ABSTRACT: Early intervention for osteoarthritis (OA) of the knee is important for ameliorating the long-term effects of disease. Current treatment goals are focused on symptom relief, but effort is being directed toward the development of disease-modifying therapies. Self-help options exemplify the “first, do no harm” principle, and several have been shown to have significant efficacy in patients with knee OA. Weight loss significantly decreases knee joint loads in obese and overweight patients with knee OA. Focused strength training has been shown to improve mobility and decrease pain. Clinical results for glucosamine/chondroitin suggest that they may provide protection against joint-space narrowing. Clinical studies of the use of canes and walking aids have indicated symptomatic benefit. A meta-analysis of trials of acupuncture for peripheral joint OA indicated benefit.
Osteoarthritis (OA) of the knee is a common and progressive disease that has a negative impact on function and quality of life. Early intervention is considered important for ameliorating the long-term effects of disease.
Although current treatment goals are focused on symptom relief, great effort is being directed toward the development of disease-modifying therapies. No current therapy for knee OA is accepted as having disease-modifying actions, but studies of several interventions have suggested potentially disease-modifying effects.
This is the second article in a 3-part series on managing early knee OA in which we review clinical results for nonpharmacological and pharmacological treatments for patients with OA and summarize data related to their potential for altering disease progression. Although such information is limited, it may help clinicians select treatments for patients who have early OA.
In the first part (“Managing Knee Osteoarthritis: Rationale for Early Treatment,” 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. This second article discusses self-help and nonpharmacological interventions. In the third article, we will provide an overview of systemic pharmacotherapy, including acetaminophen, NSAIDs/cyclooxygenase 2 inhibitors, licofelone, 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.”
EVIDENCE FOR EFFECTS ON KNEE PROGRESSION
Although there is as yet no consensus on a measure for inhibition of OA disease progression, particularly one that may be used before radiographically demonstrable disease, considering the results of clinical trials that address this issue is still useful. The following sections summarize results from studies of nonpharmacological interventions for OA that included information on effects of treatment on radiographic disease progression or candidate markers that may be predictive of this outcome.
Self-help options exemplify the “first, do no harm” principle that is fundamental to medicine, and several have been shown to have significant efficacy in patients with knee OA. Weight loss significantly decreases knee joint loads in obese and overweight patients with knee OA.1 Results from controlled clinical trials repeatedly have shown that diet, exercise, and weight loss are associated with decreased symptom severity and functional improvement in patients with knee OA.2-5
Available evidence suggests that diet, exercise, and weight loss do not have consistent significant effects on biomarkers reflective of disease progression.6 However, they have been shown to significantly decrease levels of inflammatory markers, including C-reactive protein (CRP), interleukin (IL)-6, and soluble tumor necrosis factor (TNF) receptor 1 levels in patients with knee OA.7,8
Focused strength training (supervised or done at home unsupervised) has been shown to improve mobility and decrease pain in patients with knee OA.4,9-13 However, evidence indicating that it has beneficial effects on knee OA progression is limited.
In one study, strength training was significantly more effective than range of motion exercises in slowing the rate of joint-space narrowing in older adults with knee OA.14 In another study, however, radiographic analysis showed no significant difference in results for aerobic versus resistance training or no intervention in patients with knee OA.15 More recently, in a trial of older women with knee OA, knee strength training did not result in significant changes in knee cartilage thickness or volume, subchondral bone area, or regional cartilage thickness between baseline and the end of follow-up.16
Several studies have evaluated the effects of dietary supplementation on radiographic progression and potentially related biomarkers in patients with knee OA. Dietary supplementation with glucosamine and chondroitin sulfate has been studied most extensively. Although clinical trial results have demonstrated some symptomatic benefit with these agents, there is no evidence of significant effects on radiological outcomes and biomarkers.
The long-term efficacy of glucosamine and chondroitin sulfate in patients with knee OA was evaluated in the Glucosamine/chondroitin Arthritis Intervention Trial (GAIT).17 This study enrolled 662 patients with knee OA who satisfied well-defined radiographic criteria (Kellgren-Lawrence grade 2 or 3 changes and baseline joint-space width 2 mm or more) and were treated with glucosamine (500 mg tid), chondroitin sulfate (400 mg tid), a combination of glucosamine and chondroitin sulfate, celecoxib (200 mg/d), or placebo over 24 months. The primary outcome was a 20% or greater reduction in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain scores over this period.
Compared with placebo, the odds of achieving such a reduction in WOMAC pain scores were 1.21 for celecoxib, 1.16 for glucosamine, 0.83 for combination treatment, and 0.69 for chondroitin sulfate alone. None of these differences versus placebo was statistically significant.17 Although the combination of glucosamine and chondroitin did not achieve statistical significance compared with placebo for relief of mild knee pain, it did result in statistically significant pain relief for a small subset of patients with moderate or severe knee pain. In this group, glucosamine and chondroitin provided pain relief superior to that obtained with celecoxib.
A meta-analysis of 10 clinical trials included 3803 patients.18 Chondroitin sulfate, glucosamine, or combination of these agents did not provide clinically significant pain relief in patients with knee or hip OA.
In contrast to the results of these clinical studies, glucosamine has been reported to double steady-state levels of aggrecan messenger RNA, to inhibit aggrecanase activity induced by ILs, and to decrease nitric oxide production induced by IL-1β and TNF-α in vitro.19 Glucosamine also has been shown to modulate the osteoprotegerin-receptor activator of nuclear factor kappa B (NF-κB) ligand ratio in osteoarthritic subchondral bone osteoblasts and to reduce bone resorption.20
Results from 2 meta-analyses have indicated further that administration of glucosamine/chondroitin sulfate can decrease joint-space narrowing and other radiographic markers of disease progression.21,22 In the Study on Osteoarthritis Progression Prevention, patients with knee OA who were treated for 2 years with 800 mg/d of chondroitin sulfate had a more significant reduction in joint-space width loss than patients who received placebo.23 Also, the percentage of patients with radiographic progression of 0.25 mm or greater was significantly reduced in the chondroitin sulfate group compared with the placebo group (28% vs 41%).
Delay Joint Replacement
There also is evidence to indicate that treatment with glucosamine can delay the need for joint replacement. In a study of 275 patients who were monitored for 8 years after at least 12 months of treatment with glucosamine or placebo, total knee replacement had been performed in 14.9% of 131 patients treated with placebo versus 6.3% of 144 patients who received glucosamine.24
In our experience, despite the conflicting data, glucosamine and chondroitin have played a significant role in the management of patients with knee OA. These agents have minimal adverse effects and, in some patients, can provide substantial benefit. Patients with knee OA and those with diabetes mellitus should consult their primary care physician before using glucosamine and chondroitin sulfate, and they should routinely check their fasting blood glucose level before and while they use these agents.
Adding Omega-3 Polyunsaturated Fatty Acids
The benefit of adding the omega-3 polyunsaturated fatty acids eicosapentaenoic acid and docosahexaenoic acid to glucosamine sulfate (1500 mg/d) was evaluated in a 26-week study of 177 patients with moderate to severe hip or knee OA.25 When a minimal reduction of 20% or greater on the WOMAC pain scale was used as the criterion for a response, there was no difference between results for glucosamine plus omega-3 fatty acids and glucosamine alone (92% vs 94%, respectively, for response). When a criterion of pain reduction of 80% or greater was used, the respective values were 44% and 32%. This study did not include evaluation of markers potentially associated with OA progression.
In our experience, adding 2000 mg/d of omega-3 fatty acids to other treatments provides added pain relief and reductions in joint stiffness. It also may slow blood clotting; therefore, patients should consult their primary care physician before adding omega-3 fatty acids to their treatment regimens.
Curcumin With Soy Phosphatidylcholine
A proprietary complex of curcumin with soy phosphatidylcholine has been shown to be effective for the treatment of OA. In a 3-month study of 50 patients, this treatment decreased the global WOMAC score by 58%, increased walking distance in a treadmill test from 76 m to 332 m, and decreased CRP levels from 168 to 11.3 mg/L in the subpopulation of patients with a high CRP level at baseline.26
Although the effects of curcumin on markers potentially associated with disease progression have not been evaluated in clinical trials, a combination of curcumin and resveratrol has been shown to suppress NF-κB–regulated gene products involved in inflammation, including matrix metalloproteinase (MMP)-3, MMP-9, and vascular endothelial growth factor.27 It also inhibited apoptosis of chondrocytes.
Curcumin alone has been shown to inhibit basal and IL-1β–stimulated nitric oxide, prostaglandin E2, IL-6, IL-8, and MMP-3 production by human chondrocytes in a concentration-dependent manner.28 In a study of 107 patients with knee OA who participated in a randomized trial in Thailand, 500 mg of curcumin administered 4 times a day was as effective as 400 mg of ibuprofen administered twice daily for decreasing walking pain.29
We recommend 500 mg of curcumin taken twice daily. In our experience, this regimen provides substantial pain relief. At least 2 major studies are under way to evaluate the efficacy of curcumin, which has substantial potential for managing knee OA.
Clinical studies of the use of canes and walking aids have indicated significant symptomatic benefit of these interventions, but there is no evidence of disease modification.30 Assessments of bracing, orthoses, and related interventions support the same conclusions.
Beneficial Effect of Bracing
Evidence to support the view that a brace has additional beneficial effect with respect to WOMAC, McMaster Toronto Arthritis Patient Preference Disability Questionnaire, and function test scores for patients with knee OA compared with medical treatment alone comes from the results of a Cochrane meta-analysis.31 The results also indicated that a neoprene sleeve has additional beneficial effect (WOMAC, function tests) for knee OA compared with medical treatment alone and that a brace is more effective (WOMAC, function tests) than a neoprene sleeve. The results also provided limited evidence that a laterally wedged insole decreases NSAID intake compared with a neutral insole.
None of the reviewed studies provided evidence that braces or wedged insoles significantly affect measures of disease progression or joint inflammation. Unloader bracing is bulky, and orthoses must be increased gradually to avoid exacerbation of symptoms.
This intervention has been studied extensively in patients with knee OA, and its efficacy has been evaluated in multiple meta-analyses. Assessment of results from 16 trials that included 3498 patients indicated statistically significant benefits of acupuncture for pain relief that were small and did not meet predefined thresholds for clinical relevance.32 The benefits were considered at least partially to be the result of placebo effects from incomplete blinding.
The results from an earlier analysis of 9 studies indicated no significant benefit of acupuncture versus a sham procedure.33 A meta-analysis of 18 randomized trials of acupuncture for peripheral joint OA indicated significant benefit versus sham treatment.34 PubMed searches recovered no evidence that acupuncture significantly affects radiographic measures of OA progression, biomarkers thought to reflect joint damage, or indices of inflammation.
Diet and exercise programs and curcumin supplementation are effective for decreasing OA symptoms and have been shown to lower levels of biomarkers thought to be related to disease activity. Clinical results for glucosamine/chondroitin suggest that these nutraceuticals may provide protection against joint-space narrowing in patients who have knee OA.
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