Metabolic syndrome, advanced glycation end products and knee osteoarthritis progression: a report from OAI

Purpose: There is evidence that metabolic factors play an important role in the natural history of osteoarthritis. Metabolic syndrome is associated with alterations in inflammation, superoxide anion production, advanced gylcation end products, adipokines, impaired fibrinolysis which have been shown to effect cartilage, bone, and ligament biology. Recent studies have found a cross sectional relationship metabolic syndrome and KL grade of knee OA.

Hypothesis: Participants with increased number of metabolic syndrome characteristics and higher levels of advanced glycation end products (AGEs) would be associated with more joint space narrowing and greater knee osteoarthritis progression.

Methods: A metabolic syndrome like (Metsyn) score (0,1,2,3= 3 or more components) was created with equal weight for waist circumference (35 inches in women and 40 inches for men), self-reported diabetes, dyslipidemia or hypertension at baseline. Levels of AGEs were determined using spectroscopic measurement of dermal Advanced Glycation End products (sAGE) at the 36th month visit. We measured SAGE using the SCOUT DS (Vera light Inc., Albuquerque, New Mexico). We used an excitation wavelength of 375nm and emission wavelengths of 435-660nm. This wavelength is correlated with cross-links of collagen, FAD, and NADH. A mathematical algorithm is applied to spectrum results to adjust for age, hemoglobin, skin pigmentation and light scattering. We used medial joint space width (JSW) at x=0.25 with the best responsiveness of change to quantify JSW at 48 months and the progression of OA from baseline to 48 months, with positive scores representing greater narrowing. For the progression analysis, we excluded knees with severe radiographic OA defined as the baseline Kellgren and Lawrence (KL) grade of 4 or those with primarily lateral joint space narrowing (JSN). Generalized mixed models adjusting for age, gender, and baseline KL grade and knee within person correlations were used to evaluate change in JSW.

Results: 456 individuals had sAGE data, metsyn scores and JSW evaluated. 2168 individuals had metsyn scores and JSW evaluated. Metsyn was associated with sAGE in both men and women (r=0.38, 0.21, P<.001 respectively). JSW was associated with sAGE in men r=0.11 but not women r=-0.03). Metsyn was associated with increased narrowing of JSW at 48 months, r=0.07 in men (p=0.01) but not women r=0.03 (p=0.15). Increasing tertiles of SAGE were associated with increased JSN, LS means of change in JSW= 0.25 mm, 0.35mm, 0.57 mm in men (Ptrend =0.03) but not women, LS mean of change in JSW= 0.34 mm,0.37mm, 0.24 mm(Ptrend =0.20). Increased Metsyn score was associated with increased JSN, LS means of change in JSW= 0.44 mm, 0.57mm, 0.57 mm, 0.66 mm in men (Ptrend =0.006) and in women, LS mean of change in JSW 0.47 mm,0.59mm, 0.57 mm, 0.66mm (Ptrend =0.003). Adjustment of age, race and baseline KL grade diminished above associations. Adjusted LS means change in JSW by tertile of sAGE in men were: 0.24 mm,0.32mm, 0.45 mm (Ptrend =0.19), adjusted LS mean of change in JSW by tertile of sAGE in women= 0.25 mm, 0.28mm, 0.14 mm(Ptrend =0.17). Adjusted LS Mean change in JSW by Metsyn score were 0.30 mm,0.37mm, 0.46 mm,0.38 mm in men (Ptrend =0.17) and in women, LS mean of change in JSW were 0.28 mm,0.34mm, 0.41 mm, 0.33mm (Ptrend =0.40).

Conclusions: This pilot study suggests that metabolic factors associated with metabolic syndrome and higher levels of AGEs may play a role in knee OA progression. Reductions in the association with multiple variable adjustment may represent mediators of the pathways involved in these association.