International Orthopaedics

, Volume 41, Issue 4, pp 671–679 | Cite as

Proliferative injection therapy for osteoarthritis: a systematic review

  • Mišo Krstičević
  • Milka Jerić
  • Svjetlana Došenović
  • Antonia Jeličić Kadić
  • Livia PuljakEmail author
Review Article



To systematically analyse randomised controlled trials (RCTs) about efficacy and safety of proliferative injection therapy (prolotherapy) for treatment of osteoarthritis (OA).


CENTRAL, Embase and MEDLINE were searched. Two reviewers independently conducted screening and data extraction. RCTs were assessed with the Cochrane risk of bias tool. Type of treatment, study design, dosing, efficacy outcomes and safety outcomes were analysed. The protocol was registered in PROSPERO (CRD42016035258).


Seven RCTs were included, with 393 participants aged 40-75 years and mean OA pain duration from three months to eight years. Follow-up was 12 weeks to 12 months. Studies analysed OA of the knee joint (n = 5), first carpometacarpal joint (n = 1) and finger joints (n = 1). Various types of prolotherapy were used; dextrose was the most commonly used irritant agent. All studies concluded that prolotherapy was effective treatment for OA. No serious adverse events were reported. The studies had considerable methodological limitations.


Limited evidence from low-quality studies indicates a beneficial effect of prolotherapy for OA management. The number of participants in these studies was too small to provide reliable evidence.


Current data from trials about prolotherapy for OA should be considered preliminary, and future high-quality trials on this topic are warranted.


Osteoarthritis Proliferative injection therapy Prolotherapy Dextrose Pain 



We are very grateful to Ms. Parisa Mansoori for helping us with translation of one manuscript.

Author contributions

M.K., M.J., A.J.K. and S.D. screened the bibliographic records. M.K. and M.J. extracted data. M.K. and S.D. assessed risk of bias. L.P. resolved disagreements between authors. M.K. wrote the first version of the manuscript with the help of M.J. All authors contributed to the final version of the systematic review. All authors approved final version of the systematic review.

Compliance with ethical standards

Role of funding source

The authors did not receive any extramural funding for this study apart from the institutional support of the University of Split School of Medicine and its library services for obtaining manuscripts.

Conflict of interest

The systematic review authors have no conflicts of interest to declare. Conflicts of interest in the included studies were analysed and reported in the manuscript. The majority of the included studies did not report whether there was a conflict of interest or source of funding.

Supplementary material

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Supplementary Table 1 (DOCX 24 kb)
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Supplementary Table 2 (DOCX 48 kb)
264_2017_3422_MOESM3_ESM.docx (37 kb)
Supplementary Table 3 (DOCX 36 kb)
264_2017_3422_MOESM4_ESM.docx (38 kb)
Supplementary Table 4 (DOCX 37 kb)


  1. 1.
    Cross M, Smith E, Hoy D, Nolte S, Ackerman I, Fransen M, Bridgett L, Williams S, Guillemin F, Hill CL, Laslett LL, Jones G, Cicuttini F, Osborne R, Vos T, Buchbinder R, Woolf A, March L (2014) The global burden of hip and knee osteoarthritis: estimates from the global burden of disease 2010 study. Ann Rheum Dis 73(7):1323–1330. doi: 10.1136/annrheumdis-2013-204763 CrossRefPubMedGoogle Scholar
  2. 2.
    Hochberg MC, Altman RD, April KT, Benkhalti M, Guyatt G, McGowan J, Towheed T, Welch V, Wells G, Tugwell P (2012) American College of Rheumatology 2012 recommendations for the use of nonpharmacologic and pharmacologic therapies in osteoarthritis of the hand, hip, and knee. Arthritis Care Res 64(4):465–474. doi: 10.1002/acr.21596 CrossRefGoogle Scholar
  3. 3.
    Richter M, Trzeciak T, Owecki M, Pucher A, Kaczmarczyk J (2015) The role of adipocytokines in the pathogenesis of knee joint osteoarthritis. Int Orthop 39(6):1211–1217. doi: 10.1007/s00264-015-2707-9 CrossRefPubMedGoogle Scholar
  4. 4.
    De Filippis L, Gulli S, Caliri A, Romano C, Munao F, Trimarchi G, La Torre D, Fichera C, Pappalardo A, Triolo G, Gallo M, Valentini G, Bagnato G (2004) Epidemiology and risk factors in osteoarthritis: literature review data from “OASIS” study. Reumatismo 56(3):169–184. doi: 10.4081/reumatismo.2004.169 PubMedGoogle Scholar
  5. 5.
    Glyn-Jones S, Palmer AJ, Agricola R, Price AJ, Vincent TL, Weinans H, Carr AJ (2015) Osteoarthritis. Lancet 386(9991):376–387. doi: 10.1016/S0140-6736(14)60802-3 CrossRefPubMedGoogle Scholar
  6. 6.
    Samson DJ, Grant MD, Ratko TA, Bonnell CJ, Ziegler KM, Aronson N (2007) Treatment of primary and secondary osteoarthritis of the knee. Evid Rep Technol Assess 157:1–157Google Scholar
  7. 7.
    Conaghan PG (2013) Osteoarthritis in 2012: parallel evolution of OA phenotypes and therapies. Nat Rev Rheumatol 9(2):68–70. doi: 10.1038/nrrheum.2012.225 CrossRefPubMedGoogle Scholar
  8. 8.
    Tucker JD, Ericksen JJ, Goetz LL, Elmore LW (2014) Should clinical studies involving “regenerative injection therapy,” strive to incorporate a triad of outcome measures instead of only including clinical outcome measures? Osteoarthr Cartil 22(6):715–717. doi: 10.1016/j.joca.2014.04.005 CrossRefPubMedGoogle Scholar
  9. 9.
    Trzeciak T, Richter M, Suchorska W, Augustyniak E, Lach M, Kaczmarek M, Kaczmarczyk J (2016) Application of cell and biomaterial-based tissue engineering methods in the treatment of cartilage, menisci and ligament injuries. Int Orthop 40(3):615–624. doi: 10.1007/s00264-015-3099-6 CrossRefPubMedGoogle Scholar
  10. 10.
    Distel LM, Best TM (2011) Prolotherapy: a clinical review of its role in treating chronic musculoskeletal pain. PM R 3(6 Suppl 1):S78–S81. doi: 10.1016/j.pmrj.2011.04.003 CrossRefPubMedGoogle Scholar
  11. 11.
    Vora A, Borg-Stein J, Nguyen RT (2012) Regenerative injection therapy for osteoarthritis: fundamental concepts and evidence-based review. PM R 4(5 Suppl):S104–S109. doi: 10.1016/j.pmrj.2012.02.005 CrossRefPubMedGoogle Scholar
  12. 12.
    Linetsky FS, Miguel R, Torres F (2004) Treatment of cervicothoracic pain and cervicogenic headaches with regenerative injection therapy. Curr Pain Headache Rep 8(1):41–48. doi: 10.1007/s11916-004-0039-3 CrossRefPubMedGoogle Scholar
  13. 13.
    Jensen KT, Rabago DP, Best TM, Patterson JJ, Vanderby R Jr (2008) Early inflammatory response of knee ligaments to prolotherapy in a rat model. J Orthop Res 26(6):816–823. doi: 10.1002/jor.20600 CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Yelland MJ, Glasziou PP, Bogduk N, Schluter PJ, McKernon M (2004) Prolotherapy injections, saline injections, and exercises for chronic low-back pain: a randomized trial. Spine 29(1):9–16. doi: 10.1097/01.BRS.0000105529.07222.5B, discussion 16CrossRefPubMedGoogle Scholar
  15. 15.
    Covey CJ, Sineath MH Jr, Penta JF, Leggit JC (2015) Prolotherapy: can it help your patient? J Fam Pract 64(12):763–768PubMedGoogle Scholar
  16. 16.
    Kim WM, Lee HG, Jeong CW, Kim CM, Yoon MH (2010) A randomized controlled trial of intra-articular prolotherapy versus steroid injection for sacroiliac joint pain. J Altern Complement Med 16(12):1285–1290. doi: 10.1089/acm.2010.0031 CrossRefPubMedGoogle Scholar
  17. 17.
    Bertrand H, Reeves KD, Bennett CJ, Bicknell S, Cheng A-L (2016) Dextrose prolotherapy versus control injections in painful rotator cuff tendinopathy. Arch Phys Med Rehabil 97(1):17–25. doi: 10.1016/j.apmr.2015.08.412 CrossRefPubMedGoogle Scholar
  18. 18.
    Rabago D, Slattengren A, Zgierska A (2010) Prolotherapy in primary care practice. Prim Care 37(1):65–80. doi: 10.1016/j.pop.2009.09.013 CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Rabago D, Best TM, Beamsley M, Patterson J (2005) A systematic review of prolotherapy for chronic musculoskeletal pain. Clin J Sport Med 15(5):376–380. doi: 10.1097/01.jsm.0000173268.05318.a4 CrossRefPubMedGoogle Scholar
  20. 20.
    Rahimzadeh P, Imani F, Faiz SHR, Entezary SR, Nasiri AA, Ziaeefard M (2014) Investigation the efficacy of intra-articular prolotherapy with erythropoietin and dextrose and intra-articular pulsed radiofrequency on pain level reduction and range of motion improvement in primary osteoarthritis of knee. J Res Med Sci 8:696–702Google Scholar
  21. 21.
    Jahangiri A, Moghaddam FR, Najafi S (2014) Hypertonic dextrose versus corticosteroid local injection for the treatment of osteoarthritis in the first carpometacarpal joint: a double-blind randomized clinical trial. J Orthop Sci 5:737–743. doi: 10.1007/s00776-014-0587-2 CrossRefGoogle Scholar
  22. 22.
    Eslamian F, Amouzandeh B (2015) 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 7(2):35–44. doi: 10.1177/1759720X14566618 CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Reeves KD, Hassanein K (2000) Randomized prospective double-blind placebo-controlled study of dextrose prolotherapy for knee osteoarthritis with or without ACL laxity. Altern Ther Health Med (2):68–74, 77–80Google Scholar
  24. 24.
    Reeves KD, Hassanein K (2000) Randomized, prospective, placebo-controlled double-blind study of dextrose prolotherapy for osteoarthritic thumb and finger (DIP, PIP, and trapeziometacarpal) joints: evidence of clinical efficacy. J Altern Complement Med 6(4):311–320. doi: 10.1089/10755530050120673 CrossRefPubMedGoogle Scholar
  25. 25.
    Dumais R, Benoit C, Dumais A, Babin L, Bordage R, Arcos C, Allard J, Bélanger M (2012) Effect of regenerative injection therapy on function and pain in patients with knee osteoarthritis: a randomized crossover study. Pain Med 8:990–999. doi: 10.1111/j.1526-4637.2012.01422.x CrossRefGoogle Scholar
  26. 26.
    Hashemi M, Jalili P, Mennati S, Koosha A, Rohanifar R, Madadi F, Razavi SS, Taheri F (2015) The effects of prolotherapy with hypertonic dextrose versus prolozone (intraarticular ozone) in patients with knee osteoarthritis. Anesth Pain Med (5). doi: 10.5812/aapm.27585
  27. 27.
    Hashemi SM, Madadi F, Razavi S, Nikooseresht M, Kiyabi FH, Nasiripour S (2012) Intra-articular hyaluronic acid injections vs. dextrose prolotherapy in the treatment of osteoarthritic knee pain. Tehran Univ Med J (2):119–125Google Scholar
  28. 28.
    Sit RW, Chung VC, Reeves KD, Rabago D, Chan KK, Chan DC, Wu X, Ho RS, Wong SY (2016) Hypertonic dextrose injections (prolotherapy) in the treatment of symptomatic knee osteoarthritis: a systematic review and meta-analysis. Sci Rep 6:25247. doi: 10.1038/srep25247 CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Dagenais S, Yelland MJ, Del Mar C, Schoene ML (2007) Prolotherapy injections for chronic low-back pain. Cochrane Database Syst Rev 2, CD004059. doi: 10.1002/14651858.CD004059.pub3 Google Scholar
  30. 30.
    Roberts I, Ker K (2015) How systematic reviews cause research waste. Lancet 386(10003):1536. doi: 10.1016/S0140-6736(15)00489-4 CrossRefPubMedGoogle Scholar
  31. 31.
    Handoll HHG, Langhorne P (2015) In defence of reviews of small trials: underpinning the generation of evidence to inform practice. Cochrane Database Syst Rev 11, ED000106. doi: 10.1002/14651858.ED000106 Google Scholar
  32. 32.
    Mooney V (2003) Prolotherapy at the fringe of medical care, or is it the frontier? Spine J 3(4):253–254. doi: 10.1016/S1529-9430(03)00063-9 CrossRefPubMedGoogle Scholar
  33. 33.
    Yentur EA, Okcu G, Yegul I (2003) The role of trigger point therapy in knee osteoarthritis. Pain Clin 15(4):385–390. doi: 10.1163/156856903770196746 CrossRefGoogle Scholar
  34. 34.
    Lee JH, Lee SH, Song SH (2010) Clinical effectiveness of botulinum toxin A compared to a mixture of steroid and local anesthetics as a treatment for sacroiliac joint pain. Pain Med 11(5):692–700. doi: 10.1111/j.1526-4637.2010.00838.x CrossRefPubMedGoogle Scholar
  35. 35.
    Berenfeld A, Bessing WD, Bisplinghoff U, Bittner G, Matthiesen HO, Tilscher H, Ramm S, Ebeling L, Schmitz H (1991) [Gonalgia: treatment with therapeutic local anesthesia. Results of a controlled comparative study versus diclofenac]. Fortschritte der Medizin (35):724–728Google Scholar
  36. 36.
    Down S, Waddington G, Adams R, Thomson M (2007) Movement discrimination after intra-articular local anaesthetic of the ankle joint. Br J Sports Med 8:501–505. doi: 10.1136/bjsm.2006.031468 CrossRefGoogle Scholar
  37. 37.
    Gu ZY, Wu HL, Wu QL, Cao ZQ, Zhang YX (1998) The effect of intra-articular irrigation injection therapy on osteoarthrosis of the temporomandibular joint. Chin J Dent Med 3:44–48Google Scholar
  38. 38.
    Kim K-H, Choi S-H, Kim T-K, Shin S-W, Kim C-H, Kim J-I (2005) Cervical facet joint injections in the neck and shoulder pain. J Korean Med Sci 20(4):659–662. doi: 10.3346/jkms.2005.20.4.659 CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Kopp S, Wenneberg B (1981) Effects of occlusal treatment and intraarticular injections on temporomandibular joint pain and dysfunction. Acta Odontol Scand 2:87–96. doi: 10.3109/00016358109162265 CrossRefGoogle Scholar
  40. 40.
    Rabago D, Mundt M, Zgierska A, Grettie J (2015) Hypertonic dextrose injection (prolotherapy) for knee osteoarthritis: long term outcomes. Complement Ther Med 3:388–395. doi: 10.1016/j.ctim.2015.04.003 CrossRefGoogle Scholar
  41. 41.
    Rabago D, Patterson JJ, Mundt M, Zgierska A, Fortney L, Grettie J, Kijowski R (2014) Dextrose and morrhuate sodium injections (Prolotherapy) for knee osteoarthritis: a prospective open-label trial. J Altern Complement Med 5:383–391. doi: 10.1089/acm.2013.0225 CrossRefGoogle Scholar
  42. 42.
    Rabago DP, Miller DJ, Zgierska AE, Mundt M, Kijowski RX, Jessica B, Patterson JJ (2011) Dextrose prolotherapy for knee osteoarthritis: results of a randomized controlled trial. Osteoarthr Cartil S142–s143. doi: 10.1016/S1063-4584(11)60335-X
  43. 43.
    Rabago D, Patterson JJ, Mundt M, Kijowski R, Grettie J, Segal NA, Zgierska A (2013) Dextrose prolotherapy for knee osteoarthritis: a randomized controlled trial. Ann Fam Med 3:229–237. doi: 10.1370/afm.1504 CrossRefGoogle Scholar
  44. 44.
    Rabago D, Kijowski R, Woods M, Patterson JJ, Mundt M, Zgierska A, Grettie J, Lyftogt J, Fortney L (2013) 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 11:2075–2082. doi: 10.1016/j.apmr.2013.06.025 CrossRefGoogle Scholar

Copyright information

© SICOT aisbl 2017

Authors and Affiliations

  • Mišo Krstičević
    • 1
  • Milka Jerić
    • 2
  • Svjetlana Došenović
    • 3
    • 4
  • Antonia Jeličić Kadić
    • 4
    • 5
  • Livia Puljak
    • 4
    Email author
  1. 1.Department of OrthopedicsUniversity Hospital SplitSplitCroatia
  2. 2.Department of DermatovenerologyGeneral Hospital ZadarZadarCroatia
  3. 3.Department of Anesthesiology and Intensive Care MedicineUniversity Hospital SplitSplitCroatia
  4. 4.Laboratory for Pain ResearchUniversity of Split School of MedicineSplitCroatia
  5. 5.Department of PediatricsUniversity Hospital SplitSplitCroatia

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