Drug Therapy for Osteoarthritis Treatment
The fundamental aims of osteoarthritis (OA) treatment are to relieve symptoms, improve function, delay progression, and correct deformities. Since the 1990s, international research has increasingly focused on OA treatment, categorizing therapeutic drugs into two types: those that alleviate symptoms and those that modify the disease course. Compared with other methods, drug therapy offers advantages such as accessibility, simplicity, reliable efficacy, and ease of maintenance, making it worthy of promotion in China, where this area has yet to receive widespread attention. This article provides a brief introduction to drug therapies and strategies for OA treatment, particularly for knee OA.
Anti-inflammatory and Analgesic Drugs:
Acetaminophen: Controlling pain with medication is one of the most effective approaches. For alleviating knee OA pain, acetaminophen is often the first choice abroad due to its good analgesic effect, minimal side effects, and low cost. Typically, the total daily dose should not exceed 3g, though long-term high doses may cause liver or kidney damage. If these medications prove ineffective or if patients have knee effusion or persistent pain, other drugs should be considered.
Non-steroidal Anti-inflammatory Drugs (NSAIDs): These drugs possess anti-inflammatory, analgesic, and antipyretic properties, making them suitable for OA treatment. Foreign studies indicate that aspirin, salicylic acid, phenylbutazone, indomethacin, and naproxen inhibit the synthesis of proteoglycans in cartilage matrix, which is detrimental to OA treatment and thus should be avoided or used only short-term. Other drugs like diclofenac, meloxicam, nabumetone, etodolac, sulindac, and aceclofenac do not adversely affect proteoglycan synthesis in cartilage matrix; some even promote it, making them preferable choices. As selective cyclooxygenase-2 (COX-2) inhibitors, meloxicam, etodolac, and nabumetone offer gastrointestinal safety comparable to specific COX-2 inhibitors and fewer cardiovascular and renal side effects. Long-term use for OA treatment has been reported abroad.
In the American College of Rheumatology's 2000 guidelines for hip and knee OA treatment, specific COX-2 inhibitors celecoxib and rofecoxib were included. Their efficacy is comparable to naproxen, ibuprofen, and diclofenac, but endoscopic examination shows significantly fewer ulcers compared to these control drugs. However, the guidelines note that further large-scale, long-term observations are needed to confirm differences in gastrointestinal safety between the new drugs and controls. They also point out that COX-2 inhibitors, like control drugs, can cause nephrotoxicity. Recent reports indicate over 200 cases of renal failure associated with these new drugs, highlighting that individuals with pre-existing renal disease, heart failure, liver dysfunction, hypertension, diuretic use, or angiotensin-converting enzyme inhibitor use, as well as elderly patients, are at higher risk for COX-2-induced renal injury.
Opioids: For moderate to severe knee OA patients who fail to achieve pain relief with the above treatments, U.S. scholars advocate opioids as a last resort. British scholars specify that if patients remain unresponsive to 4g of acetaminophen or 2.4g of ibuprofen daily, other anti-inflammatory drugs or opioids should be considered. Commonly used opioids include codeine and tramadol. Most clinical observations involve short-term courses, up to 6-8 weeks, averaging 19 days. Researchers found that the beneficial effects of opioids could last 1-3 years. However, adverse reactions such as nausea, vomiting, diarrhea, and sweating, as well as tolerance and potential dependency, warrant attention.
Disease-modifying Drugs:
Glucosamine sulfate: Anti-inflammatory drugs only relieve OA symptoms without altering its progression. For years, researchers have sought disease-modifying drugs to control OA development. After Germany's first clinical validation of glucosamine sulfate (GS) for OA treatment in 1969, numerous short- and long-term randomized double-blind controlled trials suggest that GS not only reduces inflammation and relieves pain but also slows the progression of knee OA. GS is considered the first disease-modifying or slow-acting drug for OA, and because in vitro experiments confirm its positive effects on cartilage metabolism, it is also called a chondroprotector.
A four-week randomized double-blind controlled study involving 200 active knee OA patients showed symptom improvement rates of 48% in the GS 1500mg/day group versus 52% in the control ibuprofen 1200mg/day group (P=0.67). However, the adverse reaction rate (mainly gastrointestinal) and withdrawal rate were 6% and 1%, respectively, in the GS group, compared to 35% and 7% in the control group (P<0.01 and P<0.05). This suggests that GS has an effect on improving knee OA symptoms comparable to ibuprofen but with greater safety.
Strong evidence for GS as a disease-modifying drug comes from recent reports. A three-year randomized double-blind controlled trial involving 212 knee OA patients conducted by Belgian, American, Italian, and British scholars showed that the mean progressive joint space narrowing confirmed by X-ray was 0.31mm in the placebo group but only 0.06mm in the GS 1500mg/day group, indicating a significant difference between the two groups. Another three-year double-blind randomized placebo-controlled study involving 202 knee OA patients conducted by Czech and Italian scholars showed no change in knee joint space narrowing in the GS 1500mg/day group compared to 0.19mm in the placebo group (P=0.001). These reports suggest that long-term GS treatment can prevent the progression of knee OA and consider GS the first modern-classified drug that improves both OA symptoms and modifies the OA disease course.
In the United States, GS or its combination with chondroitin sulfate has become a mass-market food supplement available in supermarkets. This does not diminish its status in OA treatment but instead reassures users of its safety and encourages its use. In Europe and other regions, GS remains a prescription drug. In recent years, GS has gradually gained attention from clinicians and patients in China. Initiating and persisting with GS treatment early in OA can hopefully improve its poor prognosis.
Diacerhein: Extracted from rhubarb with diacerein as the active ingredient, experimental studies show that this drug inhibits the production and release of IL-1β and oxygen free radicals, suppresses metalloproteinase activity, and stabilizes lysosomal membranes, thereby exerting anti-inflammatory effects and protecting joint cartilage, thus improving the OA disease course. This drug is classified as a slow-acting agent for OA treatment. A 16-week randomized double-blind controlled study involving 404 knee OA patients showed that 100mg/day of diacerein was the optimal dose, significantly improving patient symptoms with only transient diarrhea as an adverse reaction. Previously, European scholars reported that continuous three-year treatment with this drug for hip OA suggested its protective effect on cartilage.
Vitamins A, C, D, and E:
In recent years, some scholars have focused on vitamins as methods for preventing and improving OA pain and disability. Vitamins A, C, and E are the main antioxidants in food and have proven potential antioxidant effects on OA progression. Vitamin D affects OA through bone mineralization and cell differentiation.
Experimental and clinical studies suggest that these vitamins influence OA via at least three pathways: ① Preventing oxidative damage. Oxygen free radicals are potent cartilage-destructive substances. Reactive oxygen species produced by intra-articular cells and their involvement in oxidative damage can lead to hyaluronic acid depolymerization and degradation of proteoglycans and type II collagen. ② Regulating inflammatory responses. Degradation and loss of cartilage matrix are important features of OA. Under lipid peroxidation, arachidonic acid products release inflammatory substances, causing polymorphonuclear leukocyte chemotaxis and adhesion, which in turn promote reactive oxygen species production and proteinase release, leading to degradation of collagen and proteoglycans in the cartilage matrix. Antioxidants are crucial regulators of these reactions and can prevent excessive tissue damage. ③ Biological effects related to bone and collagen synthesis. Vitamins A and D are essential components for cell maturation and differentiation and participate in bone development and maintaining epithelial tissue integrity. Vitamin C participates in collagen production and glycosaminoglycan synthesis, and vitamin C deficiency may correlate with reduced integrity of extracellular matrix in articular cartilage and increased matrix turnover in OA.
Despite this, there are few reports of treating OA solely with these vitamins. One report indicated that among 29 OA patients treated with 600mg/day of vitamin E for ten days, 52% experienced significant pain relief compared to only 4% in the placebo group. Thus, using these vitamins as supplementary treatments for OA appears beneficial.
Intra-articular Viscosupplementation:
High-viscosity synovial fluid provides nearly frictionless surfaces for joint movement, which is crucial for normal joint function. In OA, hyaluronic acid is destroyed, reducing synovial fluid viscosity, eliminating lubrication, and losing smooth joint surface motion, leading to further joint damage. Data confirms that intra-articular supplementation with high-molecular-weight hyaluronic acid helps relieve joint pain, increase range of motion, eliminate synovitis, and delay disease progression. This drug is primarily used for knee OA, suitable for patients with poor response to conventional treatment or unable to tolerate analgesics or NSAIDs.
Hyaluronic acid preparations are extracted and purified from rooster combs, so they are contraindicated in individuals allergic to chickens or eggs. Domestically available formulations, such as sodium hyaluronate injection 2ml once weekly for five consecutive weeks as one course, maintain efficacy for about six months. Imported formulations, such as sodium hyaluronate, 2ml once weekly for three consecutive times as one course, maintain efficacy for about one year.
Treatment Strategies for OA:
The strategy of early, active, combined, and long-term treatment for rheumatoid arthritis (RA), which emerged around the 1990s, greatly improved the prognosis of the disease and has been widely accepted and applied. Similar to RA, adverse outcomes of OA involve joint disability, functional loss, and possibly shortened lifespan. Therefore, a treatment strategy for OA should focus on early diagnosis, early treatment, and long-term courses. That is, prevention and comprehensive treatment should begin when patients present symptoms but before significant changes occur in joint cartilage, joint space narrowing, or visible osteophytes, followed by long-term follow-up.
Source: Arthritis Treatment Network http://www.chinakry.com/guanjieyanzhiliao1.asp