From Modic to Disc Endplate Bone Marrow Complex - The Natural Course and Clinical Implication of Vertebral Endplate Changes

Abstract

Study Design

Review article.

Objectives

A review of literature on the epidemiology, natural course, pathobiology and clinical implications of vertebral endplate changes.

Methods

A literature search was performed using the Cochrane Database of Systematic Reviews, EMBASE, and PubMed. Studies published over the last 10 years were analysed. The searches were performed using Medical Subject Headings terms, and the subheadings used were “Vertebral endplate changes”, “Modic changes”, “Disc Endplate Bone Marrow complex”.

Results

The disc, endplate (EP), and bone marrow region of the spine constitute a unified morphological and functional unit, with isolated degeneration of any one structure being uncommon. Disc degeneration causes endplate defects, which result in direct communication and a constant cross-talk between the disc and the vertebral body. This may result in a persistent inflammatory state of the vertebral bone marrow, serving as a major pain generator. This review article focuses on vertebral endplate changes and how the current understanding has progressed from the Modic classification to the Disc Endplate Bone Marrow complex classification. It provides a clear portrayal of the natural course of these alterations and their clinical implications in low back pain.

Conclusions

In light of the heightened interest and current prominence of vertebral endplate changes within the spine community, we must progress beyond the Modic changes to achieve a comprehensive understanding. The DEBM complex classification will play a major part in disc degeneration research and clinical care, representing a considerable advancement in our understanding of the vertebral endplate changes over the classical Modic changes.

Keywords

vertebral endplate changes modic changes intervertebral disc disc endplate bone marrow complex back pain disc degeneration

Introduction

Spine surgery has witnessed tremendous technological advancements in diagnosis and therapeutics over the last 2 decades. However, despite these advances, nearly 80% of the people presenting with a history of low back pain are still categorized as non-specific low back pain (NSLBP) with poor treatment outcomes. This leads to poor satisfaction among patients, with a heavy bearing on the health costs thereby highlighting the need to identify these specific etiological subgroups for formulating treatment strategies.¹

The vertebral endplate (VEP) is an important structure that plays a crucial role in preserving the structural and functional integrity of the intervertebral discs. It facilitates the transfer of nutrients and evenly distributes the compressive force from the disc to the trabecular network of the vertebral body.² The presence of degenerative changes in the vertebral endplate and subchondral bone marrow was initially observed by de Roos et al in 1987.³ However, the significance of these endplate-marrow changes has been debated ever since the description of 3 different marrow signal changes adjacent to endplates by Modic in 1988.⁴ Studies have reported that about 22% (range 12%-37%) of patients with nonspecific chronic LBP have Modic changes.⁵ Patients with these Modic changes have more severe symptoms, recurrent episodes, longer duration of pain, poor response to therapy, disturbed sleep, and higher complications following surgery and are now considered as a separate group.^5-9

Modic changes depict only changes in the subchondral region of the bone marrow, which may be highly limited given that it ignores the additional changes in the vertebral end plate region, such as those in the peripheral nucleus pulposus and the cartilaginous and bony end plate. All of these components rely on each other for their anatomical structure and physiological functioning, and therefore any alteration in one component will result in corresponding changes in the others.¹⁰ Since the vertebral end plate changes are currently receiving a lot of attention from the spine community, we must proceed past the Modic changes to have a thorough understanding of the endplate changes.

This narrative review is a comprehensive review describing the whole spectrum of vertebral endplate changes including its original description, evolution, epidemiology, etiopathogenesis and clinical implications, as well as recent advancement.

Normal Anatomy of IVD

The normal intervertebral disc (IVD) consists of 2 components: the outer annulus fibrosis (AF) region and the central nucleus pulposus (NP). The AF is composed of fibroblast-like cells with elongated nuclei arranged within concentric layers of collagen fibres.¹¹ The extracellular matrix (ECM) of the AF can be characterised as a fibrocartilaginous structure mostly composed of collagen-I fibres, which make up 60% of its total dry weight. It has a relatively low amount of proteoglycans (25%) and exhibits low water retention.^12,13 The main purpose of the disc is to ensure the structural stability and containment of the nucleus pulposus within its centre.¹² The NP is a gelatinous structure composed of chondrocyte-like cells that produce collagen II. The collagen fibres include several proteoglycans, primarily aggrecan, which play a crucial role in retaining water.^11-13 The main purpose of the NP is to provide hydrostatic pressure to counteract axial compression.¹³

Natural Course of IVD Degeneration

Intervertebral disc degeneration appears to be an irreversible condition that can initiate as early as the second decade of life.¹² At the onset of degeneration, the initial molecular alteration is a decline in the NP’s capacity to retain water, leading to a subsequent decrease in hydrostatic pressure.¹³ These alterations lead to a decrease in intervertebral disc height. Over time, the collagen fibres and other ECM components of both the NP and AF undergo degradation and decrease in quantity.¹⁴ The existing damage is exacerbated by the upregulation of degradative processes, including apoptosis, inflammation, and matrix metalloproteinases (MMPs).^15-17

AF and NP Changes

Increased stress on the AF can result in the formation of cracks and cavities, which can further advance to clefts and fissures.¹⁸ Disruption of the structural integrity of the annulus fibrosus can lead to the occurrence of disc herniation. On magnetic resonance imaging (MRI), the hyperintense signal of the nucleus on T2-weighted images (WI) has been found to have a direct relationship with the concentration of proteoglycan in the nucleus pulposus. Additionally, the loss of signal in the disc is associated with the advancement of degenerative processes.^5,19 Pfirrmann et al devised a grading system and algorithm that relies on MRI signal intensity, disc structure, and differentiation between the nucleus pulposus, annulus fibrosus, and disc height.¹⁹

Endplate Changes

End plates are essential for maintaining the mechanical environment and providing sufficient nutrition to avascular discs. Degenerative alterations are characterised by the presence of end plate damage. MRI-based classification of end plate type provides a precise way of distinguishing between healthy, ageing, and degenerative discs. Six different types of end plates have been identified based on the severity of the damage. Type I is a normal end plate. Type II indicates thin end plates without obvious breaks. Type III shows focal defects in the end plate without changes in the subchondral bone. Type IV signifies breaks that involve less than 25% of the surface and are usually accompanied by changes in the adjacent bone marrow. Type V refers to large end plate defects, up to 50% of the surface, with associated bone marrow changes. Type VI represents extensive damage to almost the entire end plate. Fractures in the end plate cause a rapid decrease in pressure in the nucleus pulposus, resulting in the movement of the nucleus pulposus material into the vertebral body.²⁰ The presence of an inflammatory response and swelling, known as edema, can be observed on MRI scans as alterations in the bone marrow, also referred to as Modic changes. The precise factors responsible for degenerative alterations in the bone marrow, known as Modic changes, remain uncertain.

Historical Background

DeRoos in 1987, studied 58 degenerated discs and found alterations in the marrow signal intensity adjacent to the intervertebral discs in 50% of discs.³ Three patterns were described based on the short and long repetition times and echo times. This was the first study to establish marrow signal intensity changes related to degenerated discs as well as propose that the intervertebral disc, endplate, and bone marrow functioned together and that changes in any one affected the other. In addition to this, they also proposed that changes in the end plate preceded the changes in the disc which coincides well with the studies by the authors of this review.

The first pattern which showed increased signal intensity on both pulse sequences suggested a local increase in marrow fat. This resulted from a conversion of normal hemopoietic marrow to fatty marrow which in turn was the result of injury to the end-plates, choking the nutrient diffusion into the disc as well as atrophy of the endplate vascular network causing local ischemia. The second pattern was described as a low signal intensity on both pulse sequences and indicated either sclerosis or fibrosis adjacent to the degenerated disc. The last pattern showing high signal intensity on long TR/TE and low intensity on short TR/TE indicated an increase in the water fraction of the marrow space.³

In the following year, Michael T. Modic studied the frequency and location of marrow signal changes as well as their association with degenerative disc disease.⁴ To determine the reliability of these marrow changes, they also studied the constancy of these marrow signal changes with time. These were ultimately correlated with chemical shift imaging and histologic changes. Following the initial classification into 2 types, the most popular and currently used classification into the 3 Modic types was established⁴ (Figure 1). Type 1 Modic changes (MC) are characterized by hypo-intense and hyper-intense signal changes on T1-weighted and T2-weighted images, respectively implying significant bone turnover. Type 2 MC is characterised by T1W and T2W hyper-intensity and decreased bone turnover. Type 3 MC is characterized by hypointense T1W and T2W MRI images, related to subchondral bone sclerosis.^4,5

Figure 1.

Types of Modic changes. T1W and T2W images showing A) Type 1 Modic change. (B) Type 2 Modic change. Different types of Modic change involving C) Two adjacent endplates. (D) Entire endplate. (E) Anterior part. (F) Posterior part.

The histological findings of the Modic change describe the constant interactions between the marrow and bone compartments in MC.²¹ In his original study, Modic studied 474 lumbar MR images. MC types 1 and 2 were seen in 4% and 16% of the images, respectively. Only less than 1% of MRIs showed Modic type 3 changes. His study concluded that the 3 Modic types represented varying stages of the same pathological process. While a histological correlation was determined, the study did not evaluate a clinical correlation.^4,5

Recently, Rajasekaran et al developed the “Disc- End Plate- Bone Marrow Complex (DEBC)” classification based on the changes observed in the Short Tau Inversion Recovery (STIR) sequence.²² It may be crucial to take into account the disc-end plate-bone narrow complex as a whole and use the STIR sequence to distinguish between fat, sclerosis, and edema because a break in the vertebral end plate creates disc-done marrow contact, which may result in severe autoimmune inflammation, neovascularization, and disc degeneration.²³ The classification included 4 types (Figure 2). Type A DEBC shows T1 hypo, T2 hyper, and STIR hyperintensity signal change and represents an ongoing ‘acute active inflammatory process. Disc hyperintensity may or may not be present and the EP is often indistinct with possible erosions. Type B DEBC shows edema in STIR interspersed with either fat or sclerosis and indicates a state of ‘chronic persistent inflammation. Disc hyperintensity may or may not be present and the EP shows erosions. Type C DEBC shows hyperintensity in both T1 and T2 and hypointensity in STIR and indicates a state of ‘latency’ with no element of acute activity. Type D DEBC shows hypointense signals on all 3 sequences 1 and indicates a state of ‘inactivity’. There is no hyperintensity in discs or EP erosions (Table 1 and 2).²²

Figure 2.

DEBC classification. T1W, T2W and STIR images showing Type A DEBC (a,b,c), Type B DEBC (d,e,f), Type C DEBC (g,h, i) and Type D DEBC (j,k,l).

Table 1.

DEBC Classification Based on T1W, T2Wand STIR.

Type	T1W	T2W	STIR
A	Hypointensity	Hyperintensity	Hyperintensity
B	Hyperintensity	Hyperintensity	Hyperintensity
C	Hyperintensity	Hyperintensity	Hypointensity
D	Hypointensity	Hypointensity	Hypointensity

Table 2.

Radiological Basis for Classification of DEBC.

Components of DEBC	Type A (Acute/Active)	Type B Chronic/Persistent)	Type C (Latent)	Type D (Healed)
Subchondral bone	Edema	Fat and Edema	Fat	Sclerosis
Endplate	Indistinct Endplate erosion +	Endplate erosion +	Endplate erosion +	Endplate erosion +
Disc hyperintensity	+	+	_	_

Epidemiology

There is a wide variation in the literature concerning the prevalence of MC. The prevalence is reported to be around 0.5% to 47.1% in the asymptomatic population .^24-26 The wide variation in prevalence may be due to the difference in inclusion criteria concerning the size and volume of Modic changes included. Most of the studies show that MCs are more frequent in men. Recently, Chen et al observed that MC 1 is more prevalent in males, while MC type 2 is prevalent in females. There is no evidence of an ethnic predilection for MC across the world .²⁷ A study by Kanna et al reported a prevalence of 13% in a study population of 809 Indian patients, while Vredeveld et al in their study reported a prevalence of 28.6% among European military personnel.^24,26 The commonest sub-type reported by most studies is MC 2 followed by MC 1, while few studies have described a higher prevalence of MC 1. This discrepancy may result from a difference in the age of the population included as well as the symptoms. Concerning the number of segments involved, Kanna et al reported single-, two-, three- and four- or multi-level involvement in 60%, 30%, 5%, and 5% of patients, respectively.²⁴ MCs were more frequently seen at the lower lumbar levels (L4-S1). The study also documented L4-5 to be the most commonly involved level (30.7% of patients), followed by L5-S1 (26.3%), L3-4 (23.9%), L2-3 (12.4%), and L1-2 (6.8%). Based on the location of the Modic change in relation to the endplate (T2 image), they can be further divided into Entire, Central, Anterior, and Posterior⁹ (Figure 2).

Modic change especially Type 2 MC is more prevalent in people who are over 50 years old.^27,28 Nevertheless, the total occurrence ranges from 0.5 to 1.9% in adolescents and young adults, compared to 5.8 to 47.1% in middle-aged or older persons.^29-32 Modic change in lumbar magnetic resonance imaging (MRI) is more commonly found in the anterior third of the vertebral body, particularly in association with severe degenerative disc disease (DDD) or disc herniation (DH).³³ Studies conducted in recent times have shown that there is a significant correlation between sagittal spinopelvic alignment and MC. Zehra et al found that there was a higher occurrence of MC in patients with a low pelvic incidence (≤42°).³⁴ On the other hand, Chen et al discovered a stronger connection between a high lumbar lordosis (LL) and a higher L4-5 lordotic angle with MC.²⁷

Etiology and Pathobiology

The etiopathogenesis of VEP changes is complicated and controversial. It has a multifactorial pathophysiology and dynamic presentation (Figure 3). The reason for only a certain proportion of patients with DDD developing MC remains unclear. The commonly associated risk factors include elderly age, male sex, diabetes mellitus, smoking, genetic factors, obesity, and higher occupational loads. The most common risk factor for MC, however, is the presence of disc degeneration. The 2 most popular theories concerning Modic changes are the more traditional mechanical theory and the infective theory, the latter gradually gaining a wider acceptance among the spine fraternity.

Figure 3.

Multifactorial pathophysiology of modic changes.

Mechanical Theory

The strong association between MCs, severely degenerated discs and previous disc herniation, leads to the hypothesis that MC may be caused by mechanical stress.^33,35-38 Herniation and disc degeneration cause a loss of nuclear material, which may in turn increase the shear forces on the endplates. This ultimately results in micro-fractures within the endplates. Additionally, the toxic nucleus tissue may invade the endplate and vertebral bone initiating an inflammatory response. It may not only be nucleus material entering the vertebrae but also as suggested by Crock, that after the damage of a disc, irritating substances are produced, draining into the vertebral body and causing an autoimmune reaction.³⁹ This mechanical theory is supported by the fact that histological findings of the MC type 1 demonstrate disruption of the end plates with evidence of chronic repetitive trauma. In further support of the mechanical theory, several studies have reported that MC type 1 disappears or evolves into type 2 after osteosynthesis (providing stabilization to heal the microfractures) which probably leads to lesser pain.^40-42

However, there are several factors against the trauma theory as the etiology of Modic changes. Chronic repetitive trauma does not explain the most common paradiscal pattern of involvement of the Modic changes as trauma most commonly involves the superior endplate alone or superior and inferior endplate of the same vertebra rather than end plates on either side of the disc space. Similarly, the involvement of the posterior endplate and subchondral bone without the involvement of the anterior endplate cannot be explained by trauma. Studies utilizing multimodal imaging identified endplate changes in CT which were typical of infective changes.⁴³

Infective Theory

Following a breach of the outer annulus fibrous in conjunction with a herniation, new capillarization occurs around the extruded nucleus pulposus material within a short period of time, and inflammation with the presence of macrophages occurs.^44-48 In this special environment, it might be possible for the anaerobic bacteria to enter the disc through the breach, causing a low virulent and slowly developing infection in the disc. Since the disc is an avascular structure, it is an ideal environment for the growth of anaerobic bacteria. The infection may therefore result in local tissue inflammation with edema, and due to the production of cytokines known to affect the bone; this is leading to MC type 1 in the endplates and subchondral marrow (Figure 4). Several studies have shown vertebral endplate changes and marrow edema to be observed in conjunction with discitis.^49-52 However, due to the low virulence of these anaerobic bacteria, the inflammatory response and erosive changes are not as strong as seen in discitis caused by more aggressive strains of bacteria eg, Staphylococcus aureus. Infections in the discs with low virulent anaerobic bacteria are therefore rarely diagnosed as discitis because the tissue reactions in the disc are slow and less destructive and therefore poorly illuminated on MRI. This lack of virulence is probably also one of the reasons why the infection properly does not spread to aerobic tissues like the vertebrae, together with the severe difficulties the anaerobic bacteria would have to survive in the highly aerobic environment in the vertebrae and especially in the MC type 1 hence this is hyper vascularised tissue. Manniche et al utilized the fluorescent in situ hybridization (FISH) technique to confirm the existence of Cutibacterium acnes biofilm and inflammation in the disc tissues of individuals with disc herniation, despite the absence of other signs of infection. According to their report, antibiotic treatment may be helpful for a specific subset of patients with MC who have an underlying infection of low virulence.⁵³ In a recent systematic review conducted by Jha et al, a similar finding was identified, highlighting the necessity for more clinical investigations to determine the role of infectious causes in a specific subgroup of MC.⁵⁴

Figure 4.

Proof of Concept of Modic changes. Modic changes are due to intense inflammation, secondary to exposure of the nucleus pulposus material to the bone marrow due to endplate damage, or a bacterial inoculum secondary to annulus fibrosis rupture. This results in modic changes resulting in disc degeneration.

Rajasekaran et al performed a multimodal imaging study of end-plate changes, by utilizing CT. The results of the study showed that the endplate changes in patients with Modic change, had typical features of infection (Figure 5). These findings further provided proof of concept and in addition to other findings were used to evolve a scoring system termed Endplate Infection Probability Score (EIPS) that could help determine the probable cause of MC. The study showed that nearly 70% of patients with Modic changes had higher EIPS highlighting high infection possibility.⁴³

Figure 5.

CT images in patients with Modic changes showing extensive endplate erosion involving nearly 50% of the endplate (C) which is not depicted in MRI (A, B). Punctate endplate erosion (F) in patients with Type 2 Modic change (D, E). Eccentric endplate erosion (I) involving the anterior half of the endplate is seen in Type 2 Modic changes (G, H).

Various studies have unraveled the molecular mechanisms in patients with Modic changes.^55-57 Rajasekaran et al, in their study, performed mass spectrometric analysis and a comparative proteomic analysis of 14 discs with and 10 discs without MC. The findings showed that several components of the extracellular matrix, namely collagens and proteoglycans, namely vesican and biglycan, were downregulated in MC. Similarly, the presence of inflammatory molecules like Plasminogen (PLG), angiogenin (ANG), fibroblast growth factor-binding protein 2 (FGFBP2), and ferritin (FTL) etc were solely expressed in the MC group. The study identified a total of 50 proteins involved in the host defense response, with 14 of them being specifically associated with MC.⁵⁵ The metabolite-protein interaction analysis uncovered a notable relationship among 19 proteins, namely related to the ubiquitin-mediated proteasome degradative process. Additionally, there was an association observed between the metabolite glutamic acid and patients with Modic changes. These findings provide additional support for the concept that MC indicates a severe inflammatory condition and that the activation of the body’s defense mechanisms and immune pathways promotes the development of infectious causes.

Autoimmunity

Once the disc has completed its embryonic development, the nucleus pulposus (NP) does not have any direct interaction with the systemic circulation. Therefore, NPs retain their ability to protect themselves from immune responses and possess the Fas ligand, which can trigger cell death (apoptosis). When there is injury to the end plate, the nucleus pulposus (NP) is found in the same location as the immune cells of the basement membrane (BM).⁵⁸ After being exposed to the immune system, NP cells are identified as “foreign” and this leads to the initiation of an autoimmune response. These tissues have shown elevated levels of cytokines, macrophages, and activated T- and B-cells⁵⁹ Disc cartilage proteoglycans can potentially stimulate an autoimmune response by increasing lymphocyte transformation and monocyte infiltration.⁶⁰

Genetic Association

Rajasekaran et al conducted a comprehensive study of the genetic links between degenerative disc disease (DDD) and several morphological characteristics such as disc degeneration (DD), disc herniation (DH), Modic changes (MC), endplate degeneration (ED), and Schmorl’s nodes (SN). The researchers discovered a genetic link between MC and the vitamin D receptor (VDR) and matrix-metalloproteinase-20 (MMP20) genes.^61,62 Similarly, Biczo found strong connections between specific lumbar degenerative disc disease (DDD) endophenotypes and VDR variants gene.⁶³

Clinical Implication of Vertebral Endplate Changes

Endplate Changes and Low Back Pain

Due to the highly innervated nature of the endplate, any damage or defect is very likely to cause pain. Several studies investigating endplate lesions have established a significant correlation with low back pain.^64-66 Moreover, research has indicated that endplate pathologies may have a higher concentration of nerve fibres compared to disc pathologies, making them a significant source of pain.^33,64 Differences in the size or shape of the endplate defect can result in varying pain profiles.^65,66 Several prior studies have investigated this potential and have successfully shown that endplate defects of ‘big’ size are more strongly linked to disc degeneration and discomfort compared to abnormalities of ‘small’ size.^66,67 In a recent study conducted by Farshad-Amacker et al, it was found that endplate abnormalities occupying 50% or more of the endplate area were more likely to be a risk factor for disc degeneration and Modic alterations.¹⁰ However, it is important to note that these attempts only provided a qualitative grading rather than precise measurements.^35,36 The degeneration of the endplate caused the nerves to spread further due to mechanical stimulation and biochemical sensitization. This ultimately resulted in damage to the nerve fibres that extend from the vertebra to the disc, leading to lower back pain.²²

Modic Changes and Low Back Pain

Various studies have demonstrated a significant association between MC and non-specific LBP.^6,65,66 While the former 2 studies did not find a correlation between the Modic types and LBP, Brinjikji et al described a correlation between LBP and MC 1. Various studies have reported that the prevalence of MC in LBP patients varies from 8 to 80.1%.^6,27,28 However, among the 3 types, MC 1 has been most commonly associated with LBP.²⁷ Rajasekaran et al, in their study, demonstrated a characteristic type of pain in nearly 50% of patients with Modic changes as compared to less than 25% the non-Modic patients.⁴³ The pain was more severe as determined by the numeric pain rating scale, more frequent, and lasting longer with a poorer response to conservative therapy.

Recent literature, however, indicates a poor association between MC and LBP. Herlin et al published a meta-analysis including 31 studies.²⁸ The study failed to establish a statistically significant association between any type of MC or their sizes and prevalence and or severity of LBP and or activity limitation. In a population-based study involving 478 participants, there was no statistically significant correlation between the presence of MC and LBP over the past 12 months, or during a lifetime.⁶⁷ Of all the different MRI parameters, damage to the EPs showed a significant association with LBP. The study concluded that ED, rather than MC or DD was the frequently underestimated, and independent predictive factor for LBP and a significant confounder for other MRI findings. Lack of uniformity concerning the nomenclature of MC is one of the major issues highlighted in recent literature.

Modic vs DEBC

The disc, cartilaginous and bony endplate, and subchondral bone are not just adjacent structures but also work together to maintain structural integrity and support physiological function. In a study done by Rajasekaran et al, misclassification of nearly 51.8% of patients occurred when solely concentrating on the subchondral bone. In their investigation, STIR accurately diagnosed 58% of end-plates as chronic persistent type (Type B), which were previously misclassified as healing or healed. Using STIR and incorporating disc intensity and EP erosions, the researchers found that 3.4% of patients in the control group and 21.75% in the LBP group were reassigned to a newly identified ‘chronic persistence’ (Type B of DEBC) group. This group had the highest occurrence and impact on the likelihood of requiring surgery and developing an infection.²²

Diagnostic Dilemma

Differentiating MC from spondylodiscitis continues to pose a significant challenge. Schwarz-Nemec et al reported that endplate contour, the extent of edema, and T1-signal ratios of MC 1 (extent of 31.96%, T1 signal ratio of 0.83), early spondylodiscitis (56.42%; 0.60) and severe spondylodiscitis (91.84%; 0.61) are significantly different.⁶⁸ The use of short tau inversion recovery (STIR) sequences in MRI for assessing Modic’s lesion has been discussed.²² Recently, Kristoffersen et al reported good inter-observer reliability for the interpretation of STIR sequence signal hyper-intensity in Modic’s lesion.⁶⁹ These STIR hyper-intense lesions, indicating inflammation or edema, have been correlated with early infection or painful MC. Especially in young patients the most common differential diagnosis to be ruled out for MC1 is inflammatory spondyloarthropathy (SpA).^70,71

Treatment Implications

There is growing evidence of the association of MC with infection as evident from the study by Albert et al who demonstrated significant success with the use of antibiotics in patients with Modic changes.⁷² However, a part of the spine community considers MCs as “incidental” lesions on MRI, and also, it is unclear if the presence of MC itself is an indication for treatment in patients with chronic LBP.

Role of Conservative Treatment

Currently, the etiology of low back pain induced by MCs remains ambiguous or indeterminate. Patients diagnosed with MC are consistently treated based on the clinical management principles for chronic low back pain (LBP). Non-surgical treatments, including spinal manipulation and exercise, are equally effective as surgery in reducing pain intensity, but they come at a lower cost and a reduced risk of complications.⁷³ Exercise therapy is commonly prescribed for the management of chronic low back pain with MC.⁷⁴ Nevertheless, considering the histological appearance of MCs with microfractures at the endplate, engaging in intense weight-bearing exercise can impede the healing process of these microfractures. Consequently, patients with MCs may have a reduced likelihood of experiencing improvement with exercise therapy. A study conducted by Jensen et al. in 2012 supports this perspective, however, exercise therapy may have a limited therapeutic impact, in individuals with the MC 1.⁷⁵

Spinal manipulation is a widely recognised technique for treating chronic LBP. While the 2 studies conducted by Annen et al^76,77 focused on distinct research populations, their consistent findings indicate that spinal manipulation could be regarded as a viable alternative treatment for patients with MCs. It is challenging to obtain robust evidence for clinical practice through individual studies that focus on specific therapies. The use of physiotherapy for MCs is still in the early stages of investigation and requires additional validation.

The presence of chronic LBP in MC is not only associated with the activation of mechanoreceptors due to endplate microfracture, but it also results in the activation of chemoreceptors through the production of pro-inflammatory substances.⁷⁸ The pharmacological properties of calcitonin, as observed in animal research, include the maintenance of subchondral and trabecular microstructure and the promotion of the cartilaginous phase of fracture healing.⁷⁹ These effects may explain the findings described by Zhou et al who reported a significant decrease in the LBP in patients with MC 1.⁸⁰ On the other hand, Zolendronic acid, which belongs to the group of bisphosphonates, hinders the release of pro-inflammatory cytokines like interleukin 1 (IL-1), TNF-α, and IL-6 and significantly reduces bone marrow edema.⁸¹ It produces its clinical effects by disrupting the degenerative process of MCs and hastening the conversion of MC1 to MC2. Studies have shown that though Glucosamine sulphate (GS) can decelerate the degradation of cartilage by blocking IL-1β, individuals with MCs did not experience any positive effects from its use.⁸² This suggests that IL-1β may have minimal involvement in the pathophysiology of MCs, or it could indicate that GS is unable to reach the intended location due to insufficient blood flow to intervertebral discs and vertebral bodies.⁸³ Targeting the degenerative process of MCs by clinical interventions may offer innovative therapy approaches for these patients.

Shan et al demonstrated poor response to conservative treatment or the impaired resolution of the herniated discs in those patients with concomitant MC probably due to the presence of hyaline cartilage that makes the fragment less amenable to vascular infiltration and spontaneous resorption.⁸⁴

Role of Antibiotics

In 2013, Albert purported the role of infection (Cutibacterium acnes and Corynebacterium propionibacterium) in the pathophysiology of MC and endorsed the administration of antibiotic therapy (3 months course of amoxicillin-clavulanate) in a select group of patients with MC.⁷² Over the past years, concerns have been raised by clinicians given the potential risk of study bias, conflicting results in subsequent studies, and the prospect of treating a large number of LBP patients with long-term, high-dose antibiotics.^27,85 A recent multi-centred, randomized, Norwegian study has refuted this claim and strongly discouraged the use of antibiotics in MC.⁸⁶

Role of Targeted Molecular Therapy

The use of anti-inflammatory agents in the treatment of chronic LBP with Modic changes is rapidly growing. The potential anti-inflammatory molecules being considered are TNF-α inhibitors, IL-1 receptor antagonists, IL-4, TGF-β1, LIM mineralization protein-1 (LMP-1), Short stature homeobox 2 (SHOX2), growth and differentiation factor 6 (GDF-6), lactoferricin, triptolide, kaempferol, Co-Q10, Urolithin A, and sesamin. The main objective is to target the suppression of inflammatory mediators associated with discogenic pain, especially TNF-α and IL-1β. These compounds possess the potential for future pharmaceutical development aimed at treating painful disc degeneration. Out of these options, only TNF-α inhibitors, IL-1 inhibitors, TGF-β1, GDF-6, and resveratrol have been proven to effectively reduce discogenic pain. Further research is needed to determine the impact of others on pain suppression.⁸⁷

A recent systematic review reported limited evidence suggesting that patients treated with ZA and calcitonin can experience short-term symptomatic relief. Exercise and manipulation therapy may be effective only for some patients with MC. In contrast, the rationale for antibiotic treatment for MCs has not been proven. In conclusion, the current evidence does not support the effectiveness of non-surgical therapy for patients with MCs.⁸⁸

Surgical Options and Outcomes

Studies have shown mixed results concerning the surgical management of patients with MC. Djuric et al demonstrated that patients with preoperative disc inflammation in the form of MC had less satisfactory outcomes after discectomy.⁸⁹ A 2-year prospective study by Bostelmann evaluated the natural course of MC following micro-discectomies and found a significant conversion from one type to another (including both upward and downward trends), especially at 12 months in MC 2 and between 12 and 24 months in MC 1. They reiterated the fact that MCs are dynamic lesions and an assumption of its universal worsening following micro-discectomy should be reconsidered.⁹⁰ In a prospective study, Esposito et al demonstrated that the functional outcome following lumbar fusion surgery with that of MC. In their cohort, patients with MC 2 demonstrated poor outcomes following fusion, while patients with MC 1 and 3 types showed significant improvement in pain and disability.⁴² In a retrospective study by Wang et al involving patients undergoing trans-foraminal lumbar fusion, it was concluded that although the presence of MC did not negatively influence fusion rates, cage subsidence rates were found to be higher in those with both type 1 and 2 MCs.⁹¹ Liu et al demonstrated that in patients undergoing oblique lumbar inter-body fusion, the presence of MC and endplate sclerosis significantly reduced cage subsidence.⁹² In a prospective, multicenter, trial involving patients undergoing “lumbar decompression-alone” or “lumbar decompression with fusion”, Ulrich reported no significant difference in post-operative clinical outcome (until 36 months postoperatively) between patients with MC and those without MC.⁹³ Thus, although current literature indicates that patients with MC tend to show relatively poorer outcomes following conservative treatment or discectomies, there is no significant evidence either favouring definitive fusion procedures or alternative management strategies.

A recent study by Rajasekaran et al evaluated the significance of VEP changes as possible indicators of surgery and the likelihood of postoperative infection. In their study involving 1085 patients with LBP and 445 patients without LBP (controls), the odds ratio of the need for surgery was found to be high (OR = 5.2) in patients with DEBC changes. Similarly, the incidence of postoperative infection was significantly higher in patients with DEBC (2.4%), especially type B and C, when compared to patients without DEBC (0.47%).²²

Conclusion

Vertebral endplate changes, initially described as radiological changes associated with degeneration, have been probed along the lines of different aspects. It has shown to be a dynamic phenomenon, with the global spine fraternity leaning towards infection as the possible etiology. There is a significantly better understanding of the etiology and prognosis of patients with VEP changes, however, specific management for these patients is still elusive. We believe that DEBC classification is an important advance in our understanding of the vertebral endplate changes over the classical MC and will have a significant role in both clinical practice and research in disc diseases.

Footnotes

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

ORCID iDs

Shanmuganathan Rajasekaran

Karthik Ramachandran

Sri Vijay Anand K S

Rishi M. Kanna

Ajoy P. Shetty

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