Hyaluronic Acid for Treatment of Osteoarthritis of the Knee

Repeated Injections and Progression to Knee Replacement

Judith Walsh, MD, MPH



In This Article


Osteoarthritis (OA) is characterized by degeneration of cartilage and its underlying bone within a joint as well as bony overgrowth, which ultimately lead to pain and joint stiffness. Most commonly affected joints are the knees, hips, and joints in the hands and spine. OA of the weight bearing joints (e.g. knee and hip) typically have the most clinical significance. The causes of OA are presumed to be related to mechanical and molecular events in the joint. (http://www.cdc.gov/arthritis/basics/osteoarthritis.htm).

OA usually begins after the age of 40. OA affects 13.9% of adults aged 25 and older and 33.6% of those aged 65 and over (http://www.cdc.gov/arthritis/basics/osteoarthritis.htm). Among those affected, approximately one quarter of them are severely disabled.[3] Osteoarthritis is the leading cause of mobility disabilities such as difficulty walking or climbing up stairs. OA of the knee is one of five leading causes of disability among non-institutionalized adults.[4]

Knee OA is the most prevalent, followed by hip OA. Both knee and hip OA result in joint pain and stiffness which can ultimately interfere with function and restrict activities of daily living[5]

There is no cure for OA. In addition, there are currently no known therapies that can prevent progression of OA. Treatment of OA typically focuses on minimizing pain and swelling, reducing disability and improving quality of life.

Treatment typically starts with non-pharmacologic therapy approaches including exercise programs, weight loss, patient education and shoe insoles.[6] Non-pharmacologic approaches are typically tried before medications are started.

Pharmacologic treatment is typically the next step and focuses on relief of pain. Pharmacologic therapy typically includes acetominophen, nonsteroidal anti-inflammatory drugs (NSAIDs), cyclooxygenase (COX-2) inhibitors and opiates. Each of these medications can be beneficial in some patients and each is associated with characteristic side effects. Given that the patient population is typically an older one, often with other comorbid conditions, the side effects associated with long term use of some of the OA medications can be particularly problematic.

Intra-articular glucocorticoid injections are another potential component of OA treatment. These can be useful for patients who still have one or a few painful joints despite NSAID use and in patients with one or a few involved joints in whom NSAIDs are contraindicated. In a meta-analysis, glucocorticoid injections have been shown to lead to short term improvements in knee pain and function.[7]

The idea of viscosupplementation was first proposed by Balazs in 1993.[8] HA is a naturally occurring macromolecule that is an essential part of synovial fluid and is thought to contribute to its viscoelastic properties. The theory is that injection of the HA into joints with OA could restore some of the properties of the synovial fluid, and could promote endogenous synthesis of a more functional (and higher molecular weight) HA, therefore increasing mobility, decreasing pain and restoring function.

The effects of HA infections have primarily been evaluated in the knee and HA injections are only FDA approved for use in the knee. Multiple trials focusing on the knee have compared intra-articular HA to either placebo, NSAIDS or intra-articular glucocorticoids. A meta-analysis included results from 22 trials comparing intra-articular hyaluron with intra-articular placebo and found that intra-articular HA was better than placebo, but the effect was generally small.[9] A subsequent meta- analysis assessed HA and placebo groups at different time periods and found a small improvement in rest pain at 2 and 6 weeks, although the clinical significance of the difference was questioned.[10]

Studies comparing intra-articular HA to NSAIDS have led to conflicting results and have not clearly shown intra-articular HA to be superior.[11,12] Intra-articular HA has also been compared to intra-articular glucocorticoids. It seems that the benefits from each injection are somewhat similar; there were greater benefits of HA at some time points, although these benefits did not appear to be sustained long term.[13–15]

A recent Cochrane review that included a meta-analysis of 40 placebo controlled trials with five different HA products found statistically significant improvements in pain and weight bearing when results were pooled.[16] Overall, the conclusion of the Cochrane review was that viscosupplementation for knee osteoarthritis was an effective treatment for osteoarthritis of the knee with demonstrated beneficial effects on pain, function and patient global assessment. Maximum benefits appear to be achieved between five and 13 weeks, and that the effects seemed to be more prolonged that the effects of corticosteroids.

Intra-articular HA is relatively well established as a treatment option for knee OA in some patients and is recommended as a treatment option by many organizations, including the American College of Rheumatology and the Osteoarthritis Research Society International.[17,18] The American College of Rheumatology recommends intra-articular HA as a treatment option for patients with knee OA who are at increased risk for GI tract adverse events as an alternative for oral agents.[17] The Osteoarthritis Research Society International (OARSI) developed a set of evidence based, expert consensus guidelines and graded the strength of evidence for each. They recommend the consideration of intra-articular HA stating that it may be useful, and state that onset of action may be delayed but there is a prolonged duration of symptomatic benefit.[18]

Although the efficacy of intra-articular HA for pain relief and functional improvement in knee osteoarthritis has been shown, important questions about the use of intra-articular HA remain. What is the efficacy of repeated injections of HA into an affected joint? Can viscosupplementaiton reduce the need for joint replacement and or slow the progression of OA? Although intra-articular HA is being evaluated for use in many other joints, including hip, shoulder and ankle, it is not currently FDA approved for use in joints other than the knee, and thus its use in other joints will not be addressed here.

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