Losing weight yields a decrease of the pressure on the knee joint, improving physical function and biomechanics, combined with exercise. Research on biomechanics highlighted that a decrease in weight of 1 kg produces quadruple reduction of the forces acting on the knee (11). For subjects exhibiting OA symptoms, an amelioration of the symptoms has often been observed through weight loss only. Physical exercise decreased pain load [95% confidence interval (CI) of 10 to 15; 12 points/100], ameliorated the quality of life and enhanced physical function (95% CI of 8 to 13; 10 points/100) as revealed by a meta-analysis of 44 randomized controlled trials (RCTs) that evaluated routine exercise programs, land-based, against no exercise program (12). Weight loss is favored by exercise and diet. An extended RCT indicated a 4.9% loss of total body weight in nutrition intervention and 5.7% body weight decrease with a program including diet and exercise for 18 months, in subjects with arthritis (13). Cardiovascular wellbeing and weight loss are stimulated through aerobic exercise (elliptical training or swimming) concurrently protecting the damaged joint areas (12).

The most affected part of the knee joint in knee OA is the mid-section. The effectiveness of unloader knee braces in knee OA has been demonstrated by published data and in spite of the fact that 92% of these studies recommended their use, 94% of total research was not randomized or according to advisory opinion (12-14). A thorough analysis of six RCTs that compared the impact of applying a medial unloader knee brace in treating mid-section arthritis with that of a control orthosis, revealed a minor statistically significant advantage supporting the brace in pain release (95% CI of 0.13 to 0.52; standard mean difference (SMD) 0.22. Due to poor evidence, these results have uncertain clinical significance (15).

Treatment with physical strengthening exercises has as an effect, improvement of leg muscle activities particularly the quadriceps, decreasing load and knee joint stress in movement (16). A number of 26 RCTs evaluating different programs of strengthening work at the onset of knee OA were systematically reviewed and revealed moderate amelioration of physical function, pain and wellbeing (17).

Several types of analgesics are used in therapy, their selection depending on multiple factors. Nonsteroidal anti-inflammatory drugs (NSAIDs) are a heterogenous group of substances, chemically unrelated, that have similar therapeutic activities and side effects. In treating OA, NSAIDS administered orally are most frequently indicated, being prescribed to 65% of OA subjects in the US (18). The efficiency of various doses and formulations of nonsteroidal anti-inflammatory medications used in 74 RCTs to relieve OA pain was evaluated in a previous network meta-analysis, revealing diclofenac 150 mg/day as the most efficient treatment for pain relief and physical condition improvement (19). Nevertheless, there are serious cardiovascular, gastrointestinal, and renal risks in oral intake of nonsteroidal anti-inflammatory medications. Daily intake of nonsteroidal anti-inflammatory medications revealed a 4-fold increase in the risk of upper gastrointestinal bleeding, in a 280-RCT meta-analysis, showing a major growth of vascular events by one third when administering a Cox-II inhibitor (20,21). Due to their lower risk compared with oral preparations, topical NSAIDs are widely used for relieving OA pain (22). The use of topical agents is recommended by several guidelines and systematic reviews and meta-analyses indicate ketoprofen and diclofenac topical formulations to be helpful in knee OA therapy (23).

Cox-I and Cox-II are suppressed by nonspecific Cox-inhibitors (diclofenac, ibuprofen, aspirin and meloxicam) with minor selectivity in reducing prostaglandin synthesis. With high affinity for Cox-II, the selective Cox-II inhibitors (rofecoxib, celecoxib and valdecoxib) were approved due to their superior side effect profile, in gastrointestinal endoscopic trials. Compared with other NSAIDs they present reduced side effects with regard to the gastrointestinal tract and were demonstrated to be efficient in reducing OA pain. Relevant data indicate the use of NSAIDs in OA therapy, with efficient results, consistent with high-standard patient-focused evidence. However, there are adverse reactions in the renal, gastrointestinal, and cardiovascular systems that may question the use of NSAIDs in OA treatment. The literature recommends using paracetamol for level A OA, however in relieving pain NSAIDs are more efficient (24).

The efficiency and safety of opioid oral therapy gives rise to concerns. Opioids as well as nonsteroidal anti-inflammatory medicines have similar action in relieving pain in OA patients (23). Medicines obtained from opium, opiates, comprise natural products including codeine, morphine, and several semi-synthetic compounds. Opioids trigger pain control circuits from the midbrain through the rostral ventromedial medullary tract towards the spinal cord dorsal horn and restrain the transfer of nociceptive information from the spinal cord dorsal horn, thus presenting analgesic action. Opiates are categorized as follows: short-acting opioids, long-acting opioids, and partial agonists. All aforementioned categories proved efficient in relieving pain and are supported by level 3 evidence. Nevertheless, their analgesic effect is limited, these drugs producing frequent side effects, severe in certain cases with long term use. Continuous daily intake of opioid analgesics produces tolerance and physical dependence to certain extent (25).

A novel and encouraging option used to trigger injured cartilage regeneration is considered platelet-rich plasma (PRP). PRP, autologous agglomeration of human platelets in a small pool of plasma, comprises several growth factors secreted by platelets, favoring mesenchymal tissue healing. It is helpful in the therapy of articular cartilage degenerative lesions and OA. The efficiency of several types of intraarticular injections for knee OA has been evaluated in numerous studies. Corticosteroids and hyaluronic acid (HA) efficiency in treating painful knee OA was evaluated in systematic research by Rodriguez-Merchan. HA was demonstrated to be more efficient than corticosteroids in reducing pain, as 3-5 weeks of injections with HA had a pain alleviating effect duration of 5-13 weeks while corticosteroids had a pain alleviating effect duration of only 2-3 weeks (26). Randomized clinical research conducted by Raeissadat et al compared the long-term effect of intra-articular PRP and HA injections on the clinical results and the wellbeing of patients suffering from knee OA. After 12 months, both groups exhibited significantly improved bodily pain and WOMAC pain score; the PRP group exhibiting better results than the HA group (P<0.001) particularly in Kellgren stages 1 and 2. The study revealed the higher efficiency of PRP in alleviating pain in patients suffering from OA (27).

Stem cells are used in sustaining the self-healing process of damaged knee joint cartilage affected by OA. Mesenchymal stem cells (MSC) that split into chondrocytes are present in the joint fluid. The stem cell therapy consists of harvesting PRP and MSC from the patient receiving medical treatment. In order to increase cartilage, buildup MSC are separated through centrifugation and other purification steps included in the process. The existent clinical data on the stem cell therapy efficiency compared with pharmacological therapy for OA are insufficient. Taking into account the current stage of clinical trials concerning autologous stem cell therapy for knee OA, there are concerns about dosing, type of MSC, timing of intervention, mode and route of MSC delivery in clinical trials (28).

Knee debridement and lavage (rough cartilage shaving or smoothening of the damaged meniscus) are arthroscopic techniques. Theoretically, OA arthroscopy alleviates symptoms eliminating debris as well as inflammatory cytokines that generate synovitis (29,30). Loose cartilage flaps and torn meniscal parts are eliminated through debridement. The efficiency of arthroscopy in knee OA therapy is questionable (31). There is little evidence for the beneficial results of arthroscopy, although it is extensively used. Moseley et al compared arthroscopic lavage and debridement with sham surgery in a controlled trial and the arthroscopic techniques exhibited no advantage over the sham surgery (32,33). The patient selection prior to knee arthroscopy was considered significant by Dervin et al. Patients with obvious meniscus damage or cartilage flaps may be candidates for surgery (34).

In another study, arthroscopic debridement was demonstrated to temporary reduce symptoms for middle-aged patients with knee OA (35). There was an increased potential for amelioration in those patients with less advanced arthritis (as evidenced by radiography, less damage to the articular cartilage, and younger age at surgery) (36). Surgery exhibited improved results including short duration of pain and mechanical symptoms and mild to moderate radiographic phases of arthritis (37).

In the therapy of unicompartmental OA associated with varus or valgus deformation, the agreed method consists of osteotomies around the knee. This is a procedure used at the beginning of the 19th century (38). Moreover, already frequently performed at the beginning of the 20th century, osteotomies gained recognition following the findings of Gariépy, Jackson, Coventry, Waugh and others, published in the late 1950s and 1960s (39-42). In unicompartmental knee OA, osteotomy became a standard therapy alternative. The Coventry typical osteotomy consisted of closed-wedge valgization, comprising a fibula osteotomy performed near the tibial tuberosity (42). The choice of open-wedge osteotomy without applying bone graft, with no damage risk for the peroneal nerve as well as development of new plates (particularly angular stability plates) determined the orientation towards osteotomy around the knee in the last decade, particularly for younger subjects (43,44). The weightbearing axis of the lower extremity is modified through osteotomies around the knee (45). The affected section is relieved, the weight load being transferred from the damaged area through moderately overcorrecting a varus or valgus axis to alleviate pain and delay the degenerative process and joint replacement (46,47).

Adequate patient selection as well as proper evaluation of all three knee sections are essential for a favorable postoperative outcome (48,49).

For the treatment of knee OA, joint arthroplasty is considered to be safe, well-accepted, and also cost-effective. Due to the irreversibility of the procedure, undergoing a joint arthroplasty procedure is advisable only in cases in which different treatment procedures are contraindicated or have failed. The prosthetic components last ~15-20 years whereas the durability of unicompartmental arthroplasties is usually shorter. Considering this aspect, in patients younger than 60, arthroplasties should be avoided if possible. Unloading osteotomy or unicompartmental knee arthroplasty (UKA) may be considered if OA is limited to a single compartment, however, in different situations, total knee arthroplasty (TKA) with or without patellar resurfacing is recommended.

Following the studies of Marmor, published in the 90s, considerable attention was directed towards UKA (50). When only one section of the knee, the patellofemoral, medial tibiofemoral or lateral compartment, is affected by OA, UKA is recommended. Throughout the most frequent UKA, the medial tibiofemoral section is replaced with two metallic prosthetic devices, and a polyethylene inlay is inserted between them. A lateral compartment kept in good condition in relation to the cartilage and meniscus is the first requirement for successful medial UKA (51). The stability of the prosthesis is conditioned by the intact cruciate ligaments, the implant not being restricted in the sagittal plane (52).

Significant malalignment of the member represents a contraindication. The progression of OA and persisting manifestations may be determined by overcorrection of the contralateral section, which has to be prevented (53). Similarly, clinical inefficiency of the UKA as well as increased probability of revision are linked to under correction (54). A less invasive surgical method is among the benefits of UKA (55). The extensor system is not deteriorated, and the patella is not everted, allowing a faster recovery and earlier release from hospital. It maintains the bone stock, increased physiological function and regular knee kinematics (56). The result and survival associated to medial UKA have been enhanced by using modern surgical methods and implants (55). The durability of the medial UKA is ~10 years fluctuating significantly from 80.2 to 98% (57,58).

TKA has demonstrated significant effectiveness in the therapy of advanced knee OA, involving several compartments, when usual therapies fail, having as an outcome consistent amelioration in the patient mobility and quality of life (59). At present, it is the first therapy option for end-phase knee OA. Survival rates of up to 98% at 15 years were highlighted as the long-term outcome of TKA (60). Survival rates <76% at 10 years were frequently observed for younger subjects (61). Although TKA is efficient in the therapy of end-phase knee OA, postsurgical pain appears or lasts in one out of eight patients; however, they do not exhibit radiological or clinical malfunctions (62). Infections, femoropatellar problems, stiffness of the knee and loosening of components represent the most serious complications. The comorbidities of patients influence the condition of the knee and the total freedom of movement following surgery (63). Understanding the complications has allowed the treatment to be substantially improved. Subjective factors (related to the patient) in the evaluation of TKA results have proven their importance, and are necessary to consider when patients are advised before TKA. The femoropatellar joint represents a main problem in persistent postoperative pain. Patella resurfacing has not demonstrated efficiency, and the options for using patella resurfacing have not been clearly determined (64,65). The initial noninfectious recommendations for TKA revision continue to be issues concerning the femoropatellar joint and the extensor mechanism (66). To enhance the results of total knee replacement, in the last few years, improved strategies have been developed, under the influence of or related to occasionally disappointing results. The strategies aforementioned include development of the implant design (anatomic and biomechanical), improvement of the fixation technique, minimally invasive surgery (MIS), intraoperative control with computer-assisted surgery (CAS), and improved instrumentation (67).