Intervertebral disc (IVD) degeneration is a major cause of low back pain (LBP), which results in disability worldwide. However, the pathogenesis of IVD degeneration mediating LBP remains unclear. Current conservative treatments and surgical interventions are both to relieve the symptoms and minimise pain; nevertheless, they are unable to reverse the degeneration. Previous studies have shown that inflammation and nociception markers are important indicators of pain mechanisms in IVD degeneration underlying LBP. As such, multiomics profiling allows the discovery of these target markers to understand the key pathological mechanisms mediating IVD degeneration underpinnings of LBP. This article provides insights into a precision medicine approach for identifying and understanding the pathophysiology of IVD degeneration associated with LPB based on the severity of the disease from early and mild to severe degenerative stages. Molecular profiling of key markers in degenerative IVDs based on patient stratification at early, mild, and severe stages will contribute to the identification of target markers associated with signalling pathways in mediating neuroinflammation, innervation, and nociception underlying painful IVD degeneration. This approach will offer an understanding of establishing personalised clinical strategies tailored to the severity of IVD degeneration for the treatment of LBP.

Recent clinical studies have established a strong association between cigarette smoking and degenerative disc disease. Both in vitro and in vivo research indicated that cigarette smoke disrupts cellular homeostasis in the intervertebral disc (IVD), leading to spatiotemporal remodeling of the extracellular matrix, with a notable reduction in solute diffusivity within the cartilage endplate (CEP). As the CEP serves as a critical mechanical barrier and solute diffusion pathway for the IVD, both roles can be compromised by pathological changes in the tissue. This underscores the need for a more comprehensive examination of endplate remodeling during IVD degeneration, particularly in the context of cigarette smoking and cessation. The objective of this study was to perform a quantitative analysis of the structure-material property relationship changes in the endplate at tissue and cellular levels to determine how endplate mineralization progresses during IVD degeneration in the context of cigarette smoke exposure and cessation, using our previously developed Sprague-Dawley rat model. Our results indicate that cigarette smoke exposure-induced endplate remodeling is characterized by a higher CEP histological grade, increased aberrant CEP calcification level, and elevated bony endplate surface flatness score, all of which correlated with an accelerated chondrocyte cell life cycle. Smoke cessation alone was insufficient to reverse the mineralization progression in the endplate. Principal component analysis further identified alterations in endplate morphometry at the tissue level and disruptions in the chondrocyte life cycle at cellular level as key markers of degenerative remodeling. These findings establish endplate remodeling as a key indicator of smoke exposure-induced IVD degeneration and inform the development of novel therapeutic strategies aimed at preserving or improving disc health.

The cartilaginous endplate (CEP) plays a pivotal role in facilitating the supply of nutrients and, transport of metabolic waste, as well as providing mechanical support for the intervertebral disc (IVD). Recent technological advances have led to a surge in MR imaging studies focused on the CEP. This article describes the anatomy and functions of the CEP as well as MRI techniques for both qualitative and quantitative assessment of the CEP. Effective CEP MR imaging sequences require two key features: high spatial resolution and relatively short echo time. High spatial resolution spoiled gradient echo (SPGR) and ultrashort echo time (UTE) sequences, fulfilling these requirements, are the basis for most of the sequences employed in CEP imaging. This article reviews existing sequences for qualitative CEP imaging, such as the fat-suppressed SPGR and UTE, dual-echo subtraction UTE, inversion recovery prepared and fat-suppressed UTE, and dual inversion recovery prepared UTE sequences. These sequences are employed together with other techniques for quantitative CEP imaging, including measurements of T2*, T2, T1, T1ρ, magnetization transfer, perfusion, and diffusion tensor parameters. EVIDENCE LEVEL: 1 TECHNICAL EFFICACY: Stage 2.

Pear-shaped disc could increase the risk of intraoperative end-plate injury, which may lead to postoperative sclerotic Modic Changes (MCs). However, there are no studies on the relationship between pear-shaped disc and postoperative sclerotic MCs. Therefore, this study investigates the risk factors for postoperative sclerotic MCs following transforaminal lumbar interbody fusion (TLIF). Specifically, the study focuses on the impact of pear-shaped disc on the occurrence of postoperative sclerotic MCs and evaluates its influence on clinical outcomes.

A total of 411 patients undergoing TLIF between January 2018 and January 2022 were included. Among them, 50 developed postoperative sclerotic MCs, while 361 did not. The two groups were matched based on various parameters. Clinical and radiographic evaluations, including visual analogue scale (VAS), Oswestry disability index (ODI), lumbar X-ray, CT, and MRI, were performed. Statistical analysis included independent sample t test, Pearson's chi-square test, and binary logistic regression analysis.

After pairing, a total of 100 patients were included, including 50 patients in postoperative sclerotic MCs group and 50 patients in non-MCs group. There were 27 pear-shaped discs in the postoperative sclerotic MCs group, significantly higher than 7 in the non-MCs group (p < 0.001). Besides, BMI, endplate injury, and cage subsidence in the postoperative sclerotic MCs group were significantly higher than those in the non-MCs group, but the fusion rate was significantly lower than that in the non-MCs group. The postoperative and follow-up SL and surgical corrections of SL in postoperative sclerotic MCs group were significantly higher than those in non-MCs group. The independent risk factors identified for postoperative sclerotic MCs include pear-shaped disc and higher BMI.

Pear-shaped disc and higher body mass index (BMI) as independent risk factors for postoperative sclerotic MCs. Patients with sclerotic MCs exhibited a lower fusion rate, increased cage subsidence, and poorer symptom improvement compared to those without MCs.

Study DesignCross sectional comparative study.ObjectivesThe current study aims to explore the calcification potential (BMP2 expression) of intervertebral discs and its association with the presence of vertebral endplate defects visible on MRI.MethodsForty-seven herniated lumbar disc samples obtained from patients aged 20-76 (31 M/16F) undergoing surgery. Five-µm thin sections were stained with H&E in order to assign a histological degeneration score (HDS) from 0-15 on the basis of cell density (0-5), structural alterations (0-4), granular changes (0-3) and mucus degeneration (0-3). Sections were immuno-stained with anti BMP-2 antibodies to observe the calcification potential in these discs. In addition, pre-operativeT2-T1 W MRI images of the lumbar spine were analyzed for the presence and type (typical or atypical) of vertebral endplate defects, grade of disc degeneration (Pfirrmann grade I-V), presence of high intensity zones (HIZ), and Modic changes at the operated level.ResultsVertebral endplate defects, Modic changes & HIZ were observed in 81%, 29% and 21% of patients respectively. Mean HDS & BMP-2 expression was 9 ± 2 and mean 71 ± 36 spots/mm2 respectively. Discs with adjacent vertebral endplate defects showed increased cell density (P = .004), mucus degeneration (P = .002), HDS (P = .01) and BMP-2 expression (P = .01). Discs with HIZ also had increased HDS, but significance was seen with increased BMP2 expression (P = .006). HDS showed a positive correlation with BMP 2 expression (r = .30, P = .04).ConclusionThese findings suggest that the altered mechanical environment of discs is strongly associated with BMP-2 expression which is an important marker of intervertebral disc calcification.

The circadian clock orchestrates a broad spectrum of physiological processes, crucially modulating human biology across an approximate 24-hour cycle. The circadian disturbances precipitated by modern lifestyle contribute to the occurrence of low back pain (LBP), mainly ascribed to intervertebral disc degeneration (IVDD). The intervertebral disc (IVD) exhibits rhythmic physiological behaviors, with fluctuations in osmotic pressure and hydration levels that synchronized with the diurnal cycle of activity and rest. Over recent decades, advanced molecular biology techniques have shed light on the association between circadian molecules and IVD homeostasis. The complex interplay between circadian rhythm disruption and IVDD is becoming increasingly evident, with the sympathetic nervous system (SNS) emerging as a potential mediator. Synchronized with circadian rhythm through suprachiasmatic nucleus, the SNS regulates diverse physiological functions and metabolic processes, profoundly influences the structural and functional integrity of the IVD. This review synthesizes the current understanding of circadian regulation and sympathetic innervation of the IVD, highlighting advancements in the comprehension of their interactions. We elucidate the impact of circadian system on the physiological functions of IVD through the SNS, advocating for the adoption of chronotherapy as a brand-new and effective strategy to ameliorate IVDD and alleviate LBP.

Background: Chronic low back pain (LBP) has been associated with intervertebral disc (IVD) degeneration, but its association with abnormal morphology at the discovertebral junction (DVJ) is unclear. The goal of this study was to evaluate the DVJ morphology in asymptomatic (Asx) and symptomatic (Sx) subjects for LBP using ultrashort echo time (UTE) MRI. Methods: We recruited 42 subjects (12 Asx and 32 Sx). Lumbar IVD degeneration was assessed using Pfirrmann grading (1 to 5), while the abnormality of DVJ (0 = normal; 1 = focal; 2 = broad abnormality) was assessed using UTE MRI. The effects of LBP and level on the mean IVD and DVJ grades, the correlation between IVD and DVJ grade, and the effect of LBP and age on the number of abnormal DVJs within a subject were determined. Results: IVD grade was higher in Sx subjects (p = 0.013), varying with disc level (p = 0.033), adjusted for age (p < 0.01). Similarly, DVJ grade was also significantly higher in Sx subjects (p = 0.001), but it did not vary with DVJ level (p = 0.7), adjusted for age (p = 0.5). There was a weak positive (rho = 0.344; p < 0.001) correlation between DVJ and IVD grade. The total number of abnormal DVJs within a subject was higher in Sx subjects (p < 0.001), but not with respect to age (p = 0.6) due to a large spread throughout the age range. Conclusions: These results demonstrate the feasibility of using in vivo UTE MRI of the lumbar spine to evaluate the DVJ and the correlation of DVJ with LBP. This study highlights the need for a better understanding of DVJ pathology and the inclusion of DVJ assessment in routine lumbar MRI.

Lumbar intervertebral disc degeneration is thought to be the main cause of low back pain, although the mechanisms by which it occurs and leads to pain remain unclear. In healthy adult discs, vessels and nerves are present only in the outer layer of the annulus fibrosus and in the bony endplate. Animal models, and histological and biomechanical studies have shown that annulus tear or endplate injury is the initiating factor for painful disc degeneration. Injury to the disc triggers a local inflammatory repair response that activates nociceptors and promotes the synthesis of neuropeptides such as substance P and calcitonin gene-related peptide, by dorsal root ganglion neurons. These neuropeptides are transported to injured discs and act as pro-inflammatory molecules, promoting the production of an "inflammatory soup" by inducing vasodilatation and plasma extravasation as well as by promoting the release of chemical mediators from disc cells and infiltrating immune cells, causing neurogenic inflammation that leads to progressive disc degeneration and discogenic pain.

In healthy intervertebral discs (IVDs), nerves and blood vessels are present only in the outer annulus fibrosus, while in degenerative IVDs, a large amount of nerve and blood vessel tissue grows inward. Evidence supports that neurogenic inflammation produced by neuropeptides such as substance P and calcitonin gene related peptide released by the nociceptive nerve fibers innervating the IVDs plays a crucial role in the process of IVD degeneration. Recently, non-neuronal cells, including IVD cells and infiltrating immune cells, have emerged as important players in neurogenic inflammation. IVD cells and infiltrating immune cells express functional receptors for neuropeptides through which they receive signals from the nervous system. In return, IVD cells and immune cells produce neuropeptides and nerve growth factor, which stimulate nerve fibers. This communication generates a positive bidirectional feedback loop that can enhance the inflammatory response of the IVD. Recently emerging transient receptor potential channels have been recognized as contributors to neurogenic inflammation in the degenerative IVDs. These findings suggest that neurogenic inflammation involves complex pathophysiological interactions between sensory nerves and multiple cell types in the degenerative IVDs. Clarifying the mechanism of neurogenic inflammation in IVD degeneration may provide in-depth understanding of the pathology of discogenic low back pain.

Vertebrogenic pain is a documented source of anterior column chronic low back pain (CLBP) that stems from damaged vertebral endplates. Nociceptive signals are transmitted by the basivertebral nerve (BVN) and endplate damage is observed as Type 1 or Type 2 Modic changes (MC) on magnetic resonance imaging (MRI). The clinical impact and safety of intraosseous radiofrequency ablation of the BVN (BVNA) for the treatment of vertebrogenic pain has been demonstrated in three prospective clinical trials (two randomized and one single-arm study).

Report aggregate long-term BVNA outcomes at five years from three studies.

Pooled results at 5-years post-BVNA are reported for three clinical trials with similar inclusion/exclusion criteria and outcomes measurements: 1) a prospective, open label, single-arm follow-up of the treatment arm of a randomized controlled trial (RCT) comparing BVNA to sham ablation (SMART); 2) a prospective, open label, single-arm follow-up of the treatment arm of an RCT comparing BVNA to standard care (INTRACEPT); and 3) a prospective, open label, single-arm long-term follow-up study of BVNA-treated participants (CLBP Single-Arm). Paired datasets (baseline and 5-years) for mean changes in Oswestry disability index (ODI) and numeric pain scores (NPS) were analyzed using a two-sided paired t-test with a 0.05 level of significance. Secondary outcomes included responder rates, patient satisfaction, adverse events, and healthcare utilization.

Two hundred forty-nine (249) of 320 BVNA-treated participants (78 % participation rate) completed a five-year visit (mean of 5.6 years follow-up). At baseline, 71.9 % of these participants reported back pain for ≥5 years, 27.7 % were taking opioids, and 61.8 % had prior therapeutic lumbar spinal injections. Pain and functional improvements were significant at 5-years with a mean improvement in NPS of 4.32 ± 2.45 points (95 % CI 4.01, 4.63; p < 0.0001) from 6.79 ± 1.32 at baseline and a mean improvement in ODI of 28.0 ± 17.5 (95 % CI 25.8, 30.2; p < 0.0001) from 44.5 ± 11.0 at baseline. Nearly one-third (32.1 %) of patients reported being pain-free (NPS = 0) at five years, 72.7 % of patients indicated their condition improved and 68.7 % had resumed activity levels they had prior to onset of CLBP. In the sixty-nine participants taking opioids at baseline, 65.2 % were no longer taking them at 5-years, and spinal injections decreased by 58.1 %. The rate of lumbosacral treatment (therapeutic spinal injection, radiofrequency ablation, or surgery) for the same index pain source and vertebral level was 33/249 (13.2 %) at 5 years post BVNA; including a 6.0 % rate of lumbar fusion. There were no serious device or device-procedure related adverse events reported during the long-term follow-up.

In this 5-year aggregate analysis, BVNA significantly improved pain and function scores compared to baseline. Similarly, there were significant reductions in opioid consumption and spinal injections post BVNA. Data demonstrate a strong safety profile with no serious device or device-related events and low healthcare utilization rate for the same index pain source through a mean of 5.6 years. Results demonstrate that intraosseous BVNA treatment for patients with vertebrogenic pain is safe, effective, and durable through five years.

Intervertebral disc degeneration, which leads to low back pain, is the most prevalent musculoskeletal condition worldwide, significantly impairing quality of life and imposing substantial socioeconomic burdens on affected individuals. A major impediment to the development of any prospective cell-driven recovery of functional properties in degenerate IVDs is the diminishing IVD cell numbers and viability with ageing which cannot sustain such a recovery process. However, if IVD proteoglycan levels, a major functional component, can be replenished through an orthobiological process which does not rely on cellular or nutritional input, then this may be an effective strategy for the re-attainment of IVD mechanical properties. Furthermore, biomimetic proteoglycans (PGs) represent an established polymer that strengthens osteoarthritis cartilage and improves its biomechanical properties, actively promoting biological repair processes. Biomimetic PGs have superior water imbibing properties compared to native aggrecan and are more resistant to proteolytic degradation, increasing their biological half-life in cartilaginous tissues. Methods have also now been developed to chemically edit the structure of biomimetic proteoglycans, allowing for the incorporation of bioactive peptide modules and equipping biomimetic proteoglycans as delivery vehicles for drugs and growth factors, further improving their biotherapeutic credentials. This article aims to provide a comprehensive overview of prospective orthobiological strategies that leverage engineered proteoglycans, paving the way for novel therapeutic interventions in IVD degeneration and ultimately enhancing patient outcomes.

Animal laboratory study.

This study investigated the effects of Cutibacteriumacnes and Staphylococcusepidermidis on the lumbar discs of rabbits, as well as the outcomes of combined infection.

Many studies have indicated that bacterial infections are associated with lumbar disc degeneration (LDD). The most commonly cultured bacteria from disc tissues are C. acnes and S. epidermidis .

New Zealand white rabbits (n=40) were randomly divided into control, C. acnes , S. epidermidis , and C. acnes plus S. epidermidis ( i.e. , combined) groups. All groups except the control were injected with 25 μL of saline at L4-L5 and 25 μL of bacteria (1×10 7 CFU/mL) at L5-L6. All injections were performed under x-ray guidance. Weight measurements, haematological evaluations, and magnetic resonance imaging were performed after 4, 8, and 12 weeks. Histological examination and gene expression detection were performed 12 weeks after surgery.

Inflammatory factors in the blood and weight did not differ among the groups after 4, 8, and 12 weeks ( P >0.05). However, after 4 weeks, LDD occurred in the C. acnes group, and discitis occurred in the S. epidermidis and combined groups, all of which worsened after 8 weeks. After 12 weeks, the nucleus pulposus (NP) protruded and compressed the spinal cord in the C. acnes group, and tissue staining showed decreased NP tissue and cartilaginous endplate fracture. In the S. epidermidis and combined groups, the discitis was more confined, but tissue staining revealed a significant decrease in NP tissue, and loss of the normal disc structure.

In the early stage of infection in rabbits, C. acnes caused LDD, and S. epidermidis caused discitis. Coinfection with C. acnes and S. epidermidis caused discitis but was more limited in scope than infection with S. epidermidis alone.

Intervertebral disc degeneration (IDD) serves as the underlying pathology for various spinal degenerative conditions and is a primary contributor to low back pain (LBP). Recent studies have revealed a strong correlation between IDD and biological processes such as Programmed Cell Death (PCD), cellular senescence, inflammation, cell proliferation, extracellular matrix (ECM) degradation, and oxidative stress (OS). Of particular interest is the emerging evidence highlighting the significant involvement of the JNK signaling pathway in these fundamental biological processes of IDD. This paper explores the potential mechanisms through the JNK signaling pathway influences IDD in diverse ways. The objective of this article is to offer a fresh perspective and methodology for in-depth investigation into the pathogenesis of IDD by thoroughly examining the interplay between the JNK signaling pathway and IDD. Moreover, this paper summarizes the drugs and natural compounds that alleviate the progression of IDD by regulating the JNK signaling pathway. This paper aims to identify potential therapeutic targets and strategies for IDD treatment, providing valuable insights for clinical application.

Lower back pain (LBP) is a widely prevalent global health issue, affecting over half a billion people and remaining the leading cause of years lived with disability (YLDs). LBP significantly impacts healthcare systems, with substantial costs related to surgical procedures and lost workdays. Vertebrogenic back pain (VBP), characterized by specific clinical symptoms and associated with Modic changes (MC) in vertebral endplates, best seen on MRI, is a significant subset of LBP. This paper explores the pathophysiology, diagnosis, and current reports and studies focusing on VBP and the role of basivertebral nerve (BVN) ablation as a therapeutic intervention. Multiple studies, including randomized controlled trials (RCTs) and meta-analyses, demonstrate the efficacy of BVN ablation in reducing pain and improving function in patients with chronic LBP associated with MC.

Diagnostic test study.

To determine the reliability and validity or diagnostic accuracy of two previously described endplate structural defect (EPSD) assessment methods.

Studies of EPSD may further the understanding of pathoanatomic mechanisms underlying back pain. However, clinical imaging methods used to document EPSD have not been validated, leaving uncertainty about what the observations represent.

Using an evaluation manual, 418 endplates on CT sagittal slices obtained from 19 embalmed cadavers (9 men and 10 women, aged 62-91 yr) were independently assessed by two experienced radiologists and a novice for EPSD using the two methods. The corresponding micro-CT (µCT) from the harvested T7-S1 spines were assessed by another independent rater with excellent intra-rater reliability (k=0.96).

Inter-rater reliability was good for the presence (k=0.60-0.69) and fair for specific phenotypes (k=0.43-0.58) of EPSD. Erosion, for which the Brayda-Bruno classification lacked a category, was mainly (82.8%) classified as wavy/irregular, while many notched defects (n=15, 46.9%) and Schmorl's nodes (n=45, 79%) were recorded as focal defects using Feng's classification. When compared to µCT, endplate fractures (n=53) and corner defects (n=28) were routinely missed on CT. Endplates classified as wavy/irregular on CT corresponded to erosion (n=29, 21.2%), jagged defects (n=21, 15.3%), calcification (n=19, 13.9%), and other phenotypes on µCT. Some focal defects on CT represented endplate fractures (n=21, 27.6%) on µCT. Overall, with respect to the presence of an EPSD, there was a sensitivity of 70.9% and a specificity of 79.1% using Feng's method, and 79.5% and 57.5% using Brayda-Bruno's method. Poor to fair inter-rater reliability (k=0.26-0.47) was observed for defect dimensions.

There was good inter-rater reliability and evidence of criterion validity supporting assessments of EPSD presence using both methods. However, neither method contained all needed EPSD phenotypes for optimal sensitivity, and specific phenotypes were often misclassified.

During aging, the spine undergoes degenerative changes, particularly with vertebral endplate bone expansion and sclerosis, that is associated with nonspecific low back pain (LBP). We reported that parathyroid hormone (PTH) treatment could reduce vertebral endplate sclerosis and improve pain behaviors in aging, SM/J and young lumbar spine instability (LSI) mice. Aberrant innervation noted in the vertebral body and endplate during spinal degeneration was reduced with PTH treatment in aging and LSI mice as quantified by PGP9.5+ and CGRP+ nerve fibers, as well as CGRP expression in dorsal root ganglia (DRG). The neuronal repulsion factor Slit3 significantly increased in response to PTH treatment mediated by transcriptional factor FoxA2. PTH type1 receptor (PPR) and Slit3 deletion in osteoblasts prevented PTH-reduction of endplate porosity and improvement in behavior tests, whereas PPR deletion in chondrocytes continued to respond to PTH. Altogether, PTH stimulates Slit3 to repel sensory nerve innervation and provides symptomatic relief of LBP associated with spinal degeneration.

Vertebral endplate defects are often implicated in degenerative disc disorders, yet their connection to patient-reported symptoms remains unclear. COX-2 and PGE-2 are known for their roles in inflammation and pain, with EP-4 receptor involvement in pain signaling. Examining their expression in vertebral endplate tissues may provide insights into pathomechanism of low back pain.

To investigate the association between endplate defects and patient-reported symptoms and to further clarify the role of the COX-2/PGE-2/EP-4 axis in the pathogenesis of chronic low back pain.

Retrospective study.

A total of 71 patients who had undergone single-level L4/5 or L5/S1 modified laminectomy decompression preserving proximal upper laminae and transforaminal lumbar interbody fusion surgery were included in this study, including 18 patients diagnosed with lumbar disc herniation, 19 with lumbar disc herniation accompanied by degenerative lumbar spinal stenosis, and 34 with degenerative spondylolisthesis.

Demographic data, Pfirrmann grade, Modic changes, endplate defect score, visual analog scale (VAS) for back and leg pain, and Oswestry Disability Index (ODI) before surgery, 3-month and 6-month follow-up, and the percentage of immune-positive cells (COX-2, PGE-2, and EP-4) in endplate tissue sections.

Patients were divided into defect and nondefect groups according to endplate morphology on lumbar MR. All intraoperative endplate specimens were immediately fixed in 10% formaldehyde, and then embedded in paraffin 3 days later for tissue sections. The outcome measures were compared between the defect group and nondefect group. Data were analyzed using independent t-tests and χ² tests. Pearson's rank correlation test was used to assess correlations between patient-reported symptoms and the percentage of immune-positive cells in the groups. Multivariable logistic regression models using the forward stepwise likelihood ratio method were used to identify the factors that were independently associated with endplate defects.

The age of Defect group was significantly higher than that of nondefect group (52.5±7.7 vs 57.2±9.1. p=.024). There were no significant differences in gender, diagnosis, BMI, comorbidities, or surgical level between the two groups. Modic changes (Type Ⅱ/Type Ⅲ) were more common in patients of Defect group than nondefect group (38.5% vs 11.1%, p<.001), and so was disc degeneration (Pfirrmann grade Ⅳ/Ⅴ) (69.2% vs 33.3%, p<.001). Defect group had significantly higher VAS-Back (6.5±2.0 vs 4.9±1.6, p<.001) and ODI scores (62.9±10.7 vs 45.2±14.8, p<.001) than nondefect group, while there was no significant differences between the two groups during the 3 and 6-month follow-up after surgery. Histologically, Defect group was characterized by upregulation of COX-2, PGE-2, and EP-4 in endplate tissue sections. Both in defect and nondefect groups, VAS-Back showed moderate positive correlations with the expressions of COX-2 (r=0.643; r=0.558, p both<.001), PGE-2 (r=0.611; r=0.640, p both<.001), and EP-4 (r=0.643; r=0.563, p both<.001). Multivariate regression analyses reveled that percentage of COX-2-positive cells was associated with endplate defects (OR=1.509, 95%CI [1.048-2.171], p=.027), as well as percentage of PGE-2-positive (OR=1.291, 95%CI [1.106-1.508], p=.001) and EP-4-positive cells (OR=1.284, 95%CI [1.048∼2.171], p=.003).

Patients with endplate defects had worse quality of life, more severe disc degeneration and Modic changes, and up-regulated COX-2/PGE-2/EP-4 axis expression in cartilage endplates in patients with defected endplates. Inflammatory factors may significantly contribute to the onset and progression of chronic low back pain in patients with endplate defects, consequently impacting patient-reported symptoms.

Chronic low back pain (cLBP) is the most frequently reported cause of years lived with disability. Identifying the anatomical structures or dysfunction contributing to patients' symptoms is critical to guiding treatment. The etiology of back pain and differential diagnosis is often broad, ranging from non-degenerative cLBP (trauma, tumor, inflammation, infection, etc.) to degenerative (also described as nonspecific) cLBP. After eliminating suspicion for more insidious causes of cLBP, a thorough investigation can be conducted in an attempt to identify a source of degenerative cLBP. Degenerative cLBP can originate from many sources, and a detailed understanding of the structures potentially involved is invaluable for an accurate diagnosis. This review article aims to provide a broad overview of the utility of clinical history, physical exam findings, imaging findings, and diagnostic procedures in identifying the cause of patients' cLBP. We provide a framework to help guide clinicians by dividing the structures into groups as follows: anterior vertebral column, posterior vertebral column, and extra-vertebral pain. For each condition listed, we touch on the treatment options that can be considered.

Spinal pain affects individuals of all ages and is the most common musculoskeletal problem globally. Its clinical management remains a challenge as the underlying mechanisms leading to it are still unclear. Here, we report that significantly increased numbers of senescent osteoclasts (SnOCs) are observed in mouse models of spinal hypersensitivity, like lumbar spine instability (LSI) or aging, compared to controls. The larger population of SnOCs is associated with induced sensory nerve innervation, as well as the growth of H-type vessels, in the porous endplate. We show that deletion of senescent cells by administration of the senolytic drug Navitoclax (ABT263) results in significantly less spinal hypersensitivity, spinal degeneration, porosity of the endplate, sensory nerve innervation, and H-type vessel growth in the endplate. We also show that there is significantly increased SnOC-mediated secretion of Netrin-1 and NGF, two well-established sensory nerve growth factors, compared to non-senescent OCs. These findings suggest that pharmacological elimination of SnOCs may be a potent therapy to treat spinal pain.

Introduction: Many spine disorders are caused by disc degeneration or endplate defects. Because nutrients entering the avascular disc are channeled through the cartilaginous endplate (CEP), structural and compositional changes in the CEP may block this solute channel, thereby hindering disc cell function. Therefore, imaging the CEP region is important to improve the diagnostic accuracy of spine disorders. Methods: A clinically available T1-weighted and fat-suppressed spoiled gradient recalled-echo (FS-SPGR) sequence was optimized for high-contrast CEP imaging, which utilizes the short T1 property of the CEP. The FS-SPGR scans with and without breath-hold were performed for comparison on healthy subjects. Then, the FS-SPGR sequence which produced optimal image quality was employed for patient scans. In this study, seven asymptomatic volunteers and eight patients with lower back pain were recruited and scanned on a 3T whole-body MRI scanner. Clinical T2-weighted fast spin-echo (T2w-FSE) and T1-weighted FSE (T1w-FSE) sequences were also scanned for comparison. Results: For the asymptomatic volunteers, the FS-SPGR scans under free breathing conditions with NEX = 4 showed much higher contrast-to-noise ratio values between the CEP and bone marrow fat (BMF) (CNRCEP-BMF) (i.e., 7.8 ± 1.6) and between the CEP and nucleus pulposus (NP) (CNRCEP-NP) (i.e., 6.1 ± 1.2) compared to free breathing with NEX = 1 (CNRCEP-BMF: 4.0 ± 1.1 and CNRCEP-NP: 2.5 ± 0.9) and breath-hold condition with NEX = 1 (CNRCEP-BMF: 4.2 ± 1.3 and CNRCEP-NP: 2.8 ± 1.3). The CEP regions showed bright linear signals with high contrast in the T1-weighted FS-SPGR images in the controls, while irregularities of the CEP were found in the patients. Discussion: We have developed a T1-weighted 3D FS-SPGR sequence to image the CEP that is readily translatable to clinical settings. The proposed sequence can be used to highlight the CEP region and shows promise for the detection of intervertebral disc abnormalities.

Interactions between notochord and sclerotome are required for normal embryonic spine patterning, but whether the postnatal derivatives of these tissues also require interactions for postnatal intervertebral disc (IVD) growth and maintenance is less established. We report here the comparative analysis of four conditional knockout mice deficient for TonEBP, a transcription factor known to allow cells to adapt to changes in extracellular osmotic pressure, in specific compartments of the IVD. We show that TonEBP deletion in nucleus pulposus (NP) cells does not affect their survival or aggrecan expression, but promoted cell proliferation in the NP and in adjacent vertebral growth plates (GPs). In cartilage end plates/GPs, TonEBP deletion induced cell death, but also structural alterations in the adjacent NP cells and vertebral bodies. Embryonic or postnatal TonEBP loss generated similar IVD changes. In addition to demonstrating the requirement of TonEBP in the different compartments of the IVD, this comparative analysis uncovers the in vivo interdependency of the different IVD compartments during the growth of the postnatal IVD-vertebral units.

Various treatments for chronic low back pain (LBP) have been reported; among them, platelet-rich plasma (PRP) as a regenerative medicine has attracted much attention. Although Modic type 1 change (MC1) is associated with LBP, no treatment has been established so far. In addition, no studies have administered PRP to intervertebral discs (IVDs) in patients with LBP, targeting MC1 only. Thus, the purpose of this study was to determine the safety and efficacy of PRP administration to the IVDs in patients with MC1 experiencing LBP.

PRP was injected intradiscally to 10 patients with MC1 experiencing LBP. Patients were followed prospectively for up to 24 weeks after primary administration. Physical condition, laboratory data, and lumbar x-ray images were evaluated for safety assessment. Furthermore, to evaluate the effectiveness of PRP, patient-reported outcomes were considered. In addition, changes in MC1 were assessed using magnetic resonance imaging (MRI).

There were no adverse events in the laboratory data or lumbar X-ray images after administration. The mean visual analog scale, which was 70.0 ± 13.3 before the treatment, significantly decreased 1 week after PRP administration and was 39.0 ± 28.8 at the last observation. Oswestry disability index and Roland Morris disability questionnaire scores promptly improved after treatment, and both improved significantly 24 weeks after PRP administration. Follow-up MRI 24 weeks after treatment showed a significant decrease in the mean high-signal intensity of fat-suppressed T2-weighted imaging from 10.1 to 7.90 mm2 compared with that before PRP administration.

The safety and efficacy of PRP administration to the IVDs of patients with MC1 experiencing LBP were identified. Post-treatment MRI suggested improvement in inflammation, speculating that PRP suppressed inflammation and consequently relieved the patient's symptoms. Despite the small number of patients, this treatment is promising for patients with MC1 experiencing LBP. The study protocol has been reviewed and approved by the Certified Committee for Regenerative Medicine and the Japanese Ministry of Health, Labor and Welfare (Japan Registry of Clinical Trials [jRCT] No. jRCTb042210159).

Modic type 1 changes (MC1) are vertebral endplate bone marrow (BM) lesions observed on magnetic resonance images in sub-populations of chronic low back pain (CLBP) patients. The etiopathogenesis remains unknown and treatments that modify the underlying pathomechanisms do not exist. We hypothesized that two biological MC1 subtypes exist: a bacterial and a non-bacterial. This would have important implications for developing treatments targeting the underlying pathomechanisms.

Intervertebral disc (IVD) samples adjacent to MC1 (n ​= ​34) and control (n ​= ​11) vertebrae were collected from patients undergoing spinal fusion. Cutibacterium acnes (C.acnes) genome copy numbers (GCNs) were quantified in IVD tissues with 16S qPCR, transcriptomic signatures and cytokine profiles were determined in MC1 and control BM by RNA sequencing and immunoassay. Finally, we assessed if C.acnes GCNs are associated with blood plasma cytokines.

IVD tissues from control levels had <870 ​C.acnes GCNs/gram IVD. MC1-adjacent IVDs had either "low" (<870) or "high" (>870) C.acnes GCNs. MC1 patients with "high" C.acnes GCNs had upregulated innate immune cell signatures (neutrophil, macrophage/monocyte) and pro-inflammatory cytokines related to neutrophil and macrophage/monocyte function in the BM, consistent with a host defense against bacterium. MC1 patients with "low" C.acnes GCNs had increased adaptive immune cell signatures (T-and B-cell) in the BM and elevated IL-13 blood plasma levels.

Our study provides the first evidence for the existence of bacterial (C.acnes "high") and non-bacterial (C.acnes "low") subtypes in MC1 patients with CLBP. This supports the need for different treatment strategies.

Disc degeneration and vertebral endplate bone marrow lesions called Modic changes are prevalent spinal pathologies found in chronic low back pain patients. Their pathomechanisms are complex and not fully understood. Recent studies have revealed that complement system proteins and interactors are dysregulated in disc degeneration and Modic changes. The complement system is part of the innate immune system and plays a critical role in tissue homeostasis. However, its dysregulation has also been associated with various pathological conditions such as rheumatoid arthritis and osteoarthritis. Here, we review the evidence for the involvement of the complement system in intervertebral disc degeneration and Modic changes. We found that only a handful of studies reported on complement factors in Modic changes and disc degeneration. Therefore, the level of evidence for the involvement of the complement system is currently low. Nevertheless, the complement system is tightly intertwined with processes known to occur during disc degeneration and Modic changes, such as increased cell death, autoantibody production, bacterial defense processes, neutrophil activation, and osteoclast formation, indicating a contribution of the complement system to these spinal pathologies. Based on these mechanisms, we propose a model how the complement system could contribute to the vicious cycle of tissue damage and chronic inflammation in disc degeneration and Modic changes. With this review, we aim to highlight a currently understudied but potentially important inflammatory pathomechanism of disc degeneration and Modic changes that may be a novel therapeutic target.

This study characterized the regional indentation mechanics and native collagen content in cartilaginous endplates (CEPs) from the porcine cervical spine, young human lumbar spine, and aged human lumbar spine. Seventeen endplates were included in this study: six porcine cervical, nine young human lumbar, and two aged human lumbar. Width and depth measurements were obtained using a digital caliper and used to size-normalize and identify the central, anterior, posterior, and lateral regions. Regional microindentation tests were performed using a serial robot, where surface locations were loaded/unloaded at 0.1 mm/s and held at a constant 10 N force for 30 s. Loading stiffness and creep displacement were obtained from force-displacement data. Immunofluorescence staining for type I and type II collagen was subsequently performed on sagittal sections of all endplate regions. 255 images were obtained from which fluorescence intensity, sub-surface void area, and cartilage thickness were measured. CEPs from the young human lumbar spine were, on average, 27% more compliant, 0.891 mm thicker, had a lower fluorescence intensity for native collagen proteins within the cartilage (-58%) and subchondral bone (-24%), and had a sub-surface void area that was 19.7 times greater than porcine cervical CEPs. Compared to aged human lumbar CEPs, young human lumbar CEPs were 57% stiffer, 0.568 mm thicker, had a higher fluorescence intensity for native collagen proteins within the cartilage (+30%) and subchondral bone (+46%), and had a sub-surface void area that was 10.6 times smaller. Although not a perfect mechanical and structural surrogate, porcine cervical CEPs provided initial conditions that may be more representative of the young and healthy human lumbar spine compared to aged human cadaveric specimens. The indentation properties presented may have further applications to finite element models of the human lumbar spine.

The effectiveness and safety of intraosseous basivertebral nerve ablation (BVNA) for treating vertebrogenic pain is established, but low back pain-related healthcare utilization (LBPr-HU) following BVNA continues to be defined.

LBPr-HU data were pooled from 3 prospective studies. LBPr-HU categories of interest included non-invasive conservative care, opioid utilization, lumbosacral spinal injection (LSI), lumbosacral radiofrequency ablation (LRFA), and lumbosacral spinal surgery. Pre- and post-BVNA LBPr-HU were compared at both 1- and 5-years using McNemar's test for proportions and paired t-tests for means.

Two hundred forty-seven patients received BVNA and had 1-year follow-up; 205 had long-term follow-up (mean of 5.3 ± 1.33 years). Twenty-seven percent fewer participants initiated conservative care in the year post-BVNA compared to the year preceding BVNA (P < .001; 95% CI 19.8-34.5). Of 77/247 participants taking opioids at baseline, 40.3% and 61.7% fewer were taking them at one-year and 5.3 ± 1.33 years post-BVNA, respectively (P < .001). Of participants receiving LSIs in the year preceding BVNA, 81.2% fewer received LSI(s) in the year post-BVNA (P < .001; 95% CI 70.7-90.7); a 76.4% reduction in LSIs was maintained through a mean of 5.3 ± 1.33 years post-BVNA. LRFA rates were 1.6% at 1-year post-BVNA and 8.3% at 5.3 ± 1.33 years post-BVNA. Lumbar fusion surgery was 0.8% at 1-year post-BVNA and 6.5% at 5.3 ± 1.33 years post-BVNA.

In this aggregate analysis of patients with vertebrogenic pain, utilization of conservative care, opioids, LSIs, and LRFA were substantially reduced through 5 years post-BVNA compared to baseline. Lumbar fusion rates were less than half the published value at 5 years in similar populations.

Determine the effectiveness of intradiscal corticosteroid injection (IDCI) for the treatment of discovertebral low back pain.

Systematic review.

Adults with chronic low back pain attributed to disc or vertebral end plate pain, as evidenced by positive provocation discography or Modic 1 or 2 changes on magnetic resonance imaging.

Fluoroscopically guided or computed tomography-guided IDCI.

Sham/placebo procedure including intradiscal saline, anesthetic, discography alone, or other active treatment.

Reduction in chronic low back pain reported on a visual analog scale or numeric rating scale and reduction in disability reported by a validated scale such as the Oswestry Disability Index.

Four reviewers independently assessed articles published before January 31, 2023, in Medline, Embase, CENTRAL, and CINAHL. The quality of evidence was evaluated with the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) framework. The risk of bias in randomized trials was evaluated with the Cochrane Risk of Bias tool (version 2).

Of the 7806 unique records screened, 6 randomized controlled trials featuring 603 total participants ultimately met the inclusion criteria. In multiple randomized controlled trials, IDCI was found to reduce pain and disability for 1-6 months in those with Modic 1 and 2 changes but not in those selected by provocation discography.

According to GRADE, there is low-quality evidence that IDCI reduces pain and disability for up to 6 months in individuals with chronic discovertebral low back pain as evidenced by Modic 1 and 2 changes but not in individuals selected by provocation discography.

PROSPERO (CRD42021287421).

The cartilaginous endplates (CEP) are key components of the intervertebral disc (IVD) necessary for sustaining the nutrition of the disc while distributing mechanical loads and preventing the disc from bulging into the adjacent vertebral body. The size, shape, and composition of the CEP are essential in maintaining its function, and degeneration of the CEP is considered a contributor to early IVD degeneration. In addition, the CEP is implicated in Modic changes, which are often associated with low back pain. This review aims to tackle the current knowledge of the CEP regarding its structure, composition, permeability, and mechanical role in a healthy disc, how they change with degeneration, and how they connect to IVD degeneration and low back pain. Additionally, the authors suggest a standardized naming convention regarding the CEP and bony endplate and suggest avoiding the term vertebral endplate. Currently, there is limited data on the CEP itself as reported data is often a combination of CEP and bony endplate, or the CEP is considered as articular cartilage. However, it is clear the CEP is a unique tissue type that differs from articular cartilage, bony endplate, and other IVD tissues. Thus, future research should investigate the CEP separately to fully understand its role in healthy and degenerated IVDs. Further, most IVD regeneration therapies in development failed to address, or even considered the CEP, despite its key role in nutrition and mechanical stability within the IVD. Thus, the CEP should be considered and potentially targeted for future sustainable treatments.

Retrospective analysis of longitudinal data.

To assess the association between the paraspinal musculature (PM) and lumbar endplate degeneration.

The PM is essential for spinal stability, while the vertebral endplate is pivotal for nutrient transport and force distribution. The clinical importance of both has been highlighted in recent literature, though little is known about their interaction.

We identified patients with lumbar MRI scans due to low back pain, with a 3-year interval between MRI scans. Endplate damage was assessed by the total endplate score (TEPS) at each lumbar level. The PM was evaluated for its functional cross-sectional area and fatty infiltration (FI) at the L4 level. We used a generalized mixed model to analyze the association between PM parameters and TEPS at timepoint one, adjusting for age, sex, BMI, diabetes, hypertension, and smoking status. The association with the progression of endplate damage was analyzed through an ordinal regression model, additionally adjusted for TEPS at baseline.

In all, 329 patients were included, with a median follow-up time of 3.4 years. Participants had a median age of 59 and a BMI of 25.8 kg/m 2 . In the univariate analysis, FI of the posterior PM was significantly associated with TEPS at baseline (β: 0.08, P <0.001) and progression of TEPS [Odds Ratio (OR): 1.03, P =0.020] after adjustment for confounders. The β and OR in this analysis are per percent of FI. In a binary analysis, patients with FI≥40% had an OR of 1.92 ( P =0.006) for the progression of TEPS.

This is the first longitudinal study assessing the relationship between PM and endplate degeneration, demonstrating the association between PM atrophy and the progression of endplate degeneration. This insight may aid in identifying patients at risk for degenerative lumbar conditions and guide research into preventive measures.

Low back pain (LBP) is one of the most prevalent diseases affecting quality of life, with no disease-modifying therapy. During aging and spinal degeneration, the balance between the normal endplate (EP) bilayers of cartilage and bone shifts to more bone. The aged/degenerated bony EP has increased porosity because of osteoclastic remodeling activity and may be a source of LBP due to aberrant sensory innervation within the pores. We used two mouse models of spinal degeneration to show that parathyroid hormone (PTH) treatment induced osteogenesis and angiogenesis and reduced the porosity of bony EPs. PTH increased the cartilaginous volume and improved the mechanical properties of EPs, which was accompanied by a reduction of the inflammatory factors cyclooxygenase-2 and prostaglandin E2. PTH treatment furthermore partially reversed the innervation of porous EPs and reversed LBP-related behaviors. Conditional knockout of PTH 1 receptors in the nucleus pulposus (NP) did not abolish the treatment effects of PTH, suggesting that the NP is not the primary source of LBP in our mouse models. Last, we showed that aged rhesus macaques with spontaneous spinal degeneration also had decreased EP porosity and sensory innervation when treated with PTH, demonstrating a similar mechanism of PTH action on EP sclerosis between mice and macaques. In summary, our results suggest that PTH treatment could partially reverse EP restructuring during spinal regeneration and support further investigation into this potentially disease-modifying treatment strategy for LBP.

The pain in patients with Modic type 1 changes (MC1) is often due to vertebral body endplate pain, which is linked to abnormal neurite outgrowth in the vertebral body and adjacent endplate. The aim of this study was to understand the role of MC1 bone marrow stromal cells (BMSCs) in neurite outgrowth. BMSCs can produce neurotrophic factors, which have been shown to be pro-fibrotic in MC1, and expand in the perivascular space where sensory vertebral nerves are located. The study involved the exploration of the BMSC transcriptome in MC1, co-culture of MC1 BMSCs with the neuroblastoma cell line SH-SY5Y, analysis of supernatant cytokines, and analysis of gene expression changes in co-cultured SH-SY5Y. Transcriptomic analysis revealed upregulated brain-derived neurotrophic factor (BDNF) signaling-related pathways. Co-cultures of MC1 BMSCs with SH-SY5Y cells resulted in increased neurite sprouting compared to co-cultures with control BMSCs. The concentration of BDNF and other cytokines supporting neuron growth was increased in MC1 vs. control BMSC co-culture supernatants. Taken together, these findings show that MC1 BMSCs provide strong pro-neurotrophic cues to nearby neurons and could be a relevant disease-modifying treatment target.

Chronic low back pain mainly attributed to intervertebral disc (IVD) degeneration. Endogenous damage-associated molecular patterns (DAMPs) in the injured IVD, particularly mitochondria-derived nucleic acid molecules (CpG DNA), play a primary role in the inflammatory responses in macrophages. M1-type macrophages form a chronic inflammatory microenvironment by releasing pro-inflammatory factors and nerve growth factor (NGF) that induce nerve growth into the inner annulus fibrosus, resulting in persistent hyperalgesia. We fabricated an amphiphilic polycarbonate that naturally forms cationic nanoparticles (cNP) in aqueous solutions, with the hydrophobic core loaded with TrkA-IN-1, an antagonist against the NGF receptor (TrkA). The drug delivery nanoparticles were denoted as TI-cNP. TrkA-IN-1 and TI-cNP were added to the decellularized annulus fibrosus matrix (DAF) hydrogel to form hybrid hydrogels, denoted as TI-DAF and TI-cNP-DAF, respectively. As a result, TrkA-IN-1 showed a delayed release profile both in TI-DAF and TI-cNP-DAF. Each mole of cNP could bind approximately 3 mol of CpG DNA to inhibit inflammation. cNP-DAF and TI-cNP-DAF significantly inhibited the M1 phenotype induced by CpG DNA. TI-DAF and TI-cNP-DAF reduced neurite branching and axon length, and inhibited the expression of neurogenic mediators (CGRP and substance P) in the presence of NGF. Besides, TI-cNP-DAF relieved mechanical hyperalgesia, reduced CGRP and substance P expression in the dorsal root ganglion, and downregulated GFAP and c-FOS signaling in the spinal cord in the rat disc herniation model. Summarily, TI-cNP-DAF, a novel composite IVD hydrogel, efficiently mediated the inflammatory environment, inhibited nerve ingrowth and sensitization, and could be clinically applied for treating discogenic pain. STATEMENT OF SIGNIFICANCE: Discogenic lower back pain, related to intervertebral disc degeneration (IDD), imposes a tremendous health and economic burden globally. M1-type macrophages release pro-inflammatory factors and nerve growth factor (NGF) that induce nerve growth into the inner annulus fibrosus, resulting in persistent hyperalgesia and discogenic pain. Reconstructing matrix integrity and modulating the inflammatory microenvironment are promising strategies for preventing the ingrowth and activation of neurites. The TI-cNP-DAF hydrogel recovers tissue integrity, alleviates inflammation, and delivers the TrkA antagonist to inhibit the activity of NGF, thus restraining hyperinnervation and nociceptive input. Due to its simple production process, injectability, and acellular strategy, the hydrogel is operable and holds great potential for treating discogenic lower back pain.

Low back pain (LBP) is multifactorial and associated with various spinal tissue changes, including intervertebral disc fissures, vertebral pathology, and damaged endplates. However, current radiological markers lack specificity and individualized diagnostic capability, and the interactions between the various markers are not fully clear. Radiomics, a data-driven analysis of radiological images, offers a promising approach to improve evaluation and deepen the understanding of spinal changes related to LBP. This study investigated possible associations between vertebral changes and annular fissures using radiomics. A dataset of 61 LBP patients who underwent conventional magnetic resonance imaging followed by discography was analyzed. Radiomics features were extracted from segmented vertebrae and carefully reduced to identify the most relevant features associated with annular fissures. The results revealed three important texture features that display concentrated high-intensity gray levels, extensive regions with elevated gray levels, and localized areas with reduced gray levels within the vertebrae. These features highlight patterns within vertebrae that conventional classification systems cannot reflect on distinguishing between vertebrae adjacent to an intervertebral disc with or without an annular fissure. As such, the present study reveals associations that contribute to the understanding of pathophysiology and may provide improved diagnostics of LBP.

Both the diagnosis and treatment of pain are evolving, especially in interventional approaches. Diagnosis of low back pain combines old and new methodologies, in particular, it involves an expanded role for ultrasound. While low back pain is a common complaint, there are many etiologies to the condition which must be explored before a final diagnosis can be made and treatment planned. Tumors and infections are rarely involved in low back pain but should be ruled out in the initial phase itself since failing to address them early can have devastating consequences. Some invasive treatments seem promising in the management of low back pain. Treating musculoskeletal pain with regenerative medicine, such as platelet-rich plasma, holds great promise. Autologous blood products are safe and may help stimulate the body's own responses for regeneration. The so-called "orthobiologics" play a role in sports medicine and the treatment of musculoskeletal pain. Neuromodulation, especially spinal cord stimulation, is undergoing a renaissance with new waveforms, devices, and a greater albeit incomplete understanding of its mechanisms of action. Spinal cord stimulation is not a first-line therapy and not all patients or all back problems respond to this treatment. Nevertheless, the therapy can be safe, effective, and cost-effective with appropriate patient selection. Radiofrequency ablation of nerves in the form of neurotomy can be effective in reducing the pain of osteoarthritis. These procedures, including the newer cooled radiofrequency neurotomy, can restore function, reduce pain, and may potentially have an opioid-sparing effect. Technical expertise in nerve and anatomy is needed for the use of this technique. This review article aims to provide updated information on some invasive intervention techniques in pain management.

Percutaneous endoscopic interlaminar discectomy (PEID), one of the main techniques of spinal endoscopy, has achieved excellent results in treating lumbar disc herniation (LDH). However, its efficacy has not been systematically described in patients with LDH accompanied by Modic changes (MC).

The purpose of this study was to observe the clinical efficacy of PEID treatment of LDH accompanied by MC.

A total of 207 patients who underwent PEID surgery for LDH were selected. According to the existence and type of MC on preoperative lumbar magnetic resonance images (MRI), they were divided into normal group (no MC, n=117), M1 group (MC I, n=23), and M2 group (MC II, n=67). According to the severity of MC, they were divided into MA group (grade A, n=45) and MBC group (grade B and C, n=45). The visual analog scale (VAS) score, Oswestry disability index (ODI) score, Disc height index (DHI), Lumbar lordosis angle (LL) and modified Macnab criteria were used to assess clinical outcomes.

Postoperative back pain and leg pain VAS scores and ODI scores were significantly improved in all groups compared with preoperative scores. Patients with MC showed a deterioration in postoperative back pain VAS scores and ODI scores as time went by, and postoperative DHI decreased significantly compared with preoperative. Postoperative LL did not change significantly in each group. There was no significant difference in complications, recurrence rate and excellent rate between the groups.

Whether accompanied by MC or not, the efficacy of PEID for LDH was significant. However, postoperative back pain and functional status of patients with MC tend to deteriorate as time went by, especially those with type I or severe MC.

Vertebrogenic pain is an established source of anterior column chronic low back pain (CLBP) resulting from damaged vertebral endplates with pain signals transmitted by the basivertebral nerve (BVN). Type 1 or Type 2 Modic changes on magnetic resonance imaging (MRI) are objective biomarkers for vertebrogenic pain. Radiofrequency ablation of the BVN (BVNA) has demonstrated both efficacy and effectiveness for the treatment of vertebrogenic pain in two randomized trials. Here, we report 3-year aggregate results from two prospective studies of BVNA-treated patients.

Pooled results at 3 years post-BVNA are reported for two studies with similar inclusion/exclusion criteria and outcomes measurements: 1) a prospective, open label, single-arm follow-up of the treatment arm of a randomized controlled trial (RCT) comparing BVNA to standard care (INTRACEPT Trial), and 2) a prospective, open label, single cohort long-term follow-up study of BVNA-treated patients. Paired datasets (baseline and 3-years) for mean changes in Oswestry disability index (ODI) and numeric pain scores (NPS) were analyzed using a two-sided t-test with a 0.05 level of significance.

There were 95/113 (84%) BVNA patients who completed a 3-year visit across 22 study sites. At baseline, 71% of patients reported back pain for ≥5 years, 28% were taking opioids, 34% had spinal injections in the prior 12 months, and 14% had prior low back surgery. Pain and functional improvements were significant at 3 years with a mean reduction in NPS of 4.3 points from 6.7 ​at baseline (95% CI 3.8, 4.8; p<0.0001) and a mean reduction in ODI of 31.2 points from 46.1 ​at baseline (95% CI 28.4, 34.0; p<0.0001). Responder rates, using minimal clinically important differences of ≥15-points for ODI and ≥50% reduction in NPS from baseline to three years, were 85.3% and 72.6%, respectively (combined response 69.5%), with 26.3% of patients reporting 100% pain relief at 3 years. There was a 74% reduction in the use of opioids and 84% reduction in the use of therapeutic spinal interventions from baseline to 3 years. There were no serious device or device-procedure related adverse events reported through three years.

Intraosseous BVNA demonstrates statistically significant, clinically meaningful, and durable improvements in pain and function through 3 years in patients with primary vertebrogenic low back pain. BVNA-treated patients significantly reduced opioid use and interventions for low back pain.

There is an enormous body of literature that has identified the intervertebral disc as a potent pain generator. However, with regard to lumbar degenerative disc disease, the specific diagnostic criteria lack clarity and fail to capture the primary components which include axial midline low back pain with or without non-radicular/non-sciatic referred leg pain in a sclerotomal distribution. In fact, there is no specific ICD-10-CM diagnostic code to classify and define discogenic pain as a unique source of pain distinct from other recognized sources of chronic low back pain including facetogenic, neurocompressive including herniation and/or stenosis, sacroiliac, vertebrogenic, and psychogenic. All of these other sources have well-defined ICD-10-CM codes. Corresponding codes for discogenic pain remain absent from the diagnostic coding vernacular. The International Society for the Advancement of Spine Surgery (ISASS) has proposed a modernization of ICD-10-CM codes to specifically define pain associated with lumbar and lumbosacral degenerative disc disease. The proposed codes would also allow the pain to be characterized by location: lumbar region only, leg only, or both. Successful implementation of these codes would benefit both physicians and payers in distinguishing, tracking, and improving algorithms and treatments for discogenic pain associated with intervertebral disc degeneration.