July 1, 2005 — Doxycycline may slow progression of osteoarthritis (OA)
of the knee, according to the results of a randomized, double-blind
trial published in the July issue of Arthritis and Rheumatism.

"Selection of doxycycline as a potential disease-modifying OA drug was
based not on the premise that OA is an infectious disease, but rather
on results of in vitro studies showing 1) that doxycycline inhibited
the degradation of type XI collagen, one of the minor collagens of
articular cartilage, by 72-kd gelatinase; 2) that the presence of
doxycycline during activation of procollagenase resulted in generation
of low molecular weight, catalytically inactive fragments and marked
reduction in the levels of active enzyme; and 3) that doxycycline
inhibited messenger RNA for inducible nitric oxide synthase, an enzyme
present in large quantities in OA cartilage, the activity of which
results in secretion of matrix metalloproteinases (MMPs) by the
chondrocyte," write Kenneth D. Brandt, from the Indiana University
School of Medicine in Indianapolis, and colleagues.

In this study, 431 obese women age 45 to 64 years with unilateral
radiographic knee OA were randomized to receive 30 months of treatment
with 100 mg of doxycycline or placebo twice daily. The primary outcome
measure was joint space narrowing (JSN) in the medial tibiofemoral
compartment, measured manually in fluoroscopically standardized
radiographic examinations performed at baseline, 16 months, and 30
months. At six-month intervals, patients reported severity of joint
pain.

Of all randomized study subjects, 71% completed the trial and 85%
underwent radiographic examination at 30 months. In women who
completed the study per protocol, adherence to the dosing regimen was
91.8%.

Compared with the placebo group, mean loss of joint space width in the
index knee in the doxycycline group was 40% less after 16 months of
treatment (0.15 ± 0.42 mm vs 0.24 ± 0.54 mm) and 33% less after 30
months (0.30 ± 0.60 mm vs 0.45 ± 0.70 mm).

Pain scores in both treatment groups were low at baseline and remained
low during the trial, suggesting the presence of a floor effect,
because doxycycline was not associated with lower mean severity of
joint pain. However, the frequency of follow-up visits during which
the subject reported at least a 20% increase in pain in the index
knee, compared with the previous visit, was lower in the doxycycline
group.

Doxycycline had no apparent effect on either JSN or pain in the
contralateral knee. In both treatment groups, study subjects who
reported at least a 20% increase in knee pain at most follow-up visits
had more rapid JSN than did those with stable pain.

"Doxycycline slowed the rate of JSN in knees with established OA," the
authors write. "Its lack of effect on JSN in the contralateral knee
suggests that pathogenetic mechanisms in that joint were different
from those in the index knee."

Study limitations include relatively small sample size; relatively
brief duration of follow-up; highly selected population, limiting
generalizability of study results; inability to extrapolate the
results to other joint sites; and possibly incomplete blinding.

The National Institutes of Health supported this study in part. Dr.
Brandt has received consulting fees of more than $10,000 per year from
Pfizer.

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