Viscosupplementation for knee osteoarthritis
An emerging alternative tool for treating degenerative arthritis of the joint
The introduction of viscous supplements, which are injected into joints, offers an alternative treatment for patients suffering from osteoarthritis.
"We have found a new alternative, we have reviewed the evidence, and I think it's a new alternative for geriatric patients suffering from degenerative arthritis of the joint … to allow them a better quality of life," declared Dr. Edward H.M. Wang, associate professor at the University of the Philippines-Philippine General Hospital.
Wang presented evidence of the treatment during a recent symposium on Viscosupplementation for osteoarthritis of the knee organized by Vizcarra Pharmaceutical Inc.
Viscosupplementation is intraarticular therapy with elastoviscous solutions of hyaluronan or hylans. Hyaluronan, a high molecular weight polysaccharide (glucuronic acid and N-acetylglucosamine), is found ubiquitously among connective tissues. Large concentrations are also present in the joints, specifically in the articular cartilage where hyaluronan serves as a backbone for the attachment of aggrecan side chains. Together with water and type II collagen fibers, the hyaluronan-aggrecan complex forms the extracellular matrix of the articular cartilage.
Viscosity, elasticity
In the synovial fluid, hyaluronan's capacity to incorporate water into its structure gives it viscosity and elasticity so that it is able to dissipate and absorb loads thrown across the joint. It also serves as a barrier against larger molecules (antiinflammatory) and provides an effective shield for the articular pain receptors.
Noted Wang: "In the synovial fluid, it (hyaluronan) helps in the absorption of low-impact movement, as a viscous lubricant, and it can coat the articular surface. For high impact movement, it provides the elasticity and allows fluid to absorb the energy and buffer the forces across the joint."
With osteoarthritis, there is considerable decrease in the molecular weight and concentration of hyaluronan due to fragmentation of the complex, aberrant production, and dilution after exudation. The elastoviscosity is lowered, in the process "losing the properties of lubrication, protection of the articular tissues, and absorption of the loads on the joint," Wang noted.
"It is precisely the recognition of this role of hyaluronan in our joint homeostasis, then the change in the quantity and quality in osteoarthritic patients, that [gave rise to] the idea of viscosuplementation. Basically, viscosupplementation is removing the pathologic synovial fluid and replacing it with hyaluronan as an injectable into the joint," explained Wang.
Nothing new
Viscosupplementation is not necessarily new in clinical practice. For the past 20 years, it has been used in horses to treat posttraumatic arthritis. Its development is historically credited to Prof. E.A. Balazs, who formulated a form of noninflammatory sodium hyaluronan in the 1960s. It was during the 1970s, however, when the first clinical evaluation of intraarticular hyaluronan was performed. The results showed improvement in joint function and pain relief, without any notable side effects. But it was not then marketed for intraarticular use in humans.
It was later marketed as an ointment and eye-drop preparation for ophthalmic viscosurgery (Healon-Upjohn). A version for animals (Hylartin-Upjohn) was used for treatment of equine arthritis.
Cross-linked hyaluronans
In normal synovial fluid, hyaluronan molecular weight is approximately 5 x 106. Earlier hyaluronan preparations, however, had molecular weights of only between 0.5 to 1.0 x 106. Since the lower molecular weight held lower elastoviscosity, hylans were developed. Hylan is a cross-linked preparation of individual hyaluronan molecules with significantly higher molecular weights. The increase logically provided for an increase in elastoviscosity. Noted Wang: "[Hylan] seemed to be more effective in restoring synovial fluid rheology, which is basically elastoviscosity. It stays a little longer in [the] joint, and has a longer period of integrity in inflamed joints."
In osteoarthritic joints, hyaluronan and hylan are known to cause the following actions:
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Restoration of joint rheology (restores the elastoviscous properties of the synovial fluid)
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Antiinflammatory effect (inhibits the inflammatory cells--phagocytosis, prostaglandin release, lymphocyte activation--that destroy articular cartilage
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Antinociceptive effect (indirectly acts as antiinflammatory; directly, inhibits prostaglandins, entraps endogenous pain substances, coats the receptor endings of pain fibers by putting in a layer of hyaluronan
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Normalization of hyaluronan synthesis (in the process doubling hyaluronan production)
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Chondroprotection (stimulates production of tissue inhibitors of metalloproteinases, protects articular cartilage, inhibits further degradation)
Difference with Synvisc
A Cochrane Review by Bellamy et al. (Viscosupplementation for the Treatment of Osteoarthritis of the Knee) included studies of all randomized controlled trials using one or more viscosupplements. Participants were males or females with a
diagnosis of osteoarthritis of the knee, all of whom were treated with some kind of viscosupple-ment. The control involved either placebo or another form of active supplement. The outcome measures included the OMERACT III set of measures (at least one: pain, physical function, patient global assessment, joint imaging).
Since there are different types of viscosupplementations, a pooled class analysis of all the studies was done. In general, hyaluronans' efficacy was statistically significant over placebo, at treatment intervals of one to four weeks, five to 13 weeks, and 14 to 26 weeks. Also as a class, there was no significant difference with placebo with regard to systemic adverse events, while local adverse events (two to four percent) were transient.
As for Hylan G-F 20 (Synvisc), however, statistically significant positive differences against placebo were noted at all the different time intervals evaluated, indicating "evidence to support the efficacy of Hylan G-F 20," Wang noted.
Against intraarticular corticosteroid injections, Hylan G-F 20 showed no difference at one to four weeks. But there was significant statistical difference at both five to 13 and 14 to 26 weeks. The investigators noted that the results were probably due to the quick onset of action but relatively short duration of response to intraarticular steroid treatment. They said the evidence suggests that Hylan G-F 20 is comparable to intraarticular corticosteroids. Although steroids have faster onset of action, the Hylan G-F 20 has longer duration of action.
Hylan G-F 20 also showed efficacy comparable with that of nonsteroidal antiinflammatory drugs (NSAIDs), especially at five to 13 and 14 to 26 weeks. There were also significantly fewer patients with related systemic adverse events for those on Hylan G-F 20.
Hylan G-F 20 is an elastoviscous fluid containing hylan polymers in physiologic sodium chloride solution. Obtained from a rooster's comb, which has the highest concentration of hylans among animals, it comes as an injectable that can be administered into the suprapatellar pouch, medially and laterally, or directly into the joint.
Which patients benefit most from viscosupplementation, for how long?
A Canadian study (Lussier et al. 1996), showed the results were better in early and intermediate disease as against advanced or end-stage disease (p < 0.05). The benefits were apparent in 65 percent of patients for more than three months and in half for more than six months. Good response was obtained in 77 percent of patients after the first injection; the response was the same or higher (up to 86 percent) after a second injection. The average time between injections was 8.2 months. There were no systemic adverse events while local effects (pain, swelling, warmth, or redness over the joint itself) were transient and did not increase in incidence with the second or third injection.
A two-year local trial supervised by Wang and involving 52 knees of 43 patients showed similar results. Seventy-five percent of patients with severe osteoarthritis (those who refused or could not be cleared for surgery) experienced relief of symptoms. Among those who had mild to moderate osteoarthritis, 87 percent experienced improvement in their condition. Their joints "loosened," they had no pain in walking, and could function better. No adverse events were noted, according to Wang. R. Badillo II, MD
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