osteoarthritis treatment

Treatment of osteoarthritis

    Non-pharmacological treatment
    Pharmacological treatment
    Non-steroidal anti-inflammatory drugs (NSAIDs)
    Topical medications
    Intra-articular drugs
    chondroprotecting
    Conclusions

Introduction
Osteoarthritis is one of the most common causes of pain and disability in the elderly1. This condition is characterized by damage of the articular cartilage with bone remodeling and in some cases by synovitis; in severe forms there is also a narrowing of the joint space, the formation of osteophytes and alteration of the subchondral bone1. Typical radiographic alterations are found in practically all subjects over the age of 60 but only in 10-20% of cases these alterations have clinical significance1. When symptomatic, osteoarthritis can cause joint pain, movement limitations, motor instability and disability. The disease tends to affect especially the knees, the spine, the coxofemoral joints, carpo-metacarpal, proximal and proximal interphalangeal joints and the first metacarpophalangeal. Its course is variable, being able to take on a chronic character or manifest itself with acute episodes sometimes self-limiting. Arthritic pain in a characteristic way worsens with loading and activity and improves with rest. At the clinical examination, the patient accuses the palpation of the articular rheumatism, and often articular crackling, swelling and limiting movements are detectable. Osteoarthritis is not curable and the goal of therapy is to improve quality of life by controlling pain, stiffness and disability, maintaining or improving joint mobility and reducing functional limitation1. The doctor will have to achieve the set objective avoiding, where possible, therapeutic toxicity64. The purpose of this review is to analyze current therapeutic strategies (Table 1), with particular attention to pharmacological treatment. The surgical approach is beyond this treatment.

Non-pharmacological treatment
The "non-pharmacological" treatment in its various forms constitutes a therapeutic aid of fundamental importance, in particular for osteoarthritis of the knee and of the hip. Unfortunately, the potentials of this therapeutic-prophylactic intervention are not always adequately exploited, either because of simple "ignorance" or because it requires an active participation of the patient (and the doctor) that is more difficult to obtain than required by classical pharmacological therapy. . We summarize here the forms of intervention that have at their base studies acceptable on the scientific level.

Education and psychological support
Patient education, that is, a suitable information on the disease and its treatment, seems to improve pain but not joint disability2-7. As with other chronic diseases, osteoarthritis can, for obvious reasons, alter the psychological state of the patient and therefore the education of the family8 and a constant contact (verbal, telephone) with whoever takes care of following the patient (doctor or paramedical staff) 9-11. On the website www.arthritis.org you can find an example of what should be general information about the disease to be given to the patient and family members.

Physical therapy
Physical therapy is the main support for the treatment of osteoarthritis. In patients with osteoarthritis of the knees the weakness of the femoral quadriceps is common, probably with a disuse atrophy that develops due to the lack of load on the painful limb. However, recent studies have shown that quadriceps muscle weakness may be present in people with radiographic changes to osteoarthritis in the absence of a history of gonalgia-compatible history and in which muscle mass of the lower extremities has increased rather than decreased83 have also indicated that Quadriceps weakness may be a risk factor for the appearance of osteoarthritis of the knees, perhaps due to a reduced stability of the knee joint72. Several systematic reviews11-14 and some randomized controlled clinical trials15-17 show that exercise can reduce pain and disability in individuals with osteoarthritis of the hip and knee; muscle strengthening and aerobic training are the most used approaches18. In this regard, physiotherapists play an important role, both in educating the patient and in controlling his ability to correctly perform the various exercises. In osteoarthritis of the knee, to improve the functional state without exacerbating the pain, programs based on the march 19,20 also seem useful.

Other non-pharmacological approaches
Weight reduction is recommended for all patients with osteoarthritis although there is no evidence of a direct correlation between obesity and this condition. Only two studies, one randomized, placebo-controlled21, the other of cohort22, showed that weight loss may improve pain due to osteoarthritis of the knee. The rest of the affected joint can control pain in the acute phase but if prolonged (ie longer than 12-24 hours) it causes muscular atrophy and reduction of joint motility23. Data on the efficacy of transcutaneous electrical nerve stimulation (TENS) are conflicting13,24-26. The effectiveness of acupuncture is only supported by case series and uncontrolled studies27-29. The evidence in favor of the effectiveness of physical supports, such as footwear and other corrective devices, capable of improving the load distribution on the joints, are limited to 1.30.
There are no demonstrations of efficacy for local application of hot or cold 7,13, nor for the use of ultrasounds 13.31.32. Also with regard to massage therapy, osteopathy, homeopathy and thermal therapy there are no adequate studies to support its efficacy7. Finally, a precise indication for occupational therapy still needs to be defined18.
Pharmacological treatment
Symptomatic pharmacological treatment should be used in combination and not as an alternative to the non-pharmacological program.

Simple analgesics
Paracetamol
Simple analgesics were more effective than placebo in two systematic reviews that included 3 randomized controlled trials that evaluated them in osteoarthritis of the hip33,34. Two controlled clinical trials have demonstrated a comparable efficacy between paracetamol and NSAIDs (ibuprofen and naproxen) in many patients with mild or moderate pain due to osteoarthritis of the knee35,36. However, both studies have limitations. The first, in fact, in addition to including patients affected by both primitive and traumatic osteoarthritis, after 4 weeks of therapy has shown a significant improvement of pain at rest and walking in the group treated with ibuprofen; while the latter used a sub-optimal dose of the two drugs and had a high percentage of suspension. In the two groups, poor response and undesirable effects were overlapping.

Tramadol
Tramadol is a synthetic opioid that also inhibits the re-uptake of norepinephrine and serotonin by nerve cells30. The drug has been approved by the FDA for the treatment of moderate or severe osteoarthritic pain. The few studies conducted in osteoarthritis of the hip and knee indicated comparable analgesic efficacy with that of ibuprofen39. Tramadol (at the usual dose of 200-300 mg / day to be divided into 4 administrations) may be a useful adjunct in osteoarthritis not adequately controlled with NSAID40. Undesirable effects that are frequently found are drowsiness, nausea and constipation.

Association therapies
The association between paracetamol and codeine has a superior analgesic effect compared to paracetamol alone; the difference is modest, but statistically significant. Combination with codeine doses higher than 15 mg is associated with an increase in undesirable effects41. The combination of paracetamol with dextropropoxyphene resulted in uncertain benefits in the face of a higher incidence of adverse events42.
Non-steroidal anti-inflammatory drugs (NSAIDs)
Traditional NSAIDs
Traditional NSAIDs are effective in reducing pain in patients with osteoarthritis of the hip3 and knee33,34 in the short term. Many clinical studies demonstrate their superiority over placebo, although few have lasted longer than 2 years1,44,45; there is still no clear evidence of the greater efficacy compared to simple analgesics33-36. There is no evidence of superiority of one NSAID compared to another in osteoarthritis33,34, while it is known that their efficacy is dose-related46. Use of NSAIDs causes side effects in approximately 30% of patients who use it for more than 4 weeks; the most common effects are on the gastrointestinal system, but kidney problems can also occur,


hepatic, cardiovascular and cutaneous37. The toxicity varies from one NSAID to another and increases, almost linearly, with increasing the dose of the drug47. Data from epidemiological studies show that in subjects over 65 years of age, 20-30% of peptic ulcers causing hospitalization and death are attributable to the use of NSAIDs and that the risk of serious gastrointestinal events in the elderly taking NSAIDs is dose-dipendente30. A systematic review48 showed that traditional NSAIDs carry a greater risk of severe bleeding than placebo [ARI (absolute risk increase) of 0.7% with NSAID compared to placebo] and ulcers (ARI: 0.05% with NSAIDs compared to placebo); the effect is not significant but the average duration of treatment was only 2 months. A meta-analysis showed that low-dose ibuprofen is significantly less toxic than other NSAIDs (naproxen, diclofenac, acetylsalicylic acid, etc.) as these are associated with an increased risk of serious complications of the upper gastrointestinal tract of 1.6- 9.2 times49. However, this advantage is lost at the highest doses of the drug37.

New COX-2 inhibitors
Several randomized trials have shown that the new COX-2 inhibitors (celecoxib and rofecoxib) are more effective than placebo and similar to that of traditional NSAIDs in controlling pain in patients with osteoarthritis50,51. Data from endoscopy studies50,51 and a tolerability study5 suggest a lower incidence of symptomatic and complicated ulcers with the new COX-2 inhibitors compared to traditional NSAIDs. However, these data do not show that the new COX-2 inhibitors are able to reduce the incidence of major complications (bleeding, perforation or obstruction).
Topical medications
NSAIDs
Data on topical NSAIDs are contradictory. Some controlled clinical trials53,55 and a meta-analysis56 indicate a superiority of topical NSAIDs compared to placebo in reducing pain, while another clinical study found no difference between a salicylate gel and placebo57. The studies have been short-lived and, like the same meta-analysis, lend themselves to numerous methodological criticisms that call into question their conclusions; to date, many elements of uncertainty prevent data from being accepted for the effectiveness of topical NSAIDs. Clinical studies comparing topical and oral NSAIDs are few and inadequate. A good quality study, which included 235 subjects, compared piroxicam gel with oral ibuprofen and found no difference between the two treatments58. Comparison studies between topical NSAIDs and paracetamol and between NSAIDs and topical topical treatments are lacking. The most frequent undesirable effect of topical application of NSAIDs is local irritation1.

Capsaicin
A meta-analysis of three randomized controlled trials indicates that topical capsaicin has an analgesic effect superior to that of placebo and is well tolerated59. A recent study compared nitroglycerin, capsaicin and the association of the two active substances with placebo60. In addition to confirming the efficacy of capsaicin, the study also highlighted how its association with nitroglycerin can increase its effectiveness on osteoarthritis pain and improve its tolerability. Comparison studies between capsaicin and topical NSAIDs are lacking.
Intra-articular drugs
Intra-articular corticosteroids
Intra-articular corticosteroids are very often used mainly to treat synovitis-associated pain, although clinical data on their efficacy and optimal frequency of administration are poor. A systematic review (10 randomized, controlled trials) showed that injection of corticosteroids into the knee (one study used 4 injections, the remaining single injections) resulted in only a slight improvement in pain compared to placebo for a time of 1-4 settimane61. A randomized, controlled, subsequent study evaluated a single injection of corticosteroids with a 24-week follow-up demonstrating a short-term benefit (1-4 weeks) in both pain and a functional index compared to placebo (index of Lequesne) 62. A possible joint damage with the prolonged use of corticosteroid infiltrations is difficult to evaluate, both for the fact that intra-articular injections are used more frequently in patients with more severe disease, and because several factors can contribute to the progression of osteoarthritis in the long term . However, many rheumatologists recommend not to exceed 4 injections of corticosteroids for each joint within a year. If you proceed with a sterile technique, the risk of causing septic arthritis in an arthritic joint is low64.


Intra-articular irrigation closed at tidal volume (tidal irrigation)
Joint irrigation is an integral part of all arthroscopies; it is necessary to stretch the joint in order to obtain an adequate visualization and remove blood and debris that could otherwise hinder the vision. In a prospective, multicentre, randomized, single-blind, short-term study (14 weeks) involving 77 patients with mild to moderate osteoarthritis of the knees, intra-articular irrigation closed at tidal volume (performed on an outpatient basis and under local anesthesia) allowed a modest but significant improvement in pain compared to traditional systemic pharmacological treatment (NSAIDs and / or analgesics) associated with strengthening exercises of the femoral quadriceps (p <0.05) 63. Arthroscopic lavage and the cleaning and removal of cartilages can also reduce pain for periods even months.

Sodium hyaluronate and derivatives
Sodium hyaluronate and hylan G-F 20 (a hyaluronic acid derivative with higher molecular weight) were approved by the FDA for intra-articular use in patients with arthrosis gonalgia. Both are administered with weekly injections for a period of 3-5 weeks and this treatment scheme can be used at most 2 times a year. Such drugs seem slightly more effective than placebo1,65,66 and oral NSAIDs65-67 in reducing the pain of some patients with gonarthrosis although the available studies are still limited and in the short term. A controlled, randomized, multicenter, double-blind study, which enrolled 495 patients with idiopathic osteoarthritis for 6 months, showed that 5 weekly intraarticular injections of hyaluronic acid (20 mg each) allow an improvement in pain and joint function, at least as naproxen administered for 26 weeks68. In the primary and secondary objectives of the study there were no statistical differences in terms of efficacy compared to naproxen68. The injections were well tolerated; the most frequent undesirable effects were gastrointestinal disorders (29% of patients treated with the study drug compared to 41% of patients treated with naproxen), pain at the injection site of the drug (23%) and headache (18%). An 80-year-old cardiopathic patient died of acute myocardial infarction on the 53rd day of the study68. Pseudogoutosa arthritis and anaphylactic shock have also been reported1. Comparisons between hyaluronate and intraarticular steroids are lacking.

chondroprotecting
Glucosamine and chondroitin
Glucosamine is an aminomonosaccharide component of the proteoglycans of the articular cartilage. In vitro, it has proved capable of altering the metabolism of chondrocyte and this is the rationale for its use in osteoarthritis69. Chondroitin sulphate has similar effects to glucosamine, being responsible for an increase in the concentration of proteoglycans in the collagen matrix and a reduced collagenolytic activity71. A meta-analysis with an evaluation of 15 double blind, randomized, placebo-controlled studies demonstrated a moderate analgesic effect of glucosamine (0.44, 95% confidence intervals 0.24-0.64) and a greater effect of chondroitin ( 0.78, 95% confidence intervals 0.60-0.95) in the treatment of osteoarthritis 70. However, methodological problems (randomization, blindness, etc ...) may have led to an overestimation of the benefit, including the fact that almost all published works were sponsored by the manufacturer of the drug under investigation. To date, even if the drug seems safe (certainly not negligible aspect), the real effectiveness, the best route of administration and the optimal dose are unknown. Therefore, well designed clinical trials are needed, with an adequate number of patients and not sponsored.

Other drugs
Tetracycline
At present, the role of tetracyclines (minocycline and doxycycline) in treatment in osteoarthritis should still be defined, although there is evidence of their anti-inflammatory effect73-76. The efficacy of tetracyclines in reducing joint cartilage damage, highlighted in animal models of osteoarthritis77-79, supports its potential therapeutic role. Clinical studies are needed to evaluate the efficacy of these drugs in osteoarthritis.

hydroxychloroquine


Hydroxychloroquine has been used in some patients with erosive osteoarthritis and inflammation. In a retrospective assessment, 6 out of 8 patients suffering from non-responsive NSAID erosive osteoarthritis benefited from the treatment with hydroxychloroquine80. Prospective controlled studies are needed to confirm these observations.
Conclusions
Osteoarthritis still remains the most frequent cause of musculoskeletal disability in the elderly; the disease has a chronic course and variable course.
Currently available treatments aim to alleviate symptoms (pain) and improve functional disability. The non-pharmacological approach is of primary importance especially in elderly patients who are traditionally users of many drugs and therefore at greater risk of undesirable effects. Therefore, before starting medical treatment, a suitable non-pharmacological program should be undertaken that includes psychological support, patient education and physical therapy. The role of paracetamol in the treatment of osteoarthritis pain has yet to be well established. Administered at various doses (up to 4 g / day) can be effective, in the short term, like NSAIDs, in some patients with osteoarthritis with mild or moderate pain. The 1995 American College of Rheumatology guidelines for the treatment of hip and knee osteoarthritis indicate it as the first choice drug for good cost / benefit ratio (Figures 1 and 2) 81, 82. Paracetamol is preferable to NSAIDs in case of renal failure. If the pain does not improve you can switch to an NSAID (starting with low doses and then increasing) or to an opiate (eg if NSAIDs are contraindicated), possibly associated with paracetamol (eg paracetamol and codeine) or combination between an NSAID and the opiate. It should be remembered that doses of codeine above 15 mg per day may be associated with a higher incidence of side effects. Since there is no demonstration of superiority of an NSAID compared to another, the choice of the preparation should be guided by the effectiveness (to be assessed within a few days of treatment) and by individual tolerability, as well as by cost. The use of these drugs requires the usual caution, especially in elderly subjects and those at greater risk of toxicity. The new COX-2 inhibitors may be useful in the subgroup of patients with a high risk of gastrointestinal NSAID ulcers. Topical capsaicin could be tested in patients presenting pain in a single joint as it could be a reasonable alternative to systemic therapy, but the drug is not on the market in Italy and finding it abroad is complicated and very expensive. In these cases, intra-articular infiltrations of corticosteroids may also be useful "one-off", especially where signs of synovitis are evident and the possibility of simultaneously performing an arthrocentesis (eg knee). Intra-articular injections of sodium hyaluronate or its derivatives should be used with extreme caution given the limited data available and the reporting of cases of anaphylactic shock. Further data are needed on the use of tidal irrigation (sometimes it can be attempted in osteoarthritis of the knee), glucosamine and chondroitin. For the latter two drugs we are awaiting definitive results that will come from a multicenter, randomized, double-blind, placebo-controlled study of the National Institute of Health. Data for now only experimental and / or poor for tetracyclines and hydroxychloroquine.