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New Concepts for Management of Osteoarthritis in the Knee— An Interactive Forum


New Concepts for Management of Osteoarthritis in the Knee An Interactive Forum Presented by Mark D Hopkins, M.D. Board-certified Orthopedic Surgeon – PowerPoint PPT presentation

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Title: New Concepts for Management of Osteoarthritis in the Knee— An Interactive Forum

New Concepts for Management of Osteoarthritis in
the KneeAn Interactive Forum
Presented by Mark D Hopkins, M.D. Board-certified
Orthopedic Surgeon Flagstaff, Arizona
  • Discuss etiology of osteoarthritis (OA) of the
  • 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

Audience Poll
  • How many have osteoarthritis?
  • Which specialties are represented?
  • Who uses hyaluronan compounds?

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

  • Osteoarthritis is a degenerative joint disease
    resulting in cartilage erosion, subchondral bone
    remodelling, osteophyte formation, and synovial
  • Osteoarthritis has multiple origins
  • Current evidence suggests that both mechanical
    and biochemical factors play an important role in
    its progression

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

Joint deformities leading to osteoarthritis
  • Varus knee
  • Valgus knee
  • Ankle and foot problems leading to altered gait
  • Hip problems

Genetic predisposition for osteoarthritis
  • Cartilage degradation time clock
  • Starts early in some people, later in others

  • Imbalance of biosynthesis and degradation in
    cartilage, synovial fluid, bone, muscle and
  • In essence increased degradation, decreased
  • Leads to decrease in concentration and average
    molecular weight of hyaluronic acid in synovial

  • 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

ACR 2000 Guidelines Pharmacologic/Surgical
  • Mild to Moderate Pain
  • Simple analgesics (eg, acetaminophen)
  • Topical creams
  • Moderate to Severe Pain
  • Rx NSAIDs plus gastroprotective agent,or
    COX-2selective inhibitors
  • Additional
  • Therapies
  • IA hyaluronans
  • IA steroids
  • Surgical
  • Intervention
  • Total knee replacement

American College of Rheumatology Subcommittee on
Osteoarthritis Guidelines. Arthritis Rheum.
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)

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

Modified ACR 200 guidelines
  • Symptom relieving
  • Simple analgesics
  • Cox 2 inhibitors
  • Steroids
  • Knee replacement
  • Disease modifying
  • Hyaluronans
  • Glucosamine
  • Chondroitin Sulfate
  • Unloader braces
  • HTO
  • Weight loss
  • Increase muscular strength
  • Improve flexibility

What is your choice?
  • What would you want if you were the patient?
  • Crash in to icebergs?
  • Avoid them?

Product comparisons, hyaluronans
Mechanisms of Action of Hyaluronans
  • Based on research dating back to the 1980s
  • Increases the viscosity and elasticity of OA
    synovial fluid
  • Stimulates endogenous hyaluronic acid production
  • Inhibits induction and activity of degradative
  • Reduces inflammatory response
  • Analgesic effect

Increased viscosity and elasticity of synovial
  • This is a temporary effect
  • For hyalgan 24 hours
  • For supartz 24-72 hours
  • For synvisc 3-8 days

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
  • They were thought of as a lubricant for the knee
  • 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.

Possible sequelae of crosslinking
  • Some have pointed to the cause of synviscs
    inflammatory reactions being linked to its larger
  • Possible foreign body reaction
  • Possible autoimmune response

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

  • Is present as a polydisperse species with an
    average MW of up to 10,000,000 Daltons.
  • The concentration in normal synovial fluid is
  • 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.

  • 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)

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.

Stimulation of endogenous hyaluronase production
  • Receptor binding as a function of molecular

MW gt 4,000,000 maximal receptor binding, large
domains limit of sites, decrease HA production
MW 500,000-4,000,000, strong binding because of
receptors stimulated increases HA biosynthesis
MW lt 500,000, weak binding no HA synthesis
Mechanism of action of hyaluronans
  • Inhibit induction and activity of degradative
  • Hyaluronase suppresses
  • MMP-3 (matrix metalloproteinase-3) MMP-3
  • cartilage proteoglycan and type 2
  • IL-1Beta (interleukin-1 Beta) IL-1Beta is
    responsible for
  • cartilage catabolism

Mechanism of action of hyaluronans
  • Hyaluronase reduces inflammatory response
  • Hyaluronase inhibits leukocyte and mononuclear
    cell phagocytosis, adherence and mitogen-induced
  • 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

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.

  • All of the effects are centered around
  • 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.

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, were not treating the
    symptoms, we are trying to alter the course of
    the disease. Avoid the icebergs.

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 dont
    respond and some do with the same type and degree
    of osteoarthritis?
  • Which grades of osteoarthritis respond best to
    hyaluronan therapy?

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