1. health and fitness
2. disease

D 1289
OULU 2015
UNIVERSITY OF OUL U P.O. Box 8000 FI-90014 UNIVERSITY OF OULU FINLA ND
U N I V E R S I TAT I S
O U L U E N S I S
ACTA
A C TA
D 1289
ACTA
U N I V E R S I T AT I S O U L U E N S I S
Jani Takatalo
University Lecturer Santeri Palviainen
Postdoctoral research fellow Sanna Taskila
Professor Olli Vuolteenaho
Jani Takatalo
Professor Esa Hohtola
DEGENERATIVE FINDINGS
ON MRI OF THE LUMBAR
SPINE
PREVALENCE, ENVIRONMENTAL DETERMINANTS
AND ASSOCIATION WITH LOW BACK SYMPTOMS
University Lecturer Veli-Matti Ulvinen
Director Sinikka Eskelinen
Professor Jari Juga
University Lecturer Anu Soikkeli
Professor Olli Vuolteenaho
Publications Editor Kirsti Nurkkala
ISBN 978-952-62-0782-7 (Paperback)
ISBN 978-952-62-0783-4 (PDF)
ISSN 0355-3221 (Print)
ISSN 1796-2234 (Online)
UNIVERSITY OF OULU GRADUATE SCHOOL;
UNIVERSITY OF OULU,
FACULTY OF MEDICINE;
UNIVERSITY OF HELSINKI,
DEPARTMENT OF PUBLIC HEALTH,
HJELT INSTITUTE
D
MEDICA
ACTA UNIVERSITATIS OULUENSIS
D Medica 1289
JANI TAKATALO
DEGENERATIVE FINDINGS ON MRI
OF THE LUMBAR SPINE
Prevalence, environmental determinants and association
with low back symptoms
Academic dissertation to be presented with the assent of
the Doctoral Training Committee of Health and
Biosciences of the University of Oulu for public defence in
the Auditorium of Kastelli Research Centre (Aapistie 1),
on 9 May 2015, at 12 noon
U N I VE R S I T Y O F O U L U , O U L U 2 0 1 5
Copyright © 2015
Acta Univ. Oul. D 1289, 2015
Supervised by
Professor Jaro Karppinen
Docent Simo Taimela
Professor Osmo Tervonen
Reviewed by
Docent Markku Kankaanpää
Docent Kimmo Mattila
Opponent
Professor Marja Mikkelsson
ISBN 978-952-62-0782-7 (Paperback)
ISBN 978-952-62-0783-4 (PDF)
ISSN 0355-3221 (Printed)
ISSN 1796-2234 (Online)
Cover Design
Raimo Ahonen
JUVENES PRINT
TAMPERE 2015
Takatalo, Jani, Degenerative findings on MRI of the lumbar spine. Prevalence,
environmental determinants and association with low back symptoms
University of Oulu Graduate School; University of Oulu, Faculty of Medicine; University of
Helsinki, Department of Public Health, Hjelt Institute
Acta Univ. Oul. D 1289, 2015
University of Oulu, P.O. Box 8000, FI-90014 University of Oulu, Finland
Abstract
Earlier studies on lumbar degenerative imaging findings in magnetic resonance imaging (MRI)
have been done mainly in adult populations and the associations of degenerative findings with low
back pain (LBP) are controversial. Only a few studies have involved adolescents and young adults.
Heritability has been acknowledged as the only explicit risk factor of disc degeneration (DD).
This study investigated the prevalence and environmental determinant of lumbar degenerative
findings in MRI and their association with low back symptoms among young adults. The data were
based on two physical assessments, three questionnaires and one lumbar MRI that were executed
on members of the Oulu Back Study (n=558), a subsample of Northern Finland Birth Cohort 1986,
between 16 and 21 years of age.
Prevalences of lumbar DD (54%), bulging (25%), protrusion (18%) and Schmorl’s node (17%)
were high, whereas other degenerative findings were rare among young adults. Males had higher
prevalence of DD and Schmorl’s nodes than females. DD and herniations were associated with
low back symptoms. On the other hand, symptoms were present among subjects without DD or
other abnormal findings on MRI. Of the environmental determinants, high body mass index and
MRI-based obesity measurements of visceral adiposity were associated with lumbar DD among
males. Waist circumference and smoking showed a comparable association with DD among
males, but the level of physical activity was not associated with DD in either gender.
Low back symptoms are more common among young adults with a higher degree of DD or
presence of disc herniation. Smoking and overweight are associated with lumbar DD among
young male adults.
Keywords: intervertebral disc degeneration, low back pain, lumbar spine, magnetic
resonance imaging, overweight, physical activity, smoking, young adult
Takatalo, Jani, Lannerangan degeneratiiviset löydökset magneettikuvauksella.
Esiintyvys, ympäristön riskitekijät ja yhteys alaselkäoireisiin
Oulun yliopiston tutkijakoulu; Oulun yliopisto, Lääketieteellinen tiedekunta; Helsingin
yliopisto, Kansanterveystieteen osasto, Hjelt-instituutti
Acta Univ. Oul. D 1289, 2015
Oulun yliopisto, PL 8000, 90014 Oulun yliopisto
Tiivistelmä
Aikaisempia tutkimuksia magneettikuvantamisella (MK) todetuista lannerangan rappeumamuutoksista ja niiden yhteyksistä alaselkäkipuun on tehty lähinnä aikuisväestöllä ja tulokset ovat ristiriitaisia. Vain muutamia tutkimuksia on tehty alle 25-vuotiailla. Välilevyrappeuman mahdollisista riskitekijöistä vain perimästä on vahvaa näyttöä.
Tässä tutkimuksessa tarkasteltiin MK:lla todettujen lannerangan rappeumamuutosten esiintyvyyttä, niihin vaikuttavia ympäristötekijöitä ja yhteyttä alaselkäoireisiin nuorilla aikuisilla. Tutkimuksen aineisto perustui kahteen kliiniseen tutkimukseen, kolmeen kyselyyn ja yhteen
MK:een, jotka toteutettiin Pohjois-Suomen syntymäkohortti 1986:een kuuluville Oulun selkätutkimuksen koehenkilöille (n=558) 16-21 vuoden iässä.
Lannerangan välilevyrappeumalla (54 %), välilevyn pullotuksilla (bulge; 25 %), sellaisilla
välilevyn pullistumilla jotka eivät läpäisseet selkärangan takimmaista pitkittäissidettä (protruusio; 18 %) sekä päätelevyn läpi suuntautuvilla välilevyn pullistumilla (Schmorlin keräset; 17 %)
oli korkea esiintyvyys nuorilla aikuisilla, kun taas muut kuvantamislöydökset olivat harvinaisia.
Välilevyrappeuma ja Schmorlin keräset olivat yleisempiä miehillä. Sekä välilevyrappeuma että
pullistumat olivat yhteydessä alaselkäoireisiin molemmilla sukupuolilla, mutta kaikilla oireisilla
ei todettu poikkeavia löydöksiä MK:ssa. Ympäristötekijöistä korkea kehon painoindeksi ja
MK:sta mitatut rasvan määrää mittaavat muuttujat olivat miehillä yhteydessä välilevyrappeumaan. Miehillä vyötärönympärys ja tupakointi olivat heikommin yhteydessä välilevyrappeumaan, kun taas liikunta-aktiivisuus ei ollut kummallakaan sukupuolella yhteydessä rappeumaan.
Alaselkäoireet ovat yleisempiä nuorilla aikuisilla, joilla on vaikea-asteisempi välilevyrappeuma tai välilevyn pullistuma. Tupakointi ja ylipaino ovat yhteydessä lannerangan välilevyrappeumaan nuorilla aikuisilla miehillä.
Asiasanat: alaselkäkipu, fyysinen aktiivisuus, lanne-ristiselkä, magneettikuvaus, nuoret
aikuiset, tupakointi, välilevyrappeuma, ylipaino
To my family
8
Acknowledgements
This study was carried out in the Department of Physical Medicine and
Rehabilitation, Institute of Clinical Medicine, and the Department of Radiology,
Institute of Diagnostics, University of Oulu, during the years 2006–2014.
I owe my greatest and most sincere gratitude to my principal supervisor,
Professor Jaro Karppinen, who created an inspiring and positive working
atmosphere. His enthusiasm, innovativeness, enormous capacity to organize
scientific studies and availability for guidance and discussion is admirable and
deserving of respect. I am sincerely grateful to my supervisor Docent Simo
Taimela, who gave insightful and critical feedback to improve the quality of the
study. I am thankful to my supervisor Professor Osmo Tervonen, who made this
thesis possible by providing the magnetic resonance imaging facilities for
scientific use and provided his radiological expertise when it was needed.
I am grateful to Docent Jaakko Niinimäki, who introduced me to and taught
me the evaluation of lumbar magnetic resonance imaging (MRI). He also found
the time to instruct me whenever I had problems concerning imaging. I am also
grateful to Professor Roberto Blanco Sequeiros, who performed lumbar MRI
evaluations of all the subjects at such short notice and gave valuable comments on
the original publications.
I wish to thank Pertti Mutanen, M.Sc., and Jouko Remes, M.Sc., who helped
me with statistical analysis. In addition, I wish to thank Professor Emeritus Simo
Näyhä for his expertise in statistical analysis and epidemiology on the original
publications.
In addition, my warm thanks go to my co-authors Docent Eero Kyllönen,
Professor Marjo-Riitta Järvelin, Professor Raija Korpelainen, Jaana Laitinen,
Ph.D., Tuija Tammelin, Ph.D., and Dino Samartzis, Ph.D., whose expertise has
been essential for the original publications.
I appreciate the reviewers of this study, Docent Markku Kankaanpää and
Docent Kimmo Mattila, for providing valuable comments and constructive
criticism to improve this work. I also want to thank Anna Vuolteenaho for the
revision of the language.
I wish to thank my friends and colleagues Markus Paananen, Juha Auvinen,
Juhani Määttä, Paula Mikkonen and all my other friends for supporting me and
sharing their thoughts about scientific and clinical work.
I greatly acknowledge the financial support of this work granted by the
Finnish Association for the Study of Pain, Emil Aaltonen Foundation, Yrjö
9
Jahnsson Foundation, the Finnish Medical Foundation, Oulu University
Scholarship Foundation, the Finnish Society for the Study of the Spine, the
Finnish Medical Society Duodecim, Maud Kuistila Foundation, University of
Oulu Graduate School, Finnish Cultural Foundation, Finnish Association of
Orthopedic Manual Therapy and the National Doctoral Program of
Musculoskeletal Disorders and Biomaterials.
I would like to express my gratitude towards my mother Leila and father
Harri, who have encouraged me in my studies and given me support throughout
my life. I am grateful to my sisters Katja, Tanja and Krista, and my mother- and
father-in-law for sharing many valuable and relaxing moments during this journey
of mine. Finally, I owe my warmest thanks and gratitude to my wife Kaisa for her
love and care and to our son Luka, who has given me so much happiness and
reminded me of the most important things in life.
Oulu, March 18, 2015
10
Jani Takatalo
Abbreviations
AD
BMI
COR
CRP
CT
DD
DST
HIZ
HNP
ICF
LBP
LCA
MR
MRI
NFBC
OBS
OLR
SAD
SI
VST
WC
Abdominal diameter
Body mass index
Cumulative odds ratio
C-reactive protein
Computed tomography
Disc degeneration
Dorsal subcutaneous thickness
High intensity zone
Herniated nucleus pulposus
International classification of functioning, disability and health
Low back pain
Latent class analysis
Magnetic resonance
Magnetic resonance imaging
Northern Finland Birth Cohort
Oulu Back Study
Ordinal logistic regression
Sagittal abdominal thickness
Sacroiliac
Ventral subcutaneous thickness
Waist circumference
11
12
List of original articles
This thesis is based on the following original articles, which are referred in the
text by their Roman numerals.
I
Takatalo J, Karppinen J, Niinimäki J, Taimela S, Näyhä S, Järvelin M-R, Kyllönen E &
Tervonen O (2009) Prevalence of Degenerative Imaging Findings in Lumbar Magnetic
Resonance Imaging Among Young Adults. Spine 34:1716-1721
II
Takatalo J, Karppinen J, Niinimäki J, Taimela S, Näyhä S, Mutanen P, Blanco
Sequeiros R, Järvelin M-R, Kyllönen E & Tervonen O (2011) Do degenerative MRI
findings associate with low back symptoms in young Finnish adults? Spine 36:21802189
III Takatalo J, Karppinen J, Niinimäki J, Taimela S, Mutanen P, Blanco Sequeiros R,
Näyhä S, Järvelin M-R, Kyllönen E & Tervonen O (2012) Association of Modic
changes, Schmorl's nodes, spondylolytic defects, High Intensity Zone lesions, disc
herniations, and radial tears with low back symptom severity among young Finnish
adults. Spine 37:1231-1239
IV Takatalo J, Karppinen J, Taimela S, Niinimäki J, Laitinen J, Blanco Sequeiros R,
Paananen M, Remes J, Näyhä N, Tammelin T, Korpelainen R & Tervonen O (2013)
Body mass index is associated with lumbar disc degeneration in young Finnish males.
BMC Musculoskeletal Disorders, 14:87
V
Takatalo J, Karppinen J, Taimela S, Niinimäki J, Laitinen J, Blanco Sequeiros R,
Samartzis D, Tammelin T, Korpelainen R, Näyhä S, Remes J & Tervonen O (2013)
The association of abdominal obesity with lumbar disc degeneration – A magnetic
resonance imaging study. PLoS ONE 8(2): e56244
13
14
Contents
Abstract
Tiivistelmä
Abbreviations
11 List of original articles
13 Contents
15 1 Introduction
17 2 Review of the literature
19 2.1 Anatomy of the lumbar spine .................................................................. 19 2.1.1 Structure of the intervertebral discs .............................................. 21 2.1.2 Vascular supply and nutrition of the intervertebral disc ............... 23 2.1.3 Innervation of the intervertebral disc............................................ 25 2.2 Intervertebral disc degeneration .............................................................. 26 2.2.1 Prevalence .................................................................................... 28 2.2.2 Risk factors ................................................................................... 29 2.2.3 Clinical relevance ......................................................................... 31 2.3 Other degenerative findings .................................................................... 32 2.3.1 Disc contour changes .................................................................... 32 2.3.2 Annular tears ................................................................................ 33 2.3.3 Endplate changes .......................................................................... 34 2.3.4 Modic changes .............................................................................. 35 2.3.5 Spondylolytic defects ................................................................... 35 2.3.6 Clinical relevance ......................................................................... 37 3 Purpose of the study
39 4 Material and methods
41 4.1 Study population ..................................................................................... 41 4.2 Magnetic resonance imaging................................................................... 43 4.2.1 Protocols of anatomical imaging .................................................. 43 4.2.2 Definition of magnetic resonance imaging findings ..................... 43 4.2.3 MRI Adiposity measurements (V) ................................................ 50 4.3 Determinants ........................................................................................... 51 4.3.1 Low back symptoms and functional limitations (II-III) ............... 51 4.3.2 Smoking (IV) ................................................................................ 52 4.3.3 Physical activity (IV).................................................................... 52 4.4 Anthropometrics...................................................................................... 53 4.4.1 Weight, height and Body mass index (IV).................................... 53 15
4.4.2 Waist circumference (IV-V) ......................................................... 53 4.4.3 Bioelectrical impedance analyses (V) .......................................... 53 4.5 Other factors (V) ..................................................................................... 54 4.6 Statistical methods .................................................................................. 56 4.6.1 MRI measurements ........................................................................ 56 4.6.2 Latent class analysis ....................................................................... 57 4.7 Ethical considerations ............................................................................. 60 5 Results
63 5.1 Characteristics of the study population ................................................... 63 5.2 Prevalence of degenerative imaging findings (I-V) ................................ 64 5.2.1 Agreement of observers on MRI .................................................. 67 5.3 Association of lumbar magnetic resonance imaging findings with
low back symptoms and functional limitations (II-III) ........................... 67 5.4 Association of lumbar disc degeneration with body mass index,
smoking and physical activity (IV) ......................................................... 78 5.5 Association of abdominal adiposity with lumbar disc
degeneration (V)...................................................................................... 83 6 Discussion
89 6.1 Key findings ............................................................................................ 89 6.2 Prevalence of degenerative imaging findings ......................................... 90 6.2.1 Gender differences ........................................................................ 92 6.3 Association of degenerative findings with low back symptoms ............. 92 6.4 Association of degenerative findings with lifestyle factors .................... 93 6.4.1 Physical activity and sports .......................................................... 94 6.4.2 Smoking........................................................................................ 94 6.4.3 Obesity.......................................................................................... 94 6.4.4 Other lifestyle factors ................................................................... 95 6.5 Clinical relevance of degenerative findings ............................................ 95 6.6 Methodological considerations ............................................................... 97 6.6.1 Magnetic resonance imaging ...................................................... 102 6.7 Implications and future directions ......................................................... 102 7 Conclusions
105 References
107 Appendices
123 Original publications
129 16
1
Introduction
Low back pain (LBP) is a very common problem worldwide and most people
suffer from it at some point in their life (Balague et al. 2012). LBP is the most
debilitating condition worldwide, and can result in decreased physical function
and compromised quality of life (Deyo et al. 2006, Vos et al. 2012). In the United
States, between the years 2004 and 2008, over 3% of emergency room visits were due
to LBP, accounting for more than 2 million people (Waterman et al. 2012). The total
annual cost of LBP per each citizen is 250-600 US dollars (Ekman et al. 2005, Katz
2006), at least two thirds of this sum being due to indirect costs, i.e., productivity loss
(Dagenais et al. 2008, Ekman et al. 2005, Juniper et al. 2009).
The source of LBP has been under intensive investigation in the past decades. In
adult patients, disc degeneration (DD) has been claimed to be the main cause of LBP
(42%) followed by facet joint pain (31%) and sacroiliac (SI) joint pain (18%)
(DePalma et al. 2011). However, asymptomatic adults also have a high prevalence of
degenerative lumbar spine imaging findings (Boden et al. 1990, Jensen et al. 1994).
The relationship of DD and LBP is hard to verify among adults, because degeneration
progresses with age, and temporal order changes are therefore difficult to observe
without a long follow-up (Adams & Dolan 2012) . All the innervated structures in
the lumbar spine are potential pain generators (Higuchi & Sato 2002) . However,
pain is always subjectively affected by emotions and previous pain experiences
(Salzberg 2012).
The present study evaluated the prevalence of degenerative findings in lumbar
spine in young adults and their associations with low back symptoms. Furthermore,
we evaluated the association of smoking, physical activity, and obesity with lumbar
DD. Our hypotheses were that DD is already common among young adults and it is
associated with low back symptoms. Furthermore, we assumed that overweight,
smoking and physical activity would be associated with lumbar DD among young
adults.
17
18
2
Review of the literature
2.1
Anatomy of the lumbar spine
The lumbar spine consists of five vertebrae whose bodies are interposed by
intervertebral discs. The vertebral arch, the posterior part of the vertebrae, is
formed of a pair of pedicles and a pair of laminas enclosing the spinal cord. Two
superior and two inferior articular processes articulate the articular processes of
the adjacent vertebrae forming an intervertebral foramen for transmission of the
spinal nerve roots on either side. Two transverse processes and one spinous
process project laterally and dorsally, respectively, serving as attachment of
muscles and ligaments to the spine (Figs. 1–3). Anterior and posterior
longitudinal ligaments extend along the anterior and posterior surfaces of the
body of vertebrae, respectively, whereas the ligamenta flava connect the lamina of
adjacent vertebrae. The supraspinal and interspinal ligaments connect the spinous
processes. (Standring et al. cop. 2008).
19
Fig. 1. Anatomy of the lumbar vertebrae, superior view (Modified from Raj 2008,
published by permission of John Wiley and Sons, Inc.).
Fig. 2. Anatomy of the lumbar spine, superolateral view (Modified from Raj 2008,
published by permission of John Wiley and Sons, Inc.).
20
Fig. 3. Anatomy of the lumbar spine in magnetic resonance imaging, T1 (left) and T2
(right) weighted sagittal images.
2.1.1 Structure of the intervertebral discs
Intervertebral discs are located between adjacent vertebral bodies, being the chief
bond between them. Normally, the intervertebral disc is about one-third of the
height of the lumbar vertebral body and is anteriorly and posteriorly connected
with longitudinal ligaments. (Standring et al. cop. 2008). Each disc consists of
three separate compartments – nucleus pulposus, annulus fibrosus and cartilage
endplate. By the second decade, rounded chondrocyte-like cells replace initially
notochordal cells in the nucleus pulposus. Moreover, the cell density declines as
percentage of chondrocytes increases. The chondrocytes may migrate from
adjacent cartilage endplates. The mesenchyme-originated cells of the annulus
fibrosus have many characteristics of fibroblast and chondrocytes. The proportion
of fibroblasts increases outwards. (Adams & Roughley 2006, Cassinelli et al.
2001, Setton & Chen 2004, Smith et al. 2011).
21
The nucleus pulposus contains a proteoglycan called aggrecan; its anionic
glycosaminoglycan side chains of chondroitin sulfate and keratin sulfate provide
osmotic pressure to meet the compressive loading of the disc. The irregularly
arranged collagen II and elastin fibers maintain the stability between vertebrae by
preventing the disc from bulging. There is a thin fibrous membrane in the
transition zone of the nucleus pulposus and annulus fibrosus. (Adams &
Roughley 2006, Cassinelli et al. 2001, Fields et al. 2014, Setton & Chen 2004,
Smith et al. 2011).
In addition to the change of distribution of fibroblasts and chondrocytes in the
annulus fibrosus, the cell shape changes from ellipsoidal to a more rounded type
in morphology towards the nucleus pulposus (Setton & Chen 2004). Collagen
type I is the main component of the approximately twenty lamellae whose fibers
pass obliquely between vertebral bodies forming the annulus fibrosus enveloping
the nucleus pulposus (Adams & Roughley 2006, Setton & Chen 2004, Smith et
al. 2011) (Fig. 4). The amount of irregularly arranged collagen II increases
together with proteoglycans towards the nucleus pulposus (Cassinelli et al. 2001,
Smith et al. 2011). The outer regions of the annulus fibrosus are anchored
superiorly and inferiorly into the vertebral bone and cartilage endplate (Adams &
Dolan 2012, Cassinelli et al. 2001, Smith et al. 2011), and anteriorly and
posteriorly it blends with longitudinal ligaments by collagen fibers (Cassinelli et
al. 2001). Although the intervertebral disc is separated anatomically from the
adjacent vertebra by the endplate, it should be thought of as part of the
intervertebral disc (Setton & Chen 2004).
The endplate is a combination of porous subchondral bone and cartilage
(Freemont 2009). However, the hyaline cartilage of the endplate is not as
hydrated as in weight-bearing synovial joints (Urban et al. 2004). Cartilage makes
up approximately 50% of the intervertebral space at birth and functions as growth
plate for vertebral bodies, thinning to 0.6 mm, i.e., 5% of the intervertebral space,
by adulthood (Roberts et al. 2006). Nutrients have to diffuse through the dense
cartilage endplate before reaching the disc matrix, which is easily accomplished
by oxygen, amino acids and water, while anions and larger particles have
difficulties diffusing into the disc. Moreover, the higher concentration of
proteoglycans in the nucleus pulposus inhibits the diffusion of larger solutes and
anions toward the nucleus pulposus. (Grunhagen et al. 2011, Urban et al. 2004).
The endplate transfers the load to the disc and therefore it should be strong and
resistant to damage, which may explain why double-layered endplates are found
in some individuals. In a double-layered endplate the more superficial layer is
22
more porous and thinner than a single-layered endplate. Interestingly, DD is less
prevalent in the discs adjacent to double-layered as compared to single-layered
endplates. (Fields et al. 2012). By the end of the first decade, the blood flow
diminishes in the endplate, initiating the breakdown of the endplate and thereafter
of the nucleus pulposus (Boos et al. 2002a, Modic & Ross 2007); in the third
decade, degenerative histological findings are present in discs and endplates
(Boos et al. 2002a) .
Fig. 4. Anatomy of the lumbar intervertebral disc (Modified from Raj 2008, published
by permission of John Wiley and Sons, Inc.).
2.1.2 Vascular supply and nutrition of the intervertebral disc
In infants, the capillaries penetrate into the annulus, but in late childhood these
blood vessels disappear apart from some capillaries together with lymph vessels,
which penetrate only a few millimeters into the outermost annulus. In adulthood,
the intervertebral disc is the largest avascular tissue in the body. (Grunhagen et al.
2006, Grunhagen et al. 2011, Urban et al. 2004). The pairs of arteries rising from
the abdominal aorta supplying the vertebral bodies of L1 to L4 and the arteries
rising from aortic bifurcation supplying the fifth lumbar vertebral body branch
into smaller vessels, which form a complex network of capillaries that supply
nutrition to the intervertebral discs (Grunhagen et al. 2011) (Fig. 5). These
muscarinic receptor-containing capillaries (Grunhagen et al. 2011, Urban et al.
2004) penetrate the subchondral plate and terminate at the bone-cartilage endplate
23
junction (Grunhagen et al. 2006). Thus, there may be a distance of seven to eight
millimeters to the nearest blood supply from the center of the nucleus pulposus
and therefore the nutritional environment of the cells varies throughout the disc
(Urban et al. 2004). However, as in all living cells, the local nutrient and pH
levels must be maintained to prohibit cell death (Grunhagen et al. 2006).
Fig. 5. Vascular supply of the lumbar intervertebral disc (Modified from Raj 2008,
published by permission of John Wiley and Sons, Inc.).
The energy of the disc is primarily obtained through glycolysis and 24 hours
without glucose is lethal to the cells of the disc (Grunhagen et al. 2006). Lactic
acid is formed as an end product of glycolysis in hypoxic environment. It must be
transported out of the disc cells, because it lowers the pH and, thus, reduces the
rate at which cells synthesize matrix components leading to worse matrix
integrity. Lactic acid and other metabolites diffuse out of the disc into the venous
network through the endplates. (Urban et al. 2004).
There are several conditions that can affect the blood supply into the disc
(atherosclerosis, sickle cell anemia etc.). Moreover, physical inactivity or long24
term exercise may have an effect on nutrient transportation into the disc possibly
by affecting the architecture of the capillary bed at the disc-bone interface. (Urban
& Roberts 2003). When an intervertebral disc is damaged, granulation tissue with
capillaries forms into the torn fissures (Lotz & Ulrich 2006, Peng et al. 2006).
2.1.3 Innervation of the intervertebral disc
Similarly to vascular supply, the innervation of intervertebral discs is found only
in the outer annulus fibrosus in the normal disc with no differences in the density
of innervation between lumbar levels. Periannular connective tissue is more
densely innervated than the outer annulus as only a small proportion of these
nerves penetrate into the three to four outermost lamellas. (Fagan et al. 2003).
The nerves run parallel to the lamellae (Palmgren et al. 1999), only occasionally
crossing them obliquely (Ashton et al. 1994). The central endplate is much more
densely innervated than the peripheral endplate. (Fagan et al. 2003, Fields et al.
2014). The innermost three quarters of the annulus fibrosus and the entire nucleus
pulposus lack innervation (Ashton et al. 1994, Fagan et al. 2003, Palmgren et al.
1999). The vertebral body is innervated with nerves accompanying vertebral
vessels ending up at the endplate level (Fagan et al. 2003, Lotz & Ulrich 2006).
The innervating nerves of intervertebral discs arise from the sinuvertebral
nerve and sympathetic trunk. The first comes from a recurrent branch of the
ventral ramus and the latter is a branch of sympathetic ganglia coursing through
gray rami communicans to the spinal nerve. Each disc is innervated
multisegmentally, mainly ipsilaterally but contralaterally as well (Fig. 6). The
endplate is innervated from the small branch of the sinuvertebral nerve, i.e., the
basivertebral nerve. (Lotz & Ulrich 2006).
25
Fig. 6. Innervation of the lumbar intervertebral disc (Modified from Raj 2008, published
by permission of John Wiley and Sons, Inc.).
In the degenerated disc small free nerve fibers penetrate deeper into the
annulus fibrosus than in normal discs (Coppes et al. 1997, Fagan et al. 2010,
Freemont et al. 1997). This can be explained by interaction of annulus fibrosus
cells and neuron-like cells in the DD process, which enhances the production of
growth factors related to nerve ingrowth (Moon et al. 2012). Moreover, damage
in annulus fibrosus is repaired by granulation tissue, which contains nerves. Thus,
pain may originate from mechanical loading of the newly innervated degenerative
disc. (Lotz & Ulrich 2006). Moreover, it has been suggested that chemotactic
response to products of disc breakdown may enhance the sensory nerve ingrowth
into the endplate and vertebral body, which may explain severe spinal pain on
movement (Brown et al. 1997).
2.2
Intervertebral disc degeneration
Several morphological changes occur in the intervertebral disc as degeneration
progresses, which can be seen most reliably in vivo on MRI (Haughton 2006,
Samartzis et al. 2013). These findings can be demonstrated from histological
samples, but the problem with histology is that it cannot be performed in vivo.
26
Histologic features of intervertebral DD may include disc desiccation, fibrosis,
narrowing of the disc space, diffuse bulging of the annulus beyond the disc space,
extensive fissuring, mucinous degeneration of the annulus, osteophytes at the
vertebral apophyses, and defects and sclerosis of the endplates (Modic & Ross
2007). The water content in the nucleus pulposus of the intervertebral disc
diminishes as degeneration proceeds (Haughton 2006), which can be seen on
MRI. As DD progresses the intervertebral space will begin to narrow. (Luoma et
al. 2001). Narrowing of the intervertebral space can be seen on plain radiographs
as an indirect sign of DD (de Schepper et al. 2010). However, desiccation occurs
prior to intervertebral space narrowing and therefore T2-weighted images on MRI
are the most sensitive radiological tool for diagnosing early DD (Luoma et al.
2001).
Several classifications for DD have been developed based on height and
desiccation of disc on MRI. According to Pfirrmann’s classification (Pfirrmann et
al. 2001) degeneration of the disc can be classified into five phases according to
disc structure, distinction of annulus and nucleus, signal intensity and height of
intervertebral disc on T2-weighted midsagittal images (from normal discs grade I
and II to severely degenerated grade V). The decreased amount of water in the
disc leads to loss of signal intensity on T2-weighted images as a biomarker of DD
(Modic & Ross 2007). Pfirrmann grade II (minor desiccation) is classified as
normal adult disc; morphologically, mucinous material between lamellae and
irregularity in endplates is seen. As desiccation increases (grade III) flattening of
nucleus and isolated endplate tears can already be detected on MRI. On
radiographs, disc height is slightly diminished, and osteophyte formation and rim
calcification as well as sclerosis begin to be visible. Morphologically,
consolidated fibrous tissue in the nucleus area and loss of demarcation between
the nucleus and annulus is seen. Grade IV discs (disc narrowing) have
morphologically horizontal clefts parallel to the endplate and the nucleus can
reach into the outermost lamellae of the annulus (found on MRI as well). Plain
radiographs may also show Schmorl’s nodes, osteophytes and intranuclear
calcifications. Grade V is reached when endplates are almost in contact and the
disc has collapsed, while on radiographs big osteophytes are found and sclerosis
and calcification dominate. Zygapophyseal (facet) joint degeneration and
hypertrophy are secondary changes due to DD (de Schepper et al. 2010, Dunlop
et al. 1984, Varlotta et al. 2011) and can cause thickening of the ligamentum
flavum (Chokshi et al. 2010). Modic changes are vertebral subchondral bone
marrow changes visible on MRI, and they are claimed to be a specific phenotype
27
of DD (Albert et al. 2008). Modic changes will, however, be reviewed in other
degenerative findings (2.3.4).
The intervertebral disc is the first tissue to degenerate. It is challenging to
differentiate pathological DD from normal aging. (Urban & Roberts 2003). The
amount of water and proteoglycans in the disc differs between normal and
degenerated discs (grade II vs. grade III-V), but there were no significant
differences in the amount of water and proteoglycans between discs with different
degrees of degeneration (Benneker et al. 2005). In pathological DD 3% of the
disc height is lost annually, while in normal disc the height loss is 1% per year
(Adams & Dolan 2012). The endplate transfers load evenly to the disc and,
therefore, even minor endplate damage may initiate or enhance DD (Adams &
Roughley 2006). At the cellular level, disc-cell proliferation, cell death and
disorganization of annulus fibrosus lamellae occur (Roberts et al. 2006, Urban &
Roberts 2003). Several cytokines are involved in various mechanisms in the
degeneration process of the intervertebral disc by initiating the process, enhancing
the inflammation, and sensitizing the nerve endings. (Risbud & Shapiro 2014).
2.2.1 Prevalence
The prevalence of DD increases with age (Battie et al. 2004) and the distinctive
difference between aging-related and pathological DD is the age at which they
appear (Hadjipavlou et al. 2008, Taher et al. 2012). By the age of 16 years,
approximately every fifth adolescent has at least one degenerated disc (Urban &
Roberts 2003). Among males DD is more prevalent at a young age (Miller et al.
1988). A recent systematic review found widely varying prevalences, from 7% to
85%, among asymptomatic subjects and calculated a combined estimate of
prevalence of DD of 54% (Endean et al. 2011). The most commonly degenerated
levels are L4/5 and L5/S1 among adults, while disc height narrowing seems to be
most common at L4/5 (Battie et al. 2004, Teraguchi et al. 2014).
The prevalence among children, adolescents and young adults varies from 0
to 58% as shown in Table 1. Among 13-year-old Danes the prevalence at L5/S1
was 13% but much lower at other levels (L1/2 5%, L2/3 2%, L3/4 2% and L4/5
5%). A moderately degenerated disc was seen in 1.4% of the subjects. DD was
observed in 5.5% of all lumbar discs. (Kjaer et al. 2005b). In a small Finnish
case-control study with a 3-year follow-up, DD prevalence increased from 31% at
15 to 42% at 18 years. Advanced DD was reported in 11.5% and 19.4% of the
28
subjects at 15 and 18 years, respectively. The total percentage of degenerated
discs increased from 8.8% to 13%. (Erkintalo et al. 1995, Salminen et al. 1999).
Table 1. Studies presenting the prevalence of disc degeneration among children,
adolescents or young adult
Author and year
Age group
% of females
Prevalence of DD
N
Paajanen et al. 1989
19–21 y
0
LBP: 57%
LBP: 75
nLBP: 35%
nLBP: 34
Erkintalo et al. 1995
15 y and 18 y
LBP: 56 and
LBP: 42% and 58%
LBP and nLBP:
Salo et al. 1995
Paajanen et al. 1997
nLBP: 53
nLBP: 19% and 26%
78 and 62
0–14 y
56
19%
81
10–14 y and
43
LBP: 0% and 47%
10 and 70
15–19 y
nLBP: 10% and 26%
Kjaer et al. 2005a
12–14 y
53
21%
Hangai et al. 2009
18–24 y
24
42%
439
308 athl,
71 n-athl
Samartzis et al. 2011
13–20 y
54
35%
83
DD = disc degeneration; LBP = low back pain; nLBP = no low back pain; athl = athlete; n-athl = no athlete
2.2.2 Risk factors
DD has a complex multifactorial etiology (Hadjipavlou et al. 2008). Besides
aging, the most important risk factors for DD are factors related to nutrient supply
to the intervertebral disc, biomechanical factors, obesity, smoking, and genetics.
Besides these risk factors, a longitudinal study has found radial tears as a risk
factor for the progression of lumbar DD (Sharma et al. 2009), while in another
study herniations at the baseline and working in night shifts were risk factors of
DD (Elfering et al. 2002).
Disturbed nutrient supply
The failure of nutrient supply into the intervertebral disc decreases oxygen and
glucose levels, and increases acidity in the disc, potentially affecting the ability of
the disc cells to maintain and synthesize their extracellular matrix (Urban &
Roberts 2003, Urban et al. 2004). Due to the long distance of diffusion of
nutrients to the disc center, this is the site where the degenerative changes first
occur (Grunhagen et al. 2006). The nutrition supply of the disc can be affected
29
negatively by calcification of the endplates, which has been speculated to take
place due to the diminished nutrition into the endplate (Grunhagen et al. 2006,
Hadjipavlou et al. 2008, Roberts et al. 2006, Urban & Roberts 2003). Poor blood
supply due to atherosclerosis (Kauppila 2009) and high low-density lipoprotein
serum concentration (Hangai et al. 2008) has been linked to the development of
DD. However, recent studies have suggested that the metabolite transport through
the endplate increases with age suggesting a less important role for impaired
nutrition in the initiation of DD (Adams & Dolan 2012).
Biomechanical factors
Biomechanical factors include the factors that increase the mechanical stress of
the disc. The intervertebral disc is designed to sustain compression forces and
compression actually enhances the turnover of the extracellular matrix. (Iatridis et
al. 2006, Setton & Chen 2006). Endplates, however, are much more vulnerable to
compression. Endplate fractures can precipitate DD by several mechanisms.
(Hadjipavlou et al. 2008). There is no clear evidence of an association of
occupational loading or leisure time loading with DD (Battie et al. 2009, Hassett
et al. 2003), but several studies among athletes, especially in power sports, have
found an association between high level physical activity and DD (Hangai et al.
2009, Ong et al. 2003, Sward et al. 1991a, Videman et al. 1997). Moreover,
inactivity has been found to be associated with deterioration of DD in a
longitudinal study of asymptomatic adults (Elfering et al. 2002).
Obesity
Obesity is defined as body mass index (BMI) at least 30kg/m2 in adults (Cole et
al. 2000). In the literature, there is controversy about the role of obesity in lumbar
DD. Some have even found obesity to have a beneficial effect on lumbar discs
(Videman et al. 2010), while others have found obesity to be associated with
higher likelihood of lumbar DD (Liuke et al. 2005, Samartzis et al. 2011,
Samartzis et al. 2012). The possible mechanisms how obesity may influence
intervertebral disc integrity include mechanical compression, low-grade
inflammation, atherosclerosis, poor nutrient supply to the intervertebral disc, and
gene-environment interaction (Samartzis et al. 2013). In a Japanese populationbased cohort, obesity was associated with moderate/severe degree of lumbar DD
among adults (Teraguchi et al. 2014). Moreover, in a population-based cross30
sectional study of Southern Chinese juveniles (13- to 20-year-olds), overweight
and obesity were associated with overall lumbar DD score (Samartzis et al. 2011).
Smoking
In twins, smoking was weakly associated with DD. DD was classified
qualitatively which may not be an accurate method to detect the differences
among adult population due to existing age-related degenerative changes in the
disc (Battie et al. 1991). In the same twin population with a 5-year follow-up
smoking at the time of the follow-up was related with DD (Videman et al. 2008b).
In experimental models, nicotine seems to have an adverse dose- and timedependent effect on cell proliferation and extracellular matrix synthesis of the
intervertebral disc (Akmal et al. 2004, Oda et al. 2004) Smoking causes anoxia
and constriction of arterioles, which may affect the initiation of DD. Moreover,
nicotine has a toxic effect on the disc by inhibiting and down-regulating cell
proliferation and collagen genes (Hadjipavlou et al. 2008).
Genetics
Among adult twins, 30-75% of the variance in lumbar DD can be explained by
genetic influence (Näkki et al. 2014). In a 10-year follow-up study of adult twins
from the UK and Australia, signal intensity on MRI was heritable mainly in the
youngest age group (32- to 49-year-olds) (Williams et al. 2011). A recent
systematic review found only six genes with a moderate level of evidence in
lumbar DD (Eskola et al. 2012). The dynamic epigenome has been suggested as a
mechanism for gene-environmental interaction (Eskola et al. 2014).
2.2.3 Clinical relevance
Although DD is common in asymptomatic adult subjects (Boden et al. 1990),
there is growing data supporting the association of DD and LBP (Samartzis et al.
2013, Teraguchi et al. 2014). Instability may be a consequence of DD (Adams &
Dolan 2012, Fujiwara et al. 2000, Inoue & Espinoza Orias 2011, Lotz & Ulrich
2006) due to the slackening of spinal ligaments and zygapophyseal joint
osteoarthritis, which in turn increases the formation of osteophytes (Adams &
Dolan 2012). A recent systematic review found an odds ratio of 2.5 between
31
lumbar DD and LBP; however, no clear proof that LBP is attributable to DD has
been obtained among adults (Endean et al. 2011). In adolescence and early
adulthood, DD seems to be associated with LBP more strongly than later in
adulthood (Kjaer et al. 2005b, Salminen et al. 1999, Samartzis et al. 2011).
However, a new LBP episode does not coincide with new MRI changes (Carragee
et al. 2006, Carragee et al. 2005). A mild degree of DD has been claimed not to
cause symptoms (Lotz et al. 2012). On the other hand, a moderate degree of DD
is associated with duration of LBP (Borenstein et al. 2001). Among adolescents
and young adults LBP was associated with a higher number of degenerated
lumbar discs compared to non-LBP subjects (Erkintalo et al. 1995, Hangai et al.
2009). Moreover, in a Finnish study DD in adolescence (15-year-olds) was
associated with persistent recurrent or continuous LBP in young adulthood more
strongly than DD at 18 years (Salminen et al. 1999). A degenerated disc can cause
LBP by causing extra stress on other spinal tissues (i.e., zygapophyseal joints etc.)
and compression of the nerve roots (Hughes et al. 2012). Extra stress is caused by
increased segmental motion, especially torsional instability, as degeneration
progresses (Inoue & Espinoza Orias 2011).
2.3
Other degenerative findings
Other degenerative findings in the current thesis include disc contour changes
(bulging and herniation), annular tears (radial tear and high intensity zone [HIZ]
lesion), endplate changes (Schmorl’s nodes and Modic changes) and
spondylolytic defects (spondylolysis/-listhesis).
2.3.1 Disc contour changes
Disc contour changes refer to displacement of the disc beyond the edges of the
adjacent vertebral bodies. Bulging refers to disc displacement of more than 50%
of the disc’s circumference, whereas herniation refers to disc contour changes of
less than 50% of the disc’s circumference (Fardon et al. 2001). The migration of
the nucleus pulposus into the periphery of the annulus fibrosus through radial
fissure causes herniation (Adams & Dolan 2012) , which can either avulse the
endplate junction or rupture the annulus fibrosus (Rajasekaran et al. 2013,
Schmid et al. 2004). Aging, smoking and severity of DD are associated with
bulging and herniation (Boden et al. 1990, Cheung et al. 2009, Kelsey et al. 1984,
Videman et al. 2008b, Waris et al. 2007, Zou et al. 2009).
32
Herniations and bulges are typically found in the lower lumbar spine among
all age groups. (Adams & Dolan 2012, Battie et al. 2004, Kanna et al. 2014,
Kjaer et al. 2005b, Zou et al. 2009). In the literature review the prevalence of
bulging ranges from 10% to 81% (Battie et al. 2004). In a recent systematic
review, 4-76% of adults had a protrusion, while 0-24% had an extrusion (Endean
et al. 2011). No significant differences have been found between symptomatic
and asymptomatic subjects (Battie et al. 2004, Endean et al. 2011). The
prevalence of herniations did not change in a 5-year follow-up among adults
(Boos et al. 2002b) . Table 2 presents the prevalences of disc contour changes
among adolescents and young adults. No extrusions were observed among 13year-old children (Kjaer et al. 2005b).
2.3.2 Annular tears
Annular tear is defined as disruption of annular fibers from the nucleus toward the
periphery of the annulus (Fardon et al. 2001). Annular tears include radial,
peripheral and circumferential tears (Sharma et al. 2009). Radial tears are seen in
degenerated discs and they are not regarded as belonging to the normal aging
process of the disc (Hadjipavlou et al. 2008). A dorsally displaced nucleus
pulposus in radial tear can at a later stage occur as HIZ lesion in the posterior part
of the disc as a high intense body. In two small-scale (n < 80 subjects)
longitudinal studies, the progression of DD in discs with annular tear was
inconsistent (Farshad-Amacker et al. 2014, Sharma et al. 2009). Histologically,
nerves were found in cadaveric adults almost twice as often in discs with a radial
tear compared to normal discs (44% vs. 25%) (Fields et al. 2014).
The prevalence of radial tears increases with age (Cheung et al. 2009, Stadnik
et al. 1998). Among adults, the prevalence of radial tears varies between 17% and
76% (Cheung et al. 2009, Kim et al. 2013, Kjaer et al. 2005a), while among
young adults (less than 30 years) the prevalence was 10% (Cheung et al. 2009).
Table 2 presents the prevalences of radial tears among adolescents and young
adults. Similarly as in adults, the prevalence of radial tears increases from cranial
to caudal direction (Jarvik et al. 2001, Kjaer et al. 2005b) with no gender
difference (Kjaer et al. 2005b).
HIZ lesion seems to be present only in degenerated discs (Aprill & Bogduk
1992, Lam et al. 2000, Rankine et al. 1999). Histologically similar findings as in
DD are found (Peng et al. 2006). The inflammatory reaction of a HIZ lesion
seems to enhance healing of the disc (Dongfeng et al. 2011). In a longitudinal
33
study, HIZ lesions neither resolved nor improved over time (Mitra et al. 2004).
Among adults, HIZ lesion is present in 6 -56% of subjects and most of the
changes were found at the two lowest levels (Aprill & Bogduk 1992, Battie et al.
2004, Endean et al. 2011, Kjaer et al. 2005a). The prevalence of HIZ lesion is
highest in subjects in their thirties, being 24% in subjects with LBP (Park et al.
2007). Table 2 presents the prevalences of HIZ lesions among adolescents and
young adults. In a Danish study with a population-based cohort of 13-year-old
subjects, the HIZ lesion occurred more often at the two lowest lumbar levels
(Kjaer et al. 2005b).
2.3.3 Endplate changes
Endplate changes are defined as reactive vertebral body changes associated with
disc inflammation and DD or displacement of the disc through the endplate into
the centrum of the vertebral body i.e. Schmorl’s node (Fardon et al. 2001). Modic
changes are discussed in chapter 2.3.4. The cause of Schmorl’s nodes is under
debate (Kyere et al. 2012). Typically Schmorl’s nodes occur in the middle part of
the vertebral body (Dar et al. 2009, Wang et al. 2012) and adjacent to a
degenerated disc (Kyere et al. 2012, Mok et al. 2010, Williams et al. 2007). The
prevalence is higher in males and axial loading may contribute to the
development of Schmorl’s nodes (Kyere et al. 2012, Mok et al. 2010). Only a
fraction of defects found in cadaveric samples can be seen on MRI (Adams &
Dolan 2012).
Battié et al. (Battie et al. 2004) found the prevalence of the Schmorl’s nodes
to vary from 6 to 79% with predominance at upper lumbar levels (L1/2, L2/3 and
L3/4) and this observation has been supported by other studies (Mok et al. 2010,
Williams et al. 2007). In a large Southern Chinese population MRI study, the
prevalence was 16.4% in the whole study population, while among adolescents
(11- to 20-year-olds) it was ca. 10% (Mok et al. 2010). Schmorl’s nodes seem to
be rare in children under 10 years (Hamanishi et al. 1994), however,
predominance at upper lumbar levels was similar as in adults (Kjaer et al. 2005b).
Table 2 presents the prevalences of Schmorl’s nodes among adolescents and
young adults.
34
2.3.4 Modic changes
Modic changes are closely associated with DD (Chung et al. 2004, Jensen et al.
2010, Karchevsky et al. 2005) and are claimed to be a specific phenotype of DD
(Albert et al. 2008). Modic changes are classified as type I lesions (low T1- and
high T2-signals in MRI), which are associated with vascular granulation tissue
within the bone marrow indicating an ongoing degeneration; type II lesions (high
T1- and T2-signals) representing fatty replacement of the bone marrow; and type
III lesions (low T1- and T2-signals) with endplate sclerosis (Fardon et al. 2001,
Modic et al. 1988). Modic changes are typically larger in the lower lumbar spine
than in the upper spine (Jensen et al. 2009). Modic changes can change from one
to another, but usually first appears as type I. Changes can convert from type I to
type II or III and the conversion may take a long time. Whether Modic changes
normalize or convert into the other type remains unknown. (Albert et al. 2008,
Albert & Manniche 2007, Hutton et al. 2011, Jensen et al. 2009). Modic changes
are associated with age (Jensen et al. 2008).
In a systematic review, the mean prevalence of Modic changes was 36%
(range 0-90%) with no gender difference (Jensen et al. 2008). Type II changes
seem to be slightly more prevalent than type I changes, while type III changes are
more rare (Jensen et al. 2008, Karchevsky et al. 2005). Modic changes are rare
among adolescents (Table 2).
Modic changes develop typically after disc herniation around the affected
disc (Albert & Manniche 2007, Jensen et al. 2010). The determinants of Modic
changes have been evaluated among adults in cross-sectional designs and include
hard physical work in combination with overweight or smoking (Leboeuf-Yde et
al. 2008), and obesity (Kuisma et al. 2008). The endplate changes have been
associated with smoking and, in fact, endplate changes are observed more often in
current and ex-smokers (Jarvik et al. 2001).
2.3.5 Spondylolytic defects
Spondylolytic defects include both spondylolysis and spondylolisthesis.
Spondylolysis is an anatomic defect in the vertebral pars interarticularis while
spondylolisthesis refers to displacement of a vertebral body onto one below it
(Kalichman et al. 2009c). Spondylolysis is found most reliably by computer
tomography, however, MRI has been found to be an effective and reliable firstline imaging modality for diagnosis of spondylolysis among adolescents and
35
young adults. In MRI, the challenge is to distinguish between partial and
incomplete fractures as well as determine the progress of healing (Campbell et al.
2005, Leone et al. 2010). Spondylolisthesis has several etiologies; however,
spondylolysis seems to be the most common ones. Isthmic spondylolisthesis is
associated with spondylolysis and usually occurs at presacral level while
degenerative spondylolisthesis occurs most often at the two lowest lumbar levels.
Individuals with spondylolysis have been estimated to suffer at least one
significant LBP episode. (Kalichman et al. 2009c). Moreover, lumbar disc
spondylolytic defects are associated with age, but not linearly (Hamanishi et al.
1994, Leone et al. 2010, Tsirikos & Garrido 2010) . The prevalence of
degenerative spondylolisthesis increases naturally with DD (Jarvik et al. 2001,
Kalichman et al. 2009a, Kalichman et al. 2009c). Sports including spine
hyperextension and high impact of the spine may cause extra stress on the lumbar
spine during the growth spurt and lead to detrimental changes in the lamina of the
lumbar vertebrae (Kujala et al. 1996), which can together increase the risk of
spondylolysis and degenerative spondylolisthesis (Kalichman et al. 2009c, Leone
et al. 2010, Tsirikos & Garrido 2010). Inherited predisposition has been reported
for the spondylolysis, and congenital dysplasia of the pars interarticularis may
contribute to the development of fatigue fracture (Tsirikos & Garrido 2010).
The prevalence of lumbar spondylolysis was 7-9.2%. Spondylolisthesis due
to degeneration is more frequent in females than males (21.3% vs. 7.7%,
respectively). (Brooks et al. 2010, Kalichman et al. 2009c). The prevalence of
spondylolysis increases with age until adulthood and develops typically in
childhood after learning to walk (Leone et al. 2010, Tsirikos & Garrido 2010).
Degenerative spondylolisthesis is by definition age-dependent, similarly to DD
(Jarvik et al. 2001, Kalichman et al. 2009c). Spondylolytic defects are most
commonly found in the lower lumbar spine (Kalichman et al. 2009c, Ladenhauf
et al. 2013, Leone et al. 2010, Tsirikos & Garrido 2010). Table 2 presents the
prevalences of spondylolytic defects among adolescents.
In a large Finnish cross-sectional study, spondylolisthesis was associated with
high occupational loading of the low back (increased shear forces) and more than
two pregnancies (increased lordosis and shear forces) among females (Virta et al.
1992). Moreover, spondylolisthesis is more likely to progress among females
(Tsirikos & Garrido 2010).
36
Table 2. Prevalence of specific MRI findings among adolescents.
Author and year
MRI findings
Age group
% of females
Prevalence
N
Tertti et al. 1991*
Bulge/Protrusion
14 y
56.4
12%
78
Erkintalo et al. 1995
Protrusion
Protrusion
15 y
18 y
56.4
53.2
10%
21%
78
62
Kjaer et al. 2005a
Bulge
Protrusion
Extrusion
Radial tear
HIZ lesion
Schmorl’s node
Modic change**
Spondylolisthesis#
13 y
53.3
14%
3%
0%
7%
5%
3%
0.5%
3%
439
Park et al. 2007
HIZ lesion
10-19 y
20-29 y
n/a
n/a
5%
14%
n/a
n/a
13-20 y
54.2
23%
83
Bulge/Extrusion
HIZ lesion
4%
Schmorl’s node
7%
1%
Modic change
* = Same author as Erkintalo; ** = Type I; # = with or without spondylolysis; HIZ = high intensity zone; n/a
Samartzis et al. 2011
= not available
2.3.6 Clinical relevance
Although herniated disc, especially protrusion, is common in asymptomatic adults
(Boden et al. 1990, Borenstein et al. 2001, Jensen et al. 1994, Kjaer et al. 2005a),
they are claimed to be associated with LBP in adult subjects (Endean et al. 2011)
- especially extrusions occur predominantly in symptomatic subjects (Jarvik et al.
2001, Weishaupt et al. 1998). Herniations are typically resorbed over time; the
larger the herniation the better they are resorbed (Jensen et al. 2006, Kim et al.
2013).
In the population-based cohort study of 13-year-old Danish children,
protrusions were associated with seeking care from a health care professional for
LBP, especially among girls (Kjaer et al. 2005b). In a small case-control study of
14-year-old subjects, the prevalence of protrusions (also including bulges, no
axial images available) was 12% and was higher among girls with LBP than
asymptomatic subjects (Tertti et al. 1991). Of the LBP subjects, 19% had a
protrusion at 15 years, compared to none of the asymptomatic subjects (Erkintalo
37
et al. 1995). Moreover, in the same study population, subjects with a protrusion at
15 and 18 years had increased risk of recurrent or continuous LBP at 23 years
(RR 6.8 and 4.6, respectively) (Salminen et al. 1999).
There is conflicting data whether or not the prevalence of radial tears differs
between asymptomatic and symptomatic subjects (Cheung et al. 2009, Hancock
et al. 2012, Jarvik et al. 2001, Kjaer et al. 2005a, Videman & Nurminen 2004).
Some studies have shown an association between HIZ lesion and LBP (Aprill &
Bogduk 1992, Endean et al. 2011, Lam et al. 2000). On the other hand, one third
of the asymptomatic adults had a HIZ lesion (Weishaupt et al. 1998), and the
change in the HIZ lesion over time did not correlate with change in subjects’
symptoms (Mitra et al. 2004/11). Therefore, a recent review concluded that more
studies are needed to elucidate the significance of HIZ lesions in LBP among
adults (Khan et al. 2014). Interestingly, HIZ lesions had a brighter signal on MRI
among adult subjects with LBP (Liu et al. 2014). HIZ lesions were associated
with LBP (seeking care from health care professionals) among 13-year-old
females (Kjaer et al. 2005b).
The role of Schmorl’s nodes in LBP is contradictory (Kyere et al. 2012,
Williams et al. 2007). In the population-based study of Danish 13-year-old
children, endplate changes of the upper lumbar spine were found to be associated
with LBP during the last month and seeking care; however, the endplate changes
included Schmorl’s nodes and endplate defects (small cracks of endplate) (Kjaer
et al. 2005b).
Modic changes have been found more frequently in subjects with LBP
(Adams & Dolan 2012, Albert et al. 2008, Hancock et al. 2012, Jensen et al.
2008, Kuisma et al. 2007). Modic type I change seems to be more painful than
other Modic types (Jensen et al. 2014, Jensen et al. 2012, Jensen et al. 2008,
Kjaer et al. 2006, Kuisma et al. 2007), especially at L5/S1 level (Kuisma et al.
2007). Moreover, in a histological study the nerve density was higher in type I
Modic changes compared to other types of endplate changes (Fields et al. 2014).
Spondylolysis and spondylolisthesis are common in asymptomatic subjects
(Kalichman et al. 2009c, Leone et al. 2010). Furthermore, the degree of the
radiological slip does not correlate well with symptoms (Leone et al. 2010).
Spondylolysis and spondylolisthesis have been suggested to be one of the major
causes of LBP among children over 10 years (Faingold et al. 2004, Leone et al.
2010). Kjaer et al. (Kjaer et al. 2005b) reported an association of spondylolytic
defects with care seeking among 13-year-old Danish children; the association was
found especially among females.
38
3
Purpose of the study
The study questions were formulated as follows:
1.
What is the prevalence of intervertebral DD, disc contour changes, annular tears
(radial tears and HIZ lesions), Schmorl’s nodes, endplate changes and
spondylolytic defects on lumbar MRI among young Finnish adults?
Hypothesis: DD is common but other degenerative MRI findings are less
common.
2.
Are degenerative lumbar MRI findings associated with low back symptoms
among young Finnish adults?
Hypothesis: Lumbar DD, herniations, radial tears, Modic changes and
spondylolytic defects are associated with low back symptom severity.
3.
Are lifestyle factors such as smoking, BMI and physical activity among 16and 19-year-olds associated with lumbar intervertebral DD on MRI at 21
years?
Hypothesis: High BMI, smoking and high level of physical activity are
associated with lumbar DD among young adults.
4.
Are measures of abdominal adiposity such as waist circumference (WC),
body fat percentage and midsagittal abdominal MRI measures associated
with lumbar intervertebral DD?
Hypothesis: Abdominal adiposity is associated with lumbar DD among 21year-olds.
39
40
4
Material and methods
4.1
Study population
The study population was a subpopulation of the 1986 Northern Finland Birth
Cohort (NFBC 1986) (Järvelin et al. 1993). The NFBC 1986 consists of 9,479
children with an expected date of birth between July 1, 1985 and June 30, 1986 in
the two northernmost provinces of Finland, i.e., Oulu and Lapland. (Fig. 7) The
members of this large birth cohort were recruited before birth and since then,
numerous data collections have been conducted. The first health examination was
conducted when the children were 7 years and a comprehensive follow-up survey
of health and well-being and a health examination were conducted between May
2001 and April 2002 when the cohort members were 15 to 16 years old (hereafter
named the 16-year follow-up). At the 16-year follow-up, all living members of
the cohort whose addresses were known (n = 9,215) received a postal
questionnaire (Appendix) and altogether 6,795 adolescents (74%) responded and
participated in the health examination. Weight, height and WC were measured,
and data on smoking, physical activity level and sedentary behavior were
gathered with a questionnaire. A subcohort of NFBC 1986, the Oulu Back Study
(OBS) was collected between September 2003 and January 2004, when the cohort
members were 17 to 18 years (hereafter named the 18-year follow-up). All
subjects of OBS were living within a 100 km radius of the city of Oulu (n =
2,969). Of them 801 subjects had not participated in the 16-year follow-up. A
postal survey, focused on lifestyle factors, work exposure and musculoskeletal
health, was sent to the subjects. The respondents (n=1,987, 67%) were invited to a
physical examination at the Oulu Deaconess Institute between summer 2005 and
winter 2006 (hereafter named the 19-year follow-up) in which height, weight, and
WC were measured by a physiotherapist. In the 18-year questionnaire the lifestyle
factors and musculoskeletal health from the 16-year follow-up were repeated. Of
the respondents, 278 subjects had not participated in the 16-year follow-up. A
total of 874 subjects (44% of those invited) attended the 19-year follow-up, which
included a questionnaire and physical examination. They were invited to a lumbar
spine MRI, which was performed at a mean age of 21 years (range 20 to 22 years)
between spring 2007 and summer 2008 (hereafter named the 21-year follow-up).
Finally, 558 subjects (64% of those invited) attended MRI and responded to a
short questionnaire on musculoskeletal health.
41
42
November 2005 and February 2008 at a mean age of 21 years. LBP = low back pain.
examination at 19 years of age were invited to lumbar magnetic resonance imaging (MRI), which was performed between
lived within 100 km of the city of Oulu in 2003 (n=2,940) were included in the study population. Those who participated in physical
Fig. 7. Flow chart of the study population. The members of the 1986 Northern Finland Birth Cohort (NFBC 1986; n=9,479) who
4.2
Magnetic resonance imaging
4.2.1 Protocols of anatomical imaging
The MRI scans were obtained using a 1.5 Tesla scanner (Signa, General Electric,
Milwaukee, WI, USA) and phased array spine coil (USA Instruments, Aurora OH,
USA) with the imaging protocol of sagittal T1-weighted (440/14 [repetition time
milliseconds/echo time milliseconds]) spin echo, sagittal T2-weighted (3960/116) fast
spin echo, and axial T2-weighted (5160/107) fast spin echo of the entire lumbar spine.
The number of excitations for T1-weighted images was one and for T2-weighted
images four. Echo train length for axial and sagittal images was 26 and 29,
respectively. The image matrix was 256 x 224 for T1-weighted sagittal images, 448 x
224 for T2-weighted sagittal images, and 256 x 256 for T2-weighted axial images.
The field of view was 28 x 28 cm for sagittal images and 18 x 18 for axial images.
The slice thickness was 4 mm with 1-mm interslice gap.
4.2.2 Definition of magnetic resonance imaging findings
Disc degeneration (I-V)
The degree of DD was graded using T2-weighted images on the modified Pfirrmann
classification (Pfirrmann et al. 2001): grade 1 (normal shape, no horizontal bands,
distinction of nucleus and annulus is clear), grade 2 (nonhomogeneous shape with
horizontal bands, some blurring between nucleus and annulus), grade 3
(nonhomogeneous shape with blurring between nucleus and annulus, annulus shape
still recognizable), grade 4 (nonhomogeneous shape with hypointensity, annulus
shape not intact and distinction between nucleus and annulus impossible, disc height
usually decreased), and grade 5 (same as grade 4 but collapsed disc space) (Fig 8).
The Pfirrmann classification was modified, as the hyperintensity or isointensity of
intervertebral disc to cerebrospinal fluid ratios were not used as criteria for grades 1
through 3, because the cerebrospinal fluid was always hyperintense to the discs with
the MR sequences used. Grades 1 to 2 were classified as normal discs. The severity of
the DD increased with each increasing grade. Thus, grade 3 presented mild DD, grade
4 moderate DD and grade 5 severe DD. The intra- and interrater reliability of this
classification has been found to be at least good, i.e., kappa values were higher
than 0.60 (Carrino et al. 2009, Pfirrmann et al. 2001).
43
Fig. 8. Grading system for the assessment for lumbar disc degeneration according to
Pfirrmann. Figures from A to E correspond to grades from 1 to 5, respectively
(Pfirrmann et al 2001, published by permission of Wolfer Kluwer Health).
Annular tears and disc contour changes (I-III)
A radial tear in the intervertebral disc was defined as a hyperintense linear area from
the nucleus pulposus towards the outer annulus fibrosus on T2-weighted images
(Fardon et al. 2001, Osti & Fraser 1992, Yu et al. 1988, Yu et al. 1989).
HIZ lesions were defined as a high intensity signal located in the substance of the
posterior annulus fibrosus, which is brighter than the nucleus pulposus on T2weighted images (Fig. 9) (Aprill & Bogduk 1992).
44
Bulging was defined as displacement of the disc material greater than 50% of the
disc circumference (Fig. 10). Disc herniation was defined as a disc displacement of
less than 50% of the disc circumference, and subcategorized either as protrusion or
extrusion. Herniation was defined as protrusion if the greatest distance between the
edges of the disc material beyond the disc space was less than the distance between
the edges of the base in any of the same planes (Fig. 11). Extrusion was defined as
any one distance, in at least one plane, between the edges of the disc material beyond
the disc space was greater than the distance between the edges of the base (Fig. 11
and 12). The total number of herniations (protrusions and extrusions combined) and
the number of extrusions were recorded as 2 different variables. (Fardon et al. 2001).
Fig. 9. Radial tear and high intensity zone (HIZ) in sagittal magnetic resonance imaging at
L3/4 and L4/5 levels, respectively.
45
Fig. 10. Bulging in magnetic resonance imaging at L5/S1 level. Axial (left) and sagittal
(right) images. Bulging is a displacement of the disc material greater than 50% of the disc
circumference.
Fig. 11. Herniations (different types) in sagittal magnetic resonance imaging (right).
Protrusions (different sizes) at L3/4, L4/5 and L5/S1 levels. Axial (left) image at L5/S1
level. The finding was evaluated as protrusion if the greatest distance between the edges
of the disc material beyond the disc space was less than the distance between the edges
of the base in any of the same planes, and as extrusion if any one distance, in at least one
plane, between the edges of the disc material beyond the disc space was greater than the
distance between the edges of the base. Herniation at L5/S1 level is a borderline finding,
which could be defined as protrusion or extrusion. In this study two musculoskeletal
radiologists evaluated it as protrusion.
46
Fig. 12. Extrusion in magnetic resonance imaging at L5/S1 level. Axial (left) and
sagittal (right) images. Extrusion was defined as any one distance, in at least one plane,
between the edges of the disc material beyond the disc space being greater than the
distance between the edges of the base.
Modic changes (I-III)
Modic changes were graded on the basis of T1- and T2-weighted images as absent,
Type I (hypointense in T1-weighted sequences and hyperintense in T2-weighted
sequences) (Fig. 13), Type II (hyperintense in both sequences) (Fig. 14) or Type III
(hypointense in both sequences) (de Roos et al. 1987, Modic et al. 1988).
47
Fig. 13. Type I Modic change in T1- (left; hypointense) and T2-weighted (right;
hyperintense) sagittal magnetic resonance imaging at L4/5 level.
Fig. 14. Type II Modic change in T1- (left; hyperintense) and T2-weighted (right;
hyperintense) sagittal magnetic resonance imaging at L4/5 level.
Schmorl’s node and spondylolytic defect (III)
Schmorl’s nodes were defined as vertical intervertebral disc protrusion through the
endplate (Fardon et al. 2001, Hamanishi et al. 1994, Resnick & Niwayama 1978)
(Fig. 15).
48
Spondylolytic defects were evaluated from each pars interarticularis using sagittal T2weighted images. Both healed bony changes such as steps in the cortex, and sclerosis
of bone and true uni- or bilateral fractures were classified as spondylolytic defects.
(Campbell et al. 2005) (Fig. 16).
Fig. 15. Different types of Schmorl’s nodes on T1 (left) and T2 (right) sagittal images at
L1, L2 and L5 upper endplates.
49
Fig. 16. Spondylolysis/-listhesis on two images at L5/S1 level. Spondylolisthesis is
shown in midsagittal image (left) and spondylolysis in a more lateral sagittal image
(right).
4.2.3 MRI Adiposity measurements (V)
Four adiposity diameters were measured in the midsagittal slice from T2-weighted
images at the level of the lumbar spine: abdominal diameter (AD, cm), sagittal
diameter (SAD, cm), ventral subcutaneous thickness (VST, cm), and dorsal
subcutaneous thickness (DST, cm) (Fig. 2). We chose the MRI image for measuring
the adiposity diameters according to the clearest image of spinal processes and widest
cerebrospinal fluid space. The SAD and AD were defined as the narrowest diameter
from the abdominal subcutaneous fascia to the dorsal subcutaneous fascia and the
anterior border of the vertebral body, respectively, at the level of L3 or L4 vertebral
body. The VST, presenting subcutaneous adipose tissue, was measured at the same
level as SAD and AD. DST was measured perpendicular to the skin at the presacral
level, from the subcutaneous fat extending to the subcutaneous fascia between the
spinal processes of L5 and S1 (Fig. 17).
50
Fig. 17. Midsagittal image of the lumbar spine showing the level of measurement: the
abdominal diameter (AD), sagittal diameter (SAD), ventral subcutaneous thickness
(VST), and dorsal subcutaneous thickness (DST). AA, SAD, and VST are not at the
same level in the image due to technical reasons, but in the study they were measured
from the same level.
4.3
Determinants
4.3.1 Low back symptoms and functional limitations (II-III)
The questionnaire was part of a larger questionnaire filled in by the OBS subjects at
the 18-year, 19-year and 21-year follow-ups (Appendix). The questions used in the
51
current study included questions about LBP history, severity and the limitations in
function and participation. LBP history was evaluated with questions about the sixmonth prevalence of LBP and frequency of LBP episodes lasting at least 2 weeks.
LBP severity was evaluated with intensity of LBP on a 0 to 10 Numerical Rating
Scale and with two additional questions: 'Have you consulted a physician because of
LBP?' and 'Have you needed pain medication because of LBP?'. For the purpose of
evaluating functional limitation the questions 'Has your LBP restricted your daily
activities?' and 'Has LBP restricted your participation in sports?' were enquired. The
questions about LBP were supported by a drawing in which a shaded area between
the lower ribs and gluteal folds indicated the low back region for the participants. The
range of low back symptom and functional limitation score could theoretically vary
from 0 (no symptoms) to 7 (maximum symptoms).
4.3.2 Smoking (IV)
Pack-years of smoking were used to evaluate the history of smoking among the
study subjects. The number of pack-years of smoking was calculated by
multiplying the number of packs of cigarettes smoked daily by years of smoking.
Fifteen cigarettes were considered as one pack. The subjects were categorized
into three groups based on the cumulative pack-years of smoking according to the
data at the 19-year follow-up. The groups were (1) non-smokers, (2) smokers with
0.01-3.99 pack-years of smoking, and (3) smokers with at least 4 pack-years of
smoking.
4.3.3 Physical activity (IV)
The amount of physical activity outside school hours separately for moderate-tovigorous and light physical activity was evaluated by asking 'How many hours a
week do you participate in a) brisk and b) light physical activity outside school
hours?' Moreover, the adolescents were asked about their daily time spent on
physically active commuting to and from school. The response alternatives (not at
all, less than 20 min, 20-39 min, 40-59 min, and at least 1 hour per day) were
multiplied by five (five school days a week) to correspond to 0, 1, 2.5, 3.75 and 5
hours of physical activity at each intensity level per week. A metabolic equivalent
(MET) intensity value of 3 for light physical activity, 5 METs for brisk physical
activity and 4 METs for commuting physical activity were used in calculations.
Thus, 2.5 hours per week of each physical activity level corresponds to 30 MET
52
hours per week (2.5h x 3 MET + 2.5h x 4 MET + 2.5h x 5 MET). The mean value
of physical activity as MET hours per week at the 16-year and 19-year follow-ups
was used.
4.4
Anthropometrics
Anthropometrics data were available at the 16-year and 19-year follow-ups. We
calculated the difference of height, weight, BMI, and WC at both 16 and 19 years. No
anthropometric data were available at the 21-year follow-up.
4.4.1 Weight, height and Body mass index (IV)
Height and weight were measured at the physical examinations at the 16-year and
19-year follow-ups. We calculated body mass index (BMI) as weight/height2
(kg/m2) at both ages. Measured weight data was missing for eight subjects at the
16-year follow-up and was replaced by a self-reported value.
4.4.2 Waist circumference (IV-V)
WC was measured halfway between the iliac crest and the lowest rib at the 16year and 19-year follow-ups by a trained research assistant.
4.4.3 Bioelectrical impedance analyses (V)
The percentage of body fat was assessed using bioelectrical impedance (InBody,
Mega Electronics Ltd, Kuopio, Finland). The bioelectrical impedance method
measures body composition by sending a safe, low electrical current through the
body. The current passes freely through the fluids contained in muscle tissue, but
encounters difficulty/resistance when it passes through fat tissue. This resistance of
the fat tissue to the current is termed ‘bioelectrical impedance’. The resistance
difference between conductors provides the measure of the adipose tissue content of
the body. Body fat percentage was measured at the 19-year follow-up.
53
4.5
Other factors (V)
In studies I-III, the socioeconomic status of the parents of the subjects at the age
of 16 years was used to characterize the study population (I) or as a confounding
factor (II-III).
In study V, the analyses were adjusted for postural, workload, and activity
variables. These variables included heavy physical work, driving a motor vehicle,
lifting heavy objects at work, previous injury, socioeconomic status and education
(Table 3). Additional postural, workload, and activity factors (kneeling/squatting
at work, hands above shoulder level at work, awkward trunk postures, using
vibrating tool(s), sedentary work, standing or walking at work, and participation
in sports) were also considered, but they did not change the parameter estimates
and were thus omitted.
54
55
forearms, (7) Knees, (8) Ankles, feet (yes/no)
Student status
Vocational school, (4) Studying elsewhere
Current situation: (1) Not studying, (2) High school, (3)
(5) Other
White-collar worker, (3) Blue-collar worker, (4) Laborer,
Socioeconomic status Parents’ socioeconomic status: (1) Entrepreneur, (2)
Using vibrating tool(s) at work for 2 h/day
Manually lifting, carrying or pushing objects
weighing a maximum of 5 kg >2 times/min for 2
Lifting medium weight
objects at work
h/day (yes/no)
Sedentary work with limited walking (yes/no)
(3) Regularly
(1) Never, (2) Occasionally,
(yes/no)
Sedentary work
Participation in sports
Using vibrating tool(s)
h/day (yes/no)
consultation at any of these sites: (1) Head, (2) Neck,
(3) Shoulders, (4) Low back, (5) Elbows, (6) Wrists,
Hands above shoulder Work with hands above shoulder level for 1
level at work
Injuries other than a fracture requiring medical
Standing or walking for 5 h/day (yes/no)
Previous injury
work
(yes/no)
leaning forward without support for 1 h/day
Working standing or on one’s knees in a position
than 20 kg 10 times/day (yes/no)
Standing or walking at
postures
Kneeling or squatting for 1 h/day (yes/no)
work
Lifting heavy objects at Manually lifting, carrying or pushing objects heavier
for >3 months/year (yes/no)
Awkward trunk
Kneeling/squatting at
work
Very strenuous work involving lifting or carrying heavy
objects (digging, shoveling, hammering etc.) (yes/no)
Heavy physical work
Driving a motor vehicle Driving a car, tractor or other motor vehicle for 4 h/day
Phrase used in text
Definition
Phrase used in text
Definition
Variables not included in the final adjusted model
Variables included in the final adjusted model
socioeconomic status at 16 years).
Table 3. Variables checked for confounding in study V. Subjects responded to these questions at the age of 18 years (except
4.6
Statistical methods
The evaluation of selection bias was performed by comparing the MRI participants
with the rest of the OBS survey respondents (n=1,424) and the rest of the invited
subjects (n=311). The 95% confidence intervals for the prevalence of symptoms were
based on binomial distribution. The Chi square test and Fisher exact test were used in
the statistical analyses stratified by gender (I). To evaluate the association of DD (II)
and other MRI findings (III) with low back symptom and functional limitation
clusters, the prevalence of each degenerative finding at the 21-year follow-up,
together with their 95% confidence intervals (CIs), was compared between the
clusters. The Chi square test was used to test the differences of categorized sum score
of DD (II) and other MRI findings (III) in the low back symptom and functional
limitation clusters. The association of DD sum score with adiposity measures was
first inspected by comparing the mean adiposity measures between DD classes by the
use of 95% confidence intervals (CI) and one-way analysis of variance (ANOVA)
(IV). In studies II-V, we analyzed the inter-rater agreement of the DD for two
observers using kappa statistics. Values of >0.80 were considered very good, 0.61–
0.80 good, 0.41–0.60 moderate, 0.21–0.40 fair, and ≤0.20 poor for interrater
repeatability. (Altman 1999).
4.6.1 MRI measurements
In study I, three observers read the MRI images. One (medical student) evaluated DD
and Modic changes, while two more experienced observers (musculoskeletal
radiologist and physical medicine and rehabilitation physician) together evaluated
DD, Modic changes, annular tears and disc contour changes. The inter-rater
agreement in DD and Modic changes evaluation was performed with kappa statistics.
In studies II-V, two musculoskeletal radiologists, blinded to the subjects’ pain
status and each other’s evaluation, read all the degenerative imaging findings. All
discrepancies were reviewed through joint reading by the two radiologists.
One observer measured all obesity measurements on MRI (V), but 30 (5%)
randomly assigned subjects were measured by a musculoskeletal radiologist for
inter-rater reliability of abdominal measurements for two observers using
interclass coefficient correlation (ICC). The same thresholds (>0.80, 0.61–0.80,
0.41–0.60, 0.21–0.40 and ≤0.20) as in kappa statistics were used to evaluate the
interrater repeatability (V).
56
4.6.2 Latent class analysis
To form the natural clusters, i.e., individuals with similar profiles of low back
symptoms and functional limitations at the 18-, 19- and 21-year follow-ups, latent
class analysis (LCA) was used. Individuals in a cluster were similar (homogeneous,
locally independent) with respect to their symptom and functional limitation reports,
which were dichotomized (Table 4). Using the LCA method with conditional
independence assumption and Bayes’ theorem, each individual’s a posteriori
probability in each class was calculated, and they were then assigned to the latent
class cluster with the highest a posteriori probability. Bayesian information criterion
(BIC) and the Vuong-Lo-Mendell-Rubin Likelihood Ratio Test (LRT) (Muthén &
Muthén 2007, Nylund et al. 2007) were used as statistical diagnostic tools to
determine the appropriate number of clusters. Simulation studies suggest that the
model with the lowest value of BIC should be preferred. (Nylund et al. 2007). The
low p-value of LRT indicates that the estimated model with “n” clusters fits the data
better than the model with “n-1” clusters. The number of clusters was first determined
on the basis of the Likelihood Ratio Test (maximum clusters) and then checked for
compatibility with the BIC measure.
In addition, a sum score of DD was obtained by summing the DD scores at each
lumbar level. Normal discs (grades 1 and 2) were scored as 0, and with each higher
degree of DD, the score increased by one. Therefore, the sum score could
theoretically range from 0 to 15 for five lumbar discs. The idea of calculating the sum
score of DD is shown in Fig. 18. The sum score was categorized for three groups: no
DD, score from 1 to 3, and higher than 3 (II) and no DD, score from 1 to 2, and higher
than 2 (III).
In further analysis (II and III), the two most painful and the two least painful
clusters were combined (major symptom and minor symptom clusters, respectively)
to form three low back symptom clusters (response variable) to increase the power of
analysis. In study II, herniations (protrusions and extrusion combined), Modic
changes, radial tears, and spondylolytic defects were combined into a single variable
(other degenerative findings) to evaluate the association of DD severity (at least one
grade 3 DD [mild] or grade 4 DD [moderate]) with pain cluster status in the
multinomial logistic regression analysis independently from other imaging findings.
Other degenerative findings were chosen according to the earlier literature as a
potential source of low back symptoms. The multinomial logistic regression analyses
were adjusted for gender and socioeconomic status (five-item work and education
questionnaire) (Leino-Arjas et al. 1998). In study III, each of the specific MRI
57
findings was added to a model, one at a time. The analyses were adjusted for the sum
score of DD, gender, and socioeconomic status.
Table 4. Low back pain (LBP) and low back-related functional limitation questions
used for clustering with Latent Class Analysis. The same questions were used at 18,
19 and 21 years.
Question
Response options
Have you had pain or aching in your lower back
1) No; 2) Yes, but I have not consulted a
during the past six months?a
physician, physiotherapist, nurse or a health
professional because of LBP; 3) Yes, I have
consulted a physician, physiotherapist, nurse or a
health professional because of LBP
Has your LBP restricted your daily activities?b
Has LBP restricted your participation in sports?b
1) No; 2) Yes, slightly; 3) Yes, considerably
1) No; 2) Yes, I’ve had to restrict my sport
activities; 3) Yes, I had to stop my sport activities
Have you consulted a physician because of
1) No; 2) Yes
LBP?
Have you needed pain medication because of
1) No; 2) Yes
LBP?
How intense was the worst episode of LBP on a
Numerical rating scale from 0 to 10
scale from 0 (no LBP at all) to 10 (worst
imaginable pain)?c
Have you had LBP episodes lasting more than 2
1) No; 2) Yes
weeks?
a
Dichotomized as "no" vs. "any pain during the past 6 months"
b
Dichotomized as "no" vs. "any restriction"
c
Dichotomized as "<3" vs. "≥ 3"
58
Fig. 18. Sum score of disc degeneration (DD) was calculated by summing up the grades of
DD at each lumbar level. Normal disc was scored as 0, mildly degenerated disc as 1 and
moderately degenerated as 2.
The association of DD sum score (outcome) with the explanatory factors
(anthropometric measures, physical activity and smoking) was examined by ordinal
logistic regression (OLR) based on proportional odds assumption (IV) (Ananth &
Kleinbaum 1997). The outcome was the degree of DD, measured in ordered classes.
The original ranks (0 to 8) were reclassified by combining the six highest classes (3 to
8) where the numbers were small, the final response variable having ordered values i
= 1 to 4. The explanatory variables BMI, weight, height and WC were treated in
quartiles to allow for curvilinear associations. The results were expressed as
cumulative odds ratios (COR) and their 95% confidence intervals (CI). The COR
expresses the ratio of odds for having a DD sum score greater than or equal to that in
any ordered class i, compared with that in all lower classes. This method combines
the information from all ordered categories under the assumption that the odds ratios
over all pairs of categories ≥ i vs. < i are similar. The proportionality assumption was
checked by the score test (IV) and Wald test (V) using a 5% significance level
(Hosmer & Lemeshow 2000: 133-4. 286-301, Williams 2006). Each explanatory
variable was first entered alone (univariate analysis), followed by multiple regressions
based on several variables. To avoid multicollinearity of anthropometric measures,
only the strongest factors were retained in the final model. Analyses were stratified by
gender.
59
In study V OLR was used similarly as in study IV, except that outcome and
explanatory variables were sufficiently linear and were treated as such. In
instances not fulfilling this assumption (p value <0.05), separate ORs were shown
for all levels of i. We first entered each explanatory variable into the model alone
to produce crude ORs. Then we calculated adjusted ORs by entering postural,
workload, and activity variables. The latter factors were allowed for since they
could be related to the outcome and the explanatory variables and may therefore
confound the results. We did not adjust for driving a motor vehicle and lifting heavy
objects at work among women because the number of women exposed to these was
small (one and nine women, respectively). Additional postural, workload, and activity
factors were considered, but they did not change the parameter estimates and were
thus omitted. All variables regarded as confounders are explained in Table 3. All
analyses were stratified by gender. The ORs were obtained by the gologit2 procedure.
Spearman correlations were used to assess the correlation of abdominal obesity with
WC and body fat percentage. The Chi square test was used to test the differences
between genders in the prevalence of DD at each level and the sum score of DD. The
methods used in each study are summarized in Table 5.
In studies I-III all analyses were performed using SPSS software for
Windows/Mac (version 15/18, SPSS Inc., Chicago, IL), except for the LCA (II-III)
which was performed using M-Plus (version 5, Muthén & Muthén, Los Angeles, CA,
USA) The NAG Fortran Mark 21 software library (The Numerical Algorithms Group
Ltd., Oxford, UK) was used to draw statistical figures (I). In study IV, all analyses
were performed using SAS software (version 9.1, SAS Institute Inc., Cary, NC,
USA) while in study V, Stata software with gologit2 procedure (version 11,
College Station, Texas, USA) was used in all analyses.
4.7
Ethical considerations
The present study was conducted in accordance with the Declaration of Helsinki
1975. The cohort members participated voluntarily in the study, understood the study
design and gave permission to use the collected data by signing the informed consent;
consent was also obtained from their parents at the 16-year follow-up. The
participants were also aware of the group-level handling of the collected data as the
participants’ identifying information was replaced with non-identifying ID codes. The
ethical committee of Oulu University Hospital reviewed and approved the study
protocol before its initiation.
60
Table 5. Summary of methods used in thesis
Article
Study setting and
Outcome variable
Explanatory variables
Covariates
population
I
II
III
IV
Cross-sectional
DD and other MRI
n = 558
findings*
Follow-up
Low back symptoms
n = 554
and FL
Follow-up
Low back symptoms
n = 554
and FL
Follow-up
DD
n = 547
V
Cross-sectional
DD
SS and other MRI
findings
Other MRI findings
SS and sum score
of DD
BMI, smoking and
physical activity
DD
n = 558
AA, WC and body fat
HW, DV, LO, PI, SS
percentage
and education
DD, disc degeneration; SS, parent’s socioeconomic status; FL, functional limitation; MRI, magnetic
resonance imaging; BMI, body mass index; AA, abdominal adiposity; WC, waist circumference; HW,
heavy physical work; DV, driving motor vehicle; LO, lifting heavy objects at work; PI, previous
musculoskeletal injury; * bulge, herniations, radial tear, high intensity zone lesion, Schmorl’s nodes,
Modic changes and spondylolytic defects.
61
62
5
Results
5.1
Characteristics of the study population
The study population consisted of 325 (58%) females and 233 (42%) males who
were all MR scanned at the 21-year follow-up. 563 subjects volunteered for
lumbar MRI, but MR scanning was discontinued in three subjects and cancelled
in two subjects due to claustrophobia and, therefore, 558 (64% of those invited,
28% of OBS respondents and 19% of the original OBS population) subjects
underwent the whole MRI protocol. In studies II-III, the study population was
554 due to the missing symptom data for four females at the 18-year and 19-year
follow-ups. In study IV, of the 558 subjects scanned, 547 (230 males and 317
females) had BMI (measured or self-reported) available. In studies IV and V, WC
was missing in two subjects with visually observable pregnancy. In study V, body
fat percentage was missing in four subjects because they were pregnant.
There were some differences between the study population and the whole OBS
population. The MRI participants (n=561) were more likely females (58% vs.
47%), sat for shorter times (6.1 vs. 6.7 hours/day), were more physically active
(67% vs. 62% were physically active ≥2 days/week), were more likely nonsmokers (73% vs. 62%) and more likely suffered from LBP (46% vs. 40%) than
non-participants to MRI of the original OBS population (n=2,408). Moreover,
participants came from families with higher socioeconomic status slightly more
often than the non-participants (38% vs. 33%). An additional factor of interest was
the higher proportion of missing data among nonparticipants compared to
participants.
When comparing the study subjects (n=563) to the OBS postal survey
respondents (n=1,424), the male participants were more likely to report LBP (45%
vs. 41%) and have consulted a physician, physiotherapist, nurse, or a health
professional during the past 6 months (8% vs. 5%) at the 18-year follow-up. The
female participants were more likely to sit less (7.2 vs. 9.0 hours/day), be nonsmokers (63% vs. 52%) and physically active (17% vs. 11%). Again, the female
gender was over-represented in the study population (58% vs. 53%). There were no
significant differences in parents’ socioeconomic status at the 16-year follow-up.
When successfully MR-scanned participants (n=558) were compared with those
who were invited to the MRI but did not participate (n=316), the participants were
63
slightly slimmer (BMI: 21.6 vs. 22.4) but no other significant differences were
observed.
5.2
Prevalence of degenerative imaging findings (I-V)
The following prevalences of the MRI findings are reported as in studies II-V except
for bulges, which were only evaluated in study I. The prevalences of all the MRI
findings are shown in Tables 6 and 8. A total of 2,789 intervertebral discs were
evaluated of which 464 (16.6%) were degenerated. One disc was not evaluated due to
a previous operation. At least one disc was degenerated in 54.1% of the subjects and
men had a significantly higher prevalence of lumbar DD (at least one degenerated
disc) compared with women (63.1% vs. 47.7%, p<0.001). Degenerated discs were
typically observed at the two lowest lumbar levels (L4/5 and L5/S1), representing
78% of all degenerated discs, and men had a significantly higher prevalence of DD at
both levels (p=0.033 and p<0.001, respectively). Moreover, the prevalence of DD of
all the discs evaluated was higher in men than in women (19.8% vs. 14.3%, p<0.001).
Nearly half (47%) of the degenerated discs were grade 4 (moderately degenerated) at
the two lowest lumbar levels (L4/5 and L5/S1), in contrast to 16% at the higher levels.
Severe DD, i.e., grade 5, was not detected at all. Overall, moderately degenerated
discs were more commonly observed in men than in women (30% vs. 23%, p=0.062),
but the difference was insignificant.
Table 6. Prevalence of disc degeneration (%) and its confidence intervals (in brackets).
Only prevalences from studies II-V are shown.
Disc degeneration
All lumbar discs
N
2789*
% (95% CI)
17 (15-18)
2789*
7 (6-8)
558
54 (50-58)
558
26 (22-29)
L1/2
558
7 (5-9)
L2/3
558
4 (3-6)
L3/4
557*
7 (5-9)
Moderately degenerated disc
At least one disc degenerated
Moderately degenerated disc
L4/5
558
23 (20-27)
L5/S1
558
42 (38-46)
Multiple findings (at least two levels)
558
22 (19-25)
CI, confidence interval
* one disc was not evaluated due to an implant in one participant at L3/4
64
Multiple level DD, i.e., two or more degenerated discs, was observed in 123 (22%)
subjects and it was detected in males more frequently than in women (28% vs. 18%,
p=0.010); the most common pattern was a combination of DD at L4/5 and L5/S1
(53% of all cases with multiple level DD). DD was observed at a mean of 0.7 levels
(range, one to five levels) and males had a higher number of degenerated discs
compared to females (0.8 vs. 0.6, p=0.014).
The DD sum score was calculated in studies II-V and ranged from 0 to 8
(Table 7). The mean DD sum score among females was 1.0 (SD 1.4, range 0-8)
and among males 1.4 (SD 1.4, range 0-6).
Table 7. The distribution of the sum scores of disc degeneration (DD) and presence of
DD by lumbar level according to gender. The percentages (numbers) of subjects
presented.
DD sum score
Females
Males
N=325
N=233
% (N)
% (N)
0
52 (170)
37 (86)
1
19 (63)
23 (54)
2
15 (47)
20 (46)
3
6 (19)
10 (24)
4
6 (18)
7 (17)
5
1 (4)
1 (3)
6
1 (3)
1 (3)
7
-
-
8
0.3 (1)
-
p-value
0.033*
DD L1/2
7 (22)
8 (18)
0.216
DD L2/3
5 (15)
4 (9)
0.781
DD L3/4
6 (20)
8 (19)a
DD L4/5
20 (64)
28 (64)
0.003
DD L5/S1
35 (112)
52 (121)
<0.001
*
a
0.319
From chi square test (χ2 = 15.17, def= 7)
232 discs evaluated in males due to an implant in one participant at L3/4
Nearly a quarter of subjects had at least one bulging disc with no gender difference in
prevalence (Table 8). The bulging discs were typically observed at the 3 lowest levels
in both genders. The prevalence of disc bulging was 6% of all the discs analyzed, and
highest at L5/S1 (18.1%). Bulging was recorded only in study I. Every fifth of the
subjects had herniations (protrusions and extrusions combined) (Table 8). Herniations
occurred at L3/4, L4/5 and L5/S1, being most common at L5/S1 (61% of all
herniations). Only 10 females and 9 males had an extrusion, mainly located at L5/S1
65
(70% and 89%, respectively). Herniations were slightly, but statistically
insignificantly, more prevalent in men than women (24% vs. 19%). Multiple
herniations were found in 3% of the subjects with no gender difference.
Table 8. Prevalence of specific MRI findings (%) and their confidence intervals (in
brackets). Only prevalences from studies II-III are shown.
MRI findings
N
% (95% CI)
Bulging
558
25 (21-29)#
Herniation (protrusions and extrusions)
554
21 (18-24)
554
3 (2-5)
Radial tear
554
6 (4-8)
High Intensity Zone lesion
554
3 (2-5)
Modic changes
554
1 (0-1)
Schmorl’s node
554
17 (14-20)
Spondylolysis/listhesis
554
6 (4-8)
Extrusion
# Prevalence from study I; CI, confidence interval
Of all subjects, 6.2% had at least one radial tear with no significant differences
between genders (Table 8). Only one female and male subject had multiple radial
tears at L4/5 and L5/S1. The radial tears were typically located at the two lowest
intervertebral discs (89%). The prevalence of HIZ lesions (at least one level) was
3.2% without gender difference (Table 8). HIZ lesions were observed at L4/5 and
L5/S1 and no multiple findings were observed.
The prevalence of Modic changes (at least 1) was 0.7% (one male and three
females) (Table 8). There were equal amounts of type I and II changes, and one
female had both types observed at two different levels, L4/5 and L5/S1. All Modic
changes were adjacent to moderately degenerated disc (grade 4). The prevalence of
Schmorl's nodes was 17% (Table 8) and Schmorl’s nodes were more often observed
among males than females (23% vs. 13%, p=0.003). Multiple Schmorl’s nodes were
detected in 8% of the subjects. The prevalence of multiple Schmorl’s nodes was
insignificantly higher among males than among females (11% vs. 6%, p=0.055).
Spondylolytic defects were observed in 5.7% of the subjects without gender
difference (Table 8). Spondylolytic defects typically occurred at the two lowest levels
and multiple findings were not observed.
66
5.2.1 Agreement of observers on MRI
Inter-rater agreement was found to be very good (κ = 0.84) in DD and moderate (κ =
0.51) in Modic changes when two more experienced readers were compared to the
less experienced reader (I). In studies II-V, the inter-rater reliability between the
radiologists was poor for L1/2 and L2/3 DD (κ = 0.05 and 0.12, respectively) but
moderate to good for the other levels (κ = 0.41, 0.63, and 0.503 for L3/4, L4/5, and
L5/S1, respectively). In studies II-III, the inter-rater reliability between the
musculoskeletal radiologists was poor for Schmorl’s nodes (κ = 0.30), moderate for
spondylolytic defects (κ = 0.44), and at least substantial for HIZ lesions, radial tears
and herniations (κ = 0.89, 0.78 and 0.64, respectively). The inter-rater reliability was
not calculated for Modic changes due to the low prevalence (n=4).
Abdominal obesity measurements (V)
Repeatability of MRI abdominal measurements (ICC) were very good, being
0.85, 0.95, 0.91, and 0.99 for AD, SAD, VST, and DST, respectively.
5.3
Association of lumbar magnetic resonance imaging findings
with low back symptoms and functional limitations (II-III)
Clustering of the Study Population
The clustering was performed first for 468 individuals using all the available
questionnaire data. The optimal number of clusters was determined as five (minimum
BIC and p-value of 0.010 in the LRT test; Table 9). Thereafter, the rest of the subjects
with incomplete data were clustered manually without knowledge of their MRI
findings. Finally, both the questionnaire data and the MRI scans of 554 subjects (321
females and 233 males) were available.
Characteristics of Pain Clusters
The probability of low back symptoms and functional limitations was calculated in
each of the five clusters at 18, 19, and 21 years; for example, daily activities at 18
years were restricted among 54% (prevalence, 0.54) of the subjects in cluster 1,
whereas none had this functional limitation at 18 years in cluster 2 (prevalence, 0.00)
67
(Table 10). Subjects in cluster 1 (“Always Painful”) had experienced LBP and
functional limitations at all time points; cluster 2 (“Recent Onset Pain”) subjects had
no functional limitations at 18 years, intermediate limitations at 19 years, and major
limitations at 21 years; cluster 3 (“Moderately Painful”) subjects had intermediate
likelihood of functional limitations at all time points; cluster 4 (“Minor Pain”)
subjects had high likelihood of LBP during the past six months at all time points but
with no or minor functional limitations; and cluster 5 (“No Pain”) subjects had low
likelihood of both low back symptoms and functional limitations at all time points
(Table 10). The sum score of low back symptoms (maximum value, 7) was calculated
in each cluster at all time points (18, 19, and 21 years; Fig. 19).
Table 9. Clustering of the study subjects with complete questionnaire data (n=468)
using Latent Class Analysis. The optimal cluster number is bolded.
Number of Clusters
LRT p-value*
BIC
2
<0.001
8525.6
3
0.0035
8249.2
4
0.2292
8215.8
5
0.0103
8187.8
6
0.8115
8237.4
7
0.0098
8299.9
8
0.1298
8372.8
9
0.2611
8452.0
10
0.3721
8534.9
*Lo-Mendell-Rubin adjusted LRT test p-value (for n-1 vs. n clusters).
BIC = Bayesian Information Criterion
68
Fig. 19. Sum score of low back symptoms and back-related functional limitations in
each pain cluster at 18, 19 and 21 years. Cluster 1 represents “Always Painful”, 2
“Recent Onset Pain”, 3 “Moderately Painful”, 4 “Minor Pain” and 5 “No Pain” cluster.
69
Table 10. Probability of low back pain, consequences of pain and back-related
functional limitations among study subjects in the five pain clusters at 18, 19 and 21
years of age (n=563) obtained by Latent Class Analysis.
1*
2*
3*
4*
5*
N = 67
N = 57
N = 73
N = 197
N = 169
LBP during the past 6 months**
0.91
0.46
0.95
0.70
0.24
Daily activities restricted†
0.54
0.00
0.51
0.08
0.01
Sports restricted‡
0.79
0.06
0.52
0.34
0.01
Physician consultation§
0.72
0.00
0.20
0.01
0.00
Used pain medication||
0.79
0.06
0.41
0.10
0.00
LBP intensity***
0.79
0.00
0.73
0.08
0.01
LBP episode††
0.60
0.02
0.11
0.02
0.00
LBP during the past 6 months**
0.79
0.84
0.89
0.59
0.14
Daily activities restricted†
0.59
0.27
0.57
0.06
0.00
Sports restricted‡
0.79
0.58
0.54
0.22
0.00
Physician consultation§
0.84
0.25
0.25
0.02
0.00
Used pain medication||
0.93
0.33
0.43
0.06
0.01
LBP intensity***
0.90
0.40
0.65
0.12
0.00
LBP episode††
0.49
0.12
0.17
0.01
0.00
LBP during the past 6 months**
0.84
0.95
0.92
0.73
0.16
Daily activities restricted†
0.66
0.70
0.51
0.10
0.00
Sports restricted‡
0.77
0.57
0.52
0.24
0.01
Physician consultation§
0.87
0.72
0.16
0.02
0.01
Used pain medication||
0.99
0.83
0.38
0.13
0.01
LBP intensity***
0.84
0.86
0.64
0.15
0.00
LBP episode††
0.54
0.37
0.11
0.01
0.00
Low back symptoms and functional limitations
At 18 years
At 19 years
At 21 years
The scores of the included dichotomized pain variables at a given age. The scores within groups range
from 0 (none in the group had pain symptoms) to a maximum of 1 (all subjects in the group had pain
symptoms).
#
Number of subjects differs from the final number of subjects analyzed (563 vs. 554) due to missing MRI
data
*1, Always Painful; 2, Recent Onset Pain; 3, Moderately Painful; 4, Minor Pain; 5, No Pain; **Low back
pain (LBP) during the past 6 months; †LBP had restricted daily activities; ‡LBP had restricted
participation in sports; §The subject had consulted a physician because of LBP; ||The subject had taken
pain medication because of LBP; ***The intensity of the worst LBP episode was at least 3 on a 10-point
numerical rating scale; ††At least one episode (current or previous) had lasted for more than 2 weeks.
70
Association of DD with Pain Clusters
The overall and gender-specific prevalences of DD sum score groups and their CIs in
each LCA cluster are presented in Table 11. In the overall analyses, at least one
degenerated disc was found significantly more often in the two most painful clusters
than in the three least painful clusters. The “Always Painful,” “Recent Onset Pain,”
and “Moderately Painful” clusters had a higher sum score of DD than the two least
painful clusters (P=0.001) (Fig. 20). Among women, DD was most prevalent in the
“Always Painful” and “Recent Onset Pain” clusters, whereas in men, DD was most
likely to occur in the “Recent Onset Pain” and “Moderately Painful” clusters (Table
12). Overall, the prevalences of DD were higher in men than in women in all clusters
except the “Always Painful” cluster. The prevalence of grade 4 discs was higher in
the “Always Painful” cluster than in the “Minor Pain” and “No Pain” clusters (48%
CI: 36–60 vs. 13% CI: 8–18 and 19% CI: 13–24, respectively). After combining the
two most painful and two least painful clusters, the prevalence of DD was higher
(P=0.001) in the major symptom cluster than in the minor symptom cluster. Thus, the
prevalence of DD after combining the clusters was consistent with the original
findings for five clusters. The prevalence of combinations such as no DD, one grade 3
disc at any level, two grade 3 discs (any combination), or one grade 4 disc at the
upper levels (L1/2, L2/3 or L3/4) was lower or similar in the major symptoms cluster
than in the minor symptoms cluster, whereas the prevalence of all other combinations
of DD was higher in the major symptoms cluster (Table 12). In the multinomial
logistic regression analysis, DD was associated with pain cluster status independently
from other degenerative findings. Moreover, moderately degenerated discs were more
likely associated with the most severe low back symptoms than mildly degenerated
discs (Table 13).
71
Fig. 20. Prevalence of the sum score of lumbar disc degeneration at all lumbar levels
in each pain cluster. Theoretical range was 0 to 15: 0 when all lumbar discs were nondegenerated and 15 when all discs had collapsed (grade 5 on the modified Pfirrmann
scale).
Table 14 presents the prevalence of other degenerative findings and their 95%
confidence intervals in each low back symptom cluster. Compared to the “No Pain”
cluster, Schmorl’s nodes occurred more often in the “Always Painful” cluster and
HNPs in the three most painful clusters. More specifically, extrusions were most
frequent in the “Recent Onset Pain” cluster. Furthermore, the distribution of radial
tears tended to differ between the clusters. Modic changes were too rare to be
analyzed in this sample, although a gender difference seemed to exist. The
frequencies of HIZ lesions and spondylolytic defects were similar in all pain clusters.
The crude multinomial logistic analysis (Table 15) showed significantly higher odds
for having major vs. minor symptoms in cases where the MRI finding was radial tear,
herniation or Schmorl’s node. However, the significant odds ratios for findings other
than herniations were attenuated when adjusted for gender, socioeconomic status and
the DD sum score. Both the crude and adjusted odds ratios for Modic changes were
high, and although they failed to reach statistical significance, their confidence
intervals were more compatible with an association than with no association. The
odds for having intermediate vs. minor symptoms were significantly high only for
herniations, and even this attenuated to insignificance when adjusted for the factors
mentioned above.
72
73
19 (8-30)
10 (2-18)
4 (0-12)
26 (8-44)
18 (9-27)
27 (19-35)
22 (16-28)
34 (23-45)
31 (23-39)
32 (25-39)
30 (19-41)
45 (36-54)
40 (33-47)
% (95% CI)
N = 193
Minor Pain
13 (6-20)
12 (5-19)
12 (6-20)
28 (18-38)
25 (16-34)
27 (20-34)
50 (39-61)
30 (20-40)
37 (30-44)
% (95% CI)
N = 167
No Pain
<0.001
0.014
<0.001
0.012
0.089
0.012
<0.001
<0.001
<0.001
p-value#
# Chi square test for difference between groups; CI, confidence interval
No Pain (i.e., cluster 5) = subjects with low likelihood of LBP and FL at all time points
level of FL and LBP at all time points; Minor Pain (i.e., cluster 4) = subjects who had LBP during the past six months at all time points but low likelihood of FL;
(i.e., cluster 2) = subjects whose FL and LPB had increased over the follow-up; Moderately Painful (i.e., cluster 3) = subjects who experienced intermediate
Always Painful (i.e., cluster 1) = subjects who had high scores of low back pain (LPB) and functional limitations (FL) at all three time points; Recent Onset Pain
15 (3-27)
27 (12-42)
39 (22-56)
females
males
11 (0-24)
22 (13-32)
15 (0-30)
33 (22-44)
DD > 3
12 (1-23)
17 (6-28)
males
14 (6-22)
15 (6-24)
14 (2-26)
6 (0-16)
13 (1-25)
12 (6-24)
3 (0-10)
13 (4-22)
11 (4-18)
% (95% CI)
N = 73
Moderately Painful
females
DD 1-3
11 (0-22)
males
7 (0-16)
6 (0-12)
7 (1-13)
No DD
5 (0-13)
% (95% CI)
females
N = 56
% (95% CI)
N = 65
Sum score of DD
Recent Onset Pain
Always Painful
represents subjects without DD, DD 1-3 represents a sum score of 1 to 3, and DD > 3 those with a sum score of more than 3.
Table 11. The prevalence (%) of disc degeneration (DD) sum score with 95% confidence intervals in each symptom cluster. No DD
74
*
Two grade 3 discs at any level or one grade 4
2
11
11
16
17
24
9 (4-14)
8 (4-14)
13 (7-19)
23 (15-30)
20 (13-27)
2
9
5
10
20
N
27
% (95% CI)
27 (19-35)#
3 (0-6)
12 (5-20)
7 (1-13)
14 (6-22)
27 (17-38)
37 (26-48)#
% (95% CI)
Intermediate symptoms
N
3
14
21
54
72
196
1 (1-4)
4 (2-6)
6 (3-8)
15 (11-19)
20 (16-24)
54 (49-60)
% (95% CI)
Minor symptoms
Seven subjects had higher values; two with three grade 4 discs (sum score of 6), four with two grade 4 discs and two grade 3 discs (sum score of 6), and one
at any level
At least two grade 4 discs and one grade 3 disc
lowest levels
grade 4 disc or two grade 4 discs at the three
Any combination of two grade 3 discs and one
combination) or three grade 3 discs at any level
One grade 3 disc and one grade 4 disc (any
N
32
Major symptoms
with three grade 4 discs and two grade 3 disc (sum score 8); # Significant difference compared to Minor symptom cluster; CI, confidence interval
*
5 or more
4
3
One grade 3 disc at any level
1
disc at any level
All discs normal
Disc degeneration combination
0
of DD
Sum score
intermediate symptoms and minor symptoms clusters.
Table 12. The prevalence (% and their confidence intervals) and number of disc degeneration combinations in major symptoms,
Table 13. Multinomial logistic regression analysis of pain clusters according to
severity of disc degeneration (at least one grade 3 or at least one grade 4 disc) and
other degenerative findings on MRI. The analyses are adjusted for gender,
socioeconomic status and for each imaging finding (DD or other degenerative
findings).
MRI finding
Major symptoms vs.
Intermediate symptoms vs.
minor symptoms
minor symptoms
OR (95% CI)
OR (95% CI)
No DD or other degenerative findings
1.00
1.00
Disc degeneration, grade 3
1.88 (1.02-3.48)
1.91 (0.96-3.79)
Disc degeneration, grade 4
2.77 (1.38-5.57)
1.95 (0.84-4.53)
Other degenerative findings (at least one)
2.57 (1.44-4.60)
1.35 (0.65-2.80)
DD, disc degeneration; Other degenerative change included Modic changes, spondylolytic defects, radial
tears and herniations; OR, odds ratio; CI, confidence interval
75
Table 14. The percentage (95% confidence intervals) of specific degenerative MRI disc
findings in each cluster.
Always
Recent Onset
Moderately
Painful
Pain
Painful
N = 56
% (CI)
N = 73
% (CI)
N = 65
% (CI)
Specific MRI
finding
Minor Pain
No Pain
N = 193
% (CI)
N = 167
% (CI)
p-value#
Modic change
3 (0-7)
2 (0-5)
0 (-)
1 (0-2)
0 (-)
0.100
females
6 (0-15)
3 (0-9)
0 (-)
0 (-)
0 (-)
0.008
males
0 (-)
0 (-)
0 (-)
1 (0-4)
0 (-)
0.691
8 (1-14)
9 (1-16)
7 (1-13)
7 (3-10)
2 (0-5)
0.244
3 (0-9)
9 (0-19)
8 (1-16)
7 (2-11)
4 (0-7)
0.644
SLD
females
12 (1-23)
9 (0-20)
4 (0-12)
7 (1-13)
1 (0-4)
0.174
Radial tear
males
19 (9-28)
16 (6-26)
11 (4-18)
7 (4-11)
7 (3-11)
0.030
females
19 (5-32)
18 (5-31)
8 (1-16)
7 (2-11)
7 (2-13)
0.088
males
18 (5-31)
13 (0-27)
17 (2-32)
8 (2-15)
7 (2-13)
0.368
HIZ lesion
5 (0-10)
2 (0-5)
4 (0-9)
2 (0-4)
4 (0-7)
0.688
females
6 (0-15)
3 (0-9)
2 (0-6)
2 (0-4)
7 (0-12)
0.291
males
3 (0-9)
0 (-)
8 (0-19)
2 (0-7)
1 (0-4)
0.355
Herniation*
32 (21-44)
43 (30-56)
27 (17-38)
14 (9-19)
11 (6-16)
<0.001
females
38 (21-54)
36 (20-53)
20 (9-32)
11 (5-16)
13 (6-20)
<0.001
males
27 (12-43)
52 (32-73)
42 (22-61)
19 (10-29)
9 (3-15)
<0.001
0.011
Extrusion
3 (0-7)
11 (3-19)
4 (0-9)
4 (1-6)
1 (0-2)
females
3 (0-9)
12 (1-23)
2 (0-6)
2 (0-4)
0 (-)
0.004
males
3 (0-9)
9 (0-20)
8 (0-19)
7 (1-13)
1 (0-4)
0.320
Schmorl’s node
28 (17-39)
18 (8-28)
22 (12-31)
18 (12-23)
10 (6-15)
0.017
females
28 (13-44)
15 (3-27)
14 (5-24)
13 (7-19)
6 (1-11)
0.032
males
27 (12-43)
22 (5-39)
38 (18-57)
25 (15-35)
15 (7-23)
0.166
Always Painful (i.e., cluster 1) = subjects who had high scores of low back pain (LPB) and functional
limitations (FL) at all three time points; Recent Onset Pain (i.e., cluster 2) = subjects whose FL and LPB
had increased over the follow-up; Moderately Painful (i.e., cluster 3) = subjects who experienced
intermediate level of FL and LBP at all time points; Minor Pain (i.e., cluster 4) = subjects who had LBP
during the past six months at all time points but low likelihood of FL; No Pain (i.e., cluster 5) = subjects
with low likelihood of LBP and FL at all time points; SLD, spondylolytic defect; HIZ, high intensity zone;
# Chi square test for difference between groups; * Includes protrusions and extrusions; CI, 95%
confidence interval
76
77
9.13 (0.94-88.59)
1.82 (0.81-4.09)
2.70 (1.46-5.00)
1.09 (0.34-3.47)
4.15 (2.56-6.72)
1.82 (1.09-3.06)
Modic change
Spondylolisthesis/-lysis
Radial tear
High Intensity Zone lesion
Disc herniation
Schmorl’s node
1.08 (0.60-1.96)
2.49 (1.41-4.40)
0.38 (0.11-1.30)
1.52 (0.76-3.02)
1.33 (0.54-3.26)
3.94 (0.37-41.91)
1.00
OR (95% CI)
Adjusted
1.70 (0.91-3.19)
2.64 (1.45-4.82)
1.36 (0.37-5.00)
1.58 (0.69-3.65)
1.48 (0.53-4.16)
N/A -
1.00
OR (95% CI)
Adjusted
1.20 (0.57-2.51)
1.82 (0.87-3.78)
0.68 (0.17-2.77)
1.27 (0.51-3.18)
1.14 (0.36-3.64)
N/A -
1.00
Moderately Painful
OR (95% CI)
Crude
Intermediate symptoms vs. Minor symptoms
- : not applicable due to the low prevalence of Modic changes; OR, odds ratio; CI, confidence interval
Minor symptoms = subjects originally in Minor Pain and No Pain clusters
Major symptoms = subjects originally in Always Painful and Recent Onset Pain clusters; Intermediate symptoms = subjects originally in Moderate Pain cluster;
OR (95% CI)
1.00
MRI findings
Crude
Major symptoms vs. Minor symptoms
No degenerative findings (reference)
status.
findings. Numbers are crude odds ratios (OR) and ORs adjusted for gender, sum score of disc degeneration, and socioeconomic
Table 15. Multinomial logistic regression analysis major vs. minor and intermediate vs. minor low back symptoms on six MRI
5.4
Association of lumbar disc degeneration with body mass index,
smoking and physical activity (IV)
Study population characteristics
Data on height, weight and BMI were available for 550 subjects at 16 years, on
WC for 537 and 556 subjects at 16 and 19 years, respectively, and on physical
activity levels for 555 subjects, while pack-years of smoking, weight, height, and
BMI at 19 years were available for all subjects. Table 16 shows the means and
ranges for all anthropometric measures, MET hours per week, and the distribution
of the subjects by pack-years of smoking. The distributions of lumbar DD did not
differ much between the genders otherwise but there were relatively more females
than males with normal discs (Fig. 21).
Association of disc degeneration with environmental factors
The univariate analyses (Table 17) showed marked increases in cumulative odds
ratio (COR) by all anthropometric measures, from the lowest to highest quartiles,
indicating an increase in the odds of belonging to any ordinal class of DD, or a
class higher than that, compared with all lower classes. The increase of COR was
mostly monotonous but not always linear. In males, the CORs in the highest
quartiles ranged from 2.2 to 4.0, and their CIs remained well above the baseline,
while in females, the CORs were much smaller, only height at 16 years exceeding
the baseline with any certainty. All anthropometric measures showed higher
CORs at 16 years than at 19 years. Male smokers with at least four pack-years
showed a significantly high COR, and the finding was similar in females, but the
confidence interval remained too wide. Physical activity was not associated with
DD, although in females, the finding was suggestive of a U-shaped association
with the lowest COR in the II quartile.
BMI at 16 years was selected to represent anthropometry in further analyses. The
final model in Table 18 included the quartiles of BMI and physical activity, and packyears of smoking. Compared with the univariate associations in Table 17, the CORs
for BMI were slightly smaller and mostly exceeded the reference level in males but
not in females. In males, the association of smoking with DD attenuated after
multivariate analysis to borderline statistical significance, but the confidence interval
was wide and equally compatible with a 6-fold effect as with no effect. The odds
78
ratios for physical activity remained essentially unchanged. The score test indicated
no violations of the proportional odds assumption at 5% level.
Fig. 21. Prevalence of lumbar disc degeneration sum score in the whole study
population, and separately in males and females.
79
80
19 (8%)
4.00
19 (6%)
67 (21%)
239 (73%)
29.6 (2.8-64.3)
72.3 (59.0-118.5)
70.4 (59.5-100.5)
164.3 (145.0-179.0)
164.1 (134.7–179.2)
59.8 (39.9–114.1)
55.8 (37.5–94.0)
22.1 (15.8–39.9)
Both sexes
38 (7%)
104 (19%)
416 (74%)
31.7 (2.8-76.0)
76.3 (59.0-121.0)
72.7 (59.5-108.1)
170.1 (145.0-201.0)
168.9 (134.7–196.2)
66.4 (39.9–123.6)
59.9 (37.5–112.1)
22.8 (15.8–39.9)
20.9 (14.5–35.8)
555
556
537
558
550
558
550
558
550
brackets); **Years of smoking multiplied by the packs of cigarettes smoked daily
BMI, Body mass index; # Metabolic equivalent (MET) hours per week calculated from physical activity level outside school hours; * Prevalence (N, % in
37 (16%)
177 (76%)
0.01–3.99
None
Smoking (pack- years**) at 19 yr
Distributions of subjects by smoking class*
34.6 (4.0-76.0)
Physical activity level (MET hours/week#)
178.3 (158.5-201.0)
Height 19 yr (cm)
81.8 (62.5-121.0)
175.6 (158.2–196.2)
Height 16 yr (cm)
75.9 (62.5-108.1)
75.7 (52.5–123.6)
Weight 19 yr (kg)
Waist circumference 19 yr (cm)
65.6 (45.2–112.1)
Weight 16 yr (kg)
Waist circumference 16 yr (cm)
23.8 (16.0–38.1)
BMI 19 yr (kg/m2)
20.7 (14.5–35.8)
Females
Males
21.2 (15.6–33.0)
No. of valid
observations
Means (ranges) of anthropometric measures and physical activity
BMI 16 yr (kg/m2)
class.
Table 16. Means and ranges of anthropometric measures and physical activity level and the distributions of subjects by smoking
Table 17. Crude associations of lumbar disc degeneration sum score with quartiles of body mass
index (BMI), weight, height, waist circumference and physical activity level, and pack-years of
smoking. Numbers are cumulative odds ratios relative to reference (95% confidence intervals).
Quartiles (range)
Males
Females
(N=230)
(N=317)
OR (95% CI)
Quartiles (range)
OR (95% CI)
BMI at 16 years (kg/m2; quartiles)
I (15.6-19.0)
1.00
I (14.5-18.8)
1.00
II (19.1-20.6)
1.44 (0.74–2.81)
II (18.9-20.2)
0.72 (0.39–1.30)
III (20.7-22.6)
1.67 (0.85–3.26)
III (20.3-21.9)
1.04 (0.58–1.87)
IV (22.7-33.0)
2.64 (1.35–5.16)
IV (22.0-35.8)
1.33 (0.75–2.38)
BMI at 19 years (kg/m2; quartiles)
I (16.0-21.1)
1.00
I (15.8-19.7)
1.00
II (21.2-23.1)
1.54 (0.80–2.99)
II (19.8-21.5)
0.93 (0.52–1.66)
III (23.2-25.6)
1.34 (0.69–2.61)
III (21.6-23.4)
0.83 (0.47–1.49)
IV (25.7-38.1)
2.22 (1.14–4.33)
IV (23.5-39.9)
1.09 (0.61–1.92)
Weight at 16 years (kg; quartiles)
I (45.2-57.2)
1.00
I (37.5-49.9)
1.00
II (57.3-63.5)
2.04 (1.04–4.03)
II (50.0-54.0)
0.88 (0.48–1.61)
III (63.6-72.2)
2.18 (1.10–4.32)
III (54.1-60.3)
1.30 (0.72–2.34)
IV (72.3-112.1)
4.00 (2.01–7.96)
IV (60.4-94.0)
1.57 (0.88–2.81)
Weight 19 years (kg: quartiles)
I (52.5-66.9)
1.00
I (39.9-52.9)
1.00
II (67.0-73.4)
1.19 (0.61–2.32)
II (53.0-57.8)
1.24 (0.69–2.23)
III (73.5-81.5)
1.77 (0.91–3.44)
III (57.9-64.2)
1.23 (0.69–2.21)
IV (81.6-123.6)
2.72 (1.39–5.32)
IV (64.3-114.1)
1.42 (0.79–2.54)
Height at 16 years (cm; quartiles)
I (158.2-171.3)
1.00
I (134.7-160.9)
1.00
II (171.4-174.9)
2.03 (1.02–4.04)
II (161.0-164.1)
1.28 (0.70–2.35)
III (175.0-179.8)
1.97 (1.01–3.84)
III (164.2-168.0)
1.68 (0.93–3.05)
IV (179.9-196.2)
3.39 (1.72–6.70)
IV (168.1-179.2)
1.81 (1.00–3.29)
Height 19 years (cm; quartiles)
I (158.5-173.9)
1.00
I (145.0-160.9)
1.00
II (174.0-177.9)
1.01 (0.52–1.96)
II (161.0-164.4)
1.06 (0.58–1.93)
III (178.0-182.9)
1.31 (0.68–2.50)
III (164.5-167.9)
1.89 (1.04–3.42)
IV (183.0-201.0)
2.28 (1.16–4.46)
IV (168.0-179.0)
1.77 (0.98–3-18)
81
Males
Females
(N=230)
(N=317)
Quartiles (range)
OR (95% CI)
Quartiles (range)
OR (95% CI)
Waist circumference at 16 years (cm; quartiles)
I (62.5-70.4)
1.00
I (59.5-65.9)
1.00
II (70.5-74.0)
1.02 (0.52–2.01)
II (66.0-69.0)
0.78 (0.43–1.42)
III (74.1-79.0)
1.67 (0.85–3.28)
III (69.1-73.4)
0.98 (0.54–1.78)
IV (79.1-108.1)
3.11 (1.58–6.15)
IV (73.5-100.5)
1.24 (0.69–2.22)
Waist circumference at 19 years (cm; quartiles)
I (62.5-75.9)
1.00
I (59.0-66.9)
1.00
II (76.0-79.0)
1.29 (0.66–2.51)
II (67.0-70.0)
0.86 (0.48–1.52)
III (79.1-85.9)
1.50 (0.78–2.89)
III (70.1-75.0)
1.02 (0.57–1.85)
IV (86.0-121.0)
2.38 (1.23–4.62)
IV (75.1-118.5)
0.85 (0.47–1.53)
1.38 (0.77–2.47)
Physical activity level# (MET hours/week; quartiles)
I (4.0-23.9)
1.00 (0.52–1.92)
I (2.8-20.0)
II (24.0-34.9)
1.00
II (20.1-28.9)
1.00
III (35.0-45.0)
1.16 (0.61–2.24)
III (29.0-39.0)
1.26 (0.70–2.27)
IV (45.1-76.0)
1.12 (0.58–2.16)
IV (39.1-64.3)
1.53 (0.85–2.74)
Smoking (pack-years*)
#
None
1.00
None
1.00
0.01-3.99
1.49 (0.79–2.82)
0.01-3.99
1.09 (0.66–1.82)
4.00
2.53 (1.08–5.97)
4.00
1.64 (0.70–3.84)
Metabolic equivalent (MET) hours per week calculated from physical activity outside school hours
* Years of smoking multiplied by the packs of cigarettes smoked daily; OR, odds ratio; CI, confidence
interval
82
83
** Years of smoking multiplied by the packs of cigarettes smoked daily
1.00
1.09 (0.65–1.83)
1.59 (0.67–3.76)
1.38 (0.76–2.50)
1.00
1.27 (0.69–2.34)
1.52 (0.84–2.75)
1.00 (0.51–1.97)
1.00
1.27 (0.65–2.49)
1.27 (0.65–2.50)
I
II
III
IV
Smoking (pack-years**)
None
1.00
0.01-3.99
1.47 (0.76–2.83)
4.00
2.41 (0.99–5.86)
* Metabolic equivalent (MET) hours per week calculated from physical activity outside school hours; mean value at 16 and 19 years
1.00
0.67 (0.37–1.23)
0.99 (0.54–1.81)
1.29 (0.72–2.32)
COR (95% CI)
Females
N=317
1.00
1.44 (0.73–2.84)
1.64 (0.83–3.25)
2.35 (1.19–4.65)
COR (95% CI)
Males
N=230
I
II
III
IV
Physical activity level* (MET hours/week; quartiles)
BMI at 16 years (kg/m2; quartiles)
Explanatory factors
physical activity level and pack-years of smoking.
lumbar disc degeneration sum score (in four-class ordinal scale) on body mass index (BMI), weight, height, waist circumference,
Table 18. Cumulative odds ratios (COR) and their 95% confidence intervals (CI) from univariate ordinal logistic regressions of the
5.5
Association of abdominal adiposity with lumbar disc
degeneration (V)
We measured the DST of all (n= 558) participants. The VST, AD and SAD of 53 (34
males and 19 females) participants could not be measured, because the subcutaneous
fascia was not visible due to obesity. Of those 53 subjects, the VST was unmeasurable
in 43 participants (28 males and 15 females). However, the AD and SAD values were
measured as far anteriorly as possible, and the values were in the highest quartile of
both variables. WC and bioelectrical impedance measurements were available for all
males but only for 323 and 321 females, respectively.
The correlation of WC with SAD (0.74) and body fat percentage with DST (0.70)
was high, whereas a moderate correlation was found between WC (0.59) and AD, and
between body fat percentage (0.52) and VST.
WC, SAD and AD were significantly higher in males while VST, DST and
body fat percentage were significantly higher in females. The means and ranges
of the MRI obesity measures, WC and body fat percentage are shown in Table 19.
Table 20 compares the means of adiposity measures between DD classes and
shows elevated AD and SAD among men in the highest DD class. Among women,
the trends were similar as among men but did not reach statistical significance.
Ordinal logistic regression showed significant associations of DD with AD and
SAD, and a weak association with WC, but among males only (Table 21). According
to crude analyses, the odds for having DD increased by 17%, 16% and 3% per onecentimeter increase of AD, SAD and WC, respectively, at all levels of DD. When
potential confounders were taken into account, AD and SAD did not meet the
proportionality assumption. The separate ORs for each level of the outcome revealed
no increase in DD at its lowest level (class 1 vs. 0) but did show significant increases
at two higher levels of DD (50% and 67% for AD; 24% and 40% for SAD). For WC,
the OR remained unchanged after adjustment; only its confidence interval was
marginally wider. DD was not significantly associated with VST, DST or body fat
percentage, and we found no associations at all among females. To summarize these
results, abdominal obesity as measured with abdominal diameter and sagittal
abdominal diameter in lumbar MRI increases the likelihood of lumbar DD in a doserelated matter and a similar trend was seen for waist circumference.
84
85
16.1 (5.5–38.1)
Body fat (%)
1.7 (0.1–6.4)
81.8 (62.5–121.0)
Dorsal subcutaneous thickness (cm)
Waist circumference (cm)
1.6 (0.4–5.3)
17.5 (13.1–22.9)
7.2 (3.6–11.6)
Males
Ventral subcutaneous thickness (cm)
Sagittal diameter (cm)
Abdominal adiposity (cm)
Adiposity measures
26.5 (11.9–48.2)
72.3 (59.0–118.5)
2.4 (0.4–7.2)
2.0 (0.4–5.9)
16.2 (11.9–24.2)
6.7 (2.9–11.5)
Females
22.1 (5.5–48.2)
76.3 (59.0–121.0)
2.1 (0.1–7.2)
1.9 (0.4–5.9)
16.7 (11.9–24.2)
6.9 (2.9–11.6)
All
Table 19. Means (ranges) of adiposity measurements on MRI, and waist circumference and body fat percentage.
554
556
558
515
558
558
observations
Number of valid
86
80 (78–82)
16 (14–17)
Waist circumference (mm)
Body fat percentage
a
24 (23–26)
73 (71–74)
27 (26–28)
Waist circumference (cm)
Body fat percentage
From one-way ANOVA
20 (19–21)
Dorsal subcutaneous thickness (mm)
163 (159–166)
Ventral subcutaneous thickness (mm)
Sagittal abdominal diameter (mm)
Abdominal diameter (mm)
68 (65–70)
16 (13–18)
Women
16 (14–18)
Dorsal subcutaneous thickness (mm)
172 (167–176)
71 (68–74)
0
Ventral subcutaneous thickness (mm)
Sagittal abdominal diameter (mm)
Abdominal diameter (mm)
Men
Adiposity measures
26 (24–27)
71 (69–73)
23 (21–26)
21 (19–24)
161 (156–167)
65 (61–69)
16 (15–18)
83 (80–85)
17 (15–20)
16 (14–19)
171 (166–177)
68 (64–73)
1
25 (23–27)
72 (69–74)
23 (19–26)
18 (15–21)
158 (152–165)
64 (59–69)
16 (14–18)
83 (80–85)
17 (14–20)
17 (14–19)
175 (169–181)
73 (69–78)
2
Disc degeneration sum score
27 (25–29)
74 (71–76)
25 (21–28)
22 (19–25)
166 (160–173)
69 (64–74)
16 (15–18)
84 (81–86)
19 (16–22)
17 (15–20)
184 (177–190)
77 (72–81)
3-8
Table 20. Means (95% confidence intervals) of adiposity measures, classified by disc degeneration sum score.
0.186
0.286
0.803
0.151
0.357
0.304
0.940
0.106
0.300
0.834
0.012
0.048
p-valuea
321
323
325
310
325
325
233
233
233
205
233
233
N
87
233
151
1.24 (1.04–1.49)
1.40 (1.12–1.75)
Sum score 3–8 vs. 0–2
N
0.97 (0.82–1.15)
Sum score 2 vs. 0–1
151
Sum score 1 vs. 0
Sagittal abdominal diameter (cm)
1.16 (1.04–1.30)
1.67 (1.20–2.33)
233
1.50 (1.13–1.98)
Sum score 3-8 vs. 0–2
N
0.78 (0.60–1.01)
OR (95% CI)
Adjusted
a
Sum score 2 vs. 0–1
1.17 (1.01–1.36)
OR (95% CI)
Crude
Males
Sum score 1 vs. 0
Abdominal diameter (cm)
Explanatory variable
shown. Otherwise, the ORs are shown separately for each level of the outcome.
325
1.00 (0.91–1.09)
325
0.96 (0.85–1.09)
OR (95% CI)
Crude
Females
225
0.98 (0.88–1.09)
225
0.94 (0.81–1.09)
OR (95% CI)
Adjusted b
with all lower classes. In cases not violating the proportionality assumption, only the OR common to all sum score levels is
ORs indicate the relative change in odds for having a DD sum score equal to or greater than any given sum score when compared
the association between lumbar disc degeneration (DD) sum score (in four ordinal classes) and measures of abdominal obesity.
Table 21. Odds ratios (OR) and their 95% confidence intervals (CI) for crude and adjusted ordinal logistic regression analyses on
88
310
210
222
0.98 (0.94–1.02)
224
0.99 (0.96–1.02)
225
0.98 (0.79–1.21)
Adjusted for heavy physical work, previous musculoskeletal injury, socioeconomic status and education.
321
0.98 (0.94–1.01)
323
1.00 (0.98–1.03)
325
0.96 (0.81–1.15)
b
151
1.00 (0.95–1.05)
151
1.03 (0.99–1.06)
151
1.11 (0.81–1.51)
Adjusted for heavy physical work, driving a motor vehicle, lifting heavy objects at work, previous musculoskeletal injury, socioeconomic status and education.
233
1.01 (0.97–1.04)
233
1.03 (1.00–1.05)
233
1.21 (0.97–1.51)
1.00 (0.76–1.32)
OR (95% CI)
Adjusted b
a
N
Body fat percentage
N
Waist circumference (cm)
N
Dorsal subcutaneous thickness (cm)
137
1.28 (0.92–1.77)
205
Sum score 3–8 vs. 0–2
N
1.06 (0.84–1.35)
OR (95% CI)
Crude
Females
0.95 (0.72–1.24)
0.85 (0.56–1.29)
OR (95% CI)
Adjusted
a
Sum score 2 vs. 0–1
1.13 (0.85–1.51)
OR (95% CI)
Crude
Males
Sum score 1 vs. 0
Ventral subcutaneous thickness (cm)
Explanatory variable
6
Discussion
6.1
Key findings
Study question 1: What is the prevalence of intervertebral DD, disc contour
changes, annular tears (radial tears and HIZ lesions), Schmorl’s nodes,
endplate changes and spondylolytic defects on lumbar MRI among young
Finnish adults?
The results of this study indicate that DD, disc contour changes and Schmorl’s nodes
are common MRI findings in the lumbar spine among young adults aged 20 to 22
years. Radial tears and spondylolytic defects were quite frequent as well, while HIZ
lesions were relatively rare. The prevalence of extrusions and Modic changes was
very low at this age. Men had a significantly higher prevalence of DD and Schmorl’s
nodes.
Study question 2: Are degenerative lumbar MRI findings associated with low
back symptoms among young Finnish adults?
Intervertebral DD was associated with LBP severity in this population-based birth
cohort. Moreover, DD was associated with pain status independently of other imaging
findings (disc herniations, Modic changes, radial tears, and spondylolytic defects).
The association was stronger for moderately degenerated than for mildly degenerated
discs. However, degeneration was also found in one-third of asymptomatic subjects.
Herniations were associated with major low back symptoms among young Finnish
adults after adjusting for gender, socioeconomic status, and sum score of DD, while
for Schmorl’s nodes, HIZ lesions, spondylolytic defects, radial tears and Modic
changes the findings remained indeterminate, possibly due to insufficient statistical
power.
Study question 3: Are lifestyle factors such as smoking, BMI and physical
activity at 16 and 19 years of age associated with lumbar intervertebral DD
on MRI performed at 21 years?
High BMI at 16 years was associated with lumbar DD at 21 years among males.
Such associations were not observed among females. Smoking at 19 years
showed a comparable association among males. The level of physical activity was
not related with DD in either gender with any certainty.
89
Study question 4: Are measures of abdominal adiposity such as WC, body fat
percentage and midsagittal abdominal MRI measures associated with
lumbar intervertebral DD?
The MRI-based obesity measurements of visceral adiposity (SAD and AD) were
associated with DD among males, but not among females. Similarly, among
males, WC showed a comparable association with DD.
6.2
Prevalence of degenerative imaging findings
The comparison of the results of the present study with the result of adult subjects
is not feasible because the prevalence of degenerative findings increases mostly
with age. The exceptions are spondylolysis (Leone et al. 2010, Tsirikos &
Garrido 2010) and possibly Schmorl’s nodes (Mok et al. 2010) due to their
typically early occurrence in the lumbar spine. In general, there is a lack of large
population-based studies on the prevalences of MRI findings among children,
adolescents and young adults. There are no longitudinal follow-up studies done
among children, adolescents and young adults
Our results on the prevalence of DD accord with the results of previous
studies in Nordic countries (Erkintalo et al. 1995, Kjaer et al. 2005b, Paajanen et
al. 1989, Paajanen et al. 1997, Salo et al. 1995). However, the prevalences were
slightly lower in the same age group in two studies performed elsewhere (Hangai
et al. 2009, Samartzis et al. 2011). The lower prevalences may be due to the
smaller sample size in one study (Samartzis et al. 2011) and the selected
population including only university students in the other study (Hangai et al.
2009). When comparing the prevalence of DD in all lumbar discs, we had slightly
higher prevalences compared to previous studies. However, this can be explained
by age differences of the study populations and improved imaging devices.
Paajanen et al. (Paajanen et al. 1997) reported higher DD prevalence of all the
lumbar discs (22.5%), but they included subjects up to 49 years and no age
distribution data were available. Similarly as in all cited studies, we had the
highest prevalences at the two lowest lumbar levels. Moderately degenerated
discs were seen approximately in every fourth subject in the present study, which
is in line with the results of earlier studies among younger subjects (Erkintalo et
al. 1995, Kjaer et al. 2005b). Mean DD sum score has been reported in only one
small study among adolescents (Samartzis et al. 2011). Selection bias in a smallscale study may explain the higher value compared to our results (2.9 vs. 1.2).
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Modic changes are very rare among 13- to 20-year-old subjects (0.5-1.2%)
(Kjaer et al. 2005b, Samartzis et al. 2011) and our findings accord with these
studies. We found type I and II changes, whereas in the Danish study only type I
changes were observed (Kjaer et al. 2005b) among 13-year-old subjects. In
concordance with earlier suggestions that Modic changes are a specific DD
phenotype (Albert et al. 2008), Modic changes (n = 4) were found adjacent to
moderately degenerated discs in the present study.
Disc bulges are quite common already in 13-year-old children (13%) (Kjaer
et al. 2005b). The prevalence in our study was higher but it is in line with the
observations showing an increasing prevalence with age. Protrusion is quite rare
in adolescence (3-9.7%) according to previous studies (Erkintalo et al. 1995,
Kjaer et al. 2005b), but the prevalence increases quickly by the age of 20 years
(Erkintalo et al. 1995). Erkintalo et al. (Erkintalo et al. 1995) reported a
prevalence of 21% for protrusion at 18 years, which is exactly the same as in our
study. However, in the present study the herniations included protrusions and
extrusions. A few previous studies (Samartzis et al. 2011, Tertti et al. 1991)
reported combined prevalences of bulging and protrusion/extrusion, showing
prevalences comparable to other earlier studies and our results. Only one earlier
study (Kjaer et al. 2005b) has evaluated extrusions, finding none at the age of 13
years. In our study, extrusion was found rarely (3.4%), which is in line with
studies among adults with a prevalence of 0-24% (Endean et al. 2011). Moreover,
they are claimed to be rare among subjects less than 50 years (Endean et al. 2011,
Weishaupt et al. 1998).
Similarly, annular tears have not previously been commonly studied among
young subjects. In the Danish study of 13-year-olds (Kjaer et al. 2005b), annular
tears and HIZ lesions were observed in 7% and 5% of subjects, respectively. In
the present study, we found a similar prevalence of radial tears (comparable to
annular tears in Danish study) and HIZ lesions.
Schmorl’s nodes are quite rare in childhood (Hamanishi et al. 1994, Kjaer et
al. 2005b), but the prevalence increases toward adulthood (Samartzis et al. 2011)
In their 13-year-old study population Kjaer et al. (Kjaer et al. 2005b) found
Schmorl’s nodes in 2.5% of the subjects, while in a slightly older (13- to 20-yearolds) study population the prevalence was 7.2% (Samartzis et al. 2011). Our
results are in line with earlier findings as in our study population Schmorl’s nodes
were found in 17.1% of the subjects. The increase in prevalence can be explained
by the older subjects in the present study compared to the study on 13- to 20-yearolds.
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Spondylolysis and spondylolisthesis have not been properly evaluated among
children and adolescents, probably because CT is the best imaging method for
spondylolytic defects, but the radiation dosage caused by CT examination cannot
be accepted for healthy young subjects. The Danish study (Kjaer et al. 2005b) of
13-year-old subjects reported a prevalence of 2.8% for combined spondylolysis
and spondylolisthesis on MRI. Our findings are in line with previous findings
among adults (Brooks et al. 2010, Kalichman et al. 2009c).
6.2.1 Gender differences
Previous studies have found DD more often in males than in females and there is
a tendency for boys to have DD earlier than girls (Miller et al. 1988). Mean levels
of DD among 20-year-old Finnish conscripts and 13- to 20-year-old Chinese
juveniles were 1.1 and 1.3, respectively (Samartzis et al. 2011, Waris et al. 2007)
in line with our findings. Schmorl’s nodes have been reported to be more frequent
among adult males (Kyere et al. 2012, Mok et al. 2010) but no such gender
distribution is known among younger subjects. In our study males had a higher
prevalence of Schmorl’s nodes in accordance with studies on adults. Previous
studies on adults have also found spondylolysis and (degenerative)
spondylolisthesis to be more frequent among adult males and females,
respectively (Brooks et al. 2010, Kalichman et al. 2009b, Kalichman et al. 2009c,
Virta et al. 1992): however, we did not find any differences between genders.
6.3
Association of degenerative findings with low back symptoms
Only two earlier cohort studies (Kjaer et al. 2005b, Samartzis et al. 2011) and one
case-control study (Salminen et al. 1999) have evaluated the association of
lumbar degenerative findings with LBP among adolescents or young adults. Our
findings are consistent with earlier findings with regard to association of DD with
LBP. Salminen et al. (Salminen et al. 1999) reported the strongest association of
DD at 15 years with persistently recurrent LBP at 23 years. Among Chinese
juveniles, global severity of DD, i.e., the sum score of DD, and LBP were
strongly associated (Samartzis et al. 2013).
A Finnish case-control study found protrusions at 15 and 18 years to be
associated with LBP at 23 years, but the strength of association was of lesser
magnitude than for DD (Salminen et al. 1999). Among Danish children and Chinese
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juveniles, herniations were associated with LBP (Kjaer et al. 2005b, Samartzis et al.
2011). Our findings are in line with these previous findings. Moreover, we found an
association between recently increased severity of LBP and extrusions, which has not
been reported earlier among adolescents or young adults. The Danish study (Kjaer et
al. 2005b) did not find any association between annular tears and LBP, and we found
only a tendency in our subjects who were 8 years older. Two previous studies (Kjaer
et al. 2005b, Samartzis et al. 2011) have studied the association of HIZ lesions with
LBP among younger subjects (children and juveniles) with conflicting results. The
reason for that may be due to the discrepancies between pain variables. Our results
were in concordance with the results of Samartzis et al (2011). Endplate changes were
associated with LBP among 13-year-old Danish children, but they included both
Schmorl’s nodes and endplate irregularity in endplate changes (Kjaer et al. 2005b).
In the current study the prevalence of Schmorl’s nodes was nearly three times higher
compered to the Chinese study (Samartzis et al. 2011), but neither one found an
association for LBP. The frequencies of Modic changes were low in both previous
studies among teenagers (Kjaer et al. 2005b, Samartzis et al. 2011), in accordance
with the current study. However, in the current study very wide confidence intervals
were calculated (0.94–88.59) for Modic changes showing a trend for LBP and,
therefore, their role in LBP cannot be excluded. We did not find an association of
spondylolytic defects and LBP; however, such an association was found among
Danish female children (Kjaer et al. 2005b). Our findings support the hypothesis of
discogenic origin of LBP in spondylolytic defects because the adjusting for DD
attenuated the significance of spondylolytic defects. After adjusting for DD, in the
present study the only specific MRI finding significantly associated with LBP was
herniations, showing their role in LBP among young adults.
6.4
Association of degenerative findings with lifestyle factors
There is only one study on the association between lumbar degenerative MRI
findings and lifestyle factors among adolescents or young adults (Samartzis et al.
2011), which evaluated the role of physical activity (at least twice a week
involvement in exercise routine), smoking (current and duration in years), BMI
(height and weight), and history of lumbar injury causing LBP. A few studies on
young athletes have been done and these will be referred to in the physical
activity chapter.
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6.4.1 Physical activity and sports
It has been suggested that physical inactivity or long-term exercise may induce
DD (Elfering et al. 2002, Urban & Roberts 2003) , while moderate physical
activity is suggested to enhance the well-being of the disc (Adams et al. 2014).
The “right” amount of physical activity for lumbar disc well-being is unknown.
Twice a week participation in exercise routine was not associated with lumbar DD
among juvenile Chinese (Samartzis et al. 2011). We analyzed physical activity
with MET hours per week, which is a more accurate way to measure physical
activity than just asking about participation in sports, because it takes into account
the time spent in physical activity and its intensity. However, we did not find an
association between lumbar DD and physical activity, although there was trend
for a U-shaped association among females. In some sports DD has been found to
be more frequent than in age-matched, less active, but not inactive, peers (Hangai
et al. 2009, Sward et al. 1991b). A 2-year prospective study found playing a
lineman position in American football risky for progression of lumbar DD
(Nagashima et al. 2013). We did not analyze the association of sports with DD.
However, 50% and 32% of the males and females, respectively, reported
exercising briskly over three hours a week, which is more than average 18-yearold Finnish did in 2009 (Husu 2011).
6.4.2 Smoking
In the Chinese cross-sectional population-based study, no association between
smoking and DD was found (Samartzis et al. 2011). We used pack-years of
smoking in the present study and found a nearly significant association of
smoking with DD among males. In the present study, the prevalences of smoking
were similar compared to a Finnish survey (Varis & Virtanen 2013).
6.4.3 Obesity
The association between obesity and lumbar DD has only been investigated in
one earlier study. They found a dose-response relation between obesity and sum
score of DD with higher ORs in obese than in overweight subjects (Samartzis et
al. 2011). In the current study, we had similar findings although we did not
classify the subjects to overweight and obese groups but used quartiles to improve
the power of the statistical analysis. However, our lower threshold of upper
94
quartile was 22.7 kg/m2, which is approximately 1.5 units lower than the earlier
reported threshold for overweight among adolescents (males 23.9 kg/m2 and
females 24.4 kg/m2) (Cole et al. 2000). Two prior studies on adults (Liuke et al.
2005, Samartzis et al. 2012) have also found the association of overweight and
obesity with lumbar DD. In the Finnish study the effect was stronger at young age
(study population included only male subjects) (Liuke et al. 2005), while in the
latter study (Samartzis et al. 2012) the strength of associations was stronger in
obese compared to overweight subjects. Moreover, a recent study of surgical
tissue samples of intervertebral discs showed that overweight correlated with
histological degenerative abnormalities, especially among males (Weiler et al.
2011). In the present study, obesity was associated with DD irrespective of the
assessment method (BMI or MRI-based assessment), whereas no such association
was found among females.
In the Health 2000 survey, 38% of 18- to 24-year-old males and 25% of
females were overweight (Koskinen 2005). In the current study, 27.5% and
15.7% of males and females, respectively, were overweight, showing a similar
difference between genders as in Health 2000.
6.4.4 Other lifestyle factors
The association of occupational loading with lumbar DD is not clear according to
earlier studies among adults (Hassett et al. 2003). However, in the present study
the subjects were young adults with only a maximum of 3 to 5 years of full-time
occupational loading and, therefore, it is unlikely to influence lumbar DD.
Elfering et al. (Elfering et al. 2002) reported that inactivity is a risk factor for
deterioration of lumbar DD among adults. We evaluated whether total sitting time
per week (school hours were excluded) is associated with DD, but did not find an
association (data not shown). The males sat significantly more than females (6.4 h
vs. 6.0 h at 16 years, 8.1 h vs. 7.5 h at 18 years and 7.8 h vs. 6.9 h at 19 years).
6.5
Clinical relevance of degenerative findings
In the earlier studies among adolescents and young adults DD has been found to
be associated with LBP (Kjaer et al. 2005b, Salminen et al. 1999, Samartzis et al.
2011), and we obtained similar results. Compared to previous studies, we did not
rely on only one or two pain questions but combined seven questions on pain,
95
pain consequences and disability into one summary score of low back symptoms
and evaluated symptoms over a three-year period. This is an advantage of the
current study due to large individual differences in pain sensitivity (Coghill et al.
2003). It has been suggested that mild DD is not associated with LBP (Lotz et al.
2012) while moderate DD is associated with LBP among adults (Borenstein et al.
2001). Our findings are in line with these results. A DD sum score of at least 4
was significantly associated with symptoms in both genders, while a DD sum
score of 1-3 was related to symptoms only among males. However, a major
percentage of symptomatic subjects had no DD. Therefore, it is essential to
evaluate the patient’s DD in the context of symptoms. Clinically one has to
acknowledge the association of DD with osteoarthritis of the zygapophyseal joint
(Adams & Dolan 2012) and spondylolisthesis (Kalichman et al. 2009c) as a pain
source when prognosis and treatment are considered. Moreover, DD increases
with age, which makes it more complicated to distinguish discogenic pain from
normal age-related changes (Urban & Roberts 2003).
Modic changes have been associated with LBP among adults (Adams &
Dolan 2012, Albert et al. 2008, Hancock et al. 2012, Kuisma et al. 2008). Only
four subjects had Modic changes and half of them had type I changes.
Histologically type I Modic changes have been found to be more densely
innervated and therefore more likely to cause pain (Fields et al. 2014). Modic
changes occurred at the two lowest lumbar levels similarly as seen among adults
(Jensen et al. 2009), and two type II Modic changes were adjacent to a disc with a
HIZ lesion and one type I Modic change was adjacent to a disc with a protrusion.
Protrusions are typical among asymptomatic adult subjects (Boden et al.
1990, Borenstein et al. 2001, Jensen et al. 1994, Kjaer et al. 2005a), but some
studies have shown protrusions to be associated with LBP (Endean et al. 2011).
However, extrusions are more often found in symptomatic adults (Jarvik et al.
2001, Weishaupt et al. 1998). Nevertheless, protrusions were associated with
seeking care and LBP especially among adolescent females (Kjaer et al. 2005b,
Tertti et al. 1991). The prevalence of herniations was higher in our study in
subjects with persistent (3-year period) low back symptoms in both genders.
However, extrusions were more prevalent among female subjects whose back
symptoms and disability had increased enormously over the 3-year period. One
small-scale Finnish study on adolescents found that protrusion at 15 and 18 years
increased the risk of recurrent or continuous LBP at 23 years (Salminen et al.
1999). Unfortunately, our study did not include MRI performed in adolescence.
96
Thus, we do not know if symptomatic subjects had progression of disc
displacement over the 3-year period.
There are conflicting data on the association of annular tears (radial tear and
HIZ lesions) with LBP among adults (Endean et al. 2011, Jarvik et al. 2001, Khan
et al. 2014, Videman & Nurminen 2004). Radial tears were not associated with
seeking care among 13-year-old Danish children, while HIZ lesions were (Kjaer
et al. 2005b). Our results are contradictory to the Danish study, because HIZ
lesions were not associated with low back symptoms in our study. Therefore, our
results are in line with the Chinese study which did not find an association
between HIZ lesions and LBP (Samartzis et al. 2011). However, radial tears were
related to LBP in the crude model, but the association attenuated to insignificance
in the fully adjusted model. Interestingly, a recent study on adults has found an
association of brighter signal intensity of HIZ lesion with LBP (Liu et al. 2014).
However, we did not measure the brightness of the HIZ lesions.
The role of Schmorl’s nodes in LBP remains controversial among adults and
adolescents (Kjaer et al. 2005b, Kyere et al. 2012, Samartzis et al. 2011). In the
larger of the two studies done on adolescents (Kjaer et al. 2005b), they found an
association of LBP and endplate defects, which included Schmorl’s nodes and
smaller endplate cracks (defects). We did not analyze endplate defects in our
study. Schmorl’s nodes were associated with symptoms in the crude analysis but
the association was attenuated in the adjusted model. The positive association in
the crude analyses is probably due to co-occurrence of Schmorl’s nodes and DD
as suggested earlier (Williams et al. 2007).
Spondylolytic defects are associated with LBP among adolescents, especially
among females (Kjaer et al. 2005b). However, the painfulness of spondylolytic
defects may be due to DD (Dai 2000). However, in our study 25% of the
spondylolytic defects were found in subjects without DD, and 3 out of 8 of these
subjects belonged to the major symptom cluster with no other degenerative
changes in lumbar spine.
6.6
Methodological considerations
The strength of our study is its population-based birth cohort design and narrow age
range, which minimizes the confounding effect of age. However, some participation
bias is acknowledged. Only minimal differences were found between the study
population and the whole OBS population (n = 1,987). Although the participants of
the present study had slightly healthier lifestyles (non-smokers, less time spent sitting,
97
physically more active, and leaner) and came from families with higher
socioeconomic status slightly more often than the nonparticipants, a higher proportion
of them had LBP. An additional factor of interest was the higher proportion of
missing data among nonparticipants compared to participants. The data were recorded
at 16 years when the participants did not yet know about the future lumbar MRI
study. We suppose that socioeconomic factors, low education level, low occupational
status, detrimental health behavior, lack of interest in the study topic (i.e.,
musculoskeletal problems) and personality characteristics may have influenced the
willingness to participate. The respondents to the 18-year survey (n = 1,987) were
more likely to be living in two-parent families than those lost to follow-up (n = 953)
(Mikkonen et al. 2008). Of the subjects invited to the lumbar MRI (n = 874), the
nonparticipants had slightly higher BMI than the participants. However, the influence
of these differences on the observed associations would be minimal.
There are several other contributing factors in LBP than those used in our
statistical models. Determinants of LBP not evaluated in the current study
include poor coping ability, poor general health, and psychiatric comorbidities
(Chou & Shekelle 2010), psychosocial factors (Kennedy et al. 2008, Paananen et
al. 2010), insufficient quantity or quality of sleep (Auvinen et al. 2010) and
impaired motor control (Luomajoki et al. 2010). These can be classified
according to the International Classification of Functioning, Disability and Health
(ICF) model (Fig. 22). In the present study several components of ICF were
studied: body structure (MRI findings and obesity measurements), body function
(BMI, bioelectrical impedance, WC, LBP severity and history), activities (MET),
participation (influence of LBP on participation in daily activities and sports),
environmental factors and personal factors (smoking). (World Health
Organization 2013).
The main limitation of our study is the cross-sectional design of spine imaging,
which prevents us from drawing conclusions about temporal patterns between MRI
findings and symptoms because of the lack of sequential MRI scans. Therefore, the
onset and progress of DD in the lumbar spine among the study subjects still remains
unknown. However, as LBP has an early onset (Balague et al. 1999, Hestbaek et al.
2003) one would probably need a very large cohort starting in early teenage years
with annual imaging for several decades to study the natural progression of
degenerative changes and their association with symptoms. Due to the young age of
our participants, the influence of environmental factors on lumbar DD might be less
than that of genetic factors. However, some environmental factors were already
associated with DD among our young (mean age 21 years) study participants.
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Fig. 22. The International Classification of Functioning, Disability and Health (ICF) model.
Each component includes multiple domains, which consist of units of classification, i.e.,
categories (World Health Organization 2013, published by permission of World Health
Organization).
The presence of LBP, need for medication and visits to physicians, and backrelated functional limitations at 18 and 19 years of age (in addition to the date of
imaging) were elicited before any decision on lumbar MRI scanning was made, which
enabled us to depict profiles of low back symptoms for individual cohort members
during a 3-year period. A well-established clustering method, LCA, was used for
classifying the subjects into pain clusters, which allows a comprehensive evaluation
of the development of the subjects’ pain and disability over time. The 5 clusters
formed represent different degrees of severity of low back symptoms as well as
different patterns of disease fluctuation, thereby allowing for correlation of low back
symptom severity. Combining functional limitations with simple pain estimates is
also reasonable because of the large individual differences in pain sensitivity (Coghill
et al. 2003).
We evaluated the overall level of physical activity as MET hours per week,
which has not been done in earlier LBP studies. METs take into account every
physical activity level and therefore subjects who exercise actively even at a low level
may have high MET scores. MET acts as a surrogate measure of overall physical
99
activity level, not only participation in physical exercise and sports. We used the
mean of MET hours per week at 16 and 19 years as estimate of average amount of
physical activity over the three-year period. We did not, however, evaluate the
association between different sports and DD, and therefore we cannot rule out the
existence of risk sports with harmful effects on disc well-being. Assessment of
physical activity (MET hours per week) calculations was based on self-reported
values, which may have led to over-reporting of physical activity (Klesges et al.
1990). Unfortunately, more objective methods for assessment of physical activity
such as pedometers, accelometers and heart rate monitors were not available for the
present study. However, the test-retest reliability of physical activity questionnaire
has been shown to be good in 16-year-old population (Tammelin et al. 2007). The
correlation between self-rated brisk physical activity and measured aerobic fitness has
earlier also been found to be acceptable among 8- and 10-year-old schoolchildren
(Booth et al. 2001).
A further limitation is that the data on smoking consisted of self-reported values.
We used pack-years at 19 years due to lack of such data at 21 years. We assume that
young adults are more likely to underreport smoking than to overestimate it, and
hence we regard the association between smoking and DD among males plausible.
Such underestimation of smoking has been found in earlier studies (Connor Gorber
et al. 2009).
Anthropometrics (weight, height, WC) were in most cases based on measured
values. BMI was calculated using measured height and weight, but we did not use the
published cut-off values of obesity and underweight for children and adolescents
(Cole et al. 2000, Cole et al. 2007), because only a few subjects were outside the
limits of the cut-offs. Moreover, using measurements at 16 and 19 years allowed us to
evaluate the impact of persistence in anthropometric measures. We found that the
association of WC with DD was of the same magnitude as two of the MRI-based
obesity measures. This implies that WC could be used clinically as a quick, low-cost
measurement for evaluating abdominal adiposity as a risk factor of DD.
Prior studies on body composition have used several methods for body
composition, but no gold standard for this purpose exists. Underwater weighing was
earlier considered the most accurate measure, but was later replaced by DXA and
MRI (Pritchard et al. 1993). Moreover, MRI adiposity measurements have proved to
be superior to WC in the assessment of visceral abdominal fat (Yim et al. 2010). In
our study, VST and DST were not associated with DD among males, whereas two
other MRI-based obesity measures were. However, the usefulness of VST may have
been underestimated in our study because VST was unmeasurable in 43 participants.
100
Subcutaneous adipose tissue measured through MRI on the back (similar to DST) is
also believed to be a better total body adiposity estimator than WC or waist-to-hip
ratio (Kvist et al. 1988). SAD on MRI has been considered a good risk estimator of
cardiovascular diseases (Guzzaloni et al. 2009) and, moreover, SAD (Yim et al.
2010) and AD (De Lucia Rolfe et al. 2010) are regarded as good measures of
visceral adipose tissue. Fifty-three of the participants may have had even higher AD
and SAD than estimated, which would strengthen the association of these measures
with DD. We used midsagittal MR images to diminish measurement errors. In the
midsagittal images, no abdominal muscles distracted the measurements, as the ventral
starting point was linea alba. Similarly, the dorsal endpoint for SAD was the
subcutaneous fascia just beneath the spinous processes of the vertebrae. Thus the
main compartments measured in SAD were subcutaneous fat, visceral fat, bowels,
and bony spinal column. The difference between females and males can partly be
explained by the adipose tissue storage differences between genders. Most of the MRI
adiposity measurements were performed at the abdominal level, which is the main fat
storage area among males. Among females, the fat tissue is located mainly in the
thighs and buttocks (Stevens et al. 2010). In this study, we did not measure gluteal
adiposity thickness or thigh fat storage thickness, and we were not able to study the
significance of high adiposity level per se, especially among females. The hormonal
differences between genders may also have an effect. In addition, we had no exact
data on the exposure times of adiposity. We had data on weight and height at seven
years, but there was a nine-year gap before the next measurement at 16 years.
Bioelectrical impedance is widely used to measure body composition.
Bioelectrical impedance is a reasonable estimate of the body composition in
controlled conditions for generally healthy and euvolemic adults. However, several
factors may impact on the results of bioelectrical impedance measurements
(consumption of food and drink, physical activity before measurement, menstrual
cycle etc.). Moreover, several equations have been developed to estimate body
composition with bioelectrical impedance and the results are inconsistent in different
populations. Therefore, in order to have reliable results, equation should be chosen
carefully based on age, gender, level of physical activity, level of body fat and
ethnicity (Dehghan & Merchant 2008). Our study population had small age
differences and ethnicity differences were minimal.
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6.6.1 Magnetic resonance imaging
MRI is regarded as the most detailed disc imaging modality (Lotz et al. 2012).
Morphologically classified DD of the lumbar spine in cadavers correlated with DD
classification on MRI between grades 1 to 3 vs. grades 4 and 5, and the latter two
differed also significantly from each other (Benneker et al. 2005). The imaging
sequences used in the current thesis are not optimal e.g. for endplate defects, which
require methods such as ultrashort echo time MR imaging (Bae et al. 2013). We
acknowledge that it is important to further develop the MRI modalities to enhance e.g.
their diagnostic accuracy and clinical efficacy (Lotz et al. 2012).
In the evaluation of Schmorl’s nodes and Modic changes, one radiologist was
very strict about avoiding false-positive findings, whereas the other was strict about
avoiding false-negative findings. This explains the low inter-rater reliability of the
musculoskeletal radiologists. We used qualitative modified Pfirrmann classification
(Pfirrmann et al. 2001) in the assessment of DD, which is considered inferior to the
quantitative assessment of DD (Videman et al. 2008a). The inter-rater reliability for
DD between two expert musculoskeletal radiologists was moderate to good at the
three lowest levels. The kappa-values were lower than previously reported (Carrino
et al. 2009), but the disagreements were settled by consensus. However, we believe
that prevalences of DD and specific degenerative findings in the lumbar spine are
more reliable in studies II-V compared to study I. Moreover, we analyzed the
reliability of adiposity MRI measurement and found the ICC to be very good in each
adiposity measurement.
The latest lumbar disc nomenclature recommends the term radial fissure over
radial tear because tear refers to injury whereas fissure only defines a
morphologic change in the annulus. Moreover, broad-based protrusion involving
between 25% and 50% of the disc circumference has been included in disc
bulging. (Fardon et al. 2014). It might have had a slight impact on the prevalences
of protrusions in our study if we had used the new nomenclature criteria for
protrusion instead of the first version from 2001 (Fardon et al. 2001).
6.7
Implications and future directions
In general, there is a lack of large population-based studies on prevalences of
MRI findings among children, adolescents and young adults. At younger age, true
risk factors for DD may be found, because degenerative findings are less frequent
than in adulthood. We have found some contributing factors for DD among young
102
adults, but the causality of these factors with lumbar DD must be confirmed in
prospective studies.
The current study did not find an association between physical activity and
DD. However, we did not use objective measurement of physical activity.
Furthermore, compared to overall physical activity, some specific sports may be
more detrimental on spinal structures.
Obesity has been suggested to be a low-grade inflammatory condition
(Samartzis et al. 2013), which may have an effect on several structures and
organs. We found that obesity at 16 years of age was associated with DD in
males, but we did not measure C-reactive protein (CRP). In future, it would be
interesting to study the relationship of CRP and other biomarkers with DD.
Additionally, longitudinal evaluation of lumbar degenerative findings is needed in
order to evaluate the effect of environmental exposures such as continuing
smoking, quitting smoking and gaining or losing weight on incident imaging
findings.
Finally, several LBP classifications have been developed over the years to
explain this economically burdening disease. Although we found an association of
lumbar DD and low back symptom severity, 46% of the nearly asymptomatic or
asymptomatic subjects had at least one degenerated disc while 27% of the
symptomatic subjects did not have DD. Several authors (Boden et al. 1990,
Borenstein et al. 2001, Jensen et al. 1994) have suggested that only a small
proportion of patients with LBP can be explained explicitly by structural changes
while the majority of symptomatic subjects have functional or psychosocial
problems with central sensitization (O’Sullivan et al 2005). In future, besides
structural changes, these movement control impairments should be studied more
carefully as they might help us find the subgroups of LBP explaining the patients’
symptoms.
103
104
7
Conclusions
Lumbar DD, disc bulges, Schmorl’s nodes and protrusions are common while Modic
changes and disc extrusions are rare among young adults aged 21 years. DD and
herniations are more common in men than women, whereas HIZ lesions are more
frequently found in women.
DD and herniation were more prevalent in young adult subjects who had at least
moderately disabling LBP over a three-year follow-up period, from 18 to 21 years, or
recent onset severe disabling pain. Our results support the concept that an
intervertebral disc can be the pain generator of LBP. However, the clinical relevance
of DD and herniations on MRI must be evaluated in the context of symptoms, because
degenerative findings were present also in asymptomatic subjects. Moreover, the
prevalence of most of the specific MRI findings was low, which is why their role in
disabling LBP remains unclear.
BMI, WC and measures of abdominal obesity on MRI (sagittal diameter and
abdominal diameter) were associated with DD among young males. Moreover, having
smoked at least four pack-years showed a comparable association in males. Physical
activity had no significant association with DD in either gender. BMI, WC, measures
of abdominal obesity on MRI and smoking should be taken into account when
assessing the ‘risk profile’ of an individual’s susceptibility for DD.
105
106
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Appendix
123
Original publications
This thesis is based on the following original articles, which are referred in the
text by their Roman numerals.
I
II
III
IV
V
Takatalo J, Karppinen J, Niinimäki J, Taimela S, Näyhä S, Järvelin M-R, Kyllönen E &
Tervonen O (2009) Prevalence of Degenerative Imaging Findings in Lumbar Magnetic
Resonance Imaging Among Young Adults. Spine 34(16): 1716-1721.
Takatalo J, Karppinen J, Niinimäki J, Taimela S, Näyhä S, Mutanen P, Blanco
Sequeiros R, Järvelin M-R, Kyllönen E & Tervonen O (2011) Do degenerative MRI
findings associate with low back symptoms in young Finnish adults? Spine 36(25):
2180-2189.
Takatalo J, Karppinen J, Niinimäki J, Taimela S, Mutanen P, Blanco Sequeiros R,
Näyhä S, Järvelin M-R, Kyllönen E & Tervonen O (2012) Association of Modic
changes, Schmorl's nodes, spondylolytic defects, High Intensity Zone lesions, disc
herniations, and radial tears with low back symptom severity among young Finnish
adults. Spine, 37(14):1231-1239.
Takatalo J, Karppinen J, Taimela S, Niinimäki J, Laitinen J, Blanco Sequeiros R,
Paananen M, Remes J, Näyhä N, Tammelin T, Korpelainen R & Tervonen O (2013)
Body mass index is associated with lumbar disc degeneration in young Finnish males.
BMC Musculoskeletal Disorders, 14:87
Takatalo J, Karppinen J, Taimela S, Niinimäki J, Laitinen J, Blanco Sequeiros R,
Samartzis D, Tammelin T, Korpelainen R, Näyhä S, Remes J & Tervonen O (2013)
The association of abdominal obesity with lumbar disc degeneration – A magnetic
resonance imaging study. PLoS ONE 8(2): e56244
Reprinted with permission from Lippincott Williams & Wilkins (I-III), BioMed
Central (IV), and PLoS ONE (V).
Original publications are not included in the electronic version of the dissertation.
129
130
ACTA UNIVERSITATIS OULUENSIS
SERIES D MEDICA
1273. Häkli, Sanna (2014) Childhood hearing impairment in northern Finland :
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1274. Lehto, Liisa (2014) Interactive two-step training and management strategy for
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1277. Laitala, Anu (2014) Hypoxia-inducible factor prolyl 4-hydroxylases regulating
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1279. Kallankari, Hanna (2014) Perinatal factors as predictors of brain damage and
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1283. Orajärvi, Marko (2015) Effect of estrogen and dietary loading on rat condylar
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1285. Ylimäki, Eeva-Leena (2015) Ohjausintervention vaikuttavuus elintapoihin ja
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1286. Rautiainen, Jari (2015) Novel magnetic resonance imaging techniques for articular
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1287. Juola, Pauliina (2015) Outcomes and their predictors in schizophrenia in the
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U N I V E R S I T AT I S O U L U E N S I S
Jani Takatalo
University Lecturer Santeri Palviainen
Postdoctoral research fellow Sanna Taskila
Professor Olli Vuolteenaho
Jani Takatalo
Professor Esa Hohtola
DEGENERATIVE FINDINGS
ON MRI OF THE LUMBAR
SPINE
PREVALENCE, ENVIRONMENTAL DETERMINANTS
AND ASSOCIATION WITH LOW BACK SYMPTOMS
University Lecturer Veli-Matti Ulvinen
Director Sinikka Eskelinen
Professor Jari Juga
University Lecturer Anu Soikkeli
Professor Olli Vuolteenaho
Publications Editor Kirsti Nurkkala
ISBN 978-952-62-0782-7 (Paperback)
ISBN 978-952-62-0783-4 (PDF)
ISSN 0355-3221 (Print)
ISSN 1796-2234 (Online)
UNIVERSITY OF OULU GRADUATE SCHOOL;
UNIVERSITY OF OULU,
FACULTY OF MEDICINE;
UNIVERSITY OF HELSINKI,
DEPARTMENT OF PUBLIC HEALTH,
HJELT INSTITUTE
D
MEDICA