Clinical efficacy and safety of glucosamine, chondroitin sulphate, their combination, celecoxib or placebo taken to treat osteoarthritis of the knee: 2-year results from GAIT.

BACKGROUND: Knee osteoarthritis (OA) is a major cause of pain and functional limitation in older adults, yet longer-term studies of medical treatment of OA are limited. OBJECTIVE: To evaluate the efficacy and safety of glucosamine and chondroitin sulphate (CS), alone or in combination, as well as celecoxib and placebo on painful knee OA over 2 years. METHODS: A 24-month, double-blind, placebo-controlled study, conducted at nine sites in the US ancillary to the Glucosamine/chondroitin Arthritis Intervention Trial, enrolled 662 patients with knee OA who satisfied radiographic criteria (Kellgren/Lawrence grade 2 or 3 changes and baseline joint space width of at least 2 mm). This subset continued to receive their randomised treatment: glucosamine 500 mg three times daily, CS 400 mg three times daily, the combination of glucosamine and CS, celecoxib 200 mg daily, or placebo over 24 months. The primary outcome was a 20% reduction in Western Ontario and McMaster University Osteoarthritis Index (WOMAC) pain over 24 months. Secondary outcomes included an Outcome Measures in Rheumatology/Osteoarthritis Research Society International response and change from baseline in WOMAC pain and function. RESULTS: Compared with placebo, the odds of achieving a 20% reduction in WOMAC pain were celecoxib: 1.21, glucosamine: 1.16, combination glucosamine/CS: 0.83 and CS alone: 0.69, and were not statistically significant. CONCLUSIONS: Over 2 years, no treatment achieved a clinically important difference in WOMAC pain or function as compared with placebo. However, glucosamine and celecoxib showed beneficial but not significant trends. Adverse reactions were similar among treatment groups and serious adverse events were rare for all treatments.

The burden of osteoarthritis: clinical and quality-of-life issues.

Osteoarthritis (OA), the most common form of arthritis, is a potentially devastating joint disease, affecting 27 million US adults. Its pathophysiology is marked by a gradual degenerative process accompanied by low-grade inflammation, and, although there is a strong correlation between age and OA risk, the abnormal changes that occur in the articular cartilage of people with OA differ notably from the typical changes associated with joint aging in several important ways. Risk factors for OA are multiple and span a variety of risk domains, such as lifestyle issues (eg, obesity and engagement in manual labor), genetic predisposition, sex and ethnicity (risk is higher in women and African Americans), and comorbidities. Clinical outcomes for people with OA typically involve pain, limitations of daily living activities, and overall diminution of quality of life (QOL). The need to evaluate the degree of this burden, as well as to determine treatment approaches and measure their success, requires instruments for measuring QOL. The 2 most commonly used instruments to measure QOL in OA are the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and the Medical Outcomes Study 36-Item Short-Form Health Survey. Both provide useful global information to the clinician and researcher alike about pain and function in patients with OA, although the WOMAC is more often used in the clinical setting as it is self-administered. A number of other pain and function-specific measures are also available that may provide additional insight into patient status when used in combination with global QOL instruments.

Assessing single joints in arthritis clinical trials.

The need to develop validated outcome measures to assess response to therapies in single joints has been recognized. In 2004, a task force was established to assess established and novel outcome measures in accordance with the OMERACT filter (truth, discrimination, and feasibility) for single joint assessment. This report describes the proceedings of the single joint assessment special interest group (SIG) at OMERACT 9, including an updated literature review of imaging of the knee joints, with a focus on the extent to which these modalities fulfill the OMERACT filter. A series of studies are reported that examine patient reported, clinical examination, and imaging outcomes in therapeutic studies in knee arthritis. A summary of discussions from the meeting are presented that raise many of the ongoing challenges in establishing appropriate domains to evaluate a range of conditions and potential therapeutic interventions. Because of emerging drug candidates and modalities targeting individual joints, the ongoing work of this SIG is providing the evidence base that can be used to establish a core domain set to incorporate as outcomes in future studies.

The effect of glucosamine and/or chondroitin sulfate on the progression of knee osteoarthritis: a report from the glucosamine/chondroitin arthritis intervention trial.

OBJECTIVE: Osteoarthritis (OA) of the knee causes significant morbidity and current medical treatment is limited to symptom relief, while therapies able to slow structural damage remain elusive. This study was undertaken to evaluate the effect of glucosamine and chondroitin sulfate (CS), alone or in combination, as well as celecoxib and placebo on progressive loss of joint space width (JSW) in patients with knee OA. METHODS: A 24-month, double-blind, placebo-controlled study, conducted at 9 sites in the United States as part of the Glucosamine/Chondroitin Arthritis Intervention Trial (GAIT), enrolled 572 patients with knee OA who satisfied radiographic criteria (Kellgren/Lawrence [K/L] grade 2 or grade 3 changes and JSW of at least 2 mm at baseline). Patients with primarily lateral compartment narrowing at any time point were excluded. Patients who had been randomized to 1 of the 5 groups in the GAIT continued to receive glucosamine 500 mg 3 times daily, CS 400 mg 3 times daily, the combination of glucosamine and CS, celecoxib 200 mg daily, or placebo over 24 months. The minimum medial tibiofemoral JSW was measured at baseline, 12 months, and 24 months. The primary outcome measure was the mean change in JSW from baseline. RESULTS: The mean JSW loss at 2 years in knees with OA in the placebo group, adjusted for design and clinical factors, was 0.166 mm. No statistically significant difference in mean JSW loss was observed in any treatment group compared with the placebo group. Treatment effects on K/L grade 2 knees, but not on K/L grade 3 knees, showed a trend toward improvement relative to the placebo group. The power of the study was diminished by the limited sample size, variance of JSW measurement, and a smaller than expected loss in JSW. CONCLUSION: At 2 years, no treatment achieved a predefined threshold of clinically important difference in JSW loss as compared with placebo. However, knees with K/L grade 2 radiographic OA appeared to have the greatest potential for modification by these treatments.

Treatment of persistent shoulder pain with sodium hyaluronate: a randomized, controlled trial. A multicenter study.

BACKGROUND: Presently, there are no approved nonoperative therapies for the ongoing treatment of persistent shoulder pain. Preliminary data suggest that intra-articular sodium hyaluronate injections may be beneficial for the treatment of persistent shoulder pain resulting from various etiologies. The present study evaluated the efficacy and safety of sodium hyaluronate (Hyalgan; molecular weight, 500 to 730 kDa) for these patients. METHODS: Six hundred and sixty patients with persistent shoulder pain and limitation resulting from glenohumeral joint osteoarthritis, rotator cuff tear, and/or adhesive capsulitis who had had a failure of conventional therapy were enrolled in this double-blind, randomized, phosphate-buffered saline solution-controlled study, and 456 patients completed twenty-six weeks of follow-up. Patients were randomized to receive either five weekly intra-articular injections of sodium hyaluronate, three weekly intra-articular injections of sodium hyaluronate followed by two weekly intra-articular injections of saline solution, or five weekly intra-articular injections of saline solution. The main outcomes were improvement in terms of shoulder pain on movement at thirteen weeks after the initiation of treatment (as assessed with use of a 100-mm visual analog scale) and the treatment effect throughout twenty-six weeks. RESULTS: For the overall intent-to-treat population, patients who were managed with sodium hyaluronate had greater pain relief than controls did; significant differences were noted at Week 7 (for the five-injection hyaluronate group), Week 17 (for the three and five-injection hyaluronate groups), and Week 26 (for the three-injection hyaluronate group). Analysis of the stratified populations clearly established that this effect was due to benefits experienced by the patients with osteoarthritis. The treatment effect through twenty-six weeks was significant in patients with osteoarthritis in the three-injection (p = 0.003) and five-injection (p = 0.002) groups, with no significant difference for either regimen in patients without osteoarthritis. The safety profile was very favorable, with no product-related serious adverse effects and no between-group differences for any reported adverse event. CONCLUSIONS: Although the primary end point of this study (that is, improvement in terms of shoulder pain at thirteen weeks) was not achieved, the overall findings, including secondary end points, indicate that sodium hyaluronate (500 to 730 kDa) is effective and well tolerated for the treatment of osteoarthritis and persistent shoulder pain that is refractory to other standard nonoperative interventions.

Open-label study of clarithromycin in patients with undifferentiated connective tissue disease.

OBJECTIVE: The macrolide family of antibiotics (erythromycin, clarithromycin, and others), have both antimicrobial and immunomodulatory effects. This study explored the effect of clarithromycin on the clinical course of patients with undifferentiated connective tissue disease (UCTD) in a 12-week open-label study. METHODS: The diagnosis of UCTD was based on symptoms/signs of connective tissue disease, and the presence of 1 or more positive autoimmune disease tests, but with insufficient criteria to make a definitive diagnosis. Screening and monthly follow-up visits over 12 weeks included the following: history and physical examination; concurrent medications; the 68/66 tender/swollen joint count; visual analog scores 0 to 100 mm for patient and physician global assessment of disease activity, and patient pain; antinuclear antibody panel, rheumatoid factor, erythrocyte sedimentation rate, C-reactive protein, and blood chemistry. RESULTS: Seven patients with rheumatic disease were treated with clarithromycin; 6 of 7 had symptomatic relief. Two subjects treated empirically before the decision to perform an open-label study responded favorably. Four of 5 patients who completed the prospective open-label study had mean maximal improvements from baseline of 78, 75, and 79% in patient pain, patient global, and investigator global assessments, respectively. Pain relief occurred as early as 1 week. Drug withdrawal with rechallenge in 2 patients resulted in flare followed by recapture of symptomatic relief. CONCLUSIONS: Clarithromycin, a macrolide antibiotic, led to clinical improvement in patients with UCTD. Efficacy and safety data support further investigation of macrolide antibiotic use as a primary or adjunctive treatment in various connective tissue diseases.

Glucosamine, chondroitin sulfate, and the two in combination for painful knee osteoarthritis.

BACKGROUND: Glucosamine and chondroitin sulfate are used to treat osteoarthritis. The multicenter, double-blind, placebo- and celecoxib-controlled Glucosamine/chondroitin Arthritis Intervention Trial (GAIT) evaluated their efficacy and safety as a treatment for knee pain from osteoarthritis. METHODS: We randomly assigned 1583 patients with symptomatic knee osteoarthritis to receive 1500 mg of glucosamine daily, 1200 mg of chondroitin sulfate daily, both glucosamine and chondroitin sulfate, 200 mg of celecoxib daily, or placebo for 24 weeks. Up to 4000 mg of acetaminophen daily was allowed as rescue analgesia. Assignment was stratified according to the severity of knee pain (mild [N=1229] vs. moderate to severe [N=354]). The primary outcome measure was a 20 percent decrease in knee pain from baseline to week 24. RESULTS: The mean age of the patients was 59 years, and 64 percent were women. Overall, glucosamine and chondroitin sulfate were not significantly better than placebo in reducing knee pain by 20 percent. As compared with the rate of response to placebo (60.1 percent), the rate of response to glucosamine was 3.9 percentage points higher (P=0.30), the rate of response to chondroitin sulfate was 5.3 percentage points higher (P=0.17), and the rate of response to combined treatment was 6.5 percentage points higher (P=0.09). The rate of response in the celecoxib control group was 10.0 percentage points higher than that in the placebo control group (P=0.008). For patients with moderate-to-severe pain at baseline, the rate of response was significantly higher with combined therapy than with placebo (79.2 percent vs. 54.3 percent, P=0.002). Adverse events were mild, infrequent, and evenly distributed among the groups. CONCLUSIONS: Glucosamine and chondroitin sulfate alone or in combination did not reduce pain effectively in the overall group of patients with osteoarthritis of the knee. Exploratory analyses suggest that the combination of glucosamine and chondroitin sulfate may be effective in the subgroup of patients with moderate-to-severe knee pain. (ClinicalTrials.gov number, NCT00032890.).

State-of-the-art disease-modifying osteoarthritis drugs.

Significant advances have occurred in the symptomatic management of osteoarthritis over the past several decades. However, the development of so called disease-modifying osteoarthritis drugs is in a more formative stage. Although increased knowledge of osteoarthritis pathophysiologic pathways provides more rational opportunity for targeting specific elements of the degenerative process, limitations in our ability to measure disease progression/regression hamper assessment. Development of more sophisticated plain radiographic techniques and the use of additional technologies such as magnetic resonance imaging and gadolinium-enhanced magnetic resonance imaging of cartilage provide potential for more reproducible approaches. Noninvasive biomarkers that reflect structural change are the subject of intense investigation. Studies describing disease-modification effects provide optimism that disease prevention, retardation, and reversal are attainable.

An overview of treatment options for persistent shoulder pain.

Persistent shoulder pain (PSP) associated with rotator cuff disorders, glenohumeral osteoarthritis (OA), or adhesive capsulitis is a very common, often difficult-to-treat condition. The first step in nonoperative therapy for PSP in most patients is physical therapy, rest, and use of various heat modalities. Relief of pain from exercises aimed at improving strength and range of motion may be enhanced by administration of oral analgesics. Oral nonsteroidal anti-inflammatory drugs are often prescribed for patients with PSP, but their use may be complicated by gastrointestinal side effects and a potential for increased risk for serious cardiovascular events. Intra-articular corticosteroid injections have been demonstrated to provide benefit in patients with rotator cuff disorders and perhaps also in those with adhesive capsulitis. Results from both small-scale studies and a recent large-scale trial have shown that injection of sodium hyaluronate is also effective for the treatment of PSP, particularly in patients with glenohumeral OA. Additional well-controlled comparative trials are needed to define which treatment modalities are likely to be most effective in subsets of patients with PSP.

Analgesic efficacy and safety of nonprescription doses of naproxen sodium compared with acetaminophen in the treatment of osteoarthritis of the knee.

Nonprescription doses of naproxen sodium, acetaminophen, and placebo were compared to determine their efficacy and safety in osteoarthritis of the knee. In two identical multicenter, randomized, double-blind, placebo-controlled, multidose, parallel-design studies, patients with osteoarthritis aged (mean +/- SD) 60.6 +/- 12.8 years were randomized to daily doses of 660 mg naproxen sodium (440 mg naproxen sodium in patients >or=65 years), 4000 mg acetaminophen, or placebo for 7 days. Naproxen sodium (440/660 mg) provided significantly greater improvements in pain at rest, on passive motion, on weight-bearing, stiffness after rest (morning), day and night pain compared with placebo, and significantly greater relief from resting pain than acetaminophen (P < 0.05). Acetaminophen provided significantly greater improvements in day pain compared with placebo. Daily evaluations showed naproxen sodium (440/660 mg) provided superior pain relief to acetaminophen and was significantly better than acetaminophen at reducing difficulties experienced in walking several blocks and difficulties in bending, lifting, and stooping. Naproxen sodium (440/660 mg) and acetaminophen (4000 mg) were significantly more effective than placebo in improving mobility level, household tasks, and walking and bending. Patient and investigator evaluation scores were significantly higher in naproxen sodium and acetaminophen groups compared with placebo; no differences were observed between active treatments. Naproxen sodium and acetaminophen had similar safety profiles to placebo. Nonprescription doses of naproxen sodium (440/660 mg) effectively relieve pain and other symptoms of osteoarthritis. Naproxen sodium is an alternative in the initial treatment of osteoarthritis and may be preferred to acetaminophen as first-line therapy in patients with moderate or severe pain.

Understanding osteoarthritis of the knee--causes and effects.

Osteoarthritis of the knee is common, increasing with age in both women and men, but is generally more prevalent in women following the fourth decade. Osteoarthritis may be primary/idiopathic or secondary as a consequence of trauma, surgery, infection, or another disease process. Normal articular cartilage is composed of an extracellular matrix and chondrocytes. This matrix contains water, collagen fibers, and proteoglycan macromolecules cross-linked into an integrated network with hyaluronic acid. Osteoarthritis represents an imbalance in the destructive and synthetic processes of the cartilage that leads to erosion of the cartilage. In addition, there is a decreased concentration and viscosity of the synovial fluid in osteoarthritic patients, and this may decrease the lubricating and cushioning properties of the joint. There is also an underlying inflammation of the synovium, as well as damage or reactive changes in the subchondral bone. The entire process is thought to involve a complex interaction of cells and soluble mediators such as cytokines, growth factors, inflammatory mediators, metalloproteinases, and chondrodegradative enzymes. Understanding the biochemical and molecular changes that occur in the joint is requisite to the development of treatments for osteoarthritis of the knee that address both the symptoms of pain and loss of mobility as well as the underlying disease progression. The clinical goal of the management of osteoarthritis should be to treat not only the symptoms of the disease, such as pain and decreased mobility, but also the underlying pathology of the degenerative process.

Nonsurgical approaches to pain management for osteoarthritis of the knee.

The effective management of pain in osteoarthritis of the knee is complex and subject to many treatment- and patient-related variables. This article reviews the broad range of nonsurgical options available to the clinician, which include pharmacologic and nonpharmacologic measures such as weight loss, physical and occupational therapy, exercises, and the use of assistive devices. Pharmacotherapeutic options for osteoarthritis of the knee include the use of oral agents, topical creams, and intra-articular injections of hyaluronans or glucocorticoids. Since pain in the osteoarthritic knee can vary widely from patient to patient in its origins, pain management should address the individual patient's symptoms, level of pain, and functional disabilities.

Intra-articular hyaluronans in knee osteoarthritis: rationale and practical considerations.

Intra-articular hyaluronans are used to treat pain associated with osteoarthritis of the knee. Many controlled clinical studies have demonstrated their efficacy for this indication. The rationale for the use of hyaluronans therapeutically is based on observations that hyaluronic acid is an important component of the synovial fluid acting as a cushion and lubricant for the joint and also serving as a major component of the extracellular matrix of the cartilage, helping to enhance the ability of cartilage to resist shear and maintain a resiliency to compression. While intra-articular hyaluronans are indicated at this time only for the treatment of pain in osteoarthritis of the knee, there are data to suggest that they may also be useful in treating degenerative disease of other articular joints, as well as have an impact on disease progression. The mechanisms by which hyaluronans mediate their clinical benefit seem to be multifactorial and biologically related, in contrast to the notion that they provide only viscous fluid replacement. The safety profile of intra-articular hyaluronans is very favorable and, because they are used as a local therapy, there are no known drug interactions-an advantage for patients receiving treatment for comorbid conditions. Some adverse effects, such as pseudosepsis, have been associated with cross-linked hyaluronan agents and do not appear to be class related.

Hyaluronan therapy: looking toward the future.

Hyaluronan therapy has numerous medical applications, including the treatment of joint arthropathies, wound healing, prevention of postsurgical adhesions, treatment of urinary incontinence, ophthalmic surgery, and tissue augmentation and engineering. Studies have been conducted and are ongoing to evaluate the efficacy of intra-articular hyaluronans in disease modification in osteoarthritis of the knee; efficacy in disease states other than osteoarthritis; as adjunct therapy after joint surgery; and in joints other than the knee--namely the shoulder, hand, hip, temporomandibular joint, spine, foot, and ankle. Preliminary results have been promising and parallel what has been found in treatment of osteoarthritis of the knee. Research also continues into the development of chemically modified derivatized hyaluronan to optimize responses and enhance duration of action, as well as to expand the uses of this therapeutic modality.

American pain society pain questionnaire and other pain measures in the assessment of osteoarthritis pain: a pooled analysis of three celecoxib pivotal studies.

The aim of this study was to evaluate the utility of the American Pain Society (APS) questionnaire in the assessment of osteoarthritis (OA) pain and to determine the onset of action of celecoxib in the treatment of acute flare pain in patients with OA of the knee or hip. Pooled data from three pivotal, randomized, double-blind, placebo-controlled, 12-week trials of patients with OA who exhibited a flare of disease activity after withdrawal of nonsteroidal anti-inflammatory drug or analgesic therapy were evaluated. Patients completed the APS Pain Measure Questionnaire, which evaluates pain intensity and quality of life, at baseline and daily for the first 7 days of therapy. In addition, patients underwent a range of standard OA assessments to evaluate the analgesic efficacy of celecoxib up to 12 weeks. Three thousand two hundred fifty-eight patients were enrolled in the three studies, of whom 2041 completed the APS questionnaire (1010 received celecoxib, 513 received naproxen, and 518 received placebo). Within the first 24 hours, celecoxib at a dose of 200 or 400 mg/d significantly reduced the amount of acute pain experienced compared with placebo for four of the five measures, and statistical significance for the remaining parameter, "pain in the last 24 hours," was achieved on day 2. Celecoxib at a dose of 200 to 400 mg/d provided similar efficacy to naproxen at a dose of 1000 mg/d. The pain relief observed with celecoxib was maintained for the APS evaluation period. Long-term efficacy assessments showed the efficacy of 200 mg/d of celecoxib to be continuous and maintained for at least the 12 weeks of the study and that it was equivalent to 400 mg/d of celecoxib and 1000 mg/d of naproxen. This study demonstrates that the APS questionnaire is a useful measure of pain and therapeutic response in OA. Celecoxib furthermore seems to be an effective acute and chronic analgesic in OA.