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Musculoskeletal - Arthritis - OA - RA - FM

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Musculoskeletal conditions affect over 40 million people in the U.S. The three most common are Osteoarthritis, RA and  Fibromyalgia.
 
OA is the most common form of all musculoskeletal conditions affecting more than twenty million people in the U.S.
 
RA and FM are not as common.
 
Rheumatoid arthritis is a inflammatory disease of the synovium,OA is a non-inflammatory disease of the cartilage.
 
There are many different types of musculoskeletal conditions that can have a significant impact on a patient's physical and pschological functioning. There are more than 100 joints connecting the body's 206 bones.
 
Tied together by ligaments,the bones of joints are capped with a smooth substance-cartilage. This tough elastic material acts as a shock absorber and allows the bone ends to glide smoothly across each other.
 
 If the cartilage is destroyed (as in OA),the bones of joint can grind against each other causing pain,loss of mobility,deformity and dsyfunction.
 
Between the bones is a joint cavity,which gives the bones room to move. The joint space between two bones is enclosed by a capsule that's flexibile,yet strong enough to protect the joint against dislocation.
 
The inner lining of this capsule,the synovium,produces a thick fluid that lubricates and nourishes the joint. In many forms of arthritis,the synovium becomes inflamed and thickened,producing extra fluid which contains inflammatory cells. The inflamed synovium and fluid can damage the underlying bone (RA).
 
Fibromyalgia is a condition characterized by widespread muscle pain and point tenderness at various sites around the body including the upper back,buttocks,upper arms, and knees.
 
The etiology of this illness is unknown,but it has been linked to psychological stress,and biochemical abnormalities in the central nervous system.

Current therapy is aimed at reducing the pain and other symptoms associated with these conditions. Non-pharmacologic therapies play an important role in the treatment of these disorders including weight loss,exercise and physical therapy.
 
Pharmacologic therapy is aimed at pain relief and,in the case of RA, disease modification and control,in addition to these therapies that have been available for years,new therapies with fewer side effects and a more specific mechanism of action are being studied and released.
 
Tissue transplants are being researched for their potential role in the management of OA. In patients with a specific defect in the knee joint,known as osteochondritis dissecans,autogenous cartilage implantation is being studied.
 
Results to date promising,but caution is advised while more long-term and better designed studies are conducted.
 
A second procedure being studied is referred to as autogenous osteochondral grafting. Only 57 patients have been studied so far,but results have been encouraging. In this procedure,cylinders of bone and cartilage are transferred from a lesser weight-bearing position to the articular surface of the knee joint. The procedure is limited to areas where cartilage lesions are small.
 
Since cytokines have been thought to be potentially implicated that leads to OA,modulation of these compounds are being studied
 
Many of the treatment options for Fibromyalgia center around nonpharmacologic  therapies. Although this syndrome has a pain aspect, conventional treatments for pain are not always effective.
 
One of the most important aspects of the management of this disease is ensuring that patients understand this illness as much as possible and the importance of trying nonpharmacologic treatment approaches including exercise and relaxation techniques.
 
Narcotics are not recommended because of their potential for dependence and addiction with long-term use. Glucocortoids have been of little benefit and should be avoided. NSAIDs and other analgesics only partially improve symptoms for some patients with many people having no benefit.
 
Various other therapies have shown benefit in some patients with FM. The tricyclic antidepressants and the muscle relaxant,cyclobenzaprine,used before bedtime may help to restore a normal sleep pattern helping the patient to fell less fatigued. Patients should be started on regular doses of these medications and titrated upwards,based upon efficacy and side effects.
 
Depression and anxiety should be treated with appropriate interventions including psychotherapy  and drugs. Trazodone may be a useful addition in a patient with cocomittant sleep disturbances and depression.
 
Other than alprazolam, benzodiazepines should be avoided in patients with FM because of their negative effects on the sleep cycle. First and foremost patients should be educated about the disease itself before therapy due to the nature of FM.
 
The way doctors diagnose and treat people with chronic back pain may change after a report is published,funded by the Arthritis Society.
 
Rheumatoligist Dr John Esdaile's team of researchers have found that diffuse idiopathic skeletal hyperostosis (DISH)-traditionally considered a minor ailment-may actually be a disbling form of arthritis.
 
"These patients are now told there's nothing wrong with them because their x-rays appear normal to the untrained eye",said Dr. Esdaile director of research at The Arthritis Societ's British Columbia Yukon Division.
 
"Meanwhile they're enduring incredible pain." In fact 11 of 12 people who suffer from DISH receive either the wrong diagnosis,or no diagnosis at all.
 
 "The x-rays are very distinct," added Dr. Esdaile,"But it's sort of like looking at a painting-you won't notice some vital aspect until someone points it out,then you can't believe you missed it." "Because DISH doesn't fit with what the radiologists look for,they don't see it or report it,"he says.
 
Dr. Esdaile said DISH may be the second-most common type of arthritis. Before this study,fibromyalgia was considered the second-most-common form of arthritis,affecting three-in-100 Canadians.
 
The study compares patients with DISH to healthy subjects and those with lumbar spondylosis,a degenerative back disease. People with DISH suffered from more neck and back pain, difficulty swallowing,nerve abnormalities and difficulty moving their necks and backs.
 
"DISH is clearly a distinct disorder with signs and symptoms that distinguish it from other causes of spinal complaints and from healthy individuals. It has a potential to cause major disability."
 
Dr. Esdaile and his colleagues believe that DISH is also one of the few forms of arthritis to affect more men than women. While it's been nearly 100 years since scientists first described DISH this study is the first to show its considerable significance in the commmunity
 
"We have shown a tremendous need to educate rheumatoligists,from front-line physicians and radiologists as to the frequency of the disease and the tell-tale signs of it."said Dr. Esdaile.
 
"Now that we have separated it from the pack-it is its own disease-we need to research the causes and find out how to help these patients."
 
Dr. Esdaile hopes his team's research will change that as the medical community learns how to diagnose DISH through x-ray of the thoracic (mid-back) spine.----/98.

The patient is a 63-year-old  male who is a supervisor in an sailboat assembly plant. His height is 1.7 meters (5 8) and weight is 90 kg. The patient presented to his primary physician with persistent, moderate, aching pain in the right knee that began about a year ago and has become progressively worse with functional limitation. The pain is associated with stiffness that is worse on Thursday and Saturday mornings (he tours the plant on Wednesday nights and bowls in a league on Friday nights).
 
The patients past medical history is significant for inferior wall myocardial infarction 4 years prior and is status post successful angioplasty. The patient also has mild type II diabetes mellitus and a 25 pack-year history of smoking. Borderline hypertension (146/94) and overweight are other chronic health problems. His family medical history is negative for osteoarthritis and rheumatoid arthritis.
 
Medications include glyburide 10 mg/d and prophylactic aspirin 81 mg/d (for cardioprotection). Although he had been prescribed anti-hypertensive medication in the past, he is not currently utilizing this therapy. The patient admits taking occasional ibuprofen and acetaminophen for knee pain.
 
Differential Diagnosis: Physical examination revealed localized tenderness of the right knees and pain on passive motion. Pain was also elicited by holding the patella against the femur as the patient contracted his quadriceps. Marginal osteophytes were palpated and patellofemoral crepitus was noted upon flexion. There was limitation of joint motion on extension with both passive and active motion. Physical examination also revealed hard painless enlargements of the fourth and fifth distal interphalangeal (DIP) and, proximal interphalangeal (PIP) joints as well as, the second and third metacarpophalangeal (MCP) joints of the left hand, and minor limitation of motion of the left wrist.
 
X-ray studies of the right knee showed several tibio-femoral osteophytes and mild medial joint compartment narrowing. Soft tissue calcification was noted in the medial collateral ligament. With the exception of mild hypertension, the patients vital signs were within normal limits.
 
The differentiation of osteoarthritis (OA) from other disorders of the musculoskeletal system depends on a correlation of clinical, laboratory, and radiographic findings. Osteoarthritis represents several disease subsets (e.g., OA of the knee, hip, hand) leading to similar clinical and pathologic alterations.
 
Variants of the disease, such as primary generalized OA and erosive inflammatory OA, have different clinical, pathologic and radiographic findings.
 
The symptoms of primary OA are typically localized to the affected joints, usually the DIP, PIP, first carpometacarpal (CMC) joints, and hip and knee. Rarely are the MCP, wrist, elbow, or shoulder joints involved, except after trauma (secondary OA). Primary generalized OA is characterized by diffuse polyaarticular involvement, whereas erosive inflammatory OA is mainly limited to the DIP and PIP joints of the hands.
 
Rheumatoid arthritis may be difficult to differentiate from erosive OA. However, the pattern of joint involvement is of diagnostic value because RA usually affects the PIP and MCP joints as well as the wrist and carpal joints and peripheral joints elsewhere. The DIP joints are seldom involved in rheumatoid arthritis.
 
 Pseudogout syndrome or chondrocalcinosis articularis may simulate OA when low-grade arthralgias result from the presence of calcium pyrophosphate dihydrate (CPPD) crystals in synovial fluid; the pattern of arthritis often involves wrists, knees, and hips.
 
Pigmented villonodular synovitis (PVNS) is a rare disorder that may involve the synovium of joints, bursa, or tendon sheaths. Monoarticular involvement is typical, with the knee most commonly affected.
 
Clinically, patients with osteoarthritis of the knee have pain that is typically worse with weight-bearing and improved with rest, morning stiffness, and gel phenomenon, and often have tenderness to palpation, crepitus on motion, and/or limitation of joint motion. Pain is the cardinal symptom of OA and is usually aching in character and poorly localized. Although onset is usually insidious, pain is most often the reason the patient with OA will seek assistance from the physician. In knee OA, patients will most commonly describe their pain as involving the entire joint.
 
Stiffness on awakening in the morning is also a common complaint in knee OA. Such stiffness is of short duration, rarely lasting more than 15-30 minutes. Articular gelling, a transient stiffness lasting only several flexion-extension cycles, is extremely common in the lower extremity joints of elderly patients.
 
This occurs often in the absence of other symptoms of OA and follows prolonged inactivity. Compartment-directed (patellofemoral, medial and lateral tibio-femoral) crepitus has a high degree of diagnostic specificity and sensitivity for OA of the knee. Limitation of motion often develops as the disease progresses, owing to joint-surface incongruity, muscle spasms and contracture, capsular contracture, and mechanical block from osteophytes and loose bodies.
 
The patients history and signs and symptoms, such as short-term stiffness and patellofemoral crepitus, were suggestive of primary osteoarthritis of the knee. Involvement of PIP and DIP joints was also consistent with a diagnosis of OA, but involvement of other joints was atypical (MCP joints and wrist). Therefore, further diagnostic tests were conducted to rule out other forms of arthritis in the differential diagnosis.
 
No specific diagnostic laboratory abnormalities exist in primary OA, but are important in excluding other forms of arthritis in the differential diagnosis. In primary OA, the erythrocyte sedimentation rate (ESR) is usually normal and serum rheumatoid factor (RF) and antinuclear antibody are negative. An increase in ESR and positive serum RF point to a diagnosis of rheumatoid arthritis. The radiographic appearance of primary OA may be normal if the pathologic changes are sufficiently mild; however, radiographic changes may be noted as the disease progresses. Anteroposterior and lateral views are useful. Joint-space narrowing occurs as a result of degeneration and disappearance of articular cartilage, and subchondral bony sclerosis (eburnation) is noted as increased bone density.
 
Osteophytes are characteristic of primary OA. Radiological changes in rheumatoid arthritis include erosions localized in or adjacent to the involved joints. In pigmented villonodular synovitis, radiographs of the knee may appear normal or may show a periarticular soft tissue density, expansion of the suprapatellar pouch and local osseous changes confined to the patellofemoral articulation. The typical presentation is a noncalcified capsular soft-tissue mass of the knee, without bony abnormalities.
 
 Magnetic resonance imaging (MRI) is particularly useful in differentiating internal joint derangement and pigmented villonodular synovitis from osteoarthritis. In pigmented villonodular synovitis, MRI can demonstrate key diagnostic features, such as joint effusion, elevation of the joint capsule, hyperplastic synovium and low signal intensity resulting from hemosiderin deposition.
 
The synovium contains areas of void signal intensity due to hemosiderin, interspersed with increased signal from both inflammation and fat. Although useful in diagnosis, MRI is not specific for pigmented villonodular synovitis, since rheumatoid synovitis may show a similar signal pattern. However, MRI in patients with suspected PVNS may decrease the time until diagnosis, aid in preoperative planning, and may be a non-invasive method of long-term follow up for possible recurrence
 
Laboratory findings were negative for serum RF and ESR was 10 mm/h. As noted previously, anteroposterior and lateral films of the right knee revealed mild medial joint-space narrowing and marginal osteophyte formation characteristic of primary OA. Subchondral eburnation was present.
 
Films of the left hand showed degeneration of the fourth and fifth DIP and PIP joints. A detailed re-examination of the patients medical history revealed an episode of acute trauma to the left hand in 1960 as a result of an company training accident.
 
Based on the presenting signs and symptoms, radiographic films, and laboratory values, a diagnosis was made of primary patellofemoral OA of the right knee accompanied by traumatic secondary OA of the left hand. The former diagnosis was supported by the presence of predisposing risk factors for osteoarthritis.
 
Laboratory findings were negative for serum RF and ESR was 10 mm/h. As noted previously, anteroposterior and lateral films of the right knee revealed mild medial joint-space narrowing and marginal osteophyte formation characteristic of primary OA. Subchondral eburnation was present.
 
Films of the left hand showed degeneration of the fourth and fifth DIP and PIP joints. A detailed re-examination of the patients medical history revealed an episode of acute trauma to the left hand in 1959 as a result of an army training accident.
 
Based on the presenting signs and symptoms, radiographic films, and laboratory values, a diagnosis was made of primary patellofemoral OA of the right knee accompanied by traumatic secondary OA of the left hand. The former diagnosis was supported by the presence of predisposing risk factors for osteoarthritis.
 
Although the role of obesity in the etiology of OA requires further definition, a positive relation with knee OA has been demonstrated in multiple studies.In a large, randomized, controlled study in knee OA, twice daily celecoxib 50-200 mg and naproxen 500 mg produced significant improvements in mean WOMAC composite score from baseline and were significantly better than placebo (both P less than or equal to .05). Likewise, rofecoxib provides similar pain relief to ibuprofen and diclofenac in patients with osteoarthritis of the hip or knee. The CLASS trial found significantly fewer (P = .04) upper GI ulcer complications with celecoxib 400 mg twice daily than nonselective NSAIDs in aspirin nonusers.
 
Qualitatively similar findings were described in an analysis of data pooled from eight double-blind, randomized controlled trials of rofecoxib versus traditional NSAIDs and placebo. Unlike traditional NSAIDs, COX-2 specific inhibitors do not have a clinically significant effect on platelet aggregation or bleeding time. Results from the SUCCESS VI trial suggest COX-2 specific inhibitors differ in their effects on blood pressure, edema, and other cardiorenal measures. 
 
The Ulm Osteoarthritis Study, a multicenter cross-sectional survey of patients with advanced hip and knee osteoarthritis, recently showed that obesity and overweight were associated with bilateral knee OA, but not bilateral hip OA nor generalized OA. Results from a subanalysis of  a clinical study found the link between obesity and subsequent osteoarthritis persisted after controlling for serum uric acid level and physical activity level, and was strongest for persons with severest radiographic disease.
 
Obesity seems to be a mechanical rather than a systemic risk factor for OA with the knee joint being especially susceptible. Osteoarthritis has been associated with specific somatotypes; its prevalence is greater in stout individuals than thin ones. Mechanical stress related to occupation or sports activities has been also implicated in the induction of OA. A study showed a higher prevalence of OA of the knees, elbows and fingers in dock workers than age-matched civil servants. OA of the knee is also more common in females than males when adjusted for age, body mass index (BMI), injury, chondrocalcinosis, and physical activity.
The goals of the management of the patient with osteoarthritis continue to include control of pain and improvement in function and health-related quality of life, with avoidance, if possible, of adverse effects of therapy. With significant improvement in the understanding of the etiopathogenesis of OA, there has been new emphasis on potential preventive measures and a more comprehensive approach to treatment. Guidelines for the management of OA of the knee have been developed and reported.
 
Several studies have reported that obese patients are more likely to experience progressive disease. Clinical studies demonstrated a high frequency of involvement of the previously uninvolved contralateral knee within a 2-year period in obese patients. Multivariate analysis of longitudinal data from another study showed that initial radiographic joint space narrowing, body mass index, symptom duration, and global severity are predictors of progression of knee OA, with joint space narrowing a strong predictor. The risk of progression in clinical OA patients with radiographic abnormalities is substantial. Rates of progression are greatest in those with established radiographic abnormalities.
 
The patient was prescribed acetaminophen 500 mg twice daily for moderate knee pain by his primary care physician and instructed to discontinue taking ibuprofen. He was also placed on a reduced sodium and low saturated fat diet, and a smoking cessation program was initiated. Weight control was stressed.
 
The patient was scheduled for routine 6-month follow-up, but missed the appointment. He continued taking acetaminophen, and subsequently increased the cardioprotective dose of aspirin to 650 mg three times daily because it helped the pain in my knee. Thirteen months after the initial diagnosis, the patient scheduled an office visit because of increased right knee pain and gnawing epigastric pain.
 
Physical examination revealed tenderness of the right knee with local inflammation and joint effusion. Mild pain on motion was also noted in the left knee. Films showed further joint space narrowing in the right knee. An erosive gastric ulcer was diagnosed by endoscopy. Studies for H. pylori were negative.
 
Aspirin was discontinued, and therapy for the ulcer was initiated with proton pump inhibitors with resolution of gastrointestinal (GI) symptoms.
 
Acetaminophen was increased to 1000 mg four times daily with only limited improvement in knee symptoms.  The patient was seen at follow-up 3 months later; he had no further GI symptoms. His joint symptoms, however, had become more severe.
 
The patient was prescribed acetaminophen 500 mg twice daily for moderate knee pain by his primary care physician and instructed to discontinue taking ibuprofen. He was also placed on a reduced sodium and low saturated fat diet, and a smoking cessation program was initiated. Weight control was stressed.
 
The patient was scheduled for routine 6-month follow-up, but missed the appointment. He continued taking acetaminophen, and subsequently increased the cardioprotective dose of aspirin to 650 mg three times daily because it helped the pain in my knee. Thirteen months after the initial diagnosis, the patient scheduled an office visit because of increased right knee pain and gnawing epigastric pain.
 
Physical examination revealed tenderness of the right knee with local inflammation and joint effusion. Mild pain on motion was also noted in the left knee. Films showed further joint space narrowing in the right knee. An erosive gastric ulcer was diagnosed by endoscopy. Studies for H. pylori were negative.
 
Aspirin was discontinued, and therapy for the ulcer was initiated with proton pump inhibitors with resolution of gastrointestinal (GI) symptoms.
 
Acetaminophen was increased to 1000 mg four times daily with only limited improvement in knee symptoms.
 
The patient was seen at follow-up 3 months later; he had no further GI symptoms. His joint symptoms, however, had become more severe.
 
According to the current 2000 American College of Rheumatology (ACR) Guidelines, nonpharmacologic therapy is the cornerstone of OA pain management, regardless of disease severity. Numerous treatment modalities may be effective, including patient education, self-management programs, weight loss (if overweight), aerobic exercise, range-of-motion exercises, muscle-strengthening exercises, etc.
 
Commonly used aerobic exercises include walking, swimming, and (stationary) bicycle riding. A supervised program of fitness walking and education improves functional status without worsening OA of the knee. The 2000 ACR Guidelines also recommend that overweight patients with hip or knee OA lose weight.
 
Pharmacotherapy therapy for pain management is most effective when combined with nonpharmacologic strategies. The 2000 ACR Guidelines indicate acetaminophen for initial use in patients with mild-to-moderate pain, but COX-2 selective inhibitors or traditional NSAIDs with gastroprotective agents, when indicated, are the initial drugs of choice for patients with moderate-to-severe pain, particularly in the presence of inflammation.
 
In patients at risk for upper GI adverse events (e.g., age greater than or equal to 65, comorbid medical conditions, history of peptic ulcer disease), COX-2 selective inhibitors are recommended. Traditional nonselective NSAIDs with gastroprotective agents are an alternative to COX-2 selective inhibitors.
 
Because the patient had several risk factors for an upper GI event, he was prescribed a COX-2 selective inhibitor, daily rofecoxib 25 mg. He also received an intraarticular glucocorticoid injection for the increasingly severe right knee pain.
 
The importance of diet and lifestyle modifications was reinforced, and he was referred to a physical therapist that instituted a daily exercise regimen. The patient was also encouraged to participate in a self-management program.
 
 In general, intraarticular glucocorticoid injections should be limited to a maximum of four injections into any single joint per year. According to the 2000 ACR Guidelines, intraarticular glucocorticoid injections are of value in the treatment of acute knee pain in patients with OA, and may be particularly beneficial in patients who have signs of local inflammation with a joint effusion.
 
 When joints are painful and swollen, aspiration of fluid followed by intraarticular injection of a glucocorticoid preparation (e.g., up to 40 mg triamcinolone hexacetonide) is an effective short-term method of decreasing pain and increasing quadriceps strength. Injection can be used as monotherapy in selected patients or as an adjunct to systemic therapy with an analgesic, a nonselective NSAID, or a COX-2 selective inhibitor.
 
At follow-up 1 month later, the pain in the right knee had improved. The patient claimed to be conscientiously following the exercise and diet regimen, however, he presented with mild ankle edema and his weight had increased 1 kg. His sitting blood pressure had also risen slightly to 150/96.
 
Conventional NSAIDs are widely recognized as causing edema and hypertension through fluid and electrolyte disturbances and other events. Hypertension and renal manifestations characterized by edema can also be seen with COX-2 specific inhibitors. However, there are differences between the frequency of these events with different COX-2 specific inhibitors and it appears from studies (SUCCESS VI) that rofecoxib is more likely to cause increases in blood pressure and edema than celecoxib. This suggests that although different COX-2 specific inhibitors are similar with respect to basic mechanisms, they differ in side-reactions and other molecule-related responses.
 
Following cessation of rofecoxib and initiation of hydrochlorothiazide therapy, the patients blood pressure returned to a level of 132/78 after approximately 3 weeks. At that time, the patient was begun on celecoxib 200 mg a day. At follow-up 1 month later, the patient described occasional mild right knee pain. On physical examination no tenderness or inflammation of the knee was noted and the ankle edema had resolved. Blood pressure was 128/74 and his weight had decreased by 1.5 kg.
 
On review of medications, the patient claimed to be taking only those prescribed and no other "medicines," but admitted taking Aleve (naproxen 220 mg) for occasional headache and glucosamine 500 mg/d obtained from a "health food store."
 
The 2000 ACR Guidelines recommend use of only a single NSAID at a time, except for concurrent use of a cardioprotective dose of aspirin (81-325 mg/day) with other NSAIDs. While a number of studies support the efficacy of both glucosamine and chondroitin sulfate for palliation of joint pain in patients with knee OA, the 2000 ACR Guidelines do not make specific recommendations about their use because of methodologic considerations, including lack of standardized case definitions and standardized outcome assessments, as well as insufficient information about study design in a number of published reports.
 
A pivotal clinical trial was conducted by the National Institutes of Health (NIH) in the treatment of patients with knee OA found that glucosamine helped some,who were treated with the agent but,as for cartridge regeneration,the report was reserved,on the cautious side..
 
In a large, randomized, controlled study in knee OA, twice daily celecoxib 50-200 mg and naproxen 500 mg produced significant improvements in mean WOMAC composite score from baseline and were significantly better than placebo (both P less than or equal to .05). Likewise, rofecoxib provides similar pain relief to ibuprofen and diclofenac in patients with osteoarthritis of the hip or knee.
 
 The CLASS trial found significantly fewer (P = .04) upper GI ulcer complications with celecoxib 400 mg twice daily than nonselective NSAIDs in aspirin nonusers. Qualitatively similar findings were described in an analysis of data pooled from eight double-blind, randomized controlled trials of rofecoxib versus traditional NSAIDs and placebo.
 
Unlike traditional NSAIDs, COX-2 specific inhibitors do not have a clinically significant effect on platelet aggregation or bleeding time. Results from the SUCCESS VI trial suggest COX-2 specific inhibitors differ in their effects on blood pressure, edema, and other cardiorenal measures.

A recent article in the Journal of the American Medical Association (JAMA 283:1469-75, 2000) by Timothy McAlindon, MD, MPH, MRCP, and colleagues from The Arthritis Center at Boston University School of Medicine concluded that trials of glucosamine and chondroitin preparations for osteoarthritis (OA) demonstrated positive effects, variably ranging from moderate to large. They voiced concerns, however, regarding the validity of such conclusions based on methodological flaws in a number of the studies and possible publication bias. With respect to methodological flaws, the main concerns were inadequate concealment of drug allocation, which affects blinding, and the absence of intent-to-treat analyses. Publication bias concerns were related to sponsorship support, and selective publication of positive trials. Despite these caveats, the authors concluded that some degree of efficacy with respect to symptomatic relief in OA appeared probable for these preparations.

These findings are in concert with conclusions in previous reviews of the use of these agents in OA. It is of interest that the authors found suggestive improvement in their meta-analysis, utilizing studies as short as four weeks' duration. Several studies of four to six months' duration have demonstrated that the efficacy differences between active agent and placebo may be greater than represented in their meta-analysis study.

A recent carefully performed study by Jean-Yves Reginster, MD, PhD, and colleagues in Belgium and presented at the ACR's 63rd Annual Scientific Meeting suggested that glucosamine, in a dose of 1500 mg daily for three years, had a structure-modifying effect on OA of the knee. Glucosamine-treated patients had an increase in joint space, contrasted with loss of joint space in the placebo-treated group. Such structure modification would of course be very exciting, particularly with an agent that appears to have low toxicity. The study has caveats, however, with respect to the radiographic technique used. Although the x-ray methodology was state-of-the-art at the time the study was initiated, more precise reproducible techniques are now available. Small changes in knee position at time of x-ray as utilized may have led to significant differences in apparent joint width. Variations in reproducibility of radiologic findings may have been further accentuated in patients taking glucosamine, who, in the presence of decreased pain, were able to more fully extend their knee, altering the apparent joint space measurement.

The National Institute of Arthritis and Musculoskeletal and Skin Diseases, in collaboration with the National Center for Complementary and Alternative Medicine, has initiated what should be a pivotal study evaluating the symptom-relieving and structure modification effects of these agents. This study, comparing glucosamine, chondroitin sulfate, a mixture of the two agents, a positive NSAID control and placebo, will evaluate symptomatic responses (pain and function) and joint space cartilage structural responses.

Although the mood of the rheumatologic community several years ago was generally skeptical regarding the use of glucosamine and chondroitin sulfate, careful review of studies now suggests that these agents may be of value in the symptomatic treatment of OA. These therapies are not without risk. Glucosamine should not be taken in those with allergy to shellfish, coumadin levels maybe affected by chondroitin sulfate, and recent reports have shown that glucosamine might raise blood insulin levels in diabetics. Since these agents do not fall under the FDA approval process, the rigor of the investigations and claims cited should be carefully scrutinized. Nonetheless, based on the data we now have, it appears not unreasonable for physicians to concur in the use of glucosamine and chondroitin sulfate for OA, after discussing that unknowns remain regarding the efficacy, tolerability, and toxicity of these agents.