Hyaluronic Acid Injections: Viscosupplementation

RONALD A. NAVARRO AND JULIAN PAUL BALLESTEROS

With the rise in participation in both organized and recreational sports in the United States, the number of athletes with sports-related medical complaints has grown.¹ Acute injuries to joints and subacute or chronic joint pain are prevalent among athletes of all levels and are common reasons for visits to the general orthopaedist. Presently, a narrow spectrum of satisfactory nonoperative treatment regimens is available for such patients. The introduction of viscosupplementation via intraarticular injection of hyaluronic acids (HAs) offers an intriguing potential solution for many chondral pathologies in athletes.

Basic Science of Viscosupplementation

Numerous published reports have advocated the use of HA viscosupplementation in patients with symptomatic osteoarthritis, especially of the knee.^2–10 Understanding the mechanism of action of HAs is necessary to extrapolate the benefits of their use to patient-athletes. HAs are included in a class of molecules known as glycosaminoglycans (GAGs), and are composed of repeating polysaccharide units of glucuronic acid and N-acetylglu-cosamine. They are found in all human tissues, with the highest concentration in connective tissues and body fluids, especially synovial fluid.¹¹ In the extracellular matrix of articular cartilage, HAs provide intricate mechanical stability for both the chondrocytes that reside there and the type II collagen molecules that the cells manufacture.¹² The occurrence of HAs in synovial fluid is also pivotal in the maintenance of articular cartilage. Because of the large molecular weight [up to 10 × 10⁶ dalton (d)] of HAs, synovial fluid acts as a non-Newtonian solution. Therefore, it serves as a lubricant during normal movements of the joint (high viscosity/low elasticity) and as a shock absorber when more severe loading forces are withstood (low viscosity/high elasticity³). Much of the role HAs play in both articular cartilage and synovial fluid is understood because of research regarding osteoarthritis, a state in which it is known that HA concentration and molecular weight is significantly decreased.^13,14 These findings have also been noted in athletes and attributed to the cyclic loading impact sustained during athletic participation that can initiate or propagate such changes.^15,16 The lack of abundant, physiologically sound hyaluronan molecules deters the usual joint lubrication and protection, which leads to breakdown of cartilage matrix constitution, inflammatory changes, and the pain described by patients with degenerative joint disease.

Types of Commercially Available Hyaluronic Acids

There are currently three preparations of hyaluronan that are approved in the United States for intraarticular therapy in patients with arthritis pain of the knee. Sodium hyaluronate (Hyalgan®, Sanofi-Synthelabo, New York, NY) and hylan G-F 20 (Synvisc®, Wyeth Pharmaceuticals, Madison, NJ) were approved by the Food and Drug Administration in 1997; sodium hyaluronate (Supartz®, Smith and Nephew, Memphis, TN) was approved in 2001.17–19 All three are extracted from rooster combs but purified differently by each manufacturer. Other HA therapies are available overseas or are still in development. The main differences in the forms available in the United States are based on preparation, molecular weight, dose, and frequency of administration as intraarticular injections for patients with osteoarthritis of the knee. Synvisc is a much larger molecule than the other two, averaging more than 6000 kd (compared with average molecular weights of 500–730 kd and 620–1170 kd for Hyalgan and Supartz, respectively) by virtue of the cross-linking of hyaluronan molecules.

The importance of molecular weight differences is debatable. It was initially thought that viscosupplementation should consist of hyaluronan molecules of higher molecular weight than those naturally occurring to restore synovial fluid viscosity by resisting breakdown and catabolism. On the other hand, smaller HA molecules should theoretically have the ability to more effectively penetrate articular cartilage to restore the matrix and chondrocyte support lost in arthritic tissue. In fact, there are data to support some therapeutic benefit of small, moderate, and large preparations of HAs.^5,6,20–23 Furthermore, despite evidence demonstrating that actual intraarticular duration of exogenous HAs is between one and a few days, clinical pain relief has been shown to persist for months, suggesting an in vivo biologic modification of joint architecture.^2,7,24–26 A more viscous and elastic HA is seen in the synovial fluid.¹⁴ HAs have been seen to promote endogenous HA synthesis and inhibit induction of degradative enzymes.²¹ Additional benefits of antiinflammatory activity by inhibition of induction of proinflammatory signals²⁷ as well as a direct analgesic effect via nociceptors have also been documented.²⁸ Most of the commercial preparations call for between three and five injections, given once per week over 3 to 5 weeks.²⁹

Adverse Effects of Hyaluronic Acids

To date, the most common adverse effect of intraarticular viscosupplementation with HA has been acute local inflammatory reactions, which is reflected in the prescribing information of all three commercially available preparations.^17–19 It is difficult to determine the rate with which these reactions occur or the magnitude of their severity due to the different incidences published in the literature; however, in general HA injections have been well tolerated.^9,30 Characterized by pain, effusions, and warmth with difficulty ambulating, most of these episodes were mild and lasted no more than a few days.³¹ Although under investigation, the mechanism of these reactions remains unclear. Serum antibodies to chicken serum proteins were found in one patient, suggesting the reactions could be due to allergic response to HA injection components.³¹ Another possibility for such reactions may be extraarticular soft tissue injections, as was demonstrated by a study determining that intraarticular needle placement accuracy may be as low as 71% depending on the experience of the administrator and which approach is used.³²

Additionally, no known contraindications due to drug interactions have been reported thus far, and HAs have not been associated with abnormalities in liver or renal laboratory values.³² Continued monitoring for and reporting of adverse effects of HA use is warranted.

Hyaluronic Acid and Osteoarthritis

Forster and Straw³³ recently studied 38 patients with symptomatic knee arthritis without mechanical symptoms and randomized them to HA injections versus arthroscopic washout. Pre- and postintervention assessments with a visual analog scale (VAS) for pain, Knee Society function score, and the Lequesne Index revealed no difference between the groups at all data collection points up to 1 year. The authors concluded that HA therapy can be considered an alternative to arthroscopy in this patient group, but results can be strengthened with longer follow-up.

Jubb et al³⁴ compared HA therapy with saline placebo and investigated the structural changes, as measured by joint space narrowing (JSN) within the medial knee. Patients received either three weekly injections of commercially available HA or a placebo vehicle of saline. The course was repeated twice more at four monthly intervals and concomitant treatment with analgesics or NSAIDs was allowed. At 52 weeks 319 out of 408 total had completed the study (HA: n = 160, saline: n = 159). Only 273 were included in the primary analysis and there was no statistically significant difference between the groups. When assessing for baseline JSN, a difference was measured. In those with radiologically milder disease at baseline and receiving HA, the JSN was significantly reduced compared with placebo (p = .02). This assessment is supported by the belief that HA can work better if there is cartilaginous substrate it can work with. Patients with milder disease have less wear of native articular cartilage and therefore have a cartilaginous substrate where the exogenous HA can have an effect.

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