Current Concepts of Prolotherapy in Orthopedic Surgery

Authors

1 Department of Orthopedic Surgery, Gulhane Military Medicine Academy, Ankara, Turkey

2 Department of Sports Medicine, Gulhane Military Medicine Academy, Ankara, Turkey

3 Department of Orthopedic Surgery, Haydarpasa Gulhane Military Medicine Academy, Istanbul, Turkey

Abstract

Context
Prolotherapy is a popular injection-based complementary treatment, which has shown promising results in the treatment of sprained and degenerated ligaments, and damaged dense connective tissues’ structures. More research was conducted in this area and many authors declared successful results for different indications.


Evidence Acquisition
The purpose of this study was to present a literature review regarding the current concepts of prolotherapy injections and improvements in the orthopedic clinical care practice. The Medline and PubMed databases were searched for the articles related to prolotherapy injections in the field of orthopedic surgery and additionally the reference list of each article was also included to provide a comprehensive evaluation.


Results
Numerous studies have been conducted on prolotherapy injections for different indications for orthopedics clinical care practice. Prolotherapy injections have successfully used for major orthopedic procedures in terms of rotator cuff lesions, knee ligamentous lesions, osteoarthritis-cartilage defects, and ligament-tendon injuries. Most of the studies showed that prolotherapy provided faster and better healing of tissues.


Conclusions
There is a great interest to prolotherapy in orthopedic clinics, especially to manage musculoskeletal lesions. More research conducted in this area and many authors declared successful results in their studies. In spite of this increasing trend for prolotherapy injections, there were only one or two clinical studies investigated prolotherapy injections for different indications and most of them have limited participants, short-term follow-up or poor quality studies. There is still need for further high-quality studies investigated optimal strategy of the injections of prolotherapy.

Highlights

1. Kelsey J. Epidemiology of musculoskeletal disorders. New York: Oxford University Press; 1982.

 

2. Lawrence RC, Hochberg MC, Kelsey JL, McDuffie FC, Medsger TA, Felts WR, et al. Estimates of the prevalence of selected arthritic and musculoskeletal diseases in the United States. J Rheumatol. 1989;16(4):427–41. [PubMed: 2746583].

 

 3. Bilgic S, Durusu M, Aliyev B, Akpancar S, Ersen O, Yasar SM, et al. Comparison of two main treatment modalities for acute ankle sprain. Pak J Med Sci. 2015;31(6):1496–9. doi: 10.12669/pjms.316.8210. [PubMed: 26870123].

 

4. Distel LM, Best TM. Prolotherapy: a clinical review of its role in treating chronic musculoskeletal pain. PM R. 2011;3(6 Suppl 1):S78–81. doi: 10.1016/j.pmrj.2011.04.003. [PubMed: 21703585].

 

5. Taylor M. Prolotherapy for peripheral joints. Australasian Musculoskeletal Medicine. 2004;9(1):38.

 

6. Seven MM, Koca K, Akpancar S, Turkkan S, Uysal B, Yildiz Y, et al. Prolotherapy Injections in the Treatment of Overuse Injuries. BMMR. 2016;19(3):113–5.

 

7. Kannus P. Tendon pathology: basic science and clinical applications. Sports Exercise and Injury. 1997;3(2):62–75.

 

8. 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. doi: 10.1016/j.ctim.2015.04.003. [PubMed: 26051574].

 

 9. Hashemi M, Jalili P, Mennati S, Koosha A, Rohanifar R, Madadi F, et al. The Effects of Prolotherapy With Hypertonic Dextrose Versus Prolozone (Intraarticular Ozone) in Patients With Knee Osteoarthritis. Anesth pain med. 2015;5(5).

 

10. Hauser RA, Sprague IS. Outcomes of prolotherapy in chondromalacia patella patients: improvements in pain level and function. Clin Med Insights Arthritis Musculoskelet Disord. 2014;7:13–20. doi: 10.4137/CMAMD.S13098. [PubMed: 24596471].

 

11. Hackett GS, Hemwall GA, Montgomery GA. Ligament and Tendon Relaxation Treated by Prolotherapy. 1956 First Edition Charles C. Thomas, Publisher. Gustav A. Hemwall, Publisher. Institute in Basic Life Principles. Oak Brook, IL; 1991.

 

12. Rabago D, Slattengren A, Zgierska A. Prolotherapy in primary care practice. Prim Care. 2010;37(1):65–80. doi: 10.1016/j.pop.2009.09.013. [PubMed: 20188998].

 

13. Scarpone M, Rabago D, Zgierska A, Arbogest J, Snell E. . The efficacy of prolotherapy for lateral epicondylosis: a pilot study. Clin J Sport Med. 2008;18(3):248–54. doi: 10.1097/JSM.0b013e318170fc87. [PubMed: 18469566].

 

14. Di Paolo S, Gesualdo L, Ranieri E, Grandaliano G, Schena FP. High glucose concentration induces the overexpression of transforming growth factor-beta through the activation of a plateletderived growth factor loop in human mesangial cells. Am J Pathol. 1996;149(6):2095–106. [PubMed: 8952542].

 

15. Murphy M, Godson C, Cannon S, Kato S, Mackenzie HS, Martin F, et al. Suppression subtractive hybridization identifies high glucose levels as a stimulus for expression of connective tissue growth factor and other genes in human mesangial cells. J Biol Chem. 1999;274(9):5830– 4. [PubMed: 10026205].

 

16. Krump E, Nikitas K, Grinstein S. Induction of tyrosine phosphorylation and Na+/H+ exchanger activation during shrinkage of human neutrophils. J Biol Chem. 1997;272(28):17303–11. [PubMed: 9211867].

 

17. Lyftogt J. Subcutaneous prolotherapy treatment of refractory knee, shoulder, and lateral elbow pain. Australasian Musculoskeletal Med. 2007;12(2):110.

 

18. Reeves KD, Fullerton BD, Topol G. Evidence-based regenerative injection therapy (prolotherapy) in sports medicine.The Sports Medicine Resource Manual. Saunders (Elsevier); 2008. pp. 611–9.

 

19. Jensen KT, Rabago DP, Best TM, Patterson JJ, Vanderby R. Early inflammatory response of knee ligaments to prolotherapy in a rat model. J Orthop Res. 2008;26(6):816–23. doi: 10.1002/jor.20600. [PubMed: 18240327].

 

20. Jensen KT, Rabago DP, Best TM, Patterson JJ, Vanderby R. Response of knee ligaments to prolotherapy in a rat injury model. Am J Sports Med. 2008;36(7):1347–57. doi: 10.1177/0363546508314431. [PubMed: 18310313].

 

21. Reeves KD, Hassanein K. Randomized, prospective, placebocontrolled double-blind study of dextrose prolotherapy for osteoarthritic thumb and finger (DIP, PIP, and trapeziometacarpal) joints: evidence of clinical efficacy. J Altern Complement Med. 2000;6(4):311–20. doi: 10.1089/10755530050120673. [PubMed: 10976977].

 

 22. 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. 2000;6(2):68–74. [PubMed: 10710805].

 

23. Dechow E, Davies RK, Carr AJ, Thompson PW. A randomized, doubleblind, placebo-controlled trial of sclerosing injections in patients with chronic low back pain. Rheumatology (Oxford). 1999;38(12):1255– 9. [PubMed: 10587555].

 

24. Khan SA, Kumar A, Varshney MK, Trikha V, Yadav CS. Dextrose prolotherapy for recalcitrant coccygodynia. J Orthop Surg (Hong Kong). 2008;16(1):27–9. [PubMed: 18453654].

 

25. Miller MR, Mathews RS, Reeves KD. Treatment of painful advanced internal lumbar disc derangement with intradiscal injection of hypertonic dextrose. Pain Physician. 2006;9(2):115–21. [PubMed: 16703971].

 

26. Maxwell NJ, Ryan MB, Taunton JE, Gillies JH, Wong AD. Sonographically guided intratendinous injection of hyperosmolar dextrose to treat chronic tendinosis of the Achilles tendon: a pilot study. AJR Am J Roentgenol. 2007;189(4):W215–20. doi: 10.2214/AJR.06.1158. [PubMed: 17885034].

 

27. Holmich P, Uhrskou P, Ulnits L, Kanstrup IL, Nielsen MB, Bjerg AM, et al. Effectiveness of active physical training as treatment for longstanding adductor-related groin pain in athletes: randomised trial. Lancet. 1999;353(9151):439–43. doi: 10.1016/S0140-6736(98)03340-6. [PubMed: 9989713].

 

 28. Chen CM, Chen JS, Tsai WC, Hsu HC, Chen KH, Lin CH. Effectiveness of device-assisted ultrasound-guided steroid injection for treating plantar fasciitis. Am J Phys Med Rehabil. 2013;92(7):597–605. doi: 10.1097/PHM.0b013e318278a831. [PubMed: 23221670].

 

29. Tsai WC, Hsu CC, Chen CP, Chen MJ, Yu TY, Chen YJ. Plantar fasciitis treated with local steroid injection: comparison between sonographic and palpation guidance. J Clin Ultrasound. 2006;34(1):12–6. doi: 10.1002/jcu.20177. [PubMed: 16353228].

 

30. Rabago D, Patterson JJ, Mundt M, Kijowski R, Grettie J, Segal NA, et al. Dextrose prolotherapy for knee osteoarthritis: a randomized controlled trial. Ann Fam Med. 2013;11(3):229–37. doi: 10.1370/afm.1504. [PubMed: 23690322].

 

31. Ekinci S, Tatar O, Akpancar S, Turgut H, Seven MM. A New Treatment Option in Osteoarthritis: Prolotherapy Injections. J Arthritis. 2016;5(197 in press).

 

32. Rabago D, Zgierska A, Fortney L, Kijowski R, Mundt M, Ryan M, et al. Hypertonic dextrose injections (prolotherapy) for knee osteoarthritis: results of a single-arm uncontrolled study with 1-year follow-up. J Altern Complement Med. 2012;18(4):408–14. doi: 10.1089/acm.2011.0030. [PubMed: 22515800].

 

33. Kim J. The effect of prolotherapy for osteoarthritis of the knee. J Korean Acad Rehabil Med. 2002;26:445–8.

 

34. Reeves KD, Hassanein KM. Long-term effects of dextrose prolotherapy for anterior cruciate ligament laxity. Altern Ther Health Med. 2003;9(3):58–62. [PubMed: 12776476].

 

35. Rahimzadeh P, Imani F, Faiz SH, Entezary SR, Nasiri AA, Ziaeefard M. 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. 2014;19(8):696–702. [PubMed: 25422652].

 

36. Felson DT. An update on the pathogenesis and epidemiology of osteoarthritis. Radiologic Clinics of North America. 2004;42(1):1–9. doi: 10.1016/s0033-8389(03)00161-1.

 

37. Wheaton M, Jensen N. The ligament injury connection to osteoarthritis. Journal of Prolotherapy. 2010;2(1):294–304.

 

38. Carayannopoulos A, Borg-Stein J, Sokolof J, Meleger A, Rosenberg D. Prolotherapy versus corticosteroid injections for the treatment of lateral epicondylosis: a randomized controlled trial. PM R. 2011;3(8):706– 15. doi: 10.1016/j.pmrj.2011.05.011. [PubMed: 21871414].

 

39. Baker CL. Shoulder impingement and rotator cuff lesions. The Hughston Clinic Sports Medicine Book. Baltimore. United States: Md: Lippincott Williams and Wilkins; 1995.

 

40. Bishay V, Gallo RA. The evaluation and treatment of rotator cuff pathology. Prim Care. 2013;40(4):889–910. doi: 10.1016/j.pop.2013.08.006. [PubMed: 24209724].

 

41. Wilson JJ, Best TM. Common overuse tendon problems: A review and recommendations for treatment. Am Fam Physician. 2005;72(5):811–8. [PubMed: 16156339].

 

42. Seven MM, Koca K, Akpancar S, Turkkan S, Uysal B, Yildiz Y, et al. Promising Results of Prolotherapy in an Elderly Male with Bilateral Partial Rotator Cuff Lesions. BMMR. 2016.

 

43. Lee DH, Kwack KS, Rah UW, Yoon SH. Prolotherapy for Refractory Rotator Cuff Disease: Retrospective Case-Control Study of 1- Year Follow-Up. Arch Phys Med Rehabil. 2015;96(11):2027–32. doi: 10.1016/j.apmr.2015.07.011. [PubMed: 26254952].

 

44. Bertrand H, Reeves KD, Bennett CJ, Bicknell S, Cheng AL. Dextrose Prolotherapy Versus Control Injections in Painful Rotator Cuff Tendinopathy. Arch Phys Med Rehabil. 2016;97(1):17–25. doi: 10.1016/j.apmr.2015.08.412. [PubMed: 26301385].

 

 45. Riddle DL, Pulisic M, Sparrow K. Impact of demographic and impairment-related variables on disability associated with plantar fasciitis. Foot Ankle Int. 2004;25(5):311–7. [PubMed: 15134611].

 

46. Tu P, Bytomski JR. Diagnosis of heel pain. Am Fam Physician. 2011;84(8):909–16. [PubMed: 22010770].

 

 47. Davis PF, Severud E, Baxter DE. Painful heel syndrome: results of nonoperative treatment. Foot Ankle Int. 1994;15(10):531–5. [PubMed: 7834059].

 

 48. Ryan MB, Wong AD, Gillies JH, Wong J, Taunton JE. Sonographically guided intratendinous injections of hyperosmolar dextrose/lidocaine: a pilot study for the treatment of chronic plantar fasciitis. Br J Sports Med. 2009;43(4):303–6. doi: 10.1136/bjsm.2008.050021. [PubMed: 19019908].

 

49. Griffith CJ, LaPrade RF, Johansen S, Armitage B, Wijdicks C, Engebretsen L. Medial knee injury: Part 1, static function of the individual components of the main medial knee structures. Am J Sports Med. 2009;37(9):1762–70. doi: 10.1177/0363546509333852. [PubMed: 19609008].

 

50. Ada AM, Yavuz F. Treatment of a medial collateral ligament sprain using prolotherapy: a case study.Altern Ther Health Med. 2015;21(4):68–71. [PubMed: 26030118].

 

51. Zhang Y, Niu J, Kelly-Hayes M, Chaisson CE, Aliabadi P, Felson DT. Prevalence of symptomatic hand osteoarthritis and its impact on functional status among the elderly: The Framingham Study. Am J Epidemiol. 2002;156(11):1021–7. [PubMed: 12446258].

 

52. Joshi R. Intraarticular corticosteroid injection for first carpometacarpal osteoarthritis. J Rheumatol. 2005;32(7):1305–6. [PubMed: 15996069].

 

53. Jahangiri A, Moghaddam FR, Najafi S. 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. 2014;19(5):737–43. doi: 10.1007/s00776-014-0587-2. [PubMed: 25158896].

 

54. Liu YK, Tipton CM, Matthes RD, Bedford TG, Maynard JA, Walmer HC. An in situ study of the influence of a sclerosing solution in rabbit medial collateral ligaments and its junction strength. Connect Tissue Res. 1983;11(2-3):95–102. [PubMed: 6224646].

 

55. Maynard JA, Pedrini VA, Pedrini-Mille A, Romanus B, Ohlerking F. Morphological and biochemical effects of sodium morrhuate on tendons. J Orthop Res. 1985;3(2):236–48. doi: 10.1002/jor.1100030214. [PubMed: 3998899].

Keywords


1. Kelsey J. Epidemiology of musculoskeletal disorders. New York: Oxford University Press; 1982.

 2. Lawrence RC, Hochberg MC, Kelsey JL, McDuffie FC, Medsger TA, Felts WR, et al. Estimates of the prevalence of selected arthritic and musculoskeletal diseases in the United States. J Rheumatol. 1989;16(4):427–41. [PubMed: 2746583].

 3. Bilgic S, Durusu M, Aliyev B, Akpancar S, Ersen O, Yasar SM, et al. Comparison of two main treatment modalities for acute ankle sprain. Pak J Med Sci. 2015;31(6):1496–9. doi: 10.12669/pjms.316.8210. [PubMed: 26870123].

 4. Distel LM, Best TM. Prolotherapy: a clinical review of its role in treating chronic musculoskeletal pain. PM R. 2011;3(6 Suppl 1):S78–81. doi: 10.1016/j.pmrj.2011.04.003. [PubMed: 21703585].

 5. Taylor M. Prolotherapy for peripheral joints. Australasian Musculoskeletal Medicine. 2004;9(1):38.

 6. Seven MM, Koca K, Akpancar S, Turkkan S, Uysal B, Yildiz Y, et al. Prolotherapy Injections in the Treatment of Overuse Injuries. BMMR. 2016;19(3):113–5.

7. Kannus P. Tendon pathology: basic science and clinical applications. Sports Exercise and Injury. 1997;3(2):62–75.

8. 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. doi: 10.1016/j.ctim.2015.04.003. [PubMed: 26051574].

9. Hashemi M, Jalili P, Mennati S, Koosha A, Rohanifar R, Madadi F, et al. The Effects of Prolotherapy With Hypertonic Dextrose Versus Prolozone (Intraarticular Ozone) in Patients With Knee Osteoarthritis. Anesth pain med. 2015;5(5).

10. Hauser RA, Sprague IS. Outcomes of prolotherapy in chondromalacia patella patients: improvements in pain level and function. Clin Med Insights Arthritis Musculoskelet Disord. 2014;7:13–20. doi: 10.4137/CMAMD.S13098. [PubMed: 24596471].

11. Hackett GS, Hemwall GA, Montgomery GA. Ligament and Tendon Relaxation Treated by Prolotherapy. 1956 First Edition Charles C. Thomas, Publisher. Gustav A. Hemwall, Publisher. Institute in Basic Life Principles. Oak Brook, IL; 1991.

12. Rabago D, Slattengren A, Zgierska A. Prolotherapy in primary care practice. Prim Care. 2010;37(1):65–80. doi: 10.1016/j.pop.2009.09.013. [PubMed: 20188998].

13. Scarpone M, Rabago D, Zgierska A, Arbogest J, Snell E. . The efficacy of prolotherapy for lateral epicondylosis: a pilot study. Clin J Sport Med. 2008;18(3):248–54. doi: 10.1097/JSM.0b013e318170fc87. [PubMed: 18469566].

14. Di Paolo S, Gesualdo L, Ranieri E, Grandaliano G, Schena FP. High glucose concentration induces the overexpression of transforming growth factor-beta through the activation of a plateletderived growth factor loop in human mesangial cells. Am J Pathol. 1996;149(6):2095–106. [PubMed: 8952542].

15. Murphy M, Godson C, Cannon S, Kato S, Mackenzie HS, Martin F, et al. Suppression subtractive hybridization identifies high glucose levels as a stimulus for expression of connective tissue growth factor and other genes in human mesangial cells. J Biol Chem. 1999;274(9):5830– 4. [PubMed: 10026205].

 16. Krump E, Nikitas K, Grinstein S. Induction of tyrosine phosphorylation and Na+/H+ exchanger activation during shrinkage of human neutrophils. J Biol Chem. 1997;272(28):17303–11. [PubMed: 9211867].

17. Lyftogt J. Subcutaneous prolotherapy treatment of refractory knee, shoulder, and lateral elbow pain. Australasian Musculoskeletal Med. 2007;12(2):110.

 18. Reeves KD, Fullerton BD, Topol G. Evidence-based regenerative injection therapy (prolotherapy) in sports medicine.The Sports Medicine Resource Manual. Saunders (Elsevier); 2008. pp. 611–9.

19. Jensen KT, Rabago DP, Best TM, Patterson JJ, Vanderby R. Early inflammatory response of knee ligaments to prolotherapy in a rat model. J Orthop Res. 2008;26(6):816–23. doi: 10.1002/jor.20600. [PubMed: 18240327].

20. Jensen KT, Rabago DP, Best TM, Patterson JJ, Vanderby R. Response of knee ligaments to prolotherapy in a rat injury model. Am J Sports Med. 2008;36(7):1347–57. doi: 10.1177/0363546508314431. [PubMed: 18310313]. 21. Reeves KD, Hassanein K. Randomized, prospective, placebocontrolled double-blind study of dextrose prolotherapy for osteoarthritic thumb and finger (DIP, PIP, and trapeziometacarpal) joints: evidence of clinical efficacy. J Altern Complement Med. 2000;6(4):311–20. doi: 10.1089/10755530050120673. [PubMed: 10976977].

22. 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. 2000;6(2):68–74. [PubMed: 10710805].

23. Dechow E, Davies RK, Carr AJ, Thompson PW. A randomized, doubleblind, placebo-controlled trial of sclerosing injections in patients with chronic low back pain. Rheumatology (Oxford). 1999;38(12):1255– 9. [PubMed: 10587555].

24. Khan SA, Kumar A, Varshney MK, Trikha V, Yadav CS. Dextrose prolotherapy for recalcitrant coccygodynia. J Orthop Surg (Hong Kong). 2008;16(1):27–9. [PubMed: 18453654].

25. Miller MR, Mathews RS, Reeves KD. Treatment of painful advanced internal lumbar disc derangement with intradiscal injection of hypertonic dextrose. Pain Physician. 2006;9(2):115–21. [PubMed: 16703971].

 26. Maxwell NJ, Ryan MB, Taunton JE, Gillies JH, Wong AD. Sonographically guided intratendinous injection of hyperosmolar dextrose to treat chronic tendinosis of the Achilles tendon: a pilot study. AJR Am J Roentgenol. 2007;189(4):W215–20. doi: 10.2214/AJR.06.1158. [PubMed: 17885034].

 27. Holmich P, Uhrskou P, Ulnits L, Kanstrup IL, Nielsen MB, Bjerg AM, et al. Effectiveness of active physical training as treatment for longstanding adductor-related groin pain in athletes: randomised trial. Lancet. 1999;353(9151):439–43. doi: 10.1016/S0140-6736(98)03340-6. [PubMed: 9989713].

28. Chen CM, Chen JS, Tsai WC, Hsu HC, Chen KH, Lin CH. Effectiveness of device-assisted ultrasound-guided steroid injection for treating plantar fasciitis. Am J Phys Med Rehabil. 2013;92(7):597–605. doi: 10.1097/PHM.0b013e318278a831. [PubMed: 23221670].

29. Tsai WC, Hsu CC, Chen CP, Chen MJ, Yu TY, Chen YJ. Plantar fasciitis treated with local steroid injection: comparison between sonographic and palpation guidance. J Clin Ultrasound. 2006;34(1):12–6. doi: 10.1002/jcu.20177. [PubMed: 16353228].

 30. Rabago D, Patterson JJ, Mundt M, Kijowski R, Grettie J, Segal NA, et al. Dextrose prolotherapy for knee osteoarthritis: a randomized controlled trial. Ann Fam Med. 2013;11(3):229–37. doi: 10.1370/afm.1504. [PubMed: 23690322].

31. Ekinci S, Tatar O, Akpancar S, Turgut H, Seven MM. A New Treatment Option in Osteoarthritis: Prolotherapy Injections. J Arthritis. 2016;5(197 in press).

32. Rabago D, Zgierska A, Fortney L, Kijowski R, Mundt M, Ryan M, et al. Hypertonic dextrose injections (prolotherapy) for knee osteoarthritis: results of a single-arm uncontrolled study with 1-year follow-up. J Altern Complement Med. 2012;18(4):408–14. doi: 10.1089/acm.2011.0030. [PubMed: 22515800].

 33. Kim J. The effect of prolotherapy for osteoarthritis of the knee. J Korean Acad Rehabil Med. 2002;26:445–8.

34. Reeves KD, Hassanein KM. Long-term effects of dextrose prolotherapy for anterior cruciate ligament laxity. Altern Ther Health Med. 2003;9(3):58–62. [PubMed: 12776476].

35. Rahimzadeh P, Imani F, Faiz SH, Entezary SR, Nasiri AA, Ziaeefard M. 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. 2014;19(8):696–702. [PubMed: 25422652].

36. Felson DT. An update on the pathogenesis and epidemiology of osteoarthritis. Radiologic Clinics of North America. 2004;42(1):1–9. doi: 10.1016/s0033-8389(03)00161-1.

 37. Wheaton M, Jensen N. The ligament injury connection to osteoarthritis. Journal of Prolotherapy. 2010;2(1):294–304.

 38. Carayannopoulos A, Borg-Stein J, Sokolof J, Meleger A, Rosenberg D. Prolotherapy versus corticosteroid injections for the treatment of lateral epicondylosis: a randomized controlled trial. PM R. 2011;3(8):706– 15. doi: 10.1016/j.pmrj.2011.05.011. [PubMed: 21871414].

39. Baker CL. Shoulder impingement and rotator cuff lesions. The Hughston Clinic Sports Medicine Book. Baltimore. United States: Md: Lippincott Williams and Wilkins; 1995.

 40. Bishay V, Gallo RA. The evaluation and treatment of rotator cuff pathology. Prim Care. 2013;40(4):889–910. doi: 10.1016/j.pop.2013.08.006. [PubMed: 24209724].

41. Wilson JJ, Best TM. Common overuse tendon problems: A review and recommendations for treatment. Am Fam Physician. 2005;72(5):811–8. [PubMed: 16156339].

42. Seven MM, Koca K, Akpancar S, Turkkan S, Uysal B, Yildiz Y, et al. Promising Results of Prolotherapy in an Elderly Male with Bilateral Partial Rotator Cuff Lesions. BMMR. 2016.

43. Lee DH, Kwack KS, Rah UW, Yoon SH. Prolotherapy for Refractory Rotator Cuff Disease: Retrospective Case-Control Study of 1- Year Follow-Up. Arch Phys Med Rehabil. 2015;96(11):2027–32. doi: 10.1016/j.apmr.2015.07.011. [PubMed: 26254952].

44. Bertrand H, Reeves KD, Bennett CJ, Bicknell S, Cheng AL. Dextrose Prolotherapy Versus Control Injections in Painful Rotator Cuff Tendinopathy. Arch Phys Med Rehabil. 2016;97(1):17–25. doi: 10.1016/j.apmr.2015.08.412. [PubMed: 26301385].

45. Riddle DL, Pulisic M, Sparrow K. Impact of demographic and impairment-related variables on disability associated with plantar fasciitis. Foot Ankle Int. 2004;25(5):311–7. [PubMed: 15134611].

46. Tu P, Bytomski JR. Diagnosis of heel pain. Am Fam Physician. 2011;84(8):909–16. [PubMed: 22010770].

47. Davis PF, Severud E, Baxter DE. Painful heel syndrome: results of nonoperative treatment. Foot Ankle Int. 1994;15(10):531–5. [PubMed: 7834059].

48. Ryan MB, Wong AD, Gillies JH, Wong J, Taunton JE. Sonographically guided intratendinous injections of hyperosmolar dextrose/lidocaine: a pilot study for the treatment of chronic plantar fasciitis. Br J Sports Med. 2009;43(4):303–6. doi: 10.1136/bjsm.2008.050021. [PubMed: 19019908].

49. Griffith CJ, LaPrade RF, Johansen S, Armitage B, Wijdicks C, Engebretsen L. Medial knee injury: Part 1, static function of the individual components of the main medial knee structures. Am J Sports Med. 2009;37(9):1762–70. doi: 10.1177/0363546509333852. [PubMed: 19609008]. 50. Ada AM, Yavuz F. Treatment of a medial collateral ligament sprain using prolotherapy: a case study.Altern Ther Health Med. 2015;21(4):68–71. [PubMed: 26030118].

51. Zhang Y, Niu J, Kelly-Hayes M, Chaisson CE, Aliabadi P, Felson DT. Prevalence of symptomatic hand osteoarthritis and its impact on functional status among the elderly: The Framingham Study. Am J Epidemiol. 2002;156(11):1021–7. [PubMed: 12446258].

52. Joshi R. Intraarticular corticosteroid injection for first carpometacarpal osteoarthritis. J Rheumatol. 2005;32(7):1305–6. [PubMed: 15996069].

53. Jahangiri A, Moghaddam FR, Najafi S. 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. 2014;19(5):737–43. doi: 10.1007/s00776-014-0587-2. [PubMed: 25158896].

54. Liu YK, Tipton CM, Matthes RD, Bedford TG, Maynard JA, Walmer HC. An in situ study of the influence of a sclerosing solution in rabbit medial collateral ligaments and its junction strength. Connect Tissue Res. 1983;11(2-3):95–102. [PubMed: 6224646].

 55. Maynard JA, Pedrini VA, Pedrini-Mille A, Romanus B, Ohlerking F. Morphological and biochemical effects of sodium morrhuate on tendons. J Orthop Res. 1985;3(2):236–48. doi: 10.1002/jor.1100030214. [PubMed: 3998899].