Viscosupplementation for the Osteoarthritis of the Knee
Dr. Vladimir Bobic
Consultant Orthopaedic Knee Surgeon
Chester Knee Clinic
The Grosvenor Nuffield Hospital
(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 aetiology of OA remains
unknown biomechanical stresses and biochemical changes in the articular
cartilage, subchondral 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 hyluronan 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).
use of viscosupplementation is based on observation that there is a
decrease in viscosity and elasticity of the synovial fluid
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
synovial fluid, which may help relieve the signs and symptoms
related to osteoarthritis and improve function. In vitro 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).
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).
(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
notion of supplementing osteoarthritic synovial fluid
with exogenous hyaluronate stems from the fact that the molecular weight and
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.
goal of viscosupplementation is to increase the molecular weight and
concentration of hyaluronate in arthritic joints so that the intra-articular
milieu more closely resembles that of healthy synovial fluid.
mechanism of action by
which viscosupplementation alleviates arthritic knee pain is a subject of
debate. It has been proposed that exogenous viscoelastic substances act
biomechanically by providing a “cushioning” effect. 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. One manufacturer has cross-linked
hyaluronate chains in an effort to further enhance the molecular weight
(and, hence, the viscoelasticity) of its product, Hylan G-F 20 (Synvisc™).
A synthetic hyaluronic acid Arthrease™ is not cross-linked,
but does have a high molecular weight. Arthrease™ has to be stored
within a controlled temperature range of 2-8 C0 . It contains
no animal protein and no residual cross linking reagents. Several
studies have suggested that viscosupplements with higher molecular weights
have greater therapeutic efficacy (6, 7).
Molecular Weight (daltons)
injection per week for 5 weeks
from chicken combs
(Synvisc™, Genzyme Biosurgery)
injection per week for 3 weeks
synthetic hyaluronic acid
to healthy synovial fluid
1 injection per week for 3 weeks
in healthy synovial fluid
4 million to 6 million
in osteoarthritic synovial fluid
1 million to 4 million
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
haluronic 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
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).
There are 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. More research is needed to evaluate
whether or not viscosupplementation has disease-altering properties in addition
to its apparent palliative characteristics. (3, 6).
Viscosupplementation is a proven adjunct to the treatment armamentarium of
general practitioners and surgeons. A number of recent
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).
Clinical Assessment Parameters
et al., 1997
injections of Hyalgan, every 3 months, for a year
index (functional impairment), AIMS2 (quality of life)
study suggests that repeated injections of hyaluronan might delay
structural progression of the disease.
et al., 1995
G-F 20 vs continuous NSAIDs
single-blind, prospective, muticenter
equivalent to continuous NSAIDs at 12-week follow-up
et al., 1999
G-F 20 vs a low molecular weight hyaluronate
double-blind, prospective, multicenter
G-F 20 significantly better than low molecular weight hyaluronate
at 12 week follow-up
et al., 2001
Care (according to ACR guidelines) with or without hylan G-F 20
provide strong evidence for adoption of treatment with hylan G-F
20 in patients with knee OA. Good value for money.
clinical trials of intraarticular hyaluronan preparations, pain relief
among those who completed the study was significantly greater than that
seen after intraarticular 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 intraarticular
glucocorticoids. Although pain relief is achieved more slowly with
hyaluronan injections than with intraarticular glucocorticoid injections,
the effect may last considerably longer with hyaluronan injections (17).
The price for the course of HA ranges from approx. £200 to £300 in the
UK. In our own experience on 104 patients, in Liverpool and Chester (with
Hyalgan™, Synvisc™, Orthovisc™ and Arthrease™), from 1999 to 2002,
the average duration of pain relief was seven months, but approximately
10% of patients did not experience any significant pain relief. We did not
observe any significant complications. The only reported adverse effects
were injection site pain in five patients (lasting less than 24 hours),
and exacerbated knee effusion in two patients.
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 Synvisc™ before the first
clinical trials. Preclinical studies showed that Synvisc™ 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 Synvisc. No cases of
anaphylaxis or anaphylactoid reactions have been reported in connection
with Synvisc™ treatment. However, anaphylactic-like reactions have been
reported following intra-articular Hyalgan™ injections (18).
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
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).
Market Analysis19 : the reimbursement of
hyaluronic acid therapy varies greatly from market to market, particularly
in Europe, and has become more important in some of these markets than
efficacy or product reputation. Despite
claims and reasonable clinical evidence from manufacturers of efficacy and
specific product advantages, many end-users remain sceptical that
hyaluronic acid viscosupplementation is truly an effective treatment for
osteoarthritis of the knee. Therefore companies must increase physician
and surgeon confidence through detailed clinical studies specifically
designed to address these concerns.
The US will become the largest market for HA
manufacturers and distributors, valued at $235 million in 2001, despite
per capita usage of only 8.5% of that seen in Austria. The Austrian market is growing at a very slow pace, because
of extremely high per capita usage. In
contrast, the UK market is growing at a higher rate, but surgeon and GP
scepticism, infrastructure problems, and lack of funds
interfere with wider acceptance of viscosupplement therapy. In the
UK there are additional difficulties with “evidence-based-medicine”
approach of some NHS Trusts, which are unnecessarily restrictive, and in
reality based on rationing policies. At the same time most orthopaedic
surgeons recommend and use a wide range of expensive oral NSAIDs, a
combination of intra-articular steroids and local anaesthetic injections,
and arthroscopic debridements and washouts, without any restrictions.
As evident from the table below, the $563.9 million global market for
hyaluronic acid is dominated by Japan and the US, with the European market
accounting for a comparatively small level of sales. While Japan accounted
for 47% of the global market value in 2001, nearly 86% of the total number
of HA injections were administered in Japan.
Low prices in Japan, and high prices in US, account for the
discrepancy between comparative market values and comparative market
Market Share by Value, %, 2001
Value: $563.9 million
A T A M O N I T O R
In France, the product is only reimbursed at 50% of the price, with only
one product reimbursed in 2001. In Spain, the use of hyaluronic acid is
very low, due to lack of reimbursement. In Italy, the market is fairly
mature, with hyaluronic acid viscosupplementation first utilized in 1987
when Fidia launched Hyalgan to the market.
Fidia’s product continues to dominate the market, which reached
345,000 injections in 2001. The largest HA market in Europe is Germany.
The German HA market continues to exhibit impressive growth despite a
relatively high market volume, forecasted to approach 1,000,000 units sold
in 2002. The young US market remains the fastest growing market, and in
2002 will become the highest value HA market in the world.
Only three products currently competing on the US market are
contributing to increased awareness and acceptance of hyaluronic acid
among end-users and patients.
economic costs of OA of the knee are enormous. If viscosupplementation
does indeed reduce and defer the need for surgical procedures like
arthroscopic knee washouts and debridements, and total knee replacements,
the cost savings will be considerable. Even more important will be the
diminution of the risks associated with anaesthetic and surgical
procedures. However, 3 or 5 weekly injections are quite awkward for most
clinicians and patients. One single injection, which lasts long enough,
would be much more useful.
is no doubt that viscosupplementation represents valuable addition to current
treatments for osteoarthritis and an alternative treatment when other forms of
medical treatment are contraindicated or have failed.
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Reference code DMHC1776, Publication date: June 2002. www.datamonitor.com.