Lifestyle and physical therapyWeight management

This represents one of core treatments for knee OA, in combination with exercise and self-management programmes. SIOT strongly recommended core treatment in early onset OA and in mild/moderate OA, as well as in severe cases. Weight loss is considered to be effective in those who are overweight [body mass index (BMI) ≥ 25 kg/m2) or obese (BMI ≥ 30 kg/m2). Specifically, loss of ≥ 5% of body weight can be associated with changes in clinical and functional outcomes [4].

Self-management and education

SIOT consider self-management and education one of the core treatments together with weigh management and exercises. Structured patient education programmes aim to inform patients about their condition and the available treatment strategies, to reduce the likelihood of disease progression and severity. Awareness regarding OA aetiology, risk factors (especially if modifiable), expected prognosis and therapeutic strategies can help to reduce misunderstandings and mistakes in patients (for example, the misconception that physical exercise can be harmful to the joints). Education of family members can also be useful. Self-management and education are also strongly recommended by the OARSI [9], EULAR [2], AAOS [5, 6] and ESCEO [8].

Balneotherapy/spa therapy

Balneotherapy represents a conservative treatment that may have beneficial effects on pain and stiffness, with a tolerable economic profile [10]. It consists of the use of thermal waters that are therapeutically active by virtue of mineral composition, mud and natural gas. In numerous papers, balneotherapy is described as a treatment with favourable results [11, 12]. SIOT moderately recommend the use in mild OA.

Canes, walking sticks, crutches, walkers

Depending on the severity of the disease and the needs of each patient, these devices can aid walking, significantly reducing the load on the lower limbs, improving stability and assisting movement. The risk of falls also appears to be reduced [4, 11]. Walking assist devices are strongly recommended in patients with symptomatic knee OA.

Exercise (land and water based)

For individuals with knee OA, the types of exercises performed on land include muscle strengthening, aerobic stretching and neuromuscular balance exercises, and more. [13] However, most importantly, any proposed programme should be based on patient needs [8, 9]. Water offers natural resistance, which helps strengthen muscles [14, 15]; evidence shows that exercise in water provides improvements in pain and quality of life in people who are unable to perform land-based exercise due to pain. SIOT consider land and/or aquatic exercise one of core treatments together with weight loss and self-management and education.

Pulsed electromagnetic field therapy (PEMT).

Evidence that PEMT significantly improves pain and function in people with knee OA is low in quality due to the short-term nature of the follow-ups described in the literature [16]. Thus, further studies with long-term follow-ups should be performed. Cardiovascular deficiencies, blood sugar levels disorders, blood coagulation diseases and anti-coagulant therapies are relative contraindications in PEMF treatment [5, 17]. There is a lack of consensus in literature about duration, frequency, and intensity of PEMF therapy sessions [18].

Nevertheless, PEMT has proved therapeutically effective for bone- and cartilage-related pathologies and can be used to reduce pain and stiffness [19].

PEMT may be used to improve pain and/or function in patients with mild knee OA [20]; therefore, the SIOT recommendation is moderate.

Bisphosphonate

Bisphosphonates are anti-resorptive agents (currently used in the treatment of osteoporosis). They represent a potential candidate for osteoarthritis therapy [21, 22]. Results from evidences using bisphosphonates in OA have been encouraging but controversial: some studies suggest neridronate is effective in OA treatment [23], while others contend that clodronate could play a role as a disease-modifying drug. OARSI is weakly favourable to risedronato due to the few studies in literature supporting its application as a reducer of the marker of cartilage degradation (CTX-II) which may contribute to slow the radiological progression of OA, particularly in patients who are not overweight [24, 25]. On the other side, AAOS and ACR do not recommend their use [5, 26]. Limitations of the studies included differences in the bisphosphonate analysed, the dose and the route of administration [27]. Future studies are needed: SIOT recommendation on their use is inconclusive.

Oxygen–ozone therapy (O3 therapy)

Ozone is known for its anti-inflammation effect and its work on cellular metabolism [28]. In knee OA, O3 therapy is described as a safe approach with encouraging effects [29] with respect to pain control and functional recovery in the short-to-middle term [30], with an almost null adverse event rate [31] especially in combination with other treatments [28].It is contraindicated in patients with a significant deficit of G-6PD, in pregnancy, in case of hyperthyroidism, thrombocytopenia and serious cardio-vascular instability [32]. SIOT recommendation to its use in knee OA is limited.

Transcutaneous electrical nerve stimulation (TENS)

TENS uses a low-voltage electrical current delivered through electrodes attached to the patient’s skin to stimulate peripheral nerve activity (neuromodulation) [33,34,35]. TENS can be generally delivered at two different dosing, high frequency (50e100 Hz) and low frequency (2e10 Hz): the use of TENS is not recommended in people with pacemakers and women who are pregnant should not apply TENS in the abdominal or pelvic regions [5]. The literature on this is highly heterogeneous, and the available clinical trials are characterised by short follow-up periods. Thus, SIOT consider the available evidence insufficient to recommend this procedure [16].

First-line pharmacological treatment (management of acute symptoms)Acetaminophen (or paracetamol)

This is generally used to treat mild-to-moderate pain [36]. It is weakly recommended as an initial pharmacological approach in the presumption of its overall safety [8, 37]. However, while the OARSI recommends against its use in both the short and long term, the ESCEO and ACR make a weak recommendation for its use in the short term, and the AAOS strongly recommends its use [5, 5, 38]. SIOT moderately recommend acetaminophen at doses no greater than 3 g/day in mild/moderate OA if not contraindicated (in cases of hypersensitivity to acetaminophen, severe hepatic impairment or severe active liver disease) [5].

Topical non-steroidal anti-inflammatory drugs (NSAIDs).

Topical use of NSAIDs is recommended as first-line treatment, particularly in patients with comorbidities, owing to their proven efficacy and low risk of gastrointestinal (GI), cardiovascular or renal adverse events (OARSI, ACR, ESCEO, AAOS). Topical NSAIDs can be applied as gel, cream, spray or patch formulations to the skin of the affected area [4, 8]. SIOT strongly recommend their use in patients with comorbidities with symptomatic knee OA.

Second-line pharmacological treatment (management of persistent symptoms)Oral NSAIDs

Oral NSAIDs are strongly recommended for use in knee OA. They are more effective than acetaminophen in most people (OARSI, ACR, ESCEO, AAOS). The potential harms of NSAIDs are well known and include GI, renal and cardiovascular adverse effects. Elderly people, who are at higher risk of OA, are also at higher risk of experiencing these side effects. Therefore, these drugs should be used with caution in elderly patients [39].

SIOT recommends the use of non-selective NSAIDs, preferably with the addition of a proton pump inhibitor (PPI) or selective COX-2 inhibitors [40]. For individuals with GI comorbidities, selective COX-2 inhibitors and non-selective NSAIDs in combination with a PPI are conditionally recommended due to their benefits regarding pain. Doses should be as low as possible, and NSAID treatment should be continued for as short period as possible.

Third-line pharmacological treatment (management of refractory symptoms)Duloxetine (anti-depressant drug)

The analgesic efficacy of duloxetine in central pain is presumably due to its influence on the descending pathways of pain inhibition, it is contraindicated in patients with liver failure or severe renal dysfunction, uncontrolled angle-closure glaucoma and concurrent or recent therapy with monoamine oxidase (MAO).

The OARSI [3], ACR [4] and ESCEO [37, 41] recommend this drug in patients with knee OA and widespread pain and/or depression. The AAOS does not provide any recommendations on its use [5, 5] Evidence suggests that duloxetine presents with some tolerability issues, being associated with adverse events such as nausea, dry mouth, drowsiness, fatigue, constipation, decreased appetite and hyperhidrosis [4].

SIOT conditionally recommended duloxetine as the last line of pharmacological therapy in patients who are candidate for surgery treatment.

Opioids (oral)

Opioids can be appropriate for use if other therapies are ineffective or if feasible surgical options are lacking. The OARSI does not recommend opioid use in patients who have persistent symptoms over a long period of time, due to the risk for development of tolerance [38]. Therefore, they should only be used for short periods and as a last resort [3, 5, 6, 26] before considering switching to surgical treatment. SIOT recommend the use of oral opioids in short-term therapy in patients with refractory OA who are awaiting planned surgical treatment [11].

Opioids (transdermal)

In opioid-tolerant individuals, SIOT encourages the use of transdermal patch, rather than oral formulations. The indications are the same as for oral opioids: patients on the waiting list for surgery, with refractory symptoms. This formulation has delayed onset of effects but prolonged duration of action [26]. Application to the skin avoids first-pass hepatic metabolism, increasing bioavailability and limiting fluctuations in plasma concentration. However, the OARSI recommendations [3] discourage the use of opioids with transdermal patch formulation following poorly documented clinical benefits and the high risk of addiction and adverse events [11].

Diacerein and IL1-inhibition.

These drugs are a group of agents able to block the activity of a proinflammatory cytokine, IL-1, which is believed to play a role in inducing the degradation of cartilage matrix through the upregulation of proteolytic enzymes [38]. The ESCEO working group underline that the benefits of diacerein are more than its risks and confirms that it can be an option for knee OA treatment [42].

Diacerein should be avoided in patients with a propensity for diarrhoea and could be useful in patients with contraindications to NSAIDs [43].

However, SIOT do not recommend the use, due to its cost and limited benefits.

Chronic pharmacological treatmentsGlucosamine and chondroitin

Glucosamine and chondroitin are strongly recommended against for knee OA, even though they are commonly used in clinical practice. To date, the available studies are burdened by several discrepancies and biases. The OARSI and ACR, strongly recommend against the use of glucosamine and chondroitin, AOOS [5, 5] consider this therapy helpful in improving functional outcomes in patients with mild/moderate knee OA, and conversely, ESCEO [37] guidelines recommend these treatments as first-line therapy.

The SIOT recommendation to use glucosamine and chondroitin is weak, and is limited for individuals with chronic knee osteoarthritis [16]. According to data sheets, adults should take these supplements orally twice a year, for almost 2 months each day at doses of 1200 mg of glucosamine and chondroitin.

Allergies to shellfish, asthma or patients using warfarin or diabetes drugs are considered conditions that do not preclude the use of glucosamine, but individuals with these conditions should be closely monitored for any potential side effects including bloating, nausea, diarrhea and constipation [43].

Intra-articular injection treatments: first line (acute symptoms)Corticosteroids (intra-articular injection)

Intra-articular glucocorticoid injections are strongly recommended for patients with knee OA to relieve pain in the short term (2–4 weeks). However, clinicians should be cautious about the potential damage of repeated and long-term use (> 6 weeks) [44]. The AAOS provide a moderate recommendation for use, focusing on the risks associated with repeated injections, while other societies such as the OARSI, ACR and ESCEO recommend short-term treatment. SIOT encourage the use in patients with acute episodes of disease exacerbation once a week for not more than 3 weeks [45], even though literature did not generally provide insights into a recommended schedule for repeated injections. The repeated use of intra-articular glucocorticoids, particularly in mild-to-moderate stages of knee OA severity, may have negative effects, according to recent studies [46].

Absolute contraindications to the use of corticosteroid injections are infection, sepsis and bacteremia, and joint instability. Juxta-articular osteoporosis (because of the risk of subchondral osteonecrosis and weakening of the joint structures), coagulopathy and long-term therapy are relative contraindications [47].

Intra-articular injection treatments: first line (chronic therapy)Hyaluronic acid

Intra-articular hyaluronic acid (IAHA) shows a more favourable long-term safety profile [40] than intra-articular corticosteroids. However, according to the OARSI, ACR and AAOS, there is little evidence regarding effectiveness [3, 5, 26]. IAHA are ideal for patients who do not have adequate pain relief from oral medications (NSAID, acetaminophen), exercise and physical therapy, or patients with existing renal or gastrointestinal intolerance for NSAIDs [48].

There is no absolute contraindication of intra-articular injection of HA other than acute inflammation in the joint cavity, although the drug effect may be reduced in the following cases. It is prohibited for use in diseases such as extensive bone edema, bone fissure or stress necrosis on magnetic resonance imaging (MRI), and acute diseases such as gout [5] and scleroderma [49].

SIOT recommend IAHA once a week for 2–4 weeks, this treatment can be repeated after 12 months in patients without knee swelling or flares: low-molecular-weight hyaluronic acid is recommended for early/mild knee OA, while high-molecular-weight intra-articular hyaluronic acid is preferable in patient with severe OA who either are poor surgical candidates or must postpone total knee replacement [27,