Disc degeneration and chronic low back pain: an association which becomes nonsignificant when endplate changes and disc contour are taken into account

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1 Neuroradiology (2014) 56:25 33 DOI /s y DIAGNOSTIC NEURORADIOLOGY Disc degeneration and chronic low back pain: an association which becomes nonsignificant when endplate changes and disc contour are taken into account Francisco M. Kovacs & Estanislao Arana & Ana Royuela & Ana Estremera & Guillermo Amengual & Beatriz Asenjo & Helena Sarasíbar & Isabel Galarraga & Ana Alonso & Carlos Casillas & Alfonso Muriel & Carmen Martínez & Víctor Abraira Received: 24 August 2013 /Accepted: 14 October 2013 /Published online: 5 November 2013 # Springer-Verlag Berlin Heidelberg 2013 Abstract Introduction The objective of this study was to assess the association between severe disc degeneration (DD) and low back pain (LBP). Methods Acase control study was conducted with 304 subjects, aged 35 50, recruited in routine clinical practice across six hospitals; 240 cases (chronic LBP patients with a median pain duration of 46 months) and 64 controls (asymptomatic subjects without any lifetime history of significant LBP). The following variables were assessed once, using previously validated methods: gender, age, body mass index (BMI), lifetime smoking exposure, degree of physical activity, severity of LBP, disability, and findings on magnetic resonance (MRI) (disc degeneration, Modic changes (MC), disc protrusion/hernia, annular tears, spinal stenosis, and spondylolisthesis). Radiologists who interpreted MRI were blinded to the subjects' characteristics. A multivariate logistic regression model assessed the association between severe DD and chronic LBP, adjusting for gender, age, BMI, physical activity, MC, disc protrusion/hernia, and spinal stenosis. Results Severe DD at 1 level was found in 46.9 % of the controls and 65.8 % of the cases. Crude odds ratio (95 % CI), for suffering chronic LBP when having severe DD, was 2.06 (1.05; 4.06). After adjusting for MC and disc protrusion/ hernia, it was 1.81 (0.81; 4.05). Electronic supplementary material The online version of this article (doi: /s y) contains supplementary material, which is available to authorized users. F. M. Kovacs Departamento Científico, Fundación Kovacs, Paseo de Mallorca 36, Palma de Mallorca, Spain F. M. Kovacs: E. Arana : A. Estremera : G. Amengual : B. Asenjo : H. Sarasíbar: I. Galarraga : A. Alonso : C. Casillas : C. Martínez Spanish Back Pain Research Network, Fundación Kovacs, Paseo de Mallorca 36, Palma de Mallorca, Spain E. Arana (*) Servicio de Radiología, Fundación Instituto Valenciano de Oncología, Prof Beltrán Báguena, 19, Valencia, Spain aranae@uv.es A. Royuela: A. Muriel : V. Abraira CIBER Epidemiología y Salud Pública (CIBERESP), Madrid, Spain A. Royuela: A. Muriel : V. Abraira Unidad de Bioestadística Clínica, IRYCIS, Hospital Ramón y Cajal, Ctra. Colmenar Km. 9.1, Madrid, Spain A. Estremera: G. Amengual : H. Sarasíbar : C. Martínez Hospital Son Llàtzer, Ctra. De Manacor, Km. 4, Palma de Mallorca, Spain B. Asenjo Hospital Carlos Haya, Avda Carlos Haya s/n, Málaga, Spain I. Galarraga Hospital de Manacor, Ctra. De Manacor s/n, Manacor, Mallorca, Spain A. Alonso Fundación Jiménez Díaz, Avda. Reyes Católicos 2, Madrid, Spain C. Casillas Instituto de Traumatología Unión de Mutuas, Av. del Lledó, 67, Castellón, Spain

2 26 Neuroradiology (2014) 56:25 33 Conclusions The association between severe DD and LBP ceases to be significant when adjusted for MC and disc protrusion/hernia. These results do not support that DD as a major cause of chronic LBP. Keywords Low back pain. Vertebral endplate changes. Disk degeneration. Magnetic resonance imaging. Lumbar spine Abbreviations BMI Body mass index DD Disc degeneration LBP Low back pain P25 25th percentile P75 75th percentile RMQ Roland Morris Questionnaire VAS Visual analog scale Introduction Low back pain (LBP) has a lifetime prevalence of up to 84 % [1] and is the main cause of disability worldwide [2]. The process of disc degeneration disease (DD) is similar to aging, although at a faster pace [3, 4]. Some clinicians consider DD a potential cause of chronic LBP [5]. However, virtually all healthy subjects above a certain age show DD on magnetic resonance imaging (MRI) [3], and none of the currently available diagnostic procedures allow identifying the subjects in whom it may cause LBP [6]. In fact, controversy exists regarding the correlation between DD and current or future symptoms [3, 7, 8]. Inconsistencies in the definitions of DD and LBP, use of non-validated methods for assessing DD and LBP, and lack of adjustment for potential confounders, as well as other methodological shortcomings, impede drawing firm conclusions from the case control and prospective studies which have assessed their association and led to inconsistent results [7]. Moreover, these studies were conducted with North American and Scandinavian subjects [9 12], while genetic factors influence DD and no study has assessed this association in Southern Europe. Therefore, the objective of this study was to assess the association between severe DD and chronic LBP in Spanish subjects, following standardized definitions, using previously validated methods and adjusting for potential confounders. Methods This was a case control study conducted in radiological departments at six hospitals across six cities in Spain, between June and December The study protocol was approved by the institutional review boards of the participating hospitals. Subjects All subjects (cases and controls) were aged years and had been prescribed an MRI. Cases were submitted to lumbar MRI for chronic LBP (i.e., lasting 90 days) [12], with or without leg pain. Controls had been prescribed a cranial MRI for headache which turned out to be normal, did not present LBP and, according to their statements and medical records, either had no history of LBP or had experienced only one episode in their life, lasting less than 7 days. Exclusion criteria were: ethnically not Spanish, history of spine surgery, current pregnancy, vertebral fractures, red flags for fractures or potential underlying systemic diseases, and signs suggesting cauda equina syndrome [8]. Sample size was established at 294 subjects (235 cases and 59 controls) based on the following assumptions: the prevalence of DD among chronic LBP patients would be 60 %, and 30 % among asymptomatic controls [13, 15], with an alpha error of 0.05, a statistical power of 95 %, a ratio of cases per controls of 4:1, and a percentage of subjects with missing data precluding inclusion in the regression models 25 %. Procedure All subjects referred to the radiology departments of the participating hospitals for a lumbar MRI for LBP, or for a cranial MRI for headache, were screened. Those complying with the inclusion criteria were included in the study after signing the corresponding informed consent. Neither subjects nor physicians received compensation for participating in this study. Controls were invited to participate once the recruiting radiologist had established that the cranial MRI was normal. Once included, all cases and controls underwent a lumbar MRI and were assigned a number code, which substituted their name on the self-administered questionnaire and the images. Only the study coordinator (FMK), who did not interpret any images, had access to the name corresponding to each code. Radiologists read images at their own institutions and were blinded to patients' identities and clinical data. Data were introduced into a database at a central coordination office by two administrative assistants who separately double checked that the data introduced coincided with the questionnaires. At the analysis phase, the code assigned to each subject made it possible to pair each subject's clinical data with the MRI. When data analysis started, the statisticians were given the key, contained within the code, which made it possible to distinguish cases from controls. This procedure ensured that (a) radiologists were unaware of whether the images they were reading corresponded to a

3 Neuroradiology (2014) 56: case or a control ; (b) they were blinded to subject's demographic and clinical characteristics; (c) the researchers who were aware of the code identifying each subject as a case or a control did not read the images; and (d) only the statisticians and the auxiliary personnel who handed the selfadministered questionnaire to the subjects had access to subjects' demographic and clinical data. Clinical assessment All subjects (cases and controls) underwent the same assessment. The self-administered questionnaire gathered data on subjects' age (date of birth), gender, height (centimeters), weight (kilogram), lifetime smoking exposure (pack-years smoked), duration of pain (asking separately whether pain had lasted for 90 days and date of appearance), degree of physical activity, current pain severity, and disability. Physical activity was assessed through a previously validated questionnaire, which gathered data on job, physical requirements during work, daily activities and leisure, and mean time per week spent on activities implying an increase in heart and breathing rates [16]. Pain intensity was measured with a 10-cm visual analog scale (VAS) and LBP-related disability with the validated Spanish version of the Roland Morris questionnaire (RMQ) [17, 18]. Subjects completed all the self-administered questionnaires by themselves, in private. The only instructions they received were those included in the validated instruments measuring physical activity, pain intensity, and disability [16 18]. MRI evaluation Fig. 1 Sagittal T1- (a) and T2- (b) weighted images from a symptomatic subject ( case ). Modic change types I and III, and disc bulging, are seen at the L1 L2 level. At the L5 S1 level, Modic change type II and a localized endplate defect are seen All examinations were performed on six 1.5 T MR imaging systems with a six-channel phased-array spine coil and with patients in supine position, following standard imaging protocols (Supplementary Table) [12, 14]. Findings on MRI were reported using the previously validated Spanish version of the Nordic Modic Consensus Group Classification, which includes the standardized report of findings related to disc degeneration (Pfirrmann's grades I, II, III, IV, or V ), vertebral endplate changes at each vertebral level (type, Modic types I, II, and III, intravertebral location, intravertebral volume, maximum height, endplate area, osteophytes, localized endplate defects, Schmorl's nodes, and irregular endplates), disc protrusion ( normal disc contour, bulging, focal protrusion, or extrusion ), spondylolisthesis (yes/ no), and spinal stenosis (yes/no) (Figs. 1 and 2) [19 21]. MRIs were interpreted by eight radiologists. Their postresidency experience as radiologists ranged from 13 to 19 years, and their experience interpreting spine imaging ranged between 8 and 13 years. They were trained in different institutions without fellowships. The mean (25th percentile (P25); 75th percentile (P75)) kappa values for their interobserver agreement when assessing disc degeneration, disc contour abnormalities, and Modic changes using the methods implemented in this study have shown to be (0.393; Fig. 2 Sagittal T1- (a ) and T2- (b ) weighted images from an asymptomatic subject (control). Modic change type II, disc bulging, focal protrusion, irregular endplate, localized endplate defects, and osteophytes are seen at the L4 L5 level. At the L5 S1 level, disc bulging, Modic type II changes, and osteophytes are seen

4 28 Neuroradiology (2014) 56: ), (0.401; 0.547), and (0.325; 0.559), respectively [19], which is in line with the values reported in the literature irrespective of the classification system used [22, 23]. Data analysis At the analysis phase, the degree of physical activity was classified as extremely intense vs. not extremely intense [16], lifetime exposure to smoking was defined as the number of packs smoked during the patients' lifetime [22], disc degeneration at any lumbar level was dichotomized into Pfirrmann's grades I + II + III ( no/mild disc degeneration ) vs. IV + V ( severe disc degeneration ), Modic changes were dichotomized as no vs. yes (at any vertebral level, irrespective of type or location), and disc protrusion was dichotomized into no (normal disc contour or bulging) vs. yes (focal protrusion or extrusion). Absolute and relative frequencies were used to describe categorical variables. For continuous ones, medians and interquartile range, or mean and SD, were used depending on whether data were normally distributed. Chi-square test was used to compare the proportion of subjects showing severe DD between cases and controls. In order to control for potential confounders, a multivariate logistic regression was performed to estimate the association between severe DD and chronic LBP. Based on previous studies, the variables which were included in the maximal model were age (years), gender, body mass index (BMI; kilograms per square meter), extremely intense physical activity, Modic changes (yes/no), disc protrusion/herniation (yes/no), and spinal stenosis (yes/no) [3, 14, 24, 25]. A backward strategy was used; those variables which changed 10 % of the effect size when they were eliminated from the model were considered as confounders. The collinearity of the maximal models was evaluated using the criteria proposed by Belsley [26], and the significance level was set at 5 %. Stata (version 11.0; Stata Corp., College Station, TX, USA) program was used for analysis. Results Among the 84 subjects without LBP who were screened, 17 reported having had 1 relevant LBP episode in their lives, and medical records showed that three more had requested medical care for this reason. Among the 287 LBP patients who were screened, 47 had pain lasting less than 90 days. Therefore, 304 subjects (64 controls and 240 cases) were included. A flow diagram showing screening, enrollment, and study participants is presented in Fig. 3, following STROBE guidelines [27]. Among controls, median age was 45 years and 45.3 % were women. Among cases, median age was 43 years, and 55.0 % were women. Table 1 details sample characteristics. There were some missing values due to questions that patients left unanswered in the questionnaires (Table 1). The variable with the highest rate of missing data was the date when pain began, which was left unanswered by 55 out of the 240 chronic LBP patients (Table 1). Characteristics of patients who answered and did not answer this question were very similar (Table 2). Nevertheless, it was hypothesized that differences between patients who did and did not answer this question might exist. Therefore, a sensitivity analysis was performed, in which these 55 cases were excluded. The number of discs showing each grade of disc degeneration in male and females is shown in Table 3. Severe disc degeneration at 1 level was present in 46.9 % out of the 64 subjects without LBP and in 65.8 % out of the 240 LBP patients (p =0.006; Table 1). Results were consistent in the sensitivity analysis which only included the 185 patients who provided data on the exact duration of pain (46.9 vs %, p =0.011). In the regression models, Modic changes and disc protrusion/herniation were identified as confounders of the association between severe DD and LBP. Before adjusting for these variables, the odds ratio (OR) (95 % confidence interval (CI)) for suffering from chronic low back pain when having severe DD was 2.06 (1.05; 4.06). After adjusting for them, the odds ratio was 1.81 (0.81; 4.05; Table 4). Results were very similar in the sensitivity analysis which only included the 185 patients who provided data on the exact duration of pain. In this analysis, the same variables were confounders and, once results were adjusted, OR was 1.71 (0.75; 3.89). Discussion Results from this study suggest that persons with severe DD may have 81 % higher odds of suffering from chronic LBP, but the 95 % CI for this estimator is , indicating that this result is not significant. In fact, these results show that the association between severe DD and chronic LBP is not significant when Modic changes and disc contour abnormalities are considered. This study was powered to show a significant association between LBP and severe DD anticipating that the prevalence of the latter across cases and controls would be 60 vs. 30 %, respectively, while the prevalence actually found turned out to be 65.8 and 46.9 % (i.e., an OR of 1.8). Therefore, an alternative explanation could be that this study was underpowered, which impeded this association from reaching statistical significance. It is impossible to rule out that this possibility and, given these results, DD may or may not be a cause of chronic LBP. In fact, the 95 % CI for the odds ratio on

5 Neuroradiology (2014) 56: Fig. 3 Flow diagram shows screening, enrollment, and study participant details Patients referred for Lumbar MRI for chronic low back pain (cases), or Cranial MRI for headache, which turned out to be normal (controls) Cases (LBP patients) Assessed for eligibility (n = 287) Not eligible (n=47) LBP < 90 days Controls (neither LBP nor history of significant LBP) Assessed for eligibility (n = 84) Not eligible (n=20) History of LBP Were included and underwent a lumbar MRI (n=240) Were included and underwent a lumbar MRI (n=64) Provided exact date of pain appearance (n=185) Did not provide exact date of pain appearance (n=65) Total enrolled and analyzed (n =240) Total enrolled and analyzed (n =64) Analysis of data Logistic regression including all subjects (240 cases + 64 controls) Sensitivity analysis: Logistic regression including only the cases which provided data on exact duration of pain (185 cases + 64 controls) Consistent results this association is wide, and some previous case/control studies have found statistically significant ORs for reporting pain when having DD [9, 10]. However, should there be a significant association between severe DD and chronic LBP, the corresponding OR would be <4.1. Association does not necessarily mean causation, but it is highly unlikely that a major causal, predisposing, or triggering factor will not show a strong, significant association with the corresponding condition. Moreover, differences across this study and those which reported a significant association [9, 10] can be explained by differences in methods and especially by the fact that in the current study, statistical analysis accounted for potential confounders [7]. In fact, unadjusted results showed an OR (95 % CI) of 2.06

6 30 Neuroradiology (2014) 56:25 33 Table 1 Sample characteristics Variable N d LBP patients (240 subjects) N d Subjects without LBP (64 subjects) Age (years) a (38; 47) (41; 47) Gender b Male 108 (45.0) 35 (54.7) Female 132 (55.0) 29 (45.3) Body mass index (BMI) (kg/m 2 ) a (22.4; 27.3) (21.9; 27.4) Lifetime smoking (packs-year) a (0.0; 11.2) 60 3 (0; 11) Extremely intense physical activity b (25.6) 48 9 (18.8) Severity of low back pain (VAS) a, e (2; 7) 52 0 (0; 0) Reported leg pain b (53.3) 64 0 (0.0) Severity of leg pain (VAS) a, e, f (3; 8) 52 0 (0; 0) Duration of pain (months) a (11; 112) 64 Disability (RMQ) a, g (3; 12) 6 1 (1; 1) Severe disc degeneration b, c (65.8) (46.9) Modic changes (any type) b (80.4) (87.5) High intensity zones (54.6) (48.4) Schmorl nodes (14.2) (23.4) Osteophytes (84.6) (87.5) Disk protrusion/hernia h (91.3) (80.0) Spondylolisthesis (7.1) 64 4 (6.2) Spinal stenosis (64.2) (60.9) a Median (P25; P75) b n(%) c p value for the comparison of the proportion of severe disc degeneration among subjects without LBP compared to LBP patients (0.006) d Number of subjects in each group, for whom data on the corresponding variable were available (i.e., subjects who answered the corresponding question or in whom the variable was applicable, e.g., age, gender, weight, height, etc.) e Values for VAS range from 0 to 10, from better to worse f Median (P25; P75) value for subjects reporting leg pain g Values for RMQ range from 0 to 24, from better to worse h Disk protrusion/hernia includes focal protrusion and extrusion (1.05; 4.06), which is in line with results from those studies [9, 10], but results from the adjusted analysis show that the association ceases to be significant when Modic changes and disc protrusion/hernia are taken into account [12]. Furthermore, severe DD is to be expected in middle-aged subjects [3, 7, 9 14] and those included in this study represent two extreme clinical scenarios; controls were not defined as asymptomatic subjects, but as asymptomatic subjects without any lifetime significant history of LBP. Conversely, cases were not defined as subjects with LBP, but as chronic LBP patients in whom a lumbar MRI was prescribed. Lumbar spine MRI is usually prescribed for nonspecific LBP when pain fails to improve despite treatment [8, 18], and patients with a median pain duration of approximately 4 years can be considered the worst clinical cases (Table 2) [8, 28]. Results from this study are consistent with the evidence suggesting that DD is not a major cause of LBP in routine practice [3, 7]. Approximately half of the asymptomatic subjects without a significant lifetime history of LBP showed severe DD, and Modic changes were more prevalent among asymptomatic controls than among cases (Table 2). This is consistent with previous studies, which have shown that Modic changes are the radiological finding which correlates more strongly with DD among Southern European subjects [14], but are not associated with LBP [29]. For ethical and operational reasons, controls were recruited among subjects with a normal cranial MRI, which had been requested for headache. Since the lifetime prevalence of LBP is over 70 % [1], at the design phase, it was considered unrealistic to exclude all the subjects reporting having had a single, minor, <7-day-long LBP episode. However, controls denied having suffered a single LBP episode in their life, and this was consistent with their medical records. It is impossible to completely rule out recall bias, especially if related to mild, short-lived episodes which did not require medical care. Nevertheless, this does not question the results of this study;

7 Neuroradiology (2014) 56: Table 2 Characteristics of LBP patients who provided and did not provide data on the exact duration of pain Variable N All LBP patients, n =240 N Patients who provided data on the exact duration of pain, n =185 N Patients who did not provide data on the exact duration of pain, n =55 Age (years) a (38; 47) (38; 46) (38; 48) Gender b Male 108 (45.0) 80 (43.2) 28 (50.9) Female 132 (55.0) 105 (56.8) 27 (49.1) Body mass index (BMI) (kg/m 2 ) a (22.4; 27.3) (22.2; 27.3) (22.6; 26.8) Lifetime smoking (packs-year) a (0.0; 11.8) (0; 12) (0; 10) Extremely intense physical activity b (25.6) (29.0) 44 6 (13.6) Severity of low back pain (VAS) a, e (2; 7) (2; 7) 50 3 (2; 6) Reported leg pain b Severity of leg pain (VAS) a, e, f (4; 8) (4; 8) 27 5 (3; 7) Disability (RMQ) a, g (3; 12) (3; 12) 50 5 (1; 9) Severe disc degeneration b (65.8) (64.9) (69.1) Modic changes (any type) b (80.4) (79.5) (83.6) High intensity zones (54.6) (52.4) (61.8) Schmorl nodes (14.2) (11.9) (21.8) Osteophytes (84.6) (81.6) (94.6) Disk protrusion/hernia h (91.3) (88.7) (100) Spondylolisthesis (any degree) (7.1) (7.0) 55 4 (7.3) Spinal stenosis (64.2) (60.5) (76.4) a Median (P25; P75) b n (%) c p value for the comparison of the proportion of severe disc degeneration among subjects without LBP compared to LBP patients (0.006) d Number of subjects in each group, for whom data on the corresponding variable were available (i.e., subjects who answered the corresponding question or in whom the variable was applicable, e.g., age, gender, weight, height, etc.) e Values for VAS range from 0 to 10, from better to worse f Median (P25; P75) value for subjects reporting leg pain g Values for RMQ range from 0 to 24, from better to worse h Disk protrusion/hernia includes focal protrusion and extrusion Table 3 Disc degeneration in male and female subjects included in the study Gender Disc degeneration Number of discs showing each grade of degeneration (L1 L2 to L5 S1) None 1 disc 2 discs 3 discs 4 discs 5 discs Male Grade I GradeII Grade III Grade IV GradeV Female Grade I GradeII Grade III Grade IV GradeV

8 32 Neuroradiology (2014) 56:25 33 Table 4 Results from the regression analysis Crude analysis OR (95 % CI) Adjusted analysis a OR (95 % CI) Severe disc degeneration 2.06 (1.05; 4.06) 1.81 (0.81; 4.05) a Adjusted by Modic changes and disc protrusion/herniation. Variables included in the maximal model were gender, age, BMI, physical activity, Modic changes, disc protrusion/hernia, and spinal stenosis it is not biologically plausible for a constant, progressive condition, such as severe DD, to cause no more than a single, short-lived episode of LBP throughout a patient's lifetime. Moreover, if this were the case, severe DD would continue to be clinically irrelevant. Subjects were recruited consecutively in routine practice across six cities in five different regions in the country, all those who complied with inclusion criteria were included, and the prevalence of DD found among patients in this study is very similar to the one found in a previous study conducted in this geographical environment [14]. All this suggests that generalizability of results from the current study to middleaged Spanish subjects is not a major concern. This study has some weaknesses and limitations. Due to its cross-sectional, case control study design, it does not rule out the possibility that severe DD predicts the appearance of LBP in the future or influences its prognosis. However, the available evidence does not support these hypotheses [3, 11, 30, 31]. The regression analyses on the association between severe DD and chronic LBP did not adjust for some imaging findings which might be associated with LBP, such as annular tears or facet degeneration. However, the clinical relevance of these findings is controversial [3, 5, 7, 11, 12, 28, 32]. Psychological variables, such as fear avoidance beliefs and catastrophizing, were not gathered in this study. However, their influence appears to be greater on disability than on pain [33] and has shown to be either irrelevant or nonexistent in the cultural setting where this study took place [34, 35]. It might be argued that having included patients with referred pain down to the leg, and with disc protrusion or hernia on MRI, may have diluted the potential association between severe DD and chronic LBP. Although it is impossible to completely rule out this possibility, at the design phase of this study, it was decided to include these patients because the inflammatory cascade potentially triggered by DD can cause nerve irritation and leg pain [3], and disc protrusion or hernia can be seen in MRI of asymptomatic, healthy subjects [12, 30, 32]. Moreover, it was felt that excluding patients with leg pain might reduce the representativeness of the sample and the clinical interest of results. Therefore, it was decided to include the average chronic LBP patient in whom an MRI was prescribed in routine practice, either with or without leg pain, and adjust results for the presence of disc protrusion/hernia on MRI. In conclusion, this study suggests that the association between severe DD and LBP ceases to be significant when adjusted for Modic changes and disc protrusion/hernia. These results do not support DD as a major cause of chronic LBP. Acknowledgments This study was funded by The Kovacs Foundation, a not-for-profit institution specializing in back pain research, with no links to the health industry. 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