Previous studies have demonstrated that MRI-detected BMLs are predictors of cartilage loss in the tibiofemoral compartments of the knee [3
]. In contrast, our results showed that cartilage damage at baseline, as well as cartilage loss over time, is associated with incident BMLs in the same subregion of the tibiofemoral compartments. The reciprocal relationship might be explained by the close interrelation between subchondral bone and articular cartilage in the pathogenesis of knee OA.
BMLs are a highly variable feature in patients with or at risk for knee OA, and their size may increase or decrease over time [2
]. Felson et al. [1
] demonstrated that BMLs are powerful predictors of radiographic progression of knee OA. Fluctuations in the size of the lesion over time seem to have a direct effect on progression of knee OA. Roemer et al. [3
] showed that subregions within the knee having incident and progressive BMLs demonstrate a higher risk of cartilage loss at follow-up. Hunter et al. [5
] demonstrated that, compared to stable BMLs, enlarging lesions are strongly associated with cartilage loss at follow-up. Other recent studies have also demonstrated the predictive effect of BMLs on cartilage loss [11
], and such lesions were also shown to predict a worse outcome in subjects with OA at baseline, increasing the risk of total knee arthroplasty compared with subjects without lesions [12
]. However, both studies [11
] used inappropriate MRI techniques to assess BMLs [29
], making the interpretation of their results unclear. It has been hypothesized that cartilage loss is secondary to BMLs, as the integrity of the cartilage may be dependent on the mechanical properties of the underlying subchondral bone. Because of the stiffness and higher local mineral density of areas of subchondral bone with BMLs, the bone may be incapable of dissipating the forces on the joint during loading, thereby transmitting more load onto overlying cartilage, and causing the cartilage to breakdown [31
]. Previous experimental studies (animal models) with histological assessment of the subchondral bone and the articular cartilage also support that damage to the subchondral bone may lead to adjacent cartilage damage [32
On the other hand, our results showed that preserved hyaline cartilage lowers the risk of developing BMLs. We suggest that this may relate to the ability of intact cartilage to distribute compressive loads so that the maximal stress from these loads is diminished. When cartilage’s collagen network is damaged, its effectiveness in serving this function should decline. In fact, previous studies have shown that factors that lead to increased loading on the tibiofemoral compartments, such as knee malalignment and meniscal pathology, are related to BMLs [1
]. We controlled for these factors in our analysis, so that we could focus on cartilage integrity as a protective risk factor.
Mechanical limb alignment is thought to directly affect location, prevalence, and change in BMLs, as medial knee lesions occur mainly in individuals with varus-aligned limbs, and lateral lesions occur mostly in those with valgus-aligned limbs [1
]. One could argue that the increased load on the tibiofemoral compartments due to malalignment could be directly responsible for adjacent cartilage loss, and BMLs would play a secondary role, as such lesions are highly associated with knee malalignment. This is supported by previous work from Felson et al., in which the predictive effect of BMLs on cartilage loss was evident only when there was no adjustment for knee malalignment: making the adjustment greatly diluted the effect [1
Pathology involving the menisci, which are responsible for load-bearing and shock absorption in the tibiofemoral compartments [36
], has been shown to be related to concomitant BMLs. Meniscal pathology is highly associated with and predicts lesions in the same tibiofemoral compartments [18
]. Thus, loss of meniscal function may increase loading to the underlying subchondral bone, leading to BMLs.
In the present study, we hypothesized that subregions in the tibiofemoral compartments with cartilage damage might develop BMLs longitudinally, as the diminished integrity of the cartilage could alter its biomechanical properties and thus its response to loading, which in turn could increase loading on the adjacent subchondral bone. The results from our study support such a hypothesis, with the association of both cartilage damage and cartilage loss over time with incident BMLs demonstrated in both tibiofemoral compartments. In contrast to the previously demonstrated effect of BMLs on cartilage loss, which may be influenced by knee malalignment, the association of cartilage damage and cartilage loss over time with incident BMLs in the tibiofemoral compartments is independent of knee malalignment, as well as of other factors that can increase loading to the tibiofemoral subchondral bone, such as meniscal tears and meniscal extrusion. One previous study demonstrated that cartilage defects predicted an increase in BMLs over time in the tibiofemoral compartments [39
In the subregional approach used initially for testing the associations, one could argue that excluding only subregions with prevalent BMLs may have introduced bias, since other subregions in the same compartment or in the contralateral compartment could have prevalent BMLs. It is not known if the risk of incident BMLs is higher in subregions of knees with baseline BMLs in other tibiofemoral subregions. For that reason, we performed additional analyses after excluding all knees with any prevalent BML in any tibiofemoral subregion, and we found that the associations with incident BMLs remained significant for prevalent cartilage damage, and were significant and even stronger for incident cartilage loss and progression of cartilage loss.
In the present study, we only considered MRI-detected edema like BMLs since only such pattern of subchondral BMLs demonstrated strong evidence to be clinically relevant regarding progression of knee OA and knee symptoms, independently of the presence of other MRI features [1
]. Other possible patterns of degenerative changes in the subchondral bone detected on MRI such as sclerosis and cysts did not demonstrate to be clinically relevant independently of other features [40
There are some limitations to this study. First, the MRIs were presented sequentially, and readers were aware of the chronological order of images. This could, perhaps, bias the readers to expect more change. On the other hand, it has been found that when readers are blinded to chronological order, sensitivity to clinically relevant changes actually decreases, compared to unblinded assessment [42
]. Further, previous analysis in this study sample showed comparable weighted kappa coefficients when assessing a subset of randomly selected knees blinded to time point [4
]. Second and unfortunately, MRI does not allow for separate assessment of two adjacent structures such as subchondral bone and articular cartilage, as both are visualized within the same image and specific features (such as cartilage damage and BMLs) cannot be separately blinded. Third, one could argue that the image quality of 1.0T MRI is inferior to 1.5T systems. However, WORMS scoring using a 1.0T dedicated extremity MRI is possible with a moderate to high degree of agreement and accuracy compared with WORMS assessment of 1.5T large-bore MRI [24
]. Fourth, even though we could prove a strong association of cartilage damage and cartilage loss over time with incident BMLs, we cannot be sure about the chronological order of these structural changes (e.g. cartilage loss precedes BMLs) as we assessed only two distinct time points. This is true especially for BMLs, which vary widely over time [2
]. Only repeated examinations with at least 3 points of observation at shorter intervals could demonstrate the chronological order of these features. Finally, there are radiological differential diagnoses for degenerative BMLs, the most common being traumatic bone contusions [45
]. We carefully excluded knees with an unequivocal radiologic differential diagnosis prior to analysis.
In summary, we demonstrated that prevalent cartilage damage and cartilage loss over time are strongly associated with incident BMLs in the same subregion of the tibiofemoral compartments. We adjusted our results for known mechanical factors that can increase loading to the tibiofemoral compartments such as knee malalignment, meniscal damage, and meniscal extrusion, which suggests that cartilage damage and cartilage loss may be independent predictors of incident BMLs. In light of previous work, our findings support the concept of the “osteochondral unit” and the close interrelation of cartilage and subchondral bone. Once damage to the articular cartilage surface or the subchondral bone is apparent the risk of structural deterioration in the adjacent tissue seems to be markedly increased.