Doxycycline may slow joint space narrowing (JSN) in the medial tibiofemoral compartment among patients with knee osteoarthtis (OA), according to results from a placebo-controlled trial published in the July 2005 issue of Arthritis and Rheumatism. The antibiotic, which researchers hope may be a disease modifying osteoarthritis drug (DMOAD), did not reduce severity of joint pain.
In the study of 431 overweight women with moderately advanced OA in one knee, those who received 100 mg doxycycline twice daily for 30 months showed 40% and 33% less JSN at 16 and 30 months, respectively, compared with patients taking placebo.
Laboratory and preclinical evidence suggests that doxycycline inhibits the degradation of type XI collagen, a minor collagen associated with articular cartilage, according to the researchers, headed by Kenneth D. Brandt, MD, of the division of rheumatology, Indiana University School of Medicine, Indianapolis.
The new research is "very interesting, and it has a basic science rationale behind it because we know that doxycycline inhibits collagenase enzymes, which we think are important in the matrix breakdown in OA, says Roland Moskowitz, MD, director of the division of rheumatic disease at University Hospitals of Cleveland and professor of medicine at Case Western Reserve University, both in Cleveland, Ohio. "If we can slow this down, we may be able to slow down and retard progression in disease."
However, despite significantly slowing of disease progression, doxycycline did not reduce the severity of joint pain, a result, the researchers point out, that may have been due to the low pain scores at baseline in both treatment groups.
Doxycycline significantly reduced the frequency with which subjects reported increases in knee pain of 20% or greater above the threshold documented at their previous semi-annual visit. Severity of joint pain was assessed every 6 months, after a washout period for all nonsteroidal anti-inflammatory drugs (NSAIDs) and other analgesics.
In both knees, the rate of JSN was more than twice as rapid among participants who reported frequent increases in knee pain as those with stable pain scores, which may validate the clinical importance of retardation of articular cartilage, the researchers point out.
Disease-free knees not affected
In the study, doxycycline had no effect on JSN or pain in disease-free knees. "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," they conclude.
Dr. Brandt and colleagues selected this particular patient population because previous data have shown that 47% of obese women with unilateral OA will develop radiographic evidence of incident OA in the contralateral knee within 2 years.
Fewer than 5% of all subjects reported side effects. Vaginitis, sun sensitivity, and gastrointestinal (GI) symptoms, all of which are recognized side effects of doxycycline, occurred more frequently in the active treatment group, the researchers report. Subjects in the active treatment group, however, experienced the unexpected side benefits of fewer urinary tract and upper respiratory tract infections than their placebo counterparts.
Are DMOADs really the answer?
In an editorial accompanying the new study, Paul Dieppe, MD, rheumatologist at the University of Bristol in Bristol, UK, tempers the enthusiasm for doxycycline as well as other potential and existing DMOADs.2
"We should not be chasing drugs as a means of modifying the outcome of OA; rather, we should be looking at simple ways to achieve the benefits that accompany mechanical interventions, such as joint distraction and osteotomy," he writes.
He also suggests that while the new study shows that some pharmacologic interventions may reduce the rate of cartilage loss, the link between the slowing of structural damage and pain reduction is not firmly established.
A DMOAD is "the holy grail we are all looking for," Dr. Moskowitz tells CIAOMed. Just as biologics and traditional disease modifying antirheumatic drugs are now used early in RA, "this would be the same leap in terms of a therapeutic approach, as we would be moving from treating symptoms to disease modifications," he says.
Still, Dr. Moskowitz concedes that doxycycline may not be the right agent because it can cause various side effects. "I would not be rushing to put everyone on doxycycline by any means," he says.
References:
- Brandt KD, Mazzuca SA, Katz BP, et al. Effects of doxycycline on progression of osteoarthritis: results of a randomized, placebo-controlled double blind trial. Arthritis Rheum. 2005;l52:2015-2025.
- Dieppe P. Disease modification in osteoarthritis: are drugs the answer? Arthritis Rheum. 2005;52:1956-1959.