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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.