It is well known that knee osteoarthritis (KOA) is a disease of the whole joint, characterized by loss of osteochondral integrity, including destruction of articular cartilage pathophysiological changes in the underlying subchondral bone, such as subchondral bone marrow lesions (BMLs), osteophytes and bone sclerosis. There is evidence that changes in the subchondral bone microarchitecture may precede cartilage loss, and are thus important to understanding the pathogenesis and progression of OA. Animal models of OA have shown a predictable disease progression in OA, in which initial attrition of subchondral bone is followed by sclerotic changes, increased anisotropy and an increase in the plate:rod ratio.
ContentIn human patients, the sequence of KOA subchondral bone changes is less well understood. To gain insight into the osteochondral unit in KOA, we have used a multimodal approach to characterise the subchondral bone across the tibial plateau, using tibial plateaus taken from patients with KOA at total knee arthroplasty, as well as controls without KOA. We have been particularly interested in zones of subchondral bone represented by BMLs, which seem to correspond to the most severe OA changes. BMLs have acquired considerable clinical interest, since they appear to inform on clinically important changes in the subchondral bone, and thus might be useful as imaging biomarkers for both disease progression and response to treatment of KOA. Subchondral bone in BML zones was characterized by a number of important differences from healthy bone: vascular changes, increased bone matrix microdamage, increased resorptive sites, increased osteoid, and a focal sclerotic appearance, in both the subchondral plate and the underlying trabeculae. These changes correlated with the degree of degradation of the adjacent cartilage (1).
Micro-CT of the whole tibial plateaus showed key subregion-specific differences between non-OA controls, KOA without BMLs and KOA with BMLs. Limiting analyses to tibial plateaus containing a BML in the anterior medial (AM) compartment (the most frequent site of BMLs), between-group comparisons showed that the AM region of the OA-BML group had significantly higher histological cartilage degeneration (OARSI grade) (P<.0001, P<.05), thicker subchondral plate (P<.05, P<.05), trabeculae that are more anisotropic (P<.0001, P<.05), well connected (P<.05), and more plate-like (P<0.05, P<0.05), compared to controls and OA-no BML at this site. OA-no BML had significantly higher OARSI grade (P<.0001), and lower trabecular number (P<.05) compared to controls.
The subchondral trabecular bone micro-CT data were subjected to ITS analysis for plate-and-rod-based microstructural analysis. The subchondral bone of OA tibial plateaus containing BMLs was characterized by increased plate bone volume fraction (pBV/TV), (p=0.003), plate trabecular number (pTb.N), (p=0.04), and both rod and plate trabecular thickness (rTb.Th and pTb.Th) (p<0.0001 for both). Comparison between the anterior medial region (representing BML bone) and posterior medial region (representing no-BML) in OA subjects indicated that the anterior medial subregion representing BML bone is characterised by a greater number of plate and rod like trabeculae (p<0.0001 for all parameters) compared with posterior medial (no BML) bone. These differences also associated positively with increased OARSI grade in the BML region.
To investigate the nature of the bone matrix in the sclerotic BML regions of subchondral bone, Raman microspectroscopy analysis and quantitative backscattered electron imaging (qBEI) were performed. qBEI was used to determine bone mineralization density distribution and osteocyte and mineralized lacunar density. Raman spectra provided a distinct chemical fingerprint of each patient’s tibial bone sample. In particular, phosphate-to-amide I, phosphate-to-proline and phosphate-to-amide III were all reduced in the BML zones compared to control (p<0.002, p<0.02, p<0.03, respectively), suggesting lower mineralized bone matrix in BML bone. Consistent with this, the qBEI bone mineralization density distribution for OA-BML was shifted to low mineralization density compared to control (p<0.002), combined with an increased peak width compared to both OA-no BML (p<0.05) and control (p<0.002). The size and density of osteocyte lacunae did not differ between groups. However, the density of mineralized lacunae in bone from BML zones was lower compared to control (p<0.005). Thus, tibial BMLs in knee OA patients are characterized by low bone mineralization, in relation to the organic phase, together with greater mineral heterogeneity and a reduced number of mineralized osteocytes.
Taken together, our data support the concept of the sclerotic bone in BMLs representing localized areas of active bone remodeling in response to chronic bone injury in OA.
1. D. Muratovic, F. Cicuttini, A. Wluka, D. Findlay, Y. Wang, S. Otto, D. Taylor, J. Humphries, Y. Lee, A. Labrinidis, R. Williams, J. Kuliwaba, Bone marrow lesions detected by specific combination of MRI sequences are associated with severity of osteochondral degeneration, Arthritis Res Ther 18 (2016) 54.