Prolotherapy for Knee Osteoarthritis: A Descriptive Review

  • Bobby Nourani
  • David RabagoEmail author
Musculoskeletal Rehabilitation (NA Segal, Section Editor)
Part of the following topical collections:
  1. Musculoskeletal Rehabilitation


Knee osteoarthritis (KOA) is a common chronic disease of high patient and societal impact. The etiology is multifactorial; pain sources include both intra- and extra-articular tissues. A number of alternative therapies have been assessed for KOA. Patients are often refractory to best-practice conservative management, and the development of new therapy has been called for by national health services groups. Prolotherapy is an outpatient therapy for chronic musculoskeletal pain including KOA. Protocols include injection at attachments of soft-tissue supportive structures such as ligaments and tendons, and within intra-articular spaces. Although the understanding of mechanism is not well understood, a small but growing body of literature suggests that prolotherapy may be appropriate therapy for carefully selected patients refractory to conventional treatment. This article summarizes evidence from basic and clinical science for use of prolotherapy among patients with KOA.


Knee osteoarthritis KOA Prolotherapy Chronic pain Rehabilitation Review 



We acknowledge the significant contributions to prolotherapy of Jeffrey J Patterson, DO. He was the primary injector in the studies by Rabago et al., and the inspiration for this work. Jeff was a compassionate physician, generous mentor and dear friend who dedicated his life to improving the human condition.


Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Felson DT. Epidemiology of osteoarthritis. In: Brandt KD, Doherty M, Lohmander LS, editors. Osteoarthritis. Oxford: Oxford University Press; 2003. p. 9–16.Google Scholar
  2. 2.
    Lawrence RC, Felson DT, Helmick CG, et al. Estimates of the prevalence of arthritis and other rheumatic conditions in the United States. Part II. Arthritis Rheum. 2008;58:26–35.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Samson DJ, Grant MD, Ratko TA, Bonnell CJ, Ziegler KM, Aronson N. Treatment of primary and secondary osteoarthritis of the knee. Agency for Healthcare Research and Quality (Publication No. 07-E012): Evidence Report/Technology Assessment: Prepared by Blue Cross and Blue Shield Association Technology Evaluation Center Evidence-Based Practice Center under Contract No. 290-02-0026). Rockville, MD. 2007;157.Google Scholar
  4. 4.
    Altman RD. Recommendations for the medical management of osteoarthritis of the hip and knee: 2000 update. American College of Rheumatology Subcommittee on Osteoarthritis Guidelines. Arthritis Rheum. 2000;43:1905–15.CrossRefGoogle Scholar
  5. 5.
    Little CV, Parsons T. Herbal therapy for treating osteoarthritis. Cochrane Database Syst Rev. 2001;1:CD002947.PubMedGoogle Scholar
  6. 6.
    Morelli V, Naquin C, Weaver V. Alternative therapies for traditional disease states: osteoarthritis. Am Fam Physician. 2003;15:339–44.Google Scholar
  7. 7.
    Richmond J, Hunter D, Irrgang J, et al. Treatment of osteoarthritis of the knee (nonarthroplasty). J Am Acad Orthop Surg. 2009;17(9):591–600.PubMedPubMedCentralGoogle Scholar
  8. 8.
    Rath L. Knee replacement and revision surgeries on the rise. 2015; Accessed 17 Nov 2015.
  9. 9.
    Skou ST, Roos EM, Laursen MB, et al. A randomized, controlled trial of total knee replacement. N Engl J Med. 2015;373(17):1597–606.CrossRefPubMedGoogle Scholar
  10. 10.
    National Research Council. Initial national priorities for comparative effectiveness research. Washington, DC: The National Academies Press; 2009.Google Scholar
  11. 11.
    Schultz L. A treatment for subluxation of the temporomandibular joint. JAMA. 1937;109(13):1032–5.CrossRefGoogle Scholar
  12. 12.
    • Hackett GS, Hemwall GA, Montgomery GA. Ligament and tendon relaxation treated by prolotherapy. 5th ed. Oak Park: Gustav A. Hemwall; 1993. Originally published in the 1950s, this text establishes the intellectual foundation of prolotherapy. The injection protocols used in the studies reviewed in this paper have their origin in this bookGoogle Scholar
  13. 13.
    DeChellis DM, Cortazzo MH. Regenerative medicine in the field of pain medicine: prolotherapy, platelet-rich plasma, and stem cell therapy-theory and evidence. Tech Reg Anesth Pain Manag. 2011;15:74–80.CrossRefGoogle Scholar
  14. 14.
    Rabago D, Slattengren A, Zgierska A. Prolotherapy in primary care. Prim Care. 2010;37:65–80.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Banks A. A rationale for prolotherapy. J Orthop Med. 1991;13:54–9.Google Scholar
  16. 16.
    Jensen K, Rabago D, Best TM, Patterson JJ, Vanderby R. Early inflammatory response of knee ligaments to prolotherapy in a rat model. J Orthop Res. 2008;26:816–23.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    • Jensen KT, Rabago D, Best TM, Patterson JJ, Vanderby R. Longer term response of knee ligaments to prolotherapy in a rat injury model. Am J Sports Med. 2008;36:1347–57. This basic science paper evaluated dextrose in a stretch injury rat model. It reported biological changes compared to control injection, including increased surface area of medial collateral ligaments in response to prolotherapy. Google Scholar
  18. 18.
    Yoshi T, Zhao C, Schmelzer JD, Low PA, An K, Amadio A. The effects of hypertonic dextrose injection on connective tissue and nerve conduction through the rabbit carpal tunnel. Arch Phys Med Rehabil. 2009;90:333–9.CrossRefGoogle Scholar
  19. 19.
    • Rabago D, Kijowski R, Woods M, et al. Association between disease-specific quality-of-life and magnetic resonance imaging outcomes in a clinical trial of prolotherapy for knee osteoarthritis. Arch Phys Med Rehabil. 2013;94(11):2075–82. This study reported that prolotherapy, as a treatment for knee osteoarthritis, does not slow or reverse cartilage volume loss in knee osteoarthritis as assessed by MRI. However, researchers found that among prolotherapy recipients, but not control therapy recipients, cartilage volume stability on MRI predicted pain score change, suggesting that the mechanism of action of prolotherapy may include pain-specific neural effects.Google Scholar
  20. 20.
    Lyftogt J. Pain conundrums: which hypothesis? Central nervous system sensitization versus peripheral nervous system autonomy. Australas Musculoskelet Med. 2008;13:72–4.Google Scholar
  21. 21.
    Donaldson LF. Neurogenic mechanisms in arthritis. In: Jancso G, editor. Neurogenic inflammation in health and disease, vol. 8. Amsterdam: Elsevier; 2009. p. 211–41.CrossRefGoogle Scholar
  22. 22.
    Nagy I, Paule CC, White JPM. Molecular mechanisms of TRPV1-mediated pain. Neuroimmune Biol. 2009;8:75–99.CrossRefGoogle Scholar
  23. 23.
    • Rabago D, Best TM, Beamsley M, Patterson J. A systematic review of prolotherapy for chronic musculoskeletal pain. Clin J Sport Med. 2005;15(5):376–80. This systematic review assessed the total prolotherapy literature through 2005. Reports were largely limited to successful cases and retrospective and prospective case series, but a series of higher quality randomized controlled trials reported mixed outcomes for low back pain.Google Scholar
  24. 24.
    Yelland MJ, Del Mar C, Pirozo S, Schoene ML. Prolotherapy injections for chronic low back pain: a systematic review. Spine. 2004;29:2126–33.CrossRefPubMedGoogle Scholar
  25. 25.
    Shuman D. Sclerotherapy: statisitics on its effectiveness of unstable joint conditions. Osteopat Prof. 1954;11–15:37–8.Google Scholar
  26. 26.
    Reeves KD, Hassanein K. Randomized prospective double-blind placebo-controlled study of dextrose prolotherapy for knee osteoarthritis with or without ACL laxity. Altern Ther Health Med. Mar 2000;6(2):68–74, 77–80.Google Scholar
  27. 27.
    • Rabago D, Zgierska A, Fortney L, et al. Hypertonic dextrose injections (prolotherapy) for knee osteoarthritis: an uncontrolled study with one-year follow-up. J Altern Complement Med. 2012;18:408–14. This open-label study using validated self-reported outcome measures was the first to suggest that a “whole joint” prolotherapy injection protocol using both intra- and extra-articular dextrose injections has a potential benefit for knee osteoarthritis. Google Scholar
  28. 28.
    Bellamy N, Buchanan WW, Goldsmith CH, Campbell J, Stitt LW. Validation study of WOMAC: a health status instrument for measuring clinically important patient relevant outcomes to antirheumatic drug therapy in patients with osteoarthritis of the hip or knee. J Rheumatol. 1988;15(12):1833–40.PubMedGoogle Scholar
  29. 29.
    Ehrich E, Davies G, Watson D, Bolognese J, Seidenberg B, Bellamy N. Minimal perceptible clinical improvement with the Western Ontario and McMaster Universities osteoarthritis index questionnaire and global assessments in patients with osteoarthritis. J Rheumatol. 2000;27(11):2635–41.PubMedGoogle Scholar
  30. 30.
    Tubach F, Wells G, Ravaud P, Dougados M. Minimal clinically important difference, low disease activity state, and patient acceptable symptom state: methodological issues. J Rheumatol. 2005;32(10):2025–9.PubMedGoogle Scholar
  31. 31.
    Altman RD. Criteria for classification of clinical osteoarthritis. J Rheumatol Suppl. 1991;27:10–2.PubMedGoogle Scholar
  32. 32.
    •• Dumais R, Benoit C, Dumais A, et al. Effect of regenerative injection therapy on fuction and pain in patients with knee osteoarthitis: a randomized crossover study. Pain Med. 2012;13:990–9. This randomized study reported that prolotherapy is an effective treatment for symptomatic knee osteoarthritis compared to unblinded control. Google Scholar
  33. 33.
    •• Rabago D, Patterson JJ, Mundt M, et al. Dextrose prolotherapy for knee osteoarthritis: a randomized controlled trial. Ann Fam Med. 2013;11(3):229–37. This benchmark randomized controlled trial reported that prolotherapy for knee osteoarthritis is statistically superior to blinded control injection therapy and non-blinded, at-home exercise by margins that meet criteria for clinical importance. It suggests that prolotherapy, for this condition, is both efficacious and effective. Google Scholar
  34. 34.
    Grote W, DeLucia R, Waxman R, Zgierska A, Wilson JJ, Rabago D. Repair of a complete anterior cruciate tear using prolotherapy: a case report. Int Musculoskelet Med. 2009;31(4):159–65.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Scarpone M, Rabago D, Zgierska A, Arbogest J, Snell ED. The efficacy of prolotherapy for lateral epicondylosis: a pilot study. Clin J Sport Med. 2008;18:248–54.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Rabago D, Patterson JJ, Mundt M, et al. Dextrose and morrhuate sodium injections (prolotherapy) for knee osteoarthritis: the results of a prospective open label trial. J Altern Complement Med. 2014;20(5):383–91.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Hunter DJ, Niu J, Zhang Y, et al. Change in cartilage morphometry: a sample of the progression cohort of the osteoarthritis initiative. Ann Rheum Dis. 2009;68:349–56.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    • Rabago D, Mundt M, Zgierska A, Grettie J. Hypertonic dextrose injection (prolotherapy) for knee osteoarthritis: long term outcomes. Complement Ther Med. 2015;23(3):388–95. The long-term effects of prolotherapy for participants with knee osteoarthritis were assessed in this study. Researchers found prolotherapy recipients continued to improve through an average of 2.5 ± 0.6 years. However, the cohort was divided between “responders” and “non-responders.” The majority of participants (82 %) reported continued improved outcomes at the long-term follow-up, but a minority of participants (18 %) worsened compared to baseline status. Google Scholar

Copyright information

© Springer Science + Business Media New York 2016

Authors and Affiliations

  1. 1.Department of Family Medicine and Community HealthUniversity of Wisconsin School of Medicine and Public HealthMadisonUSA

Personalised recommendations