Prolotherapy injections for knee osteoarthritis

Marc Darrow, MD, JD

Over the past few decades Prolotherapy, the injection of sugar solution and other substances in and around a painful joint, has become an increasingly popular alternative to surgery and steroid injections.

Prolotherapy is given as an injection of a mild irritant (something that causes inflammation), often dextrose (a simple sugar), into a specific area of the body that is arthritic, worn down, or injured.  When the irritant is injected into the knee, it causes the body’s immune system to stimulate the inflammatory process. While it may seem counterintuitive to create more inflammation, it is in fact inflammation that is part of the body’s natural healing response. This burst of increased inflammation attracts fibroblasts (immature cells present in connective tissue) and chondrocytes (cells that produce cartilage) and brings them to the area of degeneration or injury.

These cells rebuild the collagen (more specifically, what is called the “collagen matrix” of the tissue) and enable it to strengthen and restore the body part in many cases to pre-injury status.

In a November 2023 paper (1) , 15 knee osteoarthritis patients who had moderate knee pain were given an ultrasound-guided intra-articular prolotherapy injection. The patients between 50-85 years old  were then followed for a three month period following the injection. The researcher team lead by the Mayo Clinic Jacksonville Campus and Duke University wrote of the results: “This case series examined the safety and cost-effectiveness of prolotherapy as a treatment for knee osteoarthritis. We found a statistically significant improvement in patients’ self-reported functioning and pain scores between the baseline and one-month, two-month, and three-month periods. A significant improvement in function occurred between the baseline and one-month time periods and the pain reduction was sustained throughout the two-month and three-month periods. Collectively, the results support prolotherapy as an efficacious treatment for knee osteoarthritis by reducing pain and improving function.”

Prolotherapy compared to Hyaluronic injections

In a September 2022 study (2), researchers compared the effectiveness of dextrose prolotherapy injections to hyaluronic acid injections in knee osteoarthritis patients. The researchers noted that while intra-articular hyaluronic acid injections are recommended in the treatment of knee osteoarthritis dextrose prolotherapy has been reported as effective and safe. The aim of their research was to evaluate the effectiveness of dextrose prolotherapy and compare it to hyaluronic acid injections. The measure of comparison would be pain reduction and functional improvement in data taken from 395 patients who participated in previous research studies. The researchers reported that initially there was no statistically significant differences recorded in short-term effectiveness found between prolotherapy and hyaluronic acid treatments in pain control, however, in the sub-analysis that included only the studies that used intra-articular injections, prolotherapy was found to be more effective a treatment. Prolotherapy seems, according to the researchers, 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 compared to Platelet Rich Plasma Injections and exercise therapy

In a September 2022 study (3) researchers demonstrated the effectiveness of Platelet Rich Plasma and dextrose Prolotherapy treatments in knee osteoarthritis. In this study of 108 patients diagnosed with knee osteoarthritis, researchers retrospectively evaluated outcomes in patients divided into three groups:

  • 35 patients who would receive prolotherapy treatments
  • 35 patient who would receive Platelet Rich Plasma injections, and
  • 38 patients who were given exercise therapy.

At baseline, one month and three month follow up, the patients were assed with:

  • Visual Analogue Scale (VAS) scoring. An assessment of pain measured on a scale of 0 – 10.
  • and The Western Ontario McMaster University Osteoarthritis Index (WOMAC) a standardized questionnaire the helps doctors understand the patients joint pain and function.

Results: “At the first and third months, all groups showed a substantial improvement in the Visual Analogue Scale (with) activity, (and at) resting and WOMAC values as compared to before treatment. When the groups were compared, the VAS activity, resting, and WOMAC values in PRP and prolotherapy improved significantly in the first and third months compared to the exercise group. At one month, there was a statistically significant improvement in VAS activity and WOMAC pain and total scores compared to PRP and prolotherapy, but this improvement was not significant at 3 months (at this point the PRP and prolotherapy were measuring similar outcomes).

Conclusion: “Pain and disability were significantly improved with prolotherapy and PRP compared with exercise therapy. Although PRP is more effective than PRL 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.”

Combined intra-articular injection of hypertonic dextrose prolotherapy and hyaluronic acid for knee osteoarthritis

An August 2022 study (4) compared a combined intra-articular injection of hypertonic dextrose prolotherapy and hyaluronic acid for knee osteoarthritis patients.

  • 104 participants diagnosed with Kellgren-Lawrence knee osteoarthritis grade 2 or grade 3 were recruited into this study.
  • The participants were randomized to receive hyaluronic acid and hypertonic dextrose injection or hyaluronic acid and normal saline.
  • Ultrasound-guided knee intra-articular injections were administered once a week for 3 weeks.

“The primary outcomes were performance-based physical function measures (regular and fastest walking speed, stair climbing time, and chair rising time), and the secondary outcomes were the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and Knee Injury and Osteoarthritis Outcome Score (KOOS). The outcome measures were assessed before the injections and at 1 week and 1, 3, and 6 months after the injections.”

Results: The researchers reported: “Significant intergroup difference-in-differences favoring the treatment group (hyaluronic acid and hypertonic dextrose injection) were observed for improvements in stair climbing time and WOMAC physical function at 6 months.” The hyaluronic acid and hypertonic dextrose injection group also showed better results  for regular and fastest walking speed and chair rising time; WOMAC stiffness and physical function; and Knee Injury and Osteoarthritis Outcome Score (KOOS) for pain), other symptoms, and quality of life.

Conclusions: “Compared with hyaluronic acid and normal saline co-injections, hyaluronic acid and hypertonic dextrose plus dextrose coinjections resulted in more significant improvements in stair climbing time and physical function at 6 months, effectively decreased pain, and improved physical function and physical functional performance from 1 week to 6 months. Hyaluronic acid and hypertonic dextrose co-injections could be a suitable adjuvant therapy for patients with knee osteoarthritis.”

A March 2023 paper (5) compared intra-articular injection outcomes of different injection treatments including autologous conditioned serum, botulinum neurotoxin type A, corticosteroids, dextrose prolotherapy, hyaluronic acid, mesenchymal stem cells, ozone, platelet-rich plasma, plasma rich in growth factor, and stromal vascular fraction of adipose tissue. What they found was no matter the injection, when it was combined with physical therapy, the injection worked better. Some injections worked better than others. The researchers demonstrated that:

  • Prolotherapy injections plus physical therapy was ranked the most effective strategy for pain reduction and global function recovery,
  • Mesenchymal stem cells (MSC) plus physical therapy was the most optimal option for walking capability restoration.

Related articles

Research comparing different types of knee injections

Marc Darrow MD JD



1 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).
2 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.
3 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.
4 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 Apr 16.
5 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 sciences24(7), p.6078.



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