Vertebral bone marrow (Modic) changes

Genetic disposition and MCs

Research has demonstrated a close association between the genome and back pain [ ]. In the United Kingdom, twin study genetic heritability was found to be one of the major risk factors for reported episodes of severe LBP. Several gene variants have been linked with an increased genetic disposition to disc degeneration and LBP.

The association between gene variants and MCs has been investigated across studies. Karppinen et al. [ ] did in 2008 show that genetic variations in the interleukin-1A and matrix metalloproteinase-3 gene together were significantly associated with MC2. In 2019 a genome-wide meta-analysis identified a genetic locus on chromosome 9 associated with MCs [ ]. Rajasekaran et al. [ ] performed a proteomic analysis of intervertebral disc tissue to investigate the biological changes of MCs at the molecular level. They found 45 proteins specific for MC patients and in particular 14 host defense response proteins with altered pathways. Another study using proteomic analysis comparing endplate avulsion and MCs found significant alteration of nine proteins compared to patients without MCs [ ]. In 2022 a study by Vigeland et al. [ ] found that the expression of 37 genes was associated with STIR signal volume in patients with MC1. Gene sets related to interferon signaling, mitochondrial metabolism, and defense response to virus were significantly upregulated in all analyses. These results indicate that inflammation and immunological defense are important factors in MC biology in patients with LBP.

In summary, studies indicate that there is a genetic component to MC that includes altered signaling, metabolism, and host defense response.

Structural disc damage and inflammatory response

Structural disc damage through endplate damage or disc herniation induces the development of MCs [ ], and MCs are rarely seen at structurally intact disc levels (see Chapter 1 ) [ , ]. When the endplate damages, the disc depressurizes, and this alters the mechanical environment of the intervertebral disc and causes progressive structural change to the motion segment [ ]. Endplate defects are associated with MC development fairly consistently across studies [ ]. Extracellular matrix changes have been observed in cartilage endplate with MCs as shown in a study investigating 40 patients with MCs and 20 patients without, where expression of a disintegrin-like and metalloprotease with thrombospondin motifs 5 (ADAMTS-5), catabolic enzyme, and tumor necrosis factor-α (TNF-α) was significantly upregulated in cartilage endplates of those having MCs [ ].

Disc herniation is a potential predisposing factor to MCs [ , ], as it can also generate endplate junction injury. Disc herniation occurs more frequently as a result of endplate junction failure rather than annulus fibrosus rupture as previously thought [ , ]. Moreover, studies have shown that extruded discs have been shown to comprise cartilage endplate and are significantly associated with MCs [ , ].

Structural disc damage leads to change in diffusion and thereby metabolism of the intervertebral disc cells with increased production of proinflammatory cytokines, leading to an inflammatory response. The cytokines could migrate from the intervertebral disc and endplate into the vertebral bone marrow [ , ]. Structural damage in a depressurized disc could induce a persistent inflammation stimulus and attempts to heal, leading to a so-called frustrated healing response and, consequently, MC development [ ]. To support this, crosstalk between bone marrow with MCs and the adjacent disc has been discovered at a cellular level [ ]. Low-grade inflammation, determined by increased serum high-sensitivity C-reactive protein (hs-CRP) concentration, has been found to associate with MC1 [ ] but this finding has not been validated. Additionally, findings on the association of genetic variations in the interleukin-1 (IL-1) cluster and the matrix metalloproteinase-3 gene with MC support the role of innate immunity in MCs [ , ]. A study explored serum biomarkers among patients with chronic LBP and MCs and found several suppressed biomarkers among patients with MCs, and to date no serum biomarkers have been identified able to distinguish Modic types [ ].

Modic changes are associated with increased expression of TNF-α [ ] and TNF-immunoreactive cells in the endplate [ ]. Increased oxidative and nitrosative stress factors, leading to the production of proinflammatory cytokines such as TNF-α, interleukin-8 (IL-8), and prostaglandin E2 (PGE2), have also been linked to MC1 [ ]. In addition, macrophage migration inhibitory factor was found to be highly expressed in the cartilage endplate chondrocytes among subjects with MC1 suggesting, again, increased proinflammatory cytokine secretion [ ].

As MCs are lesions of the vertebral bone marrow, the role of osteoclasts has also been studied. Theoretically, metabolic pathways of bone remodeling could be important in MC. Messenger RNA of cytokines related to osteoclast proliferation and differentiation, such as macrophage colony-stimulating factor-1 (M–CSF–1), receptor activator nuclear factor kappa-β ligand, and osteoclast-associated receptor, were significantly more expressed in the herniated disc tissue samples with MCs at the operating level than in tissue samples without MCs, suggesting osteoclast involvement in the development of MCs [ ]. In addition, upregulation of pro-osteoclastic CSF-1 and peroxisome proliferator-activated receptor-γ and downregulation of interleukin-4 (IL-4) and osteoprotegerin have been seen at disc levels with MC2 [ ]. Increased sclerosis has been reported to be present on radiographs and computed tomography in vertebrae with MCs [ , ].

There are histologic studies that support inflammatory response to herniated tissue material. Herniated tissue upregulates vascular endothelial growth factor, which further stimulates angiogenesis [ , ]. In addition, herniated tissue shows an abundance of macrophages [ ]. When the disc degenerates due to structural changes, compressive stress loads are highly altered in the disc. This leads to neovascularization and neoinnervation that increase the metabolics, especially in the endplate and outer annulus fibrosus [ ]. Both angiogenesis and macrophage infiltration strengthen the inflammatory response. The derangement of annulus fibrosus and/or endplate enables a convenient route for cytokines to migrate into the vertebral bone.

Atypical mechanical loading

Atypical mechanical loading to vertebrae can be due to asymmetrical loading or increased shear stress of the motion segment (see Chapter 2 ). Asymmetrical loading is seen in scoliosis. Wu et al. [ ] studied patients with degenerative lumbar scoliosis and found MCs to be more prevalent among patients with scoliosis than without. Furthermore, usually, MCs are located on the concave side of the apex vertebrae where the mechanical load is greater ( Fig. 11.5 ) [ ].

Increased shear stress in the lumbar structures and vertebrae is the result of structural changes leading to an altered mechanical environment in the disc [ , ] (see Chapter 8 ). Increased shear stress leads to minor fracture of the endplate [ ] and, as a consequence, enhances ascending inflammatory response from the disc into the vertebral bone marrow, leading to MC development [ ]. Indeed, MC1s have been found to demonstrate fissuring and disruption of the endplate [ , ]. Increased shear stress could also influence the shape of the endplate. Irregular endplates were associated with greater translational motion and higher prevalence of MCs compared to concave or flat endplates [ ]. In addition, longitudinal follow-up of surgical fusion studies gives an interesting insight into the role of instability and the effect of stabilization on MCs (see below Surgical options) ( Fig. 11.6 ) [ , ].