Historical Background:

Osteoarthritis affects 12-15% of Americans. (Hawker G. update on the epidemiology of the rheumatic diseases.  Curr Opin Rheumatol 1997;9:90-4)  Current treatments affect the symptoms but not the disease.  Glucosamine, a monosaccharide naturally obtained from chitin, has been investigated as a possible disease modifying supplement since after ingestion it has been shown to be absorbed in the joints, since it is a key component of the extracellular matrix of cartilage, since there are some prospective double blind studies showing equivalence to non steroidal anti-inflammatories (Reichelt et al 1994 Efficacy and safety of intramuscular glucosamine sulfate in osteoarthritis of the knee Arzneimittelforschung 1994;444(1):75-80, Vaz Al et al Double blind clinical evaluation of the relative efficacy of ibuprofen and glucosamine sulfate in the management of osteoarthrosis of the knee in out-patients.  Curr Med Res Opin 1982:8:145-9, ) and since there are so many subjective reports of symptomatic improvement by arthritis patients worldwide.  This combination of reports has led to the sale of 1 billion glucosamine pills in the U.S in 1999.

Several studies have documented that glucosamine is absorbed by the gastrointestinal tract with 26% bioavailability and incorporated into plasma proteins. (Setnikar I et al: Pharmacokinetics of glucosamine in the dog and man. Arzneimittelforschung  1986;36:729-35).  The supplement has anti-inflammatory properties but not analgesic properties. (Setnikar et al: Antireactive properties of glucosamine sulfate. Arzneimittelforschung 1991:41:157-61.  Clinical symptoms have improved as early as 1 week and persisted up to 4 weeks after discontinuation of the glucosamine. (Drovanti A et al: Therapeutic activity of oral glucosamine sulfate in osteoarthrosis; a placebo controlled double blind investigation.  Clin Ther 1980:3:260-72.)  However claims of chondroprotection or improvement in cartilage healing have not well been documented.

Glucosamine and Chondroitin Sulfate References

Karel Pavelká, MD, PhD; Jindriska Gatterová, MD; Marta Olejarová, MD; Stanislav Machacek, MD; Giampaolo Giacovelli, PhD; Lucio C. Rovati, MD. Glucosamine Sulfate Use and Delay of Progression of Knee Osteoarthritis A 3-Year, Randomized, Placebo-Controlled, Double-blind Study. Arch Intern Med. 2002;162:2113-2123 

Reginster JY, Gillot V, Bruyere O, Henrotin Y. Evidence of nutriceutical effectiveness in the treatment of osteoarthritis. Curr Rheumatol Rep 2000; 2: 472-77.

Constantz RB. Hyaluronan, glucosamine and chondroitin sulfate: roles for therapy in arthritis? In: Kelley WN, Harris ED, Ruddy S, Sledge CB, eds. Textbook of rheumatology. Philadelphia: WB Saunders, 1998.

Deal CL, Moskowitz RW. Nutraceuticals as therapeutic agents in osteoarthritis: the role of glucosamine, chondroitin sulfate, and collagen hydrolysate. Rheum Dis Clin North Am 1999; 25: 379-95.

McAlindon TE, LaValley MP, Gulin JP, Felson DT. Glucosamine and chondroitin for treatment of osteoarthritis: a systematic quality assessment and meta-analysis. JAMA 2000; 283: 1469-75.

Osteoarthritis Cartilage 1998 May;6 Suppl A:6-13

Protective effect of exogenous chondroitin 4,6-sulfate in the acute degradation of articular cartilage in the rabbit.

Uebelhart D, Thonar EJ, Zhang J, Williams JM

Department of Clinical Neurosciences and Dermatology, University Hospital of Geneva, Switzerland.

The injection of 2.0 mg chymopapain into the adolescent rabbit knee causes severe loss of articular cartilage proteoglycans (PG). Although chondrocytes attempt to restore lost PG, failure to repair ensues. Pure chondroitin 4,6-sulfate (Condrosulf, IBSA Lugano, Switzerland) has been used in clinical studies of human osteoarthritis (OA) as a slow-acting drug for OA (SYSADOA). Using our model of articular cartilage injury, we examined the effects of oral and intramuscular administration of Condrosulf after chymopapain-induced cartilage injury. In this study, animals received an injection of 2.0 mg chymopapain (Chymodiactin, Boots Pharmaceuticals) into the left knee and were sacrificed after 84 days. The contralateral right knee served as a noninjected control. Some animals received oral Condrosulf while others received intramuscular injections of Condrosulf. Serum keratan sulfate (KS) levels were monitored to ensure degradation of the cartilage PG. Those animals not exhibiting at least a 100% increase of serum KS following chymopapain injection were excluded from the study. At sacrifice, cartilage PG contents were markedly reduced in animals receiving an injection of 2.0 mg chymopapain with no further treatment. In contrast, oral administration of Condrosulf beginning 11 days prior to chymopapain injury resulted in significantly higher (P = 0.0036) cartilage PG contents. Intramuscular administration of Condrosulf resulted in higher, but less significantly so (P = 0.0457), cartilage PG contents. These results suggest that daily Condrosulf treatment prior to and continuing after chymopapain injury may have a protective effect on the damaged cartilage, allowing it to continue to re-synthesize matrix PG after the treatment is discontinued.

PMID: 9743813, UI: 98416455

Am J Vet Res 1999 Dec;60(12):1552-7

Scintigraphic evaluation of dogs with acute synovitis after treatment with glucosamine hydrochloride and chondroitin sulfate.

Canapp SO Jr, McLaughlin RM Jr, Hoskinson JJ, Roush JK, Butine MD

Department of Clinical Sciences, College of Veterinary Medicine, Kansas State University, Manhattan 66506, USA.

[Medline record in process]

OBJECTIVE: To evaluate the effects of orally administered glucosamine hydrochloride (GlAm)-chondroitin sulfate (CS) and GlAm-CS-S-adenosyl-L-methionine (SAMe) on chemically induced synovitis in the radiocarpal joint of dogs. ANIMALS: 32 adult mixed-breed dogs. PROCEDURE: For 21 days, all dogs received a sham capsule (3 groups) or GlAm-CS (prior treatment group) in a double-blinded study. Unilateral carpal synovitis was induced by injecting the right radiocarpal joint with chymopapain and the left radiocarpal joint (control joint) with saline (0.9% NaCl) solution. Joints were injected on alternate days for 3 injections. After induction of synovitis, 2 groups receiving sham treatment were given GlAm-CS or GlAm-CS-SAMe. Another group continued to receive sham capsules (control group). Joint inflammation was quantified, using nuclear scintigraphy, before injection of joints and days 13, 20, 27, 34, 41, and 48 after injection. Lameness evaluations were performed daily. RESULTS: Dogs given GlAm-CS before induction of synovitis had significantly less scintigraphic activity in the soft-tissue phase 48 days after joint injection, significantly less uptake in the bone phase 41 and 48 days after joint injection, and significantly lower lameness scores on days 12 to 19, 23, and 24 after injection, compared with other groups. CONCLUSIONS AND CLINICAL RELEVANCE: Analysis of results of this study suggest that prior treatment with GlAm-CS for 21 days had a protective effect against chemically induced synovitis and associated bone remodeling. Prior treatment with GlAm-CS also reduced lameness in dogs with induced synovitis.

PMID: 10622167, UI: 20085879

Osteoarthritis Cartilage 1998 May;6 Suppl A:25-30

Efficacy and tolerability of chondroitin sulfate 1200 mg/day vs chondroitin sulfate 3 x 400 mg/day vs placebo.

Bourgeois P, Chales G, Dehais J, Delcambre B, Kuntz JL, Rozenberg S

Department of Rheumatology, Pitie Salpetriere Hospital, Paris, France.

This multicenter randomized, double-blind, controlled study was performed to compare the efficacy and tolerability of chondroitin sulfate (CS, Condrosulf, IBSA, Lugano, CH) 1200 mg/day oral gel vs CS 3 x 400 mg/day capsules vs placebo, in patients with mono or bilateral knee osteoarthritis (Kellgren and Lawrence radiographic score grade I to III). A total of 127 patients, 40 of whom were treated with CS 1200 mg/day, 43 with CS 3 x 400 mg/day and 44 with placebo, were included in the statistical analysis of this 3-month treatment study. In the CS groups, Lequesne's Index and spontaneous joint pain (VAS) showed a significant reduction of clinical symptoms (P < 0.01 for both parameters), while only a slight reduction was observed in the placebo group (P = ns for Lequesne's Index and P < 0.05 for VAS). The physician's and patient's overall efficacy assessments were significantly in favour of the CS groups (P < 0.01). The treatment carried out with the three formulations was very well tolerated. In conclusion, these results indicate that CS favours the improvement of the subjective symptoms, improving the joint mobility. An additional consideration is that the efficacy of 1200 mg CS as a single daily dose does not differ from that of 3 x 400 mg daily doses of CS for all the clinical parameters taken into consideration.

Publication Types:

• Clinical trial
• Clinical trial, phase iii
• Multicenter study
• Randomized controlled trial

PMID: 9743816, UI: 98416458

J Rheumatol 2000 Jan;27(1):205-11

A metaanalysis of chondroitin sulfate in the treatment of osteoarthritis.

Leeb BF, Schweitzer H, Montag K, Smolen JS

Lower Austrian Center for Rheumatology, Stockerau Hospital, Austria.

[Medline record in process]

OBJECTIVE: To examine the efficacy of chondroitin sulfate (CS) in the treatment of osteoarthritis (OA) on the basis of a metaanalysis of controlled clinical trials. METHODS: After personal, Medline, and Embase searches, a decision tree analysis of the available publications was performed, with respect to types of joint involvement studied, study designs, numbers of patients enrolled, and variables analyzed. The Lequesne index and pain rating on visual analog scale (VAS) were considered the main variables. Of a total of 16 publications found, 7 trials of 372 patients taking CS could be enrolled into the metaanalysis. Although all selected studies claimed to be randomized, double blind designs in parallel groups, it should be noted that CS was given along with analgesics or nonsteroidal antiiflammatory drugs, making required dosage of comedication an important factor. RESULTS: Following patients to 120 or more days, CS was shown to be significantly superior to placebo with respect to the Lequesne index and pain VAS. Pooled data confirmed these results and showed at least 50% improvement in the study variables in the CS group compared to placebo. CONCLUSION: CS may be useful in OA, but further investigations in larger cohorts of patients for longer time periods are needed to prove its usefulness as a symptom modifying drug in OA.

PMID: 10648040, UI: 20112566

Altern Med Rev 1998 Feb;3(1):27-39

The role of glucosamine sulfate and chondroitin sulfates in the treatment of degenerative joint disease.

Kelly GS

Successful treatment of osteoarthritis must effectively control pain, and should slow down or reverse progression of the disease. Biochemical and pharmacological data combined with animal and human studies demonstrate glucosamine sulfate is capable of satisfying these criteria. Glucosamine sulfate's primary biological role in halting or reversing joint degeneration appears to be directly due to its ability to act as an essential substrate for, and to stimulate the biosynthesis of, the glycosaminoglycans and the hyaluronic acid backbone needed for the formation of proteoglycans found in the structural matrix of joints. Chondroitin sulfates, whether they are absorbed intact or broken into their constituent components, similarly provide additional substrates for the formation of a healthy joint matrix. Evidence also supports the oral administration of chondroitin sulfates for joint disease, both as an agent to slowly reduce symptoms and to reduce the need for non-steroidal anti-inflammatory drugs. The combined use of glucosamine sulfate and chondroitin sulfates in the treatment of degenerative joint disease has become an extremely popular supplementation protocol in arthritic conditions of the joints. Although glucosamine sulfate and chondroitin sulfates are often administered together, there is no information available to demonstrate the combination produces better results than glucosamine sulfate alone.

Publication Types:

• Review
• Review, tutorial

PMID: 9600024, UI: 98262758

Osteoarthritis Cartilage 1998 May;6 Suppl A:14-21

Anti-inflammatory activity of chondroitin sulfate.

Ronca F, Palmieri L, Panicucci P, Ronca G

Department of Human and Environmental Sciences, University of Pisa, Italy.

The pharmacokinetics of chondroitin sulfate (CS, Condrosulf, IBSA, Lugano, Switzerland) were investigated in rats and in healthy volunteers using CS tritiated at the reducing end and CS labeled with 131I or 99mTc respectively. A rapid absorption of orally administered CS is observed in rats and in humans when the drug is dissolved in water. Lower and delayed absorption is observed when CS is administered in gastroresistant capsules. The absolute bio-availability is 15 and 12% for rats and humans respectively. The CS shows a tropism for cartilagineous tissues in rats and for knee tissues in humans as demonstrated by scintigraphic analysis with 99mTc-CS. Monomers, oligo and polysaccharides produced by enzymatic hydrolysis of CS appear in the blood and tissues together with native CS. The effects of partially depolymerized (m.m. 3 to 15 kD) and desulfated fractions on human leukocytes were investigated. CS and its fractions inhibit the directional chemotaxis induced by zymosan-activated serum, are able to decrease the phagocytosis and the release of lysozyme induced by zymosan and to protect the plasma membrane from oxygen reactive species. In rats the oral administration of CS significantly decreases granuloma formation due to sponge implants and cell migration and lysosomal enzyme release in carrageenan pleurisy. Compared with nonsteroidal anti-inflammatory drugs (indomethacin, ibuprofen), CS appears to be more effective on cellular events of inflammation than on edema formation. It is noteworthy that CS is devoid of dangerous effects on the stomach, platelets and kidneys. In synovial fluid of patients requiring joint aspiration, treated orally for 10 days with CS (800 mg/day) the hyaluronate concentration and the intrinsic viscosity significantly increased, while collagenolytic activity, phospholipase A2 and N-acetylglucosaminidase (NAG) decreased. These results give an insight into the mechanism of the anti-inflammatory and chondroprotective actions demonstrated by this drug in a number of clinical trials in patients with osteoarthritis.

PMID: 9743814, UI: 98416456

Medical Hypotheses. 42(5):323-7, 1994 May.

The neglect of Glucosamine as a treatment for osteoarthritis--a personal perspective. [Review]

Osteoarthritis results from progressive catabolic loss of cartilage proteoglycans, owing to an imbalance between synthesis and degradation. Standard drug therapy is only of palliative benefit and may exacerbate loss of cartilage. Glucosamine is an intermediate in mucopolysaccharide synthesis, and its availability in cartilage tissue culture can be rate-limiting for proteoglycan production. A number of double-blind studies dating from the early 1980s demonstrate that oral Glucosamine decreases pain and improves mobility in osteoarthritis, without side effects. Nevertheless, medical researchers and physicians in the US have totally ignored this rational and safe therapeutic strategy. By mechanisms that are still unclear, the natural methyl donor S-adenosylmethionine also promotes production of cartilage proteoglycans, and is therapeutically beneficial in osteoarthritis in well-tolerated oral doses. These and other safe nutritional measures supporting proteoglycan synthesis, may offer a practical means of preventing or postponing the onset of osteoarthritis in older people or athletes.

Source: Postgraduate Medicine. 93(7):129-40, 1993 May 15.
Abbreviated Source: Postgrad Med. 93(7):129-40, 1993 May 15.

Drug treatment of arthritis. Update on conventional and less conventional methods. [Review]

Spencer-Green G.

Dartmouth-Hitchcock Medical Center, Lebanon, NH 03756.

Nonsteroidal anti-inflammatory drugs comprise an important class of medications that reduce the signs and symptoms of osteoarthritis and rheumatoid arthritis. They bring relief to millions of people but do not eliminate underlying disease. Disease-modifying antirheumatic drugs also bring relief, but these drugs are often ineffective and not well tolerated. Failure to provide long-term benefits combined with the high toxicity of most of the disease-modifying agents has prompted a search for more effective treatments. New methods using modern technologies have generated much enthusiasm and hold promise for the future. In the meantime, administration of nonsteroidal anti-inflammatory drugs and judicious use of disease-modifying agents remain the cornerstone of therapy for arthritis.

Arzneimittel-Forschung 48(5):469-74, 1998 May

Efficacy and Safety of Glucosamine Sulfate Versus Ibuprofen in Patients With Knee Osteoarthritis

Qiu GX, Gao SN, Giacovelli G, Rovati L, Setnikar I

A double-blind therapeutic investigation was performed on 178 Chinese patients suffering from osteoarthritis of the knee randomized into two groups, one treated for 4 weeks with glucosamine sulfate (GS, CAS 29031-19-4, Viartril-S) at the daily dose of 1,500 mg and the other with ibuprofen (IBU, CAS 15687-27-1) at the daily dose of 1,200 mg. Knee pain at rest, at movement and at pressure, knee swelling, improvement and therapeutic utility as well as adverse events and drop-outs were recorded after 2 and 4 weeks of treatment. The variables were recorded also after 2 weeks of treatment discontinuation in order to appreciate the remnant therapeutic effect. Both GS and IBU significantly reduced the symptoms of osteoarthritis with the trend of GS to be more effective. After 2 weeks of drug discontinuation there was a remnant therapeutic effect in both groups, with the trend to be more pronounced in the GS group. GS was significantly better tolerated than IBU, as shown by the adverse drug reactions (6% in the patients of the GS group and 16% in the IBU group--p = 0.02) and by the drug-related drop-outs (0% of the patients in the GS group and 10% in the IBU group--p = 0.0017). The better tolerability of GS is explained by its mode of action, because GS specifically curbs the pathogenic mechanisms of osteoarthritis and does not inhibit the cyclo-oxygenases as the non-steroidal anti-inflammatory drugs (NSAIDs) do, with the consequent anti-inflammatory analgesic activities but also with the several adverse reactions due to this not targeted effect. The present study confirms that GS is a selective drug for osteoarthritis, as effective on the symptoms of the disease as NSAIDs but significantly better tolerated. For these properties GS seems particularly indicated in the long-term treatments needed in osteoarthritis.

Arthritis Rheum. 1999;42:S400.

Glucosamine sulfate significantly reduces progression of knee osteoarthritis over 3 years: a large, randomized, placebo-controlled, double-blind, prospective trial.

Refinster JY, Deroisy, Paul I, et al.

American College of Rheumatology 1999 Annual Scientific Meeting

The role of dietary supplements has increased as more clinical trial data have become available. Glucosamine sulfate is the most frequently used of these agents. A plenary session abstract by Reginster and colleagues[6] reported on a 3-year, randomized, placebo-controlled, double-blind, prospective trial of glucosamine sulfate vs placebo in the reduction of progression of knee OA. A total of 212 patients with OA received 1500 mg of oral glucosamine sulfate once daily vs placebo. Weight-bearing anteroposterior views of the knees were standardized at enrollment, at 1 year, and at 3 years.

The Western Ontario and McMaster University Osteoarthritis index (WOMAC) measured pain and disability. The total mean joint space width of the medial compartment of the tibiofemoral joint was assessed by digital image analysis. The placebo group had an average joint space narrowing of 0.08 to 0.1 mm/year, whereas no narrowing was noted in the glucosamine group. A slight worsening of symptoms was evident in the placebo group, while the glucosamine group had mild improvement. This study is the first to demonstrate a significant effect of glucosamine on the preservation of cartilage.

"With the aging of the U.S. population, public and professional attention toward preventing and treating joint pain is expected to skyrocket.  Today, more than 80 million people in the U.S. suffer from joint discomfort.  Half of those are afflicted with one of the many forms of arthritis, while the other half are victims of overambitious exercise, sports injuries and around-the-house accidents.  With one in five Americans now exercising regularly and the incidence of strenuous exercise among younger women increasing steadily, interest is expected to remain strong.  Of those aged 50+, 80% currently experience some form of joint discomfort.

The ranks of arthritis sufferers are expected to swell to epidemic proportions early in the next century.  By the year 2020, 60 million Americans or nearly 20% of the population will be afflicted with this disease compared to 43 million today (U.S. Center for Disease Control (CDC), 1998).  Nearly twice as many women (26 million) suffer from arthritis than men (14.2 million).

Despite promising new drug research, including the U.S. FDA's recent approval of Cox 2 inhibitors, there is no cure for arthritis.  Non-steroidal anti-inflammatory drugs (NSAIDS) are the most commonly used therapy, with side effects including ulcers, even death.  Not surprisingly, more and more Americans are turning to alternative medicine for more natural treatments.  Eisenberg's recent survey indicated that chronic pain (37%), sprains and muscle pains (26%) and arthritis (25%) represent three of the top four most cited reasons for the use of alternative medicine therapies in the U.S. (Eisenberg, 1998).  About one-third of Americans believe that herbals have a role in treating arthritis and 22% in preventing the disease (Gallup, 1998).  In desperate search of a cure, today Americans spend more than $1 billion on unproven arthritis remedies.

U.S. sales of arthritis and joint pain-related dietary supplements are approaching $750 million (Decision Research, 1998).  ...  Clearly, natural remedies without side effects will enjoy a major opportunity in the joint pain market either in place of. or addition to, these prescription alternatives."

Also See:

Glucosamine Index
Glucosamine Update
The Use of Glucosamine Sulfate in the Treatment of Osteoarthritis
Glucosamine Sulphate / Chondroitin Sulfate
Glucosamine Links