Medical Hypotheses (2008) 70, 361–368

http://intl.elsevierhealth.com/journals/mehy

Modic changes, possible causes and relation to low

back pain
H.B. Albert *, P. Kjaer, T.S. Jensen, J.S. Sorensen, T. Bendix,
Claus Manniche

All The Back Research Center, Part of Clinical Locomotion Science, University of Southern Denmark,
Lindevej 5, 5750 Ringe, Denmark

Received 3 May 2007; accepted 4 May 2007

Summary In patients with low back pain (LBP) it is only possible to diagnose a small proportion, (approximately 20%),
on a patho-anatomical basis. Therefore, the identification of relevant LBP subgroups, preferably on a patho-anatomical
basis, is strongly needed.
Signal changes on MRI in the vertebral body marrow adjacent to the end plates also known as Modic changes
(MC) are common in patients with LBP (18–58%) and is strongly associated with LBP. In asymptomatic persons the
prevalence is 12–13%. MC are divided into three different types. Type 1 consists of fibro vascular tissue, type 2
is yellow fat, and type 3 is sclerotic bone. The temporal evolution of MC is uncertain, but the time span is
years.
Subchondral bone marrow signal changes associated with pain can be observed in different specific infectious,
degenerative and immunological diseases such as osseous infections, osteoarthritis, ankylosing spondylitis and
spondylarthritis. In the vertebrae, MC is seen in relation to vertebral fractures, spondylodiscitis, disc herniation,
severe disc degeneration, injections with chymopapain, and acute Schmorl’s impressions.
The aim of this paper is to propose two possible pathogenetic mechanisms causing Modic changes. These are:
A mechanical cause: Degeneration of the disc causes loss of soft nuclear material, reduced disc height and
hydrostatic pressure, which increases the shear forces on the endplates and micro fractures may occur. The
observed MC could represent oedema secondary to the fracture and subsequent inflammation, or a result of an
inflammatory process from a toxic stimulus from the nucleus pulposus that seeps through the fractures.
A bacterial cause: Following a tear in the outer fibres of the annulus e.g. disc herniation, new capilarisation and
inflammation develop around the extruded nuclear material. Through this tissue it is possible for anaerobic
bacteria to enter the anaerobic disc and in this environment cause a slowly developing low virulent infection. The
MC could be the visible signs of the inflammation and oedema surrounding this infection, because the anaerobic
bacteria cannot thrive in the highly aerobic environment of the MC type 1.
Perspectives: One or both of the described mechanisms can – if proven – be of significant importance for this
specific subgroup of patients with LBP. Hence, it would be possible to give a more precise and relevant diagnosis

* Corresponding author. Tel.: +45 63 62 18 50; fax: +45 63 62 18 39.

E-mail address: haal@shf.fyns-amt.dk (H.B. Albert).


0306-9877/$ - see front matter c 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.mehy.2007.05.014
362
to 20–50% of patients with LBP and enable in the development of efficient treatments which might be antibiotics,
special rehabilitation programmes, rest, stabilizing exercise, or surgical fixation, depending on the underlying
cause for the MC.
c 2007 Elsevier Ltd. All rights reserved.
Introduction
Diagnosing patients with low back pain (LBP) is a
challenge for clinicians [1]. It is frequently stated
that only a small proportion (approximately 20%)
of patients with LBP can with reasonable certainty
be diagnosed based on a patho-anatomical entity
[1]. The most commonly used classification,
‘‘non-specific LBP’’ (80%), is not satisfactory nei-
ther for the patient suffering from LBP nor for
the clinician due to lack of accuracy in diagnosis
and treatment. Therefore, the identification and
diagnosis of relevant subgroups of patients with
LBP, preferably with a sound patho-anatomical ba-
sis, is strongly needed.
There is emerging evidence that signal changes
in the vertebral body marrow adjacent to the end
plates, also known as Modic changes (MC) are
rather strongly associated with LBP, and we will
in this paper argue that this should be considered
a specific and relevant subgroup of LBP patients.
Furthermore, we will outline two hypotheses on
the possible causes of MC.
End plates and vertebral body changes
Signal changes in the vertebral body marrow
adjacent to the end plates visualized by magnetic
resonance imaging (MRI) was described by de
Ross et al. [2] in 1987. These changes are accord-
ing to Modic et al. [3,4], visible as three differ-
ent types. Type 1 is seen on T2-weighted MRI
as areas of increased signal intensity and on T1-
Figure 1
Albert et al.
weighted MRI as low signal intensity extending
from the vertebral endplates into the vertebral
body. From histological studies of material har-
vested during surgery, MC type 1 have been de-
scribed as disruption and fissuring of the
endplate with regions of degeneration, regenera-
tion, and vascular granulation tissue [3]
(Fig. 1A,B). Type 2 is observed as increased signal
intensity on both T1- and T2-weighted images.
Biopsies revealed the MC type 2 to be disruption
of the end plates with increased reactive bone
and granulation tissue, and the hematopoetic ele-
ments in the vertebrae are replaced by abundant
fat (yellow marrow) [3] (Fig. 1C,D). MC type 3
are presumably bone sclerosis and are visualized
on MRI as decreased signal intensity on both T1-
and T2-weighted images [4].
Relation to low back pain
Kjaer et al. [5] observed in a sample of 412 per-
sons aged 40 from the general population a
strong association with LBP within the past year,
particularly for MC type 1. The prevalence of pain
within the last year in people with MC was 88%
and in people with no pain 12%. In the study by
Albert and Manniche [6] 166 patients with sciatica
(92% from a lumbar disc herniation) were evalu-
ated. They all had an MRI in the acute stage
and at follow-up 14 months later. At follow-up,
60% of the patients with MC suffered from LBP,
whereas in the group without MC only 20% had
LBP, OR of 6.1 (2.9–13.1) (p < 0.0001). The prev-
alence of MC increased in the 14 months from
25% to 49%.
In the study by Albert and Manniche [6] lumbar
pain was more frequent in people with MC type 1
compared to those with type 2, although not statis-
tically significant. Also Toyone et al. [10] and Kjaer
et al. [5] observed such a difference. Therefore,
MC type 1 is possibly more associated with pain
compared to type 2. The reason why MC type 1
are more painful could be that they reflect an ear-
lier and more active stage of inflammation.
Prevalence of MC
See Table 1.
Modic changes, possible causes and relation to low back pain 363

Table 1 The prevalence of Modic changes in different populations

Author Study population N Prevalence of Prevalence Prevalence Prevalence
all types of type 1 (%) type 2 (%) type 3 (%)
MC (%)
Albert and Manniche [6] Patients with acute 181 25 9 + (1% mixed 14 1
sciatica type 1and 2)
Albert and Manniche [6] Patients 14 month 166 49 29 + (5% 13 1
after acute sciatica mixed type 1
and 2)
Braithwaite [7] Patients referred to 58 48 Mainly
a discography prior type 2
to fusion
Karchevsky et al. [8] Consecutive patients 100 58 24 33 1
Kjaer et al. [5] The general 412 22 15 7
population aged 40
Kuisma et al. [59] Patients with 60 23a 2a (mixed 21a
radicular pain below type 1 and 2)
the knee
Kuisma et al. [59] As above the, 3 year 60 8a + (mixed 20a
follow-up type 1 and 2)
Mitra et al. [9] Patients with LBP or 670 18
sciatica
Modic et al. [3] Patients with LBP 474 20 4 16
and/or sciatica
Toyone et al. [10] Chronic LBP patients 500 19
Weishaupt et al. [15] Asymptomatic 60 13 3 10
people
Weishaupt et al. [13] LBP patients 50 22a 14a 9a
a
The percentage of MC are per disc, the observations per person is not available.

Discography and controls, but the number of these cytokines

Braithwaite [7] studied 58 patients with discogenic
pain who were referred to a discography prior to
fusion. Among them 48% of the patients had MC
predominantly type 2. The study showed that MC
is a highly specific indicator (specificity of 0.97)
of a painful disc. But the sensitivity was low, mean-
ing that patients can have LBP from other causes.
MC have also been shown to be painful on discogra-
phy in other studies [7,11,13] also with a low sensi-
tivity but at very high specificity, though this
relationship was not confirmed in the study by
Sandhu et al. [14] and Kokkonen et al. [12].
How can MC cause LBP?
So why does MC hurt? Ohtori [16] evacuated during
surgery the endplates of 14 LBP patients with MC
and 4 controls without MC. After preparation they
discovered that in 12(86%) of the 14 patients with
MC, as opposed to none of the controls, PGP 9.5
immunoreactive nerve fibres were located in the
endplate cartilage. Also TNF immunoreactivity
was discovered in the endplates of both patients
was significantly higher in patients with MC com-
pared to the controls, and significantly higher in
patients with MC type 1 than type 2. Regardless if
the patient had MC or not, only few PGP 9.5 immu-
noreactive fibres were present in the vertebral
bone marrow, and no TNF immunoreactivity was
observed. The presence of these proinflammatory
cytokines and SP-immunoreactive nerve fibres
may explain why MC causes pain [16].
Because MC in most cases are observed in con-
junction with a degenerated disc, Crock [17] pro-
posed the concept of ‘‘internal disc disruption’’.
According to his theory, repeated trauma to the
disc could result in the production of inflammatory
substances in the nucleus pulposus. When these
toxic chemicals diffuse through the vertebral end-
plate, it could result in a local inflammatory reac-
tion resulting in back pain.
The evolution of MC
Mitra et al. [9] studied a sub-sample of 44 patients
with Modic type 1 from a population of 670 patients
conservatively treated for LBP and/or sciatica. It
364
can be assumed that a considerable percentage of
these patients with symptoms of sciatica suffered
from a herniated disc. Over a period of 12–72
months, 37% converted fully to type 2, 15% con-
verted partially to type 2, 40% into more extensive
type 1 changes, and 8% showed no change. In the pa-
tients whose symptoms had improved, the type 1
changes had developed into type 2. In the patients
reporting a worsening of their symptoms, the type
1 changes had progressed and become worse [9].
Modic et al. [3] studied the evoluation in MC in 16 pa-
tients with LBP without sciatica. Five out of six MC
type 1 converted at least partially into type 2, while
ten patients with type 2 remained unchanged after a
period of 12–36 months [3]. Bayer et al. [61] ob-
served 55 non-surgically treated patients over a
mean period of time of 2 years. Of the MC type 1,
6% had reverted to normal, 18% of the MC type 2
had evolved either to normal or MC type 1.
MC after lumbar disc herniation
In a study by Albert and Manniche [6] 166 conserva-
tively treated patients with sciatica (predomi-
nately from a herniated disc), had an MRI at the
acute stage and again 14 months later. The preva-
lence rate of MC type 1 increased from 9% at base-
line to 29% at follow-up. The MC type 2 and type 3
changes remained stable. New MC type 1 were ob-
served in 17% of the patients. Furthermore, 11% pa-
tients who exhibited type 1 or 2 changes at
baseline developed new type 1 changes in the same
vertebrae as the previous MC was observed. None
of the patients with an intact disc developed MC
[6]. Kushima et al. [59] observed 60 patients with
a herniated disc. At baseline 23% had MC predomi-
nating type 2 changes. At 3 years follow-up, new
MC had developed in 6% of the discs predominately
type 1 or mixed type1 and 2, the majority being
localized at the level of the previously herniated
disc.
The relationship between herniated disc and MC
is also supported by the fact that more men than
women suffer from a herniated disc, and men have
a higher prevalence of MC than women [8]. The
largest proportion of MC was observed in the adja-
cent vertebrae of the L4 and L5 discs [6,8], where
95% of the herniations occur [18].
Signal changes in the bone marrow in
conjunction with immunological diseases
and bone disorders
Signal changes in the vertebral bone marrow have
been observed as a finding in several diseases,
Albert et al.
among them in immunological diseases such as
ankylosing spondylitis and Reiter’s disease [44,45].
The changes in the bone marrow in these diseases
are probably related to the auto-immune patho-
genesis of the specific disease. Although the pain
mechanism is not fully understood, signal changes
in the bone marrow, most often described as oede-
ma, are also associated with pain in a variety of
joint and bone disorders such as osteoarthritis,
degenerative facet joint disease and lumbar spon-
dylolysis [46–56].
Summary
1. Signal changes in the vertebral body marrow
adjacent to the end plates also known as Modic
changes (MC) are strongly associated with LBP.
2. MC type 1 are probably more painful than type 2.
3. The prevalence of MC amongst patients with
LBP is 18–58%, depending of the study popu-
lation.
4. MC first occurs as type 1. Type 1 can then evolve
to type 2 or convert into normal. Type 2 usually
converts to normal. The time span is years.
5. Disc herniation, severe disc degeneration, injec-
tions with chymopapain, and acute Schmorl’s
impression [29], seems capable of inducing MC.
6. Discography is painful in the discs with adjacent
MC. Discography has high specificity but low
sensitivity.
Hypotheses
Signal changes in the bone marrow are observed in
conjunction with several immunological diseases as
well as joint and bone disorders but their relation-
ship to pain and development of the diseases are
unknown. However, signal changes in the vertebral
endplate and vertebral bone marrow are on the
other hand closely linked to LBP [5–7,9,13,14].
Furthermore, disc herniation and severe disc
degeneration disc are strong risk factor for devel-
oping MC (especially type 1). Two hypotheses
regarding the pathogenesis of MC in the vertebrae
emerges from the presented data, one mechanical
and a bacterial. These may be involved, simulta-
neously, but the weighting is unknown.
Mechanical cause
The strong association between MC, severely
degenerated discs [6,20,57], and previous disc her-
niation [19], gives reasons to propose the hypothe-
sis that MC may be caused by mechanical stress.
Modic changes, possible causes and relation to low back pain
In case of a herniation and severe degeneration
the loss of nuclear material may increase the shear
forces on the endplates and micro fractures may oc-
cur. The relationship between this degenerative
state and the forces acting within the disc has been
documented by Adams et al. [21–23]. Hence, the
Modic type 1 changes might initially reflect bleeding,
oedema and vascularisation following trauma or the
oedema associated with the repair process after mi-
cro fractures within the endplate and the vertebral
bone. Another possibility is, that the toxic nucleus
tissue invades the endplate and vertebral bone
through fractures in the endplates and causes an
inflammatory response. It may not only be nucleus
material entering the vertebrae, but also as sug-
gested by Crock that after damage of a disc irritating
substances are produced, draining into the vertebral
body and causing an autoimmune reaction [17]. This
mechanical theory is supported by the fact that his-
tological findings of the MC type 1 + 2 demonstrate
disruption of the end plates with evidence of chronic
repetitive trauma [3].
Masaryk et al. [24] injected chymopapain into
the discs of 21 patients with a herniated disc. They
observed that this resulted in severe degeneration
in most of the discs, and more than 50% of the discs
developed MC type 1 in the adjacent endplates.
Endplate changes developed only around the in-
jected discs. The author’s discus whether the end-
plate changes are an inflammatory response to the
chymopapain or due to the altered biomechanics in
the degenerated disc. These observations were
confirmed by Kato et al. [25].
In further support of the mechanical theory, sev-
eral studies [26,27,58] have reported that MC type
1 disappear or evolve into type 2 after osteosynthe-
sis (providing stabilisation to heal the micro frac-
tures) which probably leads to lesser pain [26].
Not only degeneration but also loading can cause
micro fractures. van Dieen et al. [28] describe that
the vertebral endplates and trabecular bone can
fail with compression forces, and that the damage
is determined by the cross-sectional area of the
vertebrae and the bone density. This is supported
by a study of Karhevsky [8] who showed that it is
not the patient’s BMI, but the patient’s actual
weight that represents a risk factor, a bigger load
being more likely to lead to more micro fractures
or other kind of damage.
Bacterial cause
Another patho-genetic reason for the occurrence
of MC might be an infection involving low virulent
anaerobic bacteria [30,60].
365
Following a breach of the outer annulus fibrous
in conjunction with a herniation, new capilarisa-
tion occurs around the extruded nucleus pulposus
material within a short period of time [31–34],
and an inflammation with a presence of macro-
phages occurs [32–35]. In this special environ-
ment, it might be possible for the anaerobic
bacteria to enter the disc through the breach,
causing a low virulent and slowly developing infec-
tion in the disc. Due to the fact that the disc is an
avascular structure, it is an ideal environment for
the growth of anaerobic bacteria. The infection
may therefore result in local tissue inflammation
with oedema, and due to production of cytokines
known to affect the bone; this is leading to MC type
1 in the vertebral endplates and subchondral bone
marrow.
Several studies have shown vertebral endplate
changes and marrow oedema to be observed in
conjunction with discitis [41,42,62,63]. However
due to the low virulence of these anaerobic bacte-
ria, the inflammatory response and erosive changes
are not as strong as seen in discitis caused by more
aggressive strains of bacteria e.g. Staphylococcus
aureus. Infections in the discs with low virulent
anaerobic bacteria are therefore rarely diagnosed
as discitis because the tissue reactions in the disc
are slow and less destructive and therefore poorly
illuminated on MRI. This lack of virulence is proba-
bly also one of the reasons why the infection prop-
erly does not spread to aerobic tissues like the
vertebrae, together with the severe difficulties
the anaerobic bacteria would have to survive in
the highly aerobic environment in the vertebrae
and especially in the MC type 1 hence this is hyper-
vascularised tissue. In support of these observa-
tions is the study by Albert and Manniche [6] who
reported that in a group of patients with sciatica,
none of the patients with a normal disc contour
developed MC, which occurred only in patients with
an annular lesion, further a more massive lesion of
the disc resulted in a higher prevalence of newly
developed MC type 1.
Are bacteria present in or around the disc? Stir-
ling et al. who removed nuclear tissue under sterile
conditions during surgery for lumbar herniated
discs found that 53% of the patients were found
to be infected with low virulent anaerobic organ-
isms (Proprionibacterium acnes and Corynebacte-
rium propinquum) as opposed to none of the
patients who were operated for other spinal disor-
ders [36]. They therefore, hypothesised that pa-
tients with sciatica have a breach in the
structural integrity of the spinal disc, possibly from
minor trauma, which allows access by low virulent
micro organisms [36]. Coscia et al. [60] evacuated
366
tissue from cervical and lumbar herniations and re-
ported that respectively 59% and 71% of the herni-
ations were most frequently infected with P. acnes
and Staphylococcus.
How do low virulent anaerobic bacteria end up
in the herniation? These bacteria are found in all
individuals on their skin and in their oral cavities.
Small tears in the skin presents a pathway for the
bacteria into the circulatory system, which the
bacteria also frequently invade during tooth brush-
ing, but normally they do not present any health
risks due to the aerobic environment in the blood-
stream [37–40]. They can, however, impose a
health risk in patients with a special environment,
for example, in individuals with a prosthetic
device.
Macrophages are present in high numbers in the
extruded and inflamed nuclear material. Macro-
phages often carry live anaerobic bacteria, and at
their death leave live anaerobic bacteria in the nu-
cleus material.
P. acnes have been suspected to be the cause of
acne for years. However in a recent review, this
has been questioned and P. acnes is now only be-
lieved to be a significant contributor to the inflam-
mation process in acne, due to induction of various
cytokines, TNFa, IL-1, among others [38].
Two studies have showed a positive result of
antibiotic treatment of MC, though they are small
and uncontrolled. Modic identified, in 1984, 5 pa-
tients with suspected infection observed in the disc
and in the end plates. They were treated with anti-
biotics for 4 weeks and re-scanned. A change in the
signal in the central area within the disc was ob-
served suggesting both healing and degeneration.
[43] Albert et al. [30] treated 32 patients with MC
type 1 and LBP after a lumbar herniation one year
earlier. The patients reported a clinically relevant
and statistically significant improvement on all
the outcome measures both at end of treatment
and at long term follow-up.
Conclusions
Signal changes in the bone marrow are observed in
conjunction with several immunological diseases
and joint and bone disorders but their relationship
to pain and development of the diseases are un-
known. Resent research shows that signal changes
in the vertebral endplate and vertebral bone mar-
row are on the other hand closely linked to LBP.
A disc herniation or a severely degenerative disc
is a strong risk factor for developing MC (especially
type 1). These observations are the background for
two new theories regarding the pathogenesis of
Albert et al.
MC. It is important to develop these theories as a
platform for further research into this area,
1. A mechanical cause: Degeneration of the disc
causes loss of soft nuclear material, reduced
disc height and hydrostatic pressure, which
increases the shear forces on the endplates
and micro fractures may occur. The observed
MC could be the fracture oedema itself, or a
result of an inflammatory process from a toxic
stimulus from the nucleus pulposus that seeps
through the fractures.
2. A bacterial cause: Following a severe tear in
the outer fibres of the annulus as in a hernia-
tion, new capilarisation and inflammation
occurs around the extruded nuclear material.
In this special environment it is possible for
anaerobic bacteria to enter the anaerobic disc
and in this environment cause a slowly devel-
oping low virulent infection. The MC are prob-
ably the inflammation and oedema surrounding
an infection, because the anaerobic bacteria
cannot thrive in the highly aerobic environ-
ment of the MC type 1.
Perspectives
The described mechanisms can – if proven – be of
significant importance for patients with LBP. It is of
the utmost importance to ensure that patients are
given the correct diagnosis, to ensure the most
efficient information and treatment of the patient.
If patients with MC are a specific subgroup within
LBP patients, it would be possible to provide a pre-
cise and relevant diagnosis to 20–30% of patients
with LBP. This will assist in giving/developing
appropriate and efficient treatment to these pa-
tients e.g. antibiotics, specific rehabilitation pro-
grammes, rest, stabilizing exercise, surgical
fixation all depending on the underlying cause for
the MC.
An RCT utilizing antibiotics and placebo
(www.clinicaltrials.gov/ct/show/NCT00302796),
and an RCT comparing conservative treatment
(NCT00454792 ) biopsy studies of the disc and MC
to identify possible bacteria and longitudinal stud-
ies of patients with and without MC to determine
the natural course of events are underway.
Acknowledgement
We thank Alan Jordan, Ph.D. and Charlotte Leb-
oeuf-Yde, Ph.D for valuable editorial assistance.
Modic changes, possible causes and relation to low back pain 367

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