Accepted Manuscript

Phenotype profiling of Modic changes of the lumbar spine and its association with
other MRI phenotypes: a large-scale, population-based study

Juhani Määttä, MD, Jaro Karppinen, MD, PhD, Keith DK. Luk, MCh(Orth), FRCSE,
FRCSG, FRACS, FHKAM(Orth), Kenneth MC. Cheung, MBBS, MD, FRCS,
FHKCOS, FHKAM, Dino Samartzis, DSc
PII: S1529-9430(15)00649-X
DOI: 10.1016/j.spinee.2015.06.056
Reference: SPINEE 56403

To appear in: The Spine Journal

Received Date: 8 February 2015

Revised Date: 3 June 2015
Accepted Date: 22 June 2015

Please cite this article as: Määttä J, Karppinen J, Luk KD, Cheung KM, Samartzis D, Phenotype profiling
of Modic changes of the lumbar spine and its association with other MRI phenotypes: a large-scale,
population-based study, The Spine Journal (2015), doi: 10.1016/j.spinee.2015.06.056.

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 ACCEPTED MANUSCRIPT

Phenotype profiling of Modic changes of the lumbar spine and its

association with other MRI phenotypes: a large-scale, population-based
study

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Authors: 1Juhani Määttä, MD, 1,2Jaro Karppinen, MD, PhD, 3Keith DK Luk, MCh(Orth),
FRCSE, FRCSG, FRACS, FHKAM(Orth), 3Kenneth MC Cheung, MBBS, MD, FRCS,

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FHKCOS, FHKAM, 3Dino Samartzis, DSc

Affiliations: 1Medical Research Center Oulu, University of Oulu and Oulu University Hospital,

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Finland; 2Finnish Institute of Occupational Health, Health and Work Ability and Disability
Prevention Center, Oulu, Finland; and the 3Department of Orthopaedics and Traumatology, The
University of Hong Kong, Hong Kong, China

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Disclosures: The authors have no financial or competing interests in relation to this work.
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Funding: This work was supported by grants from the Hong Kong Theme-Based Research
Scheme (T12-708/12N), Hong Kong Area of Excellence programme (AoE/M-04/04), Hong
Kong Research Grants Council (17117814), International Society for the Study of the Lumbar
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Spine MacNab/LaRocca Award, and the AOSpine Spine Research Network Exchange Award

Key Words: disc; degeneration; displacement; endplate; magnetic resonance imaging;

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phenotype; Schmorl’s nodes; Modic changes; epidemiology

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Correspondence: Kenneth M.C. Cheung

Department of Orthopaedics & Traumatology
Professorial Block, 5th Floor
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102 Pokfulam Road, Pokfulam

Hong Kong, SAR, China
Tel: +852 2855 4254
Fax: +852 2817 4392
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Email: cheungmc@hku.hk
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Dino Samartzis
Department of Orthopaedics & Traumatology
Professorial Block, 5th Floor
102 Pokfulam Road, Pokfulam
Hong Kong, SAR, China
Tel: +852 2855 4254
Fax: +852 2817 4392
Email: dsamartzis@msn.com
 ACCEPTED MANUSCRIPT
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9 Phenotype profiling of Modic changes of the lumbar spine and its

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10 association with other MRI phenotypes:
11 a large-scale, population-based study

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1 ABSTRACT
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3 Background Context: Modic changes (MC) are associated with low back pain. They
4 represent vertebral endplate and adjacent vertebral marrow changes on magnetic resonance
5 imaging (MRI), classified into three types. Due to small sample sizes, patient cohorts, and
6 limited phenotype assessment, the morphology, involvement of MC and their association

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7 with other spinal phenotypes remains speculative.
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9 Purpose: We addressed and proposed a phenotypic profiling of MC and their relationship
10 with lumbar MRI phenotypes in a large-scale population-based study.

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12 Study Design/Setting: A cross-sectional study of the Hong Kong Disc Degeneration Cohort.
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Patient Sample: 1,546 Southern Chinese volunteers.
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16 Outcome Measures: Topographical and morphological dimensions of MC, presence of disc
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17 degeneration (DD) and displacement, and Schmorl’s nodes (SN) were evaluated.
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19 Methods: Axial T1- and sagittal T2-weighted MRIs (3T) were assessed.
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21 Results: 62.4% were females (mean age: 49 years). The overall prevalence of MC was
22 21.9% (6.3% Type I, 15.5% Type II). Of all MC, 76% were located at the two lowest lumbar
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23 levels. MC at the two lowest lumbar levels were more commonly located laterally (p<0.001),
24 less commonly anteriorly (p<0.001), and were more extensive horizontally (p=0.006) but not
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25 in vertical height compared to the upper levels. Type I MC were less common in the anterior
26 part (p=0.022), larger in size (height p=0.004) and affected more likely the whole horizontal
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27 plane (p=0.016) than ‘Type II’ MC. MC were associated with disc displacement, SN and DD
28 at the affected level (all p<0.001), and the strength of association increased with the size of
29 the lesion. Type I MC were associated more strongly with disc displacement (p=0.008) and
30 DD (p=0.022) than Type II MC.
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32 Conclusions: Our large-scale MRI study is the first to definitely note that MC were size- and
33 type-dependently significantly associated with disc pathology and endplate abnormalities.
34 Our phenotype profiling of MC may have clinical utility.
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1 INTRODUCTION
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3 Low back pain (LBP) is the most disabling health condition with severe socioeconomic and
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4 health-care consequences . Despite the high prevalence of such pain and its global
5 socioeconomic burden, the pathophysiology of LBP remains largely unresolved.
6 Intervertebral disc degeneration (DD) has been recognized as one of the most important risk

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7 factors of LBP 4-10 . Degenerative spine changes are mainly based on signal intensity loss, the
8 so-called “dark discs”, on T2-weighted magnetic resonance imaging (MRI) sequences.

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9 However, dark discs and many other degenerative changes have also been observed among
10 asymptomatic subjects 8, 11 , which substantiates the search for a more specific pain-related

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11 phenotype of DD.
12 Modic changes (MC) are vertebral body marrow changes adjacent to the endplates
13 visible on MRI 12 , which are claimed to represent a specific LBP imaging phenotype 13 .
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Several studies have noted the association between MC and LBP 14-17 . However, there are
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15 also contradictory results with no pain association 18, 19 . MC can be classified into different
16 types on the basis of bone marrow signal intensities. Type I changes: characterized
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17 histologically by disruption and fissuring of the endplates and vascular granulation tissue,
18 show decreased signal intensity on T1-weighted (T1w) and increased signal intensity on T2-
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19 weighted images (T2w) indicating marrow edema. Type II changes, representing fatty
20 degeneration of the adjacent vertebral marrow, show increased signal intensity on both T1w
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21 and T2w. Type III changes, representing bony sclerosis, show decreased signal intensity on
22 both T1w and T2w 12, 20, 21 . Different MC Types, mostly Types I and II or II and III, have
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23 been found to co-exist at the same adjacent vertebral body 22, 23 . Usually, the assocations of
24 Type I changes with LBP are stronger in comparison to other types 6, 15, 17 .
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25 MC have been associated with other MRI phenotypes. Several studies have found an
26 association between DD 12, 16, 20, 21, 24-27 . Disc herniations have also been associated with MC
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15, 24, 26
27 . In fact, previous disc herniation is thought to be a strong risk factor to the
28 development of new MC, especially of Type I changes 15 . Relation of other MRI phenotypes
29 (such as Schrmorl’s nodes [SN] i.e. invagination of disc material into the adjacent endplate)
30 with MC has also been suggested but not conclusively 19, 28 .
31 The precise morphology, horizontal localization and size of MC have not been
32 properly addressed. When considering the distribution, MC are usually located at the two
33 lowest lumbar levels 23, 25-27, 29-32 and they extend from the anterior to the posterior part, or
23, 29, 30, 32
34 affect the whole plane sagittally . However, the information of horizontal
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1 localization of MC adjacent to the endplate is still limited. Also, the size of MC is usually
2 noted as the height of the MC in relation to the vertebrae and more precise horizontal
3 dimensions, i.e. width, has usually been ignored. In addition, the majority of such studies
4 have been patient-based and small in sample size, with limited phenotype and statistical
5 assessment. As such, the purpose of this study was to evaluate the phenotypic characteristics
6 of MC and their relationship with other MRI phenotypes across the entire lumbar spine in a

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7 large-scale population-based study.
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10 METHODS

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12 Study population
13 The study population consisted of Southern Chinese volunteers from the Hong Kong Disc
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Degeneration Cohort Study and they were recruited by newspaper advertisements, e-mails
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7, 9, 33-38
15 and posters . The study recruited any individuals from 10 years of age or older,
16 irrespective of gender, who were cognitively capable to participate. Subjects with known
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17 spine tumors, fractures, metabolic diseases, infections, chronic inflammatory conditions,

18 marked/severe spinal deformities and recent spine surgery were not asked to enroll. Follow-
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19 up T2w sagittal and T1w axial MRIs formed the basis of the current, cross-sectional study.
20 The study population consisted of 1,604 subjects but T1w axial images were not available
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21 from 58 subjects, and thus the final study population consisted of 1,546 subjects. There were
22 no gender differences between subjects without T1w axial images and the final study
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23 population; however, the mean age was higher among excluded subjects (52 vs. 49 years,
24 p=0.005). The study was approved by the local ethics committee and informed consent was
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25 obtained from every participant. Participant demographics were obtained at the time of
26 clinical assessment between March 2009 and September 2013. MRIs were obtained around
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27 the time point of clinical assessment, mainly within three months of the clinical visit.
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29 Magnetic resonance imaging
30 All MRIs were obtained on a 3 Tesla scanner (Siemens or Phillips). For the current study
31 focusing on L1-S2, sagittal T2w MRIs entailed the following protocol: 5 mm slice thickness,
32 1 mm slice gap, field of view (FOV) of 280 mm x 240 mm, and a matrix of 448 x 336. No fat
33 suppression was used for the T2 scans. T1w axial MRIs consisted of the following protocol:

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1 4 mm slice thickness, 0.4 mm slice gap, FOV of 210 mm x 210 mm, matrix of 218 x 256, and
2 a repetition time (TR) of 500-800 (dependent on body size) and an echo time (TE) of 9.5 ms.
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4 Evaluation of magnetic resonance imaging
5 MRIs of the lumbar spines were evaluated in random order by the first observer (J.M.),
6 blinded to the clinical status of each subject. Later, J.M. re-assessed 100 MRIs for intra-

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7 observer reliability, and a second observer (D.S.) assessed in a random order 20 MRIs for
8 inter-observer reliability. Every cranial and caudal vertebral body adjacent to the endplate

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9 were evaluated separately. Upper lumbar levels were defined as levels from L1/2 to L3/4 and
10 lower levels from L4/5 to L5/S1. MC were evaluated as Type I, Type I/II, Type II, Type II/III
and Type III as previously defined in the literature (Figure 1) 12, 21-23 . The maximum height

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12 of the MC was divided to four different grades (Figure 2; Table 1). The horizontal width of
13 the MC was evaluated in nine horizontal zones (ranging from 1 to 9) and MC were evaluated
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as anterior, midpoint, posterior and lateral lesions (Figure 3, Table 1). Very small MC, such
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15 as MC in only one sagittal slice, were excluded.
16 Other MRI phenotypes, such as DD, disc herniations and SN were assessed. DD was
evaluated using the modified Pfirrmann classification 39 : grades 1 and 2 represented normal
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18 height and clear distinction of the nucleus and annulus; grade 3 normal to slightly decreased
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19 height of the intervertebral disc and unclear distinction of the nucleus and annulus; grade 4
20 moderately decreased height of the intervertebral disc and lost distinction of nucleus and
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21 annulus; and grade 5 a collapsed disc space with lost distinction of nucleus and annulus.
22 Disc displacement was evaluated as a disc bulge, protrusion or extrusion. Disc bulge
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23 was defined as a disc displacement posteriorly beyond the line of the posterior edges of the
24 adjacent vertebral bodies, disc protrusion as the nucleus displacement beyond the confines of
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25 the annulus fibrosus and extrusion as the nucleus displacement when the distance between the
26 edges of the disc material beyond the disc space is greater than the distance between the
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27 edges of the base of the disc material beyond the disc space 7, 40 . SN were assessed in every
28 rostral and caudal endplate as a local vertebral endplate defect/abnormality that is a deviation
29 of the typical concavity or flattend continuous shape of the endplate 36 .
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31 Statistical analysis
32 Prevalence of MC is given both per subject and per disc segment. The disc was recorded
33 affected if MC was noted in cranial and/or caudal vertebral bodies adjacent to the endplate.
34 The subject was recorded to have MC if he/she had MC at least at one disc level. MC were
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1 defined to be associated with SN if the same vertebral body adjacent to the endplate was
2 affected by both of them. Appropriate parametric or non-parametric tests were performed.
3 Type I MC is thought to represent a more active ongoing inflammatory process compared to
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4 other types . Therefore, we re-grouped Type I and Type I/II as ’Type I’ group in the
5 analyses. Similarly, we re-grouped Type II and Type II/III as ’Type II’ because Type II are
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6 thought to characterize fatty degeneration of the vertebral marrow . Disc bulge and

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7 protrusion were scored as 1 and extrusions as 2. For the overall lumbar disc displacement
8 score we summed the score from all five lumbar levels. Thus, the minimum value was 0 and

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9 maximum value 10. For evaluating overall lumbar DD we summed the Pfirrmann scores
10 from all five lumbar levels together. This concept of summating disc degeneration scores of

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11 individual lumbar disc levels was initially introduced by the authors. The validity and
7, 9, 33-38
12 application of this scoring method has been previously reported . We further divided
13 the summary scores into four categories: normal (Pfirrmann summary score 10), mild (scores
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11-14), moderate (scores 15-17) and severe (scores 18 or above). To evaluate the relevance
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15 of multiple SN we calculated the total lumbar SN score by adding SN of every ten endplates
16 together. Thus, the total SN score ranged from 0 to 10. Kappa analyses were conducted to
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17 assess inter- and intra-observer reliability and scored as follows: ≤0.69 were regarded as
18 poor, values of ≥0.70 were considered satisfactory, and values of ≥0.80 were considered as
exhibiting good to high reliability 41 . All the statistical analyses were performed using SPSS
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20 Statistics version 21 (Chicago, IL, USA). The threshold for statistical significance was
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21 p<0.05.
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24 RESULTS
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26 Study sample and prevalence of MC
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27 We evaluated 1,546 subjects. The mean age of the study population was 49 years with 964
28 females (62.4%). In total, 338 (21.9%) subjects had MC: n=15 (1.0%) at L1/2, n=53 (3.4%)
29 at L2/3, n=50 (3.2%) at L3/4, n=133 (8.6%) at L4/5, and n=191 (12.4%) at L5/S1. Ninety-
30 eight subjects (6.3%) had ’Type I’ MC and 240 subjects (15.5%) had ’Type II’ MC. MC
31 affected preferentially both cranial and caudal vertebral bodies adjacent to the endplate at the
32 two lowest levels, while upper levels presented more likely only cranial or caudal MC.
33 Subjects with MC were older (mean age 53 years vs. 48 years, p<0.001). There was no
34 gender difference among subjects with MC.
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1
2 Reliability of MC evaluation
3 The intra-observer reliability was high (k=0.94) regarding the presence of MC. For the height
4 of MC, intra-observer reliability ranged from 0.69 to 1.00, depending on the vertebral body
5 adjacent to the endplate. In case of the width of the MC, intra-observer reliability ranged
6 from 0.73 to 0.98, depending on the vertebral body. Inter-observer reliability was good to

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7 high of all Modic parameters (k>0.80).
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9 MC types
10 In total, 15,460 vertebral bodies adjacent to the endplates were evaluated. Of them, 686

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11 (4.4%; 338 subjects) had MC; 165 (1.1%) ’Type I’ and 521 (3.4%) ‘Type II’ MC (Table 2).
12 In total, 76% of the MC were at the two lowest levels (86% of Type I, 79% of Type I/II, 73%
13 of Type II and 83% of Type II/III, Table 2). When we compared ‘Type I’ and ‘Type II’ MC
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groups, ‘Type I’ MC were more common at the two lowest lumbar levels than ‘Type II’ MC
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15 (82% vs 74%, p=0.023).
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17 Horizontal evaluation of MC
18 Of all MC, 59 (8.6%) were in the anterior regions only, 173 (25.2%) in the three lateral
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19 regions (left or right) only, whereas in 37 (5.4%) MC affected the entire horizontal plane
20 (Table 3). When we compared ‘Type I’ and ‘Type II’ MC groups, ‘Type I’ MC were less
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21 likely to occur anteriorly only (4.2% vs. 10.0%, p=0.022) and more frequently affected the
22 entire horizontal plane (9.1% vs. 4.2%, p=0.016). ‘Type I’ MC were also more extensive
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23 horizontally (sum of all horizontal regions: 4.5 vs. 3.8, p<0.001).

24 Comparing upper and lower lumbar levels, MC at the lower lumbar levels were more
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25 extensive in horizontal size (mean horizontal size: 4.1 vs. 3.6 zones, p=0.006), more likely
26 located only in the three lateral regions (left or right, 30.2% vs. 9.6%, p<0.001), and less
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27 likely located in the anterior part only (3.1% vs. 25.9%, p<0.001) than MC at upper levels.
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29 Height of MC
30 Of all MC, 34.3% of changes had maximum height more than 25% of the relative height of
31 the vertebra (Table 3). ‘Type I’ MC were larger vertically (maximum height more than 25%
32 of the relative height of the vertebra, 43.6% vs. 31.3%, p=0.004) compared to ‘Type II’ MC.
33 Interestingly, the height of MC didn’t differ significantly between upper and lower lumbar
34 levels between different MC types or MC in general. Bigger MC in horizontal size were also
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1 bigger in height when we compared MC affecting ≥ 4 horizontal regions compared to ≤ 3
2 horizontal regions (median [IQR] of the height: 2 [1, 2] vs. 3 [2, 3], p<0.001).
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4 Association of other MRI phenotypes with MC
5 There were significant differences regarding other MRI phenotypes between disc levels with
6 and without MC. Disc levels with MC had significantly more bulges/protrusions (67.6% vs.

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7 17.9%, p<0.001) and extrusions (5.9% vs. 0.7%, p<0.001), SN at the affected side (cranial or
8 caudal) (42.6% vs. 5.8%, p<0.001) and had higher degree of DD (median [IQR] 4 [3, 5] vs. 2

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9 [2, 3], p<0.001) than those without MC at the same level (Table 4). When comparing ‘Type
10 I’ and ‘Type II’ MC regarding other MRI phenotypes, disc levels with ‘Type I’ MC had more

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11 bulges/protrusions (77.6% vs. 64.5%, p=0.008) and DD (4 [4, 5] vs. 4 [3, 4], p=0.022) than
12 disc levels with ‘Type II’ MC at the affected level. There was no significant difference
13 between SN or extrusions between the MC types (Table 4).
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When comparing disc levels with MC between bulges/protrusions and extrusions, MC
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15 with extrusions were more extensive horizontally than MC with bulges or protrusions at the
16 affected level (median [IQR] axial size of MC 4.5 [1.5, 6] vs. 3 [1.5, 4], p=0.037).
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17 Bulges/protrusions and extrusions occurred preferentially at the two lowest lumbar levels
18 compared to upper levels (82.7% vs. 48.3%, p<0.001).
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20 Overall disc degeneration and MC
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21 Overall disc degeneration (DD) was significantly associated with the presence of any MC in
22 the lumbar spine (Figure 4, Table 4). When comparing ‘Type I’ and ‘Type II’ MC there was
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23 no significant difference between the groups (general DD median [IQR] 15 [14, 17] vs. 15
24 [14, 17], respectively, p=0.10).
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25 Subjects with MC only in the anterior regions had smaller overall DD than subjects
26 with other MC localizations (general DD median [IQR] 14 [12, 15] vs. 15 [14, 17],
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27 respectively, p=0.007). Subjects with MC only at all three lateral regions (left or right) didn’t
28 differ significantly from subjects with other MC localizations regarding overall DD. Subjects
29 with at least one MC affecting at least 4 horizontal regions had higher degree of overall DD
30 than subjects with only small MC (overall DD median [IQR] 16 [14, 17] vs. 15 [13.75, 16],
31 respectively, p=0.007). Similarly, subjects with at least one MC with maximum height of ≥
32 25% of the relative height of the vertebra had higher degree of overall DD (median [IQR] 16
33 [14, 17] vs. 14 [12, 16], respectively, p<0.001) than subjects with smaller MC only.
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1 Total disc displacement score and MC
2 Subjects with any MC had significantly more disc displacements than subjects without MC
3 (total disc displacement score median [IQR] 2 [1, 3] vs. 1 [0, 2], p<0.001, Table 4). When
4 comparing MC types, there was no significant difference (Table 4). Subjects with larger MC
5 had significantly more disc displacements than subjects with only smaller MC (total disc
6 displacement score median [IQR]: at least one MC with ≥4 regions vs. ≤ 3 regions in

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7 horizontal size 2 [1, 3] vs. 2 [1, 3], respectively, p=0.027 and at least one MC with maximum
8 height of ≥ 25% of the vertebra vs. <25 % of the vertebra 2 [1, 3] vs. 2 [1, 3], respectively,

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9 p=0.002). Subjects with MC only in all three lateral regions (left or right) didn’t differ from
10 subjects with other MC localizations regarding disc displacements (p=0.28). Subjects with

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11 MC only in the anterior regions had less disc displacements in the lumbar spine than subjects
12 with other MC (total disc displacement score median [IQR] 0 [0, 2] vs. 2 [1, 3], p=0.002).
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14 Total Schmorl’s node score and MC
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15 Total lumbar SN score was significantly associated with MC: subjects with no MC had
16 significantly lower SN median score than subjects with any MC. Subjects with ‘Type I’ MC
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17 had a greater total SN score compared to subjects with ‘Type II’ MC but the difference was
18 not significant (Table 4). Subjects with at least one MC affecting at least 4 horizontal regions
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19 had a greater SN score than subjects with only small MC (median [IQR] 1 [0, 3] vs. 1 [0, 2],
20 p=0.004) and subjects with at least one MC with maximum height of ≥ 25% of the relative
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21 height of the vertebra had more SN in the lumbar spine than subjects with only smaller MC
22 (SN median score [IQR] 1 [0, 2.75] vs. 1 [0, 2], p=0.008). Subjects with MC only in all three
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23 lateral regions (left or right) had less SN in the lumbar spine compared with subjects with
24 other MC localizations (SN median score [IQR] 0 [0, 1] vs. 1 [0, 2], respectively, p<0.001).
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26
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27 DISCUSSION
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29 In this study, we described phenotypic characteristics of MC. We found MC to be associated
30 with MRI phenotypes, such as disc displacement, SN, and presence and severity of DD.
31 Moreover, we found the size, type and location (in the horizontal plane) of MC to influence
32 the association with other MRI phenotypes. Larger MC had stronger associations with other
33 MRI phenotypes than smaller ones. Type I MC were more extensive in size, affecting more

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1 likely the whole horizontal plane, and were more likely associated with disc displacement
2 than Type II MC.
3 The prevalence of MC has varied greatly between reported studies. Such discrepancy
4 could be attributed to how MC were defined, demographics of the study population, ethnic
5 variations, and whether the study sample consists of LBP patients or a general population.
6 The median prevalence in the studies has been found to be 43% in LBP patients and 6% in

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7 non-clinical populations 14 . In the general population, among Finnish men with a mean age of
8 51 years, the prevalence of MC was 55.6%, whereas among 44-year-old Danes the
prevalence of MC was 49% 24, 32 . Our study, focusing on Southern Chinese, noted a smaller

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10 prevalence (i.e. 21.9%) of MC in individuals with a mean age of 49 years. Our study is the

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11 largest and most extensive analyses of MC.
12 When considering size or ‘volume’ of MC, studies of MC usually refer either to
13 maximum height of MC to the relative height of the vertebra 31 or horizontal/vertical extent

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23, 29, 32
14 of MC . Some studies have used the so-called Nordic Modic Consensus Group
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15 classification, 42 which includes maximum height, endplate area (i.e. horizontal size) and
16 intravertebral volume (endplate area and intravertebral volume divided into <25%, 25-50%
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17 and >50%). Usually, studies have divided horizontal plane into those four different zones
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18 when considering horizontal extent . Karchevsky et al. 29 used more precise horizontal
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19 classification by dividing horizontal plane into 15 segments but there was no MC height
20 evaluation. Therefore, there is lack of more precise assessment of both height and horizontal
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21 extent of MC. To our knowledge, our study is the first population-based study to assess both
22 MC vertical height and horizontal extent in detail by noting specific horizontal zones to
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23 facilitate specific localization of the MC.

24 Evaluating horizontal location of MC more precisely allowed us to assess those
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25 changes in relation to other findings. Our results showed some differences between upper and
26 lower lumbar levels; MC in the anterior regions only were more frequent at the upper levels
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27 and MC in the three lateral regions were more frequent at the lower levels. Jensen et al. 30
28 also found, in accordance with our results, that MC at the upper lumbar levels were more
29 commonly anteriorly located. Our results showed also that ‘Type I’ MC were less commonly
30 located in the anterior part only. We assessed MC as lateral if they affected all three lateral
31 zones. Of all laterally located MC, 62% affected all three lateral zones, only 6% were located
32 only medially and there were no isolated posteriorly located lateral MC. Clinical studies
33 utilizing more precise MC evaluation would help to assess the relationship and significance
34 of differently horizontally located MC.
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1 Some studies have shown that MC are more common anteriorly than posteriorly and
2 could extend from the anterior to posterior part 29, 30, 32 . Our results support these findings as
3 we found few posterior MC only and the majority affected the whole anterior-posterior (AP)
4 diameter or were located in the anterior and mid plane. Moreover, AP measurement has been
5 used to evaluate MC horizontally in different studies. We found one fourth of MC to be
6 lateral, i.e. located only in the three lateral regions in contrast to larger MC affecting over half

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7 of the horizontal plane. Our results found that larger MC were associated more likely with
8 other MRI findings. Therefore, assessing MC in AP measurement could lead to

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9 overestimation of lateral MC as they affect whole AP diameter even though they can be only
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10 laterally located. On the contrary, Wang et al. have suggested AP measurement to be

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11 preferable index to evaluate the size of MC.
12 Interestingly, we found that MC at the lower lumbar levels were larger horizontally
13 but not vertically when compared to the upper levels. The implication of both the height and
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horizontal extent of MC is unclear. If both height and horizontal extent of MC do have a
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15 clinical relevance, then relevance of MC at the upper lumbar levels could be overestimated as
16 the size of MC is often assessed only as the height of MC. Hence, clinical studies using more
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17 precise MC evaluation are needed.

18 MC have been associated earlier with other MRI phenotypes. The associations of MC
with DD 12, 16, 20, 21, 24-27 and disc herniation are consistent in the literature, although the latter
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15, 24, 26
20 association is observed mostly with Type I changes . Our results noted strong
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21 associations of MC with DD and disc displacement. We also found that ‘Type I’ changes
22 were more associated with disc displacement at the affected level than ‘Type II’ changes but
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23 there was no significant difference regarding total disc displacement score. Our findings also
24 noted that disc displacement can co-occur in Type II MC as well. These results support the
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25 view that degenerative findings and MC tend to co-occur.

26 Relation of SN with MC has been studied infrequently with usually small sample
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19, 28
27 sizes . Recently el Barzouhi et al. 19 found an association between presence of SN and
28 MC among sciatica patients. Our findings support an association between SN and MC. This
29 association may be attributed to the altered biomechanics associated with endplate failure that
30 may further propogate progression of DD and in turn MC or as a reverse causality of MC
31 leading to an altered endplate morphology 36 .
32 MC are proposed to be caused by infectious or autoimmune etiologies 13, 43 . Our study
33 cannot refute either of the main etiological theories but it suggests that mechanical factors are
34 related to the development MC. In deed, MC existed very infrequently in a healthy disc and
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1 larger MC had stronger associations with DD and endplate changes (i.e. SN). Additionally,
2 MC at upper levels were smaller in the horizontal plane but located at transition zones
3 whereby high stress can occur. Previous studies have shown that hyperloading, either caused
4 by obesity or physical workload, is a risk factor of MC 16, 25, 29, 45 . We observed the co-
5 occurence of disc displacement, indicating mechanical failure of disc segment, with Type I
6 MC but we also noted MC at disc levels without any disc displacement. Our study is,

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7 however, cross-sectional and therefore we cannot evaluate causality. It is well possible that a
8 disc displacement, which later has resorbed completely, may have occurred at an earlier time

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9 point. Naturally, longitudinal large-scale studies and more comprehensive profiling of MC
10 would help to assess this relationship more explicitly.

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11 As any study of this nature, there were some limitations and strengths. Regarding
12 limitations of the study, for one, volunteers were recruited by newspaper advertisements, e-
13 mails and posters. This could lead to the situation where people with earlier LBP history
14
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could have been attracted to enroll in the study. However, this cohort has earlier been found
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15 to be illustrative of the general population 7, 33 . However, the strength of this study is the size
16 of the study population and the in-depth multi-parametric phenotype profiling on MRI. In
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17 addition, our study sample was homogenous, consisting of Southern Chinese, which can
18 provide a better snapshot of the MC phenotype than in a heterogenous population whereby
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19 ethnic variants may influence the true prevalence estimate.

20
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21 CONCLUSIONS
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23 Based on one of the largest population-based studies assessing lumbar phenotypes on MRI,
24 we found MC to be associated with MRI phenotypes, such as disc displacement, SN,
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25 presence and severity of DD. Furthermore, larger MC were more associated with such MRI
26 phenotypes. We found Type I MC to be more extensive and more likely associated with disc
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27 displacement at the affected disc level than Type II changes. In addition, we found the size,
28 type and location of MC to affect the association with other MRI phenotypes. This
29 strengthens the theory of heterogeneity of MC and the need to conduct a much more in-depth
30 multi-parametric phenotype profiling on MRI. Such profiling of MC would maybe clarify the
31 process of MC development. It could enhance the assessment of clinical profile as well as
32 provide a foundation to identify cases for future “omics” studies addressing diagnostics and
33 prognostic factors of MC. However, additional research is needed to further assess the

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1 multiple dimensions of MC and develop more novel imaging methods to assess MC that
2 would further aid in understanding its clinical relevance.
3

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1 38. Samartzis D, Karppinen J, Chan D, Luk KD, Cheung KM. The association of lumbar
2 intervertebral disc degeneration on magnetic resonance imaging with body mass index
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7 2001;26:1873-1878.

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12 41.
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15 42. Jensen TS, Sorensen JS, Kjaer P. Intra- and interobserver reproducibility of vertebral
16 endplate signal (modic) changes in the lumbar spine: The nordic modic consensus
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17 group classification. Acta Radiol. 2007;48:748-754.

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18 43. Ma XL, Ma JX, Wang T, Tian P, Han C. Possible role of autoimmune reaction in
19 modic type I changes. Med Hypotheses. 2011;76:692-694.
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20 44. Vital JM, Gille O, Pointillart V, et al. Course of modic 1 six months after lumbar
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21 posterior osteosynthesis. Spine (Phila Pa 1976). 2003;28:715-20; discussion 721.

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22 45. Kuisma M, Karppinen J, Haapea M, et al. Are the determinants of vertebral endplate
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25 2008;9:51.

26

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1 FIGURE LEGENDS
2
3 Figure 1. The assessment of Modic change (MC) types from T1- and T2 -weighted magnetic
4 resonance images. Type I show decreased signal intensity on T1-weighted (A) and increased
5 signal intensity on T2-weighted image (B), Type II changes show increased signal intensity
6 on both T1- (C) and T2-weighted (D) images and Type III changes show decreased signal

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7 intensity on both T1- (E) and T2-weighted (F) images.
8

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9 Figure 2: Assessment of the vertical vertebral height of Modic changes. Four grades were
10 noted based on the degree of vertebral body involvement. EP: endplate

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11
12 Figure 3: The evaluation of Modic changes (MC) in the horizontal plane of the vertebral
13 body adjacent to the endplate. The horizontal plane was divided into nine different zones
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(zones 1-9). MC was evaluated as anterior if any of the anterior zones (zone 1, 2 or 3) were
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15 affected, as medial if any of the medial zones (zone 4, 5 or 6) were affected and as posterior
16 if any of the posterior zones (zone 7, 8 or 9) were affected. MC was evaluated as lateral if all
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17 lateral zones (left: zones 1, 4 and 7, right: zones 3, 6 and 9) were affected.
18
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19 Figure 4. Prevalence of Modic changes (MC) and MC Types according to global disc
20 degeneration. “Type I” MC includes both Type I and Type I/II MC and “Type II” MC
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21 includes both Type II and Type II/III MC. Overall disc degeneration was defined as normal
22 when Pfirrmann summary score was 10, mild when score was 11-14, moderate when score
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23 was 15-17 and severe when the score was 18 or greater.

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TABLES

Variables Definition

Maximum Modic changes height of the

relative height of the vertebra

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Grade 1 Along the endplate

Grade 2 Less than 25%

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Grade 3 From 25% to 50%

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Over 50% of the relative height of the
Grade 4
vertebra

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Horizontal location

Anterior Zones 1, 2 and/or 3

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Midpoint Zones 4, 5 and/or 6

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Posterior Zones 7, 8 and/or 9

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Lateral

Left Zones 1, 4 and 7

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Right Zones 3, 6 and 9

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Horizontal width Zones from 1 to 9

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Table 1. Assessment of lumbar Modic changes on MRI.

MC was evaluated horizontally as anterior if only one or more anterior regions (zones 1-3)
were affected, midpoint if only one or more medial regions (zones 4-6) were affected and
posterior if only one or more posterior regions (zones 7-9) were affected. MC was evaluated
as lateral if it affected all three lateral zones (left: zones 1, 4 and 7, right: zones 3, 6 and 9)
(see also Figure 1).

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Modic Type

Type I Type I/II Type II Type II/III Total

n (%) n (%) n (%) n (%) n (%)

Disc level

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L1-L2 1 (1.3) 4 (4.7) 17 (3.4) 0 (0) 22 (3.2)

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L2-L3 4 (5.0) 7 (8.2) 63 (12.7) 0 (0) 74 (10.8)

L3-L4 6 (7.5) 7 (8.2) 53 (10.6) 4 (17.4) 70 (10.2)

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L4-L5 40 (50.0) 28 (32.9) 129 (25.9) 9 (39.1) 206 (30.0)

L5-S1 29 (36.3) 39 (45.9) 236 (47.4) 10 (43.5) 314 (45.8)

Total 80 (100) 85 (100)

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Table 2. The distribution of Types of Modic changes at lumbar levels. Every endplate at a
disc level from L1-S1 has been individually evaluated.
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Modic Type

Type
Type I Type I/II Type II Total
II/III
n (%) n (%) n (%) n (%)
n (%)

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Horizontal location of MC

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Anterior 3 (3.8) 4 (4.7) 52 (10.4) 0 (0) 59 (8.6)

Midpoint 1 (1.3) 0 (0) 19 (3.8) 0 (0) 20 (2.9)

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Posterior 0 (0) 0 (0) 9 (1.8) 0 (0) 9 (1.3)

Anterior and Midpoint 12 (15.0) 8 (9.4) 109 (21.9) 1 (4.3) 130 (19.0)

Midpoint and Posterior 2 (2.5)

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11 (12.9) 40 (8.0) 3 (13.0) 56 (8.2)
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Anterior and Posterior 0 (0) 0 (0) 4 (0.8) 0 (0) 4 (0.6)
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Anterior, Midpoint and Posterior 62 (77.5) 62 (72.9) 265 (53.2) 19 (82.6) 408 (59.5)
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Lateral zones * 30 (37.5) 21 (24.7) 116 (23.3) 6 (26.1) 173 (25.2)

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Horizontal zones affected by MC

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1-2 zones 9 (11.3) 13 (15.3) 131 (26.3) 2 (8.7) 155 (22.6)

3 zones 32 (40.0) 26 (30.6) 176 (35.3) 6 (26.1) 240 (35.0)

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4-5 zones 17 (21.3) 12 (14.1) 86 (17.3) 2 (8.7) 117 (17.1)

≥6 zones 22 (27.5) 34 (40.0) 105 (21.1) 13 (56.5) 174 (25.4)

Affecting whole horizontal

5 (6.3) 10 (11.8) 19 (3.8) 3 (13.0) 37 (5.4)
endplate §

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Depth of MC

Along endplate 18 (22.5) 9 (10.6) 97 (19.5) 1 (4.3) 125 (18.2)

<25% of the vertebral height 35 (43.8) 31 (36.5) 252 (50.6) 8 (34.8) 326 (47.5)

25-50% of the vertebral height 23 (28.8) 39 (45.9) 135 (27.1) 7 (30.4) 204 (29.7)

>50% of the vertebral height 4 (5.0) 6 (7.1) 14 (2.8) 7 (30.4) 31 (4.5)

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Total 80 (100) 85 (100) 498 (100) 23 (100) 686 (100)

Table 3. Evaluation of lumbar Modic changes (MC) of the horizontal location and the depth

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of MC by MC Types.
* Left or right endplate, includes all three lateral zones.
§ All nine zones

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’Type I’ ’Type II’

No MC MC p-value p-value
MC MC

MC-affected disc level

Protrusions or bulges (%) 1307 (17.9) 299 (67.6) <0.001 83 (77.6) 216 (64.5) 0.008

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Extrusions (%) 53 (0.7) 26 (5.9) <0.001 6 (5.6) 20 (6.0) 0.34

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DD, median (IQR) 2 (2, 3) 4 (3, 5) <0.001 4 (4, 5) 4 (3, 4) 0.022

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MC-affected vertebral body

adjacent to the endplate

SN (%) 860 (5.8)

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292 (42.6) <0.001 77 (46.7) 215 (41.3) 0.22
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Whole lumbar spine

Overall DD score, median

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13 (11, 14) 15 (14, 17) <0.001 15 (14, 17) 15 (14, 17) 0.10
(IQR)
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Total disc displacement

1 (0, 2) 2 (1, 3) <0.001 2 (1, 3) 2 (1, 3) 0.14
score, median (IQR)
EP

Total SN score, median (IQR) 0 (0, 1) 1 (0, 2) <0.001 1 (0, 2.25) 1 (0, 2) 0.22
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Table 4. Characteristics of other MRI phenotypes in relation to lumbar Modic changes (MC)
and MC Types. DD = disc degeneration; IQR = interquartile range; SN = Schmorl’s node
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