Ncprheum_2005_193.indd

Doxycycline and osteoarthritis:
what does it show us?
Original article Brandt KD et al. (2005) Effects of
pain and function were used as secondary doxycycline on progression of osteoarthritis. Results of a randomized, placebo-controlled, double-blind trial. Arthritis
Rheum 52: 2015–2025
A total of 431 patients were deemed eligible for KEYWORDS doxycycline, joint-space narrowing,
this trial after successfully completing the run-in osteoarthritis
period and were subsequently randomized to receive 100 mg doxycycline (n = 218) or placebo BACKGROUND
(n = 213) twice daily. A total of 307 patients Previous laboratory studies have suggested completed the study, 149 from the doxycycline that the tetracycline antibiotic doxycycline group and 158 from the placebo group. At base- can be effective in slowing the progression of line, there were no significant differences in BMI, radiographic severity, minimum JSN, pain and functional impairment in the knee and previous OBJECTIVE
treatment for OA between groups. Assessment The objective of this trial was to determine of the index knee showed significant difference whether or not doxycycline can reduce disease between the two treatment groups with respect progression in patients with OA as determined to overall rate of JSN (P = 0.009), baseline joint- space width (JSW; P <0.001) and baseline pain (P <0.0001). At 16 months, the mean ± SD loss DESIGN AND INTERVENTION
of JSW in patients in the doxycycline group was 0.15 ± 0.42 mm, compared with 0.24 ± 0.54 mm in controlled trial included obese women aged the patients receiving placebo (adjusted P = 0.027). between 45 and 64 years with unilateral knee At the end of the trial, the mean ± SD loss of JSW OA diagnosed by radiography. Patients with was 33% less in the doxycycline group, compared secondary knee OA, inflammatory arthritis or with the placebo group of patients. Analysis a history of tetracycline allergy were excluded of data on the contralateral knee showed that from this trial. Following a 30-day run-in period both at 16 months and at the end of the study, of placebo treatment, participating patients loss of JSW was similar to that observed in the were randomized to receive either doxy cycline index knee. Reports of a mean increase in pain greater than 20% in the index knee at follow-up examinations of tibiofemoral joint-space (as measured on the WOMAC pain scale) were narrowing (JSN) were performed at baseline, fewer in the patients receiving doxycycline. No 16 months and at the end of the trial. Joint pain significant effect of doxycycline was observed in was assessed at 6-month intervals throughout JSN or pain of the contralateral knee.
CONCLUSION
OUTCOME MEASURES
The authors conclude that doxycycline is effec- The primary outcome measure in this study tive in reducing the rate of JSN in patients with was the rate of JSN in the medial tibiofemoral established knee OA, but does not reduce JSN compartment of the knee. Changes in knee 66 NATURE CLINICAL PRACTICE RHEUMATOLOGY 2006 Nature Publishing Group
symptoms; end-stage patients might have little Acknowledgments
or no cartilage and constant pain. Future trials Tim D Spector
might have to be performed on both ends of Associate Editor, Nature Clinical Practice.
the clinical spectrum unless MRI allows greater The article by Brandt and colleagues details the sensitivity to bone and cartilage changes.
Competing interests
long-awaited findings of a placebo-controlled Finally, having demonstrated that these drugs study of doxycycline in obese women with can retard joint damage, the following ques- moderate knee OA. A small (33%), but significant, tion needs to be addressed: is there a need for Correspondence
beneficial change in JSN was found in the index, new drugs and would patients adhere to new more severely affected, knee and trends towards treatment? Although a few patients adhere to symptomatic differences were also observed. No treatment with long-term antibiotics, most effects of doxycycline were found in the mildly patients and their doctors would feel uneasy affected contralateral knee, however, which was about doxycycline, even if patients coped with one of the primary outcome measures. Also, the the gastrointestinal symptoms, unless they mode of action of doxy cycline is still unclear and had inoperable disease and severe pain. It has Received 13 October 2005
might involve cartilage, bone, or both.
been argued that this ‘successful’ trial might Accepted 12 December 2005
This study is important for several reasons. lead to further futile efforts to develop drugs www.nature.com/clinicalpracticedoi:10.1038/ncprheum0101 Firstly, this is a proof-of-concept study that for a condition that can be easily treated with shows that a drug can reduce cartilage changes sticking plaster, osteo tomies and joint replace- in the knee in less than 3 years. Studies of gluco- ment.5 The millions of patients who take samine have inconsistently reported similar long-term daily glucosamine or chondroitin effects, but have not been widely accepted without symptomatic relief, in the hope that it for reasons of methodology and biology, and will eventually help, suggest that there is a real a study of dia cerhein showed a smaller effect demand for disease-modifying drugs and this on the hip; treatment reduced JSN but did not nihilistic future view of pharmaceuticals for OA is not shared by most. This author would rather Secondly, the authors illustrate how difficult it take a hypothetical safe drug for years, such as a is to perform such studies effectively. This study monthly bisphosphonate, than take any chances took almost 15 years, from planning to publica- with the surgeon’s knife. Further drug studies tion, using ‘state-of-the-art’ X-ray techniques in OA are, therefore, eagerly anticipated.
which now look outdated. The study coincided References
with the lack of success of the large and expensive et al. (2001) Evaluation of the structure- risedronate OA program, which might have been modifying effects of diacerein in hip osteoarthritis: ECHODIAH, a three-year, placebo-controlled trial. partly explained by the sensitivity of the X-ray Evaluation of the chondromodulating effect of methods and lack of progressors;2 it is likely that diacerein in OA of the hip. Arthritis Rheum 44:
this will be one of the last large X-ray therapeutic et al. (2005) Effect of risedronate on joint studies performed. Meanwhile, the FDA and the structure and symptoms of knee osteoarthritis: results European Medicines Agency (EMEA) have yet to of the BRISK randomised controlled trial. Arthritis Res decide on rules for a therapeutic alternative using Ther 7: R625–R633
et al. (2004) Predictors of structural progression in knee osteoarthritis over 24 months Thirdly, it is difficult to correlate improve- [abstract #254]. Arthritis Rheum 254: S149
PRACTICE POINT
ments in JSW with symptoms. Until recently et al. (2004) Pitfalls in the accurate measurement of joint space narrowing in semiflexed, there was little supporting natural-history data, anteroposterior radiographic imaging of the knee. although larger studies are now rectifying this.3 Arthritis Rheum 50: 2508–2515
Any lack of correlation might be caused by lack 5 Dieppe P (2005) Disease modification in osteoarthritis: are drugs the answer? Arthritis Rheum 52: 1956–1959
of efficacy or X-ray sensitivity,4 but is more likely to be because of case selection. Patients TD Spector is a Consultant Rheumatologist and a with early-stage disease have sufficient cartilage Professor of Genetic Epidemiology at St Thomas’ and measurable, but only mild or intermittent, 2006 Nature Publishing Group

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