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Iranian Journal of Pharmacology & Therapeutics, Vol. 3, No. 2, 2004, pp. 61-65 Efficacy and Tolerability of Glucosamine - Chondroitin Sulphate - Methyl Sulfonyl Methane (MSM) in Osteoarthritis of Knee in Indian PatientsSudha Vidyasagar, Prabhu Mukhyaprana, U Shashikiran, Adiga Sachidananda, Sharath Rao, K. Laxmi-narayana Bairy, Shalini Adiga and B. Jayaprakash Kasturba Medical College, Manipal,
Karnataka, India, 576104. Received September 30, 2004; Code Number: pt04009 Background & Objective. Osteoarthritis is progressive
degenerative disease resulting in significant affection of joints. Nonsteroidal
anti-inflammatory drugs (NSAIDS) are widely used in this condition but are
associated with significant side effects; hence the aim of this study was to
evaluate the efficacy and tolerability of nutritional supplements such as Glucosamine,
Chondroitin sulphate and methyl sulfonyl methane in osteoarthritis as an alternative
approach for this condition. Keywords: Osteoarthritis, Glucosamine, Lequesnes index, Goniometry, Visual analog scale Osteoarthritis (OA) is the most common form of arthritis and is a leading cause of physical disability, increased health care usage, and impaired quality of life. Osteoarthritis of knee joint is the most prevalent cause of disability especially in the elderly population [1 ]. Osteoarthritis is due to degenerative process that results from metabolic, mechanical, genetic and other influences. Although non-steroidal anti-inflammatory drugs (NSAIDs) are commonly used to treat OA and have proved effective, their widespread use is associated with significant toxic effects on the gastrointestinal tract, especially in the elderly population [2 , 3 ]. Even though cyclooxygenase-2 inhibitors have a decreased gastrointestinal tract complications than conventional NSAIDs, there remains an urgent need for finding pharmacological therapies for OA that are both effective and relatively safe. Glucosamine is a hexosamine sugar and a basic building block for the biosynthesis of the glycosaminoglycans and proteoglycans that are important constituents of the articular cartilage. Chondroitin is a glycosaminoglycan that is found in the proteoglycans of articular cartilage. Both are animal products having antiarthritic and anti-inflammatory activities [4 , 5 ]. Being safe, these compounds have great utility in the treatment of OA even if they show moderate efficacy [6 , 7 ]. Glucosamine and chondroitin have been used for OA in Europe and USA for more than a decade and recently have acquired substantial popularity. A meta analysis by McAlindon and coworkers demonstrated improvement of pain in patients with OA [8 ]. Ganu and colleagues demonstrated that glucosamine reduce Metalloproteinases (MMPs) nitric oxide, and prostaglandin E2 [9 ]. All are thought to play an important role in the joint damage associated with OA. A systemic review by Richy F et al showed efficacy of glucosamine and chondroitin in knee osteoarthritis in all outcomes, including joint space narrowing [10 ]. Chondroitin was found to be effective based on Lequesnes index, visual analog scale, pain and joint mobility according to Cibere [11 ]. Methyl Sulphonyl Methane (MSM) is a naturally occurring nutrient found in normal diet [12 ]. There is a need for supplementation of MSM since it is lost in the process of cooking. MSM can restore the flexibility and permeability of the cell walls. This helps to equalize the pressure and reduce or eliminate the cause of pain. The arthritis study conducted in mice by Oregon Health Sciences University did not reveal degeneration of the articular cartilage by MSM. It can rebuild ligaments and tendons with healthy, flexible new cells [12 ]. However, there have been questions raised about the efficacy of combination as mentioned earlier. Hence this study was undertaken to evaluate efficacy and tolerability of glucosamine, chondroitin and methyl sulfonyl methane combination in the treatment of OA in Indian elderly patient population. Patients and Methods Study Design The present open label study was conducted in medicine unit of Dr. TMA Pai Hospital Udupi and Orthopedic department attached to Kasturba Medical College Hospital Manipal, India. Selection of Patients Inclusion Criteria
At the screening visit, patients medical history was taken and clinical assessment was done in detail. Patient who were diagnosed in the past according to the American College of Rheumatology were also considered for the trial if they meet the inclusion criteria. The knee joint was examined on the grounds of local examination and specific parameters for assessing the severity of arthritis subjectively as well as objectively. All patients were asked to grade the severity of pain based on visual analogue scale (VAS) ranging from no pain at the bottom of the scale to unbearable pain at the top of the 100 mm colored scale. The other variable in the scale were mild, moderate and severe pain separated by 20 mm each [14 ]. Lequesnes index (Table 1 ) which is a functional scoring system was measured accordingly [15 ]. The objective assessment of the knee joint was done by noting the presence or absence of swelling, deformities, tenderness, warmth, crepitus, joint effusion and muscle atrophy [16 ]. The joint mobility was assessed by doing goniometry of the knee joint [17 ]. Global assessment of disease was also recorded as very poor, poor, good and very good (1-4) by physician based on the VAS, Lequesnes index, joint mobility and by patient himself/herself based on his/her assessment of the disease initially and during the monthly visits [14 ].
Laboratory investigations such as Complete Blood Picture (CBP), Random Blood Sugar (RBS) and Electrocardiogram (ECG) were done before and at the end of the study. Renal and liver function tests, knee joint X-rays (Anteroposterior and Lateral) were done on each follow up and Magnetic Resonance Imaging (MRI) was done in ten patients. They were graded by a scoring system of 1-4 by the radiologist. (Table 2 ) [18 , 19 ]. Serum uric acid, and Rheumatoid factor measurement were made to exclude patients of other joint disorders in the beginning of study.
Thirty-seven patients were enrolled in the study based on the inclusion and exclusion criteria. The study was undertaken after the institutional ethical committee clearance was obtained. A written informed consent was obtained from all patients in accordance with good clinical practice guidelines. All patients were given two tablets of Cartivit (A combination of 500 mg glucosamine, 400 mg chondroitin sulphate sodium and 250 mg methyl sulfonyl methane) thrice a day by the study coordinator who also took the tablet count to quantify compliance. All patients were instructed not to take any analgesics except paracetamol (only if needed) during the study period and asked to report the number of paracetamol tablet they had taken during each visit interval. Patients were followed up at the end of four, eight and twelve weeks. The knee joint was examined on each clinical visit based on the above-mentioned parameters. Statistical analysis. The Mean±S.D of VAS, Lequesnes index, Goniometry assessment radiological index, physicians and patients assessment were taken at different clinical visits and percentage improvement at 4th, 8th and 12th week were compared with the baseline values by paired t-test using SPSS. The p-value less than 0.05 were considered as significant. The patient compliance was considered good if the patient had taken more than 80% of the tablets dispensed to him/her during a particular clinical visit. ResultsOut of the thirty-seven patients included into the study, five patients were dropped because of non-medical reasons (change of residence and personal reasons). The patient characteristics are given in the Table 3 .
Pain score (VAS) based on patients perception of pain, improved significantly (p < 0.05) from baseline score of 66.44 ± 22.28 to 39.84 ± 20.34 at the end of twelve weeks (Table 4 ). The improvement was 19.09%, 25.22% and 39.85% respectively at the end of four, eight and twelve week.
Improvement in functional status based on Lesquesnes index was also highly significant (p < 0.05). This was13.96 ± 4.74 at baseline which decreased to 8.06 ± 5.25 at end of twelve weeks (Table 4 ). The percentage improvement at 4th, 8th and 12th weeks was 17.19, 25.22 and 39.85 respectively. Joint mobility assessed by goniometry showed changes by 8th week and significant improvement by 12th weeks (Table 4 ). The percentage improvement was 9.19, 16.60 and 27.59 respectively at 4th, 8th and 12th week. There was no significant change in the radiological parameters such as X-rays and MRI of knee joint (Table 5 ). There was significant improvement in the physicians assessment of the disease as well as patients assessment (p < 0.05) (Table 5 ). The number of tablets of paracetamol used as and when required basis (sos) by patients came down from an average of four per week at the beginning of the study to two per week by four weeks. At the end of twelve weeks, only six patients needed paracetamol once a week on a sos basis. This shows that a decreased usage of analgesics, thereby less adverse effects and improved patient compliance.
The drug did not alter the biochemical markers (Table 6 ). Patient compliance was very good as adherence to the treatment was more than 80%. Only two of them had missed the treatment schedule by two days on one occasion. Two patients complained of diarrhea initially during the treatment, whose causality could not be established.
Osteoarthritis (OA) is characterized by progressive loss of articular cartilage and bony overgrowth seen mostly in elderly individuals. The initial bland progression of OA may become clinically relevant as an inflammation brought about by the increasing deposition of cartilaginous debris [20 ]. For the patient, the most important aspect of the condition is pain and associated impairment of movement [21 ]. Because cartilage is not innervated, the pain arises from secondary effects, such as synovial inflammation and fluid accumulation leading to joint capsule distension and stretching of the periosteal nerve endings. NSAIDs have been widely used in the relief of pain in-patients with osteoarthritis. Jones reported a post marketing surveillance study of sustained release form of diclofenac on 7438 osteoarthritis patients, in which the drug had to be withdrawn in 18% of the patients due to side effects [22 ]. In another study involving 336 patients with osteoarthritis over six months, Hosie et al reported that about 10% patients withdrew from the study due to adverse effects following diclofenac therapy [23 ]. Due to this fact, there has been a search for oral medication that will work to reduce patients symptoms, that will regenerate cartilage and act as anti-inflammatory without causing many side effects. Glucosamine and chondroitin combination has been used in many studies in osteoarthritis all over the world as nutritional supplements aiding cartilage repair. They are found to be uniformly safe in all studies compared to NSAIDs and almost as effective [3 , 5 , 8 ]. Muller-Fassbender et al [24 ] have demonstrated the efficacy of glucosamine-chondroitin versus ibuprofen in a double blind ,parallel group study, where they found this combination was as effective as ibuprofen with much less side effects. However there have been not many Indian studies showing efficacy of chondroitin and glucosamine in OA. A study by G H Tilve et al using oral enzyme preparation (phlegozyme) showed good improvement in joint pain, joint mobility when compared to diclofenac in active osteoarthritis [25 ]. There is no documented study on the efficacy and tolerability of combination of the Glucosamine-Chondroitin-MSM in osteoarthritis in Indian scenario. In our study MSM in combination with glucosamine and chondroitin sulfate has worked very well in all patients. The pain score was assessed using the standard visual analogue scale in which the patient identified the degree of pain with the color code. This parameter started showing improvement even at four weeks and improved steadily over eight and twelve weeks to a significant level (p < 0.05). Most patients had a good compliance with the drug. Lequesnes index, a scoring system based on functional mobility of the joint assessing patients daily activities and hence is a direct evidence of the extent of the disability. This score also showed significant improvement (p < 0.05) demonstrating that patients symptoms improved very well with this drug. Such a result was documented in earlier studies by Muller et al [24 ]. Noack et al [26 ] used this index to quantify improvement with glucosamine-chondroitin combination in a study on osteoarthritis of the knee and found this index to be a sensitive indicator of improvement. Objective evidence of improvement in joint mobility was noted with goniometry. This is a simple technique, which assesses the angle of flexion and extension in the knee joint as an index of joint mobility. This parameter started to improve early, but significant change was seen by twelfth week (p < 0.05). This seems logical; as anatomical improvements in the joint condition will take a longer time to improve after functional improvement sets in. The radiological changes in osteoarthritis as evidenced by X-ray and MRI are probably late and may not correlate with the patients symptomatology. There was no significant difference in scoring of the X-rays or MRI in the patients. Many patients may have severe functional disability in spite of near normal radiological investigations. Thus these investigations may not be useful to judge efficacy of short-term treatment with drugs in osteoarthritis. Further the anatomical changes in the joints may take a long time to regress [27 ]. Pavelka et al [28 ] used glucosamine in a randomized placebo controlled study for a three year period, and compared anatomical parameters such as joint space width, and noted that this drug retarded progression of osteoarthritis. As our study was of short duration, such a result would probably not be demonstrated. Conclusion
We would like to express our sincere thanks to Apex Laboratory, Chennai, India for the supply of the study medication.
Copyright © 2004 by Razi Institute for Drug Research (RIDR) |
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