Arthritis & Rheumatism, Volume 60,
October 2009 Abstract Supplement
The 2009 ACR/ARHP Annual Scientific Meeting
Philadelphia October 16-21, 2009.
Varus Malalignment Diminishes the Structure-Modifying Effects of Doxycycline (Doxy) in Patients with Knee Osteoarthritis
Chakr1, Rafael, Brandt2, Kenneth D., Ang1, Dennis C., Mazzuca1, Steven A.
The inconsistent results of clinical trials of structure-modifying osteoarthritis drugs (SMOADs) may be due to the presence of abnormal intra-articular stresses that preclude potential benefit from pharmacotherapy. Because varus malalignment increases loading of the medial tibiofemoral compartment and, hence, the risk of OA progression, it may attenuate the benefit of a SMOAD aimed at slowing joint damage. Herein we describe results of a recent subgroup analysis of our previously published randomized clinical trial (Arthritis Rheum 2005;52:2015) asking whether varus malalignment reduced the structure-modifying effect of doxy in OA.
In this placebo-controlled trial, 379 subjects underwent an interim (16-mo) and/or close-out (30-mo) x-ray exam. All were obese, 4564 year old women who had unilateral Kellgren and Lawrence grade 23 knee OA at baseline. The primary outcome was medial compartment joint space narrowing (JSN) measured manually in semiflexed anteroposterior radiographs acquired with standardized fluoroscopic positioning. The anatomic-axis angle (AAA) was measured in each baseline radiograph by one of two readers (inter-reader ICC = 0.95) and transformed to an estimate of the mechanical-axis angle (MAA) using a validated regression equation (MAA=0.915*AAA+13.895, R2=0.77) (Arthritis Care Res 2006;55:306). Knees with MAA<178° were classified as varus. Treatment group comparisons were performed using a mixed-effect linear model and adjusted for age, BMI, visit (16- or 30-month), clinical center and baseline joint space width.
In our published comparison with placebo, doxy slowed the annualized rate of medial JSN in index (OA) knees by 39% at 16 months (0.11 vs. 0.18 mm/yr, P=0.027) and by 33% at 30 months (0.12 vs. 0.18 mm/yr, P=0.017). Our current subgroup analyses of non-annualized JSN (table) indicated, however, that among varus OA knees, JSN occurred at similarly rapid rates in both treatment groups over both intervals (0.20 0.27 mm/yr). In contrast, among non-varus knees, 16-mo JSN in the doxy group was 43% slower than in the placebo group (0.09 vs. 0.16 mm/yr, P=0.080), and 30-mo JSN was 38% slower (0.10 vs. 0.17 mm/yr, P=0.026).
Non-annualized medial compartment JSN (Mean ± SD, mm) by treatment group: results in varus and non-varus OA knees
|Varus OA Knees||Non-varus OA Knees|
|16-mo JSN||0.26 ± 0.39||0.36 ± 0.57||0.230||0.12 ± 0.42||0.21 ± 0.52||0.080|
|N of knees||37||45||151||146|
|30-mo JSN||0.49 ± 0.64||0.55 ± 0.62||0.448||0.26 ± 0.58||0.42 ± 0.73||0.026|
|N of knees||37||42||146||138|
These post hoc analyses show that varus malalignment negated the slowing of structural progression of medial compartment OA by doxy. Given the prime importance of abnormal intra-articular stress in the etiopathogenesis of common, garden-variety OA (Brandt et al. Seminars Arthritis Rheum. In press), it is likely that other conditions which, like malalignment, increase joint loading (e.g., genetic or developmental abnormalities in joint shape, neuromuscular abnormalities that impair micro-coordination [sarcopenia, proprioceptive defects]) can also render SMOADs ineffective.
To cite this abstract, please use the following information:
Chakr, Rafael, Brandt, Kenneth D., Ang, Dennis C., Mazzuca, Steven A.; Varus Malalignment Diminishes the Structure-Modifying Effects of Doxycycline (Doxy) in Patients with Knee Osteoarthritis [abstract]. Arthritis Rheum 2009;60 Suppl 10 :829