Using a method that allows for evaluation of the association between SBA and directly overlying cartilage loss within a subregion of the knee, thereby eliminating between-person confounding, we were able to demonstrate that the baseline presence of SBA was strongly associated with cartilage loss over time occurring within the same subregion of a knee. These results were consistent in both compartments of the knee, although there was a suggestion that the effects were of a greater magnitude in specific subregions that experience greater loading.
The current method has advantages over the more standard methods of analyses in its ability to eliminate between-person and between-knee confounding. As illustrated, if one were to conduct these analyses by simply evaluating the association of any baseline SBA with any cartilage loss over time in knees across all of the individuals using generalized GEEs, adjusting for age, sex, and BMI, the OR would be 3.0, in contrast to our finding of 7.5, which is an effect estimate that is biased toward the null by more than 2-fold. Even if one were to assess the relationship between baseline SBA in a given subregion with cartilage loss within the same subregion across all of the knees using GEEs, adjusting for age, sex, and BMI, the OR would be 5.4 (95% CI 4.1–7.0). In this latter GEE approach, although the sample size is increased 10-fold compared with the former GEE approach (since the analysis is subregion based rather than knee based), the upper bound of the 95% CI excludes the effect estimate obtained in the M:N matched case–control approach. In general, one is interested in causal relationships between a risk factor and disease. As such, conditional logistic regression and random-effects models both allow the assessment of subject-specific effects while eliminating between-person confounding. Therefore, such methods generate less biased results compared with approaches using GEEs, since the latter provides a population average across the study population and remains prone to between-person bias.
These results may suggest that SBA influences overlying cartilage loss due to alterations in bone surface shape that may make cartilage more vulnerable to altered load. SBA may therefore serve as a marker of an area undergoing compressive stress in which cartilage loss is inevitable. However, a limitation to this study is that causal relationships are difficult to discern. It is possible that cartilage loss and SBA may both be features of severe disease, and that a more proximal insult has resulted in both the presence of SBA and cartilage loss. For example, bone marrow lesions have also been noted to be associated with both cartilage loss and SBA (14
). When we attempted to identify knees without any cartilage abnormalities at baseline, very few had SBA present, indicating that both seem to occur concurrently.
When we limited our analyses to different subregions, we noted that some subregions had higher associations between SBA and cartilage loss than others. This may reflect the fact that the curvature of the femur differs for the different subregions. For example, SBA may be more difficult to discern in the posterior femur. On the other hand, this may point to a stronger association occurring in specific subregions that experience greater load.
One proximal factor that may influence both SBA and cartilage loss is malalignment. Neutral limb alignment distributes load widely across an articular surface. Medial tibiofemoral knee OA is more common than lateral knee OA, likely in part because it is subject to more load than the lateral compartment. When a knee has varus malalignment, more stress is transmitted across the medial compartment. Malalignment is associated with an increased risk of structural radiographic progression in knees with existing OA and with cartilage loss in the compartment loaded by the malalignment (17
). Malalignment is also associated with ipsilateral bone marrow lesions, which are probably lesions of bone trauma deep to the subchondral plate (18
). Finally, malalignment has been associated with subchondral bone attrition on MRI cross-sectionally in a small sample of knees with existing OA (18
), as well as in the MOST cohort, in which malalignment was also associated with incident SBA in the more loaded compartment (20
). Because malalignment leads to altered stress in a joint, subchondral bone remodeling with resultant attrition can occur at those points of increased stress in response to those loads and in response to local micro-fractures as a result of those loads (21
). Therefore, the co-occurrence of SBA and cartilage loss within the same subregions of a knee, particularly for subregions thought to experience greater loading, may point to abnormal mechanical loading as a common cause of these pathologies. On the other hand, alterations in the bone surface shape resulting from SBA as well as cartilage loss changing the articular surface can in and of themselves also lead to malalignment and altered mechanical load through those regions. These intricate and complicated temporal relationships are difficult to disentangle.
In summary, the use of advanced methodology that has broad applicability to other studies of relationships between local pathologies within the knee has demonstrated that SBA is strongly associated with cartilage loss over time within the same subregion of a knee. Further studies into the temporal relationship of these findings along with the potential role of malalignment are warranted to provide additional insight into the relationship of bone pathology and cartilage loss in OA.