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Even mild intervertebral disc degeneration reduces the flexibility of the thoracic spine: an experimental study on 95 human specimens

  • Christian Liebsch
    Affiliations
    Institute of Orthopaedic Research and Biomechanics, Trauma Research Centre Ulm, Ulm University, Helmholtzstr. 14, 89081 Ulm, Baden-Wuerttemberg, Germany
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  • Hans-Joachim Wilke
    Correspondence
    Corresponding author. Institute of Orthopaedic Research and Biomechanics, Ulm University, Helmholtzstraße 14, 89081 Ulm, Germany. Tel.: +(49) 73 1500 55301; fax: +(49) 73 1500 55302.
    Affiliations
    Institute of Orthopaedic Research and Biomechanics, Trauma Research Centre Ulm, Ulm University, Helmholtzstr. 14, 89081 Ulm, Baden-Wuerttemberg, Germany
    Search for articles by this author
Open AccessPublished:June 29, 2022DOI:https://doi.org/10.1016/j.spinee.2022.06.010

      Highlights

      • Ninety-five human thoracic FSUs were tested in vitro for flexibility and disc degeneration.
      • ROM and NZ were significantly reduced for mildly and moderately degenerated discs.
      • Effects compared with non-degenerated discs were found in all motion directions.
      • Lower spinal level and male sex affected ROM and NZ more, but not higher age.
      • Literature comparison revealed large differences compared to the lumbar spine.

      Abstract

      BACKGROUND CONTEXT

      Intervertebral disc degeneration represents one of multiple potential trigger factors for reduced passive spinal mobility and back pain. The effects of age-related degenerative intervertebral disc changes on spinal flexibility were however mainly investigated for the lumbar spine in the past, while intervertebral disc degeneration is also highly prevalent in the thoracic spine.

      PURPOSE

      To evaluate the effect of the degeneration grade on the range of motion and neutral zone of the thoracic spine.

      STUDY DESIGN

      Experimental study including combined radiological grading of intervertebral disc degeneration and biomechanical testing of 95 human thoracic functional spinal units (min. n=4 per level from T1–T2 to T11–T12) from 33 donors (15 female / 18 male, mean age 56 years, age range 37–80 years).

      METHODS

      Degeneration grades of the intervertebral discs were assessed using the validated x-ray grading scheme of Liebsch et al. (0=no, 1=mild, 2=moderate, 3=severe degeneration). Motion segments were loaded with pure moments in flexion/extension, lateral bending, and axial rotation to determine range of motion and neutral zone at 5 Nm.

      RESULTS

      All tested specimens exhibited degeneration grades between zero and two. Range of motion significantly decreased for grades one and two compared with grade zero in any motion direction (p<.05), showing the strongest decrease in extension comparing grade two with grade zero (-42%), while no significant differences were detected between grades one and two. Similar trends were found for the neutral zone with the strongest decrease in extension also comparing grade two with grade zero (-47%). Donor age did not significantly affect the range of motion, whereas the range of motion was significantly reduced in specimens from male donors due to the significantly higher degeneration grade in this study.

      CONCLUSIONS

      Even mild intervertebral disc degeneration reduces the range of motion and neutral zone of the thoracic spine in any motion plane, whereas progressing degeneration does not further affect its flexibility. This is in contrast to the lumbar spine, where a more gradual decrease of flexibility was found in prior studies, which might be explained by differences between thoracic and lumbar intervertebral disc morphologies.

      CLINICAL SIGNIFICANCE

      Thoracic intervertebral disc degeneration should be considered as one of multiple potential causal factors in patients showing reduced passive mobility and middle back pain.

      Keywords

      Introduction

      The effect of intervertebral disc degeneration on the flexibility of the thoracic spine is still not well understood. Previous investigations focused on the lumbar spine due to greater osteophyte formation, endplate sclerosis, and disc height loss compared with thoracic intervertebral discs [
      • Zehra U
      • Noel-Barker N
      • Marshall J
      • Adams MA
      • Dolan P.
      Associations between intervertebral disc degeneration grading schemes and measures of disc function.
      ], potentially affecting the segmental range of motion to a larger extent than in the thoracic spine. Moreover, lumbar disc degeneration was found to be one of multiple causes for lower back pain in several studies [
      • Brinjikji W
      • Diehn FE
      • Jarvik JG
      • Carr CM
      • Kallmes DF
      • Murad MH
      • et al.
      MRI findings of disc degeneration are more prevalent in adults with low back pain than in asymptomatic controls: a systematic review and meta-analysis.
      ,
      • Zheng CJ
      • Chen J.
      Disc degeneration implies low back pain.
      ], implying higher clinical relevance of lumbar intervertebral disc degeneration due to greater flexibility, larger dimensions, and the specific morphology of lumbar intervertebral discs, while there is no clear evidence for a connection between reduced spinal flexibility and back pain so far. However, despite being less pronounced compared to the lumbar spine, age-related degenerative changes of intervertebral discs are also highly prevalent in the thoracic spine [
      • Weiler C
      • Schietzsch M
      • Kirchner T
      • Nerlich AG
      • Boos N
      • Wuertz K.
      Age-related changes in human cervical, thoracal and lumbar intervertebral disc exhibit a strong intra-individual correlation.
      ,
      • Teraguchi M
      • Yoshimura N
      • Hashizume H
      • Muraki S
      • Yamada H
      • Minamide A
      • et al.
      Prevalence and distribution of intervertebral disc degeneration over the entire spine in a population-based cohort: the Wakayama Spine Study.
      ]. While no causality is known so far, thoracic intervertebral disc degeneration was found to be significantly correlated with physical inactivity [
      • Maurer E
      • Klinger C
      • Lorbeer R
      • Rathmann W
      • Peters A
      • Schlett CL
      • et al.
      Long-term effect of physical inactivity on thoracic and lumbar disc degeneration-an MRI-based analysis of 385 individuals from the general population.
      ] and was shown to lead to inhomogeneous load distribution within the thoracic spine [
      • Adams MA
      • Pollintine P
      • Tobias JH
      • Wakley GK
      • Dolan P.
      Intervertebral disc degeneration can predispose to anterior vertebral fractures in the thoracolumbar spine.
      ], indicating a potential relationship between spinal motion and intervertebral disc degeneration in the thoracic spinal region.
      While previous findings for the lumbar spine suggest gradual decreasing range of motion in flexion/extension and lateral bending as well as slightly increasing range of motion in axial rotation with increasing, radiologically determined intervertebral disc degeneration grade [
      • Kettler A
      • Rohlmann F
      • Ring C
      • Mack C
      • Wilke H-J
      Do early stages of lumbar intervertebral disc degeneration really cause instability? Evaluation of an in vitro database.
      ,
      • Volkheimer D
      • Galbusera F
      • Liebsch C
      • Schlegel S
      • Rohlmann F
      • Kleiner S
      • et al.
      Is intervertebral disc degeneration related to segmental instability? An evaluation with two different grading systems based on clinical imaging.
      ,
      • Galbusera F
      • van Rijsbergen M
      • Ito K
      • Huyghe JM
      • Brayda-Bruno M
      • Wilke H-J
      Ageing and degenerative changes of the intervertebral disc and their impact on spinal flexibility.
      ], literature on the effect of intervertebral disc degeneration on thoracic spinal flexibility is scarce. Indeed, prior studies showed that intervertebral disc degeneration affects the kinematics and secondary motions of the thoracic spine [
      • Liebsch C
      • Jonas R
      • Wilke H-J.
      Thoracic spinal kinematics is affected by the grade of intervertebral disc degeneration, but not by the presence of the ribs: an in vitro study.
      ,
      • Paholpak P
      • Shah I
      • Acevedo-Moreno LA
      • Tamai K
      • Buser Z
      • Wang JC.
      Thoracic spine disc degeneration, translation, and angular motion: an analysis using thoracic spine kinematic MRI (kMRI).
      ] and that the intact intervertebral disc has the biggest effect of all structures on the flexibility of the thoracic spine [
      • Wilke H-J
      • Grundler S
      • Ottardi C
      • Mathew CE
      • Schlager B
      • Liebsch C
      In vitro analysis of thoracic spinal motion segment flexibility during stepwise reduction of all functional structures.
      ]. However, there are little data on the effect of degenerative disc changes on thoracic spinal flexibility parameters. In fact, a simulative study revealed that intervertebral disc degeneration has to be considered when performing simulative studies with regard to both thoracic and lumbar spinal model validation [
      • Tyndyk MA
      • McGarry JP
      • Barron V
      • McHugh PE
      • O'Mahoney D
      • Tawackoli W
      • et al.
      Effects of intervertebral disk degeneration on the flexibility of the human thoracolumbar spine.
      ], increasing the need for investigations of potential effects of intervertebral disc degeneration on thoracic spinal flexibility.
      Therefore, the aim of this experimental study was to investigate the effect of intervertebral disc degeneration on range of motion and neutral zone in a large number of motion segments of the entire thoracic spine.

      Methods

      Specimens

      A total of 95 human fresh frozen thoracic functional spinal units from 33 donors were collected for this study. The specimens were obtained from an ethically approved body donation program (Science Care Inc., Phoenix, Arizona, USA), while the usage of human specimens was approved by the ethical committee board of the University of Ulm (No. 302/14). 15 of the 33 donors were female and 18 male, altogether having an age ranging between 37 and 80 years with a mean age of 56 years. Detailed data on the donors and specimens is summarized in the supplementary material file ‘Raw data’ attached to the electronical version of this publication. The specimens were prepared for experimental testing by dissecting any fatty, muscular, and nervous tissue, leaving intact any bony, cartilaginous, and ligamentous tissue including the facet, costovertebral, and costotransverse joints and at least 2 cm of the ribs (Fig. 1). The specimens were then embedded in polymethylmethacrylate (PMMA, Technovit 3040, Heraeus Kulzer, Wehrheim, Germany), while care was taken to place the PMMA cylinders centrally, parallelly, and coaxially on both vertebral bodies. For rigid fixation within the PMMA, small screws were inserted into the upper and lower endplates of the functional spinal units. Prior to preparation and experimental testing, the specimens were stored at -20°C and thawed for about 12 hours at 5°C. In order to ensure proper and reproducible fixation within the testing apparatus, flanges were centrally attached to both PMMA cylinders. During testing, the specimens were kept moist using 0.9% saline solution.
      Fig 1
      Fig. 1Illustration of the biomechanical test setup.

      Evaluation of intervertebral disc degeneration

      Intervertebral disc degeneration was assessed by means of lateral x-rays using the validated grading system of Liebsch et al. for the thoracic spine based on plane radiographs [
      • Liebsch C
      • Tao Y
      • Kienle A
      • Wilke H-J
      Validity and interobserver agreement of a new radiographic grading system for intervertebral disc degeneration: part III. Thoracic spine.
      ], classifying thoracic intervertebral discs into no (grade 0), mild (grade 1), moderate (grade 2), and severe degeneration (grade 3). For this, the specimens were either scanned in a closed x-ray machine (Faxitron 43805N, Hewlett Packard, Palo Alto, CA, USA) using a radiolucent fixture and a tube voltage of 46.5 kV, an exposure time of 60 s, and a source-to-film distance of 60 cm, or by means of a portable X-ray source (AJEX 140 H, Ajex Meditech, Gyeonggi-do, Republic of Korea) in combination with a FCR Prima CR 391 RU X-ray film developer (Fujifilm Holdings, Tokyo, Japan) with a tube voltage of 56 kV, an exposure time of 0.8 s, and a source-to-film distance of 1 m.

      Biomechanical testing

      All specimens were quasi-statically loaded with pure moments in flexion/extension, lateral bending, and axial rotation using a well-established spine tester [
      • Wilke H-J
      • Claes L
      • Schmitt H
      • Wolf S
      A universal spine tester for in vitro experiments with muscle force simulation.
      ]. For the present study, the moment-angle data of two previously performed test series was combined and reevaluated where the same boundary conditions were used, including a constant loading rate of 1°/s, 3.5 loading cycles, testing at room temperature, and a maximum testing period of 20 hours for combined preparation and testing, except for the maximum applied moment, which was 7.5 Nm [
      • Wilke H-J
      • Herkommer A
      • Werner K
      • Liebsch C
      In vitro analysis of the segmental flexibility of the thoracic spine.
      ] for n=47 specimens of donor no. 1–25 and 5 Nm [
      • Liebsch C
      • Jonas R
      • Wilke H-J.
      Thoracic spinal kinematics is affected by the grade of intervertebral disc degeneration, but not by the presence of the ribs: an in vitro study.
      ] for n=48 specimens of donor no. 26–33, respectively (see supplementary material file ‘Raw data’). Determination of range of motion and neutral zone was performed in the same way for all 95 specimens using a custom-written Matlab script (MathWorks Inc., Natick, MA, USA), where the range of motion was determined at 5 Nm and the neutral zone at the turning point of the moment-angle curve of the third full loading cycle [
      • Wilke H-J
      • Wenger K
      • Claes L
      Testing criteria for spinal implants: recommendations for the standardization of in vitro stability testing of spinal implants.
      ].

      Statistical analysis

      Data was collected and post-processed using Microsoft Excel 2019 (Microsoft Corp., Redmond, WA, USA) and statistically evaluated using SPSS 27 (IBM Corp., Armonk, NY, USA). Since testing for normality using the Shapiro-Wilk test exhibited non-normal distribution of data for 76 of 193 evaluated groups, independent of the investigated parameter, and since sample sizes varied between 13 and 67, non-parametric tests were chosen for all evaluations in order to be consistent. For comparisons between two groups, a two-sided Mann-Whitney U test was performed, while for more than two groups, a Kruskal-Wallis test with Dunn-Bonferroni post-hoc correction combined with a pairwise Mann-Whitney U test was applied. Pearson correlation coefficients were calculated for the detection of linear relationships between age and spinal flexibility. For all statistical tests, the significance level was set to 0.05.

      Results

      Study collective

      Of the n=95 evaluated specimens, n=22 exhibited no degeneration (grade 0), n=60 mild degeneration (grade 1), and n=13 moderate degeneration (grade 2), while no specimens with severe degeneration (grade 3) were detected (Fig. 2). Per each thoracic level from T1–T2 to T11–T12, a minimum of n=4 motion segments was part of the overall collective, while the specimens were about equally distributed over the upper (T1–T5, n=32), middle (T5–T8, n=28), and lower thoracic spine (T8–T12, n=35) and there was no significant relationship between spinal region and specimen age (p>.05). Of the overall collective, n=67 specimens were from male donors and n=28 from female donors, showing a mean age of 56 years with a standard deviation of 8 years, while there were no significant differences between male and female specimens regarding age (p>.05).
      Fig 2
      Fig. 2Exemplary lateral x-rays of intervertebral discs evaluated in the present study.

      Effects of intervertebral disc degeneration

      Moment-angle diagrams overall demonstrated typical S-shaped hysteresis characteristics, while the curve shapes generally were found to be thinner and flatter for higher grades of intervertebral disc degeneration in any motion plane (Fig. 3).
      Fig 3
      Fig. 3Representative moment-angle curves illustrating the effect of intervertebral disc degeneration on the viscoelastic properties of thoracic functional spinal units in all motion planes.
      Range of motion was already significantly reduced (p<.05) in specimens with mildly degenerated discs (grade 1) compared with specimens showing no degeneration (grade 0) in flexion, extension, and both left and right lateral bending (Fig. 4). Significant reduction in the range of motion (p<.05) was also found in specimens with moderate degeneration (grade 2) compared with specimens having non-degenerated discs in flexion, extension, and left axial rotation. In any motion direction, both groups including specimens with grade 1 and 2 exhibited significant reduction of the range of motion (p<.05) compared with grade 0 when solely performing pairwise comparisons, respectively. Between grades 1 and 2, no significant differences regarding the range of motion (p<.05) were detected in any motion direction, while there was a tendency towards further decreasing range of motion in flexion, extension, as well as left and right axial rotation (Fig. 4). Largest relative decreases in range of motion of specimens with grade 1 and 2 compared with grade 0 were found in extension with 39% and 42%, respectively, whereas in axial rotation, lowest decreases were identified (20% and 28% in left, 20% and 27% in right axial rotation, respectively).
      Fig 4
      Fig. 4Boxplot diagrams illustrating the effects of intervertebral disc degeneration grades on the segmental range of motion (ROM) of the thoracic spine in all motion directions. Relative changes are given by percentage values in comparison with grade 0 (upper row) and grade 1 (lower row), respectively.
      Neutral zone was significantly reduced (p<.05) for specimens showing mild disc degeneration (grade 1) compared with specimens having non-degenerated discs (grade 0) in flexion and extension (Fig. 5). Significant reduction in neutral zone (p<.05) was further found in specimens with moderately degenerated discs (grade 2) compared with specimens exhibiting grade 0 in extension. In both left and right lateral bending, neutral zone was solely significantly reduced (p<.05) for specimens showing grade 1 compared with specimens having grade 0 when performing pairwise comparisons. Largest relative decreases in neutral zone of specimens with grade 1 and 2 compared with grade 0 were again detected in extension with 41% and 47%, respectively, while in axial rotation, lowest decreases were found (20% and 7% in left, 15% and 13% in right axial rotation, respectively).
      Fig 5
      Fig. 5Boxplot diagrams illustrating the effects of intervertebral disc degeneration grades on the segmental neutral zone (NZ) of the thoracic spine in all motion directions. Relative changes are given by percentage values in comparison with grade 0 (upper row) and grade 1 (lower row), respectively.

      Effects of spinal level

      No significant differences (p>.05) were detected between the thoracic spinal regions T1–T5, T5–T8, and T8–T12 regarding the grade of intervertebral disc degeneration (see supplementary material file ‘Results’). Range of motion and neutral zone were both significantly reduced (p<.05) in levels T5-T8 compared with levels T1–T5 in left and right lateral bending as well as in levels T8–T12 compared with levels T1–T5 in left and right lateral bending and left and right axial rotation. In flexion, the neutral zone was also found to be significantly reduced (p<.05) in levels T8–T12 compared with levels T1–T5.

      Effects of age

      Age did not significantly affect (p>.05) the degeneration grade in this study. However, when testing pairwise, there was a tendency towards higher age for grade 2 compared with grade 0 (p=.074) and even a significantly higher age (p<.05) for grade 2 compared with grade 1 (see supplementary material file ‘Results’). No significant effects of age (p>.05) were detected on range of motion and neutral zone in any motion plane, neither when comparing specimens of donors aged lower than 55 years with specimens of donors aged 55 or more years, nor when analyzing linear correlation between age and range of motion and neutral zone, respectively, in any motion direction. However, there was a slight tendency towards decreasing range of motion and neutral zone with increasing age with the Pearson correlation coefficients for the range of motion being between -0.132 and -0.181 and for the neutral zone being between -0.053 and -0.173 for any motion direction, respectively (see supplementary material file ‘Results’).

      Effects of sex

      In specimens originating from male donors, the degeneration grade was significantly higher (p<.05) compared with the specimens from female donors (see supplementary material file ‘Results’). Moreover, male sex led to significant reduction (p<.05) of both range of motion and neutral zone in any motion direction.

      Discussion

      Age-related degenerative intervertebral disc changes are supposed to be one of multiple causes for reduced passive spinal mobility and back pain. The effects of intervertebral disc degeneration on spinal flexibility, however, were predominantly studied in the lumbar spine in previous investigations. Indeed, intervertebral disc degeneration was also found to be highly prevalent in the thoracic spine, potentially being one of multiple trigger factors for middle back pain in severe cases. Therefore, the purpose of this in vitro study was to explore the effects of intervertebral disc degeneration on the flexibility of motion segments of the entire thoracic spine.
      The results of the present study revealed that the range of motion as well as the neutral zone values of thoracic spinal motion segments abruptly decrease when the respective intervertebral disc is mildly degenerated as compared to a non-degenerated disc, whereas moderate disc degeneration does not further alter the flexibility of the thoracic spine as compared to a mildly degenerated disc. In the moment-angle curves, this effect was especially illustrated when comparing the curve slope in the area of low loading, which was high in case of motion segments incorporating non-degenerated discs, resulting in high laxity of the entire motion segment in this loading range, and which was low in case of motion segments exhibiting disc degeneration, causing higher stiffness at low load level. This outcome was detected in any motion direction, which is in contrast to previous experimental findings on the lumbar spine, where gradual decrease of the range of motion was found in flexion/extension and lateral bending as well as gradual increase of the range of motion in axial rotation for increasing disc degeneration grades, respectively [
      • Kettler A
      • Rohlmann F
      • Ring C
      • Mack C
      • Wilke H-J
      Do early stages of lumbar intervertebral disc degeneration really cause instability? Evaluation of an in vitro database.
      ,
      • Volkheimer D
      • Galbusera F
      • Liebsch C
      • Schlegel S
      • Rohlmann F
      • Kleiner S
      • et al.
      Is intervertebral disc degeneration related to segmental instability? An evaluation with two different grading systems based on clinical imaging.
      ,
      • Galbusera F
      • van Rijsbergen M
      • Ito K
      • Huyghe JM
      • Brayda-Bruno M
      • Wilke H-J
      Ageing and degenerative changes of the intervertebral disc and their impact on spinal flexibility.
      ]. Potential explanations for this phenomenon might be based on differences in intervertebral disc morphology, including lower height, lower transverse plane cross-sectional area, and lower sagittal plane wedge angle in thoracic intervertebral discs compared with lumbar ones [
      • Pooni JS
      • Hukins DW
      • Harris PF
      • Hilton RC
      • Davies KE.
      Comparison of the structure of human intervertebral discs in the cervical, thoracic and lumbar regions of the spine.
      ,
      • Schlager B
      • Krump F
      • Boettinger J
      • Niemeyer F
      • Ruf M
      • Kleiner S
      • et al.
      Characteristic morphological patterns within adolescent idiopathic scoliosis may be explained by mechanical loading.
      ], as well as in additional stabilization of the thoracic spine by the rib cage, more specifically the sternocostal connection and the ligamentous stabilization of the costovertebral joints [
      • Liebsch C
      • Graf N
      • Appelt K
      • Wilke H-J
      The rib cage stabilizes the human thoracic spine: an in vitro study using stepwise reduction of rib cage structures.
      ,
      • Liebsch C
      • Wilke H-J
      Rib presence, anterior rib cage integrity, and segmental length affect the stability of the human thoracic spine: an in vitro study.
      ]. Regarding the single motion directions, range of motion and neutral zone loss was highest in extension and flexion in this study, indicating that osteophyte formation in the anterior region of the intervertebral disc is primarily responsible for motion restriction in the thoracic spine, since uniform disc narrowing in the rather flat thoracic intervertebral disc can be assumed to similarly affect the flexibility in any motion direction.
      In a previous study published by Healy et al. [
      • Healy AT
      • Mageswaran P
      • Lubelski D
      • Rosenbaum BP
      • Matheus V
      • Benzel EC
      • et al.
      Thoracic range of motion, stability, and correlation to imaging-determined degeneration.
      ], testing entire thoracic spine specimens with intact rib cage, significant correlation (p<.05) was solely found between osteophyte formation and regional range of motion in flexion/extension and lateral bending from two levels above to two levels below surgical decompression in the mid-thoracic spine, whereas no significant correlation was detected between overall intervertebral disc degeneration and total range of motion of the entire thoracic spine. However, Healy et al. used the Lane score [
      • Lane NE
      • Nevitt MC
      • Genant HK
      • Hochberg MC
      Reliability of new indices of radiographic osteoarthritis of the hand and hip and lumbar disc degeneration.
      ] for disc degeneration grading, which had been originally developed for the lumbar spine and which was not validated for thoracic intervertebral discs, neglecting differences in disc and endplate morphology. Moreover, potential effects of disc degeneration on the segmental level could not be captured by this experimental approach, which is why the results of this study are not fully comparable with the findings of the present study. In another study, Zhao et al. simulated disc degeneration in lower thoracic segments by disc dehydration and mechanically induced endplate disruption and found both increased range of motion and neutral zone [
      • Zhao F
      • Pollintine P
      • Hole BD
      • Dolan P
      • Adams MA
      Discogenic origins of spinal instability.
      ]. However, since this procedure is very likely not reflecting the age-related degeneration including gradual disc narrowing and osteophyte formation and presumably represents rather ‘endplate-driven’ disc degeneration than ‘anulus-driven’ disc degeneration according to the definition of Adams et al. [
      • Adams MA
      • Dolan P
      Intervertebral disc degeneration: evidence for two distinct phenotypes.
      ], these results are hardly comparable with the findings of the present study. Indeed, a recent prospective study of Machino et al. using lateral radiographs of a large cohort of asymptomatic subjects, detected decreasing flexion/extension range of motion with decreasing disc height in the lower thoracic spine due to age-related degenerative changes [
      • Machino M
      • Nakashima H
      • Ito K
      • Katayama Y
      • Matsumoto T
      • Tsushima M
      • et al.
      Age-related degenerative changes and sex-specific differences in osseous anatomy and intervertebral disc height of the thoracolumbar spine.
      ], which is in accordance with the findings of the present in vitro study. However, due to monosegmental testing, anterior rib cage resection, and non-physiological, level-independent load application, the results of the present study might not be directly transferrable to the in vivo situation.
      Since intervertebral disc degeneration is assumed to be associated with multiple factors, the effects of spinal level, age, and sex were additionally evaluated in this study. It was found that both range of motion and neutral zone are significantly decreased in lower compared with upper thoracic levels. Indeed, several previous studies detected higher disc degeneration [
      • Videman T
      • Battié MC
      • Gill K
      • Manninen H
      • Gibbons LE
      • Fisher LD.
      Magnetic resonance imaging findings and their relationships in the thoracic and lumbar spine. Insights into the etiopathogenesis of spinal degeneration.
      ,
      • Girard CJ
      • Schweitzer ME
      • Morrison WB
      • Parellada JA
      • Carrino JA.
      Thoracic spine disc-related abnormalities: longitudinal MR imaging assessment.
      ] as well as lower disc convexity, higher sagittal plane disc wedging, and higher average disc height in the lower thoracic region compared to the upper and mid-thoracic spine [
      • Kunkel ME
      • Herkommer A
      • Reinehr M
      • Bockers TM
      • Wilke H-J
      Morphometric analysis of the relationships between intervertebral disc and vertebral body heights: an anatomical and radiographic study of the human thoracic spine.
      ], potentially explaining reductive effects on the flexibility in the lower thoracic spinal area by higher torsional forces acting in this region [
      • Videman T
      • Battié MC
      • Gill K
      • Manninen H
      • Gibbons LE
      • Fisher LD.
      Magnetic resonance imaging findings and their relationships in the thoracic and lumbar spine. Insights into the etiopathogenesis of spinal degeneration.
      ]. However, no significant differences between the upper, middle, and lower thoracic spine regarding the degeneration grade was found in this study. In contrast, the average degeneration grade was highest in the mid-thoracic region (T5–T8), similar to the findings of a large cohort study [
      • Teraguchi M
      • Yoshimura N
      • Hashizume H
      • Muraki S
      • Yamada H
      • Minamide A
      • et al.
      Prevalence and distribution of intervertebral disc degeneration over the entire spine in a population-based cohort: the Wakayama Spine Study.
      ]. Furthermore, no significant effects of age on thoracic spinal flexibility were found in the present study, while slight tendencies towards reduced range of motion and neutral zone were observed for increasing age in any motion direction, which was also discovered in the study of Healy et al. for total thoracic spinal range of motion in any motion plane [
      • Healy AT
      • Mageswaran P
      • Lubelski D
      • Rosenbaum BP
      • Matheus V
      • Benzel EC
      • et al.
      Thoracic range of motion, stability, and correlation to imaging-determined degeneration.
      ]. Nevertheless, this finding was quite unexpected due to the fact that age was determined to be associated with thoracic intervertebral disc degeneration in several previous studies [
      • Teraguchi M
      • Yoshimura N
      • Hashizume H
      • Muraki S
      • Yamada H
      • Minamide A
      • et al.
      Prevalence and distribution of intervertebral disc degeneration over the entire spine in a population-based cohort: the Wakayama Spine Study.
      ,
      • Matsumoto M
      • Okada E
      • Ichihara D
      • Watanabe K
      • Chiba K
      • Toyama Y
      • et al.
      Age-related changes of thoracic and cervical intervertebral discs in asymptomatic subjects.
      ,
      • Goh S
      • Tan C
      • Price RI
      • Edmondston SJ
      • Song S
      • Davis S
      • et al.
      Influence of age and gender on thoracic vertebral body shape and disc degeneration: an MR investigation of 169 cases.
      ]. However, a 10-year longitudinal follow-up study on a large cohort of asymptomatic patients also showed no significant effects of age and sex on thoracic intervertebral disc degeneration [
      • Okada E
      • Daimon K
      • Fujiwara H
      • Nishiwaki Y
      • Nojiri K
      • Watanabe M
      • et al.
      Ten-year longitudinal follow-up MRI study of age-related changes in thoracic intervertebral discs in asymptomatic subjects.
      ], implying that thoracic spinal flexibility may be more dependent on biomechanical determinants rather than individual factors such as age or sex. In the present study, range of motion and neutral zone were significantly reduced in specimens from male donors compared with specimens from female donors, which might be explained by the significantly higher degeneration grade in males compared to females in the present study, which was traced to the specific study collective. Indeed, previous findings suggest greater degenerative changes in male thoracic discs [
      • Goh S
      • Tan C
      • Price RI
      • Edmondston SJ
      • Song S
      • Davis S
      • et al.
      Influence of age and gender on thoracic vertebral body shape and disc degeneration: an MR investigation of 169 cases.
      ], similar to findings for the cervical spine in a large population study [
      • Tao Y
      • Galbusera F
      • Niemeyer F
      • Samartzis D
      • Vogele D
      • Wilke H-J
      Radiographic cervical spine degenerative findings: a study on a large population from age 18 to 97 years.
      ]. Multivariate analysis would have been preferable in order to determine potential interdependencies between sex, disc degeneration, and spinal flexibility in this study. However, this was not feasible due to non-normal distribution of a large proportion of data. Therefore, the effect of sex on thoracic intervertebral disc degeneration is not fully understood yet and should therefore be evaluated in future big data studies.
      Due to the experimental design of the present study, some limitations have to be considered when interpreting the results. First of all, solely specimens exhibiting degeneration grades 0, 1, and 2 could be included in the study collective, since the specimens had been originally acquired with regard to sufficient flexibility rather than grade of intervertebral disc degeneration [
      • Liebsch C
      • Jonas R
      • Wilke H-J.
      Thoracic spinal kinematics is affected by the grade of intervertebral disc degeneration, but not by the presence of the ribs: an in vitro study.
      ,
      • Wilke H-J
      • Herkommer A
      • Werner K
      • Liebsch C
      In vitro analysis of the segmental flexibility of the thoracic spine.
      ]. However, this was accepted for the presented study as severely degenerated thoracic intervertebral discs with grade 3 generally show strong ossification [
      • Liebsch C
      • Tao Y
      • Kienle A
      • Wilke H-J
      Validity and interobserver agreement of a new radiographic grading system for intervertebral disc degeneration: part III. Thoracic spine.
      ], questioning additional acquisition and testing of grade three specimens with regard to already low flexibility in specimens with grades 1 and 2 compared with motions segments showing grade 0, presumably adding no valuable information to the outcome. Moreover, a fourth group would have led to further reduction in the statistical significance level due to post-hoc correction of multiple testing. Apart from that, it was tried to reach an equal distribution in the study collective regarding spinal level, age, and sex when ordering the specimens, having no influence on the degeneration grade in the first place. Another limitation is that about half of the specimens were loaded with pure moments of 7.5 Nm within the setting of a previous study where the flexibility was intended to be compared with lumbar spinal flexibility [
      • Wilke H-J
      • Herkommer A
      • Werner K
      • Liebsch C
      In vitro analysis of the segmental flexibility of the thoracic spine.
      ], potentially causing slightly higher range of motion values at the evaluation point of 5 Nm due to viscoelastic effects during the first two cycles of preconditioning. However, these most likely small effects could not be determined and were supposed to be neglectable with regard to almost even distributions regarding disc degeneration, spinal level, age, and sex within this subgroup, most probably not affecting the outcome of the present study. Finally, the present investigation was based on the evaluation of lateral x-rays of the intervertebral discs. Consequently, the effect of facet joint degeneration was not evaluated and should therefore be investigated in future studies. Moreover, usage of lateral x-rays potentially limited comparability with studies using magnetic resonance imaging for degeneration grading, since the two techniques were shown to result in slightly different correlations between intervertebral disc degeneration and spinal flexibility in the lumbar region [
      • Volkheimer D
      • Galbusera F
      • Liebsch C
      • Schlegel S
      • Rohlmann F
      • Kleiner S
      • et al.
      Is intervertebral disc degeneration related to segmental instability? An evaluation with two different grading systems based on clinical imaging.
      ]. Nevertheless, the results of the present study were considered as being valid due to the large sample size, balanced co-factors, and clearly defined boundary conditions.

      Conclusions

      Even mild intervertebral disc degeneration significantly reduces thoracic spinal flexibility in any motion direction for both the range of motion and the neutral zone. This is in contrast to previous findings in the lumbar spine, where a gradual decrease of flexibility in flexion/extension and lateral bending as well as a gradual increase in axial rotation were detected. Spinal level and sex were also found to play a role in this context, whereas age had no considerable impact in the present study. Future studies should therefore explore potential determinants for the specific differences among spinal regions regarding the effect of intervertebral disc degeneration on spinal flexibility.

      Declarations of Competing Interests

      The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

      Acknowledgments

      The authors gratefully acknowledge support from Andrea Herkommer, Karin Werner, and Shamila Hübner during experimental works.
      This study was funded by the Medical Faculty of the University of Ulm (grant no. L.SBN.0186 ). The authors declare to have no potential conflicts of interests to disclose.

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