Prolotherapy: A New Approach to Osteoarthritis Care?

Ryan Sciacchitano, BKin, CSCS, CISSN
Tracey Teasdale, ND, CISSN

Student Scholarship – 1st Place Research Review

Osteoarthritis (OA) is characterized by degeneration of the articular cartilage of a joint, as well as the associated joint lining, ligaments, and underlying bone.1 OA is strongly associated with advancing age, with average onset occurring in the fifth decade of life.2 An estimated 30% of Canadians have been diagnosed, 51.3% of whom are under the age of 65.2 In Canada the productivity costs of work loss (PCWL) associated with OA increased to $17.5 billion in 2008.3 The burden on the healthcare system is also alarming, with the total annual cost per patient estimated at approximately US $5700.4 This does not include the approximately 39% of people with OA who reported an inability to access needed healthcare services, most commonly due to OA’s debilitating effects.5

Currently, no cure exists for OA.1 Acupuncture6 and corticosteroid injection7 have shown the most efficacy in decreasing acute pain. However, the research examining acupuncture for OA is of poor quality,6 and corticosteroid injections have concerning systemic effects (eg, disturbed control of diabetes and hypertension, facial flushing, inhibition of the hypothalamic-pituitary-adrenal axis, sepsis, and death in very rare cases), and its long-term safety has not been addressed in a satisfactory manner.7 Joint replacement surgeries are becoming more efficacious, but the cost is overwhelming, with an estimated $42.2 billion spent on knee and hip replacements in the United States, alone, in 2009.8 This article examines the effect of prolotherapy on OA as a cost-effective approach to improving clinical outcomes.

OA Treatment Guidelines

Current conventional medical treatment for OA focuses on reducing and controlling pain, minimizing disability, and educating patients and their families about the disease.9 Non-pharmacologic treatments are considered first-line therapies, to be implemented before use of pharmacologic agents (see Table 1).10

Table 1. Conventional OA Treatments & Therapeutic Goals10,11

Treatment Treatment Goal
Rest and restricted use of affected joint Decrease pain and inflammation
Weight reduction (if necessary) Decrease stress on weight-bearing joints
Heat therapy Decrease pain
Exercise (range of motion, strengthening, and aquatic-based exercises) Increase mobility, decrease pain and stress on the joint; regular strengthening of quadriceps12 and hip abductors and adductors13 has been shown to reduce knee pain associated with OA
Occupational therapy assessment Assess current abilities in performing daily activities and potential need for ambulatory aids
Patient education programs Improve overall clinical outcomes14,15

 

If non-pharmacologic treatments are not considered satisfactory, pharmaceuticals are then considered for reduction of pain and swelling and increased joint function. They are listed in Table 2 in the typical order that a practitioner considers implementing them.

Table 2. Pharmaceutical Treatments for OA10,11

Treatment
Acetaminophen
Traditional NSAIDs (eg, aspirin, ibuprofen)
Selective COX-2 inhibitors (eg, celecoxib)
Meloxicam (COX-1 and COX-2 inhibitor; preferential for COX-2)
Opioids (eg, codeine)
Tramadol (opiate-like analgesic)
Intra-articular corticosteroid injection (eg, methylprednisolone and triamcinolone)
Hyaluronic acid injection

 

If the response to these treatments is inadequate, conventional medical practice also considers joint replacement surgery as a potential treatment.9 Good evidence exists showing significantly positive benefits on the short- and long-term quality of life in patients after this procedure.16 Osteotomy is also considered, but is less common, as it is currently viewed as a short-term measure, likely only delaying full joint replacement.17

Naturopathic medicine is becoming increasingly prominent in the treatment of OA, as recent reports suggest that approximately 60-90% of dissatisfied arthritis patients are likely to seek complementary and alternative medicine.18 Naturopathic doctors generally begin with many of the treatments listed in Table 1, and then continue with acupuncture and dietary recommendations specific to each patient. Common supplements implemented for OA are reviewed in Table 3.

Table 3. Common Naturopathic Supplements

Treatment Dose & Duration Efficacy of Treatment
Curcumin Most commonly 1 g/d in divided doses, minimum 4-6 wk Improvement in pain on Visual Analogue Scale (VAS; mean difference -2.04), and mean Western Ontario and McMaster Universities Arthritis Index (WOMAC) score of 15.3619
Vitamin D 60 000 IU/d X 10 d, then 60 000 IU once/mo X 12 mo20
50,000 IU/month X 2 y21
Improved WOMAC scores without reaching minimum clinical important difference; small decrease in short-term symptoms20

 

No change in MRI-measured tibial cartilage volume or WOMAC knee pain21

Glucosamine / Chondroitin sulfate 800 mg/d, 1-3 y

 

1500 mg/d, 1-3 y

Each individually showed no difference vs placebo after 1 year of treatment. May delay radiologic progression of OA after 2-3 years of treatment,22,23 but risk of publication bias exists,24 with some studies showing no effect.25 The combination compared similarly to celecoxib, with fewer side effects.26
Methylsulfonylmethane (MSM) 1.125 g TID X 12 wk27

 

5 g/d X 6 mo28

Small improvement in WOMAC physical function and total scores, but not in WOMAC pain or stiffness scores27

 

Compared favorably to glucosamine when combined with Boswellia28

Fish oil 1332 mg with 600 mg omega-3/d X 26 wk29

4.5 g combined EPA/DHA/d vs 0.45 g combined EPA/DHA + sunflower oil/d X 2 y30

Improves effects of glucosamine sulfate on WOMAC scale29

 

Only the 0.45 g group reached minimum 12-point improvement in WOMAC function; higher dose less effective30

Boswellia serrata 350 mg curcumin, 150 mg Boswellia (75% boswellic acids) per day X 12 wk31

333 mg Boswellia (minimum 40% boswellic acids) per day X 8 wk32

When combined with curcumin, performed better on symptom-scoring and clinical examination than celecoxib31
Decreased knee pain, increased knee flexion, and increased walking distance in a small randomized controlled trial32
Natural eggshell membrane (NEM) 500 mg/d X 30-60 d WOMAC scores did not improve significantly, although the authors calculated an NNT (number needed to treat) of 5 for a 50% reduction in pain in clinical practice. The risk of publication bias exists due to possible conflict of interest.33
Ginger 750 mg/d X 12 wk34

133 mg TID (ginger extract) X 3 wk35

Improvement on WOMAC scores; greater improvement when combined with diclofenac (which was also better than diclofenac alone)34
Inferior magnitude of effect than ibuprofen; slightly better than placebo35
Harpagophytum procumbens (devil’s claw) 2400 mg doloteffin (50 mg harpagoside) X 12 wk36

650 mg total combined devil’s claw, curcumin, bromelain; duration unknown37

2610 mg X 4 mo38

Unblinded study demonstrated improvement in total WOMAC score (mean difference 12.6) and VAS score for pain (25.8%)36
Significant reductions in both acute and chronic pain on VAS when combined with turmeric and bromelain37
At least as effective as a reference drug (diacerhein) and decreased the need for NSAIDs38

Note: For studies using the WOMAC scale, a 12-point improvement is considered the minimum clinical important difference.

Prolotherapy

Prolotherapy (from “proliferative therapy”) involves the injection of a hyperosmolar dextrose solution.39 It was formalized by George Hackett, a general surgeon in the United States, who had been using this treatment clinically for over 30 years.40 The solution acts as an irritant, which is typically injected into a joint space, tendinous insertion, or ligament. Solutions other than dextrose have been used (phenol-glycerine-glucose, and morrhuate sodium); however, the dextrose solution is most commonly researched and used clinically. The goals and suggested benefits include improved joint stability, biomechanics, and function, as well as decreased pain.41 Side effects mostly involve minor pain associated with the needle puncture, with no serious adverse effects having been reported. The purported mechanism of action is not well-defined in scientific literature.39 It is suggested that once the dextrose solution is injected, it creates an inflammatory response due to the osmotic rupture of local cells, as well as an upregulation of the expression of platelet-derived growth factors. This is considered to be effective largely because of the poor blood supply that joint cavities, tendons, and ligaments generally receive. In essence, prolotherapy recruits the body’s own cells to these damaged sights to speed healing and repair tissue that the body is notoriously slow at healing. In-vitro studies clearly indicate a rapid elevation of growth factor in chondrocytes, but this has yet to be demonstrated in vivo.41 To date, 8 human clinical trials, including 6 randomized controlled trials, have been conducted on prolotherapy for OA. Their results are summarized in Table 4.

Table 4. Prolotherapy & Existing Clinical Research

Clinical Trial % Dextrose Injection Schedule Summary of Results
Sert; 201642 Unspecified 0, 3, 6 weeks VAS score and all WOMAC scores decreased significantly in the prolotherapy group vs the saline injection group and control group at the 18-wk follow-up; all groups given the same home exercise program
Rabago; 201543 25% intra-articular, 15% extra-articular Weeks 1, 5, 9; wk 13 and 17 optional Significant improvement from baseline on WOMAC scale. Pain, stiffness, and function all improved steadily through the duration of the study, with an average improvement of 20.9 points at 52 wk. 53 participants were considered responders, while 12 saw no improvement or worsening, attributed partly to not following post-injection instructions, ie, engaging in heavy exercise soon thereafter.
Rabago; 201444 25% intra-articular, 15% extra-articular Weeks 1, 5, 9; wk 13 and 17 optional Average composite score change on WOMAC was 16.5 over 1 year. Most participants experienced near-maximum improvement by 24 wk and remained stable through 1 year.
Jahangiri; 201445 20% 1, 2, 3 months Better results were observed for the corticosteroid group at 1 mo; the groups were comparable at 2 mo; and more favorable results were observed in the prolotherapy group at 6 mo. Both groups saw improvements, but prolotherapy seemed to be more effective in terms of total function.
Rabago; 201346 25% intra-articular, 15% extra-articular Weeks 1, 5, 9; wk 13 and 17 optional The prolotherapy group showed progressive improvements over the course of 52 wk. The average improvement score at 52 wk on WOMAC was 15.32, or 24%. The control groups (saline, exercise) also showed improvement, but significantly less than the prolotherapy group.
Rabago; 201247 25% intra-articular, 15% extra-articular Weeks 1, 5, 9; wk 13 and 17 optional A 15.9 point total improvement on the WOMAC scale (36.1%) observed at 12 wk and maintained through the 52-wk study duration. Female gender, age 46-65 y, and BMI of 25 or less were associated with greater improvements.
Reeves; 200041 10% 0, 2, 4 months Pain with finger movement improved significantly more in the prolotherapy group (42%) vs control (15%). Flexion range of motion also improved more in the prolotherapy group. Pain at rest and with gripping improved more than placebo, but these outcomes were not statistically significant.
Reeves; 200048 10% 0, 2, 4 months At 6 months, pain, swelling, buckling episodes, and knee flexion range were significantly improved in the intervention group vs placebo.
At 12 months, further decrease in pain (overall 44% decrease), swelling (overall 63% decrease), knee buckling (overall 85% decreased frequency), and flexion range (overall 14 degree increase).
Statistically significant improvements were found in osteophyte grades, cartilage thickness, and proximal tibial width.

Clinical Implications

OA is a very common disorder, with an expected rise in prevalence2 that will increase the already massive burden on the healthcare system8 and workforce.5 Most current treatments are unsatisfactory, only targeting symptom management, and must be maintained for the duration of the patient’s life.

While the body of evidence may not yet be sufficient, the purported significant long-term, sustained benefit, along with the decreased use of pain medications and relative safety of the treatment, make prolotherapy a very appealing option to practitioners. However, prolotherapy cannot as yet be considered a first-line option for the treatment of OA because significant information is still lacking. As an example, standardized dosages, formulations, and treatment schedules have not been established, with some authors attributing a few adverse effects to possibly using too high of a dose and total volume of fluid in their study. This lack of consistency can lead to potential confusion when attempting to apply these results clinically. Based on the research to-date, 25% intra-articular and 15% extra-articular injections at 1, 5, and 9 weeks would be the most evidence-based approach, allowing for regeneration of both cartilage and surrounding soft tissue. Larger trials with both biomechanical and imaging measures are needed to determine the true clinical benefit of prolotherapy.

References:

  1. Centers for Disease Control and Prevention. Osteoarthritis Fact Sheet. Last updated February 2, 2017. CDC Web site. http://www.cdc.gov/arthritis/basics/osteoarthritis.htm. Accessed October 29, 2015.
  2. MacDonald KV, Sanmartin C, Langlois K, Marshall DA. Symptom onset, diagnosis and management of osteoarthritis. Modified November 27, 2015. Statistics Canada Web site. http://www.statcan.gc.ca/pub/82-003-x/2014009/article/14087-eng.htm. Accessed October 29, 2015.
  3. Sharif B, Garner R, Hennessy D, et al. Productivity costs of work loss associated with osteoarthritis in Canada from 2010 to 2031. Osteoarthritis Cartilage. 2017;25(2):249-258.
  4. Maetzel A, Li LC, Pencharz J, et al. The economic burden associated with osteoarthritis, rheumatoid arthritis, and hypertension: a comparative study. Ann Rheum Dis. 2004;63(4):395-401.
  5. Hagglund KJ, Clark MJ, Hilton SA, Hewett JE. Access to healthcare services among persons with osteoarthritis and rheumatoid arthritis. Am J Phys Med Rehabil. 2005;84(9):702-711.
  6. Corbett MS, Rice SJ, Madurasinghe V, et al. Acupuncture and other physical treatments for the relief of pain due to osteoarthritis of the knee: network meta-analysis. Osteoarthritis Cartilage. 2013;21(9):1290-1298.
  7. Kruse DW. Intraarticular cortisone injection for osteoarthritis of the hip. Is it effective? Is it safe? Curr Rev Musculoskelet Med. 2008;1(3-4):227-233.
  8. Murphy L, Helmick CG. The impact of osteoarthritis in the United States: a population-health perspective. Am J Nurs. 2012;112(3 Suppl 1):S13-S19.
  9. Brasington R, Hsia E, O’Hanlon K, Murray J. Osteoarthritis. December 10, 2010. Clinical Key – First Consult Web site. https://ezproxy.ccnm.edu:2402/#!/topic/osteoarthritis?scrollTo=%2384691. [Members-only access] Accessed October 30, 2015.
  10. Sinusas K. Osteoarthritis: diagnosis and treatment. Am Fam Physician. 2012;85(1):49-56.
  11. Manek NJ, Lane NE. Osteoarthritis: current concepts in diagnosis and management. Am Fam Physician. 2000;61(6):1795-1804.
  12. Jenkinson CM, Doherty M, Avery AJ, et al. Effects of dietary intervention and quadriceps strengthening exercises on pain and function in overweight people with knee pain: randomised controlled trial. BMJ. 2009;18;339:b3170.
  13. Bennell KL, Hunt MA, Wrigley TV, et al. Hip strengthening reduces symptoms but not knee load in people with medial knee osteoarthritis and varus malalignment: a randomised controlled trial. Osteoarthritis Cartilage. 2010;18(5):621-628.
  14. Poulsen E, Hartvigsen J, Christensen HW, et al. Patient education with or without manual therapy compared to a control group in patients with osteoarthritis of the hip. A proof-of-principle three-arm parallel group randomized clinical trial. Osteoarthritis Cartilage. 2013;21(10):1494-1503.
  15. Coleman S, Briffa NK, Carroll G, et al. A randomised controlled trial of a self-management education program for osteoarthritis of the knee delivered by health care professionals. Arthritis Res Ther. 2012;14(1):R21.
  16. Shan L, Shan B, Suzuki A, et al. Intermediate and Long-Term Quality of Life After Total Knee Replacement. J Bone Joint Surg Am. 2015;97(2):156-168.
  17. Stukenborg-Colsman C, Wirth CJ, Lazovic D, Wefer A. High tibial osteotomy versus unicompartmental joint replacement in unicompartmental knee joint osteoarthritis: 7-10-year follow-up prospective randomised study. Knee. 2001;8(3):187-194.
  18. Ahmed S, Anuntiyo J, Malemud CJ, Haqqi TM. Biological basis for the use of botanicals in osteoarthritis and rheumatoid arthritis: a review. Evid Based Complement Alternat Med. 2005;2(3):301-308.
  19. Daily J, Yang M, Park S. Efficacy of Turmeric Extracts and Curcumin for Alleviating the Symptoms of Joint Arthritis: A Systematic Review and Meta-Analysis of Randomized Clinical Trials. J Med Food. 2016;19(8):717-729.
  20. Sanghi D, Mishra A, Sharma AC, et al. Does vitamin D improve osteoarthritis of the knee: a randomized controlled pilot trial. Clin Orthop Relat Res. 2013;471(11):3556-3562.
  21. Jin X, Jones G, Cicuttini F, et al. Effect of Vitamin D Supplementation on Tibial Cartilage Volume and Knee Pain Among Patients With Symptomatic Knee Osteoarthritis: A Randomized Clinical Trial. JAMA. 2016;315(10):1005-1013.
  22. Lee YH, Woo JH, Choi SJ, et al. Effect of glucosamine or chondroitin sulfate on the osteoarthritis progression: a meta-analysis. Rheumatol Int. 2010;30(3):357-363.
  23. Hochberg MC. Structure-modifying effects of chondroitin sulfate in knee osteoarthritis: an updated meta-analysis of randomized placebo-controlled trials of 2-year duration. Osteoarthritis Cartilage. 2010;18 Suppl 1:S28-S31.
  24. Eriksen P, Bartels EM, Altman RD, et al. Risk of Bias and Brand Explain the Observed Inconsistency in Trials on Glucosamine for Symptomatic Relief of Osteoarthritis: A Meta‐Analysis of Placebo‐Controlled Trials. Arthritis Care Res (Hoboken). 2014;66(12):1844-1855.
  25. Wandel S, Jüni P, Tendal B, et al. Effects of glucosamine, chondroitin, or placebo in patients with osteoarthritis of hip or knee: network meta-analysis. BMJ. 2010;341:c4675.
  26. Hochberg MC, Martel-Pelletier J, Monfort J, et al. Combined chondroitin sulfate and glucosamine for painful knee osteoarthritis: a multicentre, randomised, double-blind, non-inferiority trial versus celecoxib. Ann Rheum Dis. 2016;75(1):37-44.
  27. Debbi E, Agar G, Fichman G, et al. Efficacy of methylsulfonylmethane supplementation on osteoarthritis of the knee: a randomized controlled study. BMC Complement Altern Med. 2011;11:50.
  28. Notarnicola A, Maccagnano G, Moretti L, et al. Methylsulfonylmethane and boswellic acids versus glucosamine sulfate in the treatment of knee arthritis: Randomized trial. Int J Immunopathol Pharmacol. 2016;29(1):140-146.
  29. Gruenwald, J, Petzold E, Busch R, et al. Effect of glucosamine sulfate with or without omega-3 fatty acids in patients with osteoarthritis. Adv Ther. 2009;26(9):858-871.
  30. Hill CL, March LM, Aitken D, et al. Fish oil in knee osteoarthritis: a randomised clinical trial of low dose versus high dose. Ann Rheum Dis. 2016;75(1):23-29.
  31. Kizhakkedath R. Clinical evaluation of a formulation containing Curcuma longa and Boswellia serrata extracts in the management of knee osteoarthritis. Mol Med Rep. 2013;8(5):1542-1548.
  32. Kimmatkar N, Thawani V, Hingorani L, Khiyani R. Efficacy and tolerability of Boswellia serrata extract in treatment of osteoarthritis of knee–a randomized double blind placebo controlled trial. Phytomedicine. 2003;10(1):3-7.
  33. Ruff K, Winkler A, Jackson R, et al. Eggshell membrane in the treatment of pain and stiffness from osteoarthritis of the knee: a randomized, multicenter, double-blind, placebo-controlled clinical study. Clin Rheumatol. 2009;28(8):907-914.
  34. Paramdeep G. Efficacy and tolerability of ginger (Zingiber officinale) in patients of osteoarthritis of knee. Indian J Physiol Pharmacol. 2013;57(2):177-183.
  35. Bliddal H, Rosetzsky A, Schlichting P, et al. A randomized, placebo-controlled, cross-over study of ginger extracts and ibuprofen in osteoarthritis. Osteoarthritis Cartilage. 2000;8(1):9-12.
  36. Wegener T, Lüpke N. Treatment of patients with arthrosis of hip or knee with an aqueous extract of devil’s claw (Harpagophytum procumbens DC.). Phytother Res. 2003;17(10):1165-1172.
  37. Conrozier T, Mathieu P, Bonjean M, et al. A complex of three natural anti-inflammatory agents provides relief of osteoarthritis pain. Altern Ther Health Med. 2014;20 Suppl 1:32-37.
  38. Leblan D, Chantre P, Fournié B. Harpagophytum procumbens in the treatment of knee and hip osteoarthritis. Four-month results of a prospective, multicenter, double-blind trial versus diacerhein. Joint Bone Spine. 2000;67(5):462-467.
  39. Distel LM, Best TM. Prolotherapy: a clinical review of its role in treating chronic musculoskeletal pain. PM R. 2011;3(6 Suppl 1):S78-S81.
  40. Hauser RA, Hauser MA. A Retrospective Study on Hackett-Hemwall Dextrose Prolotherapy for Chronic Shoulder Pain at an Outpatient Charity Clinic in Rural Illinois. J Prolotherapy. 2009;1(4):205-216.
  41. Reeves K, Hassanein K. 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. 2000;6(4):311-320.
  42. Sert A, Ozcan E, Esmaeilzadeh S. Poster 383 Effects of Dextrose Prolotherapy in the Treatment of Patients with Knee Osteoarthritis: A Randomized Controlled Trial. PM R. 2016;8(9S):S286.
  43. Rabago D, Mundt M, Zgierska A, Grettie J. Hypertonic dextrose injection (prolotherapy) for knee osteoarthritis: Long term outcomes. Complement Ther Med. 2015;23(3):388-395.
  44. Rabago D, Patterson J, Mundt M, et al. Dextrose and morrhuate sodium injections (prolotherapy) for knee osteoarthritis: a prospective open-label trial. J Altern Complement Med. 2014;20(5):383-391.
  45. Jahangiri A, Moghaddam F, 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):737-743.
  46. Rabago D, Patterson J, Mundt M, Kijowski R. Dextrose Prolotherapy for Knee Osteoarthritis: A Randomized Controlled Trial. Ann Fam Med. 2013;11(3):229-237.
  47. Rabago D, Zgierska A, Fortney L, 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):408-414.
  48. Reeves K, 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):68-74,77-80.
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Ryan Sciacchitano, BKin, CSCS, CISSN, is a 4th-year intern at the Canadian College of Naturopathic Medicine. Through his many years as an athlete, including competing for the University of Toronto varsity soccer team and Toronto FC, Ryan developed a fascination for optimal health and performance. His current goals revolve around acquiring, developing, and expanding his knowledge in order to help others realize their full potential in health and athletics.

 

Tracey Teasdale, ND, CISSN, is a naturopathic doctor and sports nutritionist in private practice in Barrie, Ontario; she is also a sports medicine clinical supervisor at the Canadian College of Naturopathic Medicine. Dr Teasdale is a published author and recipient of the Sport Information Resource Centre’s Research Development Award for her research on trigger-point therapy and pain management. Her passion lies in maximizing her patient’s potential, in both sport and life.

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