Vertebrogenic Low Back Pain

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Over the past few years, research has increasingly focused on the vertebral endplates (VEPs) – the interface between the intervertebral disc and the vertebral body – as a potential source of CLBP. Damage to the VEPs, either through injury or degenerative processes, can lead to inflammation and pain signaling, a condition termed vertebrogenic pain. Pain signals originating from these damaged endplates are transmitted via the basivertebral nerve (BVN), a nerve trunk that enters the posterior vertebral body and branches extensively to innervate the superior and inferior endplates. Histological studies have confirmed the presence of nociceptive fibers within the BVN and VEPs, with increased density observed in patients with CLBP and degenerative changes.  

This article should be read in conjunction with the article on Internal Disc Disruption.

MRI

First classified by Modic et al. in 1988, these changes are categorized into three main types based on their appearance on T1-weighted (T1w) and T2-weighted (T2w) MRI sequences.

Modic 1 is the most clinically relevant type. It reflects underlying bone marrow oedema and increased vasculairty. Histopathological studies confirm that MC1 involves the presence of fibrovascular tissue replacing normal bone marrow, disruption and fissuring of the endplate, and vascularized granulation tissue at the bone-disc junction, indicative of an active inflammatory process.

Modic Change Types

Type	Acronym	Pathophysiology		T1	T2
Modic Type 1	MC1	Active inflammation		↓	↑
Modic Type 2	MC2	Fatty replacement		↑	↑
Modic Type 3	MC3	Sclerosis		↓	↓

These types are not necessarily static and can convert over time, suggesting they may represent different stages of the same underlying pathological process. For example Mixed MC1 and MC2 is commonly seen.

The presence of MC1 or MC2 changes is strongly associated with vertebrogenic CLBP and serves as a primary inclusion criterion for targeted therapies like basivertebral nerve ablation.  

Pathophysiology

See also: Internal Disc Disruption

The pathophysiology of MC1 is complex and multifactorial, involving an intricate interplay between mechanical factors, inflammation, immune responses, and potentially (controversially) low grade infection within the discovertebral unit.

Initiating Factors: Mechanical stress on the spine, often associated with DDD or disc herniation, is considered a primary trigger. Degeneration alters disc biomechanics, increasing shear forces on the endplates, which can lead to microfractures. These endplate defects breach the barrier between the avascular, immunoprivileged nucleus pulposus (NP) and the highly vascularized vertebral bone marrow. This breach allows for the influx of inflammatory mediators, NP material (which may act as an autoantigen), or potentially bacteria into the bone marrow, initiating an inflammatory cascade. The role of low-virulence bacteria, particularly Cutibacterium acnes (formerly Propionibacterium acnes), is a subject of ongoing investigation and debate. Autoimmune reactions against exposed NP components have also been proposed as a key mechanism. Genetic susceptibility and metabolic factors like diabetes may also play a role.

Key Cytokines and Mediators: The inflammatory environment of MC1 features upregulation of pro-inflammatory cytokines, notably TNF-α, IL-1β, and IL-6, produced by infiltrating immune and possibly disc cells. These cytokines drive inflammation, matrix degradation (via MMPs), pain signaling, and alter bone metabolism. Chemokines like IL-8, CCL2, CCL3, CCL4, CXCL12, and MIF recruit macrophages and neutrophils to the site. Prostaglandin E2 (PGE2), produced via COX-2, further promotes inflammation and pain sensitization in degenerative and herniated discs associated with MC1.

Immune Cells: Both innate and adaptive immune cells contribute to MC1. Pro-inflammatory M1 macrophages infiltrate bone marrow, releasing cytokines (TNF-α, IL-1, IL-6) and promoting ECM degradation. Neutrophils, possibly recruited via TLR activation or C. acnes, enhance inflammation through NET formation and MMP-9 release. Adaptive immune cells, including T and B lymphocytes, may drive autoimmune responses to NP antigens. Mast cells, increased in painful degenerated discs, release mediators (histamine, TNF-α, IL-6, VEGF, tryptase, ADAMTS5, Substance P) that promote inflammation, catabolism, and angiogenesis. Bone marrow stromal cell (BMSC) differentiation is also influenced by the inflammatory microenvironment, favoring osteogenesis or fibrosis.

Signaling Pathways: Several intracellular pathways regulate inflammation and cellular responses in MC1. NF-κB, activated by TNF-α, IL-1β, and TLR signaling, drives pro-inflammatory gene transcription. TLR2 and TLR4 detect PAMPs (e.g., C. acnes) and DAMPs (e.g., ECM fragments), triggering NF-κB and MAPK (p38-MAPK) pathways to amplify inflammation. Complement activation (via cell death, matrix degradation, or bacteria) produces anaphylatoxins (C3a, C5a) that further promote inflammation, fibrosis, and cytokine release (IL-1β, VEGF). Dysregulation of bone metabolism pathways (RANK/RANKL/OPG, Wnt/β-catenin, Notch, Hedgehog) alters osteoclast/osteoblast activity and BMSC fate. The JAK/STAT pathway also mediates cytokine (e.g., IL-6) effects in this environment.

Vicious Cycle: MC1 pathophysiology may involve a self-perpetuating cycle: initial endplate damage (mechanical or infectious) permits disc–bone marrow communication, triggering an inflammatory response driven by immune cell recruitment and cytokine release (TNF-α, IL-1β, IL-6) via TLR and NF-κB pathways. This inflammation exacerbates matrix degradation and alters bone remodeling, promoting osteoclast activity and impairing endplate repair, thereby perpetuating disc and endplate pathology.

Subtypes: The MC1 population itself may be heterogeneous. The evidence points towards potentially distinct biological subtypes. Some cases appear strongly linked to the presence of low-virulence bacteria like C. acnes, associated with predominantly innate immune signatures involving neutrophils and macrophages.⁹ Other cases might represent a more sterile inflammatory or autoimmune reaction to exposed NP material, characterized by adaptive immune cell involvement (T-cells, B-cells).

Local vs Systemic Inflammation: The link between localized inflammation in MC1 and systemic inflammatory markers remains unclear. While MC1 is defined by local MRI and histological changes, studies show inconsistent correlations with serum cytokines (e.g., MIF, IL-6). Some report elevated levels in MC patients, others find no significant association or predictive value. This suggests local inflammation may not consistently manifest systemically, limiting the current utility of systemic biomarkers for MC1 diagnosis, stratification, or monitoring.

Clinical Features

The pain is often inflammatory in nature and can mimic spondyloarthritis in that there is commonly night pain and prolonged morning stiffness. The pain is often midline rather than lateralised as is the case in other causes of chronic low back pain. The pain can refer to the buttocks. It is not typical for pain to refer past the knee. There may be an absence of pain with extension.

There may be a mixed picture as endplate pathology commonly co-exists with annular tears which is transmitted largely via the sinuvertebral nerve rather than the basivertebral nerve. Irritation of nerve roots such as in the presence of disc herniation can further mix the clinical features.

Treatment

Prescription Medication

NSAIDs - Strong rationale for use. These target the downstream production of prostaglandins (PGE2 via COX-2) which are mediators of inflammation and pain (doesn't address upstream immune drivers). PEG2 has been implicated as one of the mediators of vertebrogenic pain. Celecoxib is typically the best first line medication to try due to GI safety. Suggested dosing is 100 to 200mg twice daily. Since COX-2 is involved in bone formation and repair, long-term use might theoretically impede the healing of endplate microfractures or slow the natural resolution process within the bone marrow (theoretical concern of slowing transition of MC1 to MC2).

Antihistamines - Highly theoretical and speculative. While mast cells are present in this condition it may not be as important as other inflammatory mediators like TNF-α, IL-1β, and PGE2. However they are safe.

Immunosuppressants - The only drug to have been studied is infliximab (which targets TNF-α) and found to be ineffective in an RCT. No one seems to have studied interleukin-1 inhibitors or methotrexate for some reason yet. There is a striking paucity of clinical trial data for targeted immunosuppressive therapies, despite decades of research implicating the immune response in this disease.

Antibiotics - Controversial. An initial double-blind RCT by Albert et al. (2013) reported significant improvements in pain and disability at 1 year with 100 days of amoxicillin-clavulanate compared to placebo in 162 patients with chronic LBP (>6 months) post-disc herniation and MC1 changes. However, a subsequent, larger (n=180), multicenter, double-blind RCT (the AIM study) using 100 days of amoxicillin (without clavulanate) versus placebo in a similar population (chronic LBP, previous herniation, MC1 or MC2) found no clinically important benefit at 1 year.

Bisphosphonates - One RCT (n=40) evaluated a single intravenous infusion of zoledronic acid (5 mg) versus placebo in patients with chronic LBP and MCs. A statistically significant but small difference in LBP intensity favoring ZA was observed at 1 month (mean difference 1.4 on a 10-cm VAS), but not at 1 year. No significant differences were found in disability (ODI) or most secondary outcomes, although NSAID use was significantly lower in the ZA group at 1 year.

Doxycycline - Broad anti-inflammatory properties means some theoretical potential for benefit, but not been specifically studied.

Supplements

Everything in this category is speculative, but are cheap and safe.

Omega-3 Fatty Acids - Not specifically studied (except in rats). but might theoretically align with some aspects of MC1 pathophysiology. They reduce production of pro-inflammatory eicosanoids (like PGE2) and cytokines (TNF-alpha, IL-6). It is thought to be generally safe.

Curcumin - Not specifically studied (except in neurons of animals). It exerts anti-inflammatory action through inhibition of the NF-κB signaling pathway. This could theoretically lead to reduced expression of NF-κB target genes, including those encoding pro-inflammatory cytokines (TNF-α, IL-1β, IL-6, IL-8), chemokines, adhesion molecules, and inflammatory enzymes like COX-2. It is generally considered safe. In osteoarthritis, it has been shown to be effective in meta-analyses, with one study showing corresponding reductions in IL-1.

Vitamin D - Low levels potentially linked to MC. Plays a role in bone homeostasis and immune regulation (promotes tolerogenic state). It inhibits B cells and T cells (e.g. shifting Th1 towards Th2 phenotypes). Can suppress various inflammatory cytokines (TNF-α, IL-1, IL-6, IFN-γ) while potentially increasing anti-inflammatory cytokines like IL-10.

Procedures

Basivertebral Nerve Ablation - Please see relevant article

Intra-discal corticosteroid injection

Epidural corticosteroid injection - Not specifically studied.

Resources

Vertebrogenic Pain - Conger 2022.pdf - 379 KB (f)