Viscosupplementation for the treatment of osteoarthritis of the knee
A wide variety of treatments for osteoarthritis of the knee are possible. Guidelines have been drawn up by the American College of Rheumatology (ACR) and the European League against Rheumatism (EULAR).  In a first group, known as the non-pharmacological interventions we find treatments such as education, exercise, life style changes and physical therapy.  A second group comprises the pharmacological treatments like pain killers and non-steroidal anti-inflammatory drugs (NSAIDs).   Intra-articular corticosteroid injections are also an option and are often used for transient symptom relief. When the more conservative measures fail, there is another option when surgery is to be avoided: viscosupplementation.  Viscosupplementation belongs in the category of localized therapy, more precisely intra-articular pharmacological therapy. 
Viscosupplementation is actually the injection of Hyaluronic Acid (HA).  HA is a major component of the synovial fluid and of the cartilage and is one of the most important components of the extracellular matrix. HA is a high-molecular-weight glycosaminoglycan composed of repeating disaccharides of glucuronic acid and N-acetylglucosamine.  
When a person has osteoarthritis of the knee, the quality of the synovial fluid decreases, but also the concentration and Molecular Weight of HA.  This can lead to pain and loss of function in the joint of the knee. Therefore, hyaluronic acid is injected so that de concentration, molecular weight characteristics in the extracellular matrix and the visco-elasticity of the synovial fluid can recover. This results in improved pain control, articular function and mobility.
There are different hyaluronic acid preparations and we can classify them in two categories: low molecular weight and high molecular weight. Two examples of hyaluronic acid products are naturally occurring hyaluronan (Hyalgan) and synthetic hylan G-F 20 (Synvisc).   
The majority of patients chooses for viscosupplementation after they failed in a program of non-pharmacological therapy, pharmacological therapy, are intolerant to these therapies or don’t want surgery.  
However the ideal person for viscosupplementation of hyaluronic acid has not yet been found. They are still searching for the ideal age, the best level of osteoarthritis as defined radio-graphically, level of symptoms and level of physical activity to get the best results from the treatment. 
Viscosupplementation proved to reduce the pain and being safe
There are many studies that compare hyaluronic acid to placebo. Some of these studies concluded that viscosupplementation of HA is effective in improving symptoms and function and decreases the pain with a modest difference versus placebo.     Viscosupplementation has been found a safe treatment, most of the patients were satisfied with this treatment.   
But there are also studies that did not find or doubt this difference.  Further research is needed to confirm that there is a certain difference in efficacy of viscosupplementation versus placebo. 
Difference in molecular weight hyaluronic acid
The difference between an intra-articular viscosupplementation with a lower (LMW), higher (HMW) and combined lower and higher molecular weight (DMW) sodium hyaluronate in osteoarthritis in the knee versus placebo has been researched. Also the long-term clinical outcome of pain at rest and following walking activities were investigated.  The outcome of this study was a significant improvement in pain and function for patients who received randomly the DMW hyaluronic acid compared to both LMW and HMW. Patients who received DMW, reduction of walking pain was significantly greater than either with the LMW or HMW groups. The DMW group experienced less pain at rest compared to LMW and HMW. Patients in the DMW group had significantly greater improvement at 16, 52 and 104 weeks compared to the other active treatment groups. 
This can be explained by two examples: naturally occurring hyaluronan (Hyalgan) and synthetic hylan G-F 20 (Synvisc).  Hylans are cross-linked hyaluronic acids, which give them a higher molecular weight and increased elastoviscous properties. 6 Because hylan has a higher molecular weight, it is more efficacious than hyaluronic acid. This is due to its enhanced elastoviscous properties and its longer period of residence in the knee joint space. 
The safety and efficacy of viscosupplementation with Hylan G-F 20 has been researched by many studies, prospective clinical trials and large retrospective studies. Hylan G-F 20 is a high molecular weight, cross-linked derivative of hyaluronan. 
Period of efficacy
There is ignorance about the period of efficacy.  Some studies say less than 34 weeks  , some say between 34 weeks and 52 weeks 3 and some studies who searched for the long term efficacy concluded that HA was still efficacious and safe at 104 weeks and more.   So, here also further research is required.
Adverse events of the viscosupplementation of HA are mild and are resolved in a short time.   The adverse events reported in the literature are fugitive pain or effusion and swelling at the injection site, erythema at the injection site and stiffness of the knee.  Further there are also rarely reported adverse events like local skin reaction, itch (pruritus), headache and fever. 
There is little evidence of a difference between the different injections of hyaluronic acid. Two studies found that adverse events occur more frequently with injections with a high molecular weight cross-linked hylan (hylan G-F 20) than with injections of a non-cross-linked low molecular weight hyaluronic acid (hyaluronic acid of bacterial origin).  
Comparison between other treatments
An exercise program is a possible treatment for osteoarthritis of the knee. Many studies suggest that exercise programs are effective to improve function, reduce the pain, decrease disability and are good to maintain range of motion, muscle strength and general health.    These exercise programs can contain a strength-training, an intensive short-term exercise training, a Disabled Arthritis Patients Post-hospitalization Intensive Exercise Rehabilitation (DAPPER) , aerobic exercise programs such as walking or swimming and quadriceps-strengthening exercise.  The best is to compare different programs, so that not only the range of motion improves but also the aerobic capacity and walking speed.   No study is found about the efficacy of the combination of exercise and viscosupplementation.
Pubmed and BIB/website vub.ac.be/BIBLIO
- Petrella R J, Decaria J, Petrella M J. Long term efficacy and safety of a combined low and high molecular weight hyaluronic acid in the treatment of osteoarthritis of the knee. Rheumatology Reports 2011; 3:16-21.
- Dennis Y, Wen M.D. Intra-articular Hyaluronic Acid Injections for Knee Osteoarthritis. Am Fam Physician 2000; 1:565-570.
- Huskin J.P., Vandekerckhove B. et al. Multicentre, prospective, open study to evaluate the safety and efficacy of hylan G-F 20 in knee osteoarthritis subjects presenting with pain following arthroscopic meniscectomy. Knee Surg Sports Traumatol Arthrosc. 2008; 16: 747–752.
- Gossec L, Dougados, M. Do intra-articular therapies work and who will benefit most? Best Practice & Research Clinical Rheumatology 2006;1:131–144.
- Chevalier X, Jerosch, J. 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; 69:113–119.
- Conroziera T, Mathieua P et al. Factors predicting long-term efficacy of Hylan GF-20 viscosupplementation in knee osteoarthritis. Joint Bone Spine Volume 2003;17:128-133.
- Bannuru R R, Natov N S, Dasi U R, Schmid C H, McAlindon T E. Therapeutic trajectory following intra-articular hyaluronic acid injection in knee osteoarthritis – meta-analysis. Osteoarthritis and Cartilage 2011;19: 611-619.
- Jüni P., Reichenbach S. et al. Efficacy and safety of intraarticular hylan or hyaluronic acids for osteoarthritis of the knee: A randomized controlled trial. Arthritis & Rheumatism 2007;11: 3610–3619.
- Patrick E, McKnight P D et al. A comparison of strength-training, self-management and the combination for early osteoarthritis of the knee. Arthritis Care Res 2010;62:45–53.
- Bulthuis Y, Drossaers-Bakker K. Arthritis patients show long-term benefits from 3 weeks intensive exercise training directly following hospital discharge. Rheumatology 2007;46:1712-1717.