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Viscosupplementation: Can It Have An Impact For Ankle Arthritis?

As a “biologic orthopedic medicine” for knee arthritis, viscosupplementation is showing off-label promise for patients with ankle arthritis. This author examines the research, shares her experience on injection therapy with hyaluronate and how it can relieve pain and restore function.

Ankle pain is a relatively common complaint from patients and it can encompass many diagnoses. As clinicians, we will determine if the condition is bony, ligamentous, capsular or from a tendon origin. Although the diagnosis may often be soft tissue in nature, at times it will truly originate from the ankle joint.

I have found that performing a simple anesthetic block into the joint can help differentiate between capsular and true joint pain. X-ray, computed tomography (CT) or magnetic resonance imaging (MRI) studies can confirm the clinician’s diagnosis. Ankle arthritis has many potential etiologies including aging, surgery, bony and soft tissue malalignment, post-fracture trauma, obesity, gout, diabetes and strenuous athletic activity.

There is a plethora of conservative treatments ranging from physical therapy to orthotic devices and weight loss. Medications include corticosteroid injections, non-steroidal anti-inflammatory drugs (NSAIDs) and narcotics.

Other treatments include surgical intervention, such as arthroscopy, arthrotomy, ankle joint replacement, fusion, microfracturing and other arthrochondrodiastasis procedures. Ankle joint surgeries are difficult at times and have very specific patient parameters and criteria, which patients may not easily meet. When considering the array of modalities in our treatment armamentarium and the potential benefits of early intervention, viscosupplementation may play a viable role for ankle arthritis in the future.

A Pertinent Overview Of Osteoarthritis
Articular cartilage consists of a high concentration of proteoglycans, hyaluronate, a collagen matrix and chondrocytes. The healthier the joints, the higher concentration of hyaluronate is present. The earliest feature of cartilage damage is the degeneration of the cartilage surfaces of the joint. Fibrillation is when the mesh of collagen fibers becomes disrupted. Type II collagen degrades.

The cartilage cells (chondrocytes) are the equivalent of the fibroblast elsewhere in the matrix and are the “control center” of the extracellular matrix in the cartilage tissue. They are responsible for the constant remodeling of the matrix. They achieve this by secreting proinflammatory cytokines, notably interleukin 1 (IL1) and tumor necrosis factor (TNF). Interleukin 1 and TNF activate matrix metalloproteinases (MMPs), the natural degraders of cartilage.

If these cells do not have a counterbalance, they will induce other substances like nitric oxide and prostaglandin (PGE2). The IL1 is one inducer of PGE2 and depending on the microenvironment, these mediators can be catabolic or anabolic. In theory, PGE generally exerts more of an anabolic effect on cartilage, increasing proteoglycan, DNA and collagen synthesis. Theoretically, PGE is a response to injury and inflammation when a joint is injured, and is the body’s way of encouraging the immune response to repair itself.

When this natural immune mediated inflammatory cascade system is “unchecked” and “off balance,” there is a vicious cycle of occasional repair and often breakdown. Typically, the catabolic state wins, especially if there are poor biomechanical factors in tow. When this occurs, it will cause the typical symptoms of stiffness, deformity and eventual osteophyte production and spurring. In healthy joints, the secretion of transforming growth factor cells (TGF-b) balances this process, which in turn stimulates the chrondocyte to secrete proteinase inhibitors, which inhibits the breakdown process. Accordingly, this normal “homeostasis” cycle repeats itself properly, creating this delicate balancing act.

Preventing the pro-inflammatory cells, stimulating TGF-b and biomechanically supporting the joint to prevent abnormal shearing of the cartilage as well as other “pro-cartilage” interventions are the wave of the future in biological orthopedics. Preserving this delicate inflammatory cascade repair is paramount to protecting the joint cartilage.  

A Closer Look At Treatment Options For Ankle Arthritis
Although there are various surgical interventions that depend on surgical training, it is typical for most clinicians to initiate the traditional treatment for ankle joint arthritis with pharmaceutical intervention either with NSAIDs, corticosteroids or narcotics.

In the past decade, the number of prescriptions written for narcotics has risen nearly 500 percent, which has led to serious overuse with the potential for dependency in some patients.1 With over 20 different drugs available, NSAIDs cause many hospital deaths numbering in the tens of thousands per year and over 100,000 hospitalizations per year due to gastrointestinal events and toxicity.2 The NSAIDs also reduce renal blood flow, which may result in renal failure in some patients and can promote fluid retention, thus diminishing the effects of other medications such as beta-blockers or antihypertensive drugs. Symptoms may temporarily improve but there is evidence that NSAIDs might be too deleterious to the cartilage.

Many scientific studies have demonstrated that NSAIDs have a negative effect on cartilage by inhibiting chondrocyte proliferation and impeding the cellular matrix components along with proteoglycan and glycosaminoglycan synthesis.3 Interleukin 1 is one of the principal cytokines, which initiates a cascade that leads to chondrocyte cell death and extracellular matrix breakdown due to the blockage of PGE2 production. The NSAIDs inhibit prostaglandins such as PGE2 from stimulating chrondrocyte DNA matrix synthesis, thereby contributing to articular cartilage degradation.

Corticosteroids may cause hypertension, diabetes, osteoporosis and even immune system impairment. It is also known that corticosteroids induce osteonecrosis due to embolization of terminal vessels, occlusion of vessels by external pressure resulting from marrow fat, hemorrhage or thrombosis, steroid-induced vasculitis, stress fractures resulting from steroid-induced reduction of osteoblastic activity, and Chandler’s syndrome with venous occlusion resulting from intracapsular swelling.

Some patient populations are more susceptible to these osteonecrosis effects. These include patients with connective tissue diseases, inflammatory bowel disease, and hematologic, metabolic and some dermatologic diseases to name a few. The orthopedic literature has described Charcot arthropathy-type changes with repeated steroid injections.4    

What You Should Know About Hyaluronate Injection
Hyaluronate influences tissue hydration, viscosity, lubrication, the production of denovo synovial synthesis, the suppression of cartilage degradation and the production of IL1. In diseased, arthritic joints, the hyaluronate molecular weight and concentration are reduced because researchers have found that hyaluronate clears at a higher rate than in normal joints due to lack of restitution for that balancing state (the natural catabolic/anabolic homeostasis that the joints go through as we stress them) as hyaluronate goes unchecked.5 Authors widely believe these products are just joint lubricators and any results would be fleeting and short-lived.6

In reality, hyaluronate products work to promote mechanical repair via increasing cartilage integrity, reduced cell death and improved joint morphology. The cellular changes include reducing synovitis, stimulating endogenous hyaluronate production and penetrating damaged cartilage to promote repair. The biochemical changes are reduction of pro-inflammatory cytokines in the cell culture, namely IL1, IL6, TNF, nitric oxide and cyclooxygenase (COX2). Hyaluronate also reduces the production of MMPs, which I previously noted as cartilage degrading enzymes, by approximately 90 percent.7 In other studies, hyaluronate lowered the expression of genes linked to osteoarthritis with and without the stimulation of IL1.8 All of these factors resulted in true functional changes such as decreased stiffness; improvement in joint function and morphology; and true analgesia via protection of pain receptors. Consistent results occurred in all the various studies.9

Hyaluronate products have become more widely available and have slight variations. There are five major trade name products. Supartz (Bioventus) has the longest use at over 20 years with more than 20 studies performed. This is the product I utilize. Hyalgan (Fidia Pharma) and Euflexxa (Ferring Pharmaceuticals) are 1% hyaluronan products. Synvisc (Sanofi-Aventis) and Orthovisc (DePuy) have 0.8% and 1.5% hyaluronan respectively. The molecular weights vary from 0.50 to 6 million Daltons among the aforementioned brands.

The injection volume is fairly consistent at 2 mL. Some products consist of a series of three injections on a weekly basis and Supartz has an indication for up to five total injections. The injectables are currently in use for arthritis of the knee, but studies are underway studying the effects for the shoulder and ankle joint arthritic conditions as well. The dosage for each injection for the five aforementioned products varies from 16 to 30 mg for the standard series.

It is interesting to note that Supartz has fewer impurities such as protein impurities, nucleic acids and bacterial endotoxin content, and has 87 percent fewer hypersensitivity reactions compared to the other four brands.10 The published studies thus far for Supartz have only involved knee joints. Ankle joint injections are not FDA approved as of yet. However, studies are underway at this time to gauge the effectiveness of Supartz for osteoarthritis in the ankle joint as well as the shoulder joint.

Side effects of Supartz in study participants reportedly include local reactions (roughly 2 to 5 percent). These local reactions include para-articular pain and swelling, which physicians treated in some studies with corticosteroids, which would negate the whole purpose of utilizing the hyaluronate product in the first place.11 I suggest these reactions may be a predictable acute TH1 pathway immune response via leukocyte migration produced during the inflammatory cascade. Had the participants waited, would they have had symptom and pain resolution?

One should not use hyaluronate products in patients who have sensitivity or allergy to poultry and products from birds (eggs or feathers), a prosthesis, infections of the joint, skin diseases in the area of injection or other issues with hyaluronate products. The use of these products has not had study in pregnant women, lactating women and children so avoidance of hyaluronate products in these patients is prudent.

The joint injection is relatively easy and one can do it with or without local anesthesia, depending on the packaging of the specific product. One can administer a separate syringe of local anesthesia first and then the physician can inject the untampered, prefilled syringe. Patients can perform normal activities of daily living but should postpone strenuous or major athletic activities for 48 hours after the injection.

In regard to the series of three injections, they occur weekly but with Supartz, one may use a total of five injections. The needle size should be 20-22 gauge due to the viscosity of the material. Traditional aseptic skin prep technique is recommended.

To date, I have had consistent patient results using Supartz off-label for ankle arthritis with no apparent side effects. With many studies on viscosupplementation performed (albeit primarily in the knee) and what I have seen using this modality off-label in the ankle, it appears that the use of viscosupplementation is safe with few side effects.

In Conclusion
I am a strong proponent of injection therapies of all types for soft tissue, bony and joint conditions. The aim is to renew cartilage, improve blood flow, reduce scar tissue, incite collagen synthesis via increasing TGF-b along with other cellular reactions. Addition of this well tolerated and studied injectable modality that has been in the marketplace for many years could have a huge impact on our podiatric patient population.

It is prudent to thoughtfully consider the choices and treatments we suggest when advising patients, especially when dealing with anatomy that generally does not repair itself well. It behooves the podiatric physician to treat and evaluate all patients biomechanically to help offload and reduce abnormal alignment issues via our traditional methods (i.e. shoes, orthotics, weight control and rehabilitative therapies), no matter what ultimate treatment route we choose.

Viscosupplementation is a new wave of “biologic orthopedic medicine” and I feel that in light of how well it has worked for knee joints, it is a modality to consider seriously for the ankle joint. Research has shown it to be a very viable, reliable, easy and generally well-tolerated treatment regimen.

Although the use of viscosupplementation for ankle joints is not covered by insurance companies as of yet, the out-of-pocket expense may outweigh the time, cost, rehabilitation and possible complications of other conservative and surgical interventions.

We should consider treatments that may enhance and/or preserve cartilage production rather than treatments that may allow faster degradation and destruction. Improving the immune response by allowing the body to heal itself with the assistance from the doctor could be the wave of the future.
 
Dr. Schoene is a sports medicine specialist and certified athletic trainer. She is a Fellow of the American College of Foot and Ankle Surgeons, the American Academy of Podiatric Sports Medicine, and the American College of Foot and Ankle Orthopedics and Medicine. Dr. Schoene has worked at the Atlanta Olympics, the World Cup Games and the Olympic Training Center. She has also worked with many professional dance companies, including the Joffrey Ballet of Chicago, Hubbard Street Dance, Inaside Chicago Dance and Ballet Chicago. Dr. Schoene has been a podiatric consultant for the DePaul University Blue Demons since 1992.

This author has no disclosures regarding any of the products mentioned in this article.

References

  1. Paulozzi LJ, Budnitz DS, Xi Y. Increasing deaths from opioid analgesics in the United States. Pharmacoepidemiol Drug Saf. 2006; 15(9):618-27.
  2. NSAIDs and adverse effects. Bandolier. Available at http://www.medicine.ox.ac.uk/bandolier/booth/painpag/nsae/nsae.html#Heading21 .
  3. Hauser RA. The acceleration of articular cartilage degeneration in osteoarthritis by nonsteroidal anti-inflammatory drugs. J Prolother. 2010; 2(1):305-22.
  4. Hagen R. Charcot-like arthropathy after intra-articular injections of corticosteroids. Tidsskr Nor Legeforen. 1971; 91(6):440-4.
  5. Dahl LB, Dahl IM, Engstrom-Laurent A, Granath K. Concentration and molecular weight of sodium hyaluronate in synovial fluid from patients with rheumatoid arthritis and other arthropathies. Ann Rheum Dis. 1985; 44(12):817-22.
  6. Mori S, Naito M, Moriyama S. Highly viscous sodium hyaluronate and joint lubrication. Int Orthop. 2002; 26(2):116-21.
  7. Kirchner M, Marshall D. A double-blind randomized controlled trial comparing alternate forms of high molecular weight hyaluronan for the treatment of osteoarthritis of the knee. Osteoarthritis Cartilage. 2006; 14(2):154-62. 
  8. James R, Kesturu G, Balian G, Chhabra B. Tendon: biology, biomechanics, repair, growth factors, and evolving treatment options. J Hand Surg Am. 2008; 33(1):102-12.
  9. Altman RD, Rosen JE, Bloch DA, Hatoum HT. Safety and efficacy of retreatment with a bioengineered hyaluronate for painful osteoarthritis of the knee: results of the open-label Extension Study of the FLEXX Trial. Osteoarthritis Cartliage. 2011; 19(10):1169-75. 
  10. Migliore A, Giovannangeli F, Bizzi E, Massafra U, Alimonti A, Laganà B, Diamanti Picchianti A, Germano V, Granata M, Piscitelli P. Viscosupplementation in the management of ankle arthritis: a review. Arch Orthop Trauma Surg. 2011; 131(1):139-47.
  11. Available at http://www.drugs.com/sfx/supartz-side-effects.html .

Editor’s note: For further reading, see “Essential Insights On Treating End-Stage Ankle Arthritis” in the April 2013 issue of Podiatry Today, “Keys To Considering Ankle Replacement In The Treatment Of Ankle Arthritis” in the September 2011 issue, or the January 2013 DPM Blog “Ankle Arthritis: To Fuse Or Not To Fuse?” by Jeffrey Bowman, DPM, MS.

For other related articles, visit www.podiatrytoday.com.

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Lisa M. Schoene, DPM, ATC, FACFAS

Comments

I too am a proponent of viscosupplementation injection for ankle arthritis but is a separate consent form being used by my colleagues since it is of- label use for the ankle and how is the injection product being billed so we are reimbursed for the product or is it cash??
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It's a travesty that an article discussing the use of viscosupplementation in the ankle in a podiatry magazine does not reference any of the two FDA pilot control studies published in JBJS and Foot and Ankle international using the ankle. Both studies were authored by DPMs and one of them is co-authored by Roy Altman, the previous editor of Osteoarthritis and Cartilage.
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