SEX-DIFFERENCES IN RADIOGRAPHIC KNEE JOINT SPACE WIDTH (JSW) ACROSS OA STAGES, AND “GENUINE” SEXUAL DIMORPHISM IN JSW AND QUANTITATIVE CARTILAGE METRICS

INTRODUCTION

Radiographic joint space width (JSW) represents the traditional outcome variable for determining structural progression in knee OA [1]. The minimal distance in the medial compartment (mmJSW) is therefore often used as an entrance criterion for disease modifying OA drug (DMOAD) trials, to warrant a dynamic window for measuring JSW reduction over time [2]. Selecting participants above a certain mmJSW threshold may, however, favor inclusion of men (who generally exhibit greater body height and potentially JSW). In addition, for various cartilage metrics it is unclear whether sex-differences are truly genuine (independence of differences in anthropometrics variables that differ between women (W) and men (M)).

OBJECTIVE

We therefore studied to what extent JSW depends on sex in healthy participants and those with radiographic OA. Since adjustment for confounders and allometric modeling has limitations, we additionally explored sex-differences in cartilage metrics in subjects without radiographic disease, after closely matching for anthropometrics variables.

METHODS

In the OAI, mmJSW measurements and medial compartment joint space narrowing (JSN) grades (OARSI atlas) were obtained from weightbearing, fixed flexion X-ray. Here we studied the right knee from OAI healthy reference cohort (HRC) participants (n=35M, n=50W) that exhibited no (radiographic) signs, symptoms, or risk factors of OA, and OAI incidence and progression cohort knees, with medial JSN0 (50M, 124W), JSN1 (98M, 160W), JSN2 (154M, 169W), and JSN3 (44M, 28W). Knees with lateral JSN>0 were excluded. Of 1113 OAI participants (HRC and incident cohort), 767 had manual quantitative femorotibial cartilage measurements. Knees of M and W were matched (1:1) with the same body height (±1cm), body mass index (BMI; ±2kg/m2), and age (±5y) amongst participants without radiographic knee OA in both knees. 63 pairs could be precisely matched.

RESULTS

A statistically significant 18% (0.8mm; p<0.001) difference of mmJSW between M vs. W was found in HRC knees and a 17% (0.8mm; p<0.001) difference in medial JSN0 knees (Fig. 1). The sex-difference became less with increasing medial JSN grade; it was only 10% (0.4mm; p<0.001) in JSN1, 12% (0.3mm; p<0.001) in JSN2, and 0% (0mm; p=0.91) in JSN3 knees (Fig. 1). After matching for height, BMI, and age, M still exhibited a 17% greater mmJSW, 11% greater femorotibial cartilage thickness, 10% greater joint surfaces, and 23% greater cartilage volume, all differences being statistically significant (p<0.01; Fig. 2). Results for the medial/lateral femorotibial compartment were similar.

CONCLUSION

mmJSW is greater in M than W, particularly prior to the onset of radiographic OA and also when matching for anthropometric variables. Previously, cartilage and meniscus metrics were found to contribute differently to mmJSW in M and W [3]; hence, mmJSW change over time may be caused by different tissue pathologies. Therefore, sex-differences at earlier disease stages must be taken into account when using mmJSW diagnostically or for inclusion in clinical trials and we recommend sex-specific thresholds to avoid a sex-bias in recruitment. We found mmJSW as well as pre-morbid cartilage metrics to be genuinely greater in M than W, independent of body height, weight/BMI, and age. This provides clues to potentially greater structural vulnerability of the female knee.