Doxycycline slows x-ray progression in knee OA, but what is the significance of this exciting finding?

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Doxycycline slows x-ray progression in knee OA, but what is the

significance of this " exciting finding " ?

Jul 7, 2005 Zosia Chustecka

Indianapolis, IN - The trial showing that the tetracycline antibiotic

doxycycline slows down the radiographic progression of osteoarthritis

(OA) in established knee OA, which has led to suggestions that the drug

may be a disease-modifying agent for osteoarthritis (DMAOA), has been

published in the July 2005 issue of Arthritis & Rheumatism [1]. The

study, involving 431 patients and headed by Dr Brandt (Indiana

University School of Medicine, Indianapolis), was first presented at

the 2003 meeting of the American College of Rheumatology and was

reported by rheumawire in detail at that time.

" This is an exciting finding, " says an accompanying commentary from Dr

Dieppe (University of Bristol, UK) [2]. However, it adds, " Many

concerns remain about the meaning, significance, and implications of

this work. " Although the effect on radiographic progression of

established knee OA was significant, there was little effect on

symptoms such as pain, leading Dieppe to comment, " I myself would not

want to take a drug that may improve my joint space width [JSW] if it

were not going to help my pain or function. "

" In my view, we should not be chasing drugs as a means of modifying the

outcome of OA, " Dieppe continues. " Rather, we should be looking at

simple ways to achieve the benefits that accompany mechanical

interventions such as joint distraction and osteotomy. . . . While I

applaud the superb work of Brandt and his colleagues, I worry that it

might, paradoxically, increase the trend toward too much

'medicalization' of people with OA as well as the rush to prescribe

drugs for them that might affect radiographic findings but with unknown

and potentially serious toxicity. "

Significant effect on x-ray progression

The trial was conducted in a group of obese women (aged 45-64 years)

who had x-ray evidence of OA in one knee but not the other when they

were assessed on a standing anteroposterior (AP) radiograph. An earlier

study in a similar group of patients had suggested that about half of

these women would develop OA in the contralateral knee within 24

months. Hence, when the trial began, Brandt et al hoped that they would

be able to investigate the effect of doxycycline on established OA in

the index knee and also study the effect of the drug on the development

of OA in the contralateral knee. However, as they explain in the

discussion, during the course of the study they realized that while the

contralateral knee was radiographically normal in the conventional

standing AP view, x-rays taking at other angles (in the lateral

semiflexed AP view and/or the patellofemoral view) showed evidence of

OA. " Hence, this study did not assess the effect of doxycycline on

incident OA in the contralateral knee, but rather on the progression of

rather mild OA in that joint, which was not apparent in the baseline

standing AP view, " they write.

The treatment group took oral doxycycline 100 mg daily for 30 months.

The drug showed a statistically significant effect on radiographic

progression of OA in the index knee: at 16 months, x-rays showed that

the mean loss of joint space width was 40% less in the group taking the

drug than the group taking placebo, and after 30 months, it was 33%

less. However, there was no difference between the drug and placebo

groups in the effect seen on the contralateral knee (the relatively

disease-free, or very mildly diseased, knee). Also, there were no

significant differences between the groups in the severity of pain

reported, although the researchers note that mean pain scores at

baseline were low and remained low throughout the trial, " suggesting

the presence of a floor effect. " There was one significant effect on

one pain measurethe doxycycline group showed a reduction in the

frequency of follow-up visits at which subjects reported a 20% or

greater increase in pain in the index knee relative to the level of

pain they had at their previous visit.

While describing these results as " promising, " the commentary asks

whether such a small statistically significant effect is of any

clinical significance. The women participating in this trial had

relatively mild knee OA and were not receiving extensive treatment for

their condition, Dieppe points out. While this situation reduces the

scope for demonstrating improvement, it also " raises the question of

whether small change in someone with early disease has much meaning in

the life of that individual. " He also wonders about how generalizable

the findings may be, pointing out that OA may be rather different in

men than in women and in early and late stages and is affected by

different factors at other sites in the body.

Adverse events that occurred more frequently in the group taking

doxycycline than placebo were " well recognized side effects " of the

drug and included monilial vaginitis, sun sensitivity, and nonspecific

gastrointestinal symptoms, the researchers note. Patients in the

treatment group reported fewer urinary-tract infections, and there was

a trend toward fewer respiratory-tract infections. The antibiotic was

investigated in OA because of its effect of inhibiting

metalloproteinases, which may prevent cartilage damage, but it also

affects bones and other tissues and enzyme systems, Dieppe comments.

This should " raise concerns about its long-term use in older people

with chronic disease, most of whom will have comorbidities, " he

cautions.

Results are " confusing "

Approached for comment, leading osteoarthritis researcher Dr

Felson (Boston University, MA), who acts as an editorial consultant to

www.jointandbone.org, describes the results of the doxycycline trials

as " confusing. " He points out: " People in this trial had two knees

affected by OA. For one knee, doxycycline protected against joint-space

loss (probably cartilage loss). For the other knee, it did not (not

even close). Further, there was no effect on knee pain. I am not

certain what to do about these findings in terms of patient treatment.

Given the absence of any effect on symptoms, I don't believe that

patients with knee OA will or should be willing to take this treatment

long term. "

" The absence of consistent results for both knees makes me skeptical

the drug had any effect, " Felson tells rheumawire, although he adds

that doxycycline does have favorable effects on OA in animal models of

disease.

In their discussion of the results, Brandt et al comment on the lack of

effect in the contralateral knee. Although the joint-space narrowing

(JSN) was identical in the treatment and placebo groups at 16 months,

the rate was numerically greater in the doxycycline group at 30 months,

although the difference was not statistically significant. " The lack of

evidence that doxycycline slowed the rate of JSN in the contralateral

knee may have been due to the fact that some matrix degradation

pathways are more important in the later stages of OA than in the

earlier stages. Doxycycline may have interfered with processes driving

cartilage breakdown in the index knee that were not (yet) operative in

the contralateral knee, " they write.

Asked whether these latest findings have practical applications as yet,

Felson says: " Here's what I'm doingfor those with knee OA, I am not

using doxycycline. In my view, this is a mechanically based disease

and, in most cases, a drug with a questionable chondroprotective effect

will not help. However, for those with generalized OA (including hand

OA and other joints), in which there are no effective drugs, I am

inclined to suggest doxycycline to patients, mostly because it's safe

and may have a protective effect on cartilage loss. In my view, persons

with generalized OA more often have a primary OA process that may

involve a predilection for cartilage loss even in a noninjurious

mechanical environment. These types of patients may be more likely to

respond. "

Sources

1. Brandt KD, Mazzuca SA, Katz BP, et al. Effects of doxycycline on

progression of osteoarthritis. Arthritis Rheum 2005; 52:2015-2025.

2. Dieppe P. Disease modification in osteoarthritis: are drugs the

answer? Arthritis Rheum 2005; 52:2015-2025.