Introduction
According to the 2017 Global Burden of Disease study, osteoarthritis is a leading cause of disability, affecting approximately 303 million people worldwide.1 It can affect any joint, but primarily affects the knee in 87% of cases. Between 2007 and 2017, osteoarthritis has lead to a 30.8% increase in years lost due to disability.1 With a growing population of obese and aging individuals, these numbers are only expected to increase in the coming years.2
Other risk factors for osteoarthritis include genetic predisposition, gender, trauma, hormones, metabolic syndromes, and chronic joint overload.3 Over the years, new evidence has shown that the cause of osteoarthritis is multifactorial, moving away from the idea of an entirely degenerative disease of cartilage. Onset of osteoarthritis is influenced by inflammation, joint mechanics, and metabolic responses of joint tissues such as cartilage, ligaments, tendons, bone, adipose, and synovial fluid cells.3 Osteoarthritis leads to an inability of articular surfaces to absorb and distribute forces adequately, resulting in joint destruction and pain.3 Current treatment options for osteoarthritis of the knee consist of conservative, nonpharmacologic management; pharmacologic therapies such as topical compounds, oral medications, and intra-articular injections; and surgical replacement of the joint for cases refractory to medical management.4–7
Of the treatment options, intra-articular injections are popular due to the side effects of oral medications and invasive surgical procedures.8 Prolotherapy, in particular, has gained much attention since its formal introduction for the treatment of musculoskeletal pain in the 1950s by George Hackett, a U.S. general surgeon.8–10 Prolotherapy is a form of regenerative therapy whose exact mechanism of action is still unclear.8 Current propositions include that injected irritants, such as hypertonic dextrose, morrhuate sodium, dextrose/phenol/glycerin solution (DPG), or platelet rich plasma (PRP), into the peri- and intra-articular spaces stimulate growth factor and cytokine production, leading to regeneration of previously damaged ligaments, tendons, and other intra-articular structures.8,11–13 Various human trials have also been conducted on the use of prolotherapy for different musculoskeletal conditions, with positive results seen for its application in osteoarthritis of the knee.14–18
With a large proportion of the world suffering from osteoarthritis, effective treatment for the alleviation of symptoms is important. While conventional treatment for osteoarthritis of the knee involves the use of topical and oral medications, behavioral modifications, and injections, the search for safe, efficacious alternatives for patients who have failed the conventional medical treatment options is imperative to reduce the need for invasive surgical procedures. In this review, we will focus on current treatment options of osteoarthritis, prolotherapy, and emerging evidence on the use of prolotherapy for the treatment of osteoarthritis of the knee.
Prolotherapy Indications
Prolotherapy has been shown to be successful in treating a variety of musculoskeletal conditions. One major indication for prolotherapy is knee osteoarthritis in patients with chronic knee pain and radiographic findings of Kellgren-Lawrence stages II-IV.14,19 Based on most recent 2019 ACR guidelines, the use of prolotherapy is in fact recommended against in patients with knee osteoarthritis citing limited number of trials, further complicated by variabilities within the methodology.6 As recent studies have been promising, with further standardization of the approach to administering prolotherapy, guidelines will likely change to reflect the outcomes of the studies.
Additionally, prolotherapy is also indicated for the treatment of other painful, prolonged conditions, including enthesopathy, tendinosis, and anterior cruciate ligament (ACL) laxity. Prolotherapy can be considered when physical therapy or surgery fails to provide a therapeutic benefit or when patients have an intolerance to NSAIDs, steroids, or opiates. Additionally, any chronic ligament or tendon pain secondary to sprains or strains may be an indication for prolotherapy treatment.20,21
Technique
Patients with knee osteoarthritis that have been chosen to undergo prolotherapy treatment should first have the knee thoroughly examined by the injector, and the tender locations on the knee should be appropriately marked. Between 0.1% to 0.5% lidocaine is often given prior to administration of the injectate to decrease pain and irritation from the irritant.22 Extra-articular injections should be performed at the major tendon and ligament insertions of the site of tenderness using a peppering technique. An infero-medial or inferolateral intra-articular approach is preferred as a suprapatellar approach predisposes the patient to accidental collision of the needle against the patella, leading to pain and possible damage to the chondral cartilage of the patella.23
Patients may be prescribed acetaminophen and/or a narcotic for pain and should be instructed to avoid taking any nonsteroidal anti-inflammatory medications (NSAIDs). Patients should be advised to rest for at least 2 to 3 days in order to allow time for the knee to heal appropriately.14 Injection intervals are typically spaced 4-6 weeks apart with individuals averaging between 4 to 6 treatments.8,20 Improvement in pain and isometric strength may be noticed after the first treatment; although, most patients do not see results until after their second or third treatment.8,20 If no improvements are seen following three prolotherapy sessions, alternative interventions should be considered.8
Formulations
The most common injectant used in prolotherapy is hypertonic dextrose (D-glucose) 10%, 12.5 %, 16.5%, 20%, and 25%. Injections are diluted with local anesthetics in 1:1, 1:2, 1:3, 1:4, or 2:5 parts. Because dextrose is a normal component of our blood chemistry and can also be administered safely in large doses, it is considered to be an ideal proliferant.21,24 Some studies have shown that a 25% dextrose solution is most appropriate in the treatment of intra-articular knee injections. If this solution proves to be ineffective, a gradual progression to sodium morrhuate (5%) is recommended.21 Sodium morrhuate (5%) is composed of 2% benzyl alcohol and sodium salts of cod liver oil. Another common formulation used is a dextrose/phenol/glycerin solution (DPG), consisting of 25% dextrose, 25% glycerin, and 2.5% phenol. DPG solutions are diluted with local anesthetics in a 1:1, 1:2, or 2:3 concentration before injection.21
Contraindications
Prolotherapy is contraindicated if a patient has allergies to anesthetic or proliferative solutions, or the ingredient components. Other contraindications for prolotherapy treatment include acute arthritis, bursitis, tendinitis, gout, complete rupture of a tendon or ligament, or rheumatoid arthritis.20,21 In addition, prolotherapy should be avoided in patients who have an active infection, cancer, or any other underlying condition that may prolong the healing process or leave the patient immunocompromised. Relative contraindications to prolotherapy include the regular usage of corticosteroids or NSAIDs, as they counteract the body’s inflammatory processes, or current long term use of narcotics, as they lower the body’s immune response.20
Side Effects
Prolotherapy is a very low-risk procedure, and complications are extremely rare. The most common side effect is soreness and swelling at the site of injection after treatment, which usually disappears within 1-2 days. Additional risks include bruising, headaches, allergic reactions, temporary numbness, and nerve irritation.20 Another less common side effect is the development of an infection following treatment.
Current Treatment Options for Osteoarthritis of the Knee
Chronic osteoarthritis of the knee leads to years of debilitating pain and disability.1 Current recommendations by the American College of Rheumatology (ACR), the American Association of Orthopedic Surgeons (AAOC), and the Osteoarthritic Research Society Initiative (OARSI) have slight variations in management, but all support early management with exercise and weight loss.4–6 Studies show that a 7-10% reduction in weight is sufficient for pain relief, improved functionality, and delayed progression of cartilage degeneration.25,26 In addition to weight loss, regular exercise has also been shown to reduce pain and disability in patients with osteoarthritis.27,28 Other nonpharmacological treatments include massage therapy and biomechanical interventions, such as braces and walking canes.6,29
The use of pharmacological therapies is another mainstay of treatment for osteoarthritis of the knee and is commonly used in conjunction with non-pharmacologic treatments. These include topical treatments, oral medications, and intraarticular injections.4–6 The use of topical capsaicin relieves osteoarthritic pain by inhibiting the release of substance P from type-C nociceptive fibers, which are responsible for the pain response.30 The ACR continues to conditionally recommend the use of topical capsaicin, while OARSI guidelines recommend against its use due to poor quality of evidence.4,6 Topical NSAIDs have also been shown to achieve pain relief equivalent to oral NSAIDs at one year, and due to fewer side effects, it is a good alternative for some patients.4–6,31 However, many continue to use oral NSAIDs as they are preferred and provide adequate pain relief faster than their topical counterpart.31 Duloxetine is also recommended for patients with concomitant depression.4,32 Other oral treatments with differing recommendations are paracetamol and tramadol.4–6
After failure of symptom relief with nonpharmacological, topical, and oral treatments, physicians proceed with intra-articular injections. Of the intra-articular injection options, steroids are widely used for short-term treatment of osteoarthritis of the knee.33,34 However, its use is controversial as studies have shown an increased loss of cartilage volume and worsening radiographic evidence of osteoarthritis with intra-articular steroid injections.33,35,36 Hence, while ACR and OARSI guidelines have recommendations for intra-articular steroid injections, the AAOS has inconclusive recommendations.4–6 Additionally, hyaluronic acid, a glycosaminoglycan and major component of synovial fluid, which is decreased in osteoarthritis of the knee, has also been used to help with long-term pain relief for osteoarthritis.4,37,38 However, ACR and AAOS guidelines recommend against its use.5,6 Other novel injectable treatment options include biological therapies such as platelet-rich plasma, prolotherapy, and stem cells. As of now, recommendations for these injections are inconclusive due to inadequate evidence.4–6
When all conservative measures have been exhausted without adequate pain relief, surgical procedures are the definitive treatment option for severe pain.7,39 However, even with total joint replacement, up to 20% of patients can have continued symptoms or postoperative dissatisfaction.7,39,40
Prolotherapy Mechanism of Action
Although the mechanism of action of prolotherapy is not entirely clear, there have been many hypotheses proposed to help rationalize its effects. The general concept is that injectectates initiate a local inflammatory response that ultimately trigger a healing cascade. Release of cytokines and growth factors, such as platelet-derived growth factor, transforming growth factor β, epidermal growth factor, insulin-like growth factor, and connective tissue growth factor, promote proliferation of fibroblasts and deposition of collagen deposition, strengthening the joint and reducing pain.20,21,24
The most common prolotherapy solutions-hypertonic dextrose, DPG, and morrhuate sodium-are thought to function through different mechanisms. Hypertonic dextrose ruptures local cells via an osmotic gradient; DPG initiates local cellular irritation; and morrhuate sodium draws inflammatory mediators, leading to scarring of pathologic neovasculature.8 Other alternatives have been proposed, such as the administration of hypertonic dextrose causes the activation of inhibitory glycine receptors, thereby causing hyperpolarization and the reduction of nociceptive transmission.41 Ultimately, these injectates converge to form larger, stronger collagen fibers that increase joint stability and thus decrease pain.
Clinical studies: effects of prolotherapy on knee osteoarthritis
Osteoarthritis continues to be a burden on not only those who suffer from it but also healthcare systems and caregivers. A study in Ontario, Canada in 2005 found that participants who reported Western Ontario and McMaster Universities Arthritis Index (WOMAC) total scores greater than or equal to 55 had a greater likelihood of incurring osteoarthritis-related costs, and those costs were three times greater than participants with WOMAC total scores less than 15.42 Several treatment options are currently available, and there are novel interventions being researched around the world; however, there continues to be a debate surrounding which options are the most efficacious in the management of osteoarthritis. Thus, the need to provide therapeutic interventions that can help abate that burden that are not only safe but also cost-effective is imperative.11
A variety of studies have been done to assess the efficacy of prolotherapy on knee osteoarthritis. However, many of those studies have been found to provide low quality evidence due to data heterogeneity.11,43,44 Prolotherapy has been found to be associated with a favorable side effect profile, high patient satisfaction, and improved knee-specific quality of life and could provide an alternative to pain-relief medications and more invasive surgical interventions such as knee replacement for the management of knee osteoarthritis.11,45 The low-quality evidence in support of prolotherapy for the treatment of osteoarthritis has resulted in its classification as a complementary therapeutic intervention. This has led to further attempts to determine if prolotherapy has similar or superior therapeutic efficacy compared to alternative treatments in the treatment of osteoarthritis.46
A blinded, randomized control trial in Hong Kong compared intra-articular hypertonic dextrose prolotherapy (containing 25% dextrose) with normal saline injection.47 They found that both the normal saline and dextrose prolotherapy groups had improved WOMAC pain scores at 52 weeks compared to baseline but, the dextrose prolotherapy group had statistically significant improvement in WOMAC pain score compared to the normal saline group.47 The study also found that dextrose prolotherapy resulted in significantly improved visual analogue scale (VAS) scores for knee pain at 52 weeks compared to normal saline.47 Previous studies have shown similar effects. A study at the University of Wisconsin found that when dextrose prolotherapy was compared to normal saline injections and home exercise programs, dextrose prolotherapy had a significantly greater improvement in WOMAC composite and knee pain scale scores from baseline at 52 weeks, however, this study used both intra-articular 25% dextrose and extra-articular 15% dextrose prolotherapy techniques.14 A randomized prospective placebo-controlled study with 68 participants in 2000 found significant improvement in knee pain as well in knees treated with dextrose prolotherapy (containing 10% dextrose) compared to those treated with an injection of .075% lidocaine in bacteriostatic water or active solution.48
Several studies have also been conducted to determine if the injection method of dextrose prolotherapy could have an impact on the effectiveness of prolotherapy in knee osteoarthritis. A randomized clinical trial published in 2017 compared intra- and periarticular 25% dextrose prolotherapy in fifty-two adults with knee osteoarthritis.49 They concluded that both intra- and periarticular dextrose prolotherapy resulted in significant improvement from baseline in VAS, Oxford knee scale (OKS), and WOMAC scores at eight weeks.49 There was no significant difference between the two different methods, suggesting that either can be used in the treatment of knee osteoarthritis.49 This is consistent with findings of a 2015 prospective study in which intra-articular 20 % dextrose prolotherapy resulted in significant improvement of total WOMAC scores.50
Interestingly, a randomized clinical trial in 2017 found a significantly greater improvement in VAS scores at five months in participants treated with periarticular prolotherapy compared to those treated with intra-articular prolotherapy.51 Interestingly, in 2012 a prospective study with 36 participants found that those who received both intra- and extra-articular dextrose prolotherapy reported significant improvement in WOMAC and KPS scores at 52 weeks in the treated knee, as well as a significant improvement of KPS scores in the untreated knee.52 Similarly, a two-arm controlled trial with 128 participants published in 2016 reported that intra-articular dextrose prolotherapy alone, as well as intra- and periarticular dextrose prolotherapy in combination, led to significant improvements in WOMAC and VAS scores from their respective baseline and when compared to physiotherapy alone.53 Additionally, they reported that those who received both intra- and periarticular dextrose prolotherapy achieved not only faster improvement in WOMAC and VAS scores but significantly better improvement in WOMAC and VAS throughout the year.53 Effectiveness of periarticular prolotherapy could possibly be explained by periarticular healing effects, where inflammatory response around the joint enhance blood perfusion to the capsular joint and thus to the cartilaginous tissue for regeneration, or by a concept similar to neural prolotherapy, where injection of dextrose promote treatment of damaged subcutaneous nerves closer to the skin.51
Intra-articular injection of platelet-rich plasma is a possible regenerative treatment option for the management of knee osteoarthritis.11 A double-blind, randomized clinical trial with 42 participants in 2018 compared the effects of intra-articular platelet-rich plasma and intra-articular 25% dextrose prolotherapy.54 Similar trends for both groups were observed in all outcomes measured, with peak improvement happening within eight weeks, followed by an insignificant decline by 24 weeks.54 They found that both platelet-rich plasma and dextrose prolotherapy significantly improved WOMAC scores over six months; however, they also observed that the improvement in WOMAC scores was greater in those treated with platelet-rich plasma than those treated with dextrose prolotherapy.54
In contrast, a randomized placebo-controlled trial in 2016 found that while both platelet-rich plasma and dextrose prolotherapy resulted in improvement of measurements of pain and function, the improvement was not significant in either group.55 A randomized clinical trial with 92 patients published in June of 2020 also found no significant improvement in WOMAC scores in those treated with 50 % dextrose prolotherapy.56 They also found no significant difference in VAS scores for knee pain intensity in the dextrose prolotherapy group compared to baseline and compared to those treated with platelet-rich plasma at one month and six months.56 The study revealed that at one month, there was no significant improvement in WOMAC scores compared to baseline in those treated with platelet-rich plasma; however, by six months, the WOMAC scores in the platelet-rich plasma group had significantly improved compared to baseline.56 Both the 2018 and the 2020 studies determined that the WOMAC improvements seen in the platelet-rich plasma group were significantly better compared to the dextrose prolotherapy group at one month and six months.54,56
Autologous conditioned serum (ACS) is a relatively newer option for the possible management of knee osteoarthritis.56 A randomized clinical trial comparing the efficacy of intra-articular autologous conditioned serum, platelet-rich plasma, and 50% dextrose prolotherapy in 92 patients with knee osteoarthritis found that VAS pain scores were significantly improved in the group receiving autologous conditioned serum at one month and six months compared to the dextrose prolotherapy group.56 WOMAC scores were also significantly improved in the autologous conditioned serum group at six months compared to baseline, in contrast to the insignificant difference found in the dextrose prolotherapy group.56 The study also reported that compared to those treated with dextrose prolotherapy, participants that were treated with autologous conditioned serum experienced a significantly better improvement in WOMAC scores at one month and six months.56
A randomized clinical trial in 2019 with 120 participants compared the effects of intra-articular 20% dextrose prolotherapy on Knee Injury and Osteoarthritis Outcome Score (KOOS) and VAS scores to the effects of intra-articular botulinum neurotoxin injections, intra-articular hyaluronic acid injections, and physical therapy.16 Researchers concluded that when used individually, botulinum neurotoxin, dextrose prolotherapy, and physical therapy all led to a reduction in KOOS and VAS scores at the end of the study with no significant difference in the reduction in either KOS or VAS between the dextrose prolotherapy group and either the botulinum neurotoxin group or the physical therapy group.16 Intra-articular dextrose prolotherapy was found to have a significantly greater improvement in KOOS and VAS scores when compared to intra-articular hyaluronic acid; however, this was also seen in comparisons of intra-articular hyaluronic acid to both physical therapy and intra-articular botulinum toxin injections.16 The study found that intra-articular dextrose prolotherapy and intra-articular botulinum toxin injection displayed similar efficacy in improving scores of stiffness, pain, daily function, sports function, and quality of life. Though, scores on symptom abatement were more significantly improved in the botulinum toxin group than the dextrose prolotherapy group.16
A randomized clinical trial, with 80 participants, in 2015 compared the efficacy of intra-articular 12.5% dextrose prolotherapy to intra-articular ozone prolotherapy in patients with knee osteoarthritis and found that both treatments resulted in significant improvements in WOMAC scores at three months with no significant difference between the two groups.57 A double-blind, randomized clinical trial with 70 participants published in 2015 compared intra-articular 25% dextrose prolotherapy to treatment options such as intra-articular erythropoietin and intra-articular radiofrequency ablation found similar evidence for the ability of both intra-articular dextrose prolotherapy and the other treatment options to significantly improve pain at three months with no significant difference between groups.58
Some research has been done to investigate the disease-modifying ability of dextrose prolotherapy in knee osteoarthritis. Using radiographic data taken at 0 months and 12 months after treatment with intra-articular 10% dextrose prolotherapy, researchers assessed osteophyte grade, cartilage thickness, distal femur width both proximal and distal to the intercondylar notch, and proximal tibial width.48 Radiographic evidence revealed stability of eleven out of thirteen variables studied, as well as a significant improvement in the final two variables, lateral patellofemoral cartilage thickness and distal femur width.48 In contrast, a clinical trial in 2013 used magnetic resonance imaging to evaluate changes in cartilage volume after 52 weeks in participants treated with dextrose prolotherapy and found no significant difference in the percent of cartilage volume lost compared to participants who received normal saline prolotherapy.59 However, they did find a correlation between change in cartilage volume and WOMAC pain subscale score in the dextrose prolotherapy group that was not present in the normal saline participants.59 Soliman et al. in 2016 used plain radiographs and ultrasound to obtain measurements of the medial collateral ligament, lateral collateral ligament, and patellar tendon dimensions as well as cartilage thickness and reported a similar effect.53 Participants that were treated with both intra- and periarticular dextrose prolotherapy, as well as those treated with only intra-articular dextrose prolotherapy, had significant improvements in ligament and tendon dimension and cartilage thickness at 12 months.53 Another study in 2016 discusses the association between intra-articular dextrose prolotherapy and chondrogenesis, in which histologic evidence of cartilage growth was observed in participants with grade IV osteoarthritis of the knee and exposed subchondral bone following treatment with intra-articular prolotherapy with 12.5% dextrose.60
While the studies referenced in this section provide evidence for the efficacy of intra-articular dextrose prolotherapy in effectively managing pain and possibly modifying disease in knee osteoarthritis, they are not without their individual limitations. The differences in outcome measurements, dosages, and quality of data make definitive conclusions difficult.44,46,61,62 Study design is variable, with some being randomized clinical trials, prospective randomized clinical trials, some with the use of blinding, others without, variable arm numbers, and variable use of controls. Population characteristics such as baseline WOMAC scores, degree of severity of osteoarthritis, gender, average age, average BMI, activity level, and previous treatments received vary considerably between studies. In addition, many studies have insufficient sample sizes, making generalization problematic. Studies had differences in injection dosages, injection schedule, number of injections, the concentration of injection substrate, and method of administering injections. Outcome measurements and follow-up times varied in many of the studies.
As mentioned in several other reviews concerning the efficacy of hypertonic dextrose prolotherapy, there is still a need for larger clinical trials with a standardized treatment regimen and long term follow up in order to accurately determine the efficacy of treatment.44,46,61 However, findings consistently show improvement in the quality of life, coupled with a minimal amount of reported adverse reactions. This suggests that hypertonic dextrose prolotherapy could be used as an alternative treatment in patients suffering from osteoarthritis that have failed to improve following treatment with more conservative or other pharmacologic treatments for osteoarthritis.
Conclusion
The current treatment of knee osteoarthritis is early management, including a variation of exercise, weight loss, muscle strengthening, and pain relief with NSAIDs or corticosteroid injections. With the projected increase in the number of individuals suffering from osteoarthritis of the knee, finding long-term treatment options that are safe and satisfactory in providing relief of symptoms is crucial to decrease the need for surgical procedures and improve quality of life. A review of current randomized controlled trials on the efficacy of prolotherapy in treating osteoarthritis of the knee reveals that prolotherapy is a promising treatment option.
Most frequently, studies have administered 3-4 injections approximately 4 weeks apart. By 8 weeks, improvements in VAS and other objectives outcomes are noted compared to baseline and these effects are shown to persist up to assessment at even 52 weeks following the first injection. The majority of trials have focused on different concentrations of dextrose administered intraarticularly. Going forward, there will need to be further standardization of the methods of administering periarticular prolotherapy if used in combination with intraarticular prolotherapy. In addition, there will also need to be further studies comparing other forms of injectate compared to dextrose, such as PRP, ozone, erythropoietin to name a few.
Numerous clinical trials show significant improvement of osteoarthritic pain of the knee without any significant side effects reported following the use of prolotherapy. Although there is heterogeneity between studies with regard to study variables, the results consistently show significant improvement in radiographic outcomes, pain scores, and quality of life with prolotherapy treatment. Prolotherapy appears to be a safe and effective alternative to physical therapy, surgery, NSAIDs, steroids, and opiates when they fail to provide clinical relief. Since osteoarthritis is a chronic condition, further studies with extended follow-up periods evaluating long-term effects of prolotherapy are also needed to fully assess its efficacy and long-term sequelae. This field of regenerative therapy would benefit from larger, standardized, long-term studies to gain further insight into treating osteoarthritis of the knee.