Glucosamine Research

Glucosamine for osteoarthritis: part I, review of the clinical evidence.

Med Health R I. 2004 Jun;87(6):176-9.

Biggee BA, McAlindon T.

Tufts-New England Medical Center, Boston, MA 02111, USA. bbiggee@tufts-nemc.org

Glucosamine is a popular nutritional supplement for OA. This supplement has shown moderate efficacy in meta-analysis and large industry-sponsored clinical trials. However, smaller independent studies have not shown significant benefit. It is difficult to compare these clinical trials due to heterogeneity in trial design, differences in glucosamine products, and differences in osteoarthritic populations being studied. The National Center for Complementary and Alternative Medicine and the National Institute of Arthritis and Musculoskeletal and Skin Disease (NIAMS/NCCAM) have funded a multicenter five arm placebo controlled study called The Glucosamine Arthritis Intervention Trial (GAIT). GAIT spans 24 weeks, enrolling 1588 subjects, at 13 centers comparing the efficacy of glucosamine sulfate, chondroitin sulfate, glucosamine with chondroitin, to placebo and compared to celecoxib for knee OA. This study may have final data in March 2005.

Glucosamine sulfate reduces osteoarthritis progression in postmenopausal women with knee osteoarthritis: evidence from two 3-year studies.

Menopause. 2004 Mar-Apr;11(2):138-43.

Bruyere O, Pavelka K, Rovati LC, Deroisy R, Olejarova M, Gatterova J, Giacovelli G, Reginster JY.

WHO Collaborating Center for Public Health Aspect of Osteoarticular Disorders, Liege, Belgium.

OBJECTIVE: To investigate the effect of glucosamine sulfate on long-term symptoms and structure progression in postmenopausal women with knee osteoarthritis (OA). DESIGN: This study consisted of a preplanned combination of two three-year, randomized, placebo-controlled, prospective, independent studies evaluating the effect of glucosamine sulfate on symptoms and structure modification in OA and post-hoc analysis of the results obtained in postmenopausal women with knee OA. Minimal joint space width was assessed at baseline and after 3 years from standing anteroposterior knee radiographs. Symptoms were scored by the algo-functional WOMAC index at baseline and after 3 years. All primary statistical analyses were performed in intention-to-treat, comparing joint space width and WOMAC changes between groups by ANOVA. RESULTS: Of 414 participants randomized in the two studies, 319 were postmenopausal women. At baseline, glucosamine sulfate and placebo groups were comparable for demographic and disease characteristics, both in the general population and in the postmenopausal women subset. After 3 years, postmenopausal participants in the glucosamine sulfate group showed no joint space narrowing [joint space change of +0.003 mm (95% CI, -0.09 to 0.11)], whereas participants in the placebo group experienced a narrowing of -0.33 mm (95% CI, -0.44 to -0.22; P < 0.0001 between the two groups). Percent changes after 3 years in the WOMAC index showed an improvement in the glucosamine sulfate group [-14.1% (95%, -22.2 to -5.9)] and a trend for worsening in the placebo group (5.4% (95% CI, -4.9 to 15.7) (P = 0.003 between the two groups). CONCLUSION: This analysis, focusing on a large cohort of postmenopausal women, demonstrated for the first time that a pharmacological intervention for OA has a disease-modifying effect in this particular population, the most frequently affected by knee OA.

Osteoarthritic patients with high cartilage turnover show increased responsiveness to the cartilage protecting effects of glucosamine sulphate.

Clin Exp Rheumatol. 2004 Jan-Feb;22(1):36-42.

Christgau S, Henrotin Y, Tanko LB, Rovati LC, Collette J, Bruyere O, Deroisy R, Reginster JY.

Nordic Bioscience A/S, Herlev, Denmark. sc@nordicbioscience.com

OBJECTIVE: Glucosamine sulphate has been shown in a large double-blind, placebo-controlled clinical trial to prevent structural damage and improve clinical symptoms of osteoarthritis (OA). We investigated whether early response in a newly developed biochemical marker of collagen type II degradation (CTX-II, CartiLaps ELISA) could reflect the long-term preservation of hyaline cartilage. METHODS: Study subjects comprised 212 knee OA patients participating in a clinical trial of the effects of glucosamine sulphate. Disease symptoms were assessed quarterly by WOMAC scoring and X-ray analysis was performed at baseline and after 3 years. Urine samples were obtained at baseline and after 1, 2 and 3 years for measurement in the CartiLaps assay. The measurements were corrected for creatinine. RESULTS: At baseline the patients had an average concentration of urinary CTX-II of 222.4 +/- 159.5 ng/mmol creatinine. This was significantly above the CTX-II levels measured in urine samples from 415 healthy controls (169.1 +/- 92.3 ng/mmol, p < 0.0001). There was no significant difference in the CTX-II response in the placebo group and the glucosamine treated group. However, those with high cartilage turnover presented a significant decrease in CTX-II after 12-month glucosamine treatment. Thus, three group with CTX II concentrations above normal average + 1SD decreased 15.5% after 12-month therapy. The 12 months change in CTX-II in OA patients with elevated CTX-II at baseline correlated with the change in average joint space width observed after 36 months (R = 0.43, p < 0.05). Increased baseline levels of CTX-II were associated with a worsening of the WOMAC index (p < 0.01). CONCLUSION: The data indicate that measurement of urinary collagen type II C-telopeptide fragments enables the identification of OA patients with high cartilage turnover who at the same time are most responsive to therapy with structure modifying drugs.

Medical management of osteoarthritis of the knee and hip joints.

Med J Aust. 2004 Mar 1;180(5):232-6.

Grainger R, Cicuttini FM.

Department of Rheumatology, Alfred Hospital, Prahran, VIC.

Osteoarthritis is a common, chronic condition which requires an individualised management plan involving multiple kinds of treatment. Exercise programs and the Arthritis Self-Management Program reduce pain and disability associated with osteoarthritis. Paracetamol is the most appropriate first-line analgesic. Non-steroidal anti-inflammatory drugs may be used as second-line analgesia on an as-needed basis (including continuous use), but must be used with caution. Cyclo-oxygenase-2-specific inhibitors are used if there are risk factors for upper-gastrointestinal complications, but only after considering cardiovascular risk. Glucosamine sulfate is a safe and effective over-the-counter treatment. Intra-articular therapies are used when others have failed.

Structural and symptomatic efficacy of glucosamine and chondroitin in knee osteoarthritis: a comprehensive meta-analysis.

Arch Intern Med. 2003 Jul 14;163(13):1514-22.

Richy F, Bruyere O, Ethgen O, Cucherat M, Henrotin Y, Reginster JY.

Faculty of Medicine, Department of Public Health, Public Health and Epidemiology, University of Liege, Liege, Belgium.

OBJECTIVE: To assess the structural and symptomatic efficacy of oral glucosamine sulfate and chondroitin sulfate in knee osteoarthritis through independent meta-analyses of their effects on joint space narrowing, Lequesne Index, Western Ontario MacMaster University Osteoarthritis Index (WOMAC), visual analog scale for pain, mobility, safety, and response to treatment. METHODS: An exhaustive systematic research of randomized, placebo-controlled clinical trials published or performed between January 1980 and March 2002 that assessed the efficacy of oral glucosamine or chondroitin on gonarthrosis was performed using MEDLINE, PREMEDLINE, EMBASE, Cochrane Database of Systematic Reviews, Current Contents, BIOSIS Previews, HealthSTAR, EBM Reviews, manual review of the literature and congressional abstracts, and direct contact with the authors and manufacturers of glucosamine and chondroitin. Inclusion, quality scoring, and data abstraction were performed systematically by 2 independent reviewers who were blinded to sources and authors. Conservative approaches were used for clear assessment of potential efficacy. RESULTS: Our results demonstrated a highly significant efficacy of glucosamine on all outcomes, including joint space narrowing and WOMAC. Chondroitin was found to be effective on Lequesne Index, visual analog scale pain, mobility, and responding status. Safety was excellent for both compounds. CONCLUSIONS: Our study demonstrates the structural efficacy of glucosamine and indistinguishable symptomatic efficacies for both compounds. Regarding the relatively sparse data on glucosamine and joint space narrowing and the absence of data on structural effects of chondroitin, further studies are needed to investigate the relationship among time, dose, patient baseline characteristics, and structural efficacy for an accurate, disease-modifying characterization of these 2 compounds.

Glucosamine: a review of its use in the management of osteoarthritis.

Drugs Aging. 2003;20(14):1041-60.

Matheson AJ, Perry CM.

Adis International Limited, Auckland, New Zealand.

Glucosamine occurs naturally in all human tissues. It stimulates the synthesis of glycosaminoglycan, proteoglycan and hyaluronic acid, although the precise mechanism of action remains to be established. Formulated as glucosamine sulphate (Dona) and various others), glucosamine has been evaluated for its efficacy in relieving the symptoms of osteoarthritis and its disease-modifying potential.In two large randomised, double-blind, multicentre studies in patients with osteoarthritis, oral or intramuscular glucosamine for 4-6 weeks was associated with a greater decrease in symptom severity (as assessed by the Lequesne index) than placebo. In addition, there was a greater proportion of responders (defined as patients with a >or=3-point reduction in the Lequesne index, along with a positive overall assessment by the investigator) at the end of the treatment period with glucosamine than with placebo. In two large 4-week trials, oral glucosamine produced similar improvements to ibuprofen in the Lequesne index in one study and in articular pain scores in the other study. In a smaller 8-week comparative trial, oral glucosamine therapy achieved a significantly greater improvement in articular pain score than ibuprofen, and the investigators rated treatment efficacy as 'good' in a significantly greater proportion of glucosamine than ibuprofen recipients. In comparison with piroxicam, glucosamine significantly improved arthritic symptoms after 12 weeks of therapy and remained effective 8 weeks after treatment was discontinued. Beneficial effects of long-term oral glucosamine therapy in preventing joint space narrowing and improving symptoms were shown in two 3-year placebo-controlled trials in a total of 414 patients with osteoarthritis. Statistically significant differences favouring glucosamine were noted in the per-protocol and intention-to-treat analyses for the primary endpoints for both joint structural changes and symptom modification. Glucosamine has a tolerability profile similar to that of placebo and is better tolerated than ibuprofen or piroxicam. In particular, glucosamine recipients had a markedly lower incidence of gastrointestinal disturbances than those receiving ibuprofen. Other adverse events reported in both glucosamine and ibuprofen recipients were pruritus or skin reactions, flushing and fatigue. In general, a lower incidence of withdrawal from clinical trials was reported for glucosamine recipients than either ibuprofen or piroxicam recipients.CONCLUSION: In short-term clinical trials, glucosamine provided effective symptomatic relief for patients with osteoarthritis of the knee. In addition, glucosamine has shown promising results in modifying the progression of arthritis over a 3-year period. Glucosamine may therefore prove to be a useful treatment option for osteoarthritis.

Glucosamine and chondroitin sulfate supplementation to treat symptomatic disc degeneration: biochemical rationale and case report.

BMC Complement Altern Med. 2003 Jun 10;3(1):2.

van Blitterswijk WJ, van de Nes JC, Wuisman PI.

Division of Cellular Biochemistry, The Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Plesmanlaan 121, 1066CX Amsterdam, The Netherlands. w.v.blitterswijk@nki.nl

BACKGROUND: Glucosamine and chondroitin sulfate preparations are widely used as food supplements against osteoarthritis, but critics are skeptical about their efficacy, because of the lack of convincing clinical trials and a reasonable scientific rationale for the use of these nutraceuticals. Most trials were on osteoarthritis of the knee, while virtually no documentation exists on spinal disc degeneration. The purpose of this article is to highlight the potential of these food additives against cartilage degeneration in general, and against symptomatic spinal disc degeneration in particular, as is illustrated by a case report. The water content of the intervertebral disc is a reliable measure of its degeneration/ regeneration status, and can be objectively determined by Magnetic Resonance Imaging (MRI) signals. CASE PRESENTATION: Oral intake of glucosamine and chondroitin sulfate for two years associated with disk recovery (brightening of MRI signal) in a case of symptomatic spinal disc degeneration. We provide a biochemical explanation for the possible efficacy of these nutraceuticals. They are bioavailable to cartilage chondrocytes, may stimulate the biosynthesis and inhibit the breakdown of their extracellular matrix proteoglycans. CONCLUSION: The case suggests that long-term glucosamine and chondroitin sulfate intake may counteract symptomatic spinal disc degeneration, particularly at an early stage. However, definite proof requires well-conducted clinical trials with these food supplements, in which disc de-/regeneration can be objectively determined by MRI. A number of biochemical reasons (that mechanistically need to be further resolved) explain why these agents may have cartilage structure- and symptom-modifying effects, suggesting their therapeutic efficacy against osteoarthritis in general.

'Natural remedies' in the treatment of osteoarthritis.

Drugs Aging. 2003;20(7):517-26.

Walker-Bone K.

Medical Research Council Environmental Epidemiology Unit, Southampton General Hospital, Southampton SO16 6YD, UK. kwb@mrc.soton.ac.uk

Osteoarthritis (OA) is a common, chronic and painful condition. It is the most common of all rheumatic disorders and is destined to become one of the most prevalent and costly diseases in our society. The conventional therapeutic options employed in the management of OA are simple analgesics and NSAIDs, but these options frequently produce sub-optimal benefit and are associated with an adverse-safety profile. Unsurprisingly patients are looking to alternative and complementary medicine. The aim of this article was to review the available literature on the effectiveness and safety of 'natural remedies' for the treatment of OA. Computerised literature searches were carried out for systematic reviews and randomised controlled trials examining the role of 'natural remedies' in the treatment of OA. There have been few randomised controlled trials of 'natural remedies' that have satisfied the internationally agreed standards. There was, however, evidence of efficacy for glucosamine, chondroitin sulfate and possibly avocado/soybean unsaponifiables for the symptomatic relief of OA. To date, it is not established whether any of the 'natural remedies' are capable of chondroprotection. Even if 'natural remedies' are only modestly effective, they are widely available and well tolerated, suggesting that they may play a significant role in the management of OA in the elderly.

Glucosamine and chondroitin sulfate are effective in the management of osteoarthritis.

J Arthroplasty. 2003 Apr;18(3 Suppl 1):5-9.

Hungerford DS, Jones LC.

Division of Arthritis Surgery, Department of Orthopaedic Surgery, Johns Hopkins University School of Medicine, G-1 Good Samaritan Professional Building, 5601 Loch Raven Boulevard, Baltimore, MD 21239, USA.

The use of glucosamine and chondroitin sulfate for the symptomatic treatment of osteoarthritis has been a subject of controversy for several reasons. First, the medical community in general took offense at the title of Theodosakis' book, The Arthritis Cure. Second, the medical community is becoming divided into "traditional" and "alternative" camps with deep skepticism between them. Third, the whole nutraceutical industry is essentially unregulated, with manufacturers making outrageous claims on products that have never been tested at all, are often of poor quality, and occasionally lacking in any active ingredient. However, for the nutriceuticals evaluated here, there is abundant in vitro, in vivo, animal clinical, and human clinical evidence of both their efficacy and safety. They deserve a prominent place in the armamentarium of nonsurgical treatment of osteoarthritis. Copyright 2003 Elsevier Inc. All rights reserved.

Glucosamine sulfate use and delay of progression of knee osteoarthritis: a 3-year, randomized, placebo-controlled, double-blind study.

Arch Intern Med. 2002 Oct 14;162(18):2113-23.

Pavelka K, Gatterova J, Olejarova M, Machacek S, Giacovelli G, Rovati LC.

Department of Medicine and Rheumatology, Charles University, Prague, Czech Republic. pavelka@revma.cz

BACKGROUND: Conventional symptomatic treatments for osteoarthritis do not favorably affect disease progression. The aim of this randomized, placebo-controlled trial was to determine whether long-term (3-year) treatment with glucosamine sulfate can modify the progression of joint structure and symptom changes in knee osteoarthritis, as previously suggested. METHODS: Two hundred two patients with knee osteoarthritis (using American College of Rheumatology criteria) were randomized to receive oral glucosamine sulfate, 1500 mg once a day, or placebo. Changes in radiographic minimum joint space width were measured in the medial compartment of the tibiofemoral joint, and symptoms were assessed using the algo-functional indexes of Lequesne and WOMAC (Western Ontario and McMaster Universities). RESULTS: Osteoarthritis was of mild to moderate severity at enrollment, with average joint space widths of slightly less than 4 mm and a Lequesne index score of less than 9 points. Progressive joint space narrowing with placebo use was -0.19 mm (95% confidence interval, -0.29 to -0.09 mm) after 3 years. Conversely, there was no average change with glucosamine sulfate use (0.04 mm; 95% confidence interval, -0.06 to 0.14 mm), with a significant difference between groups (P =.001). Fewer patients treated with glucosamine sulfate experienced predefined severe narrowings (>0.5 mm): 5% vs 14% (P =.05). Symptoms improved modestly with placebo use but as much as 20% to 25% with glucosamine sulfate use, with significant final differences on the Lequesne index and the WOMAC total index and pain, function, and stiffness subscales. Safety was good and without differences between groups. CONCLUSION: Long-term treatment with glucosamine sulfate retarded the progression of knee osteoarthritis, possibly determining disease modification.

A randomized, double-blind, placebo-controlled trial of glucosamine sulphate as an analgesic in osteoarthritis of the knee.

Hughes R, Carr A.

Rheumatology (Oxford). 2002 Mar;41(3):279-84.

St Peter's Hospital, Chertsey, Surrey, UK.

OBJECTIVES: A randomized, placebo-controlled, double-blind trial of the relative effectiveness of glucosamine sulphate and placebo in managing pain in osteoarthritis (OA) of the knee. METHODS: Eighty patients with OA of the knee were recruited from a rheumatology out-patient clinic and received either glucosamine sulphate 1500 mg daily for 6 months or dummy placebo. The primary outcome measure was patients' global assessment of pain in the affected knee. RESULTS: Area under the curve analysis for the primary outcome measure showed no difference between placebo and glucosamine [mean difference 0.15 mm, 95% confidence interval (CI) -8.78 to 9.07]. The placebo response was 33%. There was a statistically significant difference between groups in knee flexion (mean difference 13 degrees, 95% CI -23.13 to -1.97), but this difference was small and could have been due to measurement error. CONCLUSIONS: As a symptom modifier in OA patients with a wide range of pain severities, glucosamine sulphate was no more effective than placebo.

A randomized double-blind clinical trial of the effect of chondroitin sulfate and glucosamine hydrochloride on temporomandibular joint disorders: a pilot study.

Cranio. 2001 Apr;19(2):130-9.

Nguyen P, Mohamed SE, Gardiner D, Salinas T.

Louisiana State University Health Sciences Center, New Orleans, USA.

Previous studies have shown chondroitin sulfate and glucosamine hydrochloride have beneficial effects on symptoms of osteoarthritis of the knee. Our aim was to study the effect of a daily dose of 1500 mg of glucosamine hydrochloride (GH) and 1200 mg of chondroitin sulfate (CS) taken for twelve weeks on subjects diagnosed with capsulitis, disk displacement, disk dislocation, or painful osteoarthritis of the temporomandibular joint (TMJ). Forty-five subjects were enrolled in the study and were randomly assigned to either an active medication group or a placebo group. Eleven subjects were lost from the study for various reasons, resulting in fourteen subjects remaining in the active medication group and twenty subjects remaining in the placebo group. Subjects taking CS-GH had improvements in their pain as measured by one index of the McGill Pain Questionnaire, in TMJ tenderness, in TMJ sounds, and in the number of daily over-the-counter medications needed. Subjects taking the placebo medication had improvements in their pains as measured by the visual analog scale and by four indices of the McGill Pain Questionnaire. Additional studies are required to evaluate the clinical effectiveness of CS-GH and to determine the exact mechanism by which CS-GH affects the articular cartilage of synovial joints.

Glucosamine sulfate in osteoarthritis of the knee.

Osteoarthritis Cartilage. 1994 Mar;2(1):51-9.

Noack W, Fischer M, Forster KK, Rovati LC, Setnikar I.

Department of Orthopedics-Evangelisches Waldkrankenhaus, Berlin, Germany.

Glucosamine sulfate is a drug used for the treatment of osteoarthritis (OA), based on its pharmacological and metabolic activities on the cartilage and chondrocytes, complemented by mild anti-inflammatory properties and a favorable pharmacokinetic profile. The aim of this study was to define the activity and safety of glucosamine sulfate on the symptoms of patients with OA, using a multicenter, randomized, placebo-controlled, double-blind, parallel-group study design. The study included 252 outpatients with OA of the knee (Lequesne's criteria), radiological stage between I and III, and Lequesne's severity index of at least 4 points and symptoms for at least 6 months. Patients were treated with either placebo or oral glucosamine sulfate 500 mg t.i.d. for 4 weeks, with weekly, with weekly clinic visits. Responders to treatment were defined as patients with a reduction of at least 3 points in the Lequesne's index with a positive overall assessment by the investigator. The Lequesne's index was 10.6 +/- 0.45 S.E.M. points in both groups at the start of the study. This decreased to 7.45 +/- 0.5 points in the treatment group (average 3.2) and 8.4 +/- 0.4 points in the placebo group (average 2.2) (P < 0.05, Student's t-test). The responder rate in the evaluable patients was 55% with glucosamine (N = 120) vs 38% with placebo (N = 121). These proportions were 52% vs 37% in an intention-to-treat analysis (P = 0.014 and 0.016, respectively; Fisher's Exact Test). The medications were well tolerated throughout the study, with no difference between the glucosamine and placebo treated groups. It is concluded that glucosamine sulfate may be a safe and effective symptomatic Slow Acting Drug for OA.

Glucosamine and chondroitin for osteoarthritis?

McAlindon T.

Bull Rheum Dis. 2001 Jul;50(7):1-4.

Arthritis Center, Boston University Medical Center, Boston, MA, USA.

The current body of evidence currently supports modest efficacy for glucosamine and chondroitin in the treatment of OA symptoms. The products are safe and could play a valuable role in the management of this disorder. Nevertheless, further independent studies are needed to confirm these findings and to determine the clinical applicability of these compounds. Physicians need to become involved in these treatment decisions but are confused by wide variability in the formulation and purity of the numerous preparations available to consumers. The notion that glucosamine and chondroitin might have disease-modifying effects in OA is highly appealing and supported by preliminary data. Research is needed to confirm these findings and to evaluate the impact of glucosamine and chondroitin on all aspects of OA progression.

Long-term effects of glucosamine sulphate on osteoarthritis progression: a randomised, placebo-controlled clinical trial.

Lancet. 2001 Jan 27;357(9252):251-6.

Reginster JY, Deroisy R, Rovati LC, Lee RL, Lejeune E, Bruyere O, Giacovelli G, Henrotin Y, Dacre JE, Gossett C.

Bone and Cartilage Metabolism Research Unit (WHO Collaborating Center for Public Aspects of Osteoarticular Disorders), University of Liege, Belgium. jyreginster@ulg.ac.be

BACKGROUND: Treatment of osteoarthritis is usually limited to short-term symptom control. We assessed the effects of the specific drug glucosamine sulphate on the long-term progression of osteoarthritis joint structure changes and symptoms. METHODS: We did a randomised, double-blind placebo controlled trial, in which 212 patients with knee osteoarthritis were randomly assigned 1500 mg sulphate oral glucosamine or placebo once daily for 3 years. Weightbearing, anteroposterior radiographs of each knee in full extension were taken at enrolment and after 1 and 3 years. Mean joint-space width of the medial compartment of the tibiofemoral joint was assessed by digital image analysis, whereas minimum joint-space width--ie, at the narrowest point--was measured by visual inspection with a magnifying lens. Symptoms were scored by the Western Ontario and McMaster Universities (WOMAC) osteoarthritis index. FINDINGS: The 106 patients on placebo had a progressive joint-space narrowing, with a mean joint-space loss after 3 years of -0.31 mm (95% CI -0.48 to -0.13). There was no significant joint-space loss in the 106 patients on glucosamine sulphate: -0.06 mm (-0.22 to 0.09). Similar results were reported with minimum joint-space narrowing. As assessed by WOMAC scores, symptoms worsened slightly in patients on placebo compared with the improvement observed after treatment with glucosamine sulphate. There were no differences in safety or reasons for early withdrawal between the treatment and placebo groups. INTERPRETATION: The long-term combined structure-modifying and symptom-modifying effects of gluosamine sulphate suggest that it could be a disease modifying agent in osteoarthritis.

Use of glucosamine and chondroitin sulfate in the management of osteoarthritis.

J Am Acad Orthop Surg. 2001 Mar-Apr;9(2):71-8.

Brief AA, Maurer SG, Di Cesare PE.

Department of Orthopaedic Surgery, New York University-Hospital for Joint Diseases, 301 East 17th Street, New York, NY 10003, USA.

The goals of osteoarthritis therapy are to decrease pain and to maintain or improve joint function. The pharmacologic treatment of this condition has included the use of aspirin, acetaminophen, and nonsteroidal anti-inflammatory drugs. More recently, numerous studies have investigated the potential role of chondroprotective agents in repairing articular cartilage and decelerating the degenerative process. The reports of limited clinical experience with two of these agents, glucosamine and chondroitin sulfate, as well as the accompanying publicity in the popular media, have generated controversy. Advocates of these alternative modalities cite reports of progressive and gradual decline of joint pain and tenderness, improved mobility, sustained improvement after drug withdrawal, and a lack of significant toxicity associated with short-term use of these agents. Critics point out that in the great majority of the relevant clinical trials, sample sizes were small and follow-up was short-term.

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 Sep;8(5):343-50.

Das A Jr, Hammad TA.

Hendersonville Orthopedics Associates, Hendersonville, North Carolina 28739, USA.

OBJECTIVES: The objective of this study was to evaluate the oral combination of glucosamine HCl, sodium chondroitin sulfate and manganese ascorbate for the treatment of osteoarthritis (OA) of the knee. DESIGN: A randomized placebo-controlled study design was implemented. We recruited 93 patients with OA of the knee from a single center. The intervention group received 1000 mg FCHG49 glucosamine HCl, 800 mg TRH122 low molecular weight sodium chondroitin sulfate and 152 mg manganese ascorbate twice daily (Cosamin DS). Patients were evaluated initially and then every 2 months for 6 months. The primary outcome was the Lesquene Index of severity of osteoarthritis of the knee (ISK). RESULTS: Patients with radiographically mild or moderate OA (N=72) in the intervention group showed significant improvement in the ISK at 4 and 6 months (P=0.003 and P=0.04, respectively). The response rate to the medication was 52% vs a 28% response rate to placebo. Patients with radiographically severe osteoarthritis (N=21) did not show significant improvements in the ISK. There was a 17% incidence of adverse events in the intervention group and 19% in the placebo group. CONCLUSIONS: The studied combination of glucosamine HCl, sodium chondroitin sulfate and manganese ascorbate was found to be effective for the treatment of radiographically mild to moderate OA of the knee as measured by the ISK. This is the first U.S. study of these agents. Copyright 2000 OsteoArthritis Research Society International.

Natural treatments for osteoarthritis.

Altern Med Rev. 1999 Oct;4(5):330-41.

Gaby AR.

Nutritional Medicine, Bastyr University, Kenmore, WA, USA.

Osteoarthritis (OA) is the most common form of joint disease. Although OA was previously thought to be a progressive, degenerative disorder, it is now known that spontaneous arrest or reversal of the disease can occur. Conventional medications are often effective for symptom relief, but they can also cause significant side effects and do not slow the progression of the disease. Several natural substances have been shown to be at least as effective as nonsteroidal anti-inflammatory drugs at relieving the symptoms of OA, and preliminary evidence suggests some of these compounds may exert a favorable influence on the course of the disease.

Effect of glucosamine hydrochloride in the treatment of pain of osteoarthritis of the knee.

J Rheumatol. 1999 Nov;26(11):2423-30.

Houpt JB, McMillan R, Wein C, Paget-Dellio SD.

Mount Sinai Hospital Rheumatic Disease Unit, University of Toronto, Ontario, Canada. jhoupt@kingshealthcentre.ca

OBJECTIVE: Glucosamine products have been used extensively for the management of pain in osteoarthritis (OA). We investigated the efficacy of the hydrochloride salt of glucosamine on pain and disability in knee OA. METHODS: At Week -2, subjects were examined, randomized, and instructed to take only prescribed acetaminophen for pain. At Week 0 patients were examined, prescribed acetaminophen, and either placebo or glucosamine hydrochloride (glucosamine). At Week 4 the prescriptions for acetaminophen and placebo or glucosamine were renewed. At Weeks 4 and 8, patients returned diaries and unused medications, and were examined. The WOMAC questionnaire was administered at Weeks -2, 0, and 8. After completing the randomized 8 week trial, subjects were offered known glucosamine hydrochloride capsules in an 8 week open label trial, with followup telephone survey after the 8 week open label trial. RESULTS: The primary endpoint (statistically significant difference in WOMAC pain score between Week 0 and Week 8) was not met. However, positive trends were noted for the glucosamine group in 23 of 24 WOMAC questions. A significant difference was noted from Week 5 through Week 8 in the knee examination (p = 0.026) and in the response to a daily diary pain question (p = 0.018). However, responding to the question, "Are you better than at the start of the trial?", 40% of placebo and only 49% of glucosamine subjects answered in the affirmative (p = 0.58). At the end of the randomized trial, 34% of placebo and 47% of glucosamine subjects believed that they had been given glucosamine. After the end of the 8 week open label trial, 77% of the subjects were still taking glucosamine, although now obliged to pay for commercially available products. CONCLUSION: There was no significant difference in pain reduction between the glucosamine hydrochloride and placebo groups as measured by WOMAC. However, the secondary endpoints of cumulative pain reduction as measured by daily diary and knee examination were favorable, suggesting that glucosamine hydrochloride benefits some patients with knee OA.

Glucosamine sulfate for osteoarthritis.

Ann Pharmacother. 1998 May;32(5):580-7.

da Camara CC, Dowless GV.

School of Pharmacy, Campbell University, Buies Creek, NC, USA.

OBJECTIVE: To characterize the usefulness of glucosamine sulfate in the treatment of patients with osteoarthritis (OA). DATA SOURCES AND STUDY SELECTION: Pertinent citations were identified via a MEDLINE search (January 1975-March 1997). Only trials available in the English language involving human subjects, OA, and glucosamine sulfate were selected for review. DATA SYNTHESIS: OA is the most common form of arthritis and represents a major cause of morbidity and disability in the elderly. The main symptom of OA is pain and most of the commonly prescribed medications (e.g. acetaminophen, nonsteroidal antiinflammatory drugs) have been targeted at relieving the pain. Some of these medications have serious adverse effects and do not necessarily change the natural course of the disease. Glucosamine sulfate, a nutritional supplement, has recently emerged as an alternative treatment option for patients with OA. The beneficial effects of this chondroprotective agent have been reported to reverse or at least stop the progression of the disease without inducing serious adverse effects. Limited data from short-term human trials suggest that glucosamine sulfate administered orally, intravenously, intramuscularly, and intraarticularly may produce a gradual and progressive reduction in joint pain and tenderness, as well as improved range of motion and walking speed. Results of the trials have also shown that glucosamine has produced consistent benefits (> 50% overall improvement in symptom scores) in patients with OA and that, in some cases, it may be equal or superior to ibuprofen in controlling symptoms. CONCLUSIONS: There is evidence that glucosamine sulfate may provide pain relief, reduce tenderness, and improve mobility in patients with OA. Most of the current data, however, are derived from the European and Asian literature and there are no studies supporting the use of this agent in the US. The studies published to date have been done in small numbers of patients; adequate long-term trials examining the safety, efficacy, and optimal dosage requirements of glucosamine sulfate are lacking. Most of the available clinical data are difficult to interpret due to serious deficiencies in study design. Furthermore, studies evaluating the appropriate place of glucosamine sulfate in the therapeutic armamentarium of OA remain to be done.

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

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

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.

Target tissue models: cartilage changes in experimental osteoarthritis in the dog.

J Rheumatol Suppl. 1983 Dec;11:111-3.

Adams ME.

Transection of the anterior cruciate ligament in the dog knee leads to a reproducible defined osteoarthritis (OA) with erosive cartilage loss, subchrondral sclerosis, and osteophyte formation, enabling studies of cartilage biochemistry before morphological changes are apparent. As early as 1 week after operation, menisci showed increased water content , 20% loss of galactosamine, and 40% loss of glucosamine. There was increased synthesis of larger proteoglycans (PG) at 3, 6, and 12 weeks, and the synthesis was greater in the menisci than the articular cartilage. there was no apparent impairment of the PG ability to aggregate with hyaluronate.

Glucosamine sulphate: a controlled clinical investigation in arthrosis.

Pharmatherapeutica. 1981;2(8):504-8.

D'Ambrosio E, Casa B, Bompani R, Scali G, Scali M.

Efficacy and tolerance of a new preparation of pure glucosamine sulphate, in injectable and oral form, were investigated in 30 patients with osteoarthrosis. Two groups of in-patients with chronic degenerative articular disorders received daily for 7 days either 400 mg glucosamine sulphate or a piperazine/chlorbutanol combination by intravenous or intramuscular injection. During the 2 following weeks, the patients receiving glucosamine had oral glucosamine capsules (6 x 250 mg daily); the other group had placebo. Efficacy was tested by semi-quantitative scoring of pain at rest and during active and passive movements, as well as limitation of articular function, before and after 7 and 21 days of treatment. Patients were positively questioned daily for possible intolerance symptoms. Haematology, circulatory data and urine analysis were tested before and after treatment. During both initial parenteral treatments, each symptom significantly improved, but to a faster and greater extent in the group treated with glucosamine. During the maintenance period, a further improvement was recorded in the patients treated with glucosamine, whereas in those on placebo the symptom scores increased almost to the pre-treatment level. This was considered the major difference between basic therapy, such as with glucosamine, as purely symptomatic treatment. Clinical and biological tolerance were excellent with both treatments, and no definitely drug-related complaints were recorded. It is suggested that parenteral and/or oral treatment with pure glucosamine sulphate should be considered as basic therapy for the management of primary or secondary degenerative osteoarthrosis disorders.

Double-blind clinical evaluation of oral glucosamine sulphate in the basic treatment of osteoarthrosis.

Curr Med Res Opin. 1980;7(2):110-14.

Pujalte JM, Llavore EP, Ylescupidez FR.

The efficacy and tolerance of oral glucosamine sulphate were tested against placebo in a prospective double-blind trial in 20 out-patients with established osteoarthrosis. Two capsules of either glucosaminene sulphate (250 mg) or placebo were administered 3-times daily over a period of 6 to 8 weeks. Articular pain, joint tenderness and restricted movement were semi-quantitatively scored 1 to 4 every 3 days, and individually averaged over the treatment period (overall composite score). Possible side-reactions were similarly scored upon positive questioning of the patients. Haematology, erythrocyte sedimentation rate, urine analysis and X-rays were recorded before and after treatment. Significant alleviation of symptoms was associated with the use of the active drug at the prescribed dose. Similarly, patients given glucosamine sulphate experienced earlier alleviation of symptoms compared with those who had placebo. The use of glucosamine sulphate also resulted in a significantly larger proportion of patients who experienced lessening or disappearance of symptoms within the trial period. No adverse reactions were reported by the patients treated with glucosamine, and no variation in laboratory tests was recorded.