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DURHAM, N.C. -- High doses of vitamin C increase the severity of spontaneous knee osteoarthritis in an animal model of the disease, according to a new study by Duke University Medical Center researchers.

The results contradict previous short-term studies in guinea pigs and an epidemiologic study in humans that suggested vitamin C might protect against osteoarthritis, said lead investigator Virginia Kraus, M.D., associate professor of medicine at Duke University Medical Center. The study was published in the June 2004 issue of Arthritis & Rheumatism. The research was sponsored by the Arthritis Foundation and the National Institutes of Health.

In the Duke study, the researchers fed guinea pigs -- which develop knee osteoarthritis in a manner remarkably similar to humans -- low, medium and high doses of vitamin C during an eight-month period. The researchers found that high-dose guinea pigs developed more cartilage damage and had more bony spurs form in their knee joints than did the medium- and low-dose groups. The researchers' examination of the spurs revealed a possible cause for the link between vitamin C and osteoarthritis. They discovered a protein in the spurs that leads to spur formation and can be activated by vitamin C.

Because this study indicates potential drawbacks to long-term use of high-dose vitamin C supplements, adults should not supplement their dietary vitamin C levels above the recommended dietary allowance (RDA), Kraus said. The RDA for men is 90 milligrams per day and the RDA for women is 75 milligrams per day. A diet that includes five servings of fruits and vegetables a day supplies about 200 milligrams per day of vitamin C.

"It's possible that brief exposure to high levels of vitamin C offers antioxidant effects with a minimum of side effects, while prolonged exposure results in deleterious effects," Kraus said. A randomized, controlled clinical trial in humans would be required to definitely resolve the issue of vitamin C dosing, she said.

Like humans, the Hartley strain of guinea pigs lack a gene for making vitamin C, leaving them dependent on vitamin C in their diet. Each of the 46 guinea pigs followed in the study were fed standard chow supplemented by a custom-made food with three different concentrations of ascorbic acid (vitamin C). The study began when the guinea pigs were 4 months old.

The medium dose, 30 milligrams per day, was the guinea pig equivalent of the RDA for vitamin C in humans -- comparable to a person consuming five fruit and vegetable servings. The lower dose, about three milligrams per day, was the minimum necessary to prevent scurvy in the guinea pigs. The high dose was 150 milligrams per day, an amount shown to protect against surgically-induced osteoarthritis in a short-term guinea pig study. The equivalent human dose is 1,500 to 2,500 milligrams per day.

The antioxidant properties of vitamin C were posited as one explanation for the earlier positive results, because oxygen radicals can degrade collagen and proteoglycan, a connective tissue protein. The vitamin has also been shown to help collagen synthesis and stimulate production of key components of collagen.

The Duke researchers did find an association between higher levels of vitamin C and increasing collagen in knee cartilage. However, there was also a strong correlation between vitamin C dose and the severity of disease, including the number and size of osteophytes, or bony spurs at the knee joint. The researchers found an important protein in bone growth called active transforming growth factor beta almost exclusively in the osteophytes. The protein is known to cause joint degeneration and spur formation, and vitamin C can convert this protein from an inactive to an active state, Kraus said. This conversion means that vitamin C's ability to enhance collagen synthesis and activate transforming growth factor beta might be the reason guinea pigs fed high doses of vitamin C developed more osteoarthritis, she said.

Another factor considered in the study was the role of weight as a risk for osteoarthritis. The guinea pigs fed a low dose of vitamin C had a lower mean weight from 5 months to 8 months of age than the other guinea pig groups. Thus, the researchers cannot rule out weight as a protective factor for osteoarthritis between the low dose group and the other guinea pig groups. Still, the weights of the medium dose and high dose guinea pig groups were similar throughout the study, and analyses restricted to these two groups showed a significant worsening of osteoarthritis with increasing levels of vitamin C.

Collaborators on the study include Janet Huebner, Thomas Stabler, Charlene Flahiff, Loria Setton, Christian Fink and Amy Clark, all of Duke. Vladimir Vilim of the Institute of Rheumatology in Prague also contributed to the research.