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FEATURE SafetySafety && EfficacyEfficacy ofof GlucosamineGlucosamine && ChondroitinChondroitin inin OsteoarthritisOsteoarthritis by DARRELL T. HULISZ, Pharm.D., R.Ph. Assistant Professor of Family Medicine Case Western Reserve University School of Medicine; Associate Clinical Professor of Pharmacy Practice, Ohio Northern University College of Pharmacy, Ada, OH steoarthritis (OA), crepitus (crackling noise with movement) and soft also known as degen- tissue swelling.3 Inflammation, if present, is Oerative joint disease, is usually mild and localized to the affected joint. one of the most common Osteoarthritis commonly affects the knee, hip, chronic medical conditions hands, feet and spine. The disease generally pres- worldwide and is the most ents with unilateral or asymmetrical involvement common form of arthritis in of an affected joint, although bilateral or symmet- the United States.1 rical presentations may be observed in more Approximately 80% of advanced stages. The treatment of OA involves a people in Western countries combination of supportive treatment and pharma- age 75 or older have radi- cologic therapy. Additionally, nutraceutical ographic evidence of OA, alternatives, such as glucosamine and chondroitin, and about 11% of people are widely promoted and available to the general older than age 64 have public as a treatment for OA. Since pharmacists symptomatic OA of the are recognized as drug experts and are highly 2 knee. Risk factors for OA accessible to the public, they are likely to receive include obesity and activi- questions concerning the effectiveness and safety ties or occupations where Clinical studies of these agents. Thus, the purpose of this article is overuse of a joint is show these to equip pharmacists with updated information common. Those at risk agents are very concerning the safety and efficacy of glucosamine include baseball pitchers, well tolerated and chondroitin, alone and in combination, for the dancers, dock workers, and and may be management of OA. beneficial for marathon runners. osteoarthritis Osteoarthritis may also be OVERVIEW OF OSTEOARTHRITIS MANAGEMENT symptoms. the result of trauma, such as The treatment of OA involves a combination a motor vehicle accident. of supportive therapy and pharmacotherapy. The clinical features of OA include morning Nonpharmacologic measures include patient joint stiffness, joint pain that is usually worsened education, self-management programs, weight by movement and improved by rest, limited range loss (if overweight), aerobic exercise programs, of motion, gait instability, joint tenderness, bony physical therapy, range-of-motion exercises, JANUARY/FEBRUARY 2003 7 Safety & Efficacy of Glucosamine & Chondroitin in Osteoarthritis muscle-strengthening exercises, assistive devices limited value, especially in more severe cases of for ambulation, and occupational therapy. The OA. Patients with OA may need to be treated with American College of Rheumatology recommends a more potent analgesic, such as tramadol and acetaminophen as initial treatment of early OA.3 opiates. These therapies carry additional risks, However, nonsteroidal anti-inflammatory drugs such as adverse central nervous system effects (NSAIDs), such as ibuprofen, naproxen and (e.g., sedation), and have the potential for addic- diclofenac, are perhaps the most widely prescribed tion or abuse. Intra-articular injections of steroids class of medications for OA. Approximately 73 and hyaluronate are also of limited value and million NSAID prescriptions are written for an cannot be used chronically. Furthermore, even estimated 17 million Americans, and over 30 when the aforementioned medications are billion over-the-counter tablets are sold annually prescribed with great diligence, many patients do in this country alone.4 NSAIDs, when used prop- not experience adequate relief of symptoms. Thus, erly, are generally safe and well-tolerated by most the quest for compounds that are both highly effi- patients. However, some users have experienced cacious and completely safe for OA remains serious, life-threatening adverse events with these elusive. medications, particularly dangerous gastrointesti- GLUCOSAMINE AND CHONDROITIN nal (GI) events. Using the definition of a 3-mm or AS DIETARY SUPPLEMENTS greater break in the gastric mucosa, about 25% of Recently, with the release of the book entitled chronic NSAID users will have endoscopically The Arthritis Cure, describing glucosamine and detected gastric ulcers, and up to 50% will have chondroitin sulfate as effective agents for OA either a gastric or duodenal ulcer.5 The majority of treatment, consumer interest in these compounds these gastric mucosal injuries are superficial, soared, especially in the U.S.15 Another factor that asymptomatic, and often self-limited. However, prompted increases in sales of these nutraceuticals some patients develop severe erosions, or even was the passage of the Dietary Supplement Health peptic ulcers leading to GI hemorrhage, perfora- and Education Act in 1994. This legislation tion, and death. The mortality rate for permits the marketing of products claiming to NSAID-induced GI bleeding is 5%?0%, with affect the structure or function of the body as a 107,000 hospitalizations per year, at an estimated dietary supplement without requiring FDA cost of $15,000?0,000 per event; however, total approval. Glucosamine and chondroitin are direct costs may exceed $2 billion annually.6,7 marketed as dietary supplements, and as such Additionally, NSAIDs have adverse renal effects, must contain a disclaimer stating that they are not which is a major concern in elderly individuals, intended to diagnose or treat any specific medical those who are volume-depleted, and patients with condition. underlying renal insufficiency. The use of glucosamine and chondroitin for A new class of compounds, the cyclooxyge- OA is not without controversy. To provide some nase-2 (COX-II) inhibitors (e.g., celecoxib, clarification, a special subcommittee of the rofecoxib), are at least as effective as NSAIDs for American College of Rheumatology released the OA, but have significantly less adverse GI following statement last year concerning use of toxicity.8-12 However, COX-II inhibitors are not these agents for OA: completely devoid of adverse renal effects and, While a number of studies support the effi- like the NSAIDs, are associated with other cacy of both glucosamine and chondroitin sulfate systemic side effects.13,14 Local therapies, such as for palliation of joint pain in patients with knee capsaicin cream and topical salicylates, are only of OA, the subcommittee believes that it is premature 8 JANUARY/FEBRUARY 2003 Safety & Efficacy of Glucosamine & Chondroitin in Osteoarthritis to make specific recommendations about their use depleted in the matrix, which results in a loss of at this time because of methodologic considera- shock absorption and compressibility. Bone tions, including lack of standardized case responds to this with hypertrophic repair, increas- definitions and standardized outcome assess- ing the subcondral bone thickness.16,17 ments, as well as insufficient information about PROPOSED MECHANISMS OF ACTION FOR study design in a number of these published GLUCOSAMINE AND CHONDROITIN reports. A pivotal clinical trial being planned by Glucosamine is an aminomonosaccharide the NIH should help define the role of these that is part of almost all tissues in the human agents, singly and in combination, in the treatment body, including cartilage. Furthermore, it is the 3 of patients with knee OA. principal component of O- and N-linked Thus, it seems prudent and timely to review glycosaminoglycans, which form the connective the evidence from clinical trials to assist in provid- tissue matrix. Glucosamine sulfate, a salt of the ing recommendations to patients and healthcare natural aminomonosaccharide, has a relatively professionals for these compounds. low molecular weight. Following oral administra- PATHOPHYSIOLOGY tion, it is 90% absorbed, with about 8%?2% To better understand the potential for retained in the tissues.18 The chondrocytes incorpo- glucosamine and chondroitin to treat OA, a brief rate glucosamine into the proteoglycans, which overview of pathophysiology is necessary. are then excreted into the matrix. The sulfate Osteoarthritis is a degenerative disease affecting moiety specifically plays an important role in the articular cartilage, leading to acute periodic proteoglycan synthesis because the glycosamino- inflammation. Cartilage is made up of two compo- glycans are highly sulfated and may contribute to nents. The first are the chondrocytes, the cellular its therapeutic effect.18 Glucosamine bioavailability component, which are distributed in and actually after oral administration is about five times lower produce the second component, the matrix. The than after intravenous administration, likely due matrix is amorphous and made up of collagen and to the extensive first-pass effect in the liver. elastic fibers in a chondromucoid substance of Glucosamine is a slow-acting drug for OA treat- proteoglycans and glycoproteins. A protein back- ment; it may have a chondroprotective role in bone is formed from complex proteoglycans with OA.18 The chondroprotective effect includes an sulfated mucopolysaccharides, specifically chon- increase in proteoglycan synthesis that may be droitin sulfates A and C, and keratin sulfate, dose-dependent, along with effects on chondro- branching off laterally. cyte gene expression, thereby increasing