Mark E. Adams

The role of viscosupplementation with hylan G-F 20 (Synvisc®) in the treatment of osteoarthritis of the knee: a Canadian multicenter trial comparing hylan G-F 20 alone, hylan G-F 20 with non-steroidal anti-inflammatory drugs (NSAIDs) and NSAIDs alone*

To determine the safety and efficacy of viscosupplementation with hylan G-F 20, a cross-linked hyaluronan preparation, used either alone or in combination with continuous non-steroidal anti-inflammatory drug (NSAID) therapy, a randomized, controlled, multicenter clinical trial, assessed by a blinded assessor, was conducted in 102 patients with osteoarthritis (OA) of the knee. All patients were on continuous NSAID therapy for at least 30 days prior to entering the study. Patients were randomized into three parallel groups: (1) NSAID continuation plus three control arthrocenteses at weekly intervals; (2) NSAID discontinuation but with three weekly intra-articular injections of hylan G-F 20; and (3) NSAID continuation plus three injections, one every week, intra-articular injections of hylan G-F 20. Outcome measures of pain and joint function were evaluated by both the patients and an evaluator at baseline and weeks 1, 2, 3, 7 and 12, with a follow-up telephone evaluation at 26 weeks. At 12 weeks all groups showed statistically significant improvements from baseline, but did not differ from each other. A statistical test for the equivalence, the q-statistic, demonstrated that viscosupplementation with hylan G-F 20 was at least as good or better than continuous NSAID therapy for all outcome measurements except activity restriction. At 26 weeks both groups receiving hylan G-F 20 were significantly better than the group receiving NSAIDs alone. A transient local reaction was observed in three patients after hylan G-F 20 injection; only one patient withdrew from the study as a result and all recovered without any sequela. Hylan G-F 20 is a safe and effective treatment for OA of the knee and can be used either as a replacement for or an adjunct to NSAID therapy.

A Risk-Benefit Assessment of Injections of Hyaluronan and its Derivatives in the Treatment of Osteoarthritis of the Knee

AbstractHyaluronan is critical for the homeostasis of the joint as an organ, in part, because it provides the rheological properties (viscosity and elasticity) of the synovial fluid. These properties depend upon both the concentration and the molecular weight of the hyaluronan in the synovial fluid. In osteoarthritis, the hyaluronan is both smaller in size and lower in concentration. Thus, it is rational and physiologically meaningful to treat osteoarthritis with viscosupplementation, i.e. injection of material designed to increase the rheological properties of the synovial fluid.It is important, though, to assess the risks and benefits of such a physiological treatment. There are various products on the market for viscosupplementation. These include hyaluronan preparations of relatively low molecular weight (Hyalgan® and ARTZ®), a hyaluronan preparation of intermediate molecular weight, but still lower molecular weight than that of the hyaluronan in normal healthy synovial fluid (Orthovisc®), and a cross-linked hyaluronan (a hylan) of high molecular weight (Synvisc®). The evidence from in vitro and in vivo models of osteoarthritis and from clinical trials to date suggests that efficacy, as would be expected by mechanistic reasoning, depends strongly upon molecular weight.The available evidence indicates that these products differ little in the incidence and severity of adverse events (about 2 to 4%, almost always local swelling, and with no adverse sequelae). All are very well tolerated in comparison to nonsteroidal anti-inflammatory drug therapy, although direct comparisons are few. The only potentially serious adverse event is joint infection, which is rare and directly dependent upon the number of injections, among other factors. No infection has been related to contamination of any of the products. In summary, treatment with low molecular weight preparations of hyaluronan seems to be effective. However, viscosupplementation with hyaluronan preparations may have slightly higher risk and less benefit than viscosupplementation with hylans, because the relatively lower molecular weight hyaluronan preparations require more injections which may incur higher costs and theoretically an increased chance of infection. Viscosupplementation with hylans is clearly effective, and the available evidence suggests that the benefits almost certainly outweigh the risks.

The early molecular natural history of experimental osteoarthritis: I. Progressive discoordinate expression of aggrecan and type II procollagen messenger RNA in the articular cartilage of adult animals

OBJECTIVE To quantify changes in the chondrocyte metabolism of aggrecan core protein and type II procollagen messenger RNA (mRNA) during the early and middle phases of experimental osteoarthritis (OA) in animals. METHODS Experimental OA was induced by transecting the cranial cruciate ligament of the stifle joint in adult animals; articular cartilage was harvested and analyzed after 4, 10, and 32 weeks. RESULTS Northern blot analysis revealed no change in aggrecan mRNA 4 weeks after surgery compared with aggrecan mRNA in the unoperated contralateral control joints; aggrecan mRNA levels became significantly elevated by 10 and 32 weeks after surgery. In OA cartilage, type II procollagen mRNA was dramatically and progressively elevated at all times after surgery. The relative increases in type II procollagen mRNA exceeded the relative increases in aggrecan mRNA at all times after surgery, and these differences increased progressively over time. Articular chondrocytes became activated globally (total RNA increases) and specifically (mRNA increase) early after joint injury and remained activated throughout the early and middle phases of this experimental OA. CONCLUSION The early natural history of experimental OA is characterized by a progressive imbalance in the mRNA expression of aggrecan and type II procollagen in articular chondrocytes. These results suggest that the stimuli for the transcription of these 2 genes are fundamentally different in this animal model.

Hindlimb loading, morphology and biochemistry of articular cartilage in the ACL-deficient cat knee

The cat hindlimb is the best studied animal model of neuromuscular control, muscle mechanics/muscle morphology, and locomotor kinematics. Therefore, this model offers itself for intervention studies, where a musculoskeletal parameter is perturbed and the effects of this perturbation are compared with normal function. The objective of this study was to describe the effects of anterior cruciate ligament (ACL) transection in the cat knee and to correlate hindlimb loading with morphological and biochemical changes of articular cartilage. A distinct unloading of the deficient hindlimb was found when compared with the nonoperated hindlimb immediately after ACL transection, and persisted for about 16-18 weeks. Beyond about 18 weeks post-ACL transection, hindlimb loading returned to the symmetric pattern observed before surgery. In accordance with the expectations from the force-platform results, a decrease in muscle mass was found from muscles of the experimental hindlimb when compared to the mass of muscles from the contralateral hindlimb. This decrease of muscle mass was largest at 4 weeks and smallest at 35 weeks post-ACL transection. At 12 and 35 weeks post-ACL transection, cell density was increased and absolute amounts of hexuronic acid were elevated in the articular cartilage of the experimental knee compared with the corresponding values of the contralateral knee. Progressive changes of the articular cartilage towards osteoarthritis (OA) were not observed in the time frame of this experiment. The results suggest that anterior cruciate ligament transection in the cat produces initial changes in the knee that are similar to those observed previously in the dog and rabbit.

Extraction and isolation of mRNA from adult articular cartilage

We have developed a method to isolate RNA in high yield from adult articular cartilage. Homogenization of the articular cartilage with a freezer mill, extraction with 4 M guanidinium isothiocyanate/acid-phenol, and ultracentrifugation in cesium trifluoroacetate was found to be an effective and practical method for isolating a high yield of intact RNA from adult canine articular cartilage. The total RNA was suitable for Northern blot analysis. The mRNA that could then be isolated by oligo-dT affinity chromatography was found to be a suitable substrate for in vitro translation, for making a cDNA library, and for PCR amplification.

Quantitative imaging of osteoarthritis

Plain-film radiography currently remains the mainstay of imaging for diagnosis and follow-up in osteoarthritis (OA). However, recent studies have questioned some aspects of its use, particularly the correlation between radiographically evident joint-space narrowing and articular cartilage loss. The results with imaging modalities such as magnetic resonance imaging and ultrasound suggest that these methods will allow accurate noninvasive definition of the structure of articular cartilage and other soft tissues of joints. Other modalities, including microfocal radiography and high-resolution computed tomography, can produce detailed images of trabecular structure and bony alterations in osteoarthritis. Improvements in image analysis and data manipulation, including three-dimensional reconstruction and digitized storage and measurement of images, will likely enable improved quantitative assessment of the abnormalities demonstrated by these techniques. One can hope that such developments will facilitate not only improved detection and definition of OA, but also better evaluation of the effectiveness of pharmacological and physical therapy in practice and in clinical trials.

Expression of biglycan, decorin and fibromodulin in the hypertrophic phase of experimental osteoarthritis.

This study sought to assess the relative levels of the mRNAs of the core proteins of the small proteoglycans (PGs) biglycan, decorin and fibromodulin in the hypertrophic phase of the early osteoarthritis (OA) that follows joint injury. Experimental OA was induced in eight dogs by transection of the anterior cruciate ligament. Articular cartilage was harvested from each joint, the total RNA was extracted and the concentration of DNA in the cartilage was measured. The relative levels of mRNA for biglycan, decorin and fibromodulin were assessed by northern blot analyses. An increase in cartilage mass with no increase in DNA concentration confirmed that the joints were in the hypertrophic phase that follows joint injury. The total RNA per microgram of DNA was increased 2.5 times. Compared with control cartilage, the mRNA levels in osteoarthritic cartilage, when normalized to the concentration of DNA, were increased 3.9 times for biglycan, 1.2 times for decorin and 2.4 times for fibromodulin. Because these small PGs affect collagen fibrillogenesis in vitro, their discoordinate metabolism may contribute to the abnormal collagen formation and deposition that occurs in OA and to the ultimate failure of the articular cartilage.

Changes in aggrecan populations in experimental osteoarthritis.

Adult articular cartilage contains at least two distinct populations of aggrecan: one is larger and richer in chondroitin sulfate (CS), while the other is smaller with less CS. The smaller form is thought to be derived from the larger. The amount of CS in cartilage decreases with maturation and aging, mainly because of a decrease in the proportion of the larger of these two proteoglycans. In early osteoarthritis (OA) the amount and concentration of CS in cartilage increases. To test the hypothesis that an increase in the more CS-rich form of aggrecan contributes to the increase in CS in cartilage in OA, experimental OA was induced in dogs by transection of the anterior cruciate ligament, with sacrifice at various times between 2 days and 64 weeks after the operation. Proteoglycans were extracted from the articular cartilage of eight areas of the joint, fractionated, and CS was quantified by measuring hexuronate. Aggrecan populations were assessed by composite agarose-polyacrylamide gel electrophoresis. The proportion of the more CS-rich form of aggrecan increased with time after operation in all areas of the joint. This increase correlated with increases in tissue mass and hexuronate, showing that the increase in the larger, CS-rich form of aggrecan contributes to the increase in CS in the tissue. It seems paradoxical that this form of aggrecan accumulates in the tissue despite the fact that increased protease activity has been demonstrated in experimental OA.

Glucosamine in osteoarthritis

Regulation of Dietary Supplements The Dietary Supplement Health and Education Act passed by the United States Congress in 1994 permits the marketing of a product claimed to affect the structure or function of the body as a “dietary supplement” without the approval of any government agency, as long as the labeling includes a disclaimer saying that it has not been evaluated by the FDA and the product is not intended to diagnose, treat or prevent any disease. If a question about safety arises, the burden of proof is on the FDA, not the manufacturer.