Reversal of Osteoarthritis by Nutritional Intervention | Equine Clinical Research
ACA Journal of Chiropractic/November 1990
Reprinted with permission.
©1990, all rights reserved.
Research from rheumatology and orthopedic clinics from Europe on the ability to reverse osteoarthritis has been accumulating for the last 25 years. Based on these results, this article will describe a nutritional program, that in conjunction with standard therapies used for osteoarthritis, can actually reverse the course of osteoarthritis.
Osteoarthritis is a collection of ill-defined joint diseases with cartilage degeneration being a central feature.1-3 Usually, deficient cartilage repair, joint bone remodeling, and later, synovial inflammatory processes promote extensive de-generation and erosion.1-3 Osteoarthritis has the highest morbidity (incidence) of all diseases, with almost universal occurrence after 50 years of age, although not all cases are severe. However, 5 million Americans per year are disabled by osteoarthritis, which is still the primary cause of lost time from work.
The two major categories of chondroprotective nutrients are: glycosaminoglycans and antioxidants. Glycosaminoglycans (GAGs) were formerly named mucopolysaccharides, and are major structural components of cartilage and connective tissues.8 GAGs are long polymers of repeating two-sugar units, usually with sulfate groups on one type of sugar. The most common GAG is chondroitin sulfate, composed of glucuronic acid and N-acetyl galactosamine sulfate.
Chondroitin sulfate forms the bulk of GAG products previously tested and currently available. In Europe, purified chondroitin sulfate is available as both nutrient and drug. Two pharmaceutical products contain mostly chondroitin sulfates: Arteparon is synthetically sulfated purified chodroitin sulfate; Rumalon is semipurified GAGs from bovine cartilage sources. Glucosamine sulfate is another nutrient/pharmaceutical in European use, and is a single sugar precursor for chondroitin sulfate.
All GAG supplements share these common features:
Antioxidants with known chondroprotective abilities are ascorbate (vitamin C), tocopherol (vitamin E), superoxide dismutase (SOD), and catalase, and other antioxidant nutritents have shown in vitro protection. Antioxidants share common properties of inhibition of free radical damage to cartilage, modulation of immune functions to resist auto-immunity, decrease of pro-inflammatory prostaglandins, inhibition of degradative enzymes, and for vitamin C, direct anabolic stimulation of chondrocytes.
From the medical schools of Kumamoto, Matsumoto, Nagoya, Aichi, Tohuku, and Inatsuki, 26 orthopedic clinics participated in a double-blind study of 120 patients with osteoarthritis of the knee given intra-articular injections of either 1 mg arteparon (control group), or 50 mg Arteparon.Ò Five total injections were given at weekly intervals for five weeks. Assessment of treatment found that 71 percent of high-dose patients showed improvement, and that 41 percent of controls also showed improvement, a significant difference. Thus, short-term observations suggested that a form of chondroitin sulfate can improve osteoarthritic conditions.
Investigators from the Internal Medicine/Rheumatology Polyclinic of Charles University in Prague, Czechoslovakia conducted independent com-parisons of arteparon and rumalon in osteoarthritis of the knee in long-term studies lasting five and ten years.10 Fifty patients with osteoarthritis of the knee in each of three groups were given either intra-muscuiar injections of vitamin B12 (controls), arteparon (ten courses of injections at six month intervals for a total dose of 7.5 grams), or rumalon (ten courses of injections at six month intervals for a total dose of 250 ml).10 All patients were also given standard analgesics and NSAIDS.
Knee pain was decreased for two years in the control group, but afterwards, became progressively worse, even with higher NSAID doses. This is typical of standard therapy. However, knee pain was decreased quickly (within four months) and to a much greater degree with arteparon and rumalon, along with a decrease in analgesics, and continued to decrease even after five years. Likewise, measures of joint function (time to ascend and descend a 15-step staircase) were maintained for two years in each group, but thereafter, clear divergence was seen. The control group became progressively worse, while the GAG groups became progressively better. Similarly, the ability to work became worse with the control group until, after five years, all controls were unfit for work. Conversely, after five years, between 50 and 80 percent of GAG subjects were fit for work.
Another measure of response was needed for tibial osteotomy operations. For controls, 13/50 received this operation, while only 2/ 50 for each GAG group received osteotomies. Radiologic parameters showed that GAG subjects had only 1/2 to 1/3 of the adverse changes seen in the control group. The grade of osteoarthritis did not worsen in only 1/50 control subjects, but 1/3 to 1/2 of GAG subjects did not worsen. Subjective evaluations by doctors and patients also showed significant benefits for GAG subjects. Thus, by both sub-jective and objective criteria, GAG treatment significantly prevented the inevitable progression to disability, and even slowed the physical findings of osteoarthritis.
This study was preceded by a ten-year study of rumalon on hip arthritis on 112 matched pairs of subjects, which also showed remarkable prevention of progression of radiologic changes, decreases in analgesic use, and an actual decrease in lost working days for the rumalon group, compared to a steady progression to almost complete disability in the control group.10 All differences were statistically significant.
A series of investigations on the effects of glucosamine sulfate supplementation by oral route showed even more promising results. Several short-term studies found significant reductions in joint pain, analgesic use and improvements of joint function with 0.75 or 1.5 grams of daily glucosamine sulfate.12-15 One study actually took cartilage biopsies before and after four weeks of glucosamine sulfate oral supplementation in a few treated subjects.12 Electron microscopy initially showed a typical picture of established osteoarthritis. However, those given glucosamine sulfate "....showed a picture more similar to healthy cartilage."12 The results of this article strongly suggest that reversal of osteoarthritis was being accomplished after oral GAG supplementation.
The results of short-term oral GAG supplementation are even more dramatic than long-term injectable GAG treatment for several reasons:
At Tufts University in Boston, guinea pigs were fed a normal or high intake of vitamin C before, during and after surgery to induce knee osteoarthritis.20 The guinea pigs fed a standard RDA amount of vitamin C (2.4 mg daily) developed osteoarthritis, but the guinea pigs fed 150 mg of vitamin C daily developed only very minor changes.20 This in vivo work is supported by in vitro studies that showed vitamin C is chondroprotective by stimulating anabolism in cartilage cultures, and by inhibiting degradative enzymes in cartilage.20,21
Researchers in Israel gave 32 subjects with osteoarthritis 600 mg daily of vitamine E (d-alpha tocopherol acetate) for only 10 days.22 Even with this very short experimental period, significant improvements in functional assessment, pain and analgesic use were seen with vitamin E, but not with a placebo.
At Konstanz University in Hannover, West Germany, 50 subjects were given either a placebo or 400 IU of d-alpha tocopherol acetate daily for six weeks in a double-blind study.23 Significant decreases in pain and analgesic use were seen for the vitamin E group. Functional improvements were noted, but had not reached significance when the study ended.
In vitro investigations have also shown that vitamin E can inhibit effects of degradative enzymes in cartilage.20 Thus, simple studies have shown that even a single antioxidant can improve osteoarthritis symptoms without side effects. Combinations of antioxidants have yet to be investigated, and longer experimental periods are needed to confirm the effectiveness of antioxidants as chondroprotective agents, but the hypothetical and preliminary evidence is strongly suggestive that antioxidants are potent chondroprotective agents.
Thus, a growing body of clinical evidence, along with a vast literature on hypothetical mechanisms, supports the long-term use of chondroprotective nutrients (GAGs and antioxidants) for cessation or reversal of osteoarthritis, and possibly other degenerative joint diseases. Although results may or may not be noticeable within a month, lack of side effects and ability to attack the cause of arthritis are prime reasons to consider their use in routine clinical settings.
2. Mankin, H.J. Biochemical and metabolic aspects of osteoarthritis. Orthop Clin N Am 1971;2(1):19-31.
3. Brandt, K.D. Pathogenesis of osteoarthritis. In:00,1417-1432.
4. Reimann, I., Christensen, S.B., Diemer, N.H. Observations of reversibility of glycosaminoglycan depletion in articular cartilage. Clin Orthop 1982;168:258-261.
5. Radin, E.L., Burr, D.B. Hypothesis: joints can heal. Sem Arth Rheum 1984;13(3):293-302.
6. Bland, J.H., Cooper, S.M. Osteoarthritis: a review of the cell biology involved and evidence for reversibility. Management rationally related to known genesis and pathophysiology. Sem Arth Rheum 1984; 14(2):106-133.
7. Altman, R.D., Howell, D.S., Gottlieb, N.L. New directions in therapy of osteoarthritis. Sem Arth Rheum 1987;17(2, Suppl 1):1-2.
8. Varma, R.S., Varma, R. eds. Glycosaminoglycans and proteoglycans in physiological and pathological processes of body systems. Basel: Karger, 1982.
9. Burkhardt, D., Ghosh, P. Laboratory evaluation of antiarthritic drugs as potential chondroprotective agents. Sem Arth Rheum 1987;17(2)Suppl.l:3-34.
10. Rejholec, V. Long-term studies of antiosteoarthritic drugs: an assessment. Sem Arth Rheum 1987;17(2)Suppl.l:35-53.
11. Ishikawa, K., Kitagawa, T., Tanaka, T., Teravama, K., Kuriya, N., Iwata, H., Niwa, S., Sakurai, M. Clinical evaluation of the intra-articular injection of glycosaminoglycan polysulphate for osteoarthritis of the knee joint: a multicentric double blind controlled study. Z Orthop 1982;120:708-716.
12. Drovanti, A., Bignamini, A.A., Rovati, A.L. Therapeutic activity of oral glucosamine sulfate in osteoarthritis: a placebo-controlled double-blind investigation. Clin Ther 1980;3(4):260-272.
13. Vaz, A.L. Double-blind clinical evaluation of the relative efficacy of ibuprofen and glucosamine sulphate in the management of osteoarthritis of the knee in out-patients. Curr Med Res Opin 1982;8(3):145-149.
14. D'Ambrosio, E., Casa, B., Bompani, P., Scali, G., Scali, M. Glucosamine sulphate: a controlled clinical investigation in arthrosis. Pharmatherapeutica 1981;2(8):504-508.
15. Pujalte, J.M., Llavore, E., Ylescupidez, F.R. Double-blind clinical evaluation of oral glucosamine sulphate in the basic treatment of osteoarthrosis. Curr Med Res Opin 1980;7(2):110-114.
16. Swaak, A.J.G., Koster, J.F. Free radicals and arthritic diseases. Rijswijk:Eurage, 1986.
17. Greenwald, R.A. Effect of oxygen-derived free radicals on connective tissue macromolecules. In: Bannister, W.H., Bannister, J.V., eds. Biological and Clinical Aspects of Superoxide and Superoxide Dismutase. New York: Elsevier, 1980, 160-171.
18. Wong, S.F., Halliwell, B., Richmond, P., Skowroneck, W.R. The role of superoxide and hydroxyl radicals in the degradation of hyaluronic acid induced by metal ions and by ascorbic acid. J Inorg Biochem 1981;14:127-134.
19. Burkhardt, H., Schwingel, M., Menninger, H., Macarmey, H.W., Tschesche H. Oxygen radicals as effecters of cartilage destruction. Arth Rheum 1986;29(3):379-387.
20. Schwartz, E.R. The modulation of osteoarthritic development by vitamins C and E. Int J Vit Nutr Res 1984; Suppl 26:141-146.
21. Krystal, G., Morris, G.M., Sokoloff, L. Stimulation of DNA synthesis by ascorbate in cultures of articular chondrocytes. Arth Rheum 1982;25(3):318-325.
22. Machtey, I., Ouaknine, L. Tocopherol in osteoarthritis: a controlled pilot study. J Am Ger Soc 1978;26(7):328-330.
23. Blankenhorn, G. Clinical efficacy of Spondyvit (Vitamin E) in activated arthroses. A multicenter, placebo-controlled, double-blind study. Z Orthop Ihre Grenzgeb 1986; 124:340-343.
24. Christensen, K.D., Bucci, L.R. Comparison of nutritional supplement effects on functional assessments of lower back patients measured by an objective computer-assisted tester. In: Second Symposium on Nutrition and Chiropractic. Davenport: Palmer College of Chiropractic, 1989, 19-22.
25. Palmoski, M.J., Brandt, K.D. Effect of salicylate on proteoglycan metabolism in normal canine atticular cartilage in vitro. Arth Rheum 1979;22(7):746-754,
26. Palmoski, M.J., Brandt, K.D. Effects of some nonsteroidal antiinflammatory drugs on proteoglycan metabolism and organization in canine articular cartilage. Arth Rheum 1980;23(9):1010-1020.
Reprinted with permission.
©1990, all rights reserved.
Reversal of Osteoarthritis by Nutritional Intervention
Luke R. Bucci, Ph.D.
Research from rheumatology and orthopedic clinics from Europe on the ability to reverse osteoarthritis has been accumulating for the last 25 years. Based on these results, this article will describe a nutritional program, that in conjunction with standard therapies used for osteoarthritis, can actually reverse the course of osteoarthritis.
Osteoarthritis is a collection of ill-defined joint diseases with cartilage degeneration being a central feature.1-3 Usually, deficient cartilage repair, joint bone remodeling, and later, synovial inflammatory processes promote extensive de-generation and erosion.1-3 Osteoarthritis has the highest morbidity (incidence) of all diseases, with almost universal occurrence after 50 years of age, although not all cases are severe. However, 5 million Americans per year are disabled by osteoarthritis, which is still the primary cause of lost time from work.
Osteoarthritis Myths
Even now, osteoarthritis is thought to be a normal consequence of aging, caused by routine "wear and tear" on joints. Also, it is thought that cartilage cannot heal itself, which is not completely true.1-6 Of foremost importance is the notion that osteoarthritis is associated with an inevitable progression to disability, and nothing can stop or reverse the process. These concepts have been overturned by recent research findings.Evidence for Reversibility of Osteoarthritis
There is substantial evidence that osteoarthritis can be reversible.4-7 Spontaneous remissions in humans have been recorded and reported. Juvenile chronic arthritis can be halted by long-term, intense physical therapy and drugs. Chronic passive joint mobilization in animals has reversed osteoarthritis. Redistribution of joint loads by surgical techniques, polio, paralysis, and strokes has led to cessation of osteoarthritic progression. The proper types of electrical and mechanical stimulation of chondrocytes (the cells responsible for cartilage upkeep and repair) are currently being investigated. Thus, cartilage has the innate ability to repair itself if given the correct conditions.Chondroprotective Nutrients
A new term introduced from Europe describes the actions of two categories of nutrients found to aid in reversal of osteoarthritis. Chondroprotective agents promote repair of cartilage by stimulating anabolic metabolism of chondrocytes and/or inhibiting catabolic processes found in osteoarthritis.7 This concept of helping chondrocytes to heal cartilage, rather than reliance on palliative analgesics, is a relatively new concept that gets more to the actual causes of osteoarthritis, as well as treating the symptoms.The two major categories of chondroprotective nutrients are: glycosaminoglycans and antioxidants. Glycosaminoglycans (GAGs) were formerly named mucopolysaccharides, and are major structural components of cartilage and connective tissues.8 GAGs are long polymers of repeating two-sugar units, usually with sulfate groups on one type of sugar. The most common GAG is chondroitin sulfate, composed of glucuronic acid and N-acetyl galactosamine sulfate.
Chondroitin sulfate forms the bulk of GAG products previously tested and currently available. In Europe, purified chondroitin sulfate is available as both nutrient and drug. Two pharmaceutical products contain mostly chondroitin sulfates: Arteparon is synthetically sulfated purified chodroitin sulfate; Rumalon is semipurified GAGs from bovine cartilage sources. Glucosamine sulfate is another nutrient/pharmaceutical in European use, and is a single sugar precursor for chondroitin sulfate.
All GAG supplements share these common features:
- Provide precursors for GAG synthesis;
- direct inhibition of degradative enzymes (elastase, collagenase, chondroitinases);
- direct stimulation of anabolic metabolism of chondrocytes; and
- counteraction of corticosteroid and NSAID side effects.
Antioxidants with known chondroprotective abilities are ascorbate (vitamin C), tocopherol (vitamin E), superoxide dismutase (SOD), and catalase, and other antioxidant nutritents have shown in vitro protection. Antioxidants share common properties of inhibition of free radical damage to cartilage, modulation of immune functions to resist auto-immunity, decrease of pro-inflammatory prostaglandins, inhibition of degradative enzymes, and for vitamin C, direct anabolic stimulation of chondrocytes.
Clinical Results of Chondroprotective Nutrients
For over 30 years, these chondroitin sulfate forms have been used in animal and human trials against osteoarthritis.9 In fact, over 40 million dose units per year of Rumalon are given. Most of these trials have been summarized in two recent English-language reviews.9,10 However, most of the original articles are in foreign languages in journals not readily accessible in the United States.From the medical schools of Kumamoto, Matsumoto, Nagoya, Aichi, Tohuku, and Inatsuki, 26 orthopedic clinics participated in a double-blind study of 120 patients with osteoarthritis of the knee given intra-articular injections of either 1 mg arteparon (control group), or 50 mg Arteparon.Ò Five total injections were given at weekly intervals for five weeks. Assessment of treatment found that 71 percent of high-dose patients showed improvement, and that 41 percent of controls also showed improvement, a significant difference. Thus, short-term observations suggested that a form of chondroitin sulfate can improve osteoarthritic conditions.
Investigators from the Internal Medicine/Rheumatology Polyclinic of Charles University in Prague, Czechoslovakia conducted independent com-parisons of arteparon and rumalon in osteoarthritis of the knee in long-term studies lasting five and ten years.10 Fifty patients with osteoarthritis of the knee in each of three groups were given either intra-muscuiar injections of vitamin B12 (controls), arteparon (ten courses of injections at six month intervals for a total dose of 7.5 grams), or rumalon (ten courses of injections at six month intervals for a total dose of 250 ml).10 All patients were also given standard analgesics and NSAIDS.
Knee pain was decreased for two years in the control group, but afterwards, became progressively worse, even with higher NSAID doses. This is typical of standard therapy. However, knee pain was decreased quickly (within four months) and to a much greater degree with arteparon and rumalon, along with a decrease in analgesics, and continued to decrease even after five years. Likewise, measures of joint function (time to ascend and descend a 15-step staircase) were maintained for two years in each group, but thereafter, clear divergence was seen. The control group became progressively worse, while the GAG groups became progressively better. Similarly, the ability to work became worse with the control group until, after five years, all controls were unfit for work. Conversely, after five years, between 50 and 80 percent of GAG subjects were fit for work.
Another measure of response was needed for tibial osteotomy operations. For controls, 13/50 received this operation, while only 2/ 50 for each GAG group received osteotomies. Radiologic parameters showed that GAG subjects had only 1/2 to 1/3 of the adverse changes seen in the control group. The grade of osteoarthritis did not worsen in only 1/50 control subjects, but 1/3 to 1/2 of GAG subjects did not worsen. Subjective evaluations by doctors and patients also showed significant benefits for GAG subjects. Thus, by both sub-jective and objective criteria, GAG treatment significantly prevented the inevitable progression to disability, and even slowed the physical findings of osteoarthritis.
This study was preceded by a ten-year study of rumalon on hip arthritis on 112 matched pairs of subjects, which also showed remarkable prevention of progression of radiologic changes, decreases in analgesic use, and an actual decrease in lost working days for the rumalon group, compared to a steady progression to almost complete disability in the control group.10 All differences were statistically significant.
A series of investigations on the effects of glucosamine sulfate supplementation by oral route showed even more promising results. Several short-term studies found significant reductions in joint pain, analgesic use and improvements of joint function with 0.75 or 1.5 grams of daily glucosamine sulfate.12-15 One study actually took cartilage biopsies before and after four weeks of glucosamine sulfate oral supplementation in a few treated subjects.12 Electron microscopy initially showed a typical picture of established osteoarthritis. However, those given glucosamine sulfate "....showed a picture more similar to healthy cartilage."12 The results of this article strongly suggest that reversal of osteoarthritis was being accomplished after oral GAG supplementation.
The results of short-term oral GAG supplementation are even more dramatic than long-term injectable GAG treatment for several reasons:
- consistently high blood and cartilage levels of GAGs are possible with oral administration, rather than cyclic injectable administration;
- side effects are nonexistent with oral GAG administration;
- higher doses of GAGs can be maintained orally. Thus it is no surprise to find that oral GAG supplementation achieved results much faster than injectable GAG treatment.
Antioxidants as Chondroprotectors
One recent theory of osteoarthritis causation is based on free radical formation in joints as the trigger for disease prog-ression.16 Several scenarios associated with osteoarthritis are now known to cause release of free radicals in joints.16 Local ischemia in cartilage (already a hypoxic tissue) induced by chronic joint loading, abnormal joint forces, poor circulation, overexercise, trauma, auto-immune attack and even excess iron elevates levels of free radicals in joints.16 Free radicals directly attack and degrade cartilage components,17-19 triggering a synovial and immune response that promotes further cartilage damage. Because of the slow metabolism of chondrocytes, both injury and repair take months or years to become fully evident. This free radical mechanism of arthritis indicates quite logically that antioxidants may prevent or reverse formation of arthritic symptoms.At Tufts University in Boston, guinea pigs were fed a normal or high intake of vitamin C before, during and after surgery to induce knee osteoarthritis.20 The guinea pigs fed a standard RDA amount of vitamin C (2.4 mg daily) developed osteoarthritis, but the guinea pigs fed 150 mg of vitamin C daily developed only very minor changes.20 This in vivo work is supported by in vitro studies that showed vitamin C is chondroprotective by stimulating anabolism in cartilage cultures, and by inhibiting degradative enzymes in cartilage.20,21
Researchers in Israel gave 32 subjects with osteoarthritis 600 mg daily of vitamine E (d-alpha tocopherol acetate) for only 10 days.22 Even with this very short experimental period, significant improvements in functional assessment, pain and analgesic use were seen with vitamin E, but not with a placebo.
At Konstanz University in Hannover, West Germany, 50 subjects were given either a placebo or 400 IU of d-alpha tocopherol acetate daily for six weeks in a double-blind study.23 Significant decreases in pain and analgesic use were seen for the vitamin E group. Functional improvements were noted, but had not reached significance when the study ended.
In vitro investigations have also shown that vitamin E can inhibit effects of degradative enzymes in cartilage.20 Thus, simple studies have shown that even a single antioxidant can improve osteoarthritis symptoms without side effects. Combinations of antioxidants have yet to be investigated, and longer experimental periods are needed to confirm the effectiveness of antioxidants as chondroprotective agents, but the hypothetical and preliminary evidence is strongly suggestive that antioxidants are potent chondroprotective agents.
Nutrient Combination and Low Back Pain
One recent report examined the effects of several nutritional supplements on chronic low back pain in a chiropractic setting.24 Objective assessment of low back function was accomplished by a computerized testing device. Groups of six patients each were given no supplements (controls), manganese sulfate (900 mg daily), purified chondroitin sulfates (600 mg daily), or purified chondroitin sulfates with a comprehensive multiple vitamin/mineral without iron, including vitamin C and vitamin E. Improvements in strength, range of motion and pain were greatest in the combination group, and moderate in the chondroitin sulfate group, but minimal in the control and manganese sulfate groups.24 This pilot study is the first to suggest that use of chondroprotective nutrients may benefit chronic low back pain patients.Summary
Osteoarthritis can be reversible by chondroprotective agents if the following conditions are met:- cartilage remains intact over joint surfaces;
- subchondral bone is intact;
- lifestyle changes to reduce pressure on affected joint are followed;
- analgesic use is kept to a minimum or ideally, not used;
- enough time is given to properly evaluate effects, and;
- consistent, daily supplementation of chondroprotective nutrients is accompanied by a diet providing all essential nutrients.
Thus, a growing body of clinical evidence, along with a vast literature on hypothetical mechanisms, supports the long-term use of chondroprotective nutrients (GAGs and antioxidants) for cessation or reversal of osteoarthritis, and possibly other degenerative joint diseases. Although results may or may not be noticeable within a month, lack of side effects and ability to attack the cause of arthritis are prime reasons to consider their use in routine clinical settings.
References
1. Hamerman, D. The biology of osteoarthritis. N Engl J Med 1989;320(20):1322-1329.2. Mankin, H.J. Biochemical and metabolic aspects of osteoarthritis. Orthop Clin N Am 1971;2(1):19-31.
3. Brandt, K.D. Pathogenesis of osteoarthritis. In:00,1417-1432.
4. Reimann, I., Christensen, S.B., Diemer, N.H. Observations of reversibility of glycosaminoglycan depletion in articular cartilage. Clin Orthop 1982;168:258-261.
5. Radin, E.L., Burr, D.B. Hypothesis: joints can heal. Sem Arth Rheum 1984;13(3):293-302.
6. Bland, J.H., Cooper, S.M. Osteoarthritis: a review of the cell biology involved and evidence for reversibility. Management rationally related to known genesis and pathophysiology. Sem Arth Rheum 1984; 14(2):106-133.
7. Altman, R.D., Howell, D.S., Gottlieb, N.L. New directions in therapy of osteoarthritis. Sem Arth Rheum 1987;17(2, Suppl 1):1-2.
8. Varma, R.S., Varma, R. eds. Glycosaminoglycans and proteoglycans in physiological and pathological processes of body systems. Basel: Karger, 1982.
9. Burkhardt, D., Ghosh, P. Laboratory evaluation of antiarthritic drugs as potential chondroprotective agents. Sem Arth Rheum 1987;17(2)Suppl.l:3-34.
10. Rejholec, V. Long-term studies of antiosteoarthritic drugs: an assessment. Sem Arth Rheum 1987;17(2)Suppl.l:35-53.
11. Ishikawa, K., Kitagawa, T., Tanaka, T., Teravama, K., Kuriya, N., Iwata, H., Niwa, S., Sakurai, M. Clinical evaluation of the intra-articular injection of glycosaminoglycan polysulphate for osteoarthritis of the knee joint: a multicentric double blind controlled study. Z Orthop 1982;120:708-716.
12. Drovanti, A., Bignamini, A.A., Rovati, A.L. Therapeutic activity of oral glucosamine sulfate in osteoarthritis: a placebo-controlled double-blind investigation. Clin Ther 1980;3(4):260-272.
13. Vaz, A.L. Double-blind clinical evaluation of the relative efficacy of ibuprofen and glucosamine sulphate in the management of osteoarthritis of the knee in out-patients. Curr Med Res Opin 1982;8(3):145-149.
14. D'Ambrosio, E., Casa, B., Bompani, P., Scali, G., Scali, M. Glucosamine sulphate: a controlled clinical investigation in arthrosis. Pharmatherapeutica 1981;2(8):504-508.
15. Pujalte, J.M., Llavore, E., Ylescupidez, F.R. Double-blind clinical evaluation of oral glucosamine sulphate in the basic treatment of osteoarthrosis. Curr Med Res Opin 1980;7(2):110-114.
16. Swaak, A.J.G., Koster, J.F. Free radicals and arthritic diseases. Rijswijk:Eurage, 1986.
17. Greenwald, R.A. Effect of oxygen-derived free radicals on connective tissue macromolecules. In: Bannister, W.H., Bannister, J.V., eds. Biological and Clinical Aspects of Superoxide and Superoxide Dismutase. New York: Elsevier, 1980, 160-171.
18. Wong, S.F., Halliwell, B., Richmond, P., Skowroneck, W.R. The role of superoxide and hydroxyl radicals in the degradation of hyaluronic acid induced by metal ions and by ascorbic acid. J Inorg Biochem 1981;14:127-134.
19. Burkhardt, H., Schwingel, M., Menninger, H., Macarmey, H.W., Tschesche H. Oxygen radicals as effecters of cartilage destruction. Arth Rheum 1986;29(3):379-387.
20. Schwartz, E.R. The modulation of osteoarthritic development by vitamins C and E. Int J Vit Nutr Res 1984; Suppl 26:141-146.
21. Krystal, G., Morris, G.M., Sokoloff, L. Stimulation of DNA synthesis by ascorbate in cultures of articular chondrocytes. Arth Rheum 1982;25(3):318-325.
22. Machtey, I., Ouaknine, L. Tocopherol in osteoarthritis: a controlled pilot study. J Am Ger Soc 1978;26(7):328-330.
23. Blankenhorn, G. Clinical efficacy of Spondyvit (Vitamin E) in activated arthroses. A multicenter, placebo-controlled, double-blind study. Z Orthop Ihre Grenzgeb 1986; 124:340-343.
24. Christensen, K.D., Bucci, L.R. Comparison of nutritional supplement effects on functional assessments of lower back patients measured by an objective computer-assisted tester. In: Second Symposium on Nutrition and Chiropractic. Davenport: Palmer College of Chiropractic, 1989, 19-22.
25. Palmoski, M.J., Brandt, K.D. Effect of salicylate on proteoglycan metabolism in normal canine atticular cartilage in vitro. Arth Rheum 1979;22(7):746-754,
26. Palmoski, M.J., Brandt, K.D. Effects of some nonsteroidal antiinflammatory drugs on proteoglycan metabolism and organization in canine articular cartilage. Arth Rheum 1980;23(9):1010-1020.
