Longitudinal changes in tibial and femoral cartilage thickness are associated with baseline ambulatory kinetics and cartilage oligomeric matrix protein (COMP) measures in an asymptomatic aging population.

OBJECTIVE: To address the need for early knee osteoarthritis (OA) markers by testing if longitudinal cartilage thickness changes are associated with specific biomechanical and biological measures acquired at a baseline test in asymptomatic aging subjects. DESIGN: Thirty-eight asymptomatic subjects over age 45 years were studied at baseline and at an average of 7-9 year follow-up. Gait mechanics and knee MRI were measured at baseline and MRI was obtained at follow-up to assess cartilage thickness changes. A subset of the subjects (n = 12) also had serum cartilage oligomeric matrix protein measured at baseline in response to a mechanical stimulus (30-min walk) (mCOMP). Baseline measures, including the knee extension (KEM), flexion (KFM), adduction (KAM) moments and mCOMP, were tested for associations with cartilage thickness changes in specific regions of the knee. RESULTS: Cartilage change in the full medial femoral condyle (p = 0.005) and external medial femoral region (p = 0.041) was negatively associated with larger early stance peak KEM. Similarly, cartilage change in the full medial femoral region (p = 0.009) and medial femoral external region (p = 0.043) was negatively associated with larger first peak KAM, while cartilage change in the anterior medial tibia was positively associated with larger first peak KAM (p = 0.003). Cartilage change in the anterior medial tibia was also significantly associated (p = 0.011) with mCOMP levels 5.5-h post-activity (percentage of pre-activity levels). CONCLUSIONS: Interactions found between gait, mechanically-stimulated serum biomarkers, and cartilage thickness in an at-risk aging asymptomatic population suggest the opportunity for early detection of OA with new approaches that bridge across disciplines and scales.

A systems view of risk factors for knee osteoarthritis reveals insights into the pathogenesis of the disease.

Early detection of osteoarthritis (OA) remains a critical yet unsolved multifaceted problem. To address the multifaceted nature of OA a systems model was developed to consolidate a number of observations on the biological, mechanical and structural components of OA and identify features common to the primary risk factors for OA (aging, obesity and joint trauma) that are present prior to the development of clinical OA. This analysis supports a unified view of the pathogenesis of OA such that the risk for developing OA emerges when one of the components of the disease (e.g., mechanical) becomes abnormal, and it is the interaction with the other components (e.g., biological and/or structural) that influences the ultimate convergence to cartilage breakdown and progression to clinical OA. The model, applied in a stimulus-response format, demonstrated that a mechanical stimulus at baseline can enhance the sensitivity of a biomarker to predict cartilage thinning in a 5 year follow-up in patients with knee OA. The systems approach provides new insight into the pathogenesis of the disease and offers the basis for developing multidisciplinary studies to address early detection and treatment at a stage in the disease where disease modification has the greatest potential for a successful outcome.

Baseline knee adduction and flexion moments during walking are both associated with 5 year cartilage changes in patients with medial knee osteoarthritis.

OBJECTIVE: To test the hypothesis that knee cartilage changes over 5 years are associated with baseline peak knee adduction moment (KAM) and peak knee flexion moment (KFM) during early stance. DESIGN: Baseline KAM and KFM were measured in sixteen subjects with medial knee osteoarthritis (OA). Regional changes in cartilage thickness and changes in medial-to-lateral thickness ratio were quantified using magnetic resonance imaging (MRI) at baseline and again after 5 years. Multiple regression was used to determine whether baseline measures of KAM and KFM were associated with cartilage changes over 5 years. Associations with baseline pain score, Kellgren-Lawrence (KL) grade, walking speed, age, gender, and body mass index (BMI) were tested one-by-one in the presence of KAM and KFM. RESULTS: Changes over 5 years in femoral medial-to-lateral thickness ratio were associated with baseline KAM, KFM, and pain score (R(2) = 0.60, P = 0.010), and most significantly with KAM (R(2) = 0.33, P = 0.019). Changes in tibial medial-to-lateral thickness ratio were associated with baseline KAM, KFM, and walking speed (R(2) = 0.49, P = 0.039), with KFM driving this association (R(2) = 0.40, P = 0.009). Changes in medial tibial thickness were associated with baseline KAM, KFM, and walking speed (R(2) = 0.49, P = 0.041); KFM also drove this association (R(2) = 0.42, P = 0.006). CONCLUSIONS: The findings that the KAM has a greater influence on femoral cartilage change and the KFM has a greater influence on tibial cartilage change provide new insight into the tibiofemoral variations in cartilage changes associated with walking kinetics. These results suggest that both KAM and KFM should be considered when designing disease interventions as well as when assessing the risk for OA progression.

Age-related differences in sagittal-plane knee function at heel-strike of walking are increased in osteoarthritic patients.

OBJECTIVE: To compare age-related patterns of gait with patterns associated with knee osteoarthritis (OA), the following hypotheses were tested: (H1) The sagittal-plane knee function during walking is different between younger and older asymptomatic subjects; (H2) The age-related differences in H1 are increased in patients with knee OA. DESIGN: Walking trials were collected for 110 participants (1.70 ± 0.09 m, 80 ± 14 kg). There were 29 younger asymptomatic subjects (29 ± 4 years) and 81 older participants (59 ± 9 years), that included 27 asymptomatic subjects and 28 and 26 patients with moderate and severe medial knee OA. Discrete variables characterizing sagittal-plane knee function were compared among the four groups using ANOVAs. RESULTS: During the heel-strike portion of the gait cycle at preferred walking speed, the knee was less extended and the shank less inclined in the three older groups compared to the younger asymptomatic group. There were similar differences between the severe OA group and the older asymptomatic and moderate OA groups. Both OA groups also had the femur less posterior relative to the tibia and smaller extension moment than the younger group. During terminal stance, the severe OA group had the knee less extended and smaller knee extension moment than the younger asymptomatic and older moderate OA groups. CONCLUSIONS: The differences in knee function, particularly those during heel-strike which were associated with both age and disease severity, could form a basis for looking at mechanical risk factors for initiation and progression of knee OA on a prospective basis.

A relationship between mechanically-induced changes in serum cartilage oligomeric matrix protein (COMP) and changes in cartilage thickness after 5 years.

OBJECTIVE: To evaluate the hypothesis that a mechanical stimulus (30-min walk) will produce a change in serum concentrations of cartilage oligomeric matrix protein (COMP) that is associated with cartilage thickness changes on magnetic resonance imaging (MRI). METHODS: Serum COMP concentrations were measured by enzyme-linked immunosorbent assay in 17 patients (11 females, age: 59.0±9.2 years) with medial compartment knee osteoarthritis (OA) at study entry immediately before, immediately after, 3.5 h, and 5.5 h after a 30-min walking activity. Cartilage thickness changes in the medial femur and medial tibia were determined from MR images taken at study entry and at 5-year follow-up. Relationships between changes in cartilage thickness and COMP levels, with post-activity concentrations expressed as a percentage of pre-activity levels, were assessed by the calculation of Pearson correlation coefficients and by multiple linear regression analysis, with adjustments for age, sex, and body mass index (BMI). RESULTS: Changes in COMP levels 3.5 h and 5.5 h post-activity were correlated with changes in cartilage thickness in the medial femur and tibia at the 5-year follow-up. The results were strengthened after analyses were adjusted for age, sex, and BMI. Neither baseline pre-activity COMP levels nor changes in COMP levels immediately post-activity were correlated with cartilage thickness changes. CONCLUSIONS: The results of this study support the hypothesis that a change in COMP concentration induced by a mechanical stimulus is associated with cartilage thinning at 5 years. Mechanically-induced changes in mechano-sensitive biomarkers should be further explored in the context of stimulus-response models to improve the ability to assess OA progression.