Osteoarthritis and Chondroitin Sulfate

Chondroitin sulfate is a naturally occurring substance in the body. It is a major constituent of cartilage—the tough, elastic connective tissue found in the joints.

Based on the evidence of preliminary double-blind studies, chondroitin is widely used as a treatment for osteoarthritis, the typical arthritis that many people suffer as they get older. However, the supporting evidence for this use is weak.

Scientists are unsure how chondroitin sulfate works (if indeed it does).But, at its most basic level, chondroitin may help cartilage by providing it with the building blocks it needs to repair itself. Chondroitin is also believed to block enzymes that break down cartilage in the joints.^45,208 Another theory holds that chondroitin increases the amount of hyaluronic acid in the joints.²⁰⁹ Hyaluronic acid is a protective fluid that keeps the joints lubricated. Finally, chondroitin may have a mild anti-inflammatory effect.²⁰⁸

As described in the previous section, the supplement chondroitin is often combined with glucosamine. Several studies have evaluated chondroitin used alone, as well, with some positive results, both for improving symptoms and slowing the progression of the disease. On balance, however, the evidence for chondroitin’s effectiveness for osteoroarthritis remains inconsistent.¹⁹⁷

Read more details about Chondroitin Sulfate.

Symptom Relief

According to some but not all double-blind, placebo-controlled studies chondroitin may relieve symptoms of osteoarthritis.

One study enrolled 85 people with osteoarthritis of the knee and followed them for 6 months.³⁴ Participants received either 400 mg of chondroitin sulfate twice daily or placebo. At the end of the trial, doctors rated the improvement as good or very good in 69% of those taking chondroitin sulfate but in only 32% of those taking placebo.

Another way of comparing the results is to look at maximum walking speed among participants. Whereas individuals in the chondroitin group were able to improve their walking speed gradually over the course of the trial, walking speed did not improve at all in the placebo group. Additionally, there were improvements in other measures of osteoarthritis, such as pain level, with benefits seen as early as 1 month. This suggests that chondroitin was able to stop the arthritis from gradually getting worse.

Good results were seen in a 12-month, double-blind trial that compared chondroitin against placebo in 104 individuals with arthritis of the knee,35 as well as in a 12-month trial of 42 participants.³⁶

Another interesting study evaluated intermittent or “on and off” use of chondroitin.121 In this study, 120 people received either placebo or 800 mg of chondroitin sulfate daily for two separate 3-month periods over a year. The results showed that even when taken this way, use of chondroitin improved symptoms.

Benefits were also seen in two short-term trials involving a total of about 240 individuals.^37,38

Generally positive results were also seen in other studies, including one that found chondroitin about as effective as the anti-inflammatory drug diclofenac.^40-42

However, a very large (1,583-participants) and well-designed study failed to find either chondroitin or glucosamine plus chondroitin more effective than placebo.¹⁵³ When this study is pooled together with the two other best designed trials, no overall benefit is seen.185 Yet another study also failed to find benefit with glucosamine plus chondroitin.¹⁸⁷ It has been suggested that chondroitin, like glucosamine, may primarily show benefit in studies funded by manufacturers of chondroitin products.

Research Evidence for how Chondroitin Slows the Progression of Osteoarthritis

Some evidence suggests that, like glucosamine, chondroitin might slow the progression of arthritis.

An important feature of the study of 42 individuals mentioned previously was that the individuals taking a placebo showed progressive joint damage over the year, but among those taking chondroitin sulfate no worsening of the joints was seen.⁴³ In other words, chondroitin sulfate seemed to protect the joints of osteoarthritis sufferers from further damage.

A longer and larger double-blind, placebo-controlled trial also found evidence that chondroitin sulfate can slow the progression of osteoarthritis.⁴⁴ One hundred and nineteen people were enrolled in this study, which lasted a full 3 years. Thirty-four of the participants received 1,200 mg of chondroitin sulfate per day; the rest received placebo. Over the course of the study researchers took x-rays to determine how many joints had progressed to a severe stage.

During the 3 years of the study, only 8.8% of those who took chondroitin sulfate developed severely damaged joints, whereas almost 30% of those who took placebo progressed to this extent.

Similar long-term benefits were seen in two other studies, enrolling a total of more than 200 people.^45,122

Additional evidence comes from animal studies. Researchers measured the effects of chondroitin sulfate (administered both orally and via injection directly into the muscle) in rabbits, in which cartilage damage had been induced in one knee by the injection of an enzyme.⁴⁶ After 84 days of treatment, the damaged knees in the animals that had been given chondroitin sulfate had significantly more cartilage left than the knees of the untreated animals. Taking chondroitin sulfate by mouth was as effective as taking it through an injection.

Looking at the sum of the evidence, it does appear that chondroitin sulfate may actually protect joints from damage in osteoarthritis. However, the scientific record suffers from a paucity of truly independent researchers.

Chondroitin is not an essential nutrient, meaning it is not made in our bodies, and must be obtained through diet. Animal cartilage is the only dietary source of chondroitin. (When it's on your plate, animal cartilage is called gristle.) If you chew gristle, you may be able to obtain chondroitin naturally. Otherwise, you'd con obtain chondroitin in pill form from a health food store or pharmacy.

The usual dosage of chondroitin is 400 mg taken 3 times daily, indefinitely. Two studies used an "on and off" schedule of chondroitin (taking it for 3 months, going off of it for 3 months, and then taking it again).¹²¹ Other studies involved taking chondroitin daily. Regardless of which way you use it, be patient! The results are thought to take weeks to develop.

In commercial products, chondroitin is often combined with glucosamine. Preliminary information from one animal study suggests that this combination may be superior to either treatment alone.^204,205

Not all supplements are created equally! There are large differences between chondroitin products based on their chemical structure.²⁰⁶ This can be expected to lead to significant differences in absorption and hence effectiveness. Most likely, chondroitin products with physically smaller molecules (fewer than 16,900 daltons) are better absorbed. In addition, a review conducted in 2003 by the respected testing organization, Consumerlab.com, found that some products sold as providing chondroitin actually contained far less chondroitin (or even none at all) than stated on the label.²⁰⁷ It may be advisable to use the exact products that were tested in double-blind trials.

Chondroitin generally does not cause much in the way of side effects, besides occasional mild digestive distress.

However, there is one case report of an exacerbation of asthma caused by use of a glucosamine-chondroitin product.²¹⁰

In addition, there are theoretical concerns that chondroitin might have a mild blood-thinning effect, based on its chemical similarity to the anticoagulant drug heparin. Reassuringly, there are no case reports of any problems relating to this, and studies suggest that chondroitin has at most a mild anticoagulant effect.³⁶ Nonetheless, prudence suggests that, based on these findings, chondroitin should not be combined with blood-thinning drugs, such as warfarin (Coumadin), heparin, and aspirin, except under physician supervision. In addition, individuals with bleeding problems, such as hemophilia, or who are temporarily at risk for bleeding (for example, undergoing surgery or labor and delivery) should avoid chondroitin.

Interactions You Should Know About

If you are using drugs that impair blood coagulation, such as warfarin (Coumadin), heparin, aspirin, clopidogrel (Plavix), ticlopidine (Ticlid), or pentoxifylline (Trental), do not use chondroitin except under physician supervision.

1. Brandt KD. Effects of nonsteroidal anti-inflammatory drugs on chondrocyte metabolism in vitro and in vivo. Am J Med. 1987;83(5A):29-34.
   2. Brooks PM, Potter SR, Buchanan WW. NSAID and osteoarthritis—help or hindrance? J Rheumatol. 1982;9:3-5.
   3. Shield MJ. Anti-inflammatory drugs and their effects on cartilage synthesis and renal function. Eur J Rheumatol Inflamm. 1993;13:7-16.
   4. Palmoski MJ, Brandt KD. Effects of some nonsteroidal antiinflammatory drugs on proteoglycan metabolism and organization in canine articular cartilage. Arthritis Rheum. 1980;23:1010-1020.
   5. Rashad S, Revell P, Hemingway A et al. Effect of non-steroidal anti-inflammatory drugs on the course of osteoarthritis. Lancet. 1989;2:519-522.
   6. Jimenez SA. The effects of glucosamine on human chondrocyte gene expression. Presented at: The Ninth EULAR Symposium; October 7-10, 1996; Madrid, Spain.
   7. Hellio MP. The effects of glucosamine on human osteoarthritic chondrocytes. Presented at: The Ninth EULAR Symposium; October 7-10, 1996; Madrid, Spain.
   8. Setnikar I, Pacini MA, Revel L. Antiarthritic effects of glucosamine sulfate studied in animal models. Arzneimittelforschung. 1991;41:542-545.
   9. Setnikar I. Antireactive properties of "chondroprotective" drugs. Int J Tissue React. 1992;14:253-261.
   10. Crolle G, D'Este E. Glucosamine sulphate for the management of arthrosis: a controlled clinical investigation. Curr Med Res Opin. 1980;7:104-109.
   11. Qiu GX, Gao SN, Giacovelli G, et al. Efficacy and safety of glucosamine sulfate versus ibuprofen in patients with knee osteoarthritis. Arzneimittelforschung. 1998;48:469-474.
   12. Karzel K, Domenjoz R. Effects of hexosamine derivatives and uronic acid derivatives on glycosaminoglycane metabolism of fibroblast cultures. Pharmacology. 1971;5:337-345.
   13. Vidal y Plana RR, Bizzarri D, Rovati AL. Articular cartilage pharmacology: I. In vitro studies on glucosamine and non steroidal antiinflammatory drugs. Pharmacol Res Commun. 1978;10:557-569.
   14. Noack W, Fischer M, Frster KK, et al. Glucosamine sulfate in osteoarthritis of the knee. Osteoarthritis Cartilage. 1994;2:51-59.
   15. Rovati LC. A large, randomized, placebo controlled, double-blind study of glucosamine sulfate vs. piroxicam and vs. their association, on the kinetics of the symptomatic effect in knee osteoarthritis. Osteoarthritis Cartilage. 1994;2(suppl 1):56.
   16. Muller-Fassbender H, Bach GL, Haase W, et al. Glucosamine sulfate compared to ibuprofen in osteoarthritis of the knee. Osteoarthritis Cartilage. 1994;2:61-69.
   17. Qiu GX, Gao SN, Giacovelli G, et al. Efficacy and safety of glucosamine sulfate versus ibuprofen in patients with knee osteoarthritis. Arzneimittelforschung. 1998;48:469-474.
   18. Thie NM, Prasad NG, Major PW. Evaluation of glucosamine sulfate compared to ibuprofen for the treatment of temporomandibular joint osteoarthritis: a randomized double blind controlled 3 month clinical trial. J Rheumatol. 2001;28:1347-1355.
   19. Rindone JP, Hiller D, Collacott E, et al. Randomized, controlled trial of glucosamine for treating osteoarthritis of the knee. West J Med. 2000;172:91-94.
   20. Houpt JB, McMillan R, Wein C, et al. Effect of glucosamine hydrochloride in the treatment of pain of osteoarthritis of the knee. J Rheumatol. 1999;26:2423-2430.
   21. Reginster JY, Deroisy R, Rovati L, et al. Long-term effects of glucosamine sulphate on osteoarthritis progression: a randomised, placebo-controlled clinical trial. Lancet 2001;357:251-256.
   22. Das A Jr, Hammad TA. Efficacy of a combination of FCHG49 glucosamine hydrochloride, TRH122 low molecular weight sodium chondroitin sulfate and manganese ascorbate in the management of knee osteoarthritis. Osteoarthritis Cartilage. 2000;8:343-350.
   32. Conte A, Volpi N, Palmieri L, et al. Biochemical and pharmacokinetic aspects of oral treatment with chondroitin sulfate. Arzneimittelforschung. 1995;45:918-925.
   33. Hungerford DS. Treating osteoarthritis with chondroprotective agents. Orthopedic Special Edition. 1998;4:39-42.
   34. Bucsi L, Poor G. Efficacy and tolerability of oral chondroitin sulfate as a symptomatic slow-acting drug for osteoarthritis (SYSADOA) in the treatment of knee osteoarthritis. Osteoarthritis Cartilage. 1998;6(suppl A):31-36.
   35. Conrozier T. Anti-arthrosis treatments: efficacy and tolerance of chondroitin sulfates (CS 4&6) [translated from French]. Presse Med. 1998;27:1862-1865.
   36. Uebelhart D, Thonar EJ, Delmas PD, et al. Effects of oral chondroitin sulfate on the progression of knee osteoarthritis: a pilot study. Osteoarthritis Cartilage. 1998;6(suppl A):39-46.
   37. Bourgeois P, Chales G, Dehais J, et al. Efficacy and tolerability of chondroitin sulfate 1200 mg/day vs chondroitin sulfate 3 x 400 mg/day vs placebo. Osteoarthritis Cartilage. 1998;6(suppl A):25-30.
   38. Mazieres B, Loyau G, Menkes CJ, et al. Chondroitin sulfate in the treatment of gonarthrosis and coxarthrosis. 5-months result of a multicenter double-blind controlled prospective study using placebo [in French; English abstract]. Rev Rhum Mal Osteoartic. 1992;59:466-472.
   39. Das A Jr, Hammad TA. Efficacy of a combination of FCHG49 glucosamine hydrochloride, TRH122 low molecular weight sodium chondroitin sulfate and manganese ascorbate in the management of knee osteoarthritis. Osteoarthritis Cartilage. 2000;8:343-350.
   40. L'Hirondel JL. Double-blind clinical study with oral administration of chondroitin sulphate versus placebo in tibiofemoral gonarthrosis (125 patients) [in German]. Litera Rheumatol. 1992;14:77-84.
   41. Morreale P, Manopulo R, Galati M, et al. Comparison of the antiinflammatory efficacy of chondroitin sulfate and diclofenac sodium in patients with knee osteoarthritis. J Rheumatol. 1996;23:1385-1391.
   42. Mazieres B, Combe B, Phan Van A, et al. Chondroitin sulfate in osteoarthritis of the knee: a prospective, double blind, placebo controlled multicenter clinical study. J Rheumatol. 2001;28:173-181.
   43. Uebelhart D, Thonar EJ, Delmas PD, et al. Effects of oral chondroitin sulfate on the progression of knee osteoarthritis: a pilot study. Osteoarthritis Cartilage. 1998;6(suppl A):39-46.
   44. Verbruggen G, Goemaere S, Veys EM. Chondroitin sulfate: S/DMOAD (structure/disease modifying anti-osteoarthritis drug) in the treatment of finger joint OA. Osteoarthritis Cartilage. 1998;6(suppl A):37-38.
   45. Conrozier T. Anti-arthrosis treatments: efficacy and tolerance of chondroitin sulfates (CS 4&6) [translated from French]. Presse Med. 1998;27:1862-1865.
   46. Uebelhart D, Thonar EJ, Zhang J, et al. Protective effect of exogenous chondroitin 4,6-sulfate in the acute degradation of articular cartilage in the rabbit. Osteoarthritis Cartilage. 1998;6(suppl A):6-13.
   50. di Padova C. S-adenosylmethionine in the treatment of osteoarthritis. Review of the clinical studies. Am J Med. 1987;83(5A):60-65.
   51. Caruso I, Peitrogrande V. Italian double-blind multicenter study comparing S-adenosylmethionine, naproxen and placebo in the treatment of degenerative joint disease. Am J Med. 1987;83(5A):66-71.
   52. Kalbhen DA, Jansen G. Pharmacological studies on the antidegenerative effect of ademetionine in experimental osteoarthritis [in German; English abstract]. Arzneimittelforschung. 1990;40:1017-1021.
   53. Barcelo HA, Wiemeyer JC, Sagasta CL, et al. Experimental osteoarthritis and its course when treated with S-adenosyl-L-methionine (SAMe) [in Spanish; English abstract]. Rev Clin Esp. 1990;187:74-78.
   64. Jonas WB, Rapoza CP, Blair WF. The effect of niacinamide on osteoarthritis: a pilot study. Inflamm Res. 1996;45:330-334.
   65. European Scientific Cooperative on Phytotherapy. Harpagophyti radix (devil's claw). Monographs on the Medicinal Uses of Plant Drugs. Exeter, UK; 1996-1997.
   66. Leblan D, Chantre P, Fournie B. Harpagophytum procumbens in the treatment of knee and hip osteoarthritis. Four-month results of a prospective, multicenter, double-blind trial versus diacerhein. Joint Bone Spine. 2000;67:462-467.
   69. Schmid B, Ludtke R, Selbmann HK, et al. Efficacy and tolerability of a standardized willow bark extract in patients with osteoarthritis: randomized, placebo-controlled, double blind clinical trial [translated from German]. Z Rheumatol. 2000;59:314-320.
   70. European Scientific Cooperative on Phytotherapy. Salicis cortex Monographs on the Medicinal Uses of Plant Drugs. Exeter, UK; 1996-1997.
   71. Chrubasik S, Eisenberg E, Balan E, et al. Treatment of low back pain exacerbations with willow bark extract: a randomized double-blind study. Am J Med. 2000;109:9-14.
   72. Fink MG, Kunsebeck HW, Wippermann B. Effect of needle acupuncture on pain perception and functional impairment of patients with coxarthrosis [in German; English abstract]. Z Rheumatol. 2000;59:191-199.
   73. Yurtkuran M, Kocagil T. TENS, electroacupuncture and ice massage: comparison of treatment for osteoarthritis of the knee. Am J Acupunct. 1999;27:133-140.
   74. Ernst E. Acupuncture as a symptomatic treatment of osteoarthritis. A systematic review. Scand J Rheumatol. 1997;26:444-447.
   75. Takeda W, Wessel J. Acupuncture for the treatment of pain of osteoarthritic knees. Arthritis Care Res. 1994;7:118-122.
   76. Thomas M, Eriksson SV, Lundeberg T. A comparative study of diazepam and acupuncture in patients with osteoarthritis pain: a placebo-controlled study. Am J Chin Med. 1991;19:95-100.
   77. McIndoe AK, Young K, Bone ME. A comparison of acupuncture with intra-articular steroid injection as analgesia for osteoarthritis of the hip. Acupunct Med. 1995;13:67-70.
   78. Seppo Y, Junnila T. Acupuncture superior to Piroxicam in the treatment of osteoarthrosis. Am J Acupunct. 1982;10.
   79. McAlindon TE, Jacques P, Zhang Y, et al. Do antioxidant micronutrients protect against the development and progression of knee osteoarthritis? Arthritis Rheum. 1996;39:648-656.
   80. Randall C, Randall H, Dobbs F, et al. Randomized controlled trial of neetle sting for the treatment of base-of-thumb pain. J R Soc Med. 2000;93:305-309.
   81. Kulkarni RR, Patki PS, Jog VP, et al. Treatment of osteoarthritis with a herbomineral formulation: a double-blind, placebo-controlled, cross-over study. J Ethnopharmacol. 1991;33:91-95.
   82. Bui LM, Pawlowski K, Bierer TL. The influence of green-lipped mussel powder ( Perna canaliculus) on alleviating arthritic signs in dogs [abstract]. FASEB J. 2000;14:A218.
   83. Bui LM, Pawlowski K, Bierer TL. A semi-moist treat containing green-lipped mussel ( Perna canaliculus) can help to alleviate arthritic signs in dogs [abstract]. FASEB J. 2000;14:A748.
   84. Bui LM, Pawlowski K, Bierer TL. Reduction of arthritic signs in dogs fed a mainmeal dry diet containing green-lipped mussel ( Perna canaliculus) [abstract]. FASEB J. 2000;14:A748.
   85. Appelboom T, Schuermans J, Verbruggen G, et al. Symptoms modifying effect of avocado/soybean unsaponifiables (ASU) in knee osteoarthritis. A double blind, prospective, placebo-controlled study. Scand J Rheumatol. 2001;30:242-247.
   86. Mauviel A, Daireaux M, Hartmann DJ, et al. Effects of unsaponifiable extracts of avocado/soy beans (PIAS) on the production of collagen by cultures of synoviocytes, articular chondrocytes and skin fibroblasts [in French]. Rev Rhum Mal Osteoartic. 1989;56:207-211.
   87. Mauviel A, Loyau G, Pujol JP. Effect of unsaponifiable extracts of avocado and soybean (Piascledine) on the collagenolytic action of cultures of human rheumatoid synoviocytes and rabbit articular chondrocytes treated with interleukin-1 [in French; English abstract]. Rev Rhum Mal Osteoartic. 1991;58:241-245.
   88. Mazieres B, Tempesta C, Tiechard M, et al. Pathologic and biochemical effects of a lipidic avocado and soya extract on an experimental post-contusive model of OA [abstract]. Osteoarthritis Cartilage. 1993;1:46.
   89. Boumediene K, Felisaz N, Bogdanowicz P, et al. Avocado/soya unsaponifiables enhance the expression of transforming growth factor beta1 and beta2 in cultured articular chondrocytes. Arthritis Rheum. 1999;42:148-156.
   90. Henrotin YE, Labasse AH, Jaspar JM, et al. Effects of three avocado/soybean unsaponifiable mixtures on metalloproteinases, cytokines and prostaglandin E2 production by human articular chondrocytes. Clin Rheumatol. 1998;17:31-39.
   91. Maheu E, Mazieres B, Valat JP, et al. Symptomatic efficacy of avocado/soybean unsaponifiables in the treatment of osteoarthritis of the knee and hip: a prospective, randomized, double-blind, placebo-controlled, multicenter clinical trial with a six-month treatment period and a two-month followup demonstrating a persistent effect. Arthritis Rheum. 1998;41:81-91.
   92. Blotman F, Maheu E, Wulwik A, et al. Efficacy and safety of avocado/soybean unsaponifiables in the treatment of symptomatic osteoarthritis of the knee and hip: a prospective, multicenter, three-month, randomized, double-blind, placebo-controlled trial. Rev Rhum Engl Ed. 1997;64:825-834.
   93. Appelboom T, Schuermans J, Verbruggen G, et al. Symptoms modifying effect of avocado/soybean unsaponifiables (ASU) in knee osteoarthritis. A double blind, prospective, placebo-controlled study. Scand J Rheumatol. 2001;30:242-247.
   94. Altman RD, Marcussen KC. Effects of a ginger extract on knee pain in patients with osteoarthritis. Arthritis Rheum. 2001;44:2531-2538.
   95. Bliddal H, et al. A randomized, placebo-controlled, cross-over study of ginger extracts and ibuprofen in osteoarthritis. Osteoarthritis Cartilage. 2000;8:9-12
   96. Brand C, Snaddon J, Bailey M, et al. Vitamin E is ineffective for symptomatic relief of knee osteoarthritis: a six month double blind, randomised, placebo controlled study. Ann Rheum Dis. 2001;60:946-949.
   97. Singer F, Oberleitner H. Drug therapy of activated arthrosis. On the effectiveness of an enzyme mixture versus Diclofenac® [translated from German]. Wien Med Wochenschr. 1996;146:55-58.
   98. Klein G, Kullich W. Reducing pain by oral enzyme therapy in rheumatic diseases [translated from German]. Wien Med Wochenschr. 1999;149:577-580.
   99. Hughes R, Carr A. A randomized, double-blind, placebo-controlled trial of glucosamine sulphate as an analgesic in osteoarthritis of the knee. Rheumatology (Oxford). 2002;41:279-284.
   100. Piscoya J, Rodriguez Z, Bustamante SA, et al. Efficacy and safety of freeze-dried cat's claw in osteoarthritis of the knee: mechanisms of action of the species Uncaria guianensis. Inflamm Res. 2001;50:442-448.
   101. Pavelka K, Gatterova J, Olejarova M, et al. Glucosamine sulfate use and delay of progression of knee osteoarthritis: a 3-year, randomized, placebo-controlled, double-blind study. Arch Intern Med. 2002;162:2113-2213.
   102. Fink M, Karst M, Wippermann B, et al. Non-specific effects of traditional Chinese acupuncture in osteoarthritis of the hip: a randomized controlled trial. Complement Ther Med. 2001;9:82-88.
   103. D’Ambrosio E, Casa B, Bompani R, et al. Glucosamine sulphate: a controlled clinical investigation in arthrosis. Pharmatherapeutica. 1981;2:504-508.
   104. Drovanti A, Bignamini AA, Rovati AL. Therapeutic activity of oral glucosamine sulfate in osteoarthrosis: a placebo-controlled double-blind investigation. Clin Ther. 1980;3:260-272.
   105. Nguyen P, Mohamed SE, Gardiner D, et al. A randomized double-blind clinical trial of the effect of chondroitin sulfate and glucosamine hydrochloride on temporomandibular joint disorders: a pilot study. Cranio. 2001;19:130-139.
   106. Cohen M, Wolfe R, Mai T, et al. A randomized, double blind, placebo controlled trial of a topical cream containing glucosamine sulfate, chondroitin sulfate, and camphor for osteoarthritis of the knee. J Rheumatol. 2003;30:523-528.
   107. Kimmatkar N, Thawani V, Hingorani L, et al. Efficacy and tolerability of Boswellia serrata extract in treatment of osteoarthritis of knee—a randomized double blind placebo controlled trial. Phytomedicine. 2003;10:3-7.
   108. Ezzo J, Hadhazy V, Birch S, et al. Acupuncture for osteoarthritis of the knee. Arthritis and Rheum. 2001;44:819-825.
   109. Haslam R. A comparison of acupuncture with advice and exercises on the symptomatic treatment of osteoarthritis of the hip—a randomised controlled trial. Acupunct Med. 2001;19:19-26.
   110. Reeves KD, Hassanein K. Randomized prospective double-blind placebo-controlled study of dextrose prolotherapy for knee osteoarthritis with or without ACL laxity. Altern Ther Health Med. 2000;6:68-70,72-74,77-80.
   111. Reeves KD, Hassanein K. Randomized, prospective, placebo-controlled double-blind study of dextrose prolotherapy for osteoarthritic thumb and finger (DIP, PIP, and trapeziometacarpal) joints: evidence of clinical efficacy. J Altern Complement Med. 2000;6:311-320.
   112. Trock DH, Bollet AJ, Dyer RH Jr, et al. A double-blind trial of the clinical effects of pulsed electromagnetic fields in osteoarthritis. J Rheumatol. 1993;20:456-460.
   113. Trock DH, Bollet AJ, Markoll R. The effect of pulsed electromagnetic fields in the treatment of osteoarthritis of the knee and cervical spine. Report of randomized, double blind, placebo controlled trials. J Rheumatol. 1994;21:1903-1911.
   114. Jacobson JI, Gorman R, Yamanashi WS, et al. Low-amplitude, extremely low frequency magnetic fields for the treatment of osteoarthritic knees: a double-blind clinical study. Altern Ther Health Med. 2001;7:54-60,62-64,66-69.
   115. Nicolakis P, Kollmitzer J, Crevenna R, et al. Pulsed magnetic field therapy for osteoarthritis of the knee—a double-blind sham-controlled trial. Wien Klin Wochenschr. 2002;114:678-684.
   116. Jung YB, Roh KJ, Jung JA, et al. Effect of SKI 306X, a new herbal anti-arthritic agent, in patients with osteoarthritis of the knee: a double-blind placebo controlled study. Am J Chin Med. 2001;29:485-491.
   117. Garfinkel MS, Schumacher HR Jr, Husain A, et al. Evaluation of a yoga based regimen for treatment of osteoarthritis of the hands. J Rheumatol. 1994;21:2341-2343.
   118. Wluka AE, Stuckey S, Brand C, et al. Supplementary vitamin E does not affect the loss of cartilage volume in knee osteoarthritis: a 2 year double blind randomized placebo controlled study. J Rheumatol. 2002;29:2585-2591.
   119. Pavelka K, Gatterova J, Gollerova V, et al. A 5-year randomized controlled, double-blind study of glycosaminoglycan polysulphuric acid complex (Rumalon®) as a structure modifying therapy in osteoarthritis of the hip and knee. Osteoarthritis Cartilage. 2000;8:335-342
   120. Richy F, Bruyere O, Ethgen O, et al. Structural and symptomatic efficacy of glucosamine and chondroitin in knee osteoarthritis: a comprehensive meta-analysis. Arch Intern Med. 2003;163:1514-22.
   121. Uebelhart D, Malaise M, Marcolongo R et al. Intermittent treatment of knee osteoarthritis with oral chondroitin sulfate: a one-year, randomized, double-blind, multicenter study versus placebo. Osteoarthritis Cartilage. 2004;12:269-276.
   122. Uebelhart D, Malaise M, Marcolongo R et al. Intermittent treatment of knee osteoarthritis with oral chondroitin sulfate: a one-year, randomized, double-blind, multicenter study versus placebo. Osteoarthritis Cartilage. 2004;12:269-276.
   123. Najm WI, Reinsch S, Hoehler F, et al. S-Adenosyl methionine (SAMe) versus celecoxib for the treatment of osteoarthritis symptoms: A double-blind cross-over trial. BMC Musculoskelet Disord. 2004;5:6.
   124. Wolsko PM, Eisenberg DM, Simon LS et al. Double-blind placebo-controlled trial of static magnets for the treatment of osteoarthritis of the knee: results of a pilot study. Altern Ther Health Med. 2004;10:36-43.
   125. Ernst E. Avocado-soybean unsaponifiables (ASU) for osteoarthritis—a systematic review. Clin Rheumatol. 2003;22:285-288.
   126. Lequesne M, Maheu E, Cadet C et al.Structural effect of avocado/soybean unsaponifiables on joint space loss in osteoarthritis of the hip. Arthritis Rheum. 2002;47:50-58.
   127. Wigler I, Grotto I, Caspi D, Yaron M. The effects of Zintona EC (a ginger extract) on symptomatic gonarthritis. Osteoarthritis Cartilage. 2003;11:783-789.
   128. Kraemer WJ, Ratamess NA, Anderson JM et al. Effect of a cetylated fatty acid topical cream on functional mobility and quality of life of patients with osteoarthritis. J Rheumatol. 2004;31:767-74.
   129. Gemmell HA, Jacobson BH, Hayes BM. Effect of a topical herbal cream on osteoarthritis of the hand and knee: a pilot study. J Manipulative Physiol Ther. 2003;26:E15.
   130. Cho SH, Jung YB, Seong SC, et al. Clinical efficacy and safety of Lyprinol, a patented extract from New Zealand green-lipped mussel ( Perna canaliculus) in patients with osteoarthritis of the hip and knee: a multicenter 2-month clinical trial. Allerg Immunol (Paris). 2003;35:212-216.
   131. Audeval B, Bouchacourt P. Etude controle en double aveugle contra placebo de l’extrait de moule Perna canaliculus dans les gonarthrose. Gaz Med Fr. 1986;38:111-116.
   132. Caughey DE, Grigor RR, Caughey EB, et al. Perna canaliculus in the treatment of rheumatoid arthritis. Eur J Rheumatol Inflamm. 1983;6:197-200.
   133. Gibson RG, Gibson SL, Conway V, et al. Perna canaliculus in the treatment of arthritis. Practitioner. 1980;224:955-960.
   134. Gibson RG, Gibson SL. Green-lipped mussel extract in arthritis [letter]. Lancet. 1981;1:439.
   135. Gibson SLM, Gibson RG. The treatment of arthritis with a lipid extract of Perna canaliculus: a randomized trial. Comp Ther Med. 1998;6:122-6.
   136. Bui LM, Bierer TL. Influence of green lipped mussels ( Perna canaliculus) in alleviating signs of arthritis in dogs. Vet Ther. 2003;4:397-407.
   137. Moreau M, Dupuis J, Bonneau NH, Lecuyer M. Links Clinical evaluation of a powder of quality elk velvet antler for the treatment of osteoarthrosis in dogs. Can Vet J. 2004;45:133-139.
   138. Usha P.R., Naidu M.U.R. Randomised, double-blind, parallel, placebo-controlled study of oral glucosamine, methylsulfonylmethane and their combination in osteoarthritis. Clinical Drug Investigation. 2004;24:353-363.
   139. McAlindon T, Formica M, LaValley M, et al. Effectiveness of glucosamine for symptoms of knee osteoarthritis: results from an internet-based randomized double-blind controlled trial. Am J Med. 2004;117:643-649.
   140. Cibere J, Kopec JA, Thorne A, et al. Randomized, double-blind, placebo-controlled glucosamine discontinuation trial in knee osteoarthritis. Arthritis Rheum. 2004 Oct 11. [Epub ahead of print]
   141. Bjordal JM, Ljunggren AE, Klovning A, et al. Nonsteroidal anti-inflammatory drugs, including cyclo-oxygenase-2 inhibitors, in osteoarthritic knee pain: meta-analysis of randomised placebo controlled trials. BMJ. 2004 Nov 23. [Epub ahead of print]
   142. Biegert C, Wagner I, Ludtke R, et al. Efficacy and safety of willow bark extract in the treatment of osteoarthritis and rheumatoid arthritis: results of 2 randomized double-blind controlled trials. J Rheumatol. 2004;31:2121-2130.
   143. Rein E, Kharazmi A, Winther K, et al. A herbal remedy, Hyben Vital (stand. powder of a subspecies of Rosacanina fruits), reduces pain and improves general wellbeing in patients with osteoarthritis—a double-blind, placebo-controlled, randomised trial. Phytomedicine. 2004;11:383-391.
   144. Towheed T, Maxwell L, Anastassiades T, et al. Glucosamine therapy for treating osteoarthritis. Cochrane Database Syst Rev. 2005;CD002946.
   145. Kraemer WJ, Ratamess NA, Maresh CM et al. Effects of treatment with a cetylated fatty acid topical cream on static postural stability and plantar pressure distribution in patients with knee osteoarthritis. J Strength Cond Res. 2005;19:115-121.
   146. Kraemer, WJ, et al. One week of treatment with a cetylated fatty acid topical cream with menthol reduces pain and improves functional performance in patients with arthritis of the knee, elbow, and wrist. J Strength and Cond Res. 2005;19: in press.
   147. Hesslink R Jr, Armstrong D 3rd, Nagendran MV, et al. Cetylated fatty acids improve knee function in patients with osteoarthritis. J Rheumatol. 2002;29:1708-1712.
   148. Berman BM, Lao L, Langenberg P, et al. Effectiveness of acupuncture as adjunctive therapy in osteoarthritis of the knee: a randomized, controlled trial. Ann Intern Med. 2004;141:901-910.
   149. Harlow T, Greaves C, White A, et al. Randomised controlled trial of magnetic bracelets for relieving pain in osteoarthritis of the hip and knee. BMJ. 2004;329:1450-1454.
   150. Arjmandi BH, Khalil DA, Lucas EA, et al. Soy protein may alleviate osteoarthritis symptoms. Phytomedicine. 2005;11:567-575.
   151. Teekachunhatean S, Kunanusorn P, Rojanasthien N, et al. Chinese herbal recipe versus diclofenac in symptomatic treatment of osteoarthritis of the knee: a randomized controlled trial [ISRCTN70292892]. BMC Complement Altern Med. 2004 Dec 13. [Epub ahead of print].
   152. Clegg DO, Reda DJ, Harris CL, et al. Glucosamine, chondroitin sulfate, and the two in combination for painful knee osteoarthritis. N Engl J Med. 2006;354:795-808.
   153. Clegg DO, Reda DJ, Harris CL, et al. Glucosamine, chondroitin sulfate, and the two in combination for painful knee osteoarthritis. N Engl J Med. 2006;354:795-808.
   154. Witt C, Brinkhaus B, Jena S, et al. Acupuncture in patients with osteoarthritis of the knee: a randomised trial. Lancet. 2005;366:136-143.
   155. Kim LS, Axelrod LJ, Howard P, et al. Efficacy of methylsulfonylmethane (MSM) in osteoarthritis pain of the knee: a pilot clinical trial. Osteoarthritis Cartilage. 2005 Nov 22. [Epub ahead of print]
   156. Miller MJ, Mehta K, Kunte S et al. Early relief of osteoarthritis symptoms with a natural mineral supplement and a herbomineral combination: a randomized controlled trial [ISRCTN38432711]. J Inflamm (Lond). 2005 Oct 21. [Epub ahead of print]
   157. Leblan D, Chantre P, Fournie B. Harpagophytum procumbens in the treatment of knee and hip osteoarthritis. Four-month results of a prospective, multicenter, double-blind trial versus diacerhein. Joint Bone Spine. 2000;67:462-467.
   158. Chrubasik S, Model A, Black A, et al. A randomized double-blind pilot study comparing Doloteffin and Vioxx in the treatment of low back pain. Rheumatology (Oxford). 2003;42:141-148.
   159. Akhtar NM, Naseer R, Farooqi AZ, et al. Oral enzyme combination versus diclofenac in the treatment of osteoarthritis of the knee--a double-blind prospective randomized study. Clin Rheumatol. 2004;23:410-415.
   160. Klein G, Kullich W, Schnitker J, et al. Efficacy and tolerance of an oral enzyme combination in painful osteoarthritis of the hip. A double-blind, randomised study comparing oral enzymes with non-steroidal anti-inflammatory drugs. Clin Exp Rheumatol. 2006;24:25-30.
   161. Chrubasik C, Duke RK, Chrubasik S, et al. The evidence for clinical efficacy of rose hip and seed: a systematic review. Phytother Res. 2006 Jan 5. [Epub ahead of print]
   162. Winther K, Apel K, Thamsborg G, et al. A powder made from seeds and shells of a rose-hip subspecies (Rosa canina) reduces symptoms of knee and hip osteoarthritis: a randomized, double-blind, placebo-controlled clinical trial. Scand J Rheumatol. 2005;34:302-308.
   163. Modawal A, Ferrer M, Choi HK, et al. Hyaluronic acid injections relieve knee pain. J Fam Pract. 2005;54:758-767.
   164. Petrella RJ, Petrella M. A prospective, randomized, double-blind, placebo controlled study to evaluate the efficacy of intraarticular hyaluronic Acid for osteoarthritis of the knee. J Rheumatol. 2006;33:951-956.
   165. Bellamy N, Campbell J, Robinson V, et al. Viscosupplementation for the treatment of osteoarthritis of the knee. Cochrane Database Syst Rev. 2005;CD005321.
   166. Salk RS, Chang TJ, D'Costa WF, et al. Sodium hyaluronate in the treatment of osteoarthritis of the ankle: a controlled, randomized, double-blind pilot study. J Bone Joint Surg Am. 2006;88:295-302.
   167. Cobb CS, Ernst E. Systematic review of a marine nutriceutical supplement in clinical trials for arthritis: the effectiveness of the New Zealand green-lipped mussel Perna canaliculus. Clin Rheumatol. 2005 Oct 12. [Epub ahead of print].
   168. Lee JD, Park HJ, Chae Y, et al. An overview of bee venom acupuncture in the treatment of arthritis. Evid Based Complement Alternat Med. 2005;2:79-84.
   169. Scharf HP, Mansmann U, Streitberger K, et al. Acupuncture and knee osteoarthritis: a three-armed randomized trial. Ann Intern Med. 2006;145:12-20
   170. Scharf HP, Mansmann U, Streitberger K, et al. Acupuncture and knee osteoarthritis: a three-armed randomized trial. Ann Intern Med. 2006;145:12-20
   171. Kwon YD, Pittler MH, Ernst E. Acupuncture for peripheral joint osteoarthritis: A systematic review and meta-analysis. Rheumatology (Oxford). 2006 Aug 27. [Epub ahead of print]
   172. Baird CL, Sands LP. Effect of guided imagery with relaxation on health-related quality of life in older women with osteoarthritis. Res Nurs Health. 2006 Sep 14. [Epub ahead of print]
   173. Fernandez Lopez JC, Ruano-Ravina A. Efficacy and safety of intraarticular hyaluronic acid in the treatment of hip osteoarthritis: a systematic review. Osteoarthritis Cartilage. 2006 Sep 14. [Epub ahead of print]
   174. Chopra A, Lavin P, Patwardhan B, et al. A 32-week randomized, placebo-controlled clinical evaluation of RA-11, an ayurvedic drug, on osteoarthritis of the knees. J Clin Rheumatol. 2006;10:236-245.
   175. Brien S, Lewith G, Walker AF, et al. Bromelain as an adjunctive treatment for moderate-to-severe osteoarthritis of the knee: a randomized placebo-controlled pilot study. QJM. 2006;99:841-850.
   176. Yurtkuran M, Yurtkuran M, Alp A, et al. Balneotherapy and tap water therapy in the treatment of knee osteoarthritis. Rheumatol Int. 2006 Jul 11. [Epub ahead of print]
   177. Tishler M, Rosenberg O, Levy O, et al. The effect of balneotherapy on osteoarthritis. Is an intermittent regimen effective? Eur J Intern Med. 2004;15:93-96.
   178. Fioravanti A, Valenti M, Altobelli E, et al. Clinical efficacy and cost-effectiveness evidence of spa therapy in osteoarthritis. The results of "Naiade" Italian Project. Panminerva Med. 2003;45:211-217.
   179. Guillemin F, Virion JM, Escudier P, et al. Effect on osteoarthritis of spa therapy at Bourbonne-les-Bains. Joint Bone Spine. 2002;68:499-503.
   180. Sukenik S, Flusser D, Codish S, et al. Balneotherapy at the Dead Sea area for knee osteoarthritis. Isr Med Assoc J. 2000;1:83-85.
   181. Grube B, Grunwald J, Krug L, et al. Efficacy of a comfrey root (Symphyti offic. radix) extract ointment in the treatment of patients with painful osteoarthritis of the knee: Results of a double-blind, randomised, bicenter, placebo-controlled trial. Phytomedicine. 2006 Dec 12. [Epub ahead of print]
   182. Herrero-Beaumont G, Ivorra JA, Del Carmen Trabado M, et al. Glucosamine sulfate in the treatment of knee osteoarthritis symptoms: a randomized, double-blind, placebo-controlled study using acetaminophen as a side comparator. Arthritis Rheum. 2007 Jan 30. [Epub ahead of print].
   183. Brismee JM, Paige RL, Chyu MC, et al. Group and home-based tai chi in elderly subjects with knee osteoarthritis: a randomized controlled trial. Clin Rehabil. 2007;21:99-111.
   184. Deutsch L. Evaluation of the effect of neptune krill oil on chronic inflammation and arthritic symptoms. J Am Coll Nutr. 2007;26:39-48.
   185. Reichenbach S, Sterchi R, Scherer M, et al. Meta-analysis: chondroitin for osteoarthritis of the knee or hip. Ann Intern Med. 2007;146:580-590.
   186. Karagulle M, Karagulle MZ, Karagulle O, et al. A 10-day course of SPA therapy is beneficial for people with severe knee osteoarthritis: a 24-week randomised, controlled pilot study. Clin Rheumatol. 2007 Apr 13. [Epub ahead of print]
   187. Messier SP, Mihalko S, Loeser RF, et al. Glucosamine/chondroitin combined with exercise for the treatment of knee osteoarthritis: a preliminary study. Osteoarthritis Cartilage. 2007 Jun 8. [Epub ahead of print]
   188. Rossnagel K, Roll S, Willich SN. The clinical effectiveness of rosehip powder in patients with osteoarthritis [a systematic review]. MMW Fortschr Med. 2007;149:51-56.
   189. Manheimer E, Linde K, Lao L, et al. Meta-analysis: acupuncture for osteoarthritis of the knee. Ann Intern Med. 2007;146:868-877.
   190. Bruyere O, Pavelka K, Rovati LC, et al. Total joint replacement after glucosamine sulphate treatment in knee osteoarthritis: results of a mean 8-year observation of patients from two previous 3-year, randomised, placebo-controlled trials. Osteoarthritis Cartilage. 2007 Jul 26. [Epub ahead of print]
   191. Foster NE, Thomas E, Barlas P, et al. Acupuncture as an adjunct to exercise based physiotherapy for osteoarthritis of the knee: randomised controlled trial. BMJ. 2007 Aug 15. [Epub ahead of print]
   192. White A, Foster N, Cummings M, et al. The effectiveness of acupuncture for osteoarthritis of the knee: a systematic review. Acupunct Med. 2006;24(suppl):S40-S48.
   193. Lee MS, Pittler MH, Ernst E. Tai chi for osteoarthritis: a systematic review. Clin Rheumatol. 2007 Sep 14. [Epub ahead of print]
   194. Kalman DS, Heimer M, Valdeon A, et al. Effect of a natural extract of chicken combs with a high content of hyaluronic acid (Hyal-Joint®) on pain relief and quality of life in subjects with knee osteoarthritis: a pilot randomized double-blind placebo-controlled trial. Nutr J. 2008 Jan 21.
   195. Petrella RJ, Cogliano A, Decaria J. Combining two hyaluronic acids in osteoarthritis of the knee: a randomized, double-blind, placebo-controlled trial. Clin Rheumatol. 2008 Jan 17.
   196. Rozendaal RM, Koes BW, van Osch GJ, et al. Effect of glucosamine sulfate on hip osteoarthritis: a randomized trial. Ann Intern Med. 2008;148:268-277.
   197. Brien S, Prescott P, Bashir N, et al. Systematic review of the nutritional supplements dimethyl sulfoxide (DMSO) and methylsulfonylmethane (MSM) in the treatment of osteoarthritis. Osteoarthritis Cartilage. 2008 Apr 14.
   198. Kawasaki T, Kurosawa H, Ikeda H, et al. Additive effects of glucosamine or risedronate for the treatment of osteoarthritis of the knee combined with home exercise: a prospective randomized 18-month trial. J Bone Miner Metab. 2008;26:279-287.
   199. Yip YB, Tam AC. An experimental study on the effectiveness of massage with aromatic ginger and orange essential oil for moderate-to-severe knee pain among the elderly in Hong Kong. Complement Ther Med. 2008;16:131-138.
   200. Jubb R, Tukmachi E, Jones P, et al. A blinded randomised trial of acupuncture (manual and electroacupuncture) compared with a non-penetrating sham for the symptoms of osteoarthritis of the knee. Acupunct Med. 2008;26:69-78.
   201. Chen CY, Chen CL, Hsu SC, et al. Effect of magnetic knee wrap on quadriceps strength in patients with symptomatic knee osteoarthritis. Arch Phys Med Rehabil. 2008;89:2258-2264.
   202. Wandel S, Jüni P, Tendal B, et al. Effects of glucosamine, chondroitin, or placebo in patients with osteoarthritis of hip or knee: network meta-analysis. BMJ. 2010;341:c4675.
   203. Qiu GX, Weng XS, Zhang K, et al. A multi-central, randomized, controlled clinical trial of glucosamine hydrochloride/sulfate in the treatment of knee osteoarthritis. Zhonghua Yi Xue Za Zhi. 2005;85:3067-3070.
   204. Lippiello L, Woodward J, Karpman R, et al. In vivo chondroprotection and metabolic synergy of glucosamine and chondroitin sulfate. Clin Orthop. 2000;:229-240.
   205. Lippiello L, Karpman RR, Hammad T. Synergistic effect of glucosamine HCL and chondroitin sulfate on in vitro proteoglycan synthesis by bovine chondrocytes. Presented at: American Academy of Orthopaedic Surgeons 67th Annual Meeting; March 15-19, 2000; Orlando, Fla.
206. Adebowale AO, Cox DS, Liang Z, et al. Analysis of glucosamine and chondroitin sulfate content in marketed products and the Caco-2 permeability of chondroitin sulfate raw materials. J Am Nutraceutical Assoc. 2000;3:37-44.
207. Product review: joint supplements (glucosamine, chondroitin, and MSM). Consumerlab website. Available at: http://www.consumerlabs.com/results/gluco.asp. Accessed May 8, 2006.
208. Ronca F, Palmieri L, Panicucci P, et al. Anti-inflammatory activity of chondroitin sulfate. Osteoarthritis Cartilage. 1998;6(suppl A):14-21.
209. Hungerford DS. Treating osteoarthritis with chondroprotective agents. Orthopedic Special Edition. 1998;4:39-42.
210. Tallia AF, Cardone DA. Asthma exacerbation associated with glucosamine-chondroitin supplement. J Am Board Fam Pract. 2002;15:481-484.