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Viscosupplementation: Background and Use in OA

Special Report

What is Hyaluronan (HA)?

Hyaluronan, also known as sodium hyaluronate and hyaluronic acid, is a naturally occurring polysaccharide present in the fluid inside normal joints[1]. Slightly different synthetic formulations. (e.g. Synvisc, Hyalgan and Artzal) have been marketed as treatments for mild to moderate knee osteoarthritis Treatment consists of a series of weekly injections into the joint, and it may take up to two months to see the full effect of treatment. At this time, HA is approved only for use in the knee, but studies are underway looking at other joints, such as the base of the thumb, and HA has been used experimentally in the hip, shoulder, temporo-mandibular joint in the jaw, and the sacro-iliac joint in the low back.

How does HA work?

In normal knees, high levels of HA in the joint fluid make it thick and viscous, allowing the fluid to act as a lubricant and shock absorber, protecting the knee from damage during everyday stress[2]. However, in joints with OA, the level of HA in the joint fluid is lower, and the fluid becomes thinner and less dense. Injectable HA is a thick, jelly-like substance, and it was initially believed that HA treatment worked simply by replicating the physiologic state of normal knees -- like putting new oil into a rusted ball bearing[3]. However, further human and animal studies show that synthetic injectable HA only briefly remains inside the joint before absorption by the body; after a week, almost none is left in the joint. This makes it unlikely that HA's long-term therapeutic properties relate to its physical ability to diffuse high impact loads.

The actual reason for its ability to improve pain in some patients is unknown, and is probably due to a combination of factors. Synthetic HA may stimulate the body to produce more natural HA[4], or it may act as a scavenger, mopping up destructive inflammatory products produced by the damaged joint[5]. It may also inhibit production of inflammatory molecules which can lead to pain and further joint destruction[6].

What are the main side-effects?

After over 5 million injections, the most serious events reported associated with synthetic HA use are two instances of anaphylactoid reactions, which resolved without further problems[7]. A large series of 1537 HA injections showed that minor local reactions at the injection site or in the knee occurred in 2.7% of patients, with no major complications[8] A recent study of 1489 knees treated with HA confirmed these low rates of adverse events[9]. Swelling of the knee after HA injection has been documented and responds well to corticosteroids[10]. There may be an increased risk of acute local reactions with repeated series of HA injections[11]. Most randomized controlled trials show no difference in side effects between HA and placebo injections[12],[13],[14]. One large controlled trial showed a slight increase in injection site reactions with HA compared to placebo, although only <1% of patients on HA chose to stop treatment due to such reactions[7].

Other investigators have noted an amorphous intracellular material in the joint in patients with acute inflammatory reactions after HA injections, which might represent a foreign-body type reaction. All these reactions resolved with intra-articular steroids and aspiration[15]. One report describes six cases of granulomatous inflammation occurring in patients after HA injection, suggesting that HA may actually cause a more recalcitrant type of inflammation in some people[16]. Given the millions of injections of HA that have occurred worldwide over the past decade, it is doubtful that this is a significant risk of treatment. Although existing studies do not suggest an increased risk of joint infection with the use of HA, any intra-articular injection has the potential to introduce infection into the joint space. However, this is exceedingly uncommon when the injection is performed by an experienced physician under sterile conditions; the estimate of infection due to a corticosteroid injection is 1/ 17,000-1/50,000[17].

Does it matter which formulation is used?

HA comes in a variety of molecular weight preparations: moderate molecular weight native preparations, (e.g. Hyalgan 0.5-0.73 kDa, Artzal 0.5-1.0 kDa, and Orthovisc 1.5 kDa.) and high molecular weight cross-linked preparations (e.g. Synvisc 7 kDa). Although claims have been made that high weight preparations, which better approximate the weight of natural occurring HA, may work better, this does not appear to be the case[18]. The only double blind placebo controlled trial comparing different molecular weight preparations (Artzal and Synvisc) showed no difference in efficacy between the two brands[14].

What are the data in knee osteoarthritis?

The data supporting the use of HA in knee OA are controversial. While many individual studies conclude that HA improves pain and function in some people with mild to moderate knee OA[12],[19], there is some disagreement as to whether it works better than corticosteroid injections, oral medication such as non-steroidal anti-inflammatories, or even placebo injections[7],[14]. For example, one recent retrospective study comparing HA to intra-articular steroids found patients using HA had less pain than those using steroids one year after the injections[20]. However, another prospective randomized trial found that, although both treatments were moderately effective, there was no difference between steroids and HA at 6 months[21].

A number of OA experts do not find the existing data compelling enough to promote the use of HA in knee OA[22]. However, a recent meta-analysis found that Synvisc does work in the treatment of knee OA[23]. In this review, the beneficial effect of this HA appears to be clinically important, being detectable at 1-4 weeks and further developing between 5-13 weeks.

Whether these disagreements of opinion are due to flaws in study design, interpretation of results, or actual effectiveness of HA remains a point of contention. However, given the existing evidence, the enormous negative impact OA can have on a person's quality of life, and the very low risk of side-effects with HA, it remains a reasonable treatment option for some patients who have failed other conservative therapies.

Is HA disease-modifying for OA?

There are animal studies suggesting treating with HA may be beneficial to cartilage. Rabbits who were given experimental OA had less severe cartilage damage at 9 weeks if they were also treated with HA[24]. In rabbits undergoing partial meniscectomy, HA increased meniscal regrowth and slowed further cartilage degradation[25]. However, many positive reports are balanced by others that showed no effect of HA on cartilage[26],[27]. This may be a result of timing: HA given right after trauma to the joint did not appear to be beneficial, whereas giving it later made it more likely that there would be improvements in the cartilage[28],[29].

In humans, some open label trials show that HA can improve or halt the destructive joint changes associated with OA. After receiving HA, some patients had increased thickness of the superficial amorphous cartilage layer six months later[30]. Another trial suggested that treatment of HA decreased the rate of cartilage degradation compared with conventional therapy[31]. While these are provocative data, whether or not HA has long-term structural benefits on joint architecture needs to be confirmed in rigorous prospective randomized controlled trials.

Who might benefit from a trial of HA?

All patients with symptomatic knee OA should initially have appropriate physical therapy and try oral medications such as non-steroidal anti-inflammatories, COX-2 inhibitors, or acetaminophen. Corticosteroid injections may also be useful in some patients. Although existing studies have not conclusively identified a sub-set of patients who might benefit most from HA treatment, it is important to note that most studies exclude patients with severe OA, as most researchers feel HA is not effective in patients with end-stage joint destruction.

In patients with mild to moderate knee OA in whom the above therapies have not worked, or who cannot take them due to other medical problems, options for treatment of knee OA are limited. In these patients, a trial of HA is reasonable. There are no data to suggest that if one brand of HA does not work, it is worth trying another. Cost is also an important factor, as each course of HA costs hundreds of dollars. Although most insurance policies do cover HA, patients should always check with their pharmacy coverage before starting a course of therapy.

[1] Hascall VC, Fulop C, Salustri A, Goodstone N, Calabro A, Hogg M, Tammi R, Tammi M, MacCallum D. Metabolism of hyaluronan. In: Laurent T.C., ed. The Chemistry, Biology and Medical Applications of Hyaluronan and its Derivatives, p. 67-76. London: Portland Press , 1998. Vol. 72.

[2] Uebelhart D, Williams JM. Effects of hyaluronic acid on cartilage degradation. Curr Opin Rheumatol 1999 Sep;11(5):427-35. Review.

[3] Brandt KD, Smith GN, Jr., Simon LS. Intraarticular injection of hyaluronan as treatment for knee osteoarthritis: what is the evidence? Arthritis Rheum 2000; 43(6):1192-203.

[4] Ghosh P, Read R, Numata Y, Smith S, Armstrong S, Wilson D. The effects of intraarticular administration of hyaluronan in a model of early osteoarthritis in sheep. II. Cartilage composition and proteoglycan metabolism. Semin Arthritis Rheum; 1993 Jun;22(6 Suppl 1):31-42.

[5] Laurent UB, Fraser JR, Engstrom-Laurent A, Reed RK, Dahl LB, Laurent TC. Catabolism of hyaluronan in the knee joint of the rabbit. Matrix 1992 Apr; 12:130-6.

[6] Yasui T, Akatsuka M, Tobetto K, Hayaishi M, Ando T. The effect of hyaluronan on interleukin-1 alpha-induced prostaglandin E2 production in human osteoarthritic synovial cells. Agents Actions. 1992 Sep;37(1-2):155-6.

[7] Altman RD, Moskowitz R. Intraarticular sodium hyaluronate (Hyalgan) in the treatment of patients with osteoarthritis of the knee: a randomized clinical trial. Hyalgan Study Group. J Rheumatol 1998; 25:2203-12.

[8] Lussier A, Cividino AA, McFarlane CA, Olszynski WP, Potashner WJ, De Medicis R. Viscosupplementation with hylan for the treatment of osteoarthritis: findings from clinical practice in Canada. J Rheumatol 1996 Sep; 23(9):1579-85.

[9] Waddell DD, Bricker, DC. Hylan G-F 20 in Knee Osteoarthritis Patients: Low Incidence and Clinical Management of Local Adverse Events. Arthritis Rheum 2003 .Arthritis Rheum. 2003 Sep;48(9):S486. Abstract #1224.

[10] Puttick MP, Wade JP, Chalmers A, Connell DG, Rangno KK. Acute local reactions after intraarticular hylan for osteoarthritis of the knee. J Rheumatol. 1995 Jul;22(7):1311-4.

[11] Leopold SS, Warme WJ, Pettis PD, Shott S. Increased frequency of acute local reaction to intra-articular hylan GF-20 (synvisc) in patients receiving more than one course of treatment. J Bone Joint Surg Am. 2002 Sep;84-A(9):1619-23.

[12] Brandt KD, Block JA, Michalski JP, Moreland LW, Caldwell JR, Lavin PT. Efficacy and safety of intraarticular sodium hyaluronate in knee osteoarthritis. ORTHOVISC Study Group. Clin Orthop. 2001 Apr;(385):130-43.

[13] Lohmander LS, Dalen N, Englund G, et al. Intra-articular hyaluronan injections in the treatment of osteoarthritis of the knee: a randomised, double blind, placebo controlled multicentre trial. Hyaluronan Multicentre Trial Group. Ann Rheum Dis. 1996 Jul;55(7):424-31.

[14] Karlsson J, Sjogren LS, Lohmander LS. Comparison of two hyaluronan drugs and placebo in patients with knee osteoarthritis. A controlled, randomized, double-blind, parallel-design multicentre study. Rheumatology (Oxford). 2002 Nov;41(11):1240-8.

[15] Pullman-Mooar S, Mooar P, Sieck M, Clayburne G, Schumacher HR. Are there distinctive inflammatory flares after hylan g-f 20 intraarticular injections? J Rheumatol. 2002 Dec;29(12):2611-4.

[16] Chen AL, Desai P, Adler EM, Di Cesare PE. Granulomatous inflammation after Hylan G-F 20 viscosupplementation of the knee: a report of six cases. J Bone Joint Surg Am. 2002 Jul;84-A(7):1142-7.

[17] Doherty DP. Intra-articular Corticosteroid Injection for OA,. In: JH K, ed. Rheumatology. London.: Mosby:, 1998:p. 8.12.12.

[18] Aviad AD, Houpt JB. The molecular weight of therapeutic hyaluronan (sodium hyaluronate): how significant is it? J Rheumatol. 1994 Feb;21(2):297-301. Review.

[19] Huskisson EC, Donnelly S. Hyaluronic acid in the treatment of osteoarthritis of the knee. Rheumatology (Oxford). 1999 Jul;38(7):602-7.

[20] Raynauld, Jean Pierre, Charlie H. Goldsmith, Wojciech P. Olszynski, George W. Torrance, Nicholas Bellamy, Richard Polisson, Dan Pericak, Valery Walker. Effectiveness and Safety of Hylan G-F 20 Compared to Steroid Injections in Patients with Knee Osteoarthritis, American College of Rheumatology, Orlando, FLA, 2003. Presentation 1218.

[21] Leopold SS, Redd BB, Warme WJ, Wehrle PA, Pettis PD, Shott S. Corticosteroid compared with hyaluronic acid injections for the treatment of osteoarthritis of the knee. A prospective, randomized trial. J Bone Joint Surg Am. 2003 Jul;85-A(7):1197-203.

[22] Felson DT, Anderson JJ. Hyaluronate sodium injections for osteoarthritis: hope, hype, and hard truths. Arch Intern Med. 2002 Feb 11;162(3):245-7.

[23] Bellamy N J, Jane Campbell, Travis Gee, Vivian Robinson, George Wells, Robert B. Bourne. Hylan G-F 20 for Knee Osteoarthritis (OA): A Cochrane Review, American College of Rheumatology, Orlando Florida, 2003. Vol. Presentation 1824.

[24] Yoshioka M, Shimizu C, Harwood FL, Coutts RD, Amiel D. The effects of hyaluronan during the development of osteoarthritis. Osteoarthritis Cartilage. 1997 Jul;5(4):251-60.

[25] Kobayashi K, Amiel M, Harwood FL, et al. The long-term effects of hyaluronan during development of osteoarthritis following partial meniscectomy in a rabbit model. Osteoarthritis Cartilage. 2000 Sep;8(5):359-65.

[26] Sonoda M, Harwood FL, Amiel ME, et al. The effects of hyaluronan on tissue healing after meniscus injury and repair in a rabbit model. Am J Sports Med. 2000 Jan-Feb;28(1):90-7.

[27] Smith GN, Jr., Myers SL, Brandt KD, Mickler EA. Effect of intraarticular hyaluronan injection in experimental canine osteoarthritis. Arthritis Rheum. 1998 Jun;41(6):976-85.

[28] Sonoda M, Harwood FL, Wada Y, Moriya H, Amiel D. The effects of hyaluronan on the meniscus and on the articular cartilage after partial meniscectomy. Am J Sports Med. 1997 Nov-Dec;25(6):755-62.

[29] Shimizu C, Yoshioka M, Coutts RD, et al. Long-term effects of hyaluronan on experimental osteoarthritis in the rabbit knee. Osteoarthritis Cartilage. 1998 Jan;6(1):1-9.

[30] Frizziero L, Govoni E, Bacchini P. Intra-articular hyaluronic acid in the treatment of osteoarthritis of the knee: clinical and morphological study. Clin Exp Rheumatol. 1998 Jul-Aug;16(4):441-9.

[31] Listrat V, Ayral X, Patarnello F, et al. Arthroscopic evaluation of potential structure modifying activity of hyaluronan (Hyalgan) in osteoarthritis of the knee. Osteoarthritis Cartilage. 1997 May;5(3):153-60.


Headshot of Lisa A. Mandl, MD, MPH
Lisa A. Mandl, MD, MPH
Assistant Attending Physician, Hospital for Special Surgery
Assistant Research Professor of Medicine, Weill Cornell Medical College

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