- Hyaluronic Acid Injections & Arthritis
- Basic Science
- Hyaluronic Acid Injections in the Knee
- Cochrane Review of Hyaluronic Acid Injections
- Injections in Athletes
Hyaluronic Acid Injections & Osteoarthritis
Osteoarthritis (OA) is a major cause of disability. Patients with OA have pain that typically worsens with weight-bearing and activity and improves with rest. Unlike the rheumatoid arthritis (RA) inflammation is usually mild and localised in the affected joint. Although the cause of OA remains unknown, biomechanical stresses and biochemical changes in the articular cartilage, sub-chondral bone and synovial membrane, and genetic factors, are all important in its pathogenesis.
In joints affected by OA, the synovial fluid’s capacity to lubricate and to absorb impact are typically reduced. These changes are partly due to a reduction in the size and concentration of hyaluronic acid (hyaluronan) molecules naturally present in synovial fluid.
Medical management of OA of the knee is effective for many patients, but significant morbidity is common for those using non-steroidal anti-inflammatory medication (NSAIDs). Gastrointestinal toxicity has been a major problem for many patients on NSAIDs, especially for geriatric patients who need to take them for extended periods to treat chronic conditions. Although only a minority of patients using NSAIDs appear to develop serious GI problems, because of widespread usage it is estimated that there are at least 16,500 NSAID-related deaths each year in the United States among patients with osteo- and rheumatoid arthritis (1, 2). Another 76,000 end up in the hospital. The economic burden of NSAID-associated gastrointestinal disorders is enormous, with an estimated cost of $500 million.
Surgical treatment of the knee OA is effective but it is not appropriate for all stages of the disease or for all patients. It is also costly and not without risks.
With increased understanding of the pathogenesis of OA, new therapies are being developed, one of which is viscosupplementation with hyaluronic acid. A new approach in the management of OA of the knee is to inject hyaluronan or derivatives of this molecule (hylans) into the joint. In recent years, the concept of viscosupplementation has gained widespread acceptance as a new treatment for the management of OA of the knee. The safety of this treatment has been well documented in numerous clinical trials, but controversy persists regarding efficacy and cost-benefit concerns (3).
The use of viscosupplementation is based on observation that there is a decrease in viscosity and elasticity of the synovial fluid in osteoarthritis and that the native hyaluronic acid in osteoarthritic knees has a lower molecular weight than that found in normal healthy knees. Replenishing the hyaluronic acid component of normal synovial fluid may play a role in supplementing the elastic and viscous properties of synovial fluid, which may help relieve the signs and symptoms related to osteoarthritis and improve function. Studies of human synoviocytes from osteoarthritic joints have revealed that exogenous hyaluronic acid stimulates de novo synthesis of hyaluronic acid, inhibits release of arachidonic acid, and inhibits interleukin-1α induced prostaglandin E2 synthesis by human synoviocytes. (4).
Hyaluronic acid (HA) is a glycosaminoglycan that is composed of glucuronic acid and N-acetylglucosamine. It differs from other glycosaminoglycans in that it is unsulfated; also, it does not bind covalently with proteins to form proteoglycan monomers, serving instead as the backbone of proteoglycan aggregates. It is the only glycosaminoglycan that is not limited to animal tissues, being found also in bacteria. It serves as a lubricant and shock absorber in the synovial fluid, and is found in the vitreous humor of the eye. HA is not well absorbed orally, but has been widely used intraarticularly in the treatment of OA in animals and, more recently, in humans. HA is well tolerated with no demonstrable toxicity and few side effects. Because it is injected directly into the joint, its onset of action is rapid. Conversely, its route of administration does limit its therapeutic applications to some degree, and high cost is also a factor (5).
Glycosaminoglycans (GAGs) are carbohydrate polymers that are among the most abundant components of the ground substance of connective tissue throughout the body. GAG molecules are long, homogeneous, unbranched polysaccharide chains that are formed by repeating disaccharide subunits. Hyaluronate is the most abundant GAG in synovial fluid. It is produced and secreted by synoviocytes. Hyaluronate is also prevalent in the extracellular matrix of articular cartilage, where it is produced by chondrocytes and where it forms the foundation for proteoglycan aggregates. The recurring disaccharide subunit of hyaluronate consists of N-acetylglucosamine and glucuronate. These sugar subunits are joined by glycosidic bonds. These bonds are extremely flexible in solution; therefore, hyaluronate has no defined tertiary structure. The carboxylate group on the glucuronate sugar is negatively charged. Thus, hyaluronate is a polyanion chain. The recurring electronegative charges along the chain repel one another and attract water molecules. Hence, hyaluronate has been likened to a “molecular sponge.” These properties account for the viscosity and elasticity of the hyaluronate macromolecule.
Pharmacology of Viscosupplementation – The notion of supplementing osteoarthritic synovial fluid with exogenous hyaluronate stems from the fact that the molecular weight and concentration of hyaluronate in osteoarthritic synovial fluid are reduced. This phenomenon diminishes the viscosity of osteoarthritic synovial fluid. Appropriate synovial fluid viscosity is believed to be critical for maintaining normal joint lubrication and is also believed to have chondroprotective effects. It is hypothesized that the reduced concentration and decreased molecular weight of hyaluronate in osteoarthritic synovial fluid renders articular cartilage more vulnerable to mechanical and enzymatic injury.
The goal of viscosupplementation – The goal is to increase the molecular weight and concentration of hyaluronate in arthritic joints so that the intra-articular environment more closely resembles that of healthy synovial fluid.
The mechanism of action – The way viscosupplementation alleviates arthritic knee pain is a subject of debate. It has been proposed that exogenous viscoelastic substances act biomechanically by providing a “cushioning” or layer effect. It forms a viscous coating over the synovial and cartilage linings, acting as a mechanical barrier over pain receptors and inflammatory cells.
However, some authors have suggested that viscosupplements are eliminated from the knee too rapidly to exert a significant and lasting biomechanical effect. Indeed, the half-life of hyaluronate in sheep is less than 24 hours. In vitro research suggests that exogenous hyaluronate may stimulate endogenous production of additional hyaluronate by human synoviocytes. This could lead to more durable biomechanical consequences. Other studies suggest that hyaluronate supplementation has a direct anti-inflammatory effect on synoviocytes by inhibiting arachidonic acid release or by blocking prostaglandin-E2 production. It has also been suggested that exogenous hyaluronate inhibits damage mediated by oxygen free radicals and phagocytosis. Research has also found that hyaluronate may exert a direct analgesic effect on articular nociceptors. Possible mechanisms by which HA may act therapeutically include: providing additional lubrication of the synovial membrane, and controlling permeability of the synovial membrane, thereby controlling effusions. Other possible, though less certain, mechanisms include: promotion of cartilage matrix synthesis and reaggregation of preoteoglycans. Several studies have suggested that viscosupplements with higher molecular weights have greater therapeutic efficacy (6, 7).
Anti-inflammatory effect – Hyaluronic acid has both in vivo and in vitro effects on leukocyte function. These include inhibition of phagocytosis, adherence and mitogen-induced stimulation. These properties are dependant on the molecular size of hyaluronic acid. Intra-articular administration of hyaluronic acid reduces levels of inflammatory mediators, including prostaglandin and cyclic adenosine monophosphate, in the synovial fluid of patients with arthritis (3).
Analgesic activity – It seems that intra-articular hyaluronic acid modulates pain perception directly through inhibition of nociceptors or indirectly through binding of substance P – a small peptide involved in the transmission of pain signals (3).
Chondroprotective potential – There is some data from human and animal studies to suggest that viscosupplementation could have a chondroprotective effect. Listrat et al. suggest that repeated intra-articular injections of hyaluronan might delay the structural progression of osteoarthritis. (7). However, the chondroprotective effect of hyaluronic acid remains unproved.
Viscosupplementation is a proven adjunct to the treatment armamentarium of general practitioners and surgeons. A number of recent clinical trials have evaluated the efficacy and safety of intra-articular hyaluronic acid injections (8, 9, 10, 11, 12, 13, 14, 15). The reports of these studies were among those presented to the Food and Drug Administration (FDA) in the course of the process that resulted in the release of this treatment modality. The American College of Rheumatology has included viscosupplementation in the treatment algorithm for osteoarthritis of the knee (4, 16, 17).
|Study||Intervention||Design||Clinical Assessment Parameters||Conclusion||Comment|
|Listrat et al., 1997||3 injections of Hyalgan, every 3 months, for a year||Randomised, prospective||VAS (pain),|
Lequesne’s index (functional impairment), AIMS2 (quality of life)
|This study suggests that repeated injections of hyaluronan might delay structural progression of the disease.||Industry-sponsored study.|
Small sample size
|Adams et al., 1995||Hylan G-F 20 vs continuous NSAIDs||Randomised, single-blind, prospective, muticenter||VAS (pain)||Hyalgan equivalent to continuous NSAIDs at 12-week follow-up||Industry-sponsored study|
|Wobig et al., 1999||Hylan G-F 20 vs a low molecular weight hyaluronate||Randomised, double-blind, prospective, multicenter||VAS (pain)||Hylan G-F 20 significantly better than low molecular weight hyaluronate at 12 week follow-up||Industry-sponsored study|
|Bellamy et al., 2001||Appropriate Care (according to ACR guidelines) with or without hylan G-F 20 injections||Randomised, prospective, multicentre||WOMAC, and SF-36||Results provide strong evidence for adoption of treatment with hylan G-F 20 in patients with knee OA. Good value for money.||Industry-sponsored study|
Cost-effectiveness – In clinical trials of intra-articular hyaluronan preparations, pain relief among those who completed the study was significantly greater than that seen after intra-articular injection of placebo, and comparable with that seen with oral NSAIDs. In addition, pain relief among those who completed the study was comparable with greater than that with intra-articular glucocorticoids. Although pain relief is achieved more slowly with hyaluronan injections than with intra-articular glucocorticoid injections, the effect may last considerably longer with hyaluronan injections (17).
Safety – The risk of introducing infection into an OA joint is extremely low if standard aseptic technique is used. The lack of systemic side effects make the use of viscosupplementation an appealing option for the management of the knee OA. Extensive safety and toxicity tests were performed on Ostenil™ before the first clinical trials. Preclinical studies showed that Ostenil™ is nonantigenic, nontoxic, noninflammatory, and does not elicit foreign body reactions. Hyaluronan, from which hylan is derived, has been safely used in ophthalmic and orthopedic applications in millions of patients. There have been no systemic side effects attributed to Ostenil. No cases of anaphylaxis or anaphylactoid reactions have been reported in connection with Ostenil™ treatment. However, anaphylactic-like reactions have been reported following intra-articular Hyalgan™ injections (18).
Unwanted Effects – In clinical trials, transient redness, local pain, warmth, and effusion, usually lasting up to three to four days, may occur. Occasionally, severe synovitis may occur requiring treatment with intra-articular corticosteroids.
Precautions – Patients should consult their doctor or surgeon if they have a history of hypersensitivities to hyaluronan preparations or are allergic to avian proteins, feathers and egg products. Intra-articular viscosupplements should not be given to patients with an infection or skin disease around the injection site, and should not be used if venous or lymphatic stasis is present in the leg, or if the joint is severely inflamed (18).
1. Singh G, Triadafilopoulos G (1999), Epidemiology of NSAID induced gastrointestinal complications. J Rheumatol 26(suppl 56):18-24.
2. Wolfe MM, Lichtenstein DR, Singh G (1999), Gastrointestinal toxicity of nonsteroidal anti-inflammatory drugs. N Engl J Med 340(24):1888-1899.
3. Watterson JR, Esdaile JM. Viscosupplementation: Therapeutic Mechanisms and Clinical Potential in Osteoarthritis of the Knee. J Am Acad Orthop Surg 2000;8:277-284.
4. Jackson DW, Sheer MJ, Simon TM: Cartilage Substitutes: Overview of Basic Science and Treatment Options. J Am Acad Orthop Surg 2001;9:37-52.
5. Hungerford DS: Treating Osteoarthritis with Chondroprotective Agents. Orthopaedic Special Edition 1998, January-April.
6. Wright JM, Crockett HC, Dowd M: The Role of Viscosupplementation for the Osteoarthritis of the Knee. Orthopaedic Special Edition 2001;7:15-18.
7. Listrat V, Ayral X, Patarnello F, Bonvarlet JP, Simonnet J, Amor B, Dougados M. Arthroscopic evaluation of potential structure modifying activity of hyaluronan (Hyalgan) in osteoarthritis of the knee. Osteoarthritis Cart 1997;5:153-160.
8. Wöbig M, Bach G, Beks P, Dickhut A, Runzheimer J, Schwieger G, et al. The role of elasto-viscosity in the efficacy of viscosupplementation for osteoarthritis of the knee: a comparison of hylan G-F 20 and a lower-molecular-weight hyaluronan. Clint Her 1999;21(9):1549-62.
9. Adams ME, Atkinson MH, Lussier AJ, et al: The role of viscosupplementation with hylan G-F 20 (Synvisc) in the treatment of osteoarthritis of the knee: A Canadian multicenter trial comparing hylan G-F 20 alone, hylan G-F 20 with non-steroidal anti-inflammatory drugs (NSAIDs) and NSAIDs alone. Osteoarthritis Cartilage 1995;3:213-225.
10. Lussier A, Cividino AA, McFarlane CA, Olszynski WP, Potashner WJ, De Medicis R: Viscosupplementation with hylan for the treatment of Osteoarthritis: Findings from clinical practice in Canada. J Rheumatol 1996:23: 1579-1585.
11. Bellamy N, Torrance GW, Raynauld JP, Goldsmith CH, Tugwell P, Walker V, et al. A randomized controlled trial evaluating effectiveness and cost-effectiveness of Hylan G-F 20 in patients with knee osteoarthritis. Proceedings of the AAOS, 2001.
12. Altman RD, Moskowitz R: Intraarticular sodium hyaluronate (Hyalgan) in the treatment of patients with osteoarthritis of the knee: A randomized clinical trial. Hyalgan Study Group. J Rheumatol 1998;25:2203-2212.
13. Huskisson EC, Donnelly S: Hyaluronic acid in the treatment of osteoarthritis of the knee. Rheumatology (Oxford) 1999;38:602-607.
14. Lohmander LS, Dalen N, Englund G, et al: Intra-articular hyaluronan injections in the treatment of osteoarthritis of the knee: A randomised, double-blind, placebo-controlled multicentre trial. Hyaluronan Multicentre Trial Group. Ann Rheum Dis 1996;55:424-431.
15. Petrella RJ, DiSilvestro MD, Hildebrand C.: Effects of hyaluronate sodium on pain and physical functioning in osteoarthritis of the knee: a randomized, double-blind, placebo-controlled clinical trial. Arch Intern Med 2002 Feb 11;162(3):292-8.
16. Miller E H, Correspondence – Viscosupplementation: Therapeutic Mechanisms and Clinical Potential in Osteoarthritis of the Knee, J Am Acad Orthop Surg 2001;9:?.
17. American College of Rheumatology Subcommittee on Osteoarthritis Guidelines: Recommendations for the Medical Management of Osteoarthritis of the Hip and Knee. Arthritis and Rheum, 2000;43:1905-1915. www.rheumatology.org.
18. Hyaluronan or Hylans for Knee Osteoarthritis. DTB, Vol 37, No 9, September 1999, 71-72. BNF 10.1
19. Datamonitor Market Dynamics – Hyaluronic Acid Viscosupplementation, Reference code DMHC1776, Publication date: June 2002. www.datamonitor.com.
Hyaluronan – Basic Science
Article courtesy of Mr Len Funk. Hyaluronan is the general term designating the linear repeating disaccharide, (beta-D-glucuronyl-beta-D-N-acetyl-glucosamine) of very high molecular mass (upwards of 10×106 Daltons). The molecular weight of Hyaluronan varies between different tissues and species. It may also vary depending on the condition of the tissue. For example, the molecular weight of Hyaluronan in synovial fluid (normally 4-5 million Daltons) is often reduced in joint disorders. There are on average around 2500 repeating disaccharide units in endogenous Hyaluronan and the mean molecular weight is approximately 400 Daltons. However, the number of repeating disaccharides in a Hyaluronan molecule can reach 10,000 or more, with a molecular weight of around 4 million Daltons.) The term “hyaluronic acid” was adopted when the biopolymer was first isolated from the vitreous of bovine eyes in 1934. However, under physiological conditions, hyaluronan is not present in the acid form, therefore this term is redundant. The term “sodium hyaluronate” mostly designates the highly purified, narrow molecular weight range hyaluronan used as a therapeutic agent. These different terms specify only the natural, non-chemically modified biopolymer which is present in most of the body tissues. Hyaluronan is nearly ubiquitous in its distribution being present in the interstitial spaces of most animal tissues. Its principal role is as a structural element but functions may differ depending on its location in the body. Hyaluronan can also: – Play a significant role in the body during repair process, mediating cell adhesion, differentiation, motility and blood vessel growth; – Retain large quantities of water and therefore control tissue hydration; – Protect tissue against overuse and shocks by its viscoelastic properties. Hyaluronan depletion in tissues is often associated to pathological states such as some cancers, skin diseases, osteoarthritis and rheumatoid arthritis. The human joint lined by the synovial membrane and is filled with a viscous fluid called the synovial fluid (SF), which can be regarded as a modified extra-cellular fluid. Like other extra-cellular fluids, the SF acts as a transport medium supplying the articular cartilage with nutrients and oxygen and carrying away the waste products of metabolism. The main component of the SF is hyaluronan. The SF contains a complex solution of proteins, electrolytes, uric acid and glucose, in concentrations similar to blood plasma. Hyaluronan is constantly produced by the synoviocytes present in the synovial membrane and then extruded in the synovial space. There is a strict balance between its production and degradation. The SF has principally protective functions in the joint, acting as a lubricant, shock absorber and ‘filter’, and plays a key role in the maintenance of joint homeostasis. An important point of hyaluronan is that the meshworks it forms are ordered. The shapes of the hyaluronan secondary structures determine the shapes of the aggregates, and each branch in the meshwork carries with it two intrinsic directions, up or down, established by the hyaluronan chains. This ordered meshwork is of importance depending on the situation the hyaluronan solution is placed. (Balazs et al. 1993) Hyaluronan solutions, and as such the synovial fluid, are viscoelastic. This means that the solution presents viscous and elastic characteristics at the same time. The viscosity is important providing lubrication when the solution is subjected to gradual shear stress. Hyaluronan solutions present non-Newtonian behaviour. This means that the viscosity decreases when the shear stress increases thus increasing lubrication. Example: the synovial fluid lubricates the joint when walking. The elasticity is important when a sudden loading force is applied to hyaluronan solutions. In that case, hyaluronan chains first absorb the loading force and then release it in a proper manner (shock absorbing properties). Example: absorption of shocks between boneheads when running. Due to its properties in solution hyaluronan forms meshworks that restrict the free movement of cells and large molecules through the joint, acting as a sort of filter. In fact the hyaluronan meshwork forms ‘pores’ which allow the free passage of small molecules, such as nutrients, but effectively block the passage of larger molecules, such as inflammatory cells or proteins. The hyaluronan chains are constantly moving in the solution, and the effective “pores” in the network continuously change in size. Statistically, all sizes of pores can exist, but with different probabilities. This means that in principle, all molecules can pass through a hyaluronan network, but with different degrees of retardation depending on their hydrodynamic volumes. This is very important as the hyaluronan in the synovial fluid can help to modulate the inflammatory response. The hyaluronan contained in the SF also helps to form a coating layer over the entire inner surface of the joint. This layer is formed mainly from hyaluronan, in association with proteins, and is approximately 2um thick. It plays several important roles in the protection of the articular cartilage including lubrication and a ‘barrier function’. The hyaluronan layer is constantly degraded and renewed. The SF constantly supplies the hyaluronan layer with new molecules. In the healthy joint, this constant process is very important in the maintenance of joint homeostasis. Hyaluronan is present at different levels in the joint (Abatangelo et al. 1995). At each level, hyaluronan will play a different role: In the synovial tissues thus forming a protective barrier: this barrier protects the synovium against inflammatory mediators and shields pain receptors from pain mediators thus modulating pain perception; ß (fibroblast-like) cells of the synovium and is secreted into the synovial fluid.
This information is also available as a PFD. The principles behind Hyaluronan Injections are to decrease pain and improve function in patients with joint pain. Hyaluronan injections have been shown to have the following beneficial effects on joints: – They replace some of the normal ingredients found in synovial fluid (hyaluronans) improving the lubricating ability. – They help to stimulate the joint lining (the synovium) manufacture more normal synovial fluid. – The Hyaluronan coats the lining of the damaged joint surfaces, covering pain nerve endings. This reduces pain and protects the joint surfaces from joint inflammation. – Hyaluronans also act directly to reduce inflammation in a joint, like a steroid, but without the harmful side-effects of steroids. Hyaluronic Acid injections into the knee joint are a very effective tool to treat: – Patients with localized damage to the lining surface of the joint (localized chondral defect). – Patients with early stage arthritis who wish to decrease their pain and increase their function. – Patients with more advanced arthritis who would like to postpone the need for a total joint replacement. – “Athletes” involved in impact sports (running, jumping , twisting) that overload the articular cartilage of the knee. There is some evidence (Roos et al) that this can lead to increased breakdown of the lining articular cartilage. This could be one of the mechanisms pre-disposing to the accelerated development of osteoarthritis in the “athletes” at a younger age. Ostenil can & is used as one of the treatment modalities in “athletes” with early arthritis of the knee. Whether hyaluronan therapy has any effect to reduce damage to the articular cartilage that is repeatedly overloaded (as in running jumping sports) is as yet unknown, but may be possible.
The Cochrane Review of Hyaluronic Acid Injections
The Cochrane Library is a collection of databases that contain high-quality, independent evidence to inform healthcare decision-making. Cochrane reviews represent the highest level of evidence on which to base clinical treatment decisions.
In addition to Cochrane reviews, The Cochrane Library provides other sources of reliable information, from other systematic review abstracts, technology assessments, economic evaluations and individual clinical trials – all the current evidence in one single environment.
A Cochrane review has been done in 2006 on the use of Hyaluronic Acid injections in people with osteoarthritis of the knee. The review concluded that HA injections are an effective and beneficial treatment for osteoarthritis of the knee.
The review conclusion is based on evidence from the highest levels of scientific available.
Injections in athletes
Article courtesy of Mr Len Funk/a>.
Cortisone (corticosteroid) injections, for individuals subject to drug testing under WADA (most professional and Olympic sports), are banned unless the athlete seeks a theraputic use exemption (TUE), including supporting documents from a physician, while intra-articular Hyaluronan injections are not prohibited.
The directives from the UK Sport Drug Information Database states:
WADA Regulations for Corticosteroids:
|In Competition||Prohibited: S9 Glucocorticosteroids |
All glucocorticosteroids are prohibited when administered by oral, intravenous, intramuscular or rectal routes.
|Out of Competition||Not Prohibited: Not tested for Out-of-Competition: These substances are not tested for `Out-of-Competition’.|
Please be aware that if it is found in an Athlete’s system during competition (even if the substance(s) was taken prior to the competition) this will constitute a doping violation.
WADA Regulations for Hyaluronans (Hyaluronic Acid):
|In Competition||Not Prohibited: There are no WADA restrictions on the use of this substance or product in sport.|
|Out of Competition||Not Prohibited: There are no WADA restrictions on the use of this substance or product in sport.|