Supplementation of glycosaminoglycans and their precursors in osteoarthritis versus diet modification

Abstract

Dear Editor, Chondroitin sulfate (CS) is a glycosaminoglycan (GAG) and glucosamine (Ga) is an aminosaccharide acting as a substrate for biosynthesis of GAG. CS undergoes hydrolysis in the intestine; being administered orally, it can also be regarded as a source of precursors for GAG. Hyaluronic acid (HA) is a GAG used for intra-articular injections. These substances are applied for treatment of osteoarthritis and are sometimes named chondroprotectives. Evidence in favor of their effectiveness is conflicting; recent studies tend to be less affirmative than earlier ones. Despite popularity of the chondroprotectives, there is some skepticism in the scientific community.1 For example, a meta-analysis concluded that “chondroitin, glucosamine, and their combination do not have a clinically relevant effect on perceived joint pain or on joint space narrowing.”2 Another key remark has been made in: “Given that there is an effect, understanding the biochemical basis of this effect might lead to more useful supplements.”3 The point is that the biochemical basis is not understood. GAG and their precursors are not irreplaceable; they are synthesized in the body and are present in connective tissue. It appears doubtful that oral supplementation of precursors can shift an equilibrium between synthesis and degradation in the whole body to such an extent that it would be significant for articular cartilage. Furthermore, source materials such as shellfish chitin and fungi for Ga or cartilage from mammals, birds or fish for CS,4 manufacturing methods, contaminants and so on, can influence biological and pharmacological properties of CS and Ga preparations,5 as compared to natural GAG that are present in food. With regard to the intra-articular injections of HA, a meta-analysis concluded that “currently available evidence suggests that intra-articular GA is not clinically effective.”6 The evidence is conflicting; while the action mechanisms of intra-articular HA are hardly understood, apart from a temporary viscosupplementation with “lubrication at the joint surfaces.”7 Viscosity change in consequence of the HA injections can be measured (e.g. using cadaverous synovial fluid) or approximately calculated, knowing viscosity of synovial fluid, of injected solution, and corresponding volumes. Both pre- and post-treatment viscosity values were reported to be within the range of normal values.8 The lubrication effect (if any) cannot last long; no explanation has been found for the discrepancy between the relatively short intra-articular half-life of injected HA and duration of the clinical carry-over effect. The half-life of Hyalgan (sodium hyaluronate) was reported to be 17 h; the low molecular weight component of Synvisc (hylan G-F 20) forming 90% of the preparation has a half-life of 1.5 days, and the larger component, 8.8 days.8 However, carry-over effects, after the treatment has been discontinued, can be from about 3 months with the oral chondroprotectives, to 6–9 months with intra-articular formulations.9 Furthermore, HA is a polymer; according to the law of mass action, its local enrichment would shift the chemical equilibrium toward low-molecular precursors, thus indirectly contributing to reduction of viscosity. Clinical relevance of molecular mechanisms studied in vitro8 is questionable because of higher concentrations of tested substances in vitro than in vivo.4 Note that CS, Ga and HA were primarily chosen for supplementation therapy, and probability of their specific action on a molecular level may be no different from a substances taken at random. In the Russian Federation, CS, Ga and HA are named “chondroprotectors”. The treatment with these substances is not covered by medical insurance. These drugs are prescribed to osteoarthritis patients, including pensioners and people with low incomes. Many patients purchase the drugs for prolonged use.10 The question is, therefore, whether it would be more or less equivalent to recommend them a diet rich in natural GAG: beef and pork joints, tails, chicken wings and legs – or addition of minced cartilage to other food. This idea is not new; it has been discussed at conferences. To support the placebo effect, patients could be advised that such a diet will saturate their organs with precursors of articular cartilage in a similar way to drugs or dietary supplements, although an effect is not guaranteed. Considering the above, usefulness of further research on this theme appears questionable; however, if a randomized controlled trial on CS and Ga is to be planned, a cohort of patients on a diet rich in natural GAG should be included for comparison. Effectiveness of dietary supplementation of natural GAG versus CS and Ga preparations can be tried for osteoarthritis in animals, particularly dogs,11 administering them food rich in cartilage. It might be useful also to check osteoarthritis prevalence in vegetarians, receiving no exogenous supply of GAG or their direct precursors, compared to corresponding age groups in the general population.