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CME Released: 7/1/2005; Reviewed and Renewed: 6/30/2006
Valid for credit through: 6/30/2007
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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.
Arthritis Rheum. 2005;52:2015-2025
