- Email: [email protected]
Glucosamine in osteoarthritis and gastrointestinal disorders: an exemplar of the need for a paradigm shift
Medical Hypotheses (1998) 51, 347-349
© Harcourt Brace & Co. Ltd 1998
Glucosamine in osteoarthritis and gastrointestinal disorders: an exemplar of the need for a paradigm shift A. L. RUSSELL Brampton Pain Clinic, 18 Kensington Road, Suite 201, Bramalea, Ontario, L6T 4S5, Canada (Phone: ÷1 905 7922661; Fax: +1 905 792 1349)
Abstract - - Glucosamine, after a latent period, is rapidly developing a position in the treatment of osteoarthritis, as welt as a potential therapeutic place in wound healing and gastrointestinal disorders. Although recognized for a great many years, the association of gastrointestinal disorders and arthritis has been looked on as an unexplained oddity. Could this be indicative of a common etiology in the rate-limiting production of glucosamine? Could diverse presentations and pathology be due to a common-stem biochemical defect? Over the past thirty years in which I have been practising medicine, there have been many advances; however, in one of the most prevalent of conditions, osteoarthritis, treatment and management has been, to say the least, static. As a medical student, I was taught that osteoarthritis (OA) was a degenerative condition and that one treated the symptoms with acetaminophen. No thought or instruction was given to any idea of thinking how to correct or reverse the pathology. So much of medical education is based on symptomatic treatment, and the etiology of illness is given short shrift. The other tenet of teaching which has taken years to correct, has been what might be described as a unitarian theory: one etiology, one disease, one treatment. This approach was reinforced by the early and high degree of specialization of researchers and clinicians, so there was very little exchange of information between the specialties. The development of nonsteroidal antiinflammatories (NSAIDs) seemed to herald a new era with agents that were developed on a scientific basis and
would treat more than the pain of osteoarthritis. Over the years, the medical profession has become disillusioned with these agents. Firstly, NSAIDs, in the majority of cases, inhibit cartilage regeneration, aggravating the disease for which they are meant to be a treatment. The morbidity, mortality and expense is now well recognized, and the majority of NSAIDs at best can only be recognized as symptomatic treatment - - but at what cost? - - and hence the reversal to acetaminophen as a first-line treatment. With specialization, we have assumed that illnesses fit into discrete sets; however, many cross these national boundaries. One of the best examples is seen in various gastrointestinal diseases, such as Crohn's and ulcerative colitis, which have a typical arthropathy, a fact known for at least fifty years but which has not stimulated any particular thought or the key question, why? One could hypothesize that patients with premature osteoarthritis or inflammatory bowel disorders might have a genetically exaggerated ratelimiting glucosamine production.
Received 27 December 1996 Accepted 13 May 1997 347
348 It is against this setting that I became interested in glucosamine as a result of reading Mark McCarty's article 'The neglect of glucosamine as a treatment of osteoarthritis - - a personal perspective' (1). This was at a time when I was attempting to focus topical NSAIDs to avoid the systemic toxicity, again a sophisticated, symptomatic treatment (2-4). Over the years, having been disillusioned by the failure of 'folk remedies' to stand up to intensive in-vitro and in-vivo clinical studies, including double blind trials, it was with great skepticism that I looked at the subject of glucosamine. I must admit, I was astounded to find the extensive European literature and, in talking to European colleagues, to discover that they have been using glucosamine for over twenty-five years with great success. The second and most likely unique feature was the near total absence of any North American studies. It was as though the substance did not exist. Initially, having reviewed the literature, especially on toxicity, I started using glucosamine in the recommended dose of 500 mg t.i.d, for 6 weeks, increasing to 1000 mg t.i.d, if failure to respond occurred. I was truly amazed at the positive response which followed a 6-week latent period. At the time of writing this essay, I have treated in excess of three hundred patients, with only one minor side effect of nausea. Out of this use has developed a number of unique scenarios. First, a number of patients have treated their osteoarthritic pets, especially dogs, with glucosamine with such good effects that the vets in our area have now adopted this as a standard treatment. This has been followed by the development of commercial dog biscuits with glucosamine. Patients on glucosamine have so impressed their neighbours that whole streets now take glucosamine, so much so that it is impossible in Brampton to even consider a double blind study as the area is saturated, making it impossible to find naive osteoarthritis cases. Stimulated by this unique anecdotal chain reaction type trial, considerable attention has been given by the media and the academic community. A double blind study, the first in North America, is in the process of start up at the Mount Sinai Hospital, University of Toronto, a unique situation for such an august body is investigating a folklore remedy. The basic hypothesis for the action of glucosamine is that it bypasses the rate-limiting metabolic block in the conversion of glucose to glucosamine and allows increased production of proteoglycans and cartilage. One can imagine that with age and excessive wear and tear, as with athletes, the demands for proteoglycan and cartilage synthesis increases; however, is it possible that those that develop premature osteoarthritis and other disorders have a metabolic defect,
MEDICAL HYPOTHESES
limiting their production below that of a normal person? This theme has not been overlooked by the lay person, as is seen in many athletes in the USA and Europe who take prophylactic glucosamine to prevent repetitive high-intensity exercise competition from overloading cartilage production. In this lay observation may be the paradigm for prophylactic glucosamine. If this holds true for osteoarthritis, perhaps such an enzymatic bottleneck might explain other disorders and be the stem etiology of cross-organ disorders. In support of the above there is now an early but ever-expanding spectrum of the use of glucosamine in other conditions which begin to tie in a basic defect concept. The use of glucosamine for wound healing has been known since the 1960s and was recently reviewed by McCarty (5). Returning to my initial comments regarding the lack of stimulation and interest in the association of colitis and arthropathies, it is fascinating to note the possible use of glucosamine in inflammatory bowel disorders, evidence cited in US patents (6,7) and similar Canadian anecdotal observations. From the above, I hope there is enough stimulation to perhaps correct the erroneous idea of one defect, one disorder. Perhaps glucosamine will not only prove to be effective in overcoming a metabolic defect in osteoarthritis and other conditions, as mentioned above, but also develop and strengthen the idea of looking for etiologies common to multiple disorders. Finally, over the years, reading fringe medicine associated with arthritis, one has become interested and then perhaps disillusioned with shark cartilage, chondroitin and various forms of hyaluronan. At times the literature is tantalizing, with small series demonstrating a vast spectrum of action from antireactive, analgesic, antiarthritic, antimitotic and antiangiogenesis. Certainly in the case of hyaluronan the literature is quite extensive and well-based scientifically regarding its effect on vasculature and mytotic activity (8). The real fascination in the above is the fact that the common denominator of all the agents is glucosamine and it seems from what has been established and in projection that glucosamine may have been and be responsible for all the actions described or attributed to the above. If so, simplicity will be the answer to the complexity of medicine.
References 1. McCarty M F. The neglect of glucosamine as a treatment for osteoarthritis - - a personal perspective. Med Hypotheses 1994; 42: 323-327. 2. Russell A L. Piroxicam 0.5% topical gel compared to placebo in the treatment of acute soft tissue injuries: a double-blind
GLUCOSAMINE IN OSTEOARTHRITIS AND GASTROINTESTINAL DISORDERS study comparing efficacy and safety. Clin Invest Med 1993; 14:35-43 3, Russell A L, Review and evaluation of 3% diclofenac in hyaluronan DHA gel. Royal Society of Medicine Series, No. 33; 1994: 64-69. 4. Russell A L. The use of HYAL AT-2101 and diclofenac in the treatment of osteoarthritis. Royal Society of Medicine Series, No. 36; 1995: 58-65. 5. McCarty M F. Glncosamine for wound healing. Med Hypo-
349
theses 1996; 47: 273-275. 6. Prudden J F. Method and Agent for Treating Inflammatory Disorders of the Gastrointestinal Tract. United States Patent # 4,006,224, 1977. 7. Burton A F, Freeman H J. Method for Treatment of Lower Gastrointestinal Tract Disorders. United States Patent # 5,229,374, 1993. 8. Laurent T C. The biology of hyaluronan. Ciba Foundation Symposium 143. Wiley, New York: 1989.
© Harcourt Brace & Co. Ltd 1998
Glucosamine in osteoarthritis and gastrointestinal disorders: an exemplar of the need for a paradigm shift A. L. RUSSELL Brampton Pain Clinic, 18 Kensington Road, Suite 201, Bramalea, Ontario, L6T 4S5, Canada (Phone: ÷1 905 7922661; Fax: +1 905 792 1349)
Abstract - - Glucosamine, after a latent period, is rapidly developing a position in the treatment of osteoarthritis, as welt as a potential therapeutic place in wound healing and gastrointestinal disorders. Although recognized for a great many years, the association of gastrointestinal disorders and arthritis has been looked on as an unexplained oddity. Could this be indicative of a common etiology in the rate-limiting production of glucosamine? Could diverse presentations and pathology be due to a common-stem biochemical defect? Over the past thirty years in which I have been practising medicine, there have been many advances; however, in one of the most prevalent of conditions, osteoarthritis, treatment and management has been, to say the least, static. As a medical student, I was taught that osteoarthritis (OA) was a degenerative condition and that one treated the symptoms with acetaminophen. No thought or instruction was given to any idea of thinking how to correct or reverse the pathology. So much of medical education is based on symptomatic treatment, and the etiology of illness is given short shrift. The other tenet of teaching which has taken years to correct, has been what might be described as a unitarian theory: one etiology, one disease, one treatment. This approach was reinforced by the early and high degree of specialization of researchers and clinicians, so there was very little exchange of information between the specialties. The development of nonsteroidal antiinflammatories (NSAIDs) seemed to herald a new era with agents that were developed on a scientific basis and
would treat more than the pain of osteoarthritis. Over the years, the medical profession has become disillusioned with these agents. Firstly, NSAIDs, in the majority of cases, inhibit cartilage regeneration, aggravating the disease for which they are meant to be a treatment. The morbidity, mortality and expense is now well recognized, and the majority of NSAIDs at best can only be recognized as symptomatic treatment - - but at what cost? - - and hence the reversal to acetaminophen as a first-line treatment. With specialization, we have assumed that illnesses fit into discrete sets; however, many cross these national boundaries. One of the best examples is seen in various gastrointestinal diseases, such as Crohn's and ulcerative colitis, which have a typical arthropathy, a fact known for at least fifty years but which has not stimulated any particular thought or the key question, why? One could hypothesize that patients with premature osteoarthritis or inflammatory bowel disorders might have a genetically exaggerated ratelimiting glucosamine production.
Received 27 December 1996 Accepted 13 May 1997 347
348 It is against this setting that I became interested in glucosamine as a result of reading Mark McCarty's article 'The neglect of glucosamine as a treatment of osteoarthritis - - a personal perspective' (1). This was at a time when I was attempting to focus topical NSAIDs to avoid the systemic toxicity, again a sophisticated, symptomatic treatment (2-4). Over the years, having been disillusioned by the failure of 'folk remedies' to stand up to intensive in-vitro and in-vivo clinical studies, including double blind trials, it was with great skepticism that I looked at the subject of glucosamine. I must admit, I was astounded to find the extensive European literature and, in talking to European colleagues, to discover that they have been using glucosamine for over twenty-five years with great success. The second and most likely unique feature was the near total absence of any North American studies. It was as though the substance did not exist. Initially, having reviewed the literature, especially on toxicity, I started using glucosamine in the recommended dose of 500 mg t.i.d, for 6 weeks, increasing to 1000 mg t.i.d, if failure to respond occurred. I was truly amazed at the positive response which followed a 6-week latent period. At the time of writing this essay, I have treated in excess of three hundred patients, with only one minor side effect of nausea. Out of this use has developed a number of unique scenarios. First, a number of patients have treated their osteoarthritic pets, especially dogs, with glucosamine with such good effects that the vets in our area have now adopted this as a standard treatment. This has been followed by the development of commercial dog biscuits with glucosamine. Patients on glucosamine have so impressed their neighbours that whole streets now take glucosamine, so much so that it is impossible in Brampton to even consider a double blind study as the area is saturated, making it impossible to find naive osteoarthritis cases. Stimulated by this unique anecdotal chain reaction type trial, considerable attention has been given by the media and the academic community. A double blind study, the first in North America, is in the process of start up at the Mount Sinai Hospital, University of Toronto, a unique situation for such an august body is investigating a folklore remedy. The basic hypothesis for the action of glucosamine is that it bypasses the rate-limiting metabolic block in the conversion of glucose to glucosamine and allows increased production of proteoglycans and cartilage. One can imagine that with age and excessive wear and tear, as with athletes, the demands for proteoglycan and cartilage synthesis increases; however, is it possible that those that develop premature osteoarthritis and other disorders have a metabolic defect,
MEDICAL HYPOTHESES
limiting their production below that of a normal person? This theme has not been overlooked by the lay person, as is seen in many athletes in the USA and Europe who take prophylactic glucosamine to prevent repetitive high-intensity exercise competition from overloading cartilage production. In this lay observation may be the paradigm for prophylactic glucosamine. If this holds true for osteoarthritis, perhaps such an enzymatic bottleneck might explain other disorders and be the stem etiology of cross-organ disorders. In support of the above there is now an early but ever-expanding spectrum of the use of glucosamine in other conditions which begin to tie in a basic defect concept. The use of glucosamine for wound healing has been known since the 1960s and was recently reviewed by McCarty (5). Returning to my initial comments regarding the lack of stimulation and interest in the association of colitis and arthropathies, it is fascinating to note the possible use of glucosamine in inflammatory bowel disorders, evidence cited in US patents (6,7) and similar Canadian anecdotal observations. From the above, I hope there is enough stimulation to perhaps correct the erroneous idea of one defect, one disorder. Perhaps glucosamine will not only prove to be effective in overcoming a metabolic defect in osteoarthritis and other conditions, as mentioned above, but also develop and strengthen the idea of looking for etiologies common to multiple disorders. Finally, over the years, reading fringe medicine associated with arthritis, one has become interested and then perhaps disillusioned with shark cartilage, chondroitin and various forms of hyaluronan. At times the literature is tantalizing, with small series demonstrating a vast spectrum of action from antireactive, analgesic, antiarthritic, antimitotic and antiangiogenesis. Certainly in the case of hyaluronan the literature is quite extensive and well-based scientifically regarding its effect on vasculature and mytotic activity (8). The real fascination in the above is the fact that the common denominator of all the agents is glucosamine and it seems from what has been established and in projection that glucosamine may have been and be responsible for all the actions described or attributed to the above. If so, simplicity will be the answer to the complexity of medicine.
References 1. McCarty M F. The neglect of glucosamine as a treatment for osteoarthritis - - a personal perspective. Med Hypotheses 1994; 42: 323-327. 2. Russell A L. Piroxicam 0.5% topical gel compared to placebo in the treatment of acute soft tissue injuries: a double-blind
GLUCOSAMINE IN OSTEOARTHRITIS AND GASTROINTESTINAL DISORDERS study comparing efficacy and safety. Clin Invest Med 1993; 14:35-43 3, Russell A L, Review and evaluation of 3% diclofenac in hyaluronan DHA gel. Royal Society of Medicine Series, No. 33; 1994: 64-69. 4. Russell A L. The use of HYAL AT-2101 and diclofenac in the treatment of osteoarthritis. Royal Society of Medicine Series, No. 36; 1995: 58-65. 5. McCarty M F. Glncosamine for wound healing. Med Hypo-
349
theses 1996; 47: 273-275. 6. Prudden J F. Method and Agent for Treating Inflammatory Disorders of the Gastrointestinal Tract. United States Patent # 4,006,224, 1977. 7. Burton A F, Freeman H J. Method for Treatment of Lower Gastrointestinal Tract Disorders. United States Patent # 5,229,374, 1993. 8. Laurent T C. The biology of hyaluronan. Ciba Foundation Symposium 143. Wiley, New York: 1989.