prolotherapy knee osteoarthritis research: An option to knee surgery. This article presents the summarized learning points.

An April 2022 paper in the journal Aging Clinical and Experimental Research (72) assessed Prolotherapy injections for the treatment of knee osteoarthritis. Primary clinical outcomes were changes in knee pain and function scores. Secondary outcomes were adverse events related to Prolotherapy injections. At an average of about 23 weeks follow-up, Prolotherapy injection treatment significantly improved total pain and function scores compared with the control group. There were no severe adverse events related to dextrose injection reported in all the included studies. The researchers concluded: that Prolotherapy injections are a promising treatment for knee osteoarthritis with a reasonable safety profile.

A May 2020 study in the Annals of Family Medicine (73) made this simple statement at the conclusion of the research findings:

“Intra-articular dextrose prolotherapy injections reduced pain, improved function, and quality of life in patients with knee osteoarthritis compared with blinded saline injections. The procedure is straightforward and safe; the adherence and satisfaction were high.”

In this study, the research team assessed their findings in 76 patients with knee osteoarthritis:

• Patients were tested for pain and function at baseline.
• The patients were then treated with Prolotherapy or saline at 4, 8, and then 16 weeks.
• All outcomes were evaluated at baseline and at 16, 26, and 52 weeks.

Three treatments in a 12-week period and positive outcomes at 1 year. Prolotherapy reduced pain and improved function and quality of life. Further, the researchers noted: “Our findings are also consistent with other studies that have tested an intra-articular dextrose Prolotherapy protocol for knee osteoarthritis.” Let’s look at these other studies.

Another study from May 2020 published in The Journal of Alternative and Complementary Medicine (74) made these observations:

• The study included 66 patients aged 40-70 years with chronic knee pain that was not responding to conservative therapy and diagnosed with grade II or III knee osteoarthritis.
• The patients were assigned to the dextrose Prolotherapy group (22 patients), saline group (22 patients), or control group (22 patients).
• The intra- and extra-articular dextrose Prolotherapy and saline injections were administered at 0, 3, and 6 weeks. The patients were blinded to their injection group status.
• A home-based exercise program was prescribed for all patients in all three groups.
• Following pain and functional scoring outcomes, the researchers put their findings together and concluded: “These findings suggest that dextrose Prolotherapy is effective at reducing pain and improving the functional status and quality of life in patients with knee osteoarthritis.

In January 2019, David Rabago, MD, of the University of Wisconsin School of Medicine and Public Health, published research on Dextrose Prolotherapy for Symptomatic Knee Osteoarthritis in the Journal of Alternative and Complementary Medicine. (75)

Here are the learning points of that research:

• Patients received up to six Prolotherapy sessions.
• The primary data desired for analysis: Patient satisfaction with three or more Prolotherapy sessions.
• Secondary: Scoring assessment for improvement in function ability to get out of a chair, increase in walking ability, increase in the ability to climb stairs.
• Of the patients who participated in the study: “Satisfaction was high.

The study concluded “(suggested) that Prolotherapy in this primary care clinic is feasible and acceptable.” In other words, it is beneficial to patients.

In this image of a patient being prepped for and receiving Prolotherapy injections into their knee, the dots on the skin represent those areas of the knee that should receive an injection. In this particular patient, there are 50 dots on their knee. Each dot would represent where each injection would be given. This is one comprehensive Prolotherapy treatment for the knee. This is the type of treatment recommended for knee osteoarthritis.

Research: Prolotherapy treatments for patients with knee osteoarthritis showed significant improvement in scores for pain, function, and range of motion

In February 2020, Lisa May Billesberger, MD  a private practice physician in Canada teamed with Duke Anesthesiology, Duke University School of Medicine to offer a current assessment of injectable treatments for knee osteoarthritis. (76) Here are the summary points on Prolotherapy.

• Prolotherapy is a relatively simple and inexpensive treatment with a high safety profile, is something that could easily be performed in the primary care setting, and is thus worth consideration.
• The exact mechanism of Prolotherapy is not well understood, but it is thought to induce a pro-inflammatory response that results in the release of growth factors and cytokines, ultimately resulting in a regenerative process within the affected joint.
• Injection of the hyperosmolar dextrose solution might also hyperpolarize nociceptive pain fibers by forcing open potassium channels, resulting in reduced pain perception.
• In sum, Prolotherapy likely provides at least some benefit, although the quality of available data makes this statement hard to prove and it certainly does not cause harm.

Comparison research: hyaluronic acid and Prolotherapy injections

In November 2021 doctors publishing in the American Journal of Physical Medicine & Rehabilitation (77) evaluated the effectiveness of Prolotherapy for pain reduction and improvement of function in individuals with knee osteoarthritis in comparison with hyaluronic acid by meta-analysis (a review of previously published research). Six studies were included (395 participants).

Findings:

In favor of Prolotherapy

• No statistically significant differences were found between Prolotherapy and hyaluronic acid in pain control in the short term, however, the sub-analysis included only the studies that used intra-articular injection within the Prolotherapy scheme, and an effect was found in favor of the Prolotherapy groups.
• An effect was found in favor of the Prolotherapy group in the improvement in function.
• No major adverse reactions or side effects were reported in any of the studies.
• Prolotherapy appears to be an effective intervention to decrease pain and improve function in knee osteoarthritis, with efficacy similar to intra-articular injections with hyaluronic acid in the short-term follow-up.

Combining an injection of hyaluronic acid and dextrose (Prolotherapy).

An April 2022 paper in the Archives of Physical Medicine and Rehabilitation (78) wrote: “Compared with hyaluronic acid plus normal saline co-injections, hyaluronic acid plus dextrose co-injections resulted in more significant improvements in stair-climbing time and physical function at six months, effectively decreased pain, and improved physical function and physical functional performance from 1 week to six months. Hyaluronic acid plus dextrose co-injections could be a suitable adjuvant therapy for patients with knee osteoarthritis.”

Caring Medical Research – Prolotherapy for Knee Pain

In published research in the Journal of Prolotherapy, (79) Ross Hauser MD investigated the outcomes of patients receiving Prolotherapy treatment for unresolved, difficult to treat knee pain at a charity clinic in Illinois.

• 80 patients, representing a total of 119 knees, were treated quarterly with Prolotherapy.
• 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.

Prolotherapy for knee osteoarthritis

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 into 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 and all the tendon and ligament attachments there such as the LCL or lateral collateral ligament.

Comparison research

In September 2022, doctors in Turkey published their findings (80) on the effectiveness of  PRP and Prolotherapy for knee osteoarthritis.

In this study:

• A total of 108 patients with a diagnosis of knee osteoarthritis received either Prolotherapy, PRP, or exercise therapy. They were evaluated for knee pain and function at baseline, 1 month, and 3 months following treatments.
• At the start of treatments all three groups measured comparable scoring in standardized pain, function and disability surveys.
• At the first and third months, all groups showed a substantial improvement in the pain scores in activity and resting. When the groups were compared, the Prolotherapy and PRP treated patients showed significant improvement in the first and third months compared to the exercise group.
• Although PRP is more effective than Prolotherapy in the first month after treatment, Prolotherapy may be preferred due to its low cost, long-term efficacy, and low complication rates due to the periarticular (outside the knee joint) application.

We are going to cite some research that compares Prolotherapy to other treatments. We will start with this study. Then further below we will cite other studies.

In an August 2019 study, researchers published data comparing Prolotherapy to other injection techniques. The data was published in the journal Advances in Rheumatology. (81)

This study examined previous research and compared the effect of intra-articular (inside the joint) and/or extra-articular (outside and around the joint) injections of hyper dextrose Prolotherapy vs :

• hyaluronic acid,
• ozone
• radiofrequency
• PRP or Platelet Rich Plasma
• Erythropoietin. (A hormone said to activate bone marrow cells)

This is what the researchers noted:

“In terms of pain reduction and function improvement, Prolotherapy with hypertonic dextrose was more effective than infiltrations with local anesthetics, as effective as infiltrations with hyaluronic acid, ozone, or radiofrequency, and less effective than PRP and erythropoietin, with a beneficial effect in the short, medium and long term. In addition, no side effects or serious adverse reactions were reported in patients treated with hypertonic dextrose.”

To finish our comparisons first an explanation of Botox injections, then Ozone injections.

Botox for knee pain

Botox® is better known as a muscle paralyzer or relaxer and can help with muscle pain or spasms, in knee pain, it also works primarily as a “nerve blocker.” Therefore Botox® does not offer a repair of a damaged knee rather it is a suppressor of symptoms.

Some people do find pain relief. While there is not, however, a lot of research to support the use of Botox® for knee pain, some studies suggest benefits, and other comparative studies pitting Botox® against other treatments seem so-so.

In July 2019 researchers published data to suggest the benefits of Botox® in the journal Toxicon. (82) This journal studies the use of toxins in medicine.

Here are the learning points:

• In recent years, there is a growing interest in new medical applications of botulinum toxin, including pain control, osteoarthritis treatment, and wound healing. While clinical applications of botulinum toxin seem promising, existing evidence regarding the therapeutic effects is still inadequate. The aim was to assess the efficacy of a single injection of botulinum toxin into the knee joint cavity to reduce pain in elderly people.
• The researchers carried out a single group clinical trial – Thirty participants (24 women) more than 50 years of age with knee osteoarthritis were included.
• The patients received a single injection containing 250 units of Dysport (= 100 units of botulinum neurotoxin type A) diluted with 5 ml of normal saline.

What the researchers wanted to measure was:

• Improvement in knee pain
• How the patients felt about their knee pain and function.
• A single follow-up was taken 4 weeks after the injection.
  • The patients said their joint pain and stiffness, sports, the severity of symptoms, quality of life, and daily activities were improved.
• The researchers concluded that botulinum neurotoxin type A is an effective and safe initial treatment of knee osteoarthritis with clear clinical advantages.

A January 2023 paper in the journal Toxicon (83) examined the data from seven previously published studies comprising 548 patients on the effectiveness of Botulinum Toxin type A (BTA) for knee osteoarthritis symptoms. Compared with the control (saline) groups of the studies, Botulinum Toxin type A (BTA) injection exhibited greater pain reduction at four weeks posttreatment but not 8-24 weeks posttreatment. Additionally, no differences were found between Botulinum Toxin type A (BTA) injection versus control intervention on functional improvement at all time points assessed (at 4, 8, 12, and 24 weeks.) There was no significant difference in adverse event rate between the Botulinum Toxin type A (BTA) injection and the control group. This meta-analysis did suggest that intra-articular Botulinum Toxin type A (BTA) injection could be an effective and safe strategy for analgesic treatment of knee osteoarthritis in the short-term.

Comparing Botox® to other knee injection treatments

A June 2019 study in the journal Clinical Rehabilitation (84) compared the effectiveness of intra-articular injection of Botulinum toxin type A (Botox), triamcinolone hexacetonide (cortisone), and saline in primary knee osteoarthritis. The study found that cortisone injections had higher effectiveness than Botox or the saline (placebo) in the short-term assessment (four weeks) for pain in movement.

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. (85) 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.

Findings:

• 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.

Comparison of Ozone Therapy, Cortisone, Hyaluronic Acid Injections, and Dextrose Prolotherapy injections

There is a significant amount of research surrounding the use of ozone (o3) in treating various diseases. In this section, we will limit this research to comparative research.

An October 2018 study in the Journal of Pain Research (86) compared ozone treatments with Hyaluronic Acid Injections or Dextrose Prolotherapy injections as the control group.

Please note that this is not a comparison of Prolozone® to the other treatments, this is a comparison of ozone alone.

The researchers wrote that “the existing body of evidence had well demonstrated that ozone injection was evidently effective for short-term management (1–3 months) of mild-to-moderate knee osteoarthritis patients (grade I–III KLS). But the main challenge was on longer periods of time in which different studies had declared heterogeneous (or mixed) results.”

The researchers gathered dates from a series of randomized control trials and made these observations:

• The short-term effectiveness of intra-articular ozone is better than placebo (air) and corticosteroids
• The short-term effectiveness of intra-articular ozone is equal to that of dextrose Prolotherapy or hyaluronic acid injections.
• However, at 3–6 months after injections, the therapeutic efficacy of ozone decreased to a level, slightly lower than that of dextrose Prolotherapy or hyaluronic acid injections.
• After 6 months, ozone therapy was not associated with significant improvement in range of motion and functionality

---

2015 study in the journal Anesthesiology and Pain Medicine (87) showed that:

• “Prolotherapy with hypertonic dextrose or Prolozone® (intraarticular ozone injection) can be effectively used in the nonoperative management of patients with knee osteoarthritis. Prolotherapy is an injection therapy for the management of chronic musculoskeletal disorders such as knee osteoarthritis. . . Ozone is a toxic and soluble gas with high oxidative activity.
• Ozone has an antinociceptive (pain-blocking) effect
• Sixty-one percent (61%) of patients with lumbar disc herniation treated with intramuscular oxygen-ozone injection became pain-free compared with 33% of the control group.

Prolozone® is a Prolotherapy technique developed by Frank Shallenberger, MD, that utilizes ozone gas, along with other therapeutic substances to stimulate healing and reduce pain in injured soft tissues and joints. Dr. Shallenberger describes Proloze in a 2011 article in the Journal of Prolotherapy as: “a technique that marries concepts from neural therapy, Prolotherapy, and ozone therapy. It involves injecting various combinations of procaine, anti-inflammatory medications/homeopathics, vitamins, minerals, proliferative, and a mixture of ozone/oxygen gas into degenerated or injured joints, and into areas of pain. The result of this combination is nothing short of remarkable in that damaged tissues can be regenerated, and otherwise, untreatable pain can be permanently cured.”(88)

The ozone gas is produced when oxygen is exposed to an electric spark via a corona discharge ozone generator. The concentration of ozone in the final gas mixture is between 1­3%. Therapeutic injections of ozone into soft tissue structures, such as muscles, tendons, and ligaments as well as arthritic joints for the relief of pain have been utilized for decades in medical clinics around the world.

Various case series have been published documenting the analgesic effect of ozone in osteoarthritis. Double ­blind randomized ­controlled studies have also documented the therapeutic effects of Prolozone® in the treatment of low back pain with and without sciatica. As a powerful oxidizing agent, ozone has been found to have a pro-­inflammatory as well as an anti-­inflammatory effect, depending on the concentration utilized. Its proposed mechanisms for tissue repair and regeneration include the stimulating of growth factor production and release.

Another comparison of Ozone, PRP, and Hyaluronic Acid

A February 2021 study (89) compared the short and long-term efficacy of the intraarticular injections of hyaluronic acid, Platelet-Rich Plasma (PRP), plasma rich in growth factors (PRGF), and ozone in patients with knee osteoarthritis.

• 238 patients (average age about 57) with mild to moderate knee osteoarthritis were randomized into 4 groups:
  • hyaluronic acid (3 doses weekly),
  • PRP (2 doses with 3 weeks interval),
  • PRGF (2 doses with 3 weeks interval), and
  • Ozone (3 doses weekly).

Results: In 2 months of follow-up, significant improvements in pain, stiffness, and function were seen in all groups compared to the baseline, but the ozone group had the best results. In a 6-month follow up hyaluronic acid, PRP, and PRGF groups demonstrated better therapeutic effects in all scores in comparison with ozone. At the end of the 12th month, only PRGF and PRP groups had better results versus hyaluronic acid and ozone groups in all scores. Despite the fact that ozone showed better early results, its effects begin to wear off earlier than other products and ultimately disappear in 12 months.

Conclusions: Ozone injection had rapid effects and better short-term results after 2 months, but its therapeutic effects did not persist after 6 months and at the 6-month follow-up, PRP, PRGF, and hyaluronic acid were superior to ozone.

Dry Needling

A January 2023 paper in the journal BioMed Central musculoskeletal disorders (90) examined the outcome benefits of dry needling on latent and active myofascial trigger points versus oral diclofenac (NSAIDs) in patients with knee osteoarthritis. The researchers write: “Latent and active myofascial trigger points in knee-associated muscles may play a key role in pain management among patients with knee osteoarthritis.” Therefore, according to the researchers, “The aim of this study was to investigate the effect of dry needling treatment on pain intensity, disability, and range of motion (ROM) in patients with knee osteoarthritis.”

This study was conducted over a six week treatment program and a six month follow-up.

• A total of 98 patients were randomly assigned to:
  • the dry needling latent and active myofascial trigger point with stretching group or
  • the oral diclofenac with stretching group.
  • Various standardized testing scores for pain and function where then monitored.

Results: A total of 42 patients in the dry needling group and 35 patients in the diclofenac group completed the study, there was no significant difference in the general data between the two groups.

After treatments, both the groups showed a good effect in knee pain, function, and range of motion (ROM), However, the dry needling group showed a significantly better result than the diclofenac group. Especially in the results of the 6-month follow-up, the dry needling group showed much better results than the diclofenac group.

Summary

Why nothing is helping your knee pain. Research: NSAIDs, painkillers, corticosteroid injections offer little help in the long-term

A March 2022 paper in the Journal of orthopaedic translation (91) discusses the urgent need for new treatments for knee pain: “Non-steroidal anti-inflammatory drugs (NSAIDs), analgesics, intra-articular corticosteroid injections are of little value in the long term, and opioids may have ominous consequences. Radiotherapy of knee osteoarthritis has no added value. Physical therapy, exercises, weight loss, and lifestyle modifications may give pain relief, improve physical functioning and quality of life. However, none of them has articular cartilage regenerating potential. In the research above we demonstrated that certain injections may offer the articular cartilage regenerating potential looked for by researchers.

We hope you found this article informative and it helped answer many of the questions you may have surrounding these various injection treatments. If you have questions you can get help and information from our Caring Medical staff

References

1 Stone S, Malanga GA, Capella T. Corticosteroids: Review of the History, the Effectiveness, and Adverse Effects in the Treatment of Joint Pain. Pain Physician. 2021 Jan;24(S1):S233-S246. PMID: 33492920.
2 Matzkin EG, Curry EJ, Kong Q, Rogers MJ, Henry M, Smith EL. Efficacy and treatment response of intra-articular corticosteroid injections in patients with symptomatic knee osteoarthritis. JAAOS-Journal of the American Academy of Orthopaedic Surgeons. 2017 Oct 1;25(10):703-14. [Google Scholar]
3 McAlindon TE, LaValley MP, Harvey WF, Price LL, Driban JB, Zhang M, Ward RJ. Effect of Intra-articular Triamcinolone vs Saline on Knee Cartilage Volume and Pain in Patients With Knee OsteoarthritisA Randomized Clinical Trial. JAMA. 2017;317(19):1967-1975. [Google Scholar]
4 Haslam A, Livingston C, Prasad V. Medical reversals in family practice: a review. Current Therapeutic Research. 2020 Feb 22:100579. [Google Scholar]
5 Pelletier JP, Raynauld JP, Abram F, Dorais M, Paiement P, Martel-Pelletier J. Intra-articular corticosteroid knee injection induces a reduction in meniscal thickness with no treatment effect on cartilage volume: a case-control study. Scientific reports. 2020 Aug 14;10(1):1-0.  [Google Scholar]
6 Belk JW, Keeling LE, Kraeutler MJ, Snow MG, Mei-Dan O, Scillia AJ, McCarty EC. Risk of Infection in Knee Arthroscopy Patients Undergoing Corticosteroid Injections in the Perioperative Period. Orthopaedic Journal of Sports Medicine. 2021 Aug 17;9(8):23259671211032941-. [Google Scholar]
7 Heidari P, Heidari B, Babaei M. Efficacy and predictive factors of response to intra-articular corticosteroids in knee osteoarthritis. Reumatologia/Rheumatology. 2020;58(6):424-35. [Google Scholar]
8 Hauser RA. The Deterioration of Articular Cartilage in Osteoarthritis by Corticosteroid Injections. Journal of Prolotherapy. 2009;1(2):107-23. [Google Scholar]
9 Chang CY, Mittu S, Da Silva Cardoso M, Rodrigues TC, Palmer WE, Gyftopoulos S. Outcomes of imaging-guided corticosteroid injections in hip and knee osteoarthritis patients: a systematic review. Skeletal Radiology. 2022 Dec 15:1-2.
10 Donovan RL, Edwards TA, Judge A, Blom AW, Kunutsor SK, Whitehouse MR. Effects of recurrent intra-articular corticosteroid injections for osteoarthritis at three months and beyond: a systematic review and meta-analysis in comparison to other injectables. Osteoarthritis and Cartilage. 2022 Sep 13. [Google scholar]
11 Latourte A, Rat AC, Omorou A, Ngueyon Sime W, Eymard F, Sellam J, Roux C, Ea HK, Cohen‐Solal M, Bardin T, Beaudreuil J. Do corticosteroids injections increase the risk of knee osteoarthritis progression over 5 years?. Arthritis & Rheumatology. 2022 Mar 14. [Google Scholar]
12 Wang X, Sun Q, Wang M, Chen Y, Wang Q, Liu L, Yuan Y. Electrical Dry Needling Plus Corticosteroid Injection for Osteoarthritis of the Knee: A Randomized Controlled Trial. Arch Phys Med Rehabil. 2022 Jan 25:S0003-9993(22)00158-7. [Google Scholar]
13 Altman R, Lim S, Steen RG, Dasa V. Correction: Hyaluronic acid injections are associated with delay of total knee replacement surgery in patients with knee osteoarthritis: Evidence from a Large US Health Claims Database. PLoS One. 2016 Jan 29;11(1):e0148591. [Google Scholar]
14 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. American health & drug benefits. 2015 Oct;8(7):384. [Google Scholar]
15 Dasa V, Lim S, Heeckt P. Real-world evidence for safety and effectiveness of repeated courses of hyaluronic acid injections on the time to knee replacement surgery. American journal of orthopedics (Belle Mead, NJ). 2018 Jul;47(7). [Google Scholar]
16 Malanga G, Martins D, Nalmachu S, Dona S, Niazi F, Utkina K, Farrokhyar F, Alyass A, Rosen J. Delay to TKA in Patients Treated with a Multimodal Approach Using High Molecular Weight, Biologically Derived Hyaluronic Acid. Journal of Long-Term Effects of Medical Implants. 2021;31(3). [Google Scholar]
17 Schmajuk G, Bozic KJ, Yazdany J. Using Medicare data to understand low-value health care: the case of intra-articular hyaluronic acid injections. JAMA internal medicine. 2014 Oct 1;174(10):1702-4. [Google Scholar]
18 Leopold SS. Getting Evidence Into Practice–or Not: The Case of Viscosupplementation. Clinical Orthopaedics and Related Research. 2016 Feb;474(2):285. [Google Scholar]
19 Vincent P. Intra-articular hyaluronic acid in the symptomatic treatment of knee osteoarthritis: A meta-analysis of single-injection products. Current Therapeutic Research. 2019 Jan 1;90:39-51. [Google Scholar]
20 Malanga G, Niazi F, Kidd VD, Lau E, Kurtz SM, Ong KL, Concoff AL. Knee Osteoarthritis Treatment Costs in the Medicare Patient Population. American Health & Drug Benefits. 2020 Sep;13(4):144. [Google Scholar]
21 Belk JW, Lim JJ, Keeter C, McCulloch PC, Houck DA, McCarty EC, Frank RM, Kraeutler MJ. Patients With Knee Osteoarthritis Who Receive Platelet-Rich Plasma or Bone-Marrow Aspirate Concentrate Injections Have Better Outcomes Than Patients Who Receive Hyaluronic Acid: Systematic Review and Meta-analysis. Arthroscopy: The Journal of Arthroscopic & Related Surgery. 2023 Mar 11. [Google Scholar]
22 Civinini R, Nistri L, Martini C, Redl B, Ristori G, Innocenti M. Growth factors in the treatment of early osteoarthritis. Clinical Cases in Mineral and Bone Metabolism. 2013 Jan;10(1):26. [Google Scholar]
23 McLarnon, Michael Edmund David, and Neil Heron. “Intra-Articular Platelet-Rich Plasma Injections versus Intra-Articular Corticosteroid Injections for symptomatic management of knee osteoarthritis: Systematic Review and Meta-Analysis.” BMC Musculoskeletal Disorders (2021). [Google Scholar]
24 Moretti L, Maccagnano G, Coviello M, Cassano GD, Franchini A, Laneve A, Moretti B. Platelet Rich Plasma Injections for Knee Osteoarthritis Treatment: A Prospective Clinical Study. Journal of Clinical Medicine. 2022 May 8;11(9):2640. [Google Scholar]
25 Nunes-Tamashiro JC, Natour J, Ramuth FM, Toffolo SR, Mendes JG, Rosenfeld A, Furtado RN. Intra-articular injection with platelet-rich plasma compared to triamcinolone hexacetonide or saline solution in knee osteoarthritis: A double blinded randomized controlled trial with one year follow-up. Clinical Rehabilitation. 2022 Apr 4:02692155221090407. [Google Scholar]
26 Boffa A, Filardo G. Platelet-Rich Plasma for Intra-articular Injections: Preclinical and Clinical Evidence. Methods in Molecular Biology (Clifton, NJ). 2023 Jan 1;2598:381-90. [Google Scholar]
27 Belk JW, Kraeutler MJ, Houck DA, Goodrich JA, Dragoo JL, McCarty EC. Platelet-Rich Plasma Versus Hyaluronic Acid for Knee Osteoarthritis: A Systematic Review and Meta-analysis of Randomized Controlled Trials. The American Journal of Sports Medicine. 2020 Apr 17:0363546520909397. [Google Scholar]
28 Ren H, Zhang S, Wang X, Li Z, Guo W. Role of platelet-rich plasma in the treatment of osteoarthritis: a meta-analysis. Journal of International Medical Research. 2020 Oct;48(10):0300060520964661. [Google Scholar]
29 Dong Y, Zhang B, Yang Q, Zhu J, Sun X. The effects of platelet-rich plasma injection in knee and hip osteoarthritis: a meta-analysis of randomized controlled trials. Clinical Rheumatology. 2020 Jun 12:1-5. [Google Scholar]
30 Dai WL, Zhou AG, Zhang H, Zhang J. Efficacy of platelet-rich plasma in the treatment of knee osteoarthritis: a meta-analysis of randomized controlled trials. Arthroscopy: The Journal of Arthroscopic & Related Surgery. 2017 Mar 1;33(3):659-70. [Google Scholar]
31 Singh H, Knapik DM, Polce EM, Eikani CK, Bjornstad AH, Gursoy S, Perry AK, Westrick JC, Yanke AB, Verma NN, Cole BJ, Chahla JA. Relative Efficacy of Intra-articular Injections in the Treatment of Knee Osteoarthritis: A Systematic Review and Network Meta-analysis. Am J Sports Med. 2021 Aug 17:3635465211029659. doi: 10.1177/03635465211029659. Epub ahead of print. PMID: 34403285.
32 Southworth TM, Naveen NB, Tauro TM, Leong NL, Cole BJ. The use of platelet-rich plasma in symptomatic knee osteoarthritis. The journal of knee surgery. 2019 Jan;32(01):037-45. [Google Scholar]
33 Cook CS, Smith PA. Clinical update: why PRP should be your first choice for injection therapy in treating osteoarthritis of the knee. Current reviews in musculoskeletal medicine. 2018 Dec 1;11(4):583-92. [Google Scholar]
34 Forogh B, Mianehsaz E, Shoaee S, Ahadi T, Raissi GR, Sajadi S. Effect of single injection of platelet-rich plasma in comparison with corticosteroid on knee osteoarthritis: a double-blind randomized clinical trial. The Journal of sports medicine and physical fitness. 2016;56(7-8):901. [Google Scholar]
35 Freire MR, da Silva PM, Azevedo AR, Silva DS, da Silva RB, Cardoso JC. Comparative effect between infiltration of platelet-rich plasma and the use of corticosteroids in the treatment of knee osteoarthritis: a prospective and randomized clinical trial. Revista Brasileira de Ortopedia. 2020 Oct;55(5):551-6. [Google Scholar]
36 Klein D, Bloom D, Campbell K, Gonzalez-Lomas G, Alaia M, Strauss E, Jazrawi L, Thompson K. Alpha-2-Macroglobulin Not Significantly Better Than Regular PRP For Knee Arthritis Symptoms. Orthopaedic Journal of Sports Medicine. 2020 Jul 31;8(7_suppl6):2325967120S00454. [Google Scholar]
37 Kuwasawa A, Okazaki K, Noda K, Nihei K. Clinical results of autologous protein solution injection for knee osteoarthritis with severe disease grade is inferior to mild or moderate grade. Sci Rep. 2023 Apr 19;13(1):6404.
38 Kon E, Engebretsen L, Verdonk P, Nehrer S, Filardo G. Autologous protein solution injections for the treatment of knee osteoarthritis: 3-year results. The American Journal of Sports Medicine. 2020 Sep;48(11):2703-10. [Google Scholar]
39 Belk JW, Kraeutler MJ, Houck DA, Goodrich JA, Dragoo JL, McCarty EC. Platelet-Rich Plasma Versus Hyaluronic Acid for Knee Osteoarthritis: A Systematic Review and Meta-analysis of Randomized Controlled Trials [published online ahead of print, 2020 Apr 17]. Am J Sports Med. 2020;363546520909397. doi:10.1177/0363546520909397 [Google Scholar]
40 Tavassoli M, Janmohammadi N, Hosseini A, Khafri S, Esmaeilnejad-Ganji SM. Single-and double-dose of platelet-rich plasma versus hyaluronic acid for treatment of knee osteoarthritis: A randomized controlled trial. World Journal of Orthopedics. 2019 Sep 18;10(9):310. [Google Scholar]
41 Hohmann E, Tetsworth K, Glatt V. Is platelet-rich plasma effective for the treatment of knee osteoarthritis? A systematic review and meta-analysis of level 1 and 2 randomized controlled trials. European Journal of Orthopaedic Surgery & Traumatology. 2020 Feb 14:1-3. [Google Scholar]
42 Jivan SJ, Monzavi SM, Zargaran B, Alamdari DH, Afshari JT, Etemad-Rezaie A, Sakhmaresi TA, Shariati-Sarabi Z. Comparative analysis of the effectiveness of intra-articular injection of platelet-rich plasma versus hyaluronic acid for knee osteoarthritis: results of an open-label trial. Archives of Bone and Joint Surgery. 2021 Sep;9(5):487.
43 Huang Y, Liu X, Xu X, Liu J. Intra-articular injections of platelet-rich plasma, hyaluronic acid or corticosteroids for knee osteoarthritis. Der Orthopäde. 2019 Mar 15;48(3):239-47. [Google Scholar]
44 Raeissadat SA, Ahangar AG, Rayegani SM, Sajjadi MM, Ebrahimpour A, Yavari P. Platelet-rich plasma-derived growth factor vs hyaluronic acid injection in the individuals with knee osteoarthritis: a one year randomized clinical trial. Journal of Pain Research. 2020;13:1699. [Google Scholar]
45 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. Medical science monitor: international medical journal of experimental and clinical research. 2012;18(8):HY47. [Google Scholar]
46 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. Archives of Physical Medicine and Rehabilitation. 2014 Mar 1;95(3):562-75. [Google Scholar]
47 Phillips M, Bhandari M, Grant J, Bedi A, Trojian T, Johnson A, Schemitsch E. A Systematic Review of Current Clinical Practice Guidelines on Intra-articular Hyaluronic Acid, Corticosteroid, and Platelet-Rich Plasma Injection for Knee Osteoarthritis: An International Perspective. Orthopaedic Journal of Sports Medicine. 2021 Aug 31;9(8):23259671211030272. [Google Scholar]
48 Lin X, Zhi F, Lan Q, Deng W, Hou X, Wan Q. Comparing the efficacy of different intra-articular injections for knee osteoarthritis: A network analysis. Medicine. 2022 Aug 5;101(31):e29655. [Google Scholar]
49 Delanois RE, Sax OC, Chen Z, Cohen JM, Callahan DM, Mont MA. Biologic Therapies for the Treatment of Knee Osteoarthritis: An Updated Systematic Review. The Journal of Arthroplasty. 2022 May 21. [Google Scholar]
50 Doyle EC, Wragg NM, Wilson SL. Intraarticular injection of bone marrow-derived mesenchymal stem cells enhances regeneration in knee osteoarthritis. Knee Surgery, Sports Traumatology, Arthroscopy. 2020 Dec;28(12):3827-42. [Google Scholar]
51 Shapiro SA, Kazmerchak SE, Heckman MG, Zubair AC, O’Connor MI. A Prospective, Single-Blind, Placebo-Controlled Trial of Bone Marrow Aspirate Concentrate for Knee Osteoarthritis. Am J Sports Med. 2017 Jan;45(1):82-90. doi: 10.1177/0363546516662455. Epub 2016 Sep 30. [Google Scholar]
52 Gianakos AL, Sun L, Patel JN, Adams DM, Liporace FA. Clinical application of concentrated bone marrow aspirate in orthopaedics: A systematic review. World journal of orthopedics. 2017 Jun 18;8(6):491.  [Google Scholar]
53 Shaw B, Darrow M, Derian A. Short-Term Outcomes in Treatment of Knee Osteoarthritis With 4 Bone Marrow Concentrate Injections. Clin Med Insights Arthritis Musculoskelet Disord. 2018 Jun 18;11:1179544118781080. doi: 10.1177/1179544118781080. [Google Scholar]
54 Doyle EC, Wragg NM, Wilson SL. Intraarticular injection of bone marrow-derived mesenchymal stem cells enhances regeneration in knee osteoarthritis. Knee Surgery, Sports Traumatology, Arthroscopy. 2020 Jan 31:1-6. [Google Scholar]
55 Hauser RA, Orlofsky A. Regenerative injection therapy with whole bone marrow aspirate for degenerative joint disease: a case series. Clin Med Insights Arthritis Musculoskelet Disord. 2013 Sep 4;6:65-72. doi: 10.4137/CMAMD.S10951. PMID: 24046512; PMCID: PMC3771705.  [Google Scholar]
56 Lindroos B, Suuronen R, Miettinen S. The potential of adipose stem cells in regenerative medicine. Stem Cell Reviews and Reports. 2011 Jun 1;7(2):269-91. [Google Scholar]
57 Perdisa F, Gostyńska N, Roffi A, Filardo G, Marcacci M, Kon E. Adipose-derived mesenchymal stem cells for the treatment of articular cartilage: a systematic review on preclinical and clinical evidence. Stem cells international. 2015 Jul 9;2015. [Google Scholar]
58 Freitag J, Wickham J, Shah K, Tenen A. Real-world evidence of mesenchymal stem cell therapy in knee osteoarthritis: a large prospective two-year case series. Regenerative Medicine. 2022 Mar(0). [Google Scholar]
59 Kim KI, Lee WS, Kim JH, Bae JK, Jin W. Safety and Efficacy of the Intra-articular Injection of Mesenchymal Stem Cells for the Treatment of Osteoarthritic Knee: A 5-Year Follow-up Study. Stem Cells Translational Medicine. 2022 May 14. [Google Scholar]
60 Carvalho Schweich‐Adami L, Silva RA, Menezes JN, Baranoski A, Kassuya CA, Bernardi L, Juliano Oliveira R, Conceição Milan Brochado Antoniolli‐Silva A. The intra‐articular injection of adipose‐derived stem cells decreases pain and reduces inflammation in knee osteoarthritis, with or without the addition of platelet‐rich plasma also improves functionality. Journal of tissue engineering and regenerative medicine. 2022 Oct;16(10):900-12. [Google Scholar]
61 Estrada E, Décima JL, Rodríguez M, Di Tomaso M, Roberti J. Patient-Reported Outcomes After Platelet-Rich Plasma, Bone Marrow Aspirate, and Adipose-Derived Mesenchymal Stem Cell Injections for Symptomatic Knee Osteoarthritis. Clinical Medicine Insights: Arthritis and Musculoskeletal Disorders. 2020 Jul;13:1179544120931086.
62 El-Kadiry AE, Lumbao C, Salame N, Rafei M, Shammaa R. Bone marrow aspirate concentrate versus platelet-rich plasma for treating knee osteoarthritis: a one-year non-randomized retrospective comparative study. BMC Musculoskeletal Disorders. 2022 Dec;23(1):1-4. [Google Scholar]
63 Belk JW, Lim JJ, Keeter C, McCulloch PC, Houck DA, McCarty EC, Frank RM, Kraeutler MJ. Patients With Knee Osteoarthritis Who Receive Platelet-Rich Plasma or Bone-Marrow Aspirate Concentrate Injections Have Better Outcomes Than Patients Who Receive Hyaluronic Acid: Systematic Review and Meta-analysis. Arthroscopy: The Journal of Arthroscopic & Related Surgery. 2023 Mar 11. [Google Scholar]
64 Naja M, Fernandez De Grado G, Favreau H, Scipioni D, Benkirane-Jessel N, Musset AM, Offner D. Comparative effectiveness of nonsurgical interventions in the treatment of patients with knee osteoarthritis: A PRISMA-compliant systematic review and network meta-analysis. Medicine (Baltimore). 2021 Dec 10;100(49):e28067. doi: 10.1097/MD.0000000000028067. PMID: 34889254.
65 Liao, C.D., Chen, H.C., Huang, M.H., Liou, T.H., Lin, C.L. and Huang, S.W., 2023. Comparative Efficacy of Intra-Articular Injection, Physical Therapy, and Combined Treatments on Pain, Function, and Sarcopenia Indices in Knee Osteoarthritis: A Network Meta-Analysis of Randomized Controlled Trials. International Journal of Molecular Sciences, 24(7), p.6078. [Google Scholar]
66 Olufade O, Negron G, Berrigan W, Sirutis B, Whitley J, Easley K, Chen Y, Mautner K. Amniotic dehydrated cell and protein concentrate versus corticosteroid in knee osteoarthritis: preliminary findings. Regenerative Medicine. 2022 Apr(0). [Google Scholar]
67 Araya-Quintanilla F, Cuyúl-Vásquez I, Gutiérrez-Espinoza H. Does acupuncture provide pain relief in patients with osteoarthritis knee? An overview of systematic reviews. Journal of Bodywork and Movement Therapies. 2021 Nov 2. [Google Scholar]
68 Tian H, Huang L, Sun M, Xu G, He J, Zhou Z, Huang F, Liu Y, Liang F. Acupuncture for Knee Osteoarthritis: A Systematic Review of Randomized Clinical Trials with Meta-Analyses and Trial Sequential Analyses. BioMed Research International. 2022 Apr 21;2022. [Google Scholar]
69 Chen YW, Lin YN, Chen HC, Liou TH, Liao CD, Huang SW. Effectiveness, Compliance, and Safety of Dextrose Prolotherapy for Knee Osteoarthritis: A Meta-Analysis and Metaregression of Randomized Controlled Trials. Clinical Rehabilitation. 2022 Jun;36(6):740-52. [Google Scholar]
70 Hauser RA, Lackner JB, Steilen-Matias D, Harris DK. A systematic review of dextrose prolotherapy for chronic musculoskeletal pain. Clinical Medicine Insights: Arthritis and Musculoskeletal Disorders. 2016 Jan;9:CMAMD-S39160. [Google Scholar]
71 Eslamian F, Amouzandeh B. Therapeutic effects of prolotherapy with intra-articular dextrose injection in patients with moderate knee osteoarthritis: a single-arm study with 6 months follow up. Ther Adv Musculoskelet Dis. 2015 Apr;7(2):35-44. [Google Scholar]
72 Wang J, Liang J, Yao J, Song HX, Yang XT, Wu FC, Ye Y, Li JH, Wu T. Meta-analysis of clinical trials focusing on hypertonic dextrose prolotherapy (HDP) for knee osteoarthritis. Aging clinical and experimental research. 2021 Aug 27:1-0. [Google Scholar]
73 Shan Sit RW, Keung Wu RW, Rabago D, et al. Efficacy of Intra-Articular Hypertonic Dextrose (Prolotherapy) for Knee Osteoarthritis: A Randomized Controlled Trial. Ann Fam Med. 2020;18(3):235‐242. doi:10.1370/afm.2520 [Google Scholar]
74 Sert AT, Sen EI, Esmaeilzadeh S, Ozcan E. The effects of dextrose prolotherapy in symptomatic knee osteoarthritis: a randomized controlled study. The Journal of Alternative and Complementary Medicine. 2020 May 1;26(5):409-17. [Google Scholar]
75 Rabago D, Kansariwala I, Marshall D, Nourani B, Stiffler-Joachim M, Heiderscheit B. Dextrose prolotherapy for symptomatic knee osteoarthritis: feasibility, acceptability, and patient-oriented outcomes in a pilot-level quality improvement project. The Journal of Alternative and Complementary Medicine. 2019 Apr 1;25(4):406-12. [Google Scholar]
76 Billesberger LM, Fisher KM, Qadri YJ, Boortz-Marx RL. Procedural treatments for knee osteoarthritis: a review of current injectable therapies. Pain Research and Management. 2020 Feb 18;2020. [Google Scholar]
77 Arias-Vázquez PI, Tovilla-Zárate CA, Castillo-Avila RG, Legorreta-Ramírez BG, López-Narváez ML, Arcila-Novelo R, González-Castro TB. Hypertonic dextrose prolotherapy, an alternative to intra-articular injections with hyaluronic acid in the treatment of knee osteoarthritis: systematic review and meta-analysis. American Journal of Physical Medicine & Rehabilitation. 2022 Sep 1;101(9):816-25. [Google Scholar]
78 Hsieh RL, Lee WC. Effects of intra-articular coinjections of hyaluronic acid and hypertonic dextrose on knee osteoarthritis: a prospective, randomized, double-blind trial. Archives of Physical Medicine and Rehabilitation. 2022 Aug 1;103(8):1505-14. [Google Scholar]
79 Hauser RA, Hauser MA, Cukla JK. A retrospective observational study on Hackett-Hemwall Dextrose Prolotherapy for unresolved foot and toe pain at an outpatient charity clinic in rural Illinois. J Prolotherapy. 2011;3(1):543-51. [Google Scholar]
80 Medin Ceylan C, Sahbaz T, Cigdem Karacay B. Demonstrating the effectiveness of Platelet Rich Plasma and Prolotherapy treatments in knee osteoarthritis. Irish Journal of Medical Science (1971-). 2023 Feb;192(1):193-8. [Google Scholar]
81 Arias-Vázquez PI, Tovilla-Zárate CA, Legorreta-Ramírez BG, Fonz WB, Magaña-Ricardez D, González-Castro TB, Juárez-Rojop IE, López-Narváez ML. Prolotherapy for knee osteoarthritis using hypertonic dextrose vs other interventional treatments: systematic review of clinical trials. Advances in Rheumatology. 2019 Aug 29;59. [Google Scholar]
82 Najafi S, Sanati E, Khademi M, Abdorrazaghi F, Mofrad RK, Rezasoltani Z. Intra-articular botulinum toxin type A for treatment of knee osteoarthritis: Clinical trial. Toxicon. 2019 Jul 1;165:69-77. [Google Scholar]
83 Wang C, Zhao J, Gao F, Jia M, Hu L, Gao C. The efficacy and safety of intra-articular botulinum toxin type A injection for knee osteoarthritis: A meta‐analysis of randomized controlled trials. Toxicon. 2023 Jan 11:107026. [Google Scholar]
84 Mendes JG, Natour J, Nunes-Tamashiro JC, Toffolo SR, Rosenfeld A, Furtado RN. Comparison between intra-articular Botulinum toxin type A, corticosteroid, and saline in knee osteoarthritis: a randomized controlled trial. Clinical rehabilitation. 2019 Jun;33(6):1015-26. [Google Scholar]
85 Rezasoltani Z, Azizi S, Najafi S, Sanati E, Dadarkhah A, Abdorrazaghi F. Physical therapy, intra-articular dextrose prolotherapy, botulinum neurotoxin, and hyaluronic acid for knee osteoarthritis: Randomized clinical trial. International Journal of Rehabilitation Research. 2020 Mar 4;43(3):219-27. [Google Scholar]
86 Raeissadat SA, Tabibian E, Rayegani SM, Rahimi-Dehgolan S, Babaei-Ghazani A. An investigation into the efficacy of intra-articular ozone (O2–O3) injection in patients with knee osteoarthritis: a systematic review and meta-analysis. Journal of pain research. 2018 Oct 25:2537-50. [Google Scholar]
87 Hashemi M, Jalili P, Mennati S, Koosha A, Rohanifar R, Madadi F, Razavi SS, Taheri F. The effects of prolotherapy with hypertonic dextrose versus prolozone (intraarticular ozone) in patients with knee osteoarthritis. Anesthesiology and pain medicine. 2015 Oct;5(5). [Google Scholar]
88 Shallenberger F, HMD A. Prolozone™–regenerating joints and eliminating pain. Journal of Prolotherapy. 2011 May;3(2):630-8. [Google Scholar]
89 Raeissadat SA, Ghazi Hosseini P, Bahrami MH, Salman Roghani R, Fathi M, Gharooee Ahangar A, Darvish M. The comparison effects of intra-articular injection of Platelet Rich Plasma (PRP), Plasma Rich in Growth Factor (PRGF), Hyaluronic Acid (HA), and ozone in knee osteoarthritis; a one year randomized clinical trial. BMC musculoskeletal disorders. 2021 Dec;22:1-4. [Google Scholar]
90 Ma YT, Dong YL, Wang B, Xie WP, Huang QM, Zheng YJ. Dry needling on latent and active myofascial trigger points versus oral diclofenac in patients with knee osteoarthritis: a randomized controlled trial. BMC Musculoskeletal Disorders. 2023 Dec;24(1):1-3. [Google Scholar]
91 Cao X, Cui Z, Ding Z, Chen Y, Wu S, Wang X, Huang J. An osteoarthritis subtype characterized by synovial lipid metabolism disorder and fibroblast-like synoviocyte dysfunction. Journal of orthopaedic translation. 2022 Mar 1;33:142-52. [Google Scholar]

---

This article was updated April 14, 2023

 

Were you recommended SURGERY?
Get a 2nd opinion now!

WHY TO AVOID:

• Surgery
• NSAIDs
• Cortisone Shots
• R.I.C.E.

We are an out-of-network provider. Treatments discussed on this site may or may not work for your specific condition.
© 2023 Caring Medical | All Rights Reserved | Disclaimer