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New Concepts for Management
of Osteoarthritis in the Knee—
An Interactive Forum
Presented by Mark D Hopkins, M.D.
Board-certified Orthopedic Surgeon
Flagstaff, Arizona
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Objectives
• Discuss etiology of osteoarthritis (OA) of the
knee
• Explain why hyaluronans are so important for
proper knee function
• Go over fundamental differences between the
different types of hyaluronans
• Discuss mechanisms of action of hyaluronans
• Provide an opportunity for physician exchange of
ideas and clinical experiences
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Audience Poll:
• How many have osteoarthritis?
• Which specialties are represented?
• Who uses hyaluronan compounds?
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Prevalence of osteoarthritis
• Advertisements from a recent issue of American
journal of Orthopedics
• 75% of ads covered some aspect of osteoarthritis
• -8 ads on joint replacement
• -2 on NSAID
• -3 on hyaluronans
• -4 on other osteoarthritis categories
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Osteoarthritis
• Osteoarthritis is a degenerative joint disease
resulting in cartilage erosion, subchondral bone
remodelling, osteophyte formation, and synovial
inflammation.
• Osteoarthritis has multiple origins
• Current evidence suggests that both mechanical
and biochemical factors play an important role in
its progression
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Joint injuries leading to osteoarthritis
• Articular cartilage contusions
• Partial or complete meniscectomy
• Ligamentous instability
• Overuse or repetitive trauma
• Secondary weakness in quadriceps, loss of
damping effect on knee impact
• Posttraumatic joint deformities from fractures
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Joint deformities leading to osteoarthritis
• Varus knee
• Valgus knee
• Ankle and foot problems leading to altered gait
• Hip problems
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Genetic predisposition for osteoarthritis
• Cartilage degradation time clock
• Starts early in some people, later in others
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Osteoarthritis
• Imbalance of biosynthesis and degradation in
cartilage, synovial fluid, bone, muscle and
ligaments
• In essence: increased degradation, decreased
synthesis
• Leads to decrease in concentration and average
molecular weight of hyaluronic acid in synovial
fluid
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Osteoarthritis
• Hyaluronic acid normal average molecular weight
is 7,000,000 daltons
• In knees with osteoarthritis the average
molecular weight can drop to 4,800,000 daltons
or even as low as 20,000 daltons
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ACR 2000 Guidelines—
Pharmacologic/Surgical Therapy
Mild to Moderate Pain
• Simple analgesics
(eg, acetaminophen)
• OTC NSAIDs
• Topical creams
Moderate to Severe Pain
• Rx NSAIDs plus
gastroprotective agent,
or COX-2–selective
inhibitors
Additional
Therapies
• IA hyaluronans
• IA steroids
Surgical
Intervention
• Total knee
replacement
American College of Rheumatology Subcommittee on Osteoarthritis Guidelines. Arthritis Rheum. 2000;43:1905-1915.
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How to treat osteoarthritis
• Imagine a freighter traveling towards the arctic
circle directly in to the path of icebergs
• What would you do?
• Some would not alter the course, but would
continue directly ahead and repair damages
along the way (treat symptoms)
• And if necessary replace the freighter when they
returned home. (total knee replacement)
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How to treat osteoarthritis
• Others might attempt to alter the course of the
freighter to avoid the icebergs. (disease
modifying treatments for osteoarthritis, alter the
course of the disease)
• Perhaps the treatment for osteoarthritis should
be broken down in to disease modifying or simply
symptom relieving
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Modified ACR 200 guidelines
• Symptom relieving
• Disease modifying
• Simple analgesics
• Hyaluronans
• OTC NSAID
• Glucosamine
• Cox 2 inhibitors
• Chondroitin Sulfate
• Steroids
• Unloader braces
• Knee replacement
• HTO
• Weight loss
• Increase muscular strength
• Improve flexibility
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What is your choice?
• What would you want if you were the patient?
• Crash in to icebergs?
• Avoid them?
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Product comparisons, hyaluronans
Product
Hyalgan
Synvisc
Supartz
MW (kDa)
500-730
80% 6,000
620-1,170
20% > 6,000
Manufacture
Natural
Crosslinked
Natural
Treatment
3 or 5 inj. X 20
mg/2ml
3 inj. X 16 mg/2ml
5 inj. X
25mg/2.5ml
Repeat series
FDA approved
Not FDA approved Not FDA approved
Inflammatory
reactions
0%
Stimulates
endogenous
hyaluronase
production
Yes
2.2% per
injection
No
0%
Yes
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Mechanisms of Action of Hyaluronans
Based on research dating back to the 1980’s
• Increases the viscosity and elasticity of OA
synovial fluid
• Stimulates endogenous hyaluronic acid
production
• Inhibits induction and activity of degradative
enzymes
• Reduces inflammatory response
• Analgesic effect
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Increased viscosity and elasticity of
synovial fluid
• This is a temporary effect
• For hyalgan 24 hours
• For supartz 24-72 hours
• For synvisc 3-8 days
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How important is this temporary increased
viscosity and elasticity?
• When the original patents were being developed,
it was thought that the viscosity increase was the
primary effect by which these substances
worked.
• They were thought of as a lubricant for the knee
joint.
• Synvisc was thought to be superior because of
its larger molecular weight. It would stay in the
knee longer and lubricate it better. This is why
during the development process for synvisc , it
was crosslinked.
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Possible sequelae of crosslinking
• Some have pointed to the cause of synvisc’s
inflammatory reactions being linked to its larger
size.
• Possible foreign body reaction
• Possible autoimmune response
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Stimulates endogenous hyaluronase
production
• How could injecting hyaluronase stimulate
hyaluronase production?
• One would logically think that the body would
sense the substance was increased and limit its
production.
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Hyaluronase
• Is present as a polydisperse species with an
average MW of up to 10,000,000 Daltons.
• The concentration in normal synovial fluid is
3mg/ml.
• Is responsible for the normal viscosity of synovial
fluid.
• Also lubricates the joints.
• A knee with low quantities of hyaluronase or the
wrong molecular weight is like an engine with not
enough oil or the wrong type.
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Hyaluronase
• Type B fibroblasts in synovium are responsible
for hyaluronase production.
• The response of fibroblasts to different molecular
weights of hyaluronase was studied.
• High MW fractions (4,000,000) were less
effective in stimulating hyaluronase synthesis
than lower MW (500,000-4,000,000)
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Stimulation of endogenous hyaluronase
production
• Synovial fibroblasts do not increase the
biosynthesis of hyaluronase when the
hyaluronase in their environment is of a MW
within a range which could be functionally
acceptable.
• The stimulus for increased biosynthesis of
hyaluronase only becomes operational when the
hydrodynamic size distribution of extrinsic
hyaluronase falls within a particular mean range.
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Stimulation of endogenous hyaluronase
production
• Receptor binding as a function of molecular
MW > 4,000,000
weight.
maximal receptor
MW < 500,000, weak binding no
HA synthesis
MW 500,000-4,000,000,
strong binding because #
of receptors stimulated
increases HA
biosynthesis
binding, large domains
limit # of sites,
decrease HA
production
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Mechanism of action of hyaluronans
• Inhibit induction and activity of degradative
enzymes
• Hyaluronase suppresses
•
MMP-3 (matrix metalloproteinase-3) MMP-3 degrades
•
cartilage proteoglycan and type 2 collagen
•
•
IL-1Beta (interleukin-1 Beta) IL-1Beta is responsible for
•
cartilage catabolism
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Mechanism of action of hyaluronans
• Hyaluronase reduces inflammatory response
• Hyaluronase inhibits leukocyte and mononuclear cell
phagocytosis, adherence and mitogen-induced
proliferation
• Hyaluronase protects tissues and synovial proteins from
free radicals
• Hyaluronase decreases levels of prostaglandin E2 and
cyclic AMP. HA impairs migration of AA (arachidonic acid)
away from cells. Since extracellular AA is rapidly taken up
by activated leukocytes within joints and may be
converted to inflammatory prostanoids, the observed
inhibitory effects of HA on AA release could be
considered antiinflammatory.
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Mechanism of action of hyaluronans
• Analgesic activities of hyaluronase
• By modulating inflammatory cell activities,
including their release of pro-inflammatory
mediators, cytokines and free radicals, HA could
indirectly influence the sensitization of pain
receptors in arthritic joints.
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Summary
• All of the effects are centered around
hyaluronase
• The most important effect of administering
hyaluronase in to a joint is its effect on
stimulating endogenous hyaluronase production
because it is the hyaluronase that mediates all of
the other effects.
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Summary, continued
• Only two of the substances on the market stimulate
endogenous hyaluronase production, hyalgan and
supartz.
• We have to understand that the treatment of osteoarthritis
is a long term problem. The only substance FDA
approved for repeat series is hyalgan. It makes no sense
to treat a long term problem for six months, then stop.
• Hyalgan, then, by deduction is currently the most logical
choice for the long term treatment of osteoarthritis.
Remember, we’re not treating the symptoms, we are
trying to alter the course of the disease. Avoid the
icebergs.
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Focus Questions
• Use of hyaluronans in other joints?
• What do we do when a patient does not
respond to hyaluronan treatment?
• What is the reason that some patients don’t
respond and some do with the same type and
degree of osteoarthritis?
• Which grades of osteoarthritis respond best to
hyaluronan therapy?
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Focus Questions, continued
• Does obesity play a role in response to
hyaluronase treatment?
• When a patient has a total knee on one side, do
you try hyaluronase on the other side or just go
to a TKA?
• What do you do with a patient with a meniscus
tear that may be degenerative and osteoarthritis
on the same side? TKA? Scope? Hyaluronase?
Therapy? Other?
The End
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