Osteoarthritis is a disease with great epidemiological, social and economic impact on health systems. Its treatment has focused on reducing pain and joint inflammation; In recent years, a series of drugs has appeared on the market that, in in vitro studies, show mechanisms of action that could have a disease-modifying effect, since they reduce the proinflammatory cytokines and the metalloproteinases involved in the degradation of the matrix. of cartilage and have an effect on chondrocyte antiapoptotic mechanisms. Clinical studies have shown efficacy against pain and improvement of joint function; Some studies have shown that there is no loss of joint space evaluated by conventional radiography with longitudinal follow-up of patients. The mechanisms of action in vitro that these new drugs have and the clinical evidence of their usefulness in the symptoms as well as their potential modifying effect of the natural history of osteoarthritis are discussed.
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The osteoarthritis is a disease with high epidemiological, social, and economic impact in health systems. Its treatment has been focused on diminishing pain and inflammation joint; in last years there has appeared on the market a series of drugs that, in studies in vitro show mechanisms of action that might have a modifying effect of disease, since they diminish the proinflammatory cytokines and metalloproteinases involved in degradation of cartilage matrix and it have effect in anti-apoptotics mechanisms in chondrocyte. Clinical studies have showed efficacy against pain and improving joint function; some studies have shown that there is no loss of joint space by conventional x-ray with longitudinal follow-up of patients. We describe new in vitro action mechanisms of theses new drugs and the clinical evidence of their efficacy in symptoms and potentially modifying the natural history of osteoarthritis.
Introduction
Osteoarthritis (OA) is recognized as the most prevalent joint disease in the world. It is estimated that in the United States about 20 million people are affected by this disease and within the next 2 decades this figure will double 1.2 . The prevalence of knee OA has been estimated in 18-25% of men in Eastern Europe, 24-40% of women aged 60-79 in the Netherlands 3 and 28-34% in Spain 4 In Mexico, in a national health survey, it was estimated that 26% of the Mexican population has some symptom of rheumatic disease; in general, the knee is the most affected lower joint (16%) and its prevalence increases to 35% in the eighth decade of life 5 .
Currently there are new drugs that have been used as drugs that improve the symptoms of OA, although there are data from some controlled clinical studies that could have a role as OA modifying drugs (DMOAD).
Glucosamine
Glucosamine is a glycoprotein that serves as a substrate for the biosynthesis of glycosaminoglycan chains and cartilage aggrecans 6 .
In vitro studies
In chondrocytes and synovial cells it has been shown that glucosamine sulphate (SG) reduces the production of prostaglandin E 2 and interferes in the binding of nuclear factor kB with DNA 7,8 . In chondrocytes isolated from rat cartilage, an inhibition of up to 73% of the expression of proinflammatory cytokines secondary to the administration of interleukin (IL) 1b has been demonstrated, but at supraphysiological doses 9 . In a recently published study evaluating chondrogenesis in mesenchymal stem cells (MSCs), osteoarthritic and normal human chondrocytes stimulated with and without IL-1b treated with different doses of SG, they observed that at high doses the production of IL-1b regulating the expression of type II collagen and aggrecans and inhibited the production of cartilage-degrading enzymes such as matrix metalloproteinase (MMP), 13 both in chondrocytes and CMMs that were in chondrogenesis 10 . In chondrocytes isolated from areas of irregular defibrillated cartilage of femoral heads, it was observed that with the administration of SG (50-500 mmol) adhesion to fibronectin was restored (altered situation in chondrocytes with OA) 11 . The main problem with in vitro studies is the high doses (0.50-140 mmol) of SG used in the majority, which are not achieved with the recommended administration of 1,500 mg of SG in patients with OA. 12
Clinical studies
Few controlled clinical studies have evaluated the possible modifying action of OA of glucosamine. In 2001, Reginster et al 13 published a study that included 212 patients with knee OA who randomly received SG at 1,500 mg / day or placebo for 3 years. Anteroposterior radiographs of the knees were performed in full standing position. At 3 years, patients who received placebo had a decrease in joint space (AED) of 0.31 mm (95% confidence interval [CI], 0.48 to 0.13) versus a non-significant AED in the group with SG of 0.66 mm (0.22 to 0.09 mm, p = 0.043). The authors then pointed out a possible effect of SG as a disease-modifying drug 13 . In 2002, Pavelka et al 14 conducted a study, similar to that of Reginster et al, in which they included 202 patients with knee OA. The placebo group had a progressive AED of 0.19 (95% CI, 0.29 to 0.09) mm after 3 years. Conversely, there was no change in the group with OS (0.04 mm, 95% CI, 0.06 to 0.14 mm) with significant difference between the two groups (p = 0.001). Fewer patients treated with SG had severe AED defined as> 0.5 mm: 5 and 14% (p = 0.05) 14 .
We are currently awaiting the results of the 24-month study subgroup of the Glucosamine / Chondroitin Arthritis Intervention Trial (GAIT), carried out by the National Institutes of Health of the United States, which will measure the volume of cartilage with magnetic resonance . In the first analysis of GAIT 15 to 24 weeks, there was no improvement in knee OA pain in the glucosamine group compared to the placebo group. In a subanalysis that categorized the pain at the beginning of the study, it was found that the combination of glucosamine and coindritin may have an effect in reducing pain in patients with greater pain at the beginning of the study. In this research, glucosamine hydrochloride was used and the similarity or difference of these two preparations is not known at the moment.
Chondroitin sulfate
Chondroitin sulfate (CS) belongs to the family of heteropolysaccharides called glycosaminoglycans (GAG).
In vitro and animal studies
In 1998, Bassleer et al 16 found that CS increases the production of proteoglycans, but in the presence of IL-1b inhibits the effects of CS in pro teoglycans, type II collagen and prostaglandin E 2 , which indicates that CS It has anabolic effects by increasing the synthesis of proteoglycans and anticatabolics by inhibiting IL-1. Uebelhart et al 17 , in a study in rabbits, found that in animals that did not receive CS the synthesis of proteoglycans was reduced.
Clinical studies
Most clinical studies with CS evaluate its symptomatic effect in OA 18-20 . Few studies have evaluated its disease-modifying effect. In 2004, in a study that evaluated the intermittent administration of CS at 800 mg / day for two periods of 3 months in 1 year against placebo, significant differences were found in favor of CS in reducing pain and improving joint function of the knee and preserve the joint space observed on radiographs, indicating a modulating effect of the disease. In addition to the prolonged effect of this drug 21 . However, at 2 years there were no differences in the improvement of knee pain and function in OA, but there was a difference in assessing the progression of the disease and a lower decrease in AD was observed in the chest radiographs in the group of CS 22 . The cartilage structure modifying properties of CS were also evaluated in a double-blind, placebo-controlled study, which included 119 patients with OA of the hand interphalange. The CS did not prevent the development of OA in the joints without previous involvement, but it reduced the risk of worsening of the joints with OA at the beginning of the study. 29.4% of the subjects treated with placebo developed frank erosive OA, against 8.8% of the patients treated with CS 23 .
Unsaponified oils of avocado and soy
Since the 1970s, unsaponified avocado and soybean oils (ANSAS) have been studied in different types of connective tissue diseases 24,25 .
In vitro studies
The anti-catabolic action of ANSAS and the anabolic action have been described. In culture of chondrocytes with OA inhibition of the production of MMP-3, IL-6, IL-8, NO and prostaglandin E 2 (PGE 2 ) is observed. They are all dependent on IL-1. In bovine articular chondrocytes, ANSAS stimulates the expression of the transforming growth factor b2 and the plasminogen activating inhibitor 1 26 .
Clinical studies
Only one study showed potential DMOAD effect in patients with hip OA evaluated with radiographs for 2 years; found that ANSAS reduced the progression of the disease in the subgroup of patients who had a greater degree of narrowing of the EA 27 .
Diacerein
Diacerein is a derivative of anthraquinone. The active metabolite of diacerein is the rhein, which has similarities in its chemical structure with tetracyclines. Both anti-inflammatory effects have been attributed to inhibit IL-1 and anabolic effects by promoting the production of TGFβ.
In vitro studies
Diacerein suppresses the expression of IL-1 in human chondrocytes with OA 28 and synovial cells 29 . One of the conclusions reached is that the altered production of IL-1 is secondary to the inhibition of the IL-1 conversion enzyme (ECI). By blocking the cascade of IL-1-dependent molecules, the production of NO, stromeliesin 1, collagenase and pro-inflammatory IL-6, IL-8, IL-18 30 is inhibited. In addition to the inhibition of catabolic molecules, there has been an increase in the production of GAG and collagen secondary to the increased production of TGFβ in chondrocytes treated with diacerein.
Clinical studies
There is only one study with diacerein that evaluates its possible modifying effect of OA. It is a randomized, double-blind, placebo-controlled study with 3-year follow-up. We included 507 patients with primary hip OA who received diacerein (50 mg twice daily) or placebo. The joint space was measured on pelvic radiographs every year. The percentage of radiological progression, defined by a loss of joint space of $ 0.5 mm, was significantly lower in patients receiving diacerein than in patients on placebo (47.3% and 62.3%, p = 0.007). 32
Intra-articular hyaluronic acid
Hyaluronic acid (HA) is a normal component of synovial fluid and an important glycoprotein in joint homeostasis 33 . The fact that the molecular weight and viscosity of AH are decreased in OA led to the hypothesis that the intraarticular application of AH would restore the viscoeslasticity of the synovial fluid and promote its endogenous synthesis and, consequently, the stiffness and pain in OA. would improve 34 . There are presentations with low (0.5-2 MDa) and high molecular weight (6-7 MDa).
In vitro studies
It has been observed that the treatment of human articular cartilage with 800 kDa of sodium hyaluronate inhibits the stimulation of IL-1b and of three degrading enzymes, MMP-1, MMP-3 and MMP-13, possibly through the interaction between the AH and CD44 in chondrocytes 35 . In rabbits with a cruciate lesion of the ligament, HA injections inhibited histopathologically cartilage degradation and apoptosis 36 . In different types of experimental animal models (meniscocectomy, cross-ligament injury) inhibition of cartilage degeneration has been seen 37,38 . Weekly intraarticular sodium AH (5 in total) after partial or total meniscocectomy improves collagen repair compared to saline 39 .
Clinical studies
Several works have studied the modifying effect of AH OA, but only 2 have a minimum duration of 1 year. In one of them, chondral lesions were evaluated by arthroscopy. We included 36 patients who received 3 sets of intra-articular injections in the knee. At one year of follow-up, there was less progression of the joint lesion than in the placebo group 40 . There is another study that included 408 patients with knee OA to whom intraarticular AH was applied 3 times a week every 4 months or saline. Digital radiographs of the knee with corporal load were evaluated. A total of 319 patients completed the study, but only 273 x-rays were obtained both at the beginning and at the end of the study. For the statistical analysis, two groups of patients (less severe OA and severe OA) were made based on the average width of the EA at the time of inclusion, and it was found that those who had more severe disease had lower loss of joint space at baseline. the placebo group 41 .
Conclusions
Currently there are different treatments with some scientific evidence of potential effect as modifiers of OA. The one that has done it with greater consistency until now is glucosamine and coindritin. It should be mentioned that these studies have been carried out with controlled formulas, that is, they are prepared by recognized commercial brands and are regulated by the corresponding health systems, and the medicines sold in different parts of the world, specifically in America. as "food supplements" have not shown such effects. There is still a long way to go to stop the loss and regeneration of cartilage in a sustained manner and there are several problems that we face, from the heterogeneity of the OA to the measurements used to evaluate the cartilage. The path towards an adequate real treatment of OA has only recently begun; We need to see if this is the right one or we will have to change course or even take a path.