Ross Hauser, MD., Danielle R. Steilen-Matias, MMS, PA-C.
This article is from https://caringmedical.com/prolotherapy-news/knee-osteoarthritis-injections/

In this article, we will update new research and discuss prolotherapy knee osteoarthritis injections. The knee is the most common joint treated with prolotherapy at Caring Medical. We use a comprehensive prolotherapy approach that stimulates the natural repair of connective tissue. Prolotherapy research shows significant improvement in selected patients with knee osteoarthritis. Treating the whole knee joint as opposed to selective parts of the knee is more effective in alleviating knee pain and healing the damage.

Prolotherapy is a non-surgical injection treatment that introduces small amounts of an irritant solution (simple dextrose) into the knee with the goal of helping the immune system rebuild the soft connective tissue of the knee ligaments and knee tendons to restore stability to the knee and alleviate pain and improve function. The research is well documented and will be presented below.

Introduction

As stated, for the patient, the goal of prolotherapy in chronic musculoskeletal pain and instability is the stimulation of body’s natural healing and regenerative processes in the joint that will facilitate the repair and regrowth of connective tissue, ligaments, tendons for tensile strength, and cartilage and other knee stabilizing structures.

Prolotherapy works by creating a controlled inflammation that “turns on” the healing process. The growth of new ligament and tendon tissue is then stimulated. The ligaments and tendons produced after prolotherapy appear much the same as normal tissues, except that they are thicker, stronger, and contain fibers of varying thickness, testifying to the new and ongoing creation of tissue. This is documented in the research below.

Arthritis in the knee is one of the most common complaints that patients present to us at Caring Medical. More often than not, the people who reach out to us have experienced years of traditional care for knee pain, from regularly taking NSAIDs to cortisone injections, and even arthroscopic surgery to “clean out” the knee. By the time they arrive in our office, the possibility of a future knee replacement has already been discussed with their local orthopedic surgeon as the progression of arthritis appears unstoppable. No doubt, continuing with most of the traditional pain management methods, a person will end up with a knee replacement. Preferring to not take that route, Prolotherapy can be a good to excellent alternative to surgery because it addresses the root cause of what started the arthritic progression in addition to the ongoing damage. The underlying cause of the arthritis is actually soft-tissue structural damage that leads to degenerative changes in the knee. Meniscus tears or injuries to the supporting knee ligamentous system will eventually lead to degenerative arthritis. Determine the underlying cause of the weakness and instability; stop the degenerative process with regenerative injection treatments such as prolotherapy to halt the progression of arthritis.

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 treatment will not benefit everyone. The research and evidence for how Prolotherapy may help you are presented here and intermingled with our own 30+ years of empirical observation of patient benefit.

Discussion points of this article:

• The evidence for Prolotherapy Injections for knee osteoarthritis.
• Research on the benefits of prolotherapy for knee osteoarthritis.
• Prolotherapy addresses whole knee instability.
• How does Prolotherapy work in your knees?
• How do you know if prolotherapy will work for me? Assessment: Fair candidate for polotherapy.
• Who is a candidate for prolotherapy?
• Evidence that prolotherapy injections may regrow cartilage in the knee.
• Research: significant pain relief after Prolotherapy injections in patients suffering from knee osteoarthritis.
• Research: Prolotherapy treatments for patients with knee osteoarthritis showed significant improvement in scores for pain, function, and range of motion.
• New Research comparing prolotherapy to other treatments.
• Prolotherapy and Platelet Rich Plasma.
• Prolotherapy in grade IV knee osteoarthritis.
• Quality of Life changes after prolotherapy treatment for knee osteoarthritis.
• Treatment may help prevent knee replacement.
• Prolotherapy as an alternative to knee surgery.
• Knee function and mobility improvements after prolotherapy.

The path to knee replacement is inevitable unless you address the knee as a whole and not a problem of bone on bone. Prolotherapy addresses whole knee instability.

What does the above statement mean? It means the knee is a joint that depends on all its structures to be well maintained in order for it to work properly. Knee osteoarthritis is a degenerative process that occurs over a long period of time. Patients do not wake up one day with significant knee damage. They have usually had a long medical history of knee pain treatments that have ultimately led to a recommendation for a knee replacement. In the research below you will see a discussion about intra-articular injections, which are injections that go into the knee joint directly, and extra-articular injections, which are injections that go around the knee. You will also see research on the benefits of combining both in the same Prolotherapy treatment.

The evidence for Prolotherapy Injections for knee osteoarthritis

There is a substantial amount of research on Prolotherapy knee injections. Most favorable, some findings however did not suggest superior or any benefit as compared to other injection treatments. We are going to briefly touch on older research and bring in the research updates up to November 2023.

In a study from 2009, our Caring Medical team published findings (1) that summarized the benefits of Prolotherapy.

• Prolotherapy is a “new” old treatment that has been utilized in clinical practices for over 80 years. Standardized and reviewed in clinical application by Dr. George Hackett in the 1950s, Prolotherapy has been shown to be an effective treatment in patients who suffer from joint instability due to ligament damage and overuse and related musculoskeletal and osteoarthritis.

Prolotherapy’s popularity as a treatment for chronic pain has intensified over the past two decades among both physicians and patients as clinical and anecdotal observations have proved in many cases its reliance as a non-surgical option for joint and back pain.

• Prolotherapy is a nonsurgical regenerative injection technique that introduces small amounts of an irritant solution to the site of painful and degenerated tendon insertions (entheses), joints, ligaments, and adjacent joint spaces during several treatment sessions to promote the growth of normal cells and tissues. Irritant solutions most often contain dextrose (d-glucose), a natural form of glucose normally found in the body.

The results of this research were

• 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, and crunching sensation, and an 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.

Now let’s look at the research from this paper from 2009 to 2023.

In November 2023, researchers from the Mayo Clinic Jacksonville Campus, Duke University, Eastern Virginia Medical School and Prisma Health University of South Carolina combined to issue their findings on the effectiveness of Prolotherapy for knee osteoarthritis. The findings were published in the medical journal Cureus (2). Let’s have the study authors describe the paper: ” Our case series included 15 total patients consisting of male and female patients aged 50-85 years old with a prior diagnosis of knee osteoarthritis and moderate pain. The patients completed baseline (pain, function and disability surveys) and received an ultrasound-guided intra-articular prolotherapy injection.” These 15 patients were then followed for three months by phone visit to assess the patient’s progress. Here are some of the findings from these phone surveys: “Results revealed significantly improved functional scores from the baseline period to the one-month, two-month, and three-month (check in points) . . .Participants reported significantly lower pain scores between the baseline period compared to the one-month (survey), two-month (survey) and three-month (survey) periods.” The researchers also noted that stiffness did not appear to get significantly better over the three month period.

In summary, the researchers write: “The results support a statistically significant improvement in patients’ self-reported functioning and pain scores between the baseline and one-month, two-month, and three-month periods.  . . .This study supports prolotherapy as an effective treatment option to improve pain and function in knee osteoarthritis.”

When knee replacement could not be performed on a 72-year-old woman. Prolotherapy increased joint space.

We are going to stop here at a 2012 case report published in the medical journal Anesthesiology and Pain Medicine (3) which discusses the clinical and radiological outcomes of prolotherapy in a patient whose total knee prosthesis had been planned but surgery couldn’t be performed due to other existing medical conditions. Many people reach out to us in a similar situation asking can prolotherapy help when knee replacement has been ruled out by other health issues.

• The patient was a 72-year-old woman with severe pain in her knees for over 5 years.
• Treatment methods include weight loss, decreasing the weight-bearing on the joint, stretching exercises, non-steroid anti-inflammatory and steroid drugs, and physiotherapy.
  • At the radiological evaluation, the patient was diagnosed with grade IV osteoarthritis due to significant osteophyte (bone spurs) and complete joint space narrowing.
• Six sessions of knee Prolotherapy protocol were applied to the patient, one session monthly.

Significant improvement was noted

• The osteoarthritis level of the patient was improved to grade I at radiological evaluation after a year. What does this mean? The patient’s x-ray showed an increase in joint space after one-year. This case history was cited in numerous research papers including those mentioned in this article.

Does prolotherapy regrow cartilage in the knee?

Cartilage regrowth is demonstrated by increased joint space. Many research studies, as seen here, show the varying amount of patient improvements seen in patient-reported outcomes in pain, function, and joint space. It can be theorized that many of these people find relief through the stabilization of their knees by the strengthening of the knee ligament and tendon attachments to the bone and an increase in joint space.

More evidence that prolotherapy injections may regrow cartilage in the knee.

Led by researchers at the University of California at Los Angeles (UCLA) and the Department of Biological Sciences, at the University of Southern California (USC) a June 2021 paper in the medical journal Cartilage (4) offered these observations:

“Hypertonic dextrose injections (Prolotherapy) for osteoarthritis are reported to (be able to) reduce pain. Cartilage regeneration is hypothesized as a mechanism. This in vitro study identifies a prolotherapy concentration that stimulates chondrogenic cells to increase metabolic activity and assesses whether this concentration affects collagen deposition and proliferation.”

What the researchers are doing is taking hypertonic dextrose to see if, in a lab setting, they can grow cartilage cells with it. This was their observation.

(Prolotherapy)  “solution appears to be associated with the increased metabolic activity of chondrocytes (reproduction of the cells that make cartilage), increased collagen deposition, and increased chondrocyte proliferation. These results support clinical prolotherapy research suggesting that intra-articular hypertonic dextrose joint injections reduce knee pain. Further study of Hypertonic dextrose injections and cellular processes is warranted.”

A May 2021 paper (5) found evidence that dextrose prolotherapy curtailed or stopped cartilage breakdown. Here researchers writing in the Journal of Rehabilitation Medicine (4) saw a “significant reduction in urinary C-terminal telopeptide of type II collagen” In patients who had prolotherapy compared with those who had hyaluronic acid injections. What does this mean urinary C-terminal telopeptide is a test that measures cartilage breakdown by way of collagen byproducts in the urine. Prolotherapy reduced the amount of breakdown product in the urine and thereby demonstrated a slowing or halting of the degenerative process.

Prolotherapy could regrow articular cartilage in the knee in a study of patients with an average age of 71 seventy-one.

In April 2016, A multinational team representing University researchers in Argentina and Dr. Dean Reeves from the University of Kansas Medical Center, Dr. J. Johnson from Michigan State University, and Dr. Rabago from the University of Wisconsin, School of Medicine and Public Health researchers confirmed that prolotherapy could regrow articular cartilage in the knee in a study of patients with an average age of 71 seventy-one. (6) 

Study Participants

• Six participants (1 female and 5 male) with a median age of 71 years, and an average pain duration of 9 years. Symptomatic knee osteoarthritis for at least 6 months, arthroscopy-confirmed medial compartment exposed subchondral bone (a bone-on-bone situation), and temporary pain relief with intra-articular lidocaine injection.
• Patients received an average of 6 dextrose injections and follow-up arthroscopy at 7.75 months (range 4.5-9.5 months)
• Biopsy specimens showed metabolically active cartilage with variable cellular organization, fiber parallelism, and cartilage typing patterns consistent with fibro- and hyaline-like cartilage.
• Positive clinical and chondrogenic (cartilage growth) effects were seen after Prolotherapy with hypertonic dextrose injection in participants with symptomatic grade IV Knee Osteoarthritis, suggesting disease-modifying effects and the need for confirmation in controlled studies. Minimally invasive arthroscopy (single-compartment, single-portal) enabled the collection of robust intra-articular data.

• This suggested a disease-modifying effect or a “reversal” of the disease progression.

Generally speaking, however, patients with no range of motion, and locked up or frozen knees will not benefit from Prolotherapy injections

Prolotherapy injections upregulate healing growth factors and create joint space

A January 2022 paper (7) from leading university researchers in Taiwan investigated the inflammation-related protein-expression profile characterizing the efficacy of hypertonic dextrose prolotherapy in knee osteoarthritis as prognostic markers. More simply, was the prolotherapy treatment causing healing inflammation to occur, and what was the proof it was?

The researchers recruited patients over the age of 65 who had clearly defined and diagnosed knee osteoarthritis. To test the effectiveness of Prolotherapy in this group the patients were assessed using the Western Ontario McMaster University Osteoarthritis (WOMAC) disability, function and pain index, knee X-ray evaluation, and knee joint synovial fluid analysis before and after hypertonic dextrose Prolotherapy. The expressions of inflammation-related factors were also measured.

Results: The WOMAC Index and minimum joint space width prior to receiving the intra-articular injection and at 2-week intervals were compared.

• 12 patients received clinical evaluation of 12 knee joints (one knee per patient) and knee synovial fluid samples were analyzed. In this study, after receiving hypertonic dextrose Prolotherapy, the osteoarthritis patients clearly demonstrated a significant improvement in WOMAC index and an increasing tendency in the medial minimum joint space width after the intervention. Additionally, the researchers observed a significantly associated tendency between the high-glucose treatment of knee osteoarthritis and the upregulation of signaling enzymes and proteins that facilitate cartilage repair and regrowth.

Conclusion: “These findings provide knee osteoarthritis patients receiving hypertonic dextrose Prolotherapy, which accompanies the improvement of knee pain, stiffness, and function and increasing tendency in the medial minimum joint space width (more joint space).

A healing mechanism of Prolotherapy: Knee inflammation and regulation of knee inflammation.

What is the “upregulation of healing inflammatory factors” as described in many studies? Let’s get some help with an answer from a November 2022 study published in the journal Clinics and Practice (8).

Here is what the study author’s explained: “Neurocytokines (cells that among other things communicate pain and the need for inflammation) may upregulate or downregulate neuropathic pain. “(The authors) hypothesized that dextrose (prolotherapy) injections for therapeutic purposes in painful knee osteoarthritis would favorably affect synovial-fluid neurocytokine concentrations.” In other words, prolotherapy, by rebooting and resetting the inflammation process in the knee would act as a pain killer.

Here are the findings:

• Twenty people with grade IV symptomatic knee osteoarthritis had synovial-fluid aspiration followed by prolotherapy injections, followed by the reverse after one week.
• All participants then received prolotherapy injections monthly for six months, with serial assessments of walking pain at 20 minutes for 9 months, as well as synovial-neuro cytokine-concentration measurements at one week and three months.

Results:

• Prompt and medium-term pain relief after intra-articular dextrose injection in knee osteoarthritis was accompanied by potentially favorable changes in synovial-fluid neurocytokines.

What does this mean?

Prolotherapy injections helped regulate the inflammation in the knee and created pain relief and better function. 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. (9) In this paper we explain the regulatory role of prolotherapy on inflammation by referring to previously published research in the journal Therapeutic Advances in Musculoskeletal Disease. (10)

• “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 the 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.

The Prolotherapy effect is controlled and pinpoint inflammation to damaged knee tissue

In this image of a patient being prepped for 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.

The concept of prolotherapy treatment causing healing inflammation to occur, and the outcome results of research in patients over 65 years old.

A good summary may be prolotherapy acts as an anti-inflammatory, as a painkiller, and as a growth factor to regenerate cartilage. But not for everyone.

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. (11) 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 (which makes you less susceptible to pain) 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.

General research outcomes

In the above research, we went through some of the proposed mechanisms of how prolotherapy may work. Now let’s look at general outcomes in the treatment of people 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. (12)

Here are the learning points of that research:

• Patients received up to six prolotherapy sessions.
• The primary data desired for analysis is 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.

Prolotherapy appears to be a safe and effective alternative to physical therapy, surgery, NSAIDs, steroids and opiates when they fail to provide clinical relief.

A May 2022 study in the journal Orthopedic Reviews (13) led by doctors at Georgetown University School of Medicine, Louisiana State University School of Medicine, and Creighton University School of Medicine wrote: “Numerous clinical trials show significant improvement of osteoarthritic pain of the knee without any significant side effects reported following the use of prolotherapy. Although there is heterogeneity (non-standardized or consistent application of the treatment) between studies with regard to study variables, the results consistently show significant improvement in radiographic (documented on scans) outcomes, pain scores, and quality of life with prolotherapy treatment. Prolotherapy appears to be a safe and effective alternative to physical therapy, surgery, NSAIDs, steroids and opiates when they fail to provide clinical relief.

A review of 14 Prolotherapy research studies and examination of 978 patient charts 

A June 2022 study in the journal Clinical Rehabilitation (14) assessed the effectiveness, compliance, and safety of dextrose prolotherapy for patients with knee osteoarthritis. A total of 14 previously published studies with outcomes of 978 patients were included in this meta-analysis.

• 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.
• Dextrose prolotherapy yielded greater reductions in pain score over each follow-up duration than did the placebo.
• Compared with other invasive therapies, dextrose prolotherapy generally achieved comparable effects on pain and functional outcomes for each follow-up duration.
• Subgroup results indicated that combined intra-articular and extra-articular injection techniques may have stronger effects on pain than a single intra-articular technique. (This would be the technique, as we use, for injections into and around the knee joint).

Prolotherapy outcome findings in 76 patients with knee osteoarthritis

A May 2020 study in the Annals of Family Medicine (15) made this simple statement at the conclusion of the research findings in 76 patients with knee osteoarthritis:

“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.”

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

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.

Prolotherapy outcome findings in 66 patients with knee osteoarthritis

Another study from May 2020 published in The Journal of Alternative and Complementary Medicine (16) 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 study onset, three, and six 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.

Recent research comparing Prolotherapy to other treatments

A September 2020 study published in the International Journal of Rehabilitation Research (17) 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.

In an August 2019 study, researchers published data comparing Prolotherapy to other injection techniques. The data was published in the journal Advances in Rheumatology. (18)

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.”

Prolotherapy and hyaluronic acid injections

In September 2022, a paper in the American Journal of Physical Medicine & Rehabilitation (19) compared Prolotherapy to hyaluronic acid injections in knee osteoarthritis patients. Here are the summary findings of this research:

“Intra-articular injections with hyaluronic acid are recommended in the treatment of knee osteoarthritis; however, hypertonic dextrose prolotherapy has been reported as effective and safe. The aim (of this study) was to evaluate the effectiveness of hypertonic dextrose prolotherapy for pain reduction and improvement of function in individuals with knee osteoarthritis in comparison with hyaluronic acid by meta-analysis (comparing data from previous research).”

The researchers used six previously published studies with the data of 395 patients.

The researchers reported: “Initially there were no statistically significant differences found between Prolotherapy and hyaluronic acid treatments in pain control in the short-term; however, in the subanalysis that included only the studies that used intra-articular injections, an effect was found in favor of the Prolotherapy groups. Also, 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. Hypertonic dextrose prolotherapy seems 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. Nonetheless, better-quality clinical trials are necessary.”

Prolotherapy and physical therapy

An August 2023 paper in the journal Medicine International (20) compared the effectiveness of hypertonic dextrose prolotherapy with conventional physiotherapy (physical therapy) in improving symptoms in female patients with knee osteoarthritis. In this study, 60 patients with a diagnosis of knee osteoarthritis were randomly assigned to prolotherapy (30 patients) and physical therapy (30 patients). “The patients in the prolotherapy group were treated with a dextrose injection into the knee joint (25% dextrose) and around the knee (15% dextrose) twice for one month, while those in the physical therapy group received a hot pack, transcutaneous electrical nerve stimulation and therapeutic ultrasound in five sessions a week for 4 weeks.

At one and three months post-treatment, the (standardized pain, disability, and function reported) scores of all the outcome parameters were significantly improved in the prolotherapy group compared with the physical therapy group. In both groups, a significant improvement was observed in (the pain, disability, and function scores) following the treatments, with the greatest improvement observed in the prolotherapy group. . . On the whole, the results of the present study demonstrate that both prolotherapy and physical therapy are effective treatment modalities to relieve pain and increase functionality and strength in patients with knee osteoarthritis. However, greater improvements in pain and functionality can be achieved with prolotherapy.”

Prolotherapy and Platelet-Rich Plasma

A May 2021 study in the Journal of Clinical Orthopaedics and Trauma (21) sought to explore the benefits of Prolotherapy for knee osteoarthritis and offer a comparison to Platelet-Rich Plasma

In this paper, the researchers examined previously reported research on the effectiveness of Prolotherapy on knee osteoarthritis.

In total, the researchers found eleven articles (with 837 patients examined) that met their criteria for a fair evaluation. Of these 11 articles, two were found to be a low risk for bias. What does this mean? It generally means that when there is a high risk of bias, the “biased” researchers noted that a specific treatment was working and that when they published research on the “working treatment” they had a preconceived notion that their study would demonstrate statistically what they (the administering doctors) were observed clinically. In other words, the research would conclude that the treatment was working because clinically, it was. This is considered “bias.”

So what these researchers did was take two studies that were not biased or at low risk for bias and examine them. These were their suggested findings:

• Prolotherapy was no different from Platelet-Rich Plasma on the pain subscale at the 6-month time point. (Both Prolotherapy and PRP were effective treatments).
• Prolotherapy was inferior to Platelet-Rich Plasma at 6 months on the stiffness subscale.
• Prolotherapy was found to be safe with no major adverse effects.

Conclusion: Prolotherapy in knee osteoarthritis confers potential benefits for pain but the studies are at high risk of bias. Based on two well-designed studies, dextrose Prolotherapy may be considered in knee osteoarthritis (strength of recommendation B – based on limited good evidence). This treatment is safe and may be considered in patients with limited alternative options (strength of recommendation C – based more on clinical observation than a double-blinded or placebo drive study).

PRP, Prolotherapy, and exercise therapy

A September 2022 paper (22) compared the effectiveness of PRP, Prolotherapy, and exercise therapy in knee osteoarthritis patients. In this study:

• A total of 108 patients with a diagnosis of knee osteoarthritis were divided into three groups of treatment:
  • Prolotherapy group – 35 patients.
  • PRP group – 35 patients.
  • Exercise group – 38 patients.
• Visual Analogue Scale (Pain scale from 0 – 10) and The Western Ontario McMaster University Osteoarthritis Index (to assess pain, stiffness and function) were used as outcome measures at baseline, 1 month, and 3 months.
• All three groups showed similarities in demographics and baseline assessments of pain intensity, disability, and function.
• In the first and third months, all groups showed a substantial improvement in the Visual Analogue Scale reduced pain with activity, and reduced pain with resting and the pain, stiffness, and function scores after treatments.
• When the three treatments were compared the PRP and Prolotherapy groups improved significantly in the first and third months compared to the exercise group.

Conclusion: Pain and disability were significantly improved with Prolotherapy and PRP compared with exercise therapy. 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 application.

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

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

 

Caring Medical Research – Prolotherapy for Knee Pain

In published research in the Journal of Prolotherapy, (23) 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, and 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 lives overall.

Caring Medical documents Quality of Life changes after Prolotherapy treatment for knee osteoarthritis

In the same study, we asked the patients a simple yes or no question:

• Has prolotherapy changed your life for the better?
  • 96% of patients treated answered yes.
• In quantifying the response,
  • 43% felt their life was at least radically better with prolotherapy.
  • 88% rated Prolotherapy at least very successful in treating their condition (50% or greater improvement) with 50% noting the prolotherapy to be extremely successful (75% or greater improvement).
• The percentage of patients who were able to decrease their additional pain-related treatments including chiropractic, physical therapy, acupuncture, and massage after Prolotherapy was 86%.
• The percentage of patients able to decrease their medication usage by 50% or more was 90%.

Long-term results

The patients in this study were treated four to six years prior to the publishing of this paper.

• Eighty-seven percent noted that the results of prolotherapy have mostly continued (at least 50% retained), and 52% of patients noted that their overall results have very much continued to the present (75% to 99%).
• Seventy-eight percent noted there were reasons besides the Prolotherapy effect wearing off that were causing their continued pain and/or disability.
  • Of the 78%, 42% of these believe they stopped Prolotherapy too soon (before the pain was totally gone),
  • 20% re-injured the area that had received prolotherapy,
  • 13% had a new area of pain,
  • 10% had increased life stressors, and
  • 15% had other explanations for the pain.
• Of the patients whose pain recurred after Prolotherapy was stopped, 81% are planning on receiving more Prolotherapy.

Prolotherapy used on patients who had a duration of five years of unresolved knee pain was shown in this observational study to improve their quality of life.

Patients reported:

• less pain,
• stiffness,
• disability,
• depressed and anxious thoughts,
• medication and other pain therapy usage,
• improved walking ability,
• improved range of motion,
• improved ability to work and activities of daily living.

Therefore, prolotherapy appears to be a viable treatment option for people suffering from unresolved knee pain.

Treating the whole knee

Doctors writing in the Journal of Pain Research (24) have published research supporting what we have known here for decades. To most effectively treat knee osteoarthritis with prolotherapy you must treat the whole knee and not simply the cartilage degeneration.

In this study, doctors from the University of Tehran compared results in patients who received Prolotherapy with dextrose periarticular injections around the knee joint with patients who received Prolotherapy intra-articular injections. In other words, one group received injections around the knee joint, another group received injections directly into the knee joint.

• Both peri- and intra-articular Prolotherapy patients showed reduced pain and disability of their knee osteoarthritis after 5 months of follow-up.
• Interestingly, periarticular Prolotherapy had better effects on pain scores and disability scores in some respects.
  • Periarticular Prolotherapy injections showed superior effects on healing of knee disability and pain score compared with intra-articular injections.
  • Pain score was significantly lower at 1-, 2-, 3-, 4-, and 5-month visits in the periarticular group compared with the intra-articular group.
  • Periarticular injections have been suggested in some recent reports for analgesic effect after total knee replacement
  • Periarticular injections can significantly reduce the requirements for patient-controlled analgesia and can improve patient satisfaction following total knee replacement.
• Periarticular injection showed adjuvant effects to intra-articular Prolotherapy.

An April 2023 paper in the Journal of Anesthesiology and Pain Medicine (25) assessed the therapeutic effects of combined intra (in the knee) and extra-articular (around the knee) dextrose prolotherapy on knee osteoarthritis and compared these results with those of intra-articular triamcinolone (cortisone) injection.

In this double-blind randomized clinical trial, 50 patients with knee osteoarthritis were divided into two groups. The first group received one session of dextrose prolotherapy as one intra-articular injection of 10cc dextrose 16% and periarticular intradermal injections of dextrose 12% at 4 points around the knee (2.5 cc at each point). The second group underwent therapy with one intra-articular injection of triamcinolone (40 mg).

• Compared to pretreatment, both interventions caused significant improvement in pain in 1 and 3 months postintervention
• In the first month, pain reduction was significantly better in the corticosteroid group.
• In the third month post-intervention, improvements in VAS and WOMAC components were significantly greater in the prolotherapy group.

Does Prolotherapy work for everyone?

While generally, research supports the use of dextrose prolotherapy injections, other studies suggest a more tempered enthusiasm.

How do you know if Prolotherapy will work for me? Assessment: Fair candidate for Prolotherapy

In this image, the patient has lost nearly all of her cartilage from the outside to the middle of the knee. This is displayed by the arrow. Because of this loss of cartilage and because of her limited range of motion in that knee the patient was told that she was realistic, a fair candidate. Meaning we could anticipate fair (as opposed to good or excellent) results at the outcome. In this case, the outcome exceeded expectations (this is not always the case). The patient responded very well to treatment and had improved function and quality of life. She also had a significant reduction in knee pain.

What are we seeing in this image?

This is not the best candidate for prolotherapy but a fair candidate. The arrow to the left demonstrates that this patient has lost nearly all of her cartilage at the medial side of her knee. Because of this cartilage loss and her limited range of motion revealed during her physical examination, this patient was rated a fair candidate for treatment success. Treatment outcomes were discussed with the patient, the patient decided to proceed. In this situation (which may not be typical of all situations) this patient responded very well to treatment and had significant improvement in her knee pain and quality of life.

What are we seeing in this image? A very good candidate for Prolotherapy.

In this x-ray image, we can see that this patient is suffering from a mild loss of joint space. Her range of motion on physical examination was mildly limited patient’s range of motion but we still considered this patient a very good candidate for Prolotherapy injections.

Many people may know and understand that you can continue to be active and continue to exercise while undergoing Prolotherapy treatments but may not know what that means, the truth is it means something very different for everybody. Every patient we see may have some degree of knee instability, whether mild, moderate or severe, and have their own treatment goals.  Some people want to get back to running or tennis, some people want to simply be able to walk in their house and not have pain and trust that their knee will not give out.

General principles of activity levels while undergoing Prolotherapy. Exercise can be increased as joint stability improves.

The above chart helps explain Prolotherapy injections and continued activity during treatments.

Let’s say somebody comes into the office and they have a severe instability, meaning that we’ve looked at their knee under ultrasound, we’ve done stress maneuvers to look for knee instability related to knee ligament laxity, related to their MCL, medial collateral ligament or LCL, lateral collateral ligament and let’s say we see a severe instability.

Knee Bracing

That patient may require knee bracing if their knee is very unstable. If the person feels that their knee is going to give out, that may start walking less  because they’re so afraid of falling. We may suggest and have the patient fitted for a knee brace to help give their confidence in their knee so they can continue to move through the Prolotherapy treatments.

As the patient goes through the treatment program and their instability isn’t as severe and becomes more moderate, that’s when activity level changes for the better, we’re not going to advise somebody with a severe knee instability to play tennis right away, however, as the knee gets more stable, we may start to wean them off the knee brace. We may suggest not wearing the brace if they are simply walking around their house or other milder activities. As the patient starts to regain muscle strength and walking more, the brace will be called on less and less.

Less impactful and stressful exercises

As the knee stabilizes we may suggest lower impact lower body exercises. We may start with being in the pool. Swimming, hydrotherapy or “water walking. We may suggest cycling, ellipticals, and then continue to build up to running. Eventually as the knee progresses activities such as tennis, pickleball, or soccer where a lot of stress on the knee can be handled.

Soft tissue injury and the cause of osteoarthritis

Commonly people believe osteoarthritis begins with “old age,” a past trauma, a past meniscus or arthroscopic surgery. Osteoarthritis and knee instability starts with soft tissue injury, whether through wear and tear (old age or over use) or trauma (past injuries or surgeries)

As explained in the caption of this image: 

Following a trauma, ligaments become sprained and relaxed (or loose) if left untreated. Chronic joint instability and destructive joint motion occur with continued use of the joint, ultimately leading to extensive degenerative changes and osteoarthritis.

If you sprain your knee, injured a ligament such as the MCL or LCL, what may happen is as the ligament fails to heal, or be rested, or treated, the degenerative process continues and towards the joint instability. The injured ligament is simply not strong enough to hold the knee in a stable position and your knee starts to give out and “pop out of place.”

Summary

In our research and the independent research noted in this article, we have shown that prolotherapy can help resolve chronic knee pain. In many people, the effects of prolotherapy are often permanent, future treatments are rarely needed.

The goal of the treatment is to produce articular cartilage, ligament, meniscus, and joint capsular tissue that is able to withstand the forces a person puts on them and then replenish the joint fluid sufficiently to cushion the joint effectively.

The primary cause of knee pain is knee joint instability. This can be due to a number of ligaments and tendon attachments becoming torn or degenerated, as well as damaged or removed cartilage and meniscal tissue. Prolotherapy causes a stabilization of the knee after these ligaments are treated.

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References

1 Hauser RA, Hauser MA.  A Retrospective Study on Dextrose Prolotherapy for Unresolved Knee Pain at an Outpatient Charity Clinic in Rural Illinois. Journal of Prolotherapy. 2009;1:11-21.  [Google Scholar]
2 Vomer II RP, Larick RS, Milon R, York E. The Effect of Intra-articular Hypertonic Dextrose Prolotherapy on Pain, Quality of Life, and Functional Outcomes Scores in Patients With Knee Osteoarthritis. Cureus. 2023 Nov 1;15(11). [Google Scholar]
3 Solmaz I, Deniz S, Cifci OT. Treatment of advanced stage gonarthrosis with prolotherapy: case report. Anesth Pain Med. 2013 Dec 16;4(1):e9171. doi: 10.5812/aapm.9171. [Google Scholar]
4 Johnston E, Kou Y, Junge J, Chen L, Kochan A, Johnston M, Rabago D. Hypertonic Dextrose Stimulates Chondrogenic Cells to Deposit Collagen and Proliferate. Cartilage. 2021 Jun 10:19476035211014572. [Google Scholar]
5 Waluyo Y, Bukhari A, Adnan E, Haryadi RD, Idris I, Hamid F, Usman A, Johan MP, Zainuddin AA. Changes in levels of cartilage oligomeric proteinase and urinary C-terminal telopeptide of type II collagen in subjects with knee osteoarthritis after dextrose prolotherapy: A randomized controlled trial. Journal of Rehabilitation Medicine. 2021;53(5). [Google Scholar]
6 Topol GA, Podesta LA, Reeves KD, Giraldo MM, Johnson LL, Grasso R, Jamín A, Clark T, Rabago D. Chondrogenic Effect of Intra-articular Hypertonic-Dextrose (Prolotherapy) in Severe Knee Osteoarthritis. PM R. 2016 Apr 4. pii:S1934-1482(16)30054-5.  [Google Scholar]
7 Pan PJ, Wang JC, Tsai CC, Kuo HC. Identification of early response to hypertonic dextrose prolotherapy markers in knee osteoarthritis patients by an inflammation-related cytokine array. Journal of the Chinese Medical Association. 2022 Apr 1;85(4):525-31. [Google Scholar]
8 Topol GA, Pestalardo IG, Reeves KD, Elias F, Steinmetz NJ, Cheng AL, Rabago D. Dextrose Prolotherapy for Symptomatic Grade IV Knee Osteoarthritis: A Pilot Study of Early and Longer-Term Analgesia and Pain-Specific Cytokine Concentrations. Clinics and Practice. 2022 Nov 14;12(6):926-38. [Google Scholar]
9 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]
10 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]
11 Billesberger LM, Fisher KM, Qadri YJ, Boortz-Marx RL. Procedural Treatments for Knee Osteoarthritis: A Review of Current Injectable Therapies. Pain Res Manag. 2020;2020:3873098. Published 2020 Feb 18. doi:10.1155/2020/3873098 [Google Scholar]
12 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 Jan 28. [Google Scholar]
13 Zhao AT, Caballero CJ, Nguyen LT, Vienne HC, Lee C, Kaye AD. A Comprehensive Update of Prolotherapy in the Management of Osteoarthritis of the Knee. Orthopedic Reviews. 2022 May 31;14(4):33921. [Google Scholar]
14 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]
15 Sit RW, Wu RW, Rabago D, Reeves KD, Chan DC, Yip BH, Chung VC, Wong SY. Efficacy of intra-articular hypertonic dextrose (prolotherapy) for knee osteoarthritis: a randomized controlled trial. The Annals of Family Medicine. 2020 May 1;18(3):235-42. [Google Scholar]
16 Sert AT, Sen EI, Esmaeilzadeh S, Ozcan E. The Effects of Dextrose Prolotherapy in Symptomatic Knee Osteoarthritis: A Randomized Controlled Study. J Altern Complement Med. 2020;26(5):409‐417. doi:10.1089/acm.2019.0335 [Google Scholar]
17 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. Int J Rehabil Res. 2020;43(3):219-227. doi:10.1097/MRR.0000000000000411 [Google Scholar]
18 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 Dec;59(1):1-9. [Google Scholar]
19 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]
20 Yildiz KM, Guler H, Ogut H, Yildizgoren MT, Turhanoglu AD. A comparison between hypertonic dextrose prolotherapy and conventional physiotherapy in patients with knee osteoarthritis. Medicine International. 2023 Sep 1;3(5):1-9. [Google Scholar]
21 Wee TC, Neo EJ, Tan YL. Dextrose prolotherapy in knee osteoarthritis: A systematic review and meta-analysis. Journal of Clinical Orthopaedics and Trauma. 2021 May 20. [Google Scholar]
22 Medin Ceylan C, Sahbaz T, Cigdem Karacay B. Demonstrating the effectiveness of Platelet Rich Plasma and Prolotherapy treatments in knee osteoarthritis. Ir J Med Sci. 2022 Sep 27. doi: 10.1007/s11845-022-03168-7. Epub ahead of print. PMID: 36166187. [Google Scholar]
23 Hauser RA, Hauser MA. A retrospective study on dextrose Prolotherapy for unresolved knee pain at an outpatient charity clinic in rural Illinois. Journal of Prolotherapy. 2009;1(1):11-21. [Google Scholar]
24 Rezasoltani Z, Taheri M, Mofrad MK, Mohajerani SA. Periarticular dextrose prolotherapy instead of intra-articular injection for pain and functional improvement in knee osteoarthritis. Journal of Pain Research. 2017;10:1179-1187.  [Google Scholar]
25 Bayat M, Hojjati F, Nazar NS, Modabberi M, sadat Rahimi M. Comparison of Dextrose Prolotherapy and Triamcinolone Intraarticular Injection on Pain and Function in Patients with Knee Osteoarthritis-A Randomized Clinical Trial. Anesthesiology and Pain Medicine. 2023 Apr 30;13(2). [Google Scholar]

This article was updated April 16, 2024