CME

Hyaluronic acid injections for knee osteoarthritis

Systematic review of the literature

Anita Aggarwal, MD, CCFP   Ian P. Sempowski, MD, CCFP(EM)

This article has been peer reviewed. Cet article a fait l’objet d’une évaluation externe. Can Fam Physician 2004;50:249-256.

Dr Aggarwal was a second-year family medicine resident at the time of writing, and Dr Sempowski is an Assistant Professor, in the Department of Family Medicine at Queen’s University in Kingston, Ont.

Osteoarthritis (OA), the most common form of arthritis, affects more than 10% of the population,1 is slowly progressive, and results in severe disability in the long term. Standard nonpharmacologic treatments include patient education, self-management programs, weight loss, physical and occupational therapy, exercises, and devices that assist function.2,3 Pharmacologic therapies are outlined in Table 1.2,4 Surgical therapy includes arthroscopy and joint replacement.1,2

Hyaluronic acid (HA) was first used in ophthalmology for cataract surgery in the 1970s.5,6 Intra-articular use of HA has been approved in Japan and Italy since 1987, in Canada since 1992, in most of Europe since 1995, and in the United States since 1997.6,7 A meta-analysis of eight early randomized controlled trials (RCTs) showed that patients treated with HA were doing better than untreated patients at the end of the treatment cycle and at the end of 6 months.8

Despite this, viscosupplementation for treatment of OA remains controversial and perhaps underused. The primary objective of this systematic review was to determine whether HA injections improve pain and function in patients with OA in their knees. A secondary objective was to compare HA with other therapies, such as intra-articular steroids.

Osteoarthritic joints contain synovial fluid that has become less viscous and less concentrated, and has a lower molecular weight. This means that it offers less shock absorption, lubrication, and protection of joints.8 Synovial fluid contains HA, a polysaccharide containing glucosamine and glucuronic acid.9 The mechanism of action of HA injections is unclear, but it seems to inhibit inflammatory mediators, decrease cartilage degradation, and promote cartilage matrix synthesis.2,7 It also insulates synovial pain fibres, thus decreasing perception of pain.9 Effects of HA have been found to last longer than the actual compound does, suggesting that intra-articular HA stimulates synthesis of natural HA.10

Preparations of HA can be divided into low and high-molecular-weight (Table 12,4). Contra­indications to intra-articular HA include joint or skin infection, overlying skin disease, and allergy to chicken or eggs if using a preparation derived from rooster comb.8,9

Data sources

Articles were obtained from MEDLINE, Pre-MEDLINE, and Cochrane databases from 1966 to the end of October 2002 using the MeSH terms hyaluronic acid and osteoarthritis, knee. Key words included variations of hyaluronic acid. The search was limited by clinical trials (42 trials), English language, and human studies. Additional articles were obtained by reviewing the references of selected articles. Finally, we excluded trials published before 1995 in an attempt to examine the most up-to-date methodology and outcome measures. We were left with 31 articles for critical appraisal.

Study selection

We chose primary research trials with clinical outcome measures related to treatment with HA. Studies were excluded if primary outcome measures were histologic, biologic, or arthroscopic. We were left with 18 primary research articles: 13 RCTs and five case series. Validity and applicability of the studies were assessed using published criteria for reviewing articles on therapy.10,11

Synthesis

Case series. The five case series12-16 had no control groups: two were retrospective; three were prospective (Table 212-16). They lasted from 6 months to 2.5 years. The population profile for OA was middle-aged people, more women than men.1

Three trials used three injections of high-molecular-weight HA (Synvisc®). Lussier et al13 showed that 76% of patients improved with respect to pain and activity level. Evanich et al12 showed that Synvisc decreased pain by two thirds in two thirds of treated knees, but pain relief decreased with severity of OA, and there was no significant difference in effect based on age. In addition to pain relief, Goorman et al16 found that physical and social function also improved.

The two case series using five injections of 20 mg of low-molecular-weight HA (Hyalgan®), with a possible second course, showed symptom relief from week 4 to up to 1 year.14,15 These were open-label trials and need to be interpreted with caution.

With the exception of the study by Frizziero et al,14 none of the case series used a blind observer, which could bias results. Lack of placebo control makes data interpretation difficult. Patients might also have had difficulty recalling their initial symptoms in retrospective trials. Intention-to-treat analysis was unclear in all five case series, and co­interventions were poorly documented.

Randomized controlled trials. Most of the 13 RCTs summarized in Table 35,6,17-27 lasted from 6 to 52 weeks. Nine were parallel double-blind studies; four were not.6,23,26,27 Physicians giving injections were blinded to outcome in only two studies,6,24 but blinding was difficult because HA and saline appear different due to their viscosity. All RCTs used separate assessors, except one,27 which was an effectiveness rather than an efficacy trial. Patients were not blinded to outcome in this study, nor in the two open trials.23,26 Two RCTs might have been biased because they were funded by the Hyalgan and Orthovisc groups.5,20 Heterogeneity of study design, population studied, length of follow up, and diverse outcomes made the data unsuitable for meta-analysis.

Three of the 13 RCTs involved three injections of Synvisc. The study by Wobig et al6 was triple-blinded, used intention-to-treat analysis, and excluded patients with knee effusions. Synvisc was found to be superior to placebo: pain and use of rescue medication were both reduced at weeks 12 and 26. This was one of the studies with the best methodology except that it did not account for previous intra-articular injections. Synvisc was also used in an effectiveness trial comparing appropriate care with appropriate care plus Synvisc.27 Patients taking Synvisc had significantly less pain at 1 year and lower costs per patient for other therapy or assisting devices. The third trial had three parallel treatment arms; two included use of nonsteroidal anti-inflammatory drugs (NSAIDs).16 Unfortunately, no oral placebo was used. At week 12, all three groups had improved. Those taking HA had significantly less pain at rest than those taking NSAIDs alone (the effect continued at week 26). Combination therapy was more effective than NSAIDs alone.

The remaining RCTs all studied various low-molecular-weight preparations of HA. Other medications, such as acetaminophen, were allowed; two studies allowed anti-inflammatory drugs as well.21,23 Most trials involved middle-aged people with OA defined radiographically as mild to moderate. Patients with knee effusions were often excluded; effusion was sometimes aspirated before intra-articular injections. Usually, patients were excluded if they had had intra-articular injections in the previous 3 to 12 months.

Most studies used visual analogue scales for pain as a primary measure. Four studies included function as a primary outcome.21,23,25,26 Lohmander et al18 found no difference between HA and placebo except in poststudy subgroup analysis of patients older than 60 with severe OA. Two studies found no significant differences in pain reduction in intention-to-treat analysis.5,26 Miltner et al26 showed that HA improved functional score, total work, peak torque, and pain compared with baseline with no change in the control knee from baseline. The study by Petrella et al indicated that HA was more effective than NSAIDs in reducing pain and improving function, and that this effect improved with time.25 The remaining studies showed HA to be superior to placebo in decreasing pain and stiffness for up to 6 months.

Studies involving comparisons with NSAIDs are difficult to interpret. Compared with naproxen, Hyalgan injections produced similar results with fewer gastrointestinal side effects.20 Synvisc and NSAIDs appeared similar at month 3; in combination they were better than NSAIDs alone.17 For pain with activity and function, HA was better than NSAIDs alone.25

Side effects

Side effects tended to be minor; injection site pain and swelling was the most common. In two studies, the overall local adverse reaction rate with HA was 2% or 2.7% per injection.13,27 Kotz and Kolarz15 noted 119 adverse effects in 108 patients, the most common being back pain (16.8%), injection site reaction (11.8%), and injection site pain (6.7%). Evanich et al12 found 15% of knees (11 patients) treated with HA had adverse reactions an average of 1.2 weeks after first injection. Two studies found injection site pain and swelling to be equal for HA and placebo.5,21 Another trial, however, found significantly more injection site pain with HA (23%) than with placebo (13%).20

Gastrointestinal side effects were less common with HA (29%) than with naproxen (41%) or placebo (36%).20 Systemic reactions were rare. One case of septic arthritis12; one case of cutaneous vasculitis within 1 week of injection; one case of skin peeling at week 6; and three cases of itching, cramps, or hemorrhoids were reported.8,21

Discussion

Results of studies of viscosupplementation with HA injections are difficult to interpret due to small patient numbers, lack of controls, cointerventions, placebo response after knee aspiration, and lack of blinding of injectors. Studies also used HA preparations that varied in molecular weight and had different schedules. High-molecular-weight HA might stimulate synovial cells to make endogenous HA to a greater extent than low-molecular-weight preparations. More head-to-head studies are needed.

Three case series and three RCTs of high-molecular-weight HA all showed positive effects on pain and function. Treatment with HA was superior to placebo for pain relief and need for rescue medication at weeks 12 and 26. In the effectiveness trial, HA lessened pain and reduced costs for other therapy and devices at 1 year.

The two case series using low-molecular-weight HA improved pain scores; improvement lasted from 4 weeks to 1 year. Several studies showed improvement in function, pain, stiffness, and range of motion that lasted from the first injection up to 6 months. Four studies,5,8,22,23 however, showed no significant improvement in pain or proprioception in intention-to-treat analysis.

Indications for HA include pain despite other therapy, intolerance of NSAIDs, mild-to-moderate OA, no or mild effusion, no mechanical symptoms, and severe inoperable OA. Cost is an issue with treatment. Cost in Ontario without pharmacy filling fee as of May 2003 was $125 for each syringe of Synvisc or Hyalgan.

Hyaluronic acid or steroids?

Suggested alternatives to HA include intra-articular steroids, which can decrease acute pain and joint effusion, but are limited to three or four injections per year.4 Several RCTs have shown good response at 1 and 4 weeks, but no effect thereafter.28-30 In a head-to-head RCT, Jones et al31 found that patients in the HA group experienced less pain than those receiving intra-articular steroids at 6-month follow up; however, there was a high drop-out rate, and intention-to-treat analysis showed no statistical differences.

Intra-articular steroids and HA might be good combination therapy. Grecomoro et al32 found that adding dexamethasone to the first of five Hyalgan injections decreased pain further after 2 months. The effect of steroids occurred earlier (at 4 to 6 weeks); the effect of HA was delayed but longer lived. Comparing HA injections with corticosteroids suggests that the former lasts longer but the latter works faster. Also, steroids might be more effective for joint effusion or other acute inflammation.

Further research is needed to determine whether viscosupplementation with HA alters the natural history of OA in human beings. We do not yet know what concomitant therapies should be offered to patients treated with HA and whether other joints, such as shoulders or hips, could benefit. Combination therapy requires further study.

Conclusion

Viscosupplementation with HA is a reasonable treatment for patients with mild-to-moderate OA of the knee who have ongoing pain or are unable to tolerate conservative treatment or joint replacement. The effect lasts longer with high-molecular-weight preparations, and patients can experience improvement in clinical outcomes for up to 1 year. Intra-articular HA appears to have a slower onset of action than intra-articular steroids but the effects seem to last longer. Patients should be warned of cost and of potential side effects, including local swelling.

Competing interests

None declared

Correspondence to: Dr Ian P. Sempowski, Family Medicine Centre, 220 Bagot St, PO Bag 8888, Kingston, ON K7L 5E9; telephone (613) 549-4480; fax (613) 544-9899; e-mail sempowsk@post.queensu.ca

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