Title Refined Phenotyping of Modic Changes : Imaging biomarkers ofprolonged severe low back pain and disability

Low back pain (LBP) is the world’s most disabling condition. Modic changes (MC) are vertebral bone marrow changes adjacent to the endplates as noted on magnetic resonance imaging. The associations of specific MC types and patterns with prolonged, severe LBP and disability remain speculative. This study assessed the relationship of prolonged, severe LBP and back-related disability, with the presence and morphology of lumbar MC in a large cross-sectional population-based study of Southern Chinese. We addressed the topographical and morphological dimensions of MC along with other magnetic resonance imaging phenotypes (eg, disc degeneration and displacement) on the basis of axial T1 and sagittal T2weighted imaging of L1-S1. Prolonged severe LBP was defined as LBP lasting 30 days during the past year, and a visual analog scale severest pain intensity of at least 6/10. An Oswestry Disability Index score of 15% was regarded as significant disability. We also assessed subject demographics, occupation, and lifestyle factors. In total, 1142 subjects (63% females, mean age 53 years) were assessed. Of these, 282 (24.7%) had MC (7.1% type I, 17.6% type II). MC subjects were older (P1⁄4 0.003), had more frequent disc displacements (P< 0.001) and greater degree of disc degeneration (P< 0.001) than non-MC subjects. In adjusted models, any MC (odds ratio [OR] 1.48, 95% confidence interval [CI] 1.01–2.18), MC affecting whole anterior-posterior length (OR 1.62, 95% CI 1.04–2.51), and MC affecting 2/3 posterior length (OR 2.79, 95% CI 1.17–6.65) were associated with prolonged severe LBP. Type I MC tended to (Orth), FRCSE, F , FHKAM, KCOS, FHKAM, and Dino Samartzis, DSc MC affecting 2/3 posterior length (OR 2.96, 95% CI 1.27–6.89), and extensive MC (OR 1.95, 95% CI 1.21–3.15) were associated with disability. The strength of the associations increased with the number of MC. This large-scale study is the first to definitively note MC types and specific morphologies to be independently associated with prolonged severe LBP and back-related disability. This proposed refined MC phenotype may have direct implications in clinical decision-making as to the development and management of LBP. Understanding of these imaging biomarkers can lead to new preventative and personalized therapeutics related to LBP. (Medicine 95(22):e3495) Abbreviations: AP = antero-posterior, BMI = body mass index, CI = confidence interval, DD = disc degeneration, FOV = field of view, IQR = interquartile range, LBP = low back pain, MC = Modic changes, MRI = magnetic resonance imaging, ODI = Oswestry Disability Index, OR = odds ratio, SN = Schmorl’s nodes, T1w = T1-weighted MRI, T2w = T2-weighted MRI, TE = echo time, TR = repetition time, VAS = visual analog scale. INTRODUCTION L ow back pain (LBP) is the world’s most disabling condition, resulting in tremendous socioeconomic and healthcare costs. Specific LBP phenotypes have been identified, but may only represent approximately 15% of LBP conditions. Lumbar intervertebral disc degeneration (DD) is thought to be a significant LBP risk factor. Usually, in these studies, DD has been defined as disc space narrowing and disc signal intensity loss (ie, so-called ‘‘dark discs’’), commonly represented in various classification schemes (eg, Pfirrmann classification). DD and other degenerative findings on magnetic resonance imaging (MRI) have also been described among asymptomatic subjects; therefore, more specific LBP-related MRI phenotypes would be informative. Modic changes (MC) are one potential specific LBP phenotype. MC are vertebral body marrow changes adjacent to the endplates that are visible on MRI, and are typically characterized as 3 distinct types. Type I MC display decreased signal intensity on T1-weighted (T1w) and increased signal intensity on T2-weighted images (T2w), indicating marrow edema and histologically represent disruption and fissuring of the endplates and vascular granulation tissue. Type II MC present increased signal intensity on both T1w and T2w, representing histologically fatty degeneration of the adjacent vertebral marrow. Type III MC represent decreased signal intensity on both T1w and T2w, indicating relative absence presence of bone sclerosis. When I and II or II and III, are seen at the same y, they are called mixed types (I/II or www.md-journal.com | 1 II/III, respectively). Size and location of MC have been usually evaluated according to vertical height, anteroposterior (AP) length, or involvement in the horizontal plane stratified to 4 regions. However, recently, a more extensive evaluation of the MC phenotype, in particular, its topographical characteristics, has been reported. The associations of MC with different degenerative MRI findings have largely involved DD, disc bulge or herniation, and endplate defects (ie, Schmorl’s nodes [SNs]). Demographic or lifestyle factors associated with MC include age, male sex, higher body mass index (BMI), smoking, and heavy physical work. With the exception of age, associations of MC with different demographic or lifestyle factors remain inconclusive. Modic changes, especially type I changes, have been associated with LBP in population samples, among workers, and in clinical populations. However, these studies have had at most moderate sample sizes, and insufficient assessment of spine degenerative phenotypes and confounding factors were performed. Moreover, recent studies have showed conflicting results between MC and pain, and between MC and back-related disability. Furthermore, the relation of MC with more severe LBP remains speculative. In addition, detailed MC phenotype assessment, in particular, morphological and topographical variations in relation to prolonged severe LBP and disability remains unknown. Therefore, the following study addressed the relationship of prolonged severe LBP and back-related disability with lumbar MC in a large-scale, Southern Chinese general population. More specifically, the study addressed the influence of type, location, extent, and depth of MC on pain association.