Prototipos y su diseño

4.3.1 Use of vitamin and mineral supplements for osteoarthritis

Many patients often use diet changes and/or vitamin and mineral supplements to help control pain and symptoms of rheumatic diseases, as a way of doing something to help themselves. Vitamin A, C and E are the major antioxidants in the diet and dietary supplements that have been identified as having important roles in preventing and/or improving oxidative stress caused by reactive oxygen species (ROS), part of the pathological processes associated with OA.(Rayman and Pattison, 2008, Sowers and Lachance, 1999) OA has been regarded primarily as a disorder of articular cartilage, but its other processes also play important roles in the pathophysiology of this condition, such as subchondral bone or subchondral sclerosis, and osteophytosis formation.(Iannone and Lapadula, 2003) Once cartilage damage is initiated, the stiffness of the subchondral bone may contribute to further progression and chondrocyte dysfunction.

Vitamin D also plays a role, stimulating the synthesis of proteoglycan by articular chondrocytes, influencing bone mineralisation and calcium metabolism.(McAlindon and Felson, 1997) In addition, evidence from both animal and human studies suggest that minerals including magnesium, copper, manganese, selenium and zinc have anti- inflammatory effects.(Henrotin et al., 2005, King et al., 2005, Kurz et al., 2002, Shakibaei et al., 1996)

Nonetheless the pathogenic mechanisms underlying the development of OA are not yet fully understood. It is believed there are at least four possible pathways in which these nutrients can influence OA: protecting against oxidative damage by free radicals; modulating immune responses of inflammation; regulating cellular differentiation; and forming structural components in the synthesis of bone and collagen.(Sowers and Lachance, 1999) Several clinical studies of the effectiveness of different vitamins and mineral supplements in the treatment of OA have been conducted in order to find if they are safer and more effective than non-steroidal anti-inflammatory drugs (NSAIDs) or other drugs that are associated with adverse effects during long-term use in OA patients.

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4.3.2 Clinical trials of vitamins and mineral supplements

Research into the use of vitamins in the treatment of OA has mainly focussed on the degeneration of articular cartilage and the thickening of subchondral bone and the expression of antioxidative enzymes. Therefore, joint space narrowing (JSN), cartilage volume and serum vitamin levels have typically been used as outcome variables in clinical studies.

Vitamin A

Vitamin A has two forms naturally, one which is fat-soluble retinol generally derived from animal tissue, and another is a water-soluble pro-vitamin A (also known as beta- carotene) derived from plants and converted into retinol by the liver. Although vitamin A is necessary for growth and development of bone and soft tissue based on its effect on protein synthesis and bone cell differentiation, there is no unequivocal proof that vitamin A or supplementary retinol or beta-carotene can prohibit the initiation or progression of OA.(Sowers and Lachance, 1999) One study showed there was no significant difference in serum retinol values between OA patients and a normal matched control group (p<0.3), and a correlation among the serum osteocalcin, retinol and retinol binding protein in OA patients was not demonstrated even though the mean serum osteocalcin was higher than normal in OA.(Fairney et al., 1988)

Vitamin C

Vitamin C, ascorbic acid, cannot be synthesised by human bodies and must be obtained from dietary sources. It is believed that ROS which are produced in normal metabolism or inflammatory mechanisms can lead to some age-related diseases, and that ROS can also be generated by both chondrocytes and neutrophils at joint sites and cause damage to hyaluronate and the components of cartilage matrix such as proteoglycans and collagen.(Tiku et al., 2000, Yudoh et al., 2005) A subgroup study of the Framingham Osteoarthritis Cohort Study (McAlindon et al., 1996b) indicated that moderate to high antioxidant intake, especially vitamin C, could reduce the risk of cartilage loss and so protect against OA progression based on the outcomes of osteophytosis and joint space narrowing, but there was not enough evidence to support the contention that increased intake of antioxidant nutrients could reduce the incidence of knee OA. However, a systematic review did not find convincing

69 evidence of clinical efficacy in the treatment of OA by antioxidant vitamins A, C, or E.(Canter et al., 2007)

Vitamin D

Vitamin D, a compound derived largely from the diet or from cutaneous exposure to ultraviolet light, is probably the most controversial vitamin in the treatment of OA. Because normal bone metabolism depends on the presence of vitamin D, insufficiency of vitamin D may have adverse effects on calcium metabolism, osteoblastic activity, matrix ossification and bone density.(Grant, 2006, Parfitt et al., 1982) A study investigating the association between the serum levels of vitamin D, sunlight exposure and knee cartilage volume assessed by radiograph and magnetic resonance imaging (MRI) showed serum levels of 25-hydroxyvitamin D were significantly associated with moderate-to-severe JSN of knees, and that insufficiency of vitamin D also influenced loss of cartilage volume.(Ding et al., 2009) This study did not, however, find a significant association between vitamin D insufficiency and knee cartilage defects. The study also indicated that the sunlight effect on cartilage volume was still debatable even though there was some evidence which showed less knee cartilage loss amongst patients who had more sunlight exposure, since this might be due to increased physical activities during sunlight exposure rather than the sunlight itself. Another observational study suggested that the patients with low intake of vitamin D and low serum levels of 25-hydroxyvitamin D were associated with an increased risk of progression of existing knee OA but there was no evidence to support the contention that insufficiency of vitamin D would increase the risk of developing OA in a normal knee.(McAlindon et al., 1996a) This study mainly replied on radiographic signs, a self-administrated food frequency questionnaire and blood samples as methods of assessment. Interestingly, another epidemiologic study from the same research team on the offspring of the previous cohort and another cohort found no association between vitamin D levels and increased structural damage in existing knee OA as measured by JSN (using radiography) and by cartilage loss scores on MRI.(Felson et al., 2007)

In addition, a study that investigated altered bone turnover, vitamin D and calcium regulation with knee OA in female twins did not support findings of other studies that the level of serum vitamin D increased the risk of OA (which the authors point out

70 may have been due to investigators not adjusting for the confounders age and body mass index).(Hunter et al., 2003) However this study indicated bone resorption was increased in women with knee OA as manifested by urinary deoxypridinoline (DPD), which was consistent with metabolically active subchondral bone expressed as bone turnover in OA.

A recent large scale study (1248 subjects) demonstrated that improving the vitamin D status in the elderly could protect against the development and worsening of knee OA, especially in those with low bone mineral density (BMD).(Bergink et al., 2009) The effectiveness of vitamin D in the treatment of OA is still in need of further research.

Vitamin K

Vitamin K is an important regulator of bone and cartilage mineralisation, and is usually concentrated in green leafy vegetables in the form of phylloquinone.(Booth and Suttie, 1998) Results of a study supported a significant association (p ≤ 0.03) between low plasma levels of vitamin K and the increased presence of large osteophytes in both the hand and knee, but there was only a significant link between the phylloquinone level and JSN in hand OA but not in the knee OA.(Neogi et al., 2006) In addition, the researchers admitted that it is difficult to distinguish nutrient effects from effects of a healthy lifestyle, therefore, they recommended that caution should be exercised in interpreting the results.(Neogi et al., 2006)

Minerals

As for mineral research in musculoskeletal diseases, most studies have focused on rheumatoid arthritis (RA) rather than OA. Current research data suggests that copper, zinc and iron should be taken in adequate amounts from diet in order to reduce joint inflammation, but the results have been contradictory.(Rayman and Pattison, 2008) A small sample trial indicated that a multi mineral supplement derived from seaweed (Aquamin) was associated with a significant reduction in the WOMAC pain score similar to glucosamine sulphate,(Frestedt et al., 2008) but this study was only of short duration (12 weeks treatment) and no follow-up was conducted post-cessation of treatment. These results should be verified by further research. In addition, an animal study in STR/1N mice with mechanically induced OA found that a diet supplement (vitamins and selenium) could lead to decreased degeneration grading of OA lesions

71 of articular cartilage as evaluated histologically, which might be due to the increased expression of antioxidative enzymes.(Kurz et al., 2002)