ABSTRACT: Systemic treatments for patients with osteoarthritis (OA) have been shown to have significant positive effects on biomarkers that may be associated with OA disease progression. Acetaminophen currently is recommended as a first-line treatment. NSAIDs are among the most widely used medications. Coxibs were developed to decrease GI toxicity while providing pain relief at least equivalent to that with nonselective NSAIDs. Tramadol(Drug information on tramadol) and stronger opioids are recommended for the management of moderate to severe pain related to OA. Injection of corticosteroids is effective for symptomatic treatment, but there is no evidence to support disease-modifying activity. There is limited evidence to indicate that early intervention with intra-articular hyaluronic acid may have disease-modifying chondroprotective activity and positive effects on biomarkers associated with disease progression.
Results of studies of systemic treatments for patients with osteoarthritis (OA) indicate significant positive effects on biomarkers that may be associated with disease progression but no significant effects on joint-space narrowing. Licofelone, which is still in clinical trials, has been shown to significantly reduce cartilage volume loss over time, as demonstrated by MRI in patients with knee OA.
Intra-articular injection of corticosteroids is effective for symptomatic treatment of patients who have knee OA with synovitis, but there is no evidence to support disease-modifying activity for these agents. In contrast, there is limited evidence from clinical trials supporting the view that early intervention with intra-articular hyaluronic acid (IAHA) may have radiologically demonstrable disease-modifying chondroprotective activity in patients with OA and positive effects on biomarkers that may be associated with disease progression.
This is the third article in a 3-part series on managing early knee OA. In this series, we review clinical results for nonpharmacological and pharmacological treatments for patients with OA and summarize data related to their potential for altering disease progression. Such information is limited, but it may help clinicians select treatments for patients who have early OA.
In the first part ("Managing Knee Osteoarthritis: Rationale for Early Treatment," http://www.musculoskeletalnetwork.com/osteoarthritis), we described the relationships among molecular changes, structural damage, and disease progression and the rationale for early treatment and defining disease modification. The second article ("Managing Knee Osteoarthritis: Self-Help and Nonpharmacological Interventions," http://www.musculoskeletalnetwork.com/osteoarthritis) discussed self-help and nonpharmacological interventions. In this third article, we will provide an overview of systemic pharmacotherapy, including acetaminophen, NSAIDs and selective cyclooxygenase (COX)-2 inhibitors, licofelone, diacerein(Drug information on diacerein), tramadol and other opioid analgesics, and calcitonin, as well as intra-articular treatments, including corticosteroids and hyaluronates.
Searches of studies for all therapies were carried out using PubMed. Searches for each treatment were focused on citations that included information on "disease modification," "biomarkers," "joint space," "inflammation," and "cytokines."
This agent currently is recommended as a first-line treatment for patients with OA.1,2 However, meta-analyses of clinical trial results indicate modest or no significant benefit compared with placebo in patients with this condition.3,4
Acetaminophen use also has been associated with an increased risk of GI events and liver damage,5-9 as well as increased blood pressure.10 In 2009, an FDA panel recommended lowering dosing recommendations for acetaminophen because of toxicity concerns.11
There is no evidence that acetaminophen has significant disease-modifying activity in OA. However, acetaminophen may decrease the severity of synovitis and reduce effusion.12 In our clinical experience, up to 2000 mg/d of acetaminophen has a positive effect and may reduce the need for NSAIDs.
Nonselective NSAIDs/selective COX-2 inhibitors
NSAIDs are among the medications most widely used in the United States and worldwide.13 In patients with OA, nonselective NSAIDs have been shown to be significantly superior to placebo or acetaminophen for decreasing pain and stiffness and improving function.3,4 However, the limitations of conventional NSAIDs--a high risk of GI adverse events, such as ulcers, bleeding, and death7,14,15; destabilization of blood pressure; adverse effects on renal function; and an increased risk of cardiovascular events--are well known.16,17 We recommend that if possible, NSAIDs be used intermittently, particularly in patients with diabetes mellitus who are at high risk for nephropathy, to decrease the risk of adverse events.
There is no evidence that NSAID treatment can slow radiographic disease progression in patients with knee OA, and in one study, indomethacin treatment significantly accelerated joint-space narrowing.18 Study results for naproxen and diclofenac(Drug information on diclofenac) have indicated that they can down-regulate the plasminogen activator/plasmin system and gelatinase expression during the early stage of knee OA.19,20
Results from one study showed that ibuprofen(Drug information on ibuprofen) has no significant effects on serum cartilage oligomeric matrix protein or urinary C-telopeptide of type II collagen (CTX-II) levels in patients with knee OA.21 In another trial, however, ibuprofen significantly decreased urinary CTX-II levels during knee OA flares.22 In a study of 90 patients with knee OA, nimesulide(Drug information on nimesulide)-but not ibuprofen-significantly decreased urinary CTX-II and serum levels of matrix metalloproteinase (MMP)-3 and MMP-13.23
COX-2 inhibitors, or coxibs, were developed to decrease GI toxicity while providing pain relief at least equivalent to that with nonselective NSAIDs. Clinical trial results have demonstrated effectiveness of these agents in achieving both goals. However, the GI benefit of coxibs was decreased in patients who also were receiving low-dose aspirin(Drug information on aspirin).24-28
Coxibs also may be associated with cardiorenal adverse events.17 Clinical trial results for celecoxib(Drug information on celecoxib) in patients with knee OA showed no significant effect on the progression of joint-space narrowing.29 However, studies of celecoxib, valdecoxib, rofecoxib(Drug information on rofecoxib), and etoricoxib(Drug information on etoricoxib) have indicated that each of these agents can down-regulate the plasminogen activator/plasmin system and gelatinase expression during the early stage of knee OA.20
This agent--a combination 5-lipoxygenase and COX inhibitor--and naproxen(Drug information on naproxen) were found to be equally effective in reducing symptoms in patients with knee OA.30 However, licofelone also significantly reduced cartilage volume loss over time, as demonstrated by MRI. Licofelone still is in the approval process.
This agent and its active metabolite rhein have been shown to inhibit interleukin-1ß in a dose-dependent manner, thus down-regulating inflammatory pathways involved in OA that are stimulated by this cytokine.31 In a meta-analysis of results from 19 clinical trials, diacerein was significantly more effective than placebo and equivalent to NSAIDs in relieving symptoms of knee OA.32,33 Diacerein also showed a carryover effect; significant analgesic-sparing actions persisted for up to 3 months after treatment.
Diacerein is well tolerated, with the most common adverse events involving the GI system.32-34 The agent has no significant effect on progression of joint-space narrowing in knee OA.35,36 However, the Chondromodulating Effect of Diacerein in OA of the Hip study showed that diacerein significantly slows joint-space narrowing compared with placebo in patients with hip OA.37 Three trials currently under way are aimed at gaining approval for diacerein in the United States.
Tramadol and Other Opioid Analgesics
Tramadol and stronger opioids are recommended for the management of moderate to severe pain related to OA.38 A meta-analysis of clinical trial results showed that tramadol or tramadol plus acetaminophen decreases pain intensity and improves function in patients with OA.39
Adverse events associated with tramadol and other opioid analgesics include constipation, delirium, excessive sedation, an increased risk of gait disturbance and falls, and respiratory and circulatory depression.40,41 Also, diversion and abuse of opioids are concerns.42,43 There is no evidence that these agents modify disease progression in patients with OA.
Oral calcitonin has been shown to significantly decrease type II collagen(Drug information on collagen) neoepitope, CTX-II, and MMP-13 levels in patients with knee OA, but there is no evidence that it alters radiological disease progression.44 The treatment currently is being evaluated in clinical trials.
In a meta-analysis of 28 studies (1973 patients), intra-articular corticosteroids were more effective than intra-articular saline for pain reduction and patients' global assessment at 1 week after injection.45 There also was evidence of significant pain reduction with intra-articular corticosteroids at 2 and 3 weeks after injection but no evidence to support functional improvement at these time points. At 4 to 24 weeks after injection, there was no evidence that intra-articular corticosteroids had any significant effects on pain or function.
Potential complications of intra-articular corticosteroid injection include intra-articular and periarticular calcification, cutaneous atrophy, cutaneous depigmentation, osteonecrosis, rapid destruction of the femoral head, acute synovitis, Charcot arthropathy, tendinopathy, Nicolau syndrome, and joint dislocation.46 Joint infection may occur but is rare.
There is no evidence to indicate that intra-articular corticosteroid injection modifies the course of disease in patients with OA.47 However, intra-articular methylprednisolone(Drug information on methylprednisolone) acetate reduced the number of inflammatory cells, including macrophages, lymphocytes, and mast cells, in the synovium of patients with knee OA.48 Intra-articular corticosteroids are used to manage acute joint effusion in patients with knee OA. Intra-articular corticosteroid injection is effective in this patient subgroup, in which other injectables, such as IAHA, are contraindicated.
IAHA is a well-accepted treatment for patients with knee OA for whom pharmacological interventions have not been successful or who do not have extensive inflammation with synovitis.49 Osteoarthritis Research Society International and American College of Rheumatology guidelines recommend IAHA for the treatment of patients with knee OA.50,51 A Cochrane meta-analysis supported the use of IAHA injection for knee OA, indicating that the greatest improvements in symptoms and function occur between 5 and 13 weeks after treatment.45
In a meta-analysis of 7 studies that compared IAHA, corticosteroid, and placebo injection in a total of 606 patients, effect size favored IAHA over corticosteroids at 8, 12, and 26 weeks after treatment.52 Sensitivity analyses indicated that the superiority of IAHA extends across a range of patient subtypes. Combined analysis of results from clinical trials suggested that IAHA administration may have its greatest benefit in younger patients with early OA.
Results from one meta-analysis showed that patients 65 years or older and those with the most advanced stages of arthritic change (complete loss of joint space) are less likely to improve with IAHA therapy than younger patients with less advanced disease.53 It has been suggested that intervention with IAHA be initiated earlier in patients with OA to avoid cardiovascular, GI, and renal adverse events associated with NSAIDs and coxibs and to maximize IAHA efficacy.54
Hyaluronates have a generally acceptable safety profile; injection site reactions are the most frequently reported adverse events.55,56 Less common adverse events, such as pseudosepsis, have been associated with cross-linked and avian-derived hyaluronate agents and do not appear to be class-related.57
Results from several studies have provided evidence that IAHA may have disease-modifying actions. In a large randomized trial that assessed the disease-modifying effects of IAHA in knee OA, viscosupplementation compared with placebo significantly reduced the progression of joint-space narrowing in a subset of patients with a greater joint-space width at study entry.58 However, results from another 1-year study showed no significant effect of IAHA injection on joint-space narrowing in a cohort of 301 patients with knee OA.36 MRI results from 20 patients who received 3 weekly injections of IAHA into 1 or both knees (30 knees) indicated a significant improvement in patellofemoral joint cartilage after treatment.59
In an open-label study of 5 weekly injections of IAHA, both the cartilage and the synovial membrane showed improvement when measured 6 months after the injection.60 In 9 patients with Kellgren-Lawrence grade 2 OA, the thickness of the superficial amorphous cartilage layer increased significantly between the baseline and final evaluations. A significant reduction in the thickness of the synovial membrane and in the number of infiltrating mononuclear cells indicative of reduced inflammation in the synovium also was observed.
In a study in which patients were randomized to conventional therapy and then arthroscopically evaluated for severity of chondropathy, cartilage deterioration was observed in both control and intra-articular groups.61 However, it was significantly less in the IAHA group as measured by an investigator overall visual analog scale score and Société Française d'Arthroscopie scoring. In another study of patients with symptomatic knee OA who were monitored for 2 years and evaluated with MRI, those who received 6 monthly IAHA injections without regard to symptoms had significantly better preservation of cartilage than patients in the control group (usual care without injections).62
IAHA injection has been shown to reduce levels of molecules thought to be involved in joint destruction in patients with knee OA. In one study, IAHA decreased the level of MMP-3 and the ratio of MMP-3 to tissue inhibitor of metalloproteinase-1 in the synovial fluid of patients with knee OA.63 However, in another study of patients with knee OA treated with IAHA, this intervention increased urinary CTX-II levels.64
Studies of IAHA-managed tissues from patients with knee OA have produced results suggesting potential for disease modification with this intervention. In a study of patients with early OA, administration of IAHA decreased levels of MMPs, urokinase(Drug information on urokinase)-type plasminogen activator, and plasminogen activator inhibitor in chondral, meniscal, and synovial cultures.65
In a comparison of the effects of IAHA and methylprednisolone acetate on articular cartilage and the synovium in patients with OA, the number and aggregation of synoviocytes in IAHA-treated knees decreased.48 Both treatments reduced the number of inflammatory cells, including macrophages, lymphocytes, and mast cells. IAHA also significantly improved the compactness and thickness of the amorphous superficial cartilage layer 6 months after treatment compared with baseline.
In one study, the thickness of the superficial amorphous layer was significantly increased and chondrocyte density was significantly higher with IAHA than with intra-articular corticosteroids.66 The investigators favored using IAHA as an early intervention instrument for early arthritis, when it can have the highest success rate and, possibly, slow down loss of cartilage.
Systemic treatments have been shown to have significant positive effects on biomarkers that may be associated with OA disease progression. Injection of corticosteroids is effective for symptomatic treatment, but there is no evidence to support disease-modifying activity. Limited evidence indicates that early intervention with IAHA may have disease-modifying chondroprotective activity and positive effects on biomarkers associated with disease progression. The goals of future therapies will include not only pain reduction and function improvement but also early detection and early intervention.