Viscosupplementation for treating knee osteoarthrosis: review of the literature^**

ABSTRACT

The aim here was to evaluate the evidence that might support or refute the use of intra-articular viscosupplementation in treating patients with symptomatic knee osteoarthrosis. A review of the literature was conducted using the Medline, PubMed and Cochrane Controlled Trial Register databases and Cochrane database systematic reviews (Cochrane Library). Only studies presenting a high level of evidence were taken into consideration. This study included analysis on randomized clinical trials that included at least 100 patients in each intervention group, meta-analyses and systematic reviews. Two meta-analyses, five systematic reviews and six randomized clinical trials fulfilled the inclusion criteria for this review. In the light of the best evidence available so far, there is no consensus for indicating or even for contraindicating the use of intra-articular viscosupplementation among patients with symptomatic knee osteoarthrosis (level of evidence I and degree of recommendation A). Further studies with appropriate methodology are needed to elucidate this matter.

Keywords:
Knee; Osteoarthritis; Hyaluronic acid; Viscosupplementation

Palavras-chave:
Joelho; Osteoartrite; Ácido hialurônico; Viscossuplementação

resumo

Avaliar evidências que apoiem ou refutem o uso de viscossuplementacão intra-articular no tratamento de pacientes com osteoartrose sintomática de joelho. Foi feita uma revisão da literatura com o uso dos bancos de dados Medline, Pubmed e Cochrane Controlled Trial Register e Cochrane Databases Systematic Reviews (Cochrane Library). Foram considerados apenas estudos com elevado nível de evidências. O estudo incluiu a análise de ensaios clíni cos randomizados que incluíram pelo menos 100 pacientes em cada grupo de intervenção, metanálises e revisões sistemáticas. Duas metanálises, cinco revisões sistemáticas e seis ensaios clínicos randomizados preencheram os critérios de inclusão desta revisão. Frente às melhores evidências existentes até o momento, não existe consenso para indicação e até mesmo contraindicação do uso da viscossuplementacão intra-articular em pacientes com osteoartrose sintomática do joelho (nível de evidência I e grau de recomendação A). Futuros estudos com metodologia adequada são necessários para elucidação dessa questão.

Palavras-chave:
Joelho; Osteoartrite; Ácido hialurônico; Viscossuplementação.

Introduction

Osteoarthrosis is characterized by pain and progressive joint dysfunction resulting from destruction of the cartilage and subchondral bone, with occurrences of reduction of the joint space, inflammation/synovitis and formation of periarticular osteophytes.1 2 3^and4Among the major joints, the knees are the ones most affected, such that knee osteoarthrosis gives rise to functional deficits in 10% of individuals over the age of 55 years and in 25% in cases of advanced disease.5Currently, there are no epidemiological studies in Brazil that have precisely elucidated the prevalence of osteoarthrosis or the public expenditure related to this disease. In view of the significant increase in life expectancy that has occurred in the Brazilian population and the increasing proportion of elderly people, osteoarthrosis needs to be considered to be a matter of public health interest.6

Several options for conservative treatment of osteoarthrosis exist. These include weight reduction, physiotherapy, physical exercise and extra-articular devices for functional assistance. The options for pharmacological therapy (ordinary analgesics, opioids, non-steroidal anti-inflammatory drugs and corticoids) are aimed towards pain relief. Glucosamines, diacerein and hyaluronic acid are drugs known to be modifiers of the natural history of the disease, and these promote improvement of functional and pain levels over the short term. Nonetheless, further studies are needed in order to elucidate the efficiency of drugs for avoiding disease progression. There is still no effective medication for changing the course of this disease.7^and8

Synovial fluid is composed of polysaccharides, among other elements. These contain glucosamine, glucuronic acid and hyaluronic acid, and this last substance is considered to be a key molecule in joint biomechanics. Hyaluronic acid is a biopolymer formed by glucuronic acid and N-acetylglucosamine. It has a viscous texture and is found in the synovial fluid, vitreous humour and collagenous connective tissue of numerous organisms and is an important glycosaminoglycan (GAG) in constituting the joint. This molecule is the only non-sulfated GAG. It has the capacity to become associated with proteins in order to form molecular aggregates, but it does not form proteoglycans. In joints affected by osteoarthrosis, the concentration and molecular weight of hyaluronic acid in the synovial fluid become reduced, which alters its properties through diminishing its viscosity and reducing its capacity to absorb shock and provide lubrication, and leads to damage to cartilage and increased symptoms.9 10 11 12^and13

It is believed that the mechanism of action of hyaluronic acid in joints is related to inhibition of inflammatory mediators and cartilage degeneration enzymes. This reduces cartilage degradation and increases the production of cartilaginous matrix.7 14Hyaluronic acid preparations for intra-articular use can be further divided between those of low and high molecular weight. According to some studies, there are advantages in using the high molecular weight presentation.7 8Despite the possible benefits of viscosupplementation, its use remains controversial.

The present review had the objective of assessing the current evidence supporting or contraindicating the use of intra-articular viscosupplementation with hyaluronic acid for treating knee osteoarthrosis.

Materials and methods

A review of the literature was conducted using the Medline, PubMed, Cochrane Controlled Trial Register and Cochrane Systematic Review (Cochrane Library) databases. This investigation used the keywords viscosupplementation, hyaluronic acid, osteoarthritis, randomized, review and meta-analysis. Only studies defined as presenting high-quality evidence (level A, according to the Oxford Centre for Evidence-Based Medicine),15such as systematic reviews, meta-analyses and randomized clinical trials (RCTs), were included. The population of interest included patients with symptomatic osteoarthrosis of the knee who were undergoing non-surgical treatment for painful osteoarthrosis.

The inclusion criteria for articles were as follows:

- Systematic reviews or meta-analyses on randomized clinical trials that assessed the use of intra-articular viscosupplementation for treating osteoarthrosis of the knee in humans; - Randomized controlled clinical trials (RCTs) that compared the use of viscosupplementation with placebo or other medication, were adequately designed and included at least 100 patients in each intervention (viscosupplementation or viscosupplementation and placebo).

The criteria for excluding articles were as follows:

- Studies on animals; - Studies with fewer than 100 patients in each arm of the intervention.

Results

Out of the 239 potentially eligible studies that were investigated through Medline and PubMed (keywords: viscosupplementation AND hyaluronic acid), only 13 fulfilled the inclusion criteria. Of these, six were randomized clinical trials, five were systematic reviews and two were meta-analyses. Summaries and comments relating to the studies evaluated are presented inTable 1andTable 2.16 17 18 19 20 21 22 23 24 25 26 27^and28

Table 1:
Summaries of the randomized clinical trials (RCTs) evaluated.

• RCT, randomized clinical trial; DB, double blinding; HA, hyaluronic acid; IAHA, intra-articular hyaluronic acid; SB, single-blinding

Table 2:
Summary of the meta-analysis and systematic review studies evaluated.

• RCT, randomized clinical trial; DB, double blinding; HA, hyaluronic acid; IAHA, intra-articular hyaluronic acid

Discussion

Osteoarthrosis is the commonest form of arthritis in patients over the age of 50 years and the knees are among the joints most commonly affected. Because the knees are load-bearing joints, alterations to their biomechanics lead to significant morbidity and functional limitation.6With the increase in life expectancy of the Brazilian population, osteoarthrosis is tending to become a public health problem. No studies directed towards evaluating the prevalence of osteoarthrosis or the public expenditure involved in treating it have been conducted in Brazil.6In the United States, sates of medications for treating this disease had a turnover of US$ 760 million in 2004.29

The pharmacological therapeutic options for knee arthrosis currently available have the aim of promoting pain relief and functional improvement. There are still no medications available on the market with proven influence on the progression of the disease.7^and8

In individuals with osteoarthrosis, hyaluronic acid in the synovial fluid undergoes reductions in concentration and molecular weight, which lead to loss of viscosity and, consequently, loss of the functions of lubrication and shock absorption. This process contributes towards progression of joint degeneration and activation of inflammatory pathways. .13^and30Viscosupplementation with hyaluronic acid was developed in order to promote longer-lasting pain relief and functional recovery, and to delay disease progression.¹⁷ Different mechanisms have been proposed for explaining its effect, such as stimulation of production of endogenous hyaluronic acid, suppression of degradation of the cartilaginous matrix and suppression of the inflammatory response to interleukin-1. To further increase the viscosity of hyaluronic acid and diminish joint clearance, chemically modified hyaluronic acid compounds were created such that they would have higher molecular weights (around 23 × 10⁷ Da) and also a longer half-life, which would theoretically increase the potential and duration of its effect. .31 32 33 34^and35

In a multicenter randomized controlled clinical trial with 40 months of follow-up, named the Amelia Project, Navarro-Sarabia et al.17evaluated 306 patients over the age of 45 years who presented knee osteoarthrosis (Kellgren-Lawrence grades II and III, with a minimum joint space of 2 mm). Four cycles of intra-articular injection of hyaluronic acid or placebo were performed. The patients were evaluated with regard to clinical and functional improvement and side effects. These authors concluded that the treatment was safe and that there were significant improvements in functional capacity and symptoms, in relation to the control group, with an effect that was maintained even 1 year after the last application.17

Chevalier et al.16evaluated 253 patients over the age of 40 years who presented symptomatic primary osteoarthrosis of the knee, in a multicenter double-blind randomized study with 26 weeks of follow-up. The patients received a single application of a high molecular weight compound (Hylan G-F 20) or placebo. The safety of the treatment and the clinical repercussion (WOMAC index) were evaluated and the authors concluded that the treatment was safe and that there was a significant clinical improvement among the patients who underwent viscosupplementation.

Like in the abovementioned study, in a multicenter randomized study conducted by Raynauld et al., .19255 patients who received high molecular weight hyaluronic acid or placebo were evaluated over a 1-year period. These authors found a significant difference (greater than 20% in the WOMAC score) between their groups, which demonstrates that there were benefits from viscosupplementation. In other randomized controlled trials that used high molecular weight hyaluronic acid (which are listed inTable 1), it was also concluded that there were significant clinical improvements.18

With regard to the molecular weight of the hyaluronic acid to be used, two studies compared the use of high and low molecular weight hyaluronic acid for treating osteoarthrosis. According to Raman et al.,20use of high-weight hyaluronic acid (Hylan G-F 20) has the advantage of a more long-lasting effect, but with clinical efficacy and tolerability similar to other presentations. In a clinical trial that compared three presentations of hyaluronic acid for treating osteoarthrosis of the knee, Jüni et al.21concluded that the different molecular weights of hyaluronic acid did not give rise to any significant differences.

In a systematic review of 76 studies of medium quality, Bellamy et al.26came to the conclusion that viscosupplementation was safe and led to significant clinical and functional improvements, in comparison with placebo. They also reported that the effect of this treatment was longer-lasting than that of intra-articular corticosteroids. Many of the studies included in their review presented design inadequacies.

Aggarwal and Sempowski22reviewed five case series and 13 randomized controlled trials and concluded that use of viscosupplementation for treating mild to moderate osteoarthrosis of the knee, with high molecular weight hyaluronic acid, showed significant benefits in relation to clinical improvement and durability of effect. They also demonstrated that the patients had good tolerability towards the treatment and, in comparison with use of intra-articular corticoids, the peak action occurred later and the effect was longer-lasting. Miller et al.27analyzed the effect and safety of viscosupplementation in patients with osteoarthrosis of the knee and gathered together a sample of 4866 individuals in 29 randomized clinical trials. Studies with design inadequacies or insufficient sample size were excluded. These authors concluded that viscosupplementation was effective for achieving clinical and functional improvements, as well as being safe.

In a meta-analysis, Rutjes et al.28evaluated 89 studies and 12,667 participants with knee osteoarthrosis. Their conclusion was that, because of lack of evidence of any significant clinical and functional improvement, along with the potential risk of severe adverse effects viscosupplementation should be discouraged for treating knee arthrosis.

According to the 2013 guidelines for treating osteoarthrosis of the knee,23published by the American Academy of Orthopaedic Surgeons (AAOS) after a meta-analysis that involved 14 randomized controlled trials, there is strong evidence for not recommending the use of intra-articular hyaluronic acid, because all the studies that made comparisons with a control group showed uncertainty regarding practical clinical application of the treatment. Five of the seven studies evaluated that related to molecular weight presented patients who perhaps would not represent the general condition of the population with knee osteoarthrosis. This meta-analysis was criticized in the study by Miller et al.27because of confusion in the data analysis and use of compounds that had not been approved in the United States.

Final remarks

The pattern of osteoarthrosis treatment using hyaluronic acid is extremely variable between studies. There are differences in the preparations used, number of applications, dose injected per application and number of cycles used, in addition to time differences between them. The profile of the patients analyzed in each study also varied, such that some presented young patients with mild arthrosis and others, elderly patients with severe arthrosis. The parameters for analyzing clinical and functional improvements also changed between the studies. Many of them did not have a control group and there is also a lack of studies comparing viscosupplementation with other treatments. Most of the studies are of poor quality with inadequate designs.

Conclusion

In the light of the evidence that currently exists, there is still no solid basis for indicating or even for contraindicating the use of intra-articular viscosupplementation with hyaluronic acid or its derivatives for treating symptomatic knee osteoarthrosis.

Referências

• Dieppe PA, Lohmander LS. Pathogenesis and management of pain in osteoarthritis. Lancet. 2005;365(9463):965-73.
• Holbrook AM. (Chair) for the Ontario Musculoskeletal Therapy Review Panel. In: Ontario treatment guidelines for osteoarthritis, rheumatoid arthritis, and acute musculoskeletal injury. Toronto: Queen's Printer of Ontario; 2000.
• Badley E, DesMeules M. Arthritis in Canada: an ongoing challenge. Ottawa: Health Canadá; 2003.
• Felson DT. An update on the pathogenesis and epidemiology of osteoarthritis. Radiol Clin North Am. 2002;42(1):1-9.
• Peat G, McCarney R, Croft P. Knee pain and osteoarthritis in older adults: a review of community burden and current use of primary health care. Ann Rheum Dis. 2001;60(2):91-7.
• Ministério da Saúde do Brasil. Rede Interagencial de Informações para a Saúde. Disponível em:http://tabnet.datasus.gov.br/cgi/idb2009/matriz.htm{s.d.}
  » http://tabnet.datasus.gov.br/cgi/idb2009/matriz.htm
• American College of Rheumatology Subcommittee on Osteoarthritis Guidelines. Recommendations for the medical management of osteoarthritis of the hip and knee: 2000 update. Arthritis Rheum. 2000;43(9):1905-15.
• Manek NJ, Lane NE. Osteoarthritis: current concepts in diagnosis and management. Am Fam Physician. 2000;61(6):1795-804.
• Ayral X. Injections in the treatment of osteoarthritis. Best Pract Res Clin Rheumatol. 2001;15(4):609-26.
• George E. Intra-articular hyaluronan treatment for osteoarthritis. Ann Rheum Dis. 1998;57(11):637-40.
• Simon LS. Viscosupplementation therapy with intra-articular hyaluronic acid. Fact or fantasy? Rheum Dis Clin North Am. 1999;25(2):345-57.
• Fam H, Bryant JT, Kontopoulou M. Rheological properties of synovial fluids. Biorheology. 2007;44(2):59-74.
• Dahl LB, Dahl IM, Engström-Laurent A, Granath K. Concentration and molecular weight of sodium hyaluronate in synovial fluid from patients with rheumatoid arthritis and other arthropathies.. Ann Rheum Dis 1985;44(12):817-22.
• Wen DY. Intra-articular hyaluronic acid injections for knee osteoarthritis.. Am Fam Physician 2000;62(3):565-70.
• Oxford Centre for Evidence-Based Medicine. Disponível em:http://www.cebm.net/index.aspx?o=5653{s.d.}
  » http://www.cebm.net/index.aspx?o=5653
• Chevalier X, Jerosch J, Goupille P, Van Dijk N, Luyten FP, Scott DL, et al. Single, intra-articular treatment with 6 ml hylan G-F 20 in patients with symptomatic primary osteoarthritis of the knee: a randomised, multicentre, double-blind, placebo controlled trial.. Ann Rheum Dis 2010;69(1):113-9.
• Navarro-Sarabia F, Coronel P, Collantes E, Navarro FJ, De la Serna AR, Naranjo A, et al. A 40-month multicentre, randomised placebo-controlled study to assess the efficacy and carry-over effect of repeated intra-articular injections of hyaluronic acid in knee osteoarthritis: the Amelia project.. Ann Rheum Dis 2011;70(11):1957-62.
• Wobig M, Dickhut A, Maier R, Vetter G. Viscosupplementation with hylan G-F 20: a 26-week controlled trial of efficacy and safety in the osteoarthritic knee. Clin Ther. 1998;20(3): 410-23.
• Raynauld JP, Torrance GW, Band PA, Goldsmith CH, Tugwell P, Walker V, et al. A prospective, randomized, pragmatic, health outcomes trial evaluating the incorporation of hylan G-F 20 into the treatment paradigm for patients with knee osteoarthritis (Part 1 of 2): clinical results. Osteoarthritis Cartilage. 2002;10(7):506-17.
• Raman R, Dutta A, Day N, Sharma HK, Shaw CJ, Johnson GV. Efficacy of Hylan G-F 20 and Sodium Hyaluronate in the treatment of osteoarthritis of the knee - A prospective randomized clinical trial. Knee. 2008;15(4):318-24.
• Jüni P, Reichenbach S, Trelle S, Tschannen B, Wandel S, Jordi B, et al. Viscosupplementation Trial Group. Efficacy and safety of intraarticular hylan or hyaluronic acids for osteoarthritis of the knee: a randomized controlled trial. Arthritis Rheum. 2007;56(11):3610-9.
• Aggarwal A, Sempowski IP. Hyaluronic acid injections for knee osteoarthritis. Systematic review of the literature. Can Fam Physician. 2004;50:249-56.
• Treatment of osteoarthritis of the knee - Evidence-based guideline. 2 ed. Rosemont: American Academy of Orthopaedic Surgeons; 2013.
• Modawal A, Ferrer M, Choi HK, Castle JA. Hyaluronic acid injections relieve knee pain. J Fam Pract. 2005;54(9):758-67.
• Espallargues M, Pons JM. Efficacy and safety of viscosupplementation with Hylan G-F 20 for the treatment of knee osteoarthritis: a systematic review. Int J Technol Assess Health Care. 2003;19(1):41-56.
• Bellamy N, Campbell J, Robinson V, Gee T, Bourne R, Wells G. Viscosupplementation for the treatment of osteoarthritis of the knee. Cochrane Database Syst Rev. 2006;(2):CD005321.
• Miller LE, Block JE. US-Approved intra-articular hyaluronic acid injections are safe and effective in patients with knee osteoarthritis: systematic review and meta-analysis of randomized, saline-controlled trials. Clin Med Insights Arthritis Musculoskelet Disord. 2013;6:57-63.
• Rutjes AW, Jüni P, Da Costa BR, Trelle S, Nüesch E, Reichenbach S. Viscosupplementation for osteoarthritis of the knee: a systematic review and meta-analysis. Ann Intern Med. 2012;157(3):180-91.
• United States Commetee on Health, Education, Labor, and Pensions. Subcommittee on Aging. Centre of Disease Control's role in combating the burden of arthritis. Washington: Department of Health and Human Services; 2004.
• Balazs EA, Denlinger JL. Viscosupplementation: a new concept in the treatment of osteoarthritis. J Rheumatol Suppl. 1993;39:3-9.
• Smith MM, Ghosh P. The synthesis of hyaluronic acid by human synovial fibroblasts is influenced by the nature of the hyaluronate in the extracellular environment. Rheumatol Int. 1987;7(3):113-22.
• Bagga H, Burkhardt D, Sambrook P, March L. Longterm effects of intraarticular hyaluronan on synovial fluid in osteoarthritis of the knee. J Rheumatol. 2006:946-50.
• Ghosh P. The role of hyaluronic acid (hyaluronan) in health and disease: interactions with cells, cartilage, and components of synovial fluid. Clin Exp Rheumatol. 1994;12(1):75-82.
• Yasui T, Akatsuka M, Tobetto K, Hayaishi M, Ando T. The effect of hyaluronan on interleukin-1 alpha-induced prostaglandin E2 production in human osteoarthritic synovial cells. Agents Actions. 1992;37(1-2):155-6.
• Monfort J, Nacher M, Montell E, Vila J, Verges J, Benito P. Chondroitin sulfate and hyaluronic acid (500-730 kda) inhibit stromelysin-1 synthesis in human osteoarthritic chondrocytes. Drugs Exp Clin Res. 2005;31(2):71-6.

• 1
  **Work performed at the Instituto de Ortopedia e Traumatologia de Passo Fundo, Passo Fundo, RS, Brazil

Publication Dates

• Publication in this collection
  Oct 2015

History

• Received
  03 Sept 2014
• Accepted
  18 Sept 2014