Continued from Part 1.
Discussion
OA is the most common form of arthritis, and it is often associated with significant disability and an impaired quality of life. Clinical and radiographic surveys have found that the prevalence of OA increases with age from 1% in people <30 years to 10% in those <40 years to more than 50% in individuals >60 years of age (19). Although there are no curative therapies currently available for OA, individualized treatment programs are available to help relieve pain and stiffness, and to maintain and/or improve functional status.
In the last few years, various nutritional supplements including chondroitin, glucosamine, avocado/soybean unsaponifiables and diacerein have emerged as new treatment options for osteoarthritis (20). In this study, the efficacy of UC-II was studied in patients identified with moderate to severe OA. The objective of this study was to determine the effect of UC-II on disease specific measures and blood measures of OA of the knee compared to G+C. It was hypothesized that UC-II would reduce symptoms of OA of the knee to a greater extent than G+C.
A meta-analysis of 20 randomized control studies (2570 patients) comparing the effects of glucosamine (glucosamine sulphate, GS or glucosamine HCl, GH) vs. placebo was done. Of these only eight studies met the required controlled conditions for adequate allocation concealment and received a quality score of 4 or higher (rated on the JADAD scale). These studies failed to show the benefit of glucosamine (GS or GH) for pain and WOMAC function. When all 20 studies were included in the meta-analysis, the results favored glucosamine with improvement in pain and functionality; however, the results were not uniformly positive and the parameters for WOMAC pain, daily function and stiffness did not reach statistical significance. Combinations of glucosamine and chondroitin have been studied in the “GAIT” study. These authors reported that glucosamine HCl and chondroitin sulphate alone or in combination did not reduce pain significantly in patients with OA of the knee. However in a subgroup of patients with moderate to severe knee pain the combination of compounds were found to be effective. Limitations to this study included a high rate of response to placebo (60.1%) and the fact that 78% of the participants were in the mild pain subgroup (21).
Previous studies have shown that UC-II is effective in the treatment of RA (8-11), and preliminary human (12) and animal (13-15) trials have shown it to be effective in treating OA. In obese-arthritic dogs given 4 mg or 40 mg per day UC-II for 90 days, significant declines in overall pain, pain during limb manipulation and lameness after physical exertion were noted (15). Greater improvement was observed with the 40 mg dose. No adverse effects or significant changes in serum chemistry (creatinine, blood urea nitrogen, alanine aminotransferase, and aspartate aminotransferase) were noted. Following UC-II withdrawal for a period of 30 days, all dogs experienced a relapse of overall pain, exercise-associated lameness and pain upon limb manipulation.
In a recent investigation, efficacy of UC-II was evaluated in arthritic horses (22). In this study, groups of horses were orally administered with a daily dose of placebo, UC-II at 320, 480 or 640 mg, or a combination of glucosamine (5.4 g) and chondroitin (1.8 g) for 150 days. Horses receiving placebo did not show any improvement in arthritic condition, while those receiving a daily dose of 320, 480 or 640 mg of UC-II exhibited significant reduction in arthritic pain. Although G+C treated group showed significant reduction in pain compared to baseline values, the efficacy was less as compared to that observed with UC-II treatment. In fact, UC-II at 480 or 640 mg/day was found to be more effective than G+C in treatment of arthritic pain in horses. Clinical conditions (body weight, body temperature, respiration rate, and pulse rate), and liver (bilirubin, GGT, and ALP) and kidney (BUN and creatinine) functions were not affected by UC-II treatment, suggesting that UC-II is well tolerated and does not cause any adverse effects (22).
In a preliminary trial of subjects with OA, taking a single oral daily dose of 40 mg UC-II on an empty stomach prior to bedtime for 42 consecutive days, an average of 26% reduction of pain was noted in four of five subjects in the study. No side effects were associated with treatment (12). The precise biochemical mechanism involved in UC-II induced pharmacological anti-arthritic effects in humans, dogs or horses is not clearly established. Type II collagen is the primary form of collagen contained in cartilage. Type II collagen extracts contain the amino acids found in the framework of human cartilage. In addition, these amino acids are required for the synthesis and repair of connective tissue throughout the body. These products reportedly aid in reducing the destruction of collagen within the body, may provide anti-inflammatory activity, and may improve joint flexibility (8-12).
The current study indicated that both treatments reduced the WOMAC scores, which measures the difficulty in physical function, stiffness and pain in the knee. However, treatment with UC-II was found to be more effective in reducing the WOMAC scores by 33% as compared to 14% in G+C treated groups after 90 days. Similar results were observed for VAS scores. Although both the treatments reduced the VAS score, UC-II was found to be more effective with 40% decrease after 90 days of treatment as compared to 15.4% in G+C treated groups. The Lequesne's functional index was used to determine the effect of different treatments on pain during daily activities. Treatment with UC-II reduced Lequesne's functional index by 20.1% as compared to 5.9 % in G+C treated groups. Thus, UC-II supplementation showed improvement in daily activities suggesting an improvement in overall quality of life in the patients receiving UC-II.
Acknowledgements
This research was supported by InterHealth Research Center, CA.
Conflict of Interest
The authors have declared that no conflict of interest exists.
References
1. Braham R, Dawson B, Goodman C. The effect of glucosamine supplementation on people experiencing regular knee pain. Br J Sports Med. 2003;37:4549
2. Cote LG. Management of osteoarthritis. J Am Acad Nurse Pract. 2001;13:495-501
3. Arthritis Foundation. http://www.arthritis.org/conditions/DiseaseCenter/default.asp
4. ANON. Recommendations for the medical management of osteoarthritis of the hip and knee: 2000 update. American College of Rheumatology Subcommittee on Osteoarthritis Guidelines. Arth Rheum. 2000;43:1905-1915
5. Haq I, Murphy E, Dacre J. Osteoarthritis. Postgrad Med J. 2003;79:377-383
6. Brown LP. Pet Nutraceuticals; Inter-Cal Nutraceuticals. US: Arthritis Foundation. 2005
7. Bruyere O, Reginster JY. Glucosamine and chondroitin sulfate as therapeutic agents for knee and hip osteoarthritis. Drugs Aging. 2007;24:573-580
8. Barnett ML, Kremer JM, St Clair EW, Clegg DO, Furst D, Weisman M, Fletcher MJ, Chasan-Taber S, Finger E, Morales A, Le CH, Trentham DE. Treatment of rheumatoid arthritis with oral type II collagen. Results of a multicenter, double-blind, placebo-controlled trial. Arthritis Rheum. 1998;41(2):290-7
9. Barnett ML, Combitchi D, Trentham DE. A pilot trial of oral type II collagen in the treatment of juvenile rheumatoid arthritis. Arthritis Rheum. 1996;39(4):623-8
10. Trentham DE. Evidence that type II collagen feeding can induce a durable therapeutic response in some patients with rheumatoid arthritis. Ann N Y Acad Sci. 1996;778:306-14
11. Trentham DE, Dynesius-Trentham RA, Orav EJ, Combitchi D, Lorenzo C, Sewell KL, Hafler DA, Weiner HL. Effects of oral administration of type II collagen on rheumatoid arthritis. Science. 1993;261(5129):1727-30
12. Bagchi D, Misner B, Bagchi M, Kothari SC, Downs BW, Fafard RD, Preuss HG. Effects of orally administered undenatured type II collagen against arthritic inflammatory diseases: a mechanistic exploration. Int J Clin Pharmacol Res. 2002;22(3-4):101-10
13. Deparle LA, Gupta RC, Canerdy TD, Goad JT, D'Altilio M, Bagchi M, Bagchi D. Efficacy and safety of glycosylated undenatured type-II collagen (UC-II) in therapy of arthritic dogs. J Vet Pharmacol Ther. 2005;28(4):385-90
14. D'Altilio M, Peal A, Alvey M, Simms C, Curtsinger A, Gupta RC, Canerdy TD, Goad J, Bagchi M, Bagchi D. Therapeutic efficacy and safety of undenatured type II collagen singly or in combination with glucosamine and chondroitin in arthritic dogs. Tox Mech Methods. 2007;17:189-196
15. Faria AM, Weiner HL. Oral tolerance. Immunol Rev. 2005;206:232-59
16. COSTART. Coding symbol thesaurus for adverse reaction terms. 3rd ed. Rockville, MD: Center for Drugs and Biologics, Division of Drug and Biological Products Experience. 1989
17. Bellamy N, Watson Buchanan W, Goldsmith CH, Campbell J, Stitt LW. 1988. Validation study for WOMAC: health status instrument for measuring clinically important patient relevant outcomes to antirheumatic drug therapy in patients with osteoarthritis of the hip or knee. J Rheumatol. 1988;15:1833-1840
18. Lequesne MG, Mery C, Samson M, Gerard P. Indexes of severity for osteoarthritis of the hip and knee validation-value in comparison with other assessment tests. Scand J Rheumatol. 1987;65:85-9
19. Felson DT. The epidemiology of knee osteoarthritis: Results from the Framingham Osteoarthritis Study. Semin Arthritis Rheum. 1990;20:42-50
20. Van Sasse JL, van Romunde LK, Cats A, Vanderbroucke JP. Epidemiology of osteoarthritis: Zoetermeer survey. Comparison of radiological osteoarthritis in a Dutch population with that in 10 other populations. Ann Rheum Dis. 1989;48(4):271-80
21. Clegg DO, Reda DJ, Harris CL. et al. Glucosamine, Chondroitin Sulfate, and the Two on Combination for Painful Knee Osteoarthritis. N Engl J Med. 2006;354(8):795-808
22. Gupta RC, Bagchi D, Skaggs P, Burke R, Wegford K, Goad JT, Canerdy TD, Barnett D, Bagchi M. Therapeutic efficacy of undenatured type-II collagen (UC-II) in comparison to glucosamine and chondroitin in arthritic horses. J Vet Pharmacol Ther. 2008 in press
Author contact
Correspondence to: Siba P. Raychaudhuri, [email protected]
Received 2009-7-14
Accepted 2009-10-8
Published 2009-10-9
Discussion
OA is the most common form of arthritis, and it is often associated with significant disability and an impaired quality of life. Clinical and radiographic surveys have found that the prevalence of OA increases with age from 1% in people <30 years to 10% in those <40 years to more than 50% in individuals >60 years of age (19). Although there are no curative therapies currently available for OA, individualized treatment programs are available to help relieve pain and stiffness, and to maintain and/or improve functional status.
In the last few years, various nutritional supplements including chondroitin, glucosamine, avocado/soybean unsaponifiables and diacerein have emerged as new treatment options for osteoarthritis (20). In this study, the efficacy of UC-II was studied in patients identified with moderate to severe OA. The objective of this study was to determine the effect of UC-II on disease specific measures and blood measures of OA of the knee compared to G+C. It was hypothesized that UC-II would reduce symptoms of OA of the knee to a greater extent than G+C.
A meta-analysis of 20 randomized control studies (2570 patients) comparing the effects of glucosamine (glucosamine sulphate, GS or glucosamine HCl, GH) vs. placebo was done. Of these only eight studies met the required controlled conditions for adequate allocation concealment and received a quality score of 4 or higher (rated on the JADAD scale). These studies failed to show the benefit of glucosamine (GS or GH) for pain and WOMAC function. When all 20 studies were included in the meta-analysis, the results favored glucosamine with improvement in pain and functionality; however, the results were not uniformly positive and the parameters for WOMAC pain, daily function and stiffness did not reach statistical significance. Combinations of glucosamine and chondroitin have been studied in the “GAIT” study. These authors reported that glucosamine HCl and chondroitin sulphate alone or in combination did not reduce pain significantly in patients with OA of the knee. However in a subgroup of patients with moderate to severe knee pain the combination of compounds were found to be effective. Limitations to this study included a high rate of response to placebo (60.1%) and the fact that 78% of the participants were in the mild pain subgroup (21).
Previous studies have shown that UC-II is effective in the treatment of RA (8-11), and preliminary human (12) and animal (13-15) trials have shown it to be effective in treating OA. In obese-arthritic dogs given 4 mg or 40 mg per day UC-II for 90 days, significant declines in overall pain, pain during limb manipulation and lameness after physical exertion were noted (15). Greater improvement was observed with the 40 mg dose. No adverse effects or significant changes in serum chemistry (creatinine, blood urea nitrogen, alanine aminotransferase, and aspartate aminotransferase) were noted. Following UC-II withdrawal for a period of 30 days, all dogs experienced a relapse of overall pain, exercise-associated lameness and pain upon limb manipulation.
In a recent investigation, efficacy of UC-II was evaluated in arthritic horses (22). In this study, groups of horses were orally administered with a daily dose of placebo, UC-II at 320, 480 or 640 mg, or a combination of glucosamine (5.4 g) and chondroitin (1.8 g) for 150 days. Horses receiving placebo did not show any improvement in arthritic condition, while those receiving a daily dose of 320, 480 or 640 mg of UC-II exhibited significant reduction in arthritic pain. Although G+C treated group showed significant reduction in pain compared to baseline values, the efficacy was less as compared to that observed with UC-II treatment. In fact, UC-II at 480 or 640 mg/day was found to be more effective than G+C in treatment of arthritic pain in horses. Clinical conditions (body weight, body temperature, respiration rate, and pulse rate), and liver (bilirubin, GGT, and ALP) and kidney (BUN and creatinine) functions were not affected by UC-II treatment, suggesting that UC-II is well tolerated and does not cause any adverse effects (22).
In a preliminary trial of subjects with OA, taking a single oral daily dose of 40 mg UC-II on an empty stomach prior to bedtime for 42 consecutive days, an average of 26% reduction of pain was noted in four of five subjects in the study. No side effects were associated with treatment (12). The precise biochemical mechanism involved in UC-II induced pharmacological anti-arthritic effects in humans, dogs or horses is not clearly established. Type II collagen is the primary form of collagen contained in cartilage. Type II collagen extracts contain the amino acids found in the framework of human cartilage. In addition, these amino acids are required for the synthesis and repair of connective tissue throughout the body. These products reportedly aid in reducing the destruction of collagen within the body, may provide anti-inflammatory activity, and may improve joint flexibility (8-12).
The current study indicated that both treatments reduced the WOMAC scores, which measures the difficulty in physical function, stiffness and pain in the knee. However, treatment with UC-II was found to be more effective in reducing the WOMAC scores by 33% as compared to 14% in G+C treated groups after 90 days. Similar results were observed for VAS scores. Although both the treatments reduced the VAS score, UC-II was found to be more effective with 40% decrease after 90 days of treatment as compared to 15.4% in G+C treated groups. The Lequesne's functional index was used to determine the effect of different treatments on pain during daily activities. Treatment with UC-II reduced Lequesne's functional index by 20.1% as compared to 5.9 % in G+C treated groups. Thus, UC-II supplementation showed improvement in daily activities suggesting an improvement in overall quality of life in the patients receiving UC-II.
Acknowledgements
This research was supported by InterHealth Research Center, CA.
Conflict of Interest
The authors have declared that no conflict of interest exists.
References
1. Braham R, Dawson B, Goodman C. The effect of glucosamine supplementation on people experiencing regular knee pain. Br J Sports Med. 2003;37:4549
2. Cote LG. Management of osteoarthritis. J Am Acad Nurse Pract. 2001;13:495-501
3. Arthritis Foundation. http://www.arthritis.org/conditions/DiseaseCenter/default.asp
4. ANON. Recommendations for the medical management of osteoarthritis of the hip and knee: 2000 update. American College of Rheumatology Subcommittee on Osteoarthritis Guidelines. Arth Rheum. 2000;43:1905-1915
5. Haq I, Murphy E, Dacre J. Osteoarthritis. Postgrad Med J. 2003;79:377-383
6. Brown LP. Pet Nutraceuticals; Inter-Cal Nutraceuticals. US: Arthritis Foundation. 2005
7. Bruyere O, Reginster JY. Glucosamine and chondroitin sulfate as therapeutic agents for knee and hip osteoarthritis. Drugs Aging. 2007;24:573-580
8. Barnett ML, Kremer JM, St Clair EW, Clegg DO, Furst D, Weisman M, Fletcher MJ, Chasan-Taber S, Finger E, Morales A, Le CH, Trentham DE. Treatment of rheumatoid arthritis with oral type II collagen. Results of a multicenter, double-blind, placebo-controlled trial. Arthritis Rheum. 1998;41(2):290-7
9. Barnett ML, Combitchi D, Trentham DE. A pilot trial of oral type II collagen in the treatment of juvenile rheumatoid arthritis. Arthritis Rheum. 1996;39(4):623-8
10. Trentham DE. Evidence that type II collagen feeding can induce a durable therapeutic response in some patients with rheumatoid arthritis. Ann N Y Acad Sci. 1996;778:306-14
11. Trentham DE, Dynesius-Trentham RA, Orav EJ, Combitchi D, Lorenzo C, Sewell KL, Hafler DA, Weiner HL. Effects of oral administration of type II collagen on rheumatoid arthritis. Science. 1993;261(5129):1727-30
12. Bagchi D, Misner B, Bagchi M, Kothari SC, Downs BW, Fafard RD, Preuss HG. Effects of orally administered undenatured type II collagen against arthritic inflammatory diseases: a mechanistic exploration. Int J Clin Pharmacol Res. 2002;22(3-4):101-10
13. Deparle LA, Gupta RC, Canerdy TD, Goad JT, D'Altilio M, Bagchi M, Bagchi D. Efficacy and safety of glycosylated undenatured type-II collagen (UC-II) in therapy of arthritic dogs. J Vet Pharmacol Ther. 2005;28(4):385-90
14. D'Altilio M, Peal A, Alvey M, Simms C, Curtsinger A, Gupta RC, Canerdy TD, Goad J, Bagchi M, Bagchi D. Therapeutic efficacy and safety of undenatured type II collagen singly or in combination with glucosamine and chondroitin in arthritic dogs. Tox Mech Methods. 2007;17:189-196
15. Faria AM, Weiner HL. Oral tolerance. Immunol Rev. 2005;206:232-59
16. COSTART. Coding symbol thesaurus for adverse reaction terms. 3rd ed. Rockville, MD: Center for Drugs and Biologics, Division of Drug and Biological Products Experience. 1989
17. Bellamy N, Watson Buchanan W, Goldsmith CH, Campbell J, Stitt LW. 1988. Validation study for WOMAC: health status instrument for measuring clinically important patient relevant outcomes to antirheumatic drug therapy in patients with osteoarthritis of the hip or knee. J Rheumatol. 1988;15:1833-1840
18. Lequesne MG, Mery C, Samson M, Gerard P. Indexes of severity for osteoarthritis of the hip and knee validation-value in comparison with other assessment tests. Scand J Rheumatol. 1987;65:85-9
19. Felson DT. The epidemiology of knee osteoarthritis: Results from the Framingham Osteoarthritis Study. Semin Arthritis Rheum. 1990;20:42-50
20. Van Sasse JL, van Romunde LK, Cats A, Vanderbroucke JP. Epidemiology of osteoarthritis: Zoetermeer survey. Comparison of radiological osteoarthritis in a Dutch population with that in 10 other populations. Ann Rheum Dis. 1989;48(4):271-80
21. Clegg DO, Reda DJ, Harris CL. et al. Glucosamine, Chondroitin Sulfate, and the Two on Combination for Painful Knee Osteoarthritis. N Engl J Med. 2006;354(8):795-808
22. Gupta RC, Bagchi D, Skaggs P, Burke R, Wegford K, Goad JT, Canerdy TD, Barnett D, Bagchi M. Therapeutic efficacy of undenatured type-II collagen (UC-II) in comparison to glucosamine and chondroitin in arthritic horses. J Vet Pharmacol Ther. 2008 in press
Author contact
Received 2009-7-14
Accepted 2009-10-8
Published 2009-10-9
