Alternative Medicine Review 2004 (Sep); 9 (3): 275–296 ~ FULL TEXT
Wang Y, Prentice LF, Vitetta L, Wluka AE, Cicuttini FM
Graduate School of Integrative Medicine, Swinburne University of Technology and Department of Epidemiology and Preventive Medicine, Monash University, Australia
Osteoarthritis (OA) is the most common form of joint disease and cause of musculoskeletal disability in the elderly. Conventional management of OA primarily focuses on the relief of symptoms, using agents such as analgesics and non-steroidal anti-inflammatory drugs (NSAIDs). These drugs, however, are associated with significant side effects and fail to slow the progression of OA. Several nutritional supplements have been shown to be at least as effective as NSAIDs at relieving the symptoms of OA, and preliminary evidence suggests several of these supplements may have a role in influencing the course of OA. The purpose of this article is to review the available literature on the effectiveness and safety of nutritional supplements for the treatment of OA.
From the FULL TEXT Article
A variety of reactive oxygen species (ROS) are formed continuously in tissues by endogenous and exogenous mechanisms.  There is emerging evidence that ROS may have a role in the pathogenesis of OA. [13,14] The antioxidants ascorbic acid, alpha-tocopherol, and beta-carotene are free-radical scavenging nutrients that protect
cells from damage by pro-oxidants. [15,16]
Ascorbic Acid (Vitamin C)
Ascorbic acid stimulates collagen synthesis and modestly stimulates synthesis of aggrecan (a proteoglycan present in articular cartilage).  Sulfated proteoglycan biosynthesis is significantly increased in the presence of ascorbic acid.  In human plasma, ascorbate is the only antioxidant that can completely protect lipids from detectable peroxidative damage induced by aqueous peroxyl radicals. Ascorbate appears to trap virtually all peroxyl radicals in the aqueous phase before they diffuse into the plasma lipids. Ascorbate is a highly effective antioxidant, as it not only completely protects lipids from detectable peroxidative damage, but also spares alpha-tocopherol, urate, and
Evidence from Animal Studies
In guinea pigs, which, like humans, cannot make vitamin C, supplementation with vitamin C had a protective effect on experimentally induced cartilage degeneration of the knee. [20-22] Schwartz et al investigated the effect of
variation in dietary ascorbic acid on surgically induced OA in the stifle joints of guinea pigs. [20,21]
Guinea pigs were maintained either on a high (150 mg/day) or low (2.4 mg/day) dietary intake of vitamin
The animals maintained on the high vitamin C level consistently showed less severe joint damage than animals on the lower level. In a later experiment, Meacock et al studied the appearance and progression of surgically induced OA in the
cartilage of the hind knees of guinea pigs.  The animals were maintained on either a standard diet
or a diet containing extra ascorbic acid in drinking water. It was reported that the extra ascorbic acid had a slight chondroprotective effect on the development of spontaneous lesions.
Evidence from Human Studies
In the Framingham Osteoarthritis Cohort Study, a moderate intake of vitamin C (120-200 mg/day) resulted in a three-fold lower risk of OA progression. The association was strong and highly significant, and was consistent between sexes,
among non-supplement users, and among individuals with different severities of OA. The higher vitamin C intake also reduced the likelihood of development of knee pain. Vitamin C had no significant effect on the incidence of OA.  Despite these data, few randomized, controlled trials have examined the effect of vitamin C on human OA.
A multicenter, double-blind, randomized, placebo-controlled, crossover trial was performed on 133 patients with radiographically verified symptomatic OA of the hip and/or knee joints. The patients were treated with 1 g calcium ascorbate (containing 898 mg vitamin C) or placebo daily for 14 ± 3 days, separated by 7 ± 3 days wash out. The main outcome measured was difference on the 100 mm visual analog scale (VAS) score for pain. The secondary outcomes were Lequesne score for function and patient preference. Calculated on an intention-to-treat principle and using
the VAS scale, calcium ascorbate reduced pain significantly compared to placebo. Similar superiority was found for the Lequesne index and patient preference. The demonstrated effect was less than half as pronounced as commonly reported for
NSAIDs.  Further controlled trials with longer duration are needed.
Alpha-tocopherol (vitamin E) is the only significant lipid-soluble, chain-breaking antioxidant present in plasma and red blood cells. 
In vitro and Animal Studies
In vitro and in vivo laboratory studies suggest that vitamin E may enhance chondrocyte growth, provide protection against ROS, and modulate developing OA. [25,26] In addition, vitamin E has been reported to have anti-inflammatory
activity.  Animal research demonstrates the effectiveness of vitamin E supplementation in inhibiting
the elevation of free-radical concentration associated with arthritis. 
It has been demonstrated that OA patients have dietary intakes of vitamin E lower than the Recommended Dietary Allowance.  A number of studies have examined the effect of vitamin E on both symptoms and structural changes in OA.
Effect of Vitamin E on Symptoms of OA
Several clinical studies have found therapeutic benefits of alpha-tocopherol in the symptomatic treatment of OA over a short term. [30-32] In a simple-blind, crossover study, in 32 subjects with OA, vitamin E supplementation (600 mg/day for 10 days) was significantly more effective than placebo in relieving pain in patients with established
OA.  A multicenter, placebo-controlled, doubleblind trial also demonstrated vitamin E (400 IU for six weeks) was significantly superior to placebo for relief of pain and the requirement for additional analgesic medications in 50 patients with OA.
Mobility improved in the group treated with vitamin E, although this observation did not reach statistical significance.  Short-term clinical trials with a small number of patients suggest vitamin E treatment may be more effective than placebo in relieving pain, [30,31] and may have similar efficacy to diclofenac.  Two larger studies, performed over a longer period, have provided conflicting results. A randomized, double-blind, placebo-controlled
trial of 500 IU vitamin E daily to 77 patients for six months revealed neither vitamin E nor placebo showed a significant improvement in pain, stiffness, or physical function. 
A similar result was obtained in a two-year, randomized, double-blind, placebo-controlled trial of vitamin E (500 IU daily)
in 136 patients with OA.  The positive effect of vitamin E on pain relief in OA demonstrated in short-term studies has not been supported by the results of well conducted studies over longer periods of time. Further larger studies of longer duration are warranted.
Effect on Structural Changes in OA
The Framingham Cohort Study showed higher dietary intake of vitamin E reduced the risk of OA progression in men only, while vitamin E had no significant effect on the incidence of OA.  On the other hand, a two-year, randomized,
double-blind, placebo-controlled trial examining the effect of vitamin E supplementation (500 IU) on knee cartilage volume in 136 patients with OA of the knee showed no significant effect of supplemental vitamin E or the major dietary antioxidants (vitamin C, beta-carotene, or retinol activity equivalents) on the rate of loss of tibial knee cartilage. 
Further research is required to investigate the possible effect of supplementation of vitamin E on the structural changes of OA.
Beta-carotene and other Carotenoids
Beta-carotene, an unusual type of lipid antioxidant, is neither a peroxide-decomposing preventive antioxidant nor a conventional chainbreaking antioxidant. Beta-carotene can behave as a radical-trapping antioxidant only at oxygen pressures
significantly less than 150 torr, the pressure of oxygen in normal air. At elevated oxygen pressures, beta-carotene loses its antioxidant activity and shows an autocatalytic pro-oxidant effect.  Data from the Framingham Cohort Study
showed beta-carotene reduced the risk of progression of knee OA, but only after adjustment for vitamin C intake. It had no significant effect on the incidence of OA. 
De Roos et al examined the association between carotenoids and OA with a case-control study by measuring serum levels of nine naturally occurring carotenoids and prevalent radiographic knee OA.  Except for beta-carotene, none of the compounds examined in this study had been previously evaluated for involvement in the OA disease process. Participants with serum levels of lutein or beta-cryptoxanthin in the highest tertile were approximately 70-percent less likely to have
knee OA than controls. Those in the highest tertile of trans-beta-carotene and zeaxanthin were more likely to have knee OA. Their findings in reference to beta-carotene differed from those of the Framingham cohort, in which low intake of betacarotene was associated with knee OA progression, but not incidence.
This difference may be attributable to differences in measurement of carotenoids. The De Roos study examined the relationship of serum levels of carotenoids, while the Framingham cohort study used dietary levels. [14,36]
Lutein has been the subject of considerable research as an antioxidant, particularly in the context of age-related macular degeneration, in which a low density of macular pigment is thought to be a risk factor. Lutein has been shown to increase
the level of macular pigment and has also been shown to protect liver cells from oxidative damage. [37,38] The cryptoxanthins (including betacryptoxanthin) have also been the focus of research because of their potential antioxidant properties. [39-41] However, the effects of lutein or beta-cryptoxanthin on cartilage or other joint components have not been evaluated.
Normal bone and cartilage metabolism depends on the presence of vitamin D. Suboptimal levels of vitamin D have adverse effects on calcium metabolism, osteoblastic activity, matrix ossification, bone density, and articular cartilage
turnover. [42-45] Vitamin D has a direct affect on articular cartilage by stimulating synthesis of proteoglycan by mature articular chondrocytes in tissue culture.  However, White-O’Connor et al found dietary intake of vitamin D in OA patients is below 80 percent of the Recommended Dietary Allowance. 
Low vitamin D levels are associated with progression of radiographic OA. A longitudinal study showed that hips of women with 25-hydroxy vitamin D levels in the lowest tertile had increased loss of joint space and a trend toward a greater
increase in radiographic features score. There was no association of 1,25-dihydroxy vitamin D with change in hip OA.  In the Framingham study of 556 participants, risk of OA progression increased three-fold in participants in the middle and lower tertiles for both vitamin D intake and serum levels of vitamin D. Incident OA of the knee was not
consistently related to either intake or serum levels of vitamin D. 
A similar relationship has been found between vitamin D levels and incident OA in another longitudinal study of 237 participants followed for eight years.  Subjects in the lowest and middle tertiles had a three-fold increased risk of developing incident radiographic OA, characterized by the development of joint space narrowing, compared with subjects in the highest tertile of 25-hydroxy vitamin D levels. Serum 25-hydroxy vitamin D levels were not associated with
incident OA defined by osteophytes or summary grade of radiographic features of OA (osteophytes, joint space narrowing, sclerosis, cysts and deformity). These studies suggest adequate intake of vitamin D may slow the progression and possibly
help prevent the development of OA.
Vitamin B Group
More than 50 years ago, William Kaufman reported that high-dose niacinamide, a form of vitamin B3, was beneficial in OA and rheumatoid arthritis. He documented improvements in joint function, range of motion, increased muscle strength and endurance, and reduction in erythrocyte sedimentation rate (ESR) over long periods in these patients. Reported effects began after 1-3 months on niacinamide and reached their peak between one and three years. [51,52] But his studies,
as well as similar reports by Abram Hoffer, MD,  who has treated arthritic patients with high-dose niacin or niacinamide, involved only uncontrolled series of patients.
In 1996, Jonas et al published the results of a parallel, double-blind, placebo-controlled study in which 3 g niacinamide daily was compared with placebo during three months of supplementation in 72 patients with OA.  Global arthritis impact improved by 29 percent in subjects on niacinamide and worsened by 10 percent in placebo subjects. Pain levels did not change, but those on niacinamide reduced anti-inflammatory medication by 13 percent. Niacinamide reduced ESR
by 22 percent and increased joint mobility by 4.5 degrees over controls. Side effects were mild but higher in the niacinamide group. This study suggests niacinamide may have a role in the treatment of symptoms in OA.
Folate and Cobalamin
Carmel et al studied the effect of cobalamin (vitamin B12) on the osteoblast-related proteins in 12 cobalamin-deficient patients given cobalamin replacement (form unspecified).  They found a rise in levels of serum osteocalcin, a protein dependent on vitamin K and synthesized only by osteoblasts. Skeletal alkaline phosphatase also increased. The researchers suggest osteoblast activity depends on cobalamin and bone metabolism is affected by cobalamin deficiency. While it is applicable to osteoporosis, osteoarthritis is a disease of both cartilage and the subchondral bone. There is evidence to suggest medications that affect bone (bisphosphonates) also affect formation of osteophytes in animals. 
An increased prevalence of cobalamin and folate deficiencies has been reported in elderly people. [57-60] A dietary survey of patients with OA found this population to have folate intakes lower than the Recommended Dietary Allowance. [29,47] A controlled, double-blinded, crossover study reported the effect of folate and cobalamin supplements in 26 subjects diagnosed for an average 5.7 years with idiopathic OA of the joints in the hands. For all subjects, mean right and left hand grip values were higher with combined cobalaminfolate ingestion than with other vitamin supplements
and were equivalent to NSAIDs use. The number of tender hand joints was greater in those using NSAIDs when compared to cobalaminfolate supplementation (cobalamin 20 mcg/folate 6,400 mcg daily). No side effects were recorded with the vitamin combination.
Dietary records of most of these subjects showed adequate daily dietary intake of folate and cobalamin. 
Further research is needed on vitamin deficiencies suggested as possible causes of OA, before dietary supplementation can be definitively prescribed for prevention or treatment. Similarly, the value of other nutritional supplements, including
supraphysiological doses of antioxidant vitamins, remains to be determined.