SIGNS AND SYMPTOMS 

TREATMENT 
Nonpharmacologic Measures 

Pharmacologic Agents

Acetaminophen

Topical Capsaicin

NSAIDs

NEW NSAIDs
Celecoxib

Meloxicam

Rofecoxib

Viscosupplements

Glucosamine and Chondroitin

REFERENCES

Update on Pathophysiology and Treatment 
of Osteoarthritis

Shabana Yasmin, PharmD Candidate, Helga Fayazzadeh, PharmD Candidate, Sandra Takami, PharmD Candidate, William C. Gong, PharmD, FASHP, and Mark A. Gill, PharmD, FASHP, FCCP

Yasmin, Fayazzadeh, and Takami are PharmD candidates at the University of Southern California (USC) School of Pharmacy; Dr. Gong is Associate Professor of Clinical Pharmacy at the USC School of Pharmacy; and Dr. Gill is Professor of Clinical Pharmacy at the USC School of Pharmacy. 

Introduction

It is estimated that 15.0% of the U.S. population, or approximately 40 million people in the United States, have arthritis and estimated prevalence rates are 49.4% for persons aged > 65 years.¹ The prevalence rate of self-reported arthritis in the United States is projected to increase to 18.2% (59.4 million) of the estimated population in 2020.² The main concern is the disability associated with arthritis, which is projected to increase from 2.8% of the 1990 population to 3.6% of the 2020 population.³ In addition, arthritis limits daily activities in 11.6% of persons aged > 65 years.²

Osteoarthritis (OA), also known as degenerative joint disease, is the most common type of arthritis affecting predominantly the elderly. Approximately 80% of the U.S. population > 65 years of age has OA and that figure approaches 100% with increasing age.^1,3 

Clinically defined OA based on the National Arthritis Data Workgroup (NADW) report indicates that the prevalence increases with age in both sexes but the female-to-male ratio is approximately 2:1.¹ According to estimates from the National Health and Nutrition Examination Survey I (NHANES I), radiographic OA of the knee and hip increases with age. In the knee, radiographic evidence of disease is more common in women, whereas in the hips, it is more frequent in men.¹ Radiographic OA of the tibiofemoral compartment was present in 33% of survey participants aged 63 to 93 years.¹ 

This review will describe the pathophysiology of OA and will highlight the current trends in treatment, as well as the prospect for improved therapy with emerging strategies and drugs.

Pathophysiology 

OA is characterized as a noninflammatory disorder of the joints. Deterioration and changes to the articular cartilage result in formation of new bone at the surfaces of the joints. Common joints affected are the weight-bearing joints, which include the spine, hip, knee, and ankle. Other joints affected are the small bone joints of the hands and the feet. In the early stages the cartilage is usually thicker than normal, but with progression of OA, the joint surface thins and the cartilage softens, leading to disruption in the integrity of the surface and development of clefts. This results in the formation of ulcers that extend deep into the bones. Although repair of the cartilage does occur, the resultant repair is inferior and is unable to withstand mechanical stress. Cartilage is metabolically active. However, as stress on the joints continues, the cartilage becomes hypocellular or lacks the chondrocytes to help rebuild and maintain integrity.⁴ Chondrocytes make up 5% of the cartilage. It primarily consists of water and proteoglycans compressed in a tight collagen network. Proteoglycans hold water osmotically and allow cartilage to absorb impact to joints. Figure 15 represents a diagrammatic view of the cartilage. It shows the aggrecans, which are composed of a protein core with glycosaminoglycan side chains, predominantly, chondroitin sulfate and keratan sulfate. The figure represents the cartilage structure showing resident molecules and the chondrocyte synthesizing new collagen and aggrecan (proteoglycan) molecules and the degradation of these and the resident molecules. The chondrocytes can assemble the matrix (the intercellular substance of bone tissue) using molecules like glucosamine sulfate and chondroitin sulfate. Biochemically, OA is associated with loss of glycosaminoglycans from cartilage.⁶ Osteoarthritic joints have increased activity of metalloproteinase (MMP), which is found in the matrix. MMP enzymes also degrade the extracellular matrix of cartilage. Under normal circumstances these enzymes are inactivated by the tissue inhibitors, thus maintaining its balance and the integrity of the cartilage.⁴

Figure 1 Diagrammatic Representation of Cartilage Structure

Another important feature of OA is bone remodeling and hypertrophy. Appositional bone growth occurs in the subchondral region, leading to the bony “sclerosis” seen radiographically.⁴ Growth of cartilage and bone around the joints restricts the movement of the joints causing pain and disability. 

Table 1 is a comparative chart of OA and rheumatoid arthritis. The joints that are typically affected in OA are localized joints, whereas in rheumatoid arthritis there is systemic involvement. Osteophytes, bony outgrowths, or protuberances are usually present in OA whereas they are absent in rheumatoid arthritis. Figure 2 represents the joint distribution and the systemic involvement in rheumatoid arthritis and OA

.

Table 1. Osteoarthritis and Rheumatoid Arthritis Compared

Signs and Symptoms

The clinical presentation of the disease depends on the duration, the joints affected, and the severity of the joint involvement.⁷ Pain is the most common symptom in patients with OA, associated with the use of the joints. Other symptoms include joint stiffness, limitation of movement, variable degree of local inflammation, and loss of function. The stiffness usually lasts less than 20 minutes, occurs because of inactivity of the affected joints, and resolves after movement. However, excessive use of the joints can also contribute to OA pain. On examination, affected joints have localized tenderness and firm swellings at the joint margins secondary to the bony hypertrophy.⁶ OA affects joints asymmetrically and there are no systemic symptoms when compared to rheumatoid arthritis. Primary OA is the most common form and no predisposing factor is apparent. The joints most commonly affected in primary OA are the distal and proximal interphalangeal (DIP and PIP) joints of the hands and/or the first metatarsophalangeal (MTP) joint of the toe. The bony enlargements that are present at the DIP joints are called “Heberden’s nodes” and those present at the PIP joints are called “Bouchard’s nodes” (Figure 2).⁴ Secondary OA is pathologically similar to primary OA but is attributed to an underlying cause. Secondary OA is associated with trauma and congenital or developmental metabolic, endocrine, calcium deposition, and other bone and joint diseases. Any of the joints mentioned above can be involved.⁴ As the disease progresses, there is limited range of motion secondary to loss of articular surface, capsular contracture, and mechanical blockage secondary to osteophytosis. Patients may also experience a decreased range of motion (ROM).⁷ 

Figure 2 
OA Joint Distribution versus RA Joint and Systemic Distribution. (Also shown are Bouchard’s nodes and Heberden’s nodes.)

Nonpharmacologic Measures 

Nonpharmacologic treatment of OA includes: (1) patient education in self-management programs (eg, Arthritis Foundation Self-Help Course); (2) weight loss (if overweight); (3) physical therapy: ROM exercises, muscle-strengthening exercises, and use of assistive devices of ambulation; (4) occupational therapy, including joint protection and energy conservation, use of assistive devices for activities of daily living (canes, walkers, braces, etc); (5) aerobic aquatic exercise programs; and (6) health, professional, and social support.⁸

Pharmacotherapy should play an adjunctive role to nonpharmacologic measures in the overall management of patients with symptoms caused by OA.⁹ 

Pharmacologic Agents

Acetaminophen. Based on recent safety and efficacy studies, acetaminophen is the preferred agent for OA as recommended by the American College of Rheumatology.^8,10 Acetaminophen possesses analgesic and antipyretic activity similar to aspirin; however, acetaminophen has no peripheral anti-inflammatory activity or effects on platelet function.¹¹ 

Acetaminophen inhibits the synthesis of prostaglandins in the central nervous system and peripherally blocks pain impulse generation; it produces antipyresis from inhibition of the hypothalamic heat-regulating center.¹² Acetaminophen is effective for the relief of both acute and chronic pain. It is important to note that doses effective for acute pain relief (325 to 650 mg/day) may not be effective in chronic pain states such as OA, since they may require higher daily doses.¹¹ 

Another important consideration when choosing an analgesic for OA is the physiologic basis of pain, whether it is associated with an inflammatory disease or a noninflammatory condition.³ In patients with OA, where pain is of noninflammatory origin, acetaminophen would be a more appropriate choice because of its better safety profile on gastrointestinal and hematologic systems compared to nonsteroidal anti-inflammatory drugs (NSAIDs). To optimize the benefit of a simple analgesic such as acetaminophen, it should be prescribed on a regular basis.¹³ Acetaminophen is considered the drug of first choice. If the patient does not respond to acetaminophen, topical capsaicin, aspirin, or other NSAIDs can be considered.¹³

Because there has been controversy regarding the use of acetaminophen over NSAIDs, it seems important to analyze the safety and efficacy data presented by different researchers. Bradley and coworkers¹⁰ compared the efficacy of 1,200 and 2,400 mg/day of ibuprofen with 4 grams of acetaminophen. All three groups showed similar pain improvement. Williams and associates compared patients with OA of the knee who were treated with naproxen and acetaminophen.¹⁴ They found modest improvement in pain on motion and in physicians’ global assessment in both acetaminophen and naproxen groups. Radiographic progression was similar in both treatment groups. Therefore, neither NSAIDs nor acetaminophen appear to have chondroprotective or chondrodestructive effects. Acetaminophen is reported to have similar efficacy with lesser side effects compared with NSAIDs by a number of different clinical trials.^9,14 

The usual recommended dose of acetaminophen is 325 to 650 mg every 4 to 6 hours or 1,000 mg three to four times a day, not to exceed 4 grams/day.¹² The primary concern regarding the safety of acetaminophen is hepatotoxicity and potential renal toxicity. Hepatotoxicity generally occurs as a result of an acute overdose; however, high doses of acetaminophen taken chronically can also produce hepatotoxicity.¹¹ Acetaminophen rarely causes acute tubular necrosis at therapeutic doses. Long-term acetaminophen use has been linked to chronic renal failure, an effect also reported with NSAIDs.⁹ Perneger and colleagues¹⁵ studied treated patients and control subjects of similar ages for end-stage renal dysfunction (ESRD). For each analgesic, the average use and the cumulative intake were examined for any association with ESRD. People who take high doses of acetaminophen or NSAIDs on a regular basis had an increased risk of ESRD.¹⁵ 

Topical Capsaicin. Capsaicin, a natural alkaloid, is derived from capsicum, the hot pepper plant. It is the active ingredient responsible for the irritating and burning effects of the various species of capsicum. Capsaicin depletes and prevents reaccumulation of substance P in peripheral sensory neurons. Substance P (Figure 4) is found in slow-conducting, unmyelinated type C neurons that innervate the dermis and epidermis. Substance P is thought to be the primary chemical mediator of pain, impulses from the periphery to the central nervous system. It can also be released into joint tissues, where it activates inflammatory substances involved in the development of rheumatoid arthritis. By depleting substance P, capsaicin renders skin and joints insensitive to pain since local pain impulses cannot be transmitted to the brain. When capsaicin therapy is discontinued, substance P reaccumulates and neuronal sensitivity returns to normal.¹⁶ 

Deal ¹⁷ compared capsaicin 0.025% cream and placebo in rheumatoid arthritis and OA. Significantly, more relief of pain was reported by the capsaicin-treated patients than placebo-treated patients. The only adverse reaction reported was a transient burning sensation at the application site. Other studies have reported similar results.^18-20 

For the treatment of mild or moderate pain associated with OA, adults and children older than 2 years of age may apply capsaicin 0.025% or 0.075% topically to painful joints four times a day.^17,19 It may be prudent to taper the regimen of four times a day gradually to avoid the decrease in pain relief seen with an abrupt decrease in dosage.²¹ This maintenance regimen may enhance long-term patient compliance and also result in cost savings to the patients. When recommending topical capsaicin, pharmacists should instruct patients to avoid contact with eyes and wash hands after use. If used for the treatment of hand pain, hands should be washed 30 minutes after application. Lastly, capsaicin may not be useful for all types of OA. For example, it is not particularly helpful for OA of the hip.

NSAIDs. The selection of NSAIDs is presented as the next step in the algorithm (Figure 3). The use of NSAIDs should be reserved for patients if there is inflammation or if pain is nonresponsive to other measures. 

Commonly prescribed, nonsalicylate NSAIDs include ibuprofen, naproxen, and ketoprofen, but many more agents (Table 2 ^22,23) are currently available in the United States.²⁴ At lower doses both salicylates and NSAIDs provide effective analgesia, but higher doses (eg, 4 to 6 grams/day of aspirin) are used to provide anti-inflammatory effects. Likewise, while the analgesic effect is almost immediate, the anti-inflammatory effect takes 1 to 2 weeks to become apparent.^23,25 

NSAIDs inhibit prostaglandin synthesis by blocking the activity of cyclo-oxygenase (COX).²⁶ Two isoforms of COX, COX-1 and COX-2, catalyze the biosynthesis of prostaglandins (Figure 5 ²⁷). COX-1 is constitutively expressed and is believed to be involved in production of substances such as mucus and bicarbonate that protect the gastric mucosa from injury. COX-2 is induced by the pro-inflammatory cytokines, and is thought to generate prostaglandins that mediate inflammation and pain.²² Traditional NSAIDs inhibit the activity of both COX-1 and COX-2. The nonspecific activity of these agents on the COX isoforms may account for the high incidence of side effects seen with these agents. As one would anticipate, the therapeutic anti-inflammatory properties of NSAIDs are primarily the result of inhibition of COX-2, whereas the gastrointestinal toxicity of NSAIDs is mainly the result of their ability to inhibit COX-1.²⁸ The gastrointestinal complications caused by NSAIDs include gastric and, to a lesser extent, duodenal ulcers, gastrointestinal bleeding, perforation, gastritis, and obstruction.^24,29 

The widespread use of these agents has created an important health care problem. According to Singh and Triadafilopoulos.³⁰ NSAID use accounts for up to 107,000 hospitalizations and 16,500 deaths annually. The health care cost of these hospitalizations has been estimated to be more than $2 billion annually.³⁰ According to Silverstein and associates,²⁹ risk factors for serious upper gastrointestinal complications were older age, history of peptic ulcer or bleeding, and cardiovascular disease. 

Some nonpharmacologic measures that can reduce the risk of gastrointestinal complications include advising patients to take the NSAID with food, rather than on an empty stomach.²⁵ In general, food delays absorption but does not significantly affect the total amount of drug absorbed. 

Patients should also be educated about the potential symptoms of gastric intolerance or bleeding, with instructions to discontinue the medication and consult with their physician in the event of serious problems.²⁵ Patients with a high risk of gastrointestinal intolerance may require the concomitant use of gastrointestinal-protective agents, such as the synthetic prostaglandin E analog, misoprostol.²⁵ Misoprostol (Cytotec) has mucosal-protective as well as antisecretory properties.²⁸ A typical dose of misoprostol is 100 to 200 mcg three or four times a day.²⁸ Misoprostol 200 mcg is also available in combination with 50- or 75-mg diclofenac (Arthrotec). Other available gastrointestinal-protective agents that can be coadministered with NSAIDs are the proton pump inhibitors. Because the histamine-2 (H2) receptor antagonists are effective in preventing NSAID-induced duodenal ulcers, but do not decrease the incidence of NSAID-induced gastric ulcers, they are generally not recommended for prophylaxis.^28,31

Aside from the gastrointestinal side effects observed with long-term use of NSAIDs, other side effects are also possible. For example, NSAIDs also interfere with platelet aggregation, and thus may increase the risk of bleeding. NSAIDs also may have an effect on kidney function. Our kidneys synthesize prostaglandins to help maintain blood flow when perfusion is reduced. Patients with intrinsic renal dysfunction or who have reduced renal blood flow (eg, congestive heart failure patients, elderly patients, or in combination with other nephrotoxic agents) are at higher risk for the renal complications seen with long-term use of NSAIDs.³¹ Lastly, patients using NSAIDs on a regular basis may experience sodium and water retention, which may lead to weight gain and leg edema.³¹ 

New NSAIDs: Selective COX-2 Inhibitors

Celecoxib (Celebrex). A new class of NSAID, the selective COX-2 inhibitors, that interfere primarily with the COX-2 enzyme are now available (Figure 527). Celecoxib (Celebrex), meloxicam (Mobic), and rofecoxib (Vioxx), the only selective COX-2 inhibitors currently available, have different indications. Celecoxib is indicated for both OA and rheumatoid arthritis but lacks an indication for acute pain. Rofecoxib has FDA approval for management of OA, acute pain, and primary dysmenorrhea, but does not have FDA approval for rheumatoid arthritis.^32,33 Meloxicam has FDA approval for management of OA. 

Similar to the other NSAIDs, celecoxib has no impact on the course of the disease itself, and it is useful only for pain, relief and inflammation. Furthermore, there is no evidence that the new NSAIDs are superior in effectiveness to the traditional NSAIDs, only that they cause fewer side effects.⁶ While the older NSAIDs inhibit the catalytic effect of both COX-1 and COX-2, the newer agent, celecoxib, is a much more selective inhibitor of COX-2.³⁴ At therapeutic doses of 100 to 200 mg bid, it will not inhibit COX-1.³⁴ Because of the lack of inhibitory activity against COX-1, celecoxib has not been shown to interfere with prostaglandin-dependent homeostatic processes such as upper gastrointestinal tract mucosal integrity and platelet aggregation. Its gastrointestinal safety was examined in several trials. Emery and coworkers³⁵ compared celecoxib to diclofenac. Results showed that ulcers occurred in only 4% of the celecoxib patients compared with 15% of diclofenac patients.

Simon and colleagues³⁶ compared celecoxib, naproxen, and placebo. The incidence of endoscopically determined gastrointestinal ulcers (defined as mucosal breaks of 3 mm in diameter) was found to be 4% in the placebo group, 4% for patients taking celecoxib 200 mg bid, and 6% for patients taking celecoxib 100 or 400 mg bid. On the other hand, the incidence with naproxen was 26%, which was significantly greater than with celecoxib. In terms of general safety, all doses of celecoxib were well tolerated. The most frequently occurring gastrointestinal tract adverse events were dyspepsia, diarrhea, nausea, flatulence, and abdominal pain.

Studies have shown significant differences in upper gastrointestinal tract ulceration between celecoxib and other NSAIDs, specifically naproxen and diclofenac. However, the low occurrence of endoscopically diagnosed ulcers does not translate to an equally low incidence of gastrointestinal complications (bleeding, perforation, or obstruction).³⁷ The warnings and contraindications for the COX-2 inhibitors have remained the same as those for older NSAIDs. They include the standard NSAID-class warning about adverse gastrointestinal effects from long-term use.⁶ Furthermore, these agents are contraindicated in patients who have experienced hypersensitivity reactions to aspirin or other NSAIDs. Also, since celecoxib contains a sulfonamide group, those patients with sulfa allergies should use it cautiously.⁶ 

Celecoxib is rapidly absorbed and can be taken with or without food. It has a relatively long half-life of 11 hours,³⁸ and it is metabolized in the liver by CYP2C9 and excreted in feces and urine.³⁴ Celecoxib is available in 100- and 200-mg capsules. As mentioned earlier, the recommended dosage is 200 mg/day administered as a single dose or as 100 mg bid.³⁸ 

Pharmacists dispensing celecoxib should warn patients not to use additional over-the-counter NSAIDs.⁶ Furthermore, the pharmacist should be aware that celecoxib is a CYP2D6 inhibitor and can increase the serum concentration of beta blockers, antidepressants, and antipsychotics.^34,38 Moreover, CYP2C9 inhibitors (zafirlukast, fluconazole, and fluvastatin) can increase the serum concentration of celecoxib and cause an increase in the incidence of side effects with this agent.³⁴ Patients receiving celecoxib with warfarin have developed increases in prothrombin time, sometimes associated with bleeding events, predominantly in the elderly. Celecoxib, by itself, has no effect on platelet aggregation or bleeding time at therapeutic doses and may be used in patients taking warfarin. Celecoxib can be used with warfarin when patients are monitored appropriately for changes in anticoagulant activity, particularly in the first few days. 

Meloxicam (Mobic). The FDA approved meloxicam in April 2000 to be marketed by Boehringer Ingelheim and Abbott with the indication for relief of the signs and symptoms of OA.³⁹ Efficacy and safety of meloxicam were examined in the MELISSA (Meloxicam Large-scale International Study Safety Assessment40) and SELECT (Safety and Efficacy Large-scale Evaluation of COX-inhibiting Therapies⁴¹) trials. These were international trials of acute OA in patients over 18 years old, where meloxicam was compared to diclofenac (SELECT) or piroxicam (MELISSA). Meloxicam was found to produce fewer adverse effects than diclofenac or piroxicam, particularly in regards to gastrointestinal toxicity. In addition, meloxicam was equivalent to diclofenac and piroxicam in all efficacy parameters. Subsequent analyses demonstrated fewer hospitalizations for meloxicam⁴² and fewer perforations, ulcers, or bleeds (PUBs)⁴³ with meloxicam than NSAIDs.

Meloxicam is available as a 7.5-mg tablet. It can be given without regard to meals or antacids. It is completely metabolized to inactive compounds mostly through CYP-450 2C9, but also to a lesser extent through 3A4. The drug has a long half-life (15 to 20 hours), thus allowing for once-daily dosing.³⁹ The recommended regimen is 7.5 mg daily. There is no information regarding dosing in pediatric patients. No dosage adjustment is required in mild-to-moderate hepatic or renal insufficiency. Drug interactions with angiotensin-converting enzyme (ACE) inhibitors, furosemide, thiazides, and warfarin have been observed with meloxicam as with other COX-2 inhibitors and, therefore, these drugs should be used with caution.

Rofecoxib (Vioxx). Rofecoxib, a selective COX-2 inhibitor, was FDA-approved for the treatment of pain due to OA, acute pain in adults, and menstrual pain in May 1999. Rofecoxib, in therapeutic doses, inhibits COX-2, but not COX-1, making it considerably safer for the stomach, especially for the elderly, since they are more prone to gastrointestinal complications. Unpublished data available from the manufacturer include a randomized, double-blind study of rofecoxib in 341 patients more than 80 years of age with knee and hip OA. In terms of efficacy, rofecoxib at either 12.5 mg or 25 mg daily was more effective than placebo and equal to nabumetone 1,500 mg once daily. Rofecoxib was generally safe and well tolerated.⁶ However, it is not completely void of side effects. Diarrhea, nausea, dyspepsia, abdominal pain, and lower extremity edema were the most common adverse effects. Renal toxicity and elevation in aminotransferase activity have also been reported.⁴⁴ Unlike celecoxib, rofecoxib does not contain a reactive sulfur molecule and should not cause reactions in patients allergic to sulfonamides.

Drug interactions with rofecoxib have been demonstrated with rifampin, methotrexate, warfarin, and ACE inhibitors. Rifampin may decrease the levels of rofecoxib by 50%. Rofecoxib may increase blood levels of methotrexate. Rofecoxib may increase the prothrombin time when given with warfarin.⁴⁴

Viscosupplements 

The viscosupplements are natural compounds derived from rooster combs. Patients with OA have a decreased amount of hyaluronic acid, and the viscosupplements are given as a substitute for natural hyaluronic acid in the joint fluids. Hyaluronic acid supplements act as lubricants and shock absorbers for the joints. They are indicated for patients with OA of the knees where analgesics and other measures have failed. Intra-articular injection of these supplements have been used in a number of countries as symptomatic treatment of knee OA. Two hyaluronan preparations, sodium hyaluronate (Hyalgan) and Hylan G-F20 (Synvisc), are approved by the FDA as a medical device for use in the physician’s office, and are now available for use in the United States.⁴⁵ Hyalgan is a viscous solution of sodium salt of hyaluronic acid and is extracted from rooster combs. It is given as a series of five injections directly into the knee joints at weekly intervals. Pain relief can last up to 6 months. Synvisc, on the other hand, is a series of three injections injected directly into the knee joints at weekly intervals. Pain relief with this product lasts 3 to 6 months. 

Hyaluronan injection has been shown to work in a number of different ways. It can activate synovial cells of osteoarthritic joints to stimulate the synthesis of hyaluronan, inhibit prostaglandin synthesis by affecting leukocyte adherence, proliferation, migration, and phagocytosis, and protect against cytotoxicity caused by reactive oxygen species.⁴⁵ Lohmander and associates⁴⁶ compared 25 mg of high-molecular-weight hyaluronan and vehicle. No adverse effect was reported as a result of the injection. A large-gauge needle is required for injection of these supplements; therefore, local anesthetics should be injected prior to the hyaluronan injections. If the knee is swollen, it must be aspirated before the injections. 

Glucosamine and Chondroitin

Glucosamine and chondroitin sulfate are two dietary supplements that have gained popularity over the past few years. These agents were described as effective for the treatment of symptoms of OA and may have the potential to reduce structural damage in OA cartilage. OA is a disease associated with the degeneration and remodeling of the joints. It is characterized in its earliest stages by a loss of matrix with a preferential loss of proteoglycans. The agents that help to relieve the pain do not reverse the course of the disease; therefore, there has been a search for new agents that will actually reverse the course of the disease. Hyaline cartilage, which coats the bony surfaces of all synovial joints, consists of a matrix of type II collagen fibers and proteoglycans, chondrocytes that produce this matrix, and water. The network of type II collagen fibers provides tensile strength and stiffness, while the hydrated proteoglycan gel occupies the interstices. Proteoglycans have a protein core and many negatively charged glycosaminoglycan (GAG) chains, which allow them to retain water. During load bearing, proteoglycans serve as a natural shock absorber by slowly releasing water.⁴⁷ In OA, the proteoglycan content of cartilage matrix is gradually depleted. This leads to loss of compressibility and shock absorption.⁴⁷ Glucosamine is an aminomonosaccharide, which is a component of almost all human tissues, including cartilage.⁴⁸ It is the principal component of O- and N-linked GAGs. Glucosamine is produced in the body by the addition of an amino group to glucose; this molecule is subsequently acetylated to acetyl glucosamine. Hyaluronan, keratan sulfate, and heparan sulfate are composed, in part, of repeating units of acetyl glucosamine. In keratan sulfate and heparan, sulfate is added at the 4- or 6-position of glucosamine.⁴⁸ 

The sulfate moiety plays an important role in the synthesis of proteoglycans, because the constituent GAGs are highly sulfated.⁴⁸ Depletion of organic sulfate leads to decreased synthesis of GAGs in vivo, and exogenous sulfate administration counteracts the deleterious effects of sulfate depletion. Glucosamine is available in pharmacies and health food stores as sulfate, hydrochloride, N-acetyl, and chlorhydrate salt, and as a dextroregulatory isomer. Most clinical studies have been conducted with glucosamine sulfate. The sulfate and hydrochloride forms of glucosamine differ in their purity, sodium content, bioactive glucosamine and equivalent dosages. The hydrochloride and N-acetyl forms lack the sulfate group, which may be important for therapeutic effect. There are some preparations available in the market that are combined with chondroitin sulfate, a GAG that has been reported to maintain viscosity in joints, stimulate cartilage repair, and inhibit enzymes that degrade cartilage. In contrast to glucosamine, chondroitin sulfate is larger and poorly absorbed. 

Glucosamine has been characterized as a slow-acting drug for the treatment of OA. A chondroprotective effect has not been demonstrated in vivo, but experimental evidence in vitro suggests it may play a beneficial role in cartilage metabolic responses.⁴⁸

Glucosamine has demonstrated anti-inflammatory activity. The anti-inflammatory activity of glucosamine appears related to mechanisms that are substantially different from those of NSAIDs, which act primarily through inhibition of COX. Glucosamine is ineffective as an inhibitor of COX and thus its effects are prostaglandin independent. Some of the glucosamine may be related to stimulation of proteoglycan biosynthesis. It has been suggested that the newly synthesized proteoglycans may stabilize cell membranes, resulting in an anti-inflammatory effect. Glucosamine also reduces the generation of superoxide radicals by macrophages and inhibits lysosomal enzymes. Studies have shown that the combination of diclofenac, indomethacin, or piroxicam allows a twofold to 2.7-fold decrease in the dose of NSAIDs required to suppress carrageenan-induced inflammation.⁴⁸ Two other studies also have found glucosamine sulfate 500 mg, three times daily, to be superior to placebo and as effective as ibuprofen 400 mg, three times daily.⁴⁷

Glucosamine is generally well tolerated. Adverse effects reported with glucosamine include gastrointestinal complaints, headache, leg pain, edema, and itching. There is also a concern that patients with diabetes taking glucosamine may experience increased blood glucose levels, making it necessary to monitor blood glucose more closely.⁴⁹ 

Chondroitin sulfate is a proteoglycan and, like glucosamine, has anti-inflammatory activity and affects cartilage metabolism.⁴⁸ The exact mechanism of action of chondroitin is unknown. However, it is known that chondroitin inhibits the enzymes that degrade cartilage.⁵⁰ Morreale and coworkers⁵¹ studied patients with OA of the knee receiving chondroitin sulfate or diclofenac sodium. Patients treated with the NSAID showed prompt reduction of clinical symptoms. However, those symptoms reappeared after the end of the treatment; in the chondroitin sulfate group, the therapeutic response appeared later in time but lasted for up to 3 months after the end of the treatment. Mazieres and colleagues conducted a trial designed to evaluate the effectiveness of chondroitin sulfate (Structum; available in Europe) in patients with OA of the knees and hips who received 200 mg of Structum‚ orally, four times a day for 3 months. At the end of the 3-month treatment phase, patients taking chondroitin sulfate were using significantly less NSAIDs. Overall patient and physician assessment indicated an improvement in symptoms.⁵²

While the doses for these products are not clearly established, glucosamine and chondroitin sulfate are usually given individually or as a combination as a cartilage matrix enhancer in patients with OA. Most commercially available products are a combination of glucosamine 500 mg and chondroitin sulfate 400 mg as a double-strength product. Glucosamine is generally given as 500 to 1,000 mg three times a day, and chondroitin sulfate is usually given as 400 mg three times a day either alone or in combination. After 60 days, the amount taken can be gradually decreased to a level that maintains the comfort of the individual. 

The pharmacist should advise OA patients with diabetes to keep their physicians informed prior to initiating this therapy.  Patients should also be advised that more frequent blood glucose monitoring may be necessary and that doses of their current diabetes medications may need to be adjusted. Patients should also be cautious when buying these products, since they are classified as dietary supplements. These products are not regulated by the FDA. Since they are not regulated, there is no assurance of their purity, content, bioactivity, and dose equivalence. The studies that have shown that these products are efficacious are also the ones that are somewhat biased and have limitations. Therefore, more scientific and controlled studies are necessary to document the efficacy of these products.

References

1. Lawrence RC, Helmick CG, Arnett FC, et al. Estimates of the prevalence of arthritis and selected musculoskeletal disorders in the United States. Arthritis Rheum. 1998;41:778-799.
2. Anonymous. Arthritis Prevalence and Activity Limitations—United States, 1990. MMWR Morb Mortal Wkly Rep. 1994;43:433-438.
3. Schitzer TJ: Non-NSAID pharmacologic treatment options for the management of chronic pain. Am J Med. 1998;105:45S-52S. (Abstract)
4. Brandt KD. Osteoarthritis. In: Fauci A, Braunwald E, Isselbacher K, et al eds: Harrison’s. 14th edition. New York, NY: McGraw-Hill; 2000:1935-1941.
5. Poole A, RizKalla G, Reiner A, et al. Osteoarthritis in the human knee: A dynamic process of the cartilage matrix degradation, synthesis and reorganization. In van de Berg W (ed). Joint destruction in Arthritis and Osteoarthritis. 39th ed. Basel, Switzerland 1993: 3-13.
6. Miller D. Managing osteoarthritis and pain, the role of Cox-2 inhibitors. US Pharma. 1999;119-130.
7. Bob L: Osteoarthritis, in DiPiro J, Talbert R, Yee G (eds): Pharmacotherapy: A Pathophysiologic Approach. Third edition. Stamford, Connecticut, Appleton & Lange; 1997: 1735-1753.
8. Hochberg MC: Guidelines for Management of Hip OA. Arthritis & Rheumatism 1995;38:1535-1546.
9. Griffin MR, Brandt KD, Liang MH, et al. Practical Management of Osteoarthritis: Integration of Pharmacologic and Nonpharmacologic Measures. Arch Fam Med 1995;4:1049-1055.
10. Bradley JD, Brandt KD, Katz BP, et al. Comparison of An Antiinflammatory Dose of Ibuprofen, An Analgesic dose of Ibuprofen, and Acetaminophen in the Treatment of Patients with Osteoarthritis of the Knee. The New England Journal of Medicine 1991;325:87-91.
11. Anonymous. Acetaminophen. (Computer Program). Gold Standard Multimedia Inc., Tampa, Florida. 2000.
12. AnonymousAcetaminophen., in Lacy CF, Armstrong LL, Goldman M, Lance L (eds): Drug Information Handbook-Pocket Edition.Huston, OH, Lexi-Comp Inc.; 1999: 19-20.
13. Simon LS: Osteoarthritis: A Review. Clinical Cornerstone 1999;2:26-34.(Abstract)
14. Williams HJ, Ward JR, Marlene JE, et al. Comparison of Naproxen And Acetaminophen In A Two-Year Study Of Treatment Of Osteoarthritis of the Knee. Arthritis & Rheumatism 1993;36:1196-1206.
15. Pernerger TV, Whelton PK, Klag MJ: Risk of Kidney Failure Associated With The Use Of Acetaminophen, Aspirin, And Nonsteroidal Antiinflammatory Drugs. New England Journal of Medicine 1994;331:1675-1679.
16. Capsaicin. (Computer Program). Gold Standard Multimedia Inc., Tampa, Florida. 4-19-1999.
17. Deal CL, Schnitzer T, Liostein E, et al. Treatment of Arthritis with Topical Capsaicin: A Double-Blind Trial. Clinical Therapeutics 1991;149:383-395.
18. Zhang WY, Li Wan Po A: The Effectiveness of topically applied capsaicin. Eur J Clin Pharmacol 1994;46:517-522.(Abstract)
19. Altman R, Aven A, Holmburg C, et al. Capsaicin Cream 0.025% as Monotherapy for Osteoarthritis: A Double-Blind Study. Seminars in Arthritis and Rheumatism 1994;23:25-33.
20. Deal CL: The Use of Topical Capsaicin in Managing Arthritis Pain: A Clinician's Perspective. Seminars in Arthritis and Rheumatism 1994;23:48-52.
21. Schnitzer T, Morton C, Coker S: Topical Capsaicin Therapy for Osteoarthritis Pain: Achieving a Maintenance Regimen. Seminars in Arthritis and Rheumatism 1994;23:34-40.
22. Simon LS, Weaver A, et al: Anti-inflammatory and upper gastrointestinal effects of celecoxib in rheumatoid arthritis. JAMA 1999;282:1921-1928.
23. Resman-Targoff B: Common Arthritides: Osteoarthritis, Rheumatoid Arthritis and Gout, in Carter B, Angaran D, Lake K, et al (eds): Pharmacotherapy Self-Assessment Program. Second edition. Kansas City, MO, American College of Clinical Pharmacy; 2000: 195-231.24.Rheumatoid Arthritis. www.bewell. com/hic/wcon/wcon-48.asp; 11-15-1999.
25. American College of Rheumatology Ad Hoc Committee on Clinical Guidelines: Guidelines for the management of rheumatoid arthritis. Arthritis & Rheumatism 1996;39:713-722.
26. Schuna AA: Update on treatment of rheumatoid arthritis. Journal of the American Pharmaceutical Association 1998;38:728-736.
27. Hawkey CJ: COX-2 inhibitors. Lancet 1999;353:307-314.
28. Silverstein FE: Improving the gastrointestinal safety of NSAIDs: The development of misoprostol-from hypothesis to clinical practice. Digestive Diseases & Sciences 1998;43:447-458.
29. Silverstein FE, Graham DY, Senior JR, et al. Misoprostol reduces serious gastrointestinal complications in patients with rheumatoid arthritis receiving nonsteroidal anti-Inflammatory drugs. Annals of Internal Medicine 1995;123:241-249.
30. Singh G, Triadafilopoulos G: Epidemiology of NSAID Induced Gastrointestinal Complications. J Rheumatol 1999;26:18-24.
31. JLM: Celecoxib approved as NSAID with some concessions on class warning. American Journal of Health-System Pharmacy 1999;56:403-403.
32. JLM: Second selective COX-2 inhibitor receives marketing approval. American Journal of Health-System Pharmacy 1999; 56:1294-1294.
33. Anonymous. FDA approves Vioxx for osteoarthritis, pain and menstrual pain. http://www.fda.gov/bbs/topics/ANSWERS/ANS00956.html; 5-21-1999.
34. Anonymous. Celecoxib for Arthritis. The Medical Letter 1999;41:11-12.
35. Emery P, Zeidler H, Kvien T, et al. Celecoxib versus diclofenac in long-term management of rheumatoid arthritis: randomized double-blind comparison. Lancet 1999;354:2106-2111.
36. Simon L, Weaver A, Graham D, et al. Anti-Inflammatory and Upper Gastrtointestinal Effects of Celecoxib in Rheumatoid Arthritis. JAMA 1999;282:1921-1927.
37. Miller J: Decisions loom on selective COX-2 inhibitors. American Journal of Health-System Pharmacy 1999;56(2):106-107.
38. Searle/Pfizer. Celebrex package insert. 12-31-1998. Chicago, IL, Searle & Co. 
39. Food and Drug Administration. Mobic approval.http://www.fda.gov/cder/foi/label/2000/20938lbl.pdf; 4-17-2000.
40. Hawkey C, Kahan A, Steinbruck K, et al. Gastrointestinal tolerability of meloxicam compared to diclofenac in osteoarthritis patients. International MELISSA Study Group. Meloxicam Large-scale International Study Safety Assessment. British Journal of Rheumatology 1998; 37:937-945.
41. Dequeker J, Hawkey C, Kahan A, et al. Improvement in gastrointestinal tolerability of the selective cyclooxygenase (COX)-2 inhibitor, meloxicam, compared with piroxicam: results of the Safety and Efficacy Large-scale Evaluation of COX-inhibiting Therapies (SELECT) trial in osteoarthritis. British Journal of Rheumatology 1998;37:946-951.
42. Hawkey CJ: Reduced need for hospitalization in patients taking meloxicam compared to diclofenac P037. Gut 1997; 41:88a.
43. Hawkey CJ: Reduced perforations, ulcers, bleeds and hospitalisation for gi adverse events with meloxicam compared to diclofenac and piroxicam. Gut 1998;42:6a.
44. Anonymous. Rofecoxib for Osteoarthritis and Pain. The Medical Letter 1999;41:59-61.
45. Smith GN, Myers SL, Brandt KD, et al: Effect of Intraarticular Hyaluronan Injection In Experimental Canine Osteoarthritis. Arthritis & Rheumatism 1998; 41:976-985.(Abstract)
46. Lohmander LS, Dalen N, Englund G, et al: Intra-articular Hyluronan injections in the treatment of Osteoarthritis of the knee: a randomized, double-blind, placebo controlled multicentre trial. Ann Rheum Dis 1996;55:424-431.(Abstract)
47. Runkel D, Cupp M: Glucosamine sulfate use in osteoarthritis. American Journal of Health-System Pharmacy 1999;56:276-269.
48. Deal CL, Moskowitz RW: Nutraceuticals as Therapeutic Agents in Osteoarthritis. The role of Glucosamine, Chonroitin Sulfate and Collagen Hylysate. Rheum Dis Clin North Am 1999;25:379-395.
49. Gregory P: Glucosamine and Insulin Resistance. The Pharmacist's Letter 1999;
50. Chondroitin; Glucosamine. (Computer Program). Gold Standard Multimedia, Inc., Tampa, Florida. 8-14-1999.
51. Morreale P, Manopulo R, Galati M, et al. Comparison of the Antiinflammatory Efficacy of Chondroitin Sulfate and Diclofenac Sodium in Patients with Knee Osteoarthritis. J Rheumatol 1996;23:1385-1391.
52. Mazieres B, Loyau G, Menkes C, et al. Chondroitin sulfate in the treatment of gonarthrosis and coarthrosis. 5-month result of multicenter double-blind controlled prospective study using placebo. Revue du Rheumatisme et des Maladies Osteo-Articulaires 1992;59:466-472.