Use of chondroitin sulphate and glucosamine sulphate in degenerative changes in TMJ: A systematic review

Introduction: Degenerative changes in Temporomandibular Joint (TMJ) have increased in prevalence and severity over the years. Within this context, it ́s necessary to obtain safe and effective therapies for control and management of the patient in cases of osteoarthritis and osteoarthrosis of the TMJ. Therapeutic options range from intra-articular infiltration protocols, occlusal splints, pharmacological therapies and physiotherapy and educational measures. The alternative treatment with structure-modifying agents, like as chondroitin and glucosamine sulfates, showed promising results, and especially safety. Thus, through a systematic literature review, this study aimed to analyze and discuss effectiveness and safety of chondroitin and glucosamine in degenerative changes of the TMJ.


IntRoduCtIon
Currently, musculoskeletal diseases present as a great public health problem due to the longevity observed in the world population. 2,8,9Within this context, osteoarthrosis is a frequent and important situation of morbidity and disability, especially in the second half of life, 2 increasingly affecting younger patients.Osteoarthrosis or osteoarthritis is a degenerative disease that affects joint tissues, causing damage to the articular cartilage, generating painful symptoms and functional limitations.Regarding this condition, there are few therapies with effective results. 10herapeutic modalities for the control and management of osteoarthrosis are diverse and are related to disease stage, involving patient education, exercise and medication (analgesics and non-steroidal anti-inflammatory drugs -NSAIDs).Eventually, also the orthopedic surgeries are indicated. 8In relation to drug therapies, specifically, the treatment is divided into symptoms modifying drugs and structure modifying substances. 1,23Symptoms modifier drugs have its performance related to reduction of pain and improvement of function, while the structure modifying substances have its indication associated with structural changes in the joint spaces. 7,11he use of NSAIDs has a palliative effect and can cause adverse effects in the long-term.Therefore, effective and safe treatments for the control and management of osteoarthrosis of the Temporomandibular Joint (TMJ) become necessary.Studies focused on this problem showed that the structure-modifying agents, such as chondroitin and glucosamine sulphates, showed positive results, and few or no adverse effects in the treatment of osteoarthrosis of the TMJ, which is attracting increased interest.
Thus, the aim of this systematic literature review is the discussion based on scientific evidences regarding the effectiveness of nutraceuticals, such as glucosamine and chondroitin sulphates, in the treatment of degenerative changes of the TMJ.

MAtERIAL And MEtHodS
A search in MEDLINE, Cochrane, EMBASE, PubMed, Lilacs and BBO was made in the period from 1966 to January 2009.The search descriptors used were "chondroitin", "glucosamine", "temporomandibular disorder", "craniomandibular disorder", "temporomandibular joint", "tmd", "tmj" and "osteoarthritis", which were crossed in search engines.The initial list of studies was subjected to review by two reviewers who applied inclusion criteria to determine the final sample of articles, which were evaluated by their title and abstract.If there was any disagreement between reviewers, a third opinion would be consulted after reading the full version of the article.
Inclusion criteria for selecting articles were: » Studies that have included the effects of structure-modifying agents-chondroitin sulphate and glucosamine sulphate-in situations of degenerative changes of the TMJ.» Within the context of an Evidence-Based Dentistry, were included only controlled randomized clinical trials (RCTs) and quasi-randomized double-blind, systematic reviews and meta-analysis.» Articles published from January 1966 until January 2009.» Articles written in English, Spanish and Portuguese.

RESuLtS
After applying the inclusion criteria, two doubleblind randomized clinical trials were obtained that evaluated the effectiveness of chondroitin and glucosamine sulphates in the treatment of degenerative changes of the TMJ, as shown in Table 1.Still, the Kappa agreement index between reviewers was 1.00, with no need to use a third reviewer.

dISCuSSIon
Considerations about the subject should always be done from a critical reading of the methodology used by different authors.The use of the basic principles of research allows researchers to try to control as best as possible the biases of the study, generating a higher degree of evidence.Thus, methodological criteria as sample size calculation, randomization, blinding, control of involved factors and calibration intra-and inter-examiner become important tools to qualify the level of scientific evidence generated. 30ithin the context of an Evidence-Based Dentistry, it appears that the most common types of studies published in Brazilian journals correspond to studies with low potential for direct clinical application

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Machado E, Machado P, Cunali PA and low level of evidence.The low number of studies with greater strength of evidence shows the need to expand the knowledge of evidence-based methods among researchers. 21Likewise, it is important to know, both the authors and the readers, the studies that generate the highest levels of scientific evidence, such as meta-analysis, systematic reviews and randomized clinical trials.
Glucosamine is one of the main pillars of the structural matrix of connective tissue of joints, besides to be a substrate for the synthesis of glycosaminoglycans, stimulating synthesis and inhibiting its degradation.It also has a protective effect in the body against oxidative damage. 28Otherwise chondroitin is a glycosaminoglycan found in articular cartilage proteoglycans. 32Both compounds are synthesized naturally in each joint. 29he exact mechanism of action of chondroitin sulphate 32 and glucosamine sulphate 24,32 , in the treatment of osteoarthritis, has not been fully elucidated.These substances act synergistically to stimulate glycosaminoglycan synthesis in chondrocytes.Also, combined with the antiprotease action of chondroitin sulphate, provides greater efficacy in delaying the degenerative process.On the other hand, glucosamine has little effect on the inhibition of aggrecanase and collagenase, enzymes responsible for cartilage degradation. 14ne of the criteria for determining a risk factor is the existence of a biological plausibility, in light of current knowledge, that gives meaning to the association studied.The hypotheses that sustain the plausibility should be supported in experimental studies. 3In veterinary medicine, the derivatives of chondroitin and glucosamine have been used successfully for several years in order to treat the symptoms of arthritis. 28ondroitin sulphate of low molecular weight and glucosamine hydrochloride were more effective when combined than alone in reducing the progression of articular cartilage lesions in an instability model of osteoarthritis in rabbits.Thus, it is considered that chondroitin and glucosamine sulphates have overlapping functions in the management of articular cartilage damage. 14Furthermore, treatment with chondroitin 4-sulphate decreased the severity of arthritis also in rats, showing minimal evidence of inflammation or joint destruction.Still, the administration of glycosaminoglycan also inhibited significantly increase of TNF-α. 4 Through this systematic literature review it can be verified, in the evaluation of dietary supplements such as glucosamine and chondroitin as a treatment of degenerative changes of the TMJ, that there is a very small number of randomized clinical trials regarding this therapeutic possibility, and there are no meta-analysis or systematic reviews that evaluate this question.Thus, with a small number of significant scientific evidences about the effectiveness and safety of proposed therapies, it is difficult to reach definitive conclusions and extrapolate the results to the general population.Moreover, the selected studies had small samples and a relatively short follow-up time, demonstrating the need for a larger longitudinal follow-up to evaluate the real efficacy and safety of proposed treatments.
The randomized clinical trials included in this systematic literature review compared the chondroitin and/or glucosamine to other therapies, such as NSAIDs and placebo, in cases of degenerative changes of TMJ, and found positive results in reducing pain and improving function. 19,31

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Use of chondroitin sulphate and glucosamine sulphate in degenerative changes in TMJ: A systematic review original article are few studies evaluating the TMJ in cases of osteoarthrosis and the influence of structure-modifying agents in this situation.Therefore, it is proven the need for studies based on representative samples and with long follow-up time, presenting methodological criteria such as randomization, sample size calculation, blinding, control of factors and calibration.
Regarding other joints, such as knees and hips, there was encouraging results in the use of chondroitin and/or glucosamine.Meta-analysis, 16,26 systematic reviews 33 and double-blinded randomized clinical trials 6,12,18,20,22,24 show positive results in cases of osteoarthrosis of joints, both in improving symptoms and function, when treating with chondroitin and/or glucosamine.However, other RCTs showed that these therapies involving dietary supplements have not obtained significant results or more effective than placebo. 5,13,15,27It is important to emphasize that many of these studies had limitations such as small samples, problems in the methods of allocation of the sample and methodological biases, which reduced the level of scientific evidence generated. 16,25hondroitin and glucosamine are dietary supplements sold without prescription and often without regulation and control over the quality of the substances.Thus, its indication should be made consciously and based on scientific evidences.The safety of these substances has been demonstrated in several studies, being inexistent or minimal the adverse effects such as gastrointestinal symptoms 12,24,27,31 and headaches. 13,17,24,27imilar results were also obtained in control groups.
Due to the safety of the structure-modifying agents, its indication can be useful even if the efficiency is low 16 .In treatment protocols for degenerative changes of the TMJ, chondroitin and glucosamine can be a safe alternative treatment, free from adverse effects related to therapy with NSAIDs. 31Thus, associated to protocols with intra-articular injections with corticosteroids, viscosupplementation with sodium hyaluronate, occlusal splints, drug therapies, physiotherapy and educational measures, among others, the structure-modifying agents are added, providing an arsenal in the control and management of degenerative changes of TMJ.
Regarding the recommended dose of glucosamine sulphate, various protocols are used.A daily dose of 1,500 mg, 19,29 divided into three doses (500 mg each) is the protocol of choice in cases of osteoarthritis/osteoarthrosis.Though the recommended dose for long-term use of chondroitin sulphate is 800 29 to 1,200 mg/day, 19 also divided into fractional doses, and associations between the two substances are well tolerated by patients. 29

ConCLuSIonS
» Regarding the use of chondroitin and glucosamine sulphates in the treatment of degenerative changes of the TMJ due to the small number of RCTs included in this systematic review, it lacks scientific evidences to support its indication as joint treatment protocol for TMJ.However, the included studies demonstrate that chondroitin and glucosamine showed better results than NSAIDs and placebo in the treatment of internal changes of the TMJ.» In relation to the use of chondroitin and glucosamine in other joints of the human body in cases of osteoarthrosis/osteoarthritis, such as knees and hips, studies with strong levels of evidence, such as meta-analysis, systematic reviews and RCTs demonstrate positive results using structure-modifying agents in reducing pain and improving function, being dietary supplements safe and with little or no adverse effect.» This systematic literature review showed that it is necessary further randomized clinical trials, based on representative samples and long follow-up time, to assess the effectiveness and safety of proposed treatments for the control and management of degenerative changes of the TMJ.

Table 1 -
However, what is verified is that there Characteristics of included studies.