Management of Knee Osteoarthritis PDF

Management of knee osteo    Ajuda    CME 15.0 Sign out Conteúdo  Calculadoras Interações de Medicamentos UpToDate Pathways  Voltar ...

Management of knee osteo    Ajuda    CME 15.0 Sign out Conteúdo  Calculadoras Interações de Medicamentos UpToDate Pathways  Voltar  Management of knee osteoarthritis Topic Graphics (3)    Outline authors: Leticia Alle Deveza, MD, PhD, Kim All topics are updated as new evidence becomes SUMMARY AND RECOMMENDATIONS Bennell, PhD available and our peer review process is complete. section editor: David Hunter, MD, PhD WHAT'S NEW Literature review current through: Nov 2024. deputy editor: Karen Law, MD, FACP This topic last updated: Nov 19, 2024. INTRODUCTION Contributor Disclosures DEFINITIONS GENERAL PRINCIPLES What's New APPROACH BASED ON CLINICAL Semaglutide in patients with moderate to severe knee osteoarthritis (November 2024) PRESENTATION Weight reduction through diet and exercise improves knee osteoarthritis (OA)-related pain in patients with… Mild knee osteoarthritis Read more Moderate/severe knee osteoarthritis Knee osteoarthritis with one or more joints involved What's New Patients with comorbidities Uncertain benefit of methotrexate for refractory knee osteoarthritis (August 2024) MILD KNEE OSTEOARTHRITIS Methotrexate is used in the treatment of rheumatoid arthritis; however, its role in treating osteoarthritis (… Initial lifestyle modifications Read more Exercise ◦ Land-based exercise INTRODUCTION ◦ Aquatic exercise ◦ Mind-body interventions Evidence-based approaches to the treatment of knee osteoarthritis (OA) include nonpharmacologic, pharmacologic, and surgical modalities targeted at relieving pain, improving joint function, and modifying risk factors for disease progression. Disease-modifying therapies have not demonstrated enough benefit to gain regulatory approval, although some investigational therapies appear to slow structural progression [1,2]. A holistic assessment of the patient is a paramount component of knee OA treatment. There are multiple mechanisms that can contribute to the pain experience. In addition, clinical decision-making is often influenced by specific patient and disease characteristics. This topic will provide an overview of the management of knee OA, with a focus on the management of mild knee OA. Separate topic reviews on OA as well as knee pain include the following: (See "Pathogenesis of osteoarthritis".) (See "Investigational approaches to the management of osteoarthritis".) (See "Epidemiology and risk factors for osteoarthritis".) (See "Clinical manifestations and diagnosis of osteoarthritis".) (See "Overview of the management of osteoarthritis".) (See "Management of moderate to severe knee osteoarthritis".) (See "Comorbidities that impact management of osteoarthritis".) (See "Approach to the adult with unspecified knee pain".) (See "Approach to the adult with knee pain likely of musculoskeletal origin".) (Related Pathway(s): Knee osteoarthritis: Management in adults.) DEFINITIONS These definitions are based on the severity of the impact of the disease on the person rather than on radiographic severity. Symptoms and radiographic findings often do not correlate. Moreover, these definitions are in line with a person-centered approach to management. (See "Overview of the management of osteoarthritis", section on 'Mechanisms of pain'.) Mild knee osteoarthritis – Patients with mild knee OA have low levels of or intermittent knee pain with relatively well-preserved joint function and quality of life. Moderate/severe knee osteoarthritis – Patients with moderate to severe OA have persistent pain which significantly impairs functionality, activity participation, and quality of life. (See "Management of moderate to severe knee osteoarthritis".) GENERAL PRINCIPLES All patients with OA should be thoroughly assessed with regard to: Knowledge about the disease and treatment alternatives Previous experiences with treatment Expectations of current treatment Misconceptions (eg, exercise will worsen OA or that OA will inevitably worsen) may hamper interventions if not properly identified and countered. Patient education about OA and its treatment options can occur during the clinical encounter and can be complemented with written materials and referral to national or rheumatology association websites. Creating realistic and positive expectations for treatment efficacy may enhance adherence, especially to therapies that require lifestyle changes, and has been shown to positively influence treatment outcomes. The management principles for OA, including education, self-management, and goal setting, are discussed in detail separately. (See "Overview of the management of osteoarthritis", section on 'General principles'.) The management of patients with knee OA should include a holistic assessment. The patient's response to therapy should be monitored on a regular basis. A detailed discussion on monitoring and assessment of OA patients can be found elsewhere. (See "Overview of the management of osteoarthritis", section on 'Monitoring and assessment'.) APPROACH BASED ON CLINICAL PRESENTATION Patients with knee OA may fall into different categories that must be considered when making treatment decisions. Our management approach is generally consistent with guidelines developed by professional organizations [5-9]. Mild knee osteoarthritis — Lifestyle modifications focused on education, exercise, and weight management, whether alone or in combination with topical therapies or analgesics as needed, are likely to provide adequate control of symptoms in this group of patients ( algorithm 1). Moderate/severe knee osteoarthritis — Lifestyle modifications are the first-line therapy for this group of patients. Patients with severe pain generally tolerate aquatic exercises better than land-based exercises ( algorithm 2). Special consideration should be given to other factors that may contribute to pain, such as mood disturbances, pain catastrophizing, sleep problems, and chronic widespread pain (see "Overview of the management of osteoarthritis", section on 'Factors affecting response to therapy'). Other treatment alternatives may be required, including oral nonsteroidal anti-inflammatory drugs (NSAIDs), intra-articular glucocorticoids, duloxetine, and surgery. Knee osteoarthritis with one or more joints involved — OA can be localized in the knee only or affect multiple joints. The best approach for managing patients with multijoint, symptomatic OA is to prioritize therapies that address pain in general, rather than focusing on individual joints. Local interventions such as intra-articular glucocorticoid injections, topical NSAIDs, topical capsaicin, and knee braces may help with knee pain but are likely to be insufficient to provide adequate improvement in the patient's OA symptoms as a whole. Patients with comorbidities — Knee OA often occurs with other conditions such as cardiovascular disease, diabetes, hypertension, obesity, depression, and peptic ulcer disease. In addition, knee OA is highly prevalent in the older adult population, although it is important to note that its diagnosis usually occurs earlier in life (median age 55 years) and around two-thirds of the patients are younger than 65 years [10,11]. Therapies should be chosen to minimize the potential for adverse events while optimizing function and quality of life. (See "Comorbidities that impact management of osteoarthritis".) MILD KNEE OSTEOARTHRITIS Lifestyle interventions are the cornerstone of knee OA management, regardless of severity, and can be used in combination with pharmacologic therapy ( algorithm 1). The duration of therapy depends upon the individual patient's needs; however, lifelong treatment with nonpharmacologic therapies is generally recommended in order to relieve symptoms and prevent further joint damage. (Related Pathway(s): Knee osteoarthritis: Management in adults.) Initial lifestyle modifications — Lifestyle modifications in the management of patients with mild OA include exercise and, when pertinent, weight loss. Management of mild knee Exercise — We suggest ongoing regular exercise for pain relief, functional osteoarthritis improvement, and joint protection in all patients with knee OA. Exercise, alongside weight loss when indicated, is a core component of knee OA management. All Algorithm 1 patients with knee OA should be counseled on exercise irrespective of their age, radiographic disease severity, pain intensity, functional levels, and comorbidities. For further details about exercise, an international multidisciplinary consensus process provided 54 specific evidence-informed recommendations for health practitioners to help support the delivery of best-practice therapeutic exercise for their patients with knee and/or hip OA. Land-based exercise — A Cochrane review of 54 trials concluded that there is moderate- to high-quality evidence suggesting that land-based exercise improves knee pain and function immediately after treatment. However, while the magnitude of effect with exercise appears relatively modest [15,16], findings from a network meta-analysis of 152 randomized trials suggests the effect of exercise on pain and function is comparable to the combined effect of oral nonsteroidal anti-inflammatory drugs (NSAIDs) and acetaminophen. The response to exercise may also differ depending on patient characteristics; in one meta-analysis of 31 trials, patients with more severe pain and poorer baseline function reported greater exercise benefits compared with patients with milder symptoms. Research has shown that exercise is safe [15,18] and that low- to moderate-intensity exercise is not harmful for articular cartilage in people with knee OA. In clinical practice, exercise prescription is frequently personalized according to individual assessment findings, with research showing that benefits can be gained from many different types of exercise [20,21], as well as when undertaken individually or in group settings. We often refer our patients for physical therapy to optimize the effectiveness of the exercise program. We prefer a combination of low-impact aerobic fitness training (eg, walking, cycling, rowing, and deep-water running) and lower-limb strengthening exercises, which addresses the full spectrum of impairments in most patients with knee OA. Nevertheless, exercise choice should be also based on the patient's mobility, specific impairments (eg, strength, range of motion, aerobic fitness, and balance), and preferences. As a high-impact activity, running is often perceived to be detrimental to joint health, and people with OA may be advised to avoid running. However, recreational running has not been shown to increase the risk of developing cartilage lesions or symptomatic OA , although studies on running and knee OA are scarce. For those patients who wish to run, we advocate a load management approach with attention paid to factors such as rest days, running surface, distance, speed, and footwear, as well as building up muscle strength. Stretching or flexibility exercises, particularly of the hamstrings to avoid or minimize flexion contracture of the knee, can be part of an exercise program to increase knee range of motion but should not be the sole exercise component. Aquatic exercise — Aquatic exercise also has clinically relevant effects on knee pain, function, and stiffness, but the effects are small when compared with nontreatment controls. This exercise modality is particularly useful for patients with severe pain and/or poor physical function due to its better tolerance and lower potential to cause adverse events. Mind-body interventions — We consider Tai Chi and yoga as mind-body exercise options for the rehabilitation of patients with knee OA, according to patients' preferences. Despite the limited number of large trials investigating the long-term effects of Tai Chi, it has been shown to be as effective as a standard exercise program after 12 weeks in terms of knee pain, physical function, and reduction in analgesic use, in addition to having greater improvement in depression [28,29]. Moreover, Tai Chi improves balance and is associated with a reduced falls risk in older patients with knee OA. There is less evidence for yoga. A systematic review showed limited low-quality evidence that it improves pain, physical function, and stiffness (compared with exercise and nonexercise controls). Exercise dose — At present, there is limited evidence to guide the optimal exercise dose (ie, intensity, duration, and frequency) for people with knee OA. In one study, effects of shorter exercise sessions (20 to 30 minutes, 3 times weekly) were no different from those of longer exercise sessions (70 to 90 minutes, 3 times weekly) in terms of improving pain and function associated with knee OA. In two other studies, high-intensity strength training did not result in greater benefits than low-intensity strength training [33,34]. At this stage, it would therefore seem appropriate to use doses recommended in general exercise guidelines for healthy adults, taking into account individual factors and personal goals. Interim exercise goals may also be useful. For example, 45 minutes per week of moderate to vigorous exercise has been associated with maintaining or improving to a high level of physical function , while walking 6000 steps per day may protect against developing functional limitation in people with knee OA. Adherence — The benefits of exercise are not sustained in the long term. This is largely related to decreasing adherence rates to the exercise program over time. Strategies to improve adherence should be adopted, such as patient education about OA and the benefits of exercise, goal setting, and long-term monitoring. The use of digital technologies to improve access and adherence to exercise may be of benefit for some patients [38-40]. For example, there is evidence that self-directed online programs of strengthening exercise ( mykneeexercise.org.au) and yoga ( myjointyoga.com.au) can be beneficial for patients with knee OA. (See "Overview of the management of osteoarthritis", section on 'General principles' and "Overview of the management of osteoarthritis", section on 'Monitoring and assessment'.) Weight loss — We counsel patients with knee OA who are overweight to pursue weight loss with a combination of exercise and a calorie-restricted diet. We suggest a 5 to 10 percent weight reduction within a six-month period, with periodic goal reassessment based on progress and symptoms [42-46]. Because of the substantial load placed on the knees during weight-bearing activities, maintaining an ideal body weight may improve symptoms and help preserve joint structures. In addition to the mechanical consequences of obesity and overweight to the joint, adipokines released by adipose tissue, such as leptin and adiponectin, are directly involved in the inflammatory component of OA and cartilage damage [47,48]. (See "Pathogenesis of osteoarthritis" and "Comorbidities that impact management of osteoarthritis", section on 'Obesity and weight loss'.) There are a variety of ways to achieve weight loss, including diet, exercise, pharmacotherapy, surgery, or a combination of these. While diet and exercise have been the most extensively studied, most trials suggest that the method of weight loss is less relevant than the overall amount of weight loss achieved [42-46,49,50]. In one network meta-analysis of 13 randomized trials in patients with a body mass index ≥25 kg/m2, a weight reduction of at least 7 percent was associated with significant pain relief in patients with knee OA across all weight loss strategies, including diet, exercise, behavioral support, and antiobesity medications. The combination of both calorie- restricted diet and exercise has been shown to produce greater weight loss and improved pain and function compared with minimal care or either intervention alone [40,51-54]. The use of glucagon-like peptide 1 receptor agonists and other antiobesity medications in the context of knee OA is an area of ongoing study [55,56]. In one randomized trial of 407 patients with obesity and moderate knee OA, semaglutide 2.4 mg once weekly produced greater weight reduction and improvement in pain scores over the 68- week study period. Importantly, however, the placebo group also achieved meaningful weight loss and pain score improvement with a reduced-calorie diet and exercise counseling alone (13.7 percent weight loss with semaglutide versus 3.2 percent with placebo, 95% CI 12.3-8.6, and pain score -41.7 with semaglutide versus -27.5 with placebo, 95% CI -20 to -8.3). Surgical approaches to weight loss in knee OA are even less well studied (eg, gastric bypass). The use of pharmacologic and surgical weight loss interventions in patients with knee OA remains limited due to concerns for rebound weight gain, cost, and long-term adverse effects. Inadequate response to lifestyle modifications — Pharmacologic therapy can be started in combination with or after a trial of lifestyle modifications if satisfactory pain relief is not achieved. Topical therapies ( table 1) for the treatment of mild knee OA are particularly appealing due to the frequent presence of comorbid conditions in this patient population and the relatively common side effects of other systemic treatment options. Despite the chronic nature of OA, research evidence on the long- term efficacy (≥1 year) of pharmacologic therapies is limited. Nonetheless, in our experience, topical NSAIDs, used either as needed or on a daily basis, may provide long-term benefits when combined with nonpharmacologic measures. Topical Topical analgesics for treatment of capsaicin, however, is less tolerated by patients due to the relatively high frequency of knee and hand local side effects, including a local burning sensation. We do not use topical osteoarthritis salicylates in our patients with OA. Table 1 Topical NSAIDs — We suggest topical nonsteroidal anti-inflammatory drugs (NSAIDs) rather than oral NSAIDs for patients with mild OA localized to the knee or with concomitant hand involvement, given the superficial location of these joints. A Cochrane review found that approximately 60 percent of patients achieved at least 50 percent improvement in pain with topical NSAIDs, which was comparable to the effect obtained with oral formulations and slightly better than that observed with topical placebo. The risk of gastrointestinal, kidney, and cardiovascular toxicity is much lower with topical NSAIDs as compared with the oral formulation due to the reduced systemic absorption (ie, 5- to 17-fold lower for topical diclofenac compared with oral) [59-61]. The tolerability profile is also better with topical NSAIDs, with mild skin rashes being the most commonly reported side effect. The drugs studied with the most frequency were diclofenac gel or solution and ketoprofen, applied over the affected knee two to four times daily, for the duration necessary to control symptoms. We most commonly use diclofenac gel, but the choice of topical agent may vary according to local availability and cost. Topical capsaicin — For patients with mild OA localized to the knee or a few other joints in whom other treatments are ineffective or contraindicated, we suggest topical capsaicin. Capsaicin is a substance derived from hot chili peppers with the potential to alleviate pain through the down-regulation of the TRPV1 receptor activity on nociceptive sensory neurons and the depletion of substance P. Continued use of capsaicin results in desensitization of nociceptive fibers and inhibition of pain stimulus transmission. However, the causative role of substance P depletion on pain reduction associated with capsaicin use has come into question. There are relatively few randomized controlled trials investigating topical capsaicin treatment for knee OA pain, most with a short follow-up (up to 12 weeks) and overall good methodologic quality. In most studies, topical capsaicin was superior to placebo, with an overall 33 percent pain reduction after four weeks in one study, which was significantly greater than placebo. In a 12-week randomized, multicenter trial, 113 patients received either capsaicin 0.025% cream four times daily or placebo. Capsaicin provided greater pain relief after 4 to 12 weeks and a greater number of patients on capsaicin (81 percent) compared with placebo (54 percent) were improved based on clinicians' global evaluation. Local burning sensation is the most common side effect of topical capsaicin and may occur in over half of patients. However, it is usually mild to moderate and improves with continued application. In addition, topical capsaicin should not come in contact with mucous membranes, abraded skin, eyes, or genital areas. Systemic adverse effects of capsaicin are not significantly higher compared with placebo. We prefer topical NSAIDs over capsaicin in our practice due to better tolerability and stronger evidence for efficacy. However, if there is insufficient response with one agent (eg, topical NSAIDs) after a few weeks of use, a trial of the other treatment (eg, capsaicin) can be offered as some people may benefit more from one treatment than the other. MODERATE/SEVERE KNEE OSTEOARTHRITIS The management of moderate to severe knee OA is reviewed in the algorithm and discussed in detail separately ( algorithm 2). (See "Management of moderate to severe knee osteoarthritis".) (Related Pathway(s): Knee osteoarthritis: Management in adults.) THERAPIES LACKING EFFICACY OR OF UNCERTAIN BENEFIT There are several approaches that have been used to treat patients with knee OA that Management of we generally do not recommend due to lack of sufficient evidence. These approaches moderate to severe knee osteoarthritis include nerve blocks, nerve ablation, stem cell injections, and joint distraction. In addition, there are other therapies in which the benefit remains uncertain. It would Algorithm 2 be reasonable, however, to try some of the therapies discussed below as adjunctive measures for patients who do not respond to the approach described above after consideration of potential harm, cost, and patient preference. Oral therapies Acetaminophen – Due to safety concerns pertaining to acetaminophen (paracetamol) use and an increased awareness of its negligible and non-clinically significant effects on pain [7,67-70], we do not initiate treatment with acetaminophen for knee OA in our clinical practice. In a meta-analysis including 10 trials and 3541 patients, there is high-quality evidence that acetaminophen has only small, non-clinically meaningful benefits for pain in the short term. In a subsequent network meta-analysis comparing different analgesics for the treatment of OA pain, acetaminophen was not superior when compared with placebo, irrespective of the dose (4 mm difference on a 0 to 100 mm visual analog scale [VAS]). The risk of harm, including gastrointestinal bleeding, liver toxicity, kidney failure, and cardiovascular disease, from acetaminophen is usually higher with increasing doses but may also occur at doses within the therapeutic range. This is especially concerning due to the risk of unintentional overdose, as acetaminophen is frequently combined with other common over- the-counter medications used to treat pain and cold symptoms. Opioids – We avoid using opioids whenever possible, given poor or modest efficacy and the potential for harm, especially in the older adult population. In our clinical practice, we use opioids very rarely, only in the short- term, for patients with severe pain awaiting joint replacement who are not highly vulnerable to drug dependence or misuse. We use it in the lowest dose and duration necessary to control symptoms and monitor common side effects and dependence. (See "Use of opioids in the management of chronic pain in adults".) Several studies of patients with knee OA have found the efficacy of opioids with respect to pain reduction to be similar to that of nonsteroidal anti-inflammatory drugs (NSAIDs). A meta-analysis revealed an overall small effect size (standardized mean difference [SMD] -0.28, 95% CI -0.35 to -0.20) of non-tramadol opioids on pain reduction, which corresponds to a difference of 0.7 cm on a VAS (0 to 10 cm) between opioids and placebo. Improvement in knee function was also small, and there was no influence of daily morphine equivalence dose on function. Patients receiving opioids were more likely to drop out due to adverse events and more likely to experience side effects (6.5 versus 1.7 percent and 22 versus 15 percent, respectively). In addition, a randomized trial including 240 patients with chronic back pain or hip or knee OA pain did not demonstrate a difference in pain-related function after 12 months of treatment with nonopioid versus opioid medications. Similarly, less-potent opioids likely do not offer much benefit over nonopioid medications. A network meta- analysis did not demonstrate a difference in efficacy between potent opioids (hydromorphone and oxycodone), a less potent opioid (tramadol), and NSAIDs in trials of at least eight weeks duration. In a meta-analysis of six trials representing 3611 patients with knee or hip OA, tramadol provided modest pain relief compared with placebo, but only the high dose (300 mg/day) was associated with an improvement in the function subscale of the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) compared with placebo (SMD -0.24, 95% CI -0.47 to 0.03). In addition to the known potential risks and harms of opioid use, there are some data to suggest an association between tramadol use and increased mortality among patients with OA. In a propensity score- matched study using data from 88,902 patients with OA, patients prescribed tramadol had a higher rate of mortality over the one-year follow-up period compared with commonly prescribed NSAIDs such as naproxen (hazard ratio 1.71 [95% CI 1.41-2.07]). These findings, however, may be susceptible to confounding by indication as the tramadol users had a higher comorbidity burden than patients receiving NSAIDs prior to propensity score matching. Methotrexate – Studies on the use of methotrexate in the treatment of OA have produced mixed results [76- 78]. In one randomized trial of 207 patients with refractory knee OA, treatment with methotrexate 25 mg weekly resulted in a modest reduction in mean pain scores compared with placebo at six months (mean difference 0.79 on a 10-point scale, 95% CI 0.08-1.51). This benefit was statistically significant but not clinically significant. Furthermore, symptom improvement was not sustained at 12-month follow-up; participant withdrawals and loss to follow-up from 6 to 12 months may have affected this result. Further study is needed to determine the efficacy and tolerability of methotrexate in the treatment of refractory knee OA. Intra-articular therapies Hyaluronans — The use of any intra-articular hyaluronic acid (HA) formulation is not widely recommended and not routinely used in our practice due to the lack of robust evidence demonstrating clinically relevant benefits over intra-articular placebo [6,7,79,80]. There has been a longstanding debate and conflicting data across trials and meta-analyses regarding the benefit of viscosupplementation (ie, intra-articular HA) for the treatment of symptomatic knee OA. The evidence from large, double-blinded, and high-quality trials indicates that intra-articular HA has a small, clinically irrelevant benefit over intra-articular placebo [81-83]. Moreover, intra-articular HA is associated with high costs and potential side effects such as pain flare-ups and joint infection, although the latter is a rare complication. Platelet-rich plasma — Due to the lack of solid evidence for the benefit of platelet-rich plasma (PRP) injection in patients with knee OA, we do not recommend its use. A meta-analysis of 40 trials, including 3035 patients with knee OA did not show that PRP improved pain or function compared with hyaluronic acid, intra-articular steroid, or saline. In one randomized trial of 288 patients comparing PRP with saline placebo that was included in the meta- analysis, intra-articular PRP injection demonstrated no benefit in pain or structural changes. Although initial studies had suggested benefit of PRP for knee OA symptoms, methodologic flaws, heterogeneity, and high risk of bias raised concerns that the effect could be related to confounding variables. Factors contributing to the variability between studies include differences in the number of injections (generally one to four), interval between injections, preparation of the PRP, and volume injected [84,86]. Additional information on the use of PRP for OA in general can be found elsewhere. (See "Investigational approaches to the management of osteoarthritis", section on 'Platelet-rich plasma'.) Insoles and other specialized footwear — There has been an interest in the use of insoles and other specialized footwear in an effort to reduce stress on osteoarthritic knee compartments and potentially slow disease progression. However, the data in support of these devices suggest limited clinical benefit overall. Lateral wedge insoles – Due to the evidence indicating against the use of lateral wedge insoles in medial compartment knee OA, we do not routinely suggest their use. However, medially wedged insoles for patients with lateral tibiofemoral OA and valgus deformity may be reasonably tried based on limited evidence from one study of significant improvements in pain for these patients. Nevertheless, there are few studies investigating medial wedge insoles compared with the number of studies investigating lateral wedge insoles. Lateral wedge insoles have been shown to modestly reduce the external knee adduction moment and thereby reduce medial knee joint loading. However, compared with control inserts (neutral soles), lateral wedge insoles provided no clinically significant improvement in pain in patients with medial knee OA, as examined in meta- analyses including trials with both neutral and no insole control [88,89]. Moreover, a randomized trial including 200 participants with mild to moderate medial knee OA found no differences between full-length lateral wedged insole and flat insole in medial tibial and femoral cartilage volume loss and change in size of bone marrow lesions on magnetic resonance imaging (MRI) over 12 months. Another randomized trial that involved prescreening to select those patients more likely to respond to insoles (ie, those who showed a ≥2 percent reduction in the knee adduction moment with insoles and without patellofemoral OA) found that lateral wedge insoles reduced pain more than control insoles. However, the effect of treatment was small and likely to be of clinical significance in only a minority of patients. Biomechanical footwear – OA guidelines had traditionally recommended stable supportive shoes solely on the basis of expert opinion. However, a number of footwear styles have been developed and/or marketed for knee OA including unloading shoes with variable-density midsoles and a lateral wedge insole; minimalist shoes that are flexible, flat, and non-heeled; and rocker-sole shoes with a thicker-than-normal sole and a convex curvature in the sagittal plane. There is limited evidence from clinical trials that these shoes offer no additional benefit on pain or clinically relevant effects on function, compared with conventional walking shoes [92-96]. A randomized trial supports guidelines recommending stable supportive shoes. It included 164 patients with moderate to severe symptomatic radiographic medial knee OA, and compared flat flexible shoes with stable supportive shoes. At six months, stable supportive shoes resulted in greater improvements in knee pain on walking compared with flat flexible shoes. Although the study did not compare either intervention with usual shoes, this study suggests that stable supportive shoes may be beneficial. Another biomechanical approach that used individualized biomechanical footwear based on gait analysis found a potential benefit for the use of convex pods to improve gait. A randomized trial including 220 patients with knee OA found that at 24 weeks of follow-up, patients who received this approach experienced a greater improvement in the mean standardized WOMAC pain subscore (range from 0 to 10) compared with the control footwear group (between-group difference in pain scores was -1.3 [95% CI -1.8 to -0.9]). However, the clinical relevance of this difference remains uncertain, and the cost of this approach is considerable. Nutritional supplements — A variety of nutritional supplements have been evaluated in the management of knee OA. Curcumin (turmeric) – Interest in the use of curcumin is largely based on limited data suggesting that these agents have anti-inflammatory and analgesic properties, among others. Data supporting the use of curcumin come from randomized trials and meta-analyses [99,100]. As an example, in a trial including 70 adults with knee OA with ultrasound-confirmed effusion synovitis, patients receiving Curcuma longa 1000 mg daily experienced greater pain relief at 12 weeks compared with placebo. However, the clinical importance is uncertain, as the degree of change was of a magnitude smaller than the estimated minimum clinically important difference. Measures of effusion-synovitis volume on MRI were similar between the two groups, as were adverse events. Larger trials are needed to determine the clinical relevance of these findings. Curcumin is poorly absorbed by the gastrointestinal tract; curcumin supplements formulated to enhance absorption and bioavailability are usually preferred (eg, combinations of curcumin with piperine or BioPerine, a constituent of black pepper). A rare risk of liver injury from taking Curcuma longa in supplemental dose forms has been reported. Boswellia serrata – Boswellia serrata, commonly known as Indian frankincense, has been used in traditional medicine and religious and cultural ceremonies for centuries because of its purported anti-inflammatory and antimicrobial properties. Findings from a meta-analysis of seven randomized trials comparing Boswellia serrata extract with placebo in patients with OA suggested that Boswellia serrata extract may help relieve pain, stiffness, and function. However, the quality of the trials included in the analysis was low, with unclear risk of bias in several studies. Boswellia treatment appeared to be well tolerated; however, three of the included trials did not report any data on adverse events. Glucosamine and chondroitin – In our clinical practice, we recommend against glucosamine and/or chondroitin; however, we do not discourage their use for patients who are keen to take them, especially if symptomatic benefit is achieved with their use. In general, there have been conflicting results from randomized trials evaluating the efficacy of glucosamine and chondroitin in knee OA. Results from reviews with larger, methodologically sound studies found negligible effects of glucosamine hydrochloride on knee pain, while higher doses or higher-grade formulations of glucosamine sulfate (1500 mg/day) or chondroitin (800 mg/day) showed more favorable results and may have a statistically significant but small effect on symptoms compared with placebo [105-108]. As an example, in an industry-sponsored randomized trial including 604 patients with symptomatic knee OA who were followed for six months, pharmaceutical-grade chondroitin sulfate was found to be statistically superior to placebo and similar to celecoxib in reducing pain and improving function. Either chondroitin (800 mg), celecoxib (200 mg), or placebo was given once daily in the evening. One important limitation of the study is the uncertain clinical relevance of the statistical significance for the primary outcomes, which were based on a degree of change from baseline on a VAS for pain (0 to 100 mm) and the Lequesne index (a composite score of pain and function). Also, the number of patients who achieved the minimal clinically important improvement of 20 mm on the VAS for pain was not different among the three groups. Other meta-analyses also suggested that glucosamine sulfate (1500 mg/day) and chondroitin (800 mg/day) may have small effects in delaying structural progression of OA with long-term use (two to three years) [109,110]. A strong placebo effect has been demonstrated in the studies involving these dietary supplements. This is well illustrated by the landmark Glucosamine/Chondroitin Intervention Trial (GAIT), in which around 60 percent of participants experienced at least 20 percent pain reduction irrespective of whether they received placebo, glucosamine hydrochloride, chondroitin, or the combination of both (see "Overview of the management of osteoarthritis", section on 'Factors affecting response to therapy' and "Overview of the management of osteoarthritis", section on 'Role of placebo effect'). In another multicenter randomized trial, 164 patients with moderate to severe knee OA were treated with either chondroitin sulfate plus glucosamine or placebo. At six months' follow-up, the mean reduction in the global pain score was greater in the placebo group (33 percent) compared with the chondroitin sulfate plus glucosamine group (19 percent). Limitations of the study include the small size and potentially inadequate dosing of chondroitin and glucosamine. Whether some patient subgroups may benefit more from glucosamine than others has also been investigated, but no difference from placebo was found in any of the prespecified subgroups according to baseline pain severity, body mass index, sex, presence of inflammatory signs, or radiographic severity. However, it is of note that the risk of any adverse event with these supplements is low and comparable to placebo. Due to these contradictory and still uncertain data, glucosamine and chondroitin are not endorsed by OA guidelines developed by professional organizations [6,7,79]. Others – There is limited evidence supporting the use of other nutritional supplements for knee OA. We do not routinely recommend nutritional supplements such as vitamin D, diacerein, avocado soybean unsaponifiables (ASU), and fish or krill oil due to lack of clear evidence demonstrating a clinically important benefit from these supplements. A systematic review and meta-analysis of nutritional supplements for OA of the knee, hand, or hip including 69 studies (20 different supplements) reported clinically meaningful improvements in short-term pain reduction (≤3 months) for 7 supplements (L-carnitine supplementation, Pycnogenol, curcumin, Boswellia serrata extract, Curcuma longa extract, passion fruit peel extract, and collagen hydrolysate) compared with placebo. Most of these supplements were investigated in only a limited number of small trials, and the quality of evidence for this finding was variable (very low to moderate). Six other supplements (undenatured type II collagen, ASU, methylsulfonylmethane, diacerein, glucosamine, and chondroitin) were statistically better than placebo, but it was unclear if the effects were clinically important. Among the trials reporting long-term outcomes (>6 months, n = 17), no supplement was found to have clinically important effects on pain. The meta-analysis found no increased risk of side effects of supplements compared with placebo, except for diacerein, although safety profile was investigated in only a limited number of trials. It is also important to note that most trials (64 percent) were industry funded and were considered at high or unclear risk of bias (46 and 44 percent, respectively). In another study, vitamin D supplementation had no benefit over placebo on pain and change in tibial cartilage volume over two years in a large clinical trial. A study assessing the efficacy of low- versus high-dose fish oil (0.45 and 4.5 g omega-3 fatty acids, respectively) on clinical outcomes found greater improvements in pain and function in the group receiving low-dose fish oil at two years. Adverse events were common in both groups, particularly gastrointestinal events (around 60 percent in each group) such as gastrointestinal upset and reflux. Fish oil has also been studied in rheumatoid arthritis with positive results, probably through the anti-inflammatory effects of the eicosapentaenoic and docosahexaenoic acids. However, its clinical benefit in OA is still unclear. Krill oil has also been studied in patients with knee OA, as it has potential anti-inflammatory effects and a greater bioavailability of omega-3 fatty acids compared with fish oil. In two randomized trials of patients with clinically diagnosed, mild knee OA, krill oil 2 to 4 g/day improved knee pain and stiffness; however, the benefits were modest and of uncertain clinical significance [117,118]. However, in a subsequent randomized trial of patients with radiographically diagnosed moderate or severe knee OA, krill oil 2 g/day did not improve knee pain or synovial inflammation on MRI compared with placebo. These findings do not support the use of krill oil for relieving knee pain in patients with moderate to severe knee OA. Limited evidence has also suggested that phytoflavonoids, a class of natural compounds with anti- inflammatory properties, may have beneficial effects on knee OA symptoms [120-122]. Flavocoxid, a specific type of phytoflavonoid, has been associated with reports of serious adverse events related to liver injury and hypersensitivity pneumonitis, and its use is not recommended. (See "Hepatotoxicity due to herbal medications and dietary supplements", section on 'Flavocoxid'.) Transcutaneous electrical nerve stimulation — We do not recommend transcutaneous electrical nerve stimulation (TENS) for treatment of knee OA. Its mechanism of action is based on the gate-control theory, in which modulation of the nociceptive stimulus to the brain occurs through its presynaptic inhibition in the spinal cord dorsal horn. A trial including 203 patients found no additional pain or function benefits from TENS, interferential currents, or shortwave diathermy compared with sham interventions in patients participating in an education and exercise training program. Another trial including 220 patients found no difference between TENS and placebo TENS in WOMAC pain at the end of three weeks of treatment. In addition, there is evidence indicating a significant placebo component of the effect of TENS [123,125]. Acupuncture — The use of acupuncture in the management of OA is discussed elsewhere. (See "Overview of the clinical uses of acupuncture", section on 'Knee osteoarthritis'.) Local heat and cold — Local application of heat using a heat pack or hot-water bottle as a self-management strategy may have beneficial short-term effects on pain in patients with knee OA [126-128]. In a small cohort study of patients with knee OA, local heat application in addition to routine management was associated with more improvements in pain and disability compared with routine management alone. However, there are no robust clinical trials evaluating its effectiveness. Similarly, while not well studied, some patients may find icing of the joint useful temporarily to deal with a flare in pain or increase in swelling, for example, after an activity that has exacerbated symptoms. INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.) Basics topics (see "Patient education: Osteoarthritis (The Basics)" and "Patient education: Physical activity for people with arthritis (The Basics)") Beyond the Basics topics (see "Patient education: Osteoarthritis symptoms and diagnosis (Beyond the Basics)" and "Patient education: Osteoarthritis treatment (Beyond the Basics)" and "Patient education: Arthritis and exercise (Beyond the Basics)") SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Osteoarthritis" and "Society guideline links: Meniscal injury".) PATIENT PERSPECTIVE TOPIC Patient perspectives are provided for selected disorders to help clinicians better understand the patient experience and patient concerns. These narratives may offer insights into patient values and preferences not included in other UpToDate topics. (See "Patient perspective: Knee osteoarthritis".) SUMMARY AND RECOMMENDATIONS General principles – All patients with knee osteoarthritis (OA) should be thoroughly assessed with regard to their knowledge about the disease and treatment alternatives, previous experiences with treatment, and expectations of current treatment. Patient education about OA and its treatment options can occur during the clinical encounter and can be complemented by the provision of written materials. Monitoring of the patient's response to therapy should also be done on a regular basis. (See 'General principles' above.) Approach based on clinical presentation – Treatment decisions for patients with knee OA are made based on patient presentation, rather than imaging (see 'Approach based on clinical presentation' above): Mild knee OA – Patients with mild knee OA have intermittent, low levels of knee pain with relatively well- preserved joint function and quality of life. Lifestyle modifications alone or in combination with topical analgesics as needed can provide adequate control of symptoms ( algorithm 1). (See 'Mild knee osteoarthritis' above.) - Initial treatment with exercise and, if appropriate, weight loss – For all patients with knee OA, we suggest ongoing exercise for pain relief, functional improvements, and joint protection (Grade 2B). There is no strong evidence on the best prescription of exercise modalities and dose (ie, intensity, duration, and frequency). We prefer a combination of low-impact aerobic fitness training (eg, walking, cycling, rowing, and deep-water running) and lower-limb strengthening exercises. (See 'Exercise' above.) We also counsel patients with knee OA who are overweight to follow a calorie-restricted diet. We encourage health care professionals to consult the available local community programs or refer patients to a dietitian to ensure that patients with obesity or who are overweight are offered optimal support to lose weight. (See 'Weight loss' above.) - Topical analgesics – For patients with mild OA localized to the knee or with concomitant hand involvement and persistent pain, we suggest initial treatment with a topical nonsteroidal anti- inflammatory drug (NSAID) rather than an oral NSAID (Grade 2C). The risk of gastrointestinal, kidney, and cardiovascular toxicity is much lower with topical NSAIDs as compared with its oral formulation due to the reduced systemic absorption. (See 'Topical NSAIDs' above.) For patients with mild OA localized to the knee or a few other joints in whom other treatments are ineffective or contraindicated, we suggest topical capsaicin (Grade 2C). (See 'Topical capsaicin' above.) Moderate/severe knee OA – Patients with moderate to severe OA have persistent pain which significantly impairs functionality, activity participation, and quality of life. Nonpharmacologic interventions are also first-line therapy, but other treatment alternatives are usually required, including oral NSAIDs, intra- articular glucocorticoids, duloxetine, and possibly surgery ( algorithm 2). The management of moderate to severe knee OA is discussed in detail separately. (See "Management of moderate to severe knee osteoarthritis".) Knee OA with additional joints involved – The best approach for management of patients with multijoint, symptomatic OA is to prioritize therapies that address the pain at the individual level and not the joint level. (See 'Knee osteoarthritis with one or more joints involved' above.) Patient with comorbidities – Knee OA is often comorbid with other conditions (eg, cardiovascular disease, diabetes); therapies should be chosen to minimize the potential for adverse events while optimizing function and quality of life. (See 'Patients with comorbidities' above.) Therapies of uncertain benefit – There are several therapies for knee OA of unclear or unproven benefit that we do not routinely use due to lack of sufficient data. Some may be reasonable to try as adjunctive measures for patients who do not respond to usual therapy. These include: Insoles and footwear (see 'Insoles and other specialized footwear' above) Nutritional supplements (see 'Nutritional supplements' above) Opioids (see 'Oral therapies' above) Hyaluronans (see 'Hyaluronans' above) Platelet-rich plasma (PRP) (see 'Platelet-rich plasma' above) Acetaminophen (see 'Oral therapies' above) Transcutaneous electrical nerve stimulation (TENS) (see 'Transcutaneous electrical nerve stimulation' above) Acupuncture (see 'Acupuncture' above) Local heat (see 'Local heat and cold' above) Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Eckstein F, Hochberg MC, Guehring H, et al. Long-term structural and symptomatic effects of intra-articular sprifermin in patients with knee osteoarthritis: 5-year results from the FORWARD study. Ann Rheum Dis 2021; 80:1062. 2. Conaghan PG, Bowes MA, Kingsbury SR, et al. Disease-Modifying Effects of a Novel Cathepsin K Inhibitor in Osteoarthritis: A Randomized Controlled Trial. Ann Intern Med 2020; 172:86. 3. Sakellariou G, Conaghan PG, Zhang W, et al. EULAR recommendations for the use of imaging in the clinical management of peripheral joint osteoarthritis. Ann Rheum Dis 2017; 76:1484. 4. Marszalek J, Price LL, Harvey WF, et al. Outcome Expectations and Osteoarthritis: Association of Perceived Benefits of Exercise With Self-Efficacy and Depression. Arthritis Care Res (Hoboken) 2017; 69:491. 5. Fernandes L, Hagen KB, Bijlsma JW, et al. EULAR recommendations for the non-pharmacological core management of hip and knee osteoarthritis. Ann Rheum Dis 2013; 72:1125. 6. Kolasinski SL, Neogi T, Hochberg MC, et al. 2019 American College of Rheumatology/Arthritis Foundation Guideline for the Management of Osteoarthritis of the Hand, Hip, and Knee. Arthritis Rheumatol 2020; 72:220. 7. Bannuru RR, Osani MC, Vaysbrot EE, et al. OARSI guidelines for the non-surgical management of knee, hip, and polyarticular osteoarthritis. Osteoarthritis Cartilage 2019; 27:1578. 8. Wood G, Neilson J, Cottrell E, et al. Osteoarthritis in people over 16: diagnosis and management-updated summary of NICE guidance. BMJ 2023; 380:24. 9. Rausch Osthoff AK, Niedermann K, Braun J, et al. 2018 EULAR recommendations for physical activity in people with inflammatory arthritis and osteoarthritis. Ann Rheum Dis 2018; 77:1251. 10. Losina E, Weinstein AM, Reichmann WM, et al. Lifetime risk and age at diagnosis of symptomatic knee osteoarthritis in the US. Arthritis Care Res (Hoboken) 2013; 65:703. 11. Allen KD, Thoma LM, Golightly YM. Epidemiology of osteoarthritis. Osteoarthritis Cartilage 2022; 30:184. 12. Conley B, Bunzli S, Bullen J, et al. Core Recommendations for Osteoarthritis Care: A Systematic Review of Clinical Practice Guidelines. Arthritis Care Res (Hoboken) 2023; 75:1897. 13. Holden MA, Metcalf B, Lawford BJ, et al. Recommendations for the delivery of therapeutic exercise for people with knee and/or hip osteoarthritis. An international consensus study from the OARSI Rehabilitation Discussion Group. Osteoarthritis Cartilage 2023; 31:386. 14. Fransen M, McConnell S, Harmer AR, et al. Exercise for osteoarthritis of the knee: a Cochrane systematic review. Br J Sports Med 2015; 49:1554. 15. Holden MA, Hattle M, Runhaar J, et al. Moderators of the effect of therapeutic exercise for knee and hip osteoarthritis: a systematic review and individual participant data meta-analysis. Lancet Rheumatol 2023; 5:e386.  16. Bandak E, Christensen R, Overgaard A, et al. Exercise and education versus saline injections for knee osteoarthritis: a randomised controlled equivalence trial. Ann Rheum Dis 2022; 81:537. 17. Weng Q, Goh SL, Wu J, et al. Comparative efficacy of exercise therapy and oral non-steroidal anti-inflammatory drugs and paracetamol for knee or hip osteoarthritis: a network meta-analysis of randomised controlled trials. Br J Sports Med 2023; 57:990. 18. Quicke JG, Foster NE, Thomas MJ, Holden MA. Is long-term physical activity safe for older adults with knee pain?: a systematic review. Osteoarthritis Cartilage 2015; 23:1445. 19. Bricca A, Juhl CB, Steultjens M, et al. Impact of exercise on articular cartilage in people at risk of, or with established, knee osteoarthritis: a systematic review of randomised controlled trials. Br J Sports Med 2019; 53:940. 20. Uthman OA, van der Windt DA, Jordan JL, et al. Exercise for lower limb osteoarthritis: systematic review incorporating trial sequential analysis and network meta-analysis. Br J Sports Med 2014; 48:1579. 21. Juhl C, Christensen R, Roos EM, et al. Impact of exercise type and dose on pain and disability in knee osteoarthritis: a systematic review and meta-regression analysis of randomized controlled trials. Arthritis Rheumatol 2014; 66:622. 22. Holden MA, Button K, Collins NJ, et al. Guidance for Implementing Best Practice Therapeutic Exercise for Patients With Knee and Hip Osteoarthritis: What Does the Current Evidence Base Tell Us? Arthritis Care Res (Hoboken) 2021; 73:1746. 23. Nelson AE, Allen KD, Golightly YM, et al. A systematic review of recommendations and guidelines for the management of osteoarthritis: The chronic osteoarthritis management initiative of the U.S. bone and joint initiative. Semin Arthritis Rheum 2014; 43:701. 24. Hunter DJ, Harvey W, Gross KD, et al. A randomized trial of patellofemoral bracing for treatment of patellofemoral osteoarthritis. Osteoarthritis Cartilage 2011; 19:792. 25. Khan MCM, O'Donovan J, Charlton JM, et al. The Influence of Running on Lower Limb Cartilage: A Systematic Review and Meta-analysis. Sports Med 2022; 52:55. 26. Timmins KA, Leech RD, Batt ME, Edwards KL. Running and Knee Osteoarthritis: A Systematic Review and Meta- analysis. Am J Sports Med 2017; 45:1447. 27. Bartels EM, Juhl CB, Christensen R, et al. Aquatic exercise for the treatment of knee and hip osteoarthritis. Cochrane Database Syst Rev 2016; 3:CD005523. 28. Yan JH, Gu WJ, Sun J, et al. Efficacy of Tai Chi on pain, stiffness and function in patients with osteoarthritis: a meta-analysis. PLoS One 2013; 8:e61672. 29. Wang C, Schmid CH, Iversen MD, et al. Comparative Effectiveness of Tai Chi Versus Physical Therapy for Knee Osteoarthritis: A Randomized Trial. Ann Intern Med 2016; 165:77. 30. Mat S, Tan MP, Kamaruzzaman SB, Ng CT. Physical therapies for improving balance and reducing falls risk in osteoarthritis of the knee: a systematic review. Age Ageing 2015; 44:16. 31. Lauche R, Hunter DJ, Adams J, Cramer H. Yoga for Osteoarthritis: a Systematic Review and Meta-analysis. Curr Rheumatol Rep 2019; 21:47. 32. Torstensen TA, Østerås H, LoMartire R, et al. High- Versus Low-Dose Exercise Therapy for Knee Osteoarthritis : A Randomized Controlled Multicenter Trial. Ann Intern Med 2023; 176:154. 33. Messier SP, Mihalko SL, Beavers DP, et al. Effect of High-Intensity Strength Training on Knee Pain and Knee Joint Compressive Forces Among Adults With Knee Osteoarthritis: The START Randomized Clinical Trial. JAMA 2021; 325:646. 34. de Zwart AH, Dekker J, Roorda LD, et al. High-intensity versus low-intensity resistance training in patients with knee osteoarthritis: A randomized controlled trial. Clin Rehabil 2022; 36:952. 35. Dunlop DD, Song J, Lee J, et al. Physical Activity Minimum Threshold Predicting Improved Function in Adults With Lower-Extremity Symptoms. Arthritis Care Res (Hoboken) 2017; 69:475. 36. White DK, Tudor-Locke C, Zhang Y, et al. Daily walking and the risk of incident functional limitation in knee osteoarthritis: an observational study. Arthritis Care Res (Hoboken) 2014; 66:1328. 37. Pisters MF, Veenhof C, van Meeteren NL, et al. Long-term effectiveness of exercise therapy in patients with osteoarthritis of the hip or knee: a systematic review. Arthritis Rheum 2007; 57:1245. 38. Nelligan RK, Hinman RS, Kasza J, et al. Effects of a Self-directed Web-Based Strengthening Exercise and Physical Activity Program Supported by Automated Text Messages for People With Knee Osteoarthritis: A Randomized Clinical Trial. JAMA Intern Med 2021; 181:776. 39. Allen KD, Woolson S, Hoenig HM, et al. Stepped Exercise Program for Patients With Knee Osteoarthritis : A Randomized Controlled Trial. Ann Intern Med 2021; 174:298. 40. Bennell KL, Lawford BJ, Keating C, et al. Comparing Video-Based, Telehealth-Delivered Exercise and Weight Loss Programs With Online Education on Outcomes of Knee Osteoarthritis : A Randomized Trial. Ann Intern Med 2022; 175:198. 41. Bennell KL, Schwartz S, Teo PL, et al. Effectiveness of an Unsupervised Online Yoga Program on Pain and Function in People With Knee Osteoarthritis : A Randomized Clinical Trial. Ann Intern Med 2022; 175:1345. 42. Joseph GB, McCulloch CE, Nevitt MC, et al. Effects of Weight Change on Knee and Hip Radiographic Measurements and Pain Over Four Years: Data From the Osteoarthritis Initiative. Arthritis Care Res (Hoboken) 2023; 75:860. 43. Riddle DL, Stratford PW. Body weight changes and corresponding changes in pain and function in persons with symptomatic knee osteoarthritis: a cohort study. Arthritis Care Res (Hoboken) 2013; 65:15. 44. Messier SP, Resnik AE, Beavers DP, et al. Intentional Weight Loss in Overweight and Obese Patients With Knee Osteoarthritis: Is More Better? Arthritis Care Res (Hoboken) 2018; 70:1569. 45. Christensen R, Bartels EM, Astrup A, Bliddal H. Effect of weight reduction in obese patients diagnosed with knee osteoarthritis: a systematic review and meta-analysis. Ann Rheum Dis 2007; 66:433. 46. Shahid A, Thirumaran AJ, Christensen R, et al. Comparison of weight loss interventions in overweight and obese adults with knee osteoarthritis: A systematic review and network meta-analysis of randomized trials. Osteoarthritis Cartilage 2024. 47. Gómez R, Conde J, Scotece M, et al. What's new in our understanding of the role of adipokines in rheumatic diseases? Nat Rev Rheumatol 2011; 7:528. 48. de Boer TN, van Spil WE, Huisman AM, et al. Serum adipokines in osteoarthritis; comparison with controls and relationship with local parameters of synovial inflammation and cartilage damage. Osteoarthritis Cartilage 2012; 20:846. 49. Chu IJH, Lim AYT, Ng CLW. Effects of meaningful weight loss beyond symptomatic relief in adults with knee osteoarthritis and obesity: a systematic review and meta-analysis. Obes Rev 2018; 19:1597. 50. Kopp PT, Yang C, Yang H, et al. Cost-Effectiveness of Community-Based Diet and Exercise for Patients with Knee Osteoarthritis and Obesity or Overweight. Arthritis Care Res (Hoboken) 2024; 76:1018. 51. Hall M, Castelein B, Wittoek R, et al. Diet-induced weight loss alon