Pathobiology of Modic changes

Abstract

Purpose: Low back pain (LBP) is the most disabling condition worldwide. Although LBP relates to different spinal pathologies, vertebral bone marrow lesions visualized as Modic changes on MRI have a high specificity for discogenic LBP. This review summarizes the pathobiology of Modic changes and suggests a disease model.

Methods: Non-systematic literature review.

Results: Chemical and mechanical stimulation of nociceptors adjacent to damaged endplates are likely a source of pain. Modic changes are adjacent to a degenerated intervertebral disc and have three generally interconvertible types suggesting that the different Modic change types represent different stages of the same pathological process, which is characterized by inflammation, high bone turnover, and fibrosis. A disease model is suggested where disc/endplate damage and the persistence of an inflammatory stimulus (i.e., occult discitis or autoimmune response against disc material) create predisposing conditions. The risk to develop Modic changes likely depends on the inflammatory potential of the disc and the capacity of the bone marrow to respond to it. Bone marrow lesions in osteoarthritic knee joints share many characteristics with Modic changes adjacent to degenerated discs and suggest that damage-associated molecular patterns and marrow fat metabolism are important pathogenetic factors. There is no consensus on the ideal therapy. Non-surgical treatment approaches including intradiscal steroid injections, anti-TNF-α antibody, antibiotics, and bisphosphonates have some demonstrated efficacy in mostly non-replicated clinical studies in reducing Modic changes in the short term, but with unknown long-term benefits. New diagnostic tools and animal models are required to improve painful Modic change identification and classification, and to clarify the pathogenesis.

Conclusion: Modic changes are likely to be more than just a coincidental imaging finding in LBP patients and rather represent an underlying pathology that should be a target for therapy.

Keywords: Bone marrow lesion; Endplate damage; Low back pain; Modic changes; Pathobiology.

Figures

Fig. 1

Mid-sagittal T1-weighted (left) and T2-weighted images (right) of lumbar spines showing the three types of Modic changes (arrows). a Modic change type 1 at inferior L4 and superior L5. b Modic change type 2 at inferior L5 and superior S1. c Mixed Modic change type 2/3 at superior-anterior L5 with arrowhead pointing at Modic change type 3. Modic changes type 2 are also present at inferior L4, inferior L5, and superior S1. Pure Modic changes type 3 are rare. No such MRI scans were available to us

Fig. 2

Risk factors for Modic changes. Systemic factors may also affect hyperloading and disc/endplate damage pathologies. Hyper-loading may also affect disc/endplate damage

Fig. 3

Mid-sagittal histological sections of spinal segments with bone marrow lesions characterized as Modic changes on MRI. Sections are stained with hematoxylin and eosin. Original magnifi-cations are ×0.5 (a, b), and ×10 (c–e). c and d are magnifications from the areas indicated on a and b, respectively. a, c Modic change type 1 characterized by fibrovascular tissue (asterisks) and trabecular thickening. The changes parallel endplate irregularities (arrow). b, d Modic change type 2. Fatty marrow replacement (asterisks) occurs along the entire endplates cephalad and caudad to the disc. Fibrotic tissue can be found at locations of endplate damage (arrows). e Healthy vertebral bone marrow with (Tr) trabecular bone, (AC) adipocytes, and (VS) vascular sinus

Fig. 4

The three pathobiological pillars of Modic changes

Fig. 5

Hypothetical model for the pathogenesis of Modic changes. An endplate damage is a predisposing condition for Modic changes. Endplate damage can be diagnosed with UTE and FLASH MRI sequences as well as with multidetector computed tomography (MDCT). Endplate damage triggers a healing response. The Modic etiology requires a persistent stimulus, which impedes resolution of the damage. The concomitant existence of a healing response and a persistent stimulus leads to accumulation of damage and to a ‘frustrated healing response’ characterized by chronic inflammation, high bone turnover, and fibrosis, the three pathobiological pillars of Modic changes, which can be visualized with T1-and T2-weighted MRI sequences. The severity and persistency of the stimulus as well as individual factors (pain genetics, psychosocial factors) may decide if the Modic changes become painful. Novel diagnostic tools (biomarkers, MRI) are required to distinguish painful from non-painful Modic changes

Fig. 6

Factors released by a chronically damaged disc can cause inflammation and osteoclast activation in the adjacent bone marrow. Endplate damage leads to a hydraulic disc/vertebra coupling and increased efflux of these factors into the adjacent bone marrow where they can cause Modic changes

Fig. 7

Interdependency of stromal and hematopoietic bone marrow cell differentiation and their effects on bone remodeling. Bone marrow-derived mesenchymal stem cells (BMSC) differentiate mainly into adipocytes or osteoblast cells (OBC) in a reciprocal manner. Hematopoietic stem cells (HSC) differentiate into osteoclasts (OC) besides other blood cells. Osteoblasts and osteoclasts deposit and erode the bone matrix, respectively. Fatty acids (FA) bind to PPARγ. PPARγ regulates the lineage commitment of both BMSC toward adipocytes and away from osteoblasts, and of myeloid progenitors toward OC. In adipocytes, PPARγ stimulation regulates adipokine secretion. Adipokines positively regulate osteoblastogenesis and negatively regulate osteoclastogenesis. Osteoclastogenesis is positively regulated by M-CSF and RANKL, which can be secreted by OBCs. OC secrete IGF-1 and TGFβ, which drive OBC differentiation