INTRODUCTION — 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".)
●(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 osteoarthritis (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 osteoarthritis (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 osteoarthritis (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 — Nonpharmacologic therapies alone, focusing on education, exercise, and weight management, or in combination with topical therapies or analgesics on an as-needed basis are likely to provide adequate control of symptoms in this group of patients (algorithm 1).
Moderate/severe knee osteoarthritis — Nonpharmacologic interventions 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 — Nonpharmacologic interventions are the cornerstone of knee osteoarthritis (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 nonpharmacologic measures — Nonpharmacologic interventions in the management of patients with mild OA includes exercise and, when pertinent, weight loss.
Exercise — In all patients with knee OA, we recommend ongoing regular exercise for pain relief, functional improvement, and joint protection. Exercise, alongside weight loss when indicated, is a core component of knee OA management . All 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, among which 19 were considered as "low risk of bias," concluded that there is moderate- to high-quality evidence suggesting that land-based exercise improves knee pain and function with moderate effect size immediately after treatment . This magnitude of effect is comparable with that reported for oral nonsteroidal anti-inflammatory drugs (NSAIDs) and acetaminophen, as confirmed in a network meta-analysis of 152 randomized clinical trials in knee and hip OA . Research has also shown that exercise is safe [16,17] 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 [19,20], 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 patient's mobility, specific impairments (eg, strength, range of motion, aerobic fitness, and balance), and preferences . Exercises involving high impact on the joints such as running or jumping are usually discouraged in order to avoid further joint damage, especially in cases of more advanced OA, although research evidence demonstrating an association between running and progression of knee OA is scarce . For those patients who already run or jog for exercise and develop mild symptoms of OA but wish to continue running, we advocate a load management approach with attention paid to factors such as rest days, running surface, distance and 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 [26,27]. 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 [31,32]. 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 [36-38]. 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 — Because of the substantial load placed on the knees during weightbearing activities, maintaining an ideal body weight may help preserve joint structures and improve symptoms. 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 [40,41]. Obesity is a common comorbidity with knee OA, thus weight loss is also beneficial for overall health. (See "Pathogenesis of osteoarthritis" and "Comorbidities that impact management of osteoarthritis", section on 'Obesity'.)
We encourage health care professionals to consult 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 and to maintain weight loss over the longer term . (See "Obesity in adults: Overview of management".)
We recommend a combination of a calorie-restricted diet and physical activity for people with knee OA. This is supported by results of systematic reviews showing that combined interventions can lead to greater weight loss and improved pain and function in people with knee OA compared with minimal care [43,44].
Weight loss strategies — There are a variety of ways to achieve weight loss, varying in their content, delivery methods, duration, and providers, although these have not been well studied in knee OA. There is some evidence to suggest that interventions involving very low calorie diets with meal replacements are more effective for weight loss and improving physical function than lifestyle interventions in people with OA . However, the mode of nutrition, particularly the role of protein intake, in influencing weight, body composition, muscle strength, and functional outcomes in knee OA is not clear . Telehealth can be an effective, safe, and convenient option for delivery of a diet program. A study showed that a very low calorie diet supervised by a dietitian via six videoconferencing sessions over six months combined with a physical therapist-supervised exercise program led to an approximate 8 percent loss of body weight together with small improvements in pain and function compared with the exercise program alone .
Caloric restriction, particularly in older adults, may contribute to loss of lean mass and lead to muscle weakness and should, therefore, be combined with strengthening exercises to prevent these adverse effects. Other interventions such as anti-obesity drugs (eg, orlistat) and surgical approaches (eg, gastric bypass) are less well studied in the context of OA. (See "Obesity in adults: Overview of management".)
Weight loss efficacy — Weight loss does not necessarily lead to large improvements in symptoms. In a pragmatic randomized trial of 823 patients with obesity or overweight status as well as knee OA, a community-delivered diet and exercise strategy resulted in more weight loss compared with group education meetings on health and nutrition (-7.7 versus -1.7 kg). The greater weight loss, however, was associated with only a small difference in pain reduction between the two groups (Western Ontario and McMaster Universities Osteoarthritis Index [WOMAC] knee pain score 5.0 versus 5.5 out of a scale of 10) . Analysis of observational data from the Osteoarthritis Initiative demonstrated that weight loss of at least 5 percent was associated with knee pain resolution over four years (odds ratio [OR] 1.34, 95% CI 1.08-1.67), but not hip pain resolution . The additional benefits of combining diet and exercise compared with exercise alone on pain and function have also been shown to be modest [38,44].
In other studies, a dose-response relationship between the extent of percentage change in body weight and improvement in joint symptoms has been demonstrated, with more robust effects achieved when at least a 10 percent reduction in body weight is attained [49,50]. A reasonable initial target is a 5 to 10 percent weight reduction within a six-month period , and initial goals should be reassessed periodically and individually for each patient.
Inadequate response to nonpharmacologic measures — Pharmacologic therapy can be started in combination with or after a trial of nonpharmacologic interventions, 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 capsaicin, however, is less tolerated by patients due to the relatively high frequency of local side effects, including a local burning sensation. We do not use topical salicylates in our patients with OA.
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 about 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, renal, 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) [54-56]. 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 methodological 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 physician's 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 osteoarthritis (OA) is discussed in detail separately. (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 osteoarthritis (OA) that we generally do not recommend due to lack of sufficient evidence. These approaches 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 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.
Acetaminophen — Due to safety concerns pertaining to acetaminophen (paracetamol) use and an increased awareness of its negligible and non-clinically significant effects on pain [7,62-65], we do not initiate treatment with acetaminophen for knee OA in our clinical practice. Data from a meta-analysis including 10 trials (3541 patients) revealed that there is high-quality evidence that paracetamol has only small, non-clinically meaningful benefits for pain in the short term . This finding was further strengthened by a network meta-analysis comparing different analgesics for the treatment of OA pain, which demonstrated that paracetamol was not superior when compared with placebo irrespective of the dose (4 mm difference on a 0 to 100 mm visual analogue scale [VAS]) . The risk of harm of acetaminophen is usually higher with increasing dose but may also occur at doses within the therapeutic range, including gastrointestinal bleeding, liver toxicity, renal failure, and cardiovascular disease . This is especially concerning due to the risk of unintentional overdose, as paracetamol is frequently combined with other common over-the-counter medications used to treat pain and cold symptoms.
Opioids — Due to the relatively high incidence of side effects such as drowsiness, dizziness, and nausea, and the potential to cause harm with long-term use, we avoid using opioids whenever possible, especially in the older adult population. In our clinical practice, we use opioids only in patients with severe pain awaiting joint replacement (ie, short-term use). We use it in the lowest dose and duration necessary to control symptoms and monitor common side effects. (See "Use of opioids in the management of chronic non-cancer pain".)
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 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 the benefits 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 . A meta-analysis of 6 trials representing 3611 patients with knee or hip OA demonstrated that tramadol provides 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 -0.47-0.03) .
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.
Despite these observations, high numbers of patients continued to be prescribed opiates, reflecting a need for more effective treatment alternatives. Among Medicare beneficiaries with knee OA, 9 percent used opioids chronically and 21 percent used opioids occasionally . Non-Hispanic ethnicity, divorced status, depression, Medicaid eligibility, chronic obstructive pulmonary disease, and inability to walk without assistive devices were all independently associated with chronic opioid use.
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 [6,7,72,73]. 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 [74-76]. 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 [77,79]. 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 [81,82]. 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 [85-89]. 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 and Boswellia serrata – Interest in the use of curcumin, commonly known as turmeric, and Boswellia serrata is largely based on limited data suggesting that these agents have anti-inflammatory and analgesic properties, among others . This is largely based on evidence from small studies showing benefit and no evidence of increased risk of side effects compared with placebo [92,93]. 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).
Data supporting the use of curcumin come from randomized trials and meta-analyses [92,93]. As an example, a trial including 70 adults with painful knee OA with ultrasound-confirmed effusion synovitis randomly assigned patients to receive Curcuma longa capsules (1000 mg daily) or placebo . After 12 weeks, patients who received Curcuma longa had a greater reduction in pain as measured by both a VAS (-9.1 mm [95% CI, -17.8 to -0.4 mm]) and WOMAC knee pain scale (-47.2 mm [CI, -81.2 to -13.2 mm]). Although the reduction in pain measures were statistically significant, 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.
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.
●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 [96-99]. 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) [100,101].
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 (BMI), 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 [6,7,72].
●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 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.
Limited evidence has also suggested that phytoflavonoids, a class of natural compounds with anti-inflammatory properties, may have beneficial effects on knee OA symptoms [107-109]. 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 [110,112].
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 [113-115]. 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.)
●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 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. Nonpharmacologic therapies alone or in combination with topical analgesics as needed can provide adequate control of symptoms (algorithm 1). (See 'Mild knee osteoarthritis' above.)
-Nonpharmacologic initial treatment (exercise and weight loss) – For all patients with knee OA, we recommend 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 dosage (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 NSAID rather than an oral NSAID (Grade 2C). The risk of gastrointestinal, renal, 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 nonsteroidal anti-inflammatory drugs (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 'Opioids' above)
•Hyaluronans (see 'Hyaluronans' above)
•Platelet-rich plasma (PRP) (see 'Platelet-rich plasma' above)
•Transcutaneous electrical nerve stimulation (TENS) (see 'Transcutaneous electrical nerve stimulation' above)
•Acupuncture (see 'Acupuncture' above)
•Local heat (see 'Local heat and cold' above)
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