VIEW POINT THE ROLE OF GLUCOSEAMINE SULFATE ON OSTEOARTHRITIS : AN UPDATE

Osteoarthritis, the most common form of arthritis is an age related degenerative disease of joint cartilage. It is a major cause of disability and is among the most frequent form of musculoskeletal disorder. About 40 million American has been reported to be affected by osteoarthritis. Of these 80% individual are over 50 years with twice as frequent in women as in male. At least 20 million adults suffer at any one time. So huge amount of financial loss due to actual cost of therapy as well as loss of productivity in the work place. The traditional approach to manage this problem is to use symptom modifying agents like NSAID along with physiotherapy and life style adjustment. But this fails to modify the underlying degenerative process. Moreover, there are numerous adverse effect associated with NSAID that may limit their use. Some NSAID also inhibit the synthesis of glycoseaminoglycans (GAGs) and impair the body’s ability to heal itself. ManKin et al showed that there is significant decrease in glucoseamine content of osteoarthritic cartilage. As there is continued wear and tear of normal cartilage and age related decline in glucoseamine synthesis in the body supplement of glucoseamine may be helpful to compensate the normal metabolic turnover of the extracellular matrix and to prevent the degradation of cartilage by stimulating the healing process when it is damaged. So the search for alternative pharmacotherapies that might influence the disease process but have fewer adverse effect has lead to trial with glucose amine sulfate alone or in combination with chondroitin. It has been suggested that glucose amine could be beneficial in promoting the regeneration of damaged cartilage from injury. In animal cartilage culture studies, glucoseamine was partially able to reverse the effects of some NSAIDs on inhibiting GAGs and collagen synthesis.1 VIEW POINT


Introduction:
Osteoarthritis, the most common form of arthritis is an age related degenerative disease of joint cartilage.It is a major cause of disability and is among the most frequent form of musculoskeletal disorder.About 40 million American has been reported to be affected by osteoarthritis.Of these 80% individual are over 50 years with twice as frequent in women as in male.At least 20 million adults suffer at any one time.So huge amount of financial loss due to actual cost of therapy as well as loss of productivity in the work place.The traditional approach to manage this problem is to use symptom modifying agents like NSAID along with physiotherapy and life style adjustment.But this fails to modify the underlying degenerative process.Moreover, there are numerous adverse effect associated with NSAID that may limit their use.Some NSAID also inhibit the synthesis of glycoseaminoglycans (GAGs) and impair the body's ability to heal itself.ManKin et al showed that there is significant decrease in glucoseamine content of osteoarthritic cartilage.As there is continued wear and tear of normal cartilage and age related decline in glucoseamine synthesis in the body supplement of glucoseamine may be helpful to compensate the normal metabolic turnover of the extracellular matrix and to prevent the degradation of cartilage by stimulating the healing process when it is damaged.So the search for alternative pharmacotherapies that might influence the disease process but have fewer adverse effect has lead to trial with glucose amine sulfate alone or in combination with chondroitin.It has been suggested that glucose amine could be beneficial in promoting the regeneration of damaged cartilage from injury.In animal cartilage culture studies, glucoseamine was partially able to reverse the effects of some NSAIDs on inhibiting GAGs and collagen synthesis. 1

How does glucose amine work?
Glucose amine is an amino monosaccharide normally synthesized in the body by chondrocytes and used to make glycoseaminoglycans (GAGs) and proteoglycans (PGs), the essential component of ground substance of the connective tissue.Exogenous glucose amine from dietary (aristle) or supplemental source can also be utilized by the chondrocytes to synthesize GAGs and PGs.Of the absorbed glucose amine, 25% will be excreted in urine, 65% excreted as exhaled CO 2 and only 10% is retained in tissues.Once it is taken up by the chondrocytes it act as a raw material for GAGs and PGs synthesis.The proteoglycans bind cations and water to form a viscous, elastic matrix that helps to lubricate the joints where cartilage is present.When the cartilaginous layer is compromised due to decreased synthesis or increased degradation, the loss of cushioning with resultant articular damage.So some scientist believe that glucose amine is the most important and rate limiting substance for the synthesis of healthy cartilage.
Chondroitin sulfate is also present in higher concentration in cartilage that provides its resiliency.For this chondroprotective activity, chondroitin is also being used along with glucose amine as therapy for osteoarthritis. 2,3ucose amine has numerous effects on the health of cartilage and connective tissue sythesis in the body.When supplemental glucose amine is available to chondrocytes, they produce connective tissue faster because they can skip three chemical reactions, only needing a phosphorylation to make glucose amine-6-phosphate.Glucose amine sulfate is also required for the synthesis of hyaluronic acid (HA) by the synovial membrane.HA increase the viscocity of synovial fluid and thus serves to reduce the wear and tear stress on the articular cartilage and related joint structures.Thus glucoseamine may be helpful in preventing, reversing or stabilizing the osteoarthritis. 4,5ucose amine also appears to inhibit lysosomal enzymes including collagenase and phosphorylase A 2, utilized for cartilage catabolism. 6This gives antinflammatory properties to glucoseamine without disturbing the prostaglandin biochemistry (e.i synthesis of PG).But majority adverse events of NSAID is due to inhibition of prostaglandin synthesis.In animal studies, glucose amine blocks the generation of intrarticular superoxide radicals. 7lucose amine sulfate also delivers the mineral sulfur to the joint cartilage.Sulfur stabilize the connective tissue matrix of cartilage, tendon and ligament.Sulfur also alleviate arthritic symptoms due to its antiinflammatory effect.

Debate:
All most all of the studies done on oral glucose amine have used glucose amine sulfate stabilized with NaCl salt.It supplies both glucose amine and sulfur to chondrocytes.But other form of glucose amine (Nacetyl-glucoseamine and glucoseanime hydrochloride) not providing the sulfur. 8Proponents of glucose amine hydrochloride feel that the sulfur portion of glucose amine sulfate is removed during digestion and not utilized by cartilage. 9But the proponents of glucoseaminesulfate disagree and feel that it supplies sulfur to the chondrocytes for synthesis of kertansulfate and chondroitinsulfate (GAGs). 10On the other hand, evidence for the use of chondroitin appears to be less than glucose amine.Some experts in this area concluded that adding chondroitin to glucose amine administration has not been shown to further improve the benefits available from glucose amine alone and it imposes additional cost with no added benefit.How ever the preparation of glucose amine tablet varies from country to country and different pharmaceuticals products.Some 500 mg glucoseamine sulfate tablet contain 20% sulfate and 20% sodium leaving only 300 mg of elemental glucose amine.Patients taking 3 tablets getting only 900 mg per day ei.inadequate dose. 11

Clinical studies with glucose amine sulfate.
There has been very little US research on glucose amine but in Europe, more than 300 investigation including 20 double-blind studies have been carried out on glucoseamine in the early 1980s. 8,11large number of clinical and experimental investigations to determine if oral glucoseaminesulfate supplementation can compensate for age-related decline in glucoseamine synthesis and thereby block the progression of osteoarthritis and/or reverse or repair any existing joint cartilage damage. 12,13In a recent review, the researchers indicated that glucoseamine supplementation has been shown to be effective in the treatment of osteoarthritis. 14st of the original research on glucoseamine was carried out in Europe and Asia and demonstrated impressive results.Some researchers in North America have criticised the research methodology of some of these trials and suggested their own trial before glucose amine can be recommended as a treatment for osteoarthritis. 15In 1999 and 2001 Register et al published their findings of a large randomized controlled analysis that was placebocontrolled, double blind and prospective in nature.It involved 212 patients with knee OA.Weightbearing and anteroposterior radiographs of each knee were done at 1 and 3 years.Joint space width was also measured.Symptoms and functional status were scored every 4 months using Western Ontario and Mc Master University Osteoarthritis Index (WOMAC).The two groups had comparable base line status, but after 3 years there was no further joint space narrowing in the glucose amine group.The placebo group had further joint space narrowing and objective evidence of disease progression.Further, symptoms worsend in the placebo group over the three years period but marked reduction in symptoms of OA were observed in other group.Patients in the glucoseamine group did not experience any untoward side effects. 16,17In the Lancet editorial it is stated that, it is time (for medical doctors) to accommodate the possibility that many nutritional products may have valuable therapeutic effects and to regain the credibility of the public at large. 18Further more in osteoarthritis, the joint capsule becomes thickened and the synovial fluid has a reduced concentration of lactate and glucose inhibiting the synthesis of hyaluronic acid (HA).As glucose amine takes part in the synthesis of both CS and HA, and because these two compounds are depleted in OA, it has been suggested that replacing glucoseamine could be of benefit to patients suffering from OA. Bassleer et al working with human articular chondrocyte cultures showed that not only does exogenous glucoseamine become incorporated in to mucopolysaccharides but it also appears to activate core protein synthesis in human chondrocytes.But investigations though positive, suffer from limitations of applying invitro results on human.All the variation in these studies mean that it is difficult to come to a firm conclusion as to the overall effectiveness of using glucoseamine for the treatment of osteoarthritis.

Side Effects (Adverse effect):
Although there has not been a systematic evaluation of the adverse effects associated with supplemental glucoseamine sulfate, a few studies have made mention of observed adverse effects in their individual studies, despite the small number of patients.Short term adverse effects are mild and infrequent.These are constipation, nausea, heart burn, anorexia.0][21] Recently, concern regarding the ability of glucoseamine to adversely affect glucose tolerance has been voiced. 22How ever many studies in humans have failed to demonstrate a significant effect on blood glucose at oral therapeutic dose.4][25][26][27] Thus glucoseaminesulfate supplementation is not an absolute contraindication in diabetic and pre diabetic patients.

Drug Interaction:
Glucoseamine sulfate has no potential for interactions with any other drugs as it does not bind to plasma protein and it is not metabolized via cytochrome P450 enzyme system.Steroidal or NSAID can be administered together with Glucoseamine sulfate. 28

Dosage:
For the treatment of OA, the usual daily dosage of glucoseamine sulfate is 1500mg per day which can be taken all at one time or in divided doses of 500 mg per dose.Individuals taking diuretic drugs may require an additional 500mg per day to compensate for the increased excretion rate with urine.Individuals weighing>200 pounds may also be advised to up their dosage to 2000 mg per day. 5,17,29Clinical studies have shown that "Bridge Therapy" is an effective treatment regimen where by glucoseamine sulfate is administered together with NSAID at the beginning of the therapy, for approximately 2 weeks to allow GA to start its symptom modifying effect.Then NSAID is withdrawn to prevent its side effects (GIT, Renal, Hepatic) 30 Glucose amine sulfate relieves the symptoms of OA within 2 weeks and its effect persists al least up to 8 weeks. 28

Conclusion:
In early stage of disease or injury, these factors may have a catabolic effect on the proteoglycans degradation and synthesis balance.Glucoseamine can stimulate biosynthesis of proteoglycans and restore the catabolic-anabolic balance.Some research also indicates that glucose amine may have little, if any, effect on severe cartilage injuries or advance diseases.In conclusion as osteoarthritis is a chronic condition, there is no hard evidence that supplemental glucoseamine will provide a long term cure.Most importantly, there is no enough evidence that it is safe to take the compound for an extended period.So the need for long term clinical trials has been emphasized. 31,32Thus glucose amine should be used judiciously for limited period of time, say for no more than 3 months at a time. 33But the fact is glucose amine sulfate takes 2 weeks to start its symptom relieving effect and its lasts only to up to 8 weeks.It may be due to mineral sulfur for its antiinflammatory effect.Long term cure needs its use for extended time through its disease modifying effect (if at all).Glucose amine may have its place in the athletic world as young athletes are in a never ending state of collagenous tissues damage and repair, making them primary candidates for OA in their later years (much earlier than normal individual).Glucose amine supplement may speed up the recovery process by aiding in the repair of the damaged tissues and thus slow down the progress of degenerative change of articular cartilage.
Nutrition applied to injury rehabilitation and sports medicine.CRC Press, 19 May, 1977.The role of Glucose amine sulphate and chondroitin sulfate in the treatment of degenerative joint disease.Altern Med Rev 1998; 2: 27-29.
4.Gottlieb Marcs.Conservative management of spinal osteoarthritis with glucose amine sulfate and