434
Review Clin Ter 2022; 173 (5):434-439.
Bone Marrow Edema: pathogenetic features
L. Molfetta1, A. Florian1, G. Saviola2, B. Frediani3
1
University of Genoa, School of Medical and Pharmacological Sciences, DISC Department, Research Center of Osteoporosis and
Osteoarticular Pathologies, Genoa, Italy; 2Istituti Clinici Scientifici Maugeri, IRCCS Castel Goffredo, Mantua, Italy; 3University of
Siena, Rheumatological Unit, Siena, Italy
Abstract
The term “bone marrow edema” was used for the first time in 1988
by Wilson. He noticed a high signal on fluid-sensitive sequences at MRI
located in the subchondral bone. We can find bone marrow edema in
many musculoskeletal diseases such as Inflammatory and Rheumatic
diseases (Rheumatoid Arthritis, Spondylarthritis, etc.), Osteoarthritis
(BMLs) and Bone Marrow Edema Syndromes (BMES).
This classification is based on pathophysiological, histological and
clinical differences despite the same imaging evidence. The distinction
is useful also in terms of treatment. Bisphosphonates in association
with NSAIDs or corticosteroids are the main therapy while TNF-a
Inhibitors are used for the specific inflammatory origin.
Bone marrow edema has become an important aspect to consider
in the diagnostic path of the main musculoskeletal diseases. This
paper starts from a systematic review of literature. We chose the most
decisive contributions in order to develop a better description of the
pathogenetic features about this “new” evidence. Clin Ter 2022; 173
(5):e434-439. doi: 10.7417/CT.2022.2459
Key words: bone marrow edema, inflammation, bisphosphonates,
imaging
Introduction
In 1988 an evaluation study - 10 patients with severe hip
and knee pain - found out a signal alteration in fluid-sensitive
sequences on MRI, like T2-weighted, and low signal intensi-
ty on T1-weighted. The pain disappeared without recurrence
after 13-36 months. The authors named that evidence “bone
marrow edema” assuming that was correlated to an increased
fluid component in the bone marrow. That was confirmed by
the scintigraphic evidence of hyperemia and increased bone
mineral metabolism. Because of the spontaneous resolution
they named this condition “the transient bone marrow edema
syndrome” (1). In spite of imaging evidence, histological
studies did not find any edema, creating a lot of confusion
regarding the pathophysiological features.
Correspondence: Saviola G. email: gsaviola1953@libero.it
Copyright © Società Editrice Universo (SEU)
ISSN 1972-6007
L. Molfetta, et al.
doi: 10.7417/CT.2022.2459
We distinguish bone marrow edema (BME) into three
categories: inflammatory pattern (AR, SpA), Osteoarthritis
(OA) and trauma related (BMLs) and, finally, bone marrow
edema syndromes (CRPS type 1, Transient Osteoporosis of
the Hip and Regional Migratory Osteoporosis).
Within inflammatory group the BME is evident like
osteitis, highlighting the major role of inflammatory cells
and cytokines. The BMLs correlate with edema pattern that
we can find in OA due to mechanical and inflammatory pa-
thogenesis; BE trauma-related is assimilated in the BMLs
because of the mechanical nature and imaging aspects.
Metabolic bone damage represents the main cause of the
BMES, characterizing the clinical aspects, the diagnostic
path and the therapy.
It is very difficult to describe BE due to its many mani-
festations. That fact stimulates studies aimed at describing
its pathogenetic features.
Inflammatory bone marrow edema
The ectopic lymphatic tissue is a typical manifestation in
AR. It is present at the synovial layer but also in the subchon-
dral bone marrow. Furthermore, it is visible at MRI, as BME,
few weeks before the clinical manifestations in 68-75% of
patients. Consequently, BME represents an important in-
flammation marker and the most sensitive marker of the early
phase in AR (2). The most frequent sites where we can find
BME are the wrist and the II and III metacarpophalangeal
joint which are also the most common erosion sites.
From a histological point of view the BME corresponds
to an inflammatory infiltrate with macrophages, lymphocytes
T and B, plasma cells and osteoclasts. All of this creates
the osteitis.
There are two pathogenetic hypothesis: outside-in and
inside-out. The outside-in theory says that the inflammation
begins at the synovial layer adjacent to the subchondral bone
and migrates in the bone marrow. In fact, histological studies
have shown that the lymphatic follicles are preferentially
located in the most superficial spots, where the synovial
tissue penetrates through the erosions of the cortical bone.
Several pro-inflammatory cytokines would also stimulate
Bone Marrow Edema: pathogenetic features
osteoclasts to determine bone resorption, leading first to
the formation of inflammatory cysts and then to the cortical
bone perforation. This represents the onset of the erosion
process typical of AR. Subsequentially there is the creation
of microscopical channel between synovia and bone marrow
so that the inflammation can propagate from one compart-
ment to another.
However, MRI studies have shown that the medullary
alterations are also present in early phase where there is not
communication between synovia and bone. Histologically,
areas of inflammatory infiltrates have been found in deeper
locations than the medulla-synovial junction. The latter two
aspects would be in favor of independence between osteitis
and synovitis.
The inside-out theory, on the other hand, foresees that
the inflammatory process starts from the bone marrow to-
wards the synovial membrane. However, it is more frequent
within the SpA where the inflammation is dominant in areas
of the medulla far from the synovial sites (3).
BME is considered a precursor of erosion. Its presence
increases by about 6 times this event especially if associated
with the anti-CCP antibodies, correlating with a rapid and
aggressive progression. At the articular cartilage there is also
deposition of immune complexes containing rheumatoid fac-
tor (RF), anti-CCP and anti-RA33 antibodies. Experimental
models have shown how collagen and other components of
cartilage activate the inflammatory response, suggesting
an additional pathogenetic mechanism where cartilaginous
damage or joint autoantigens induce chronic synovitis (4).
MRI is the gold standard both for the identification of
the lesion and for the characterization of the patient with
regards to the clinical aspect and prognostic judgement since
the initial stages. The BE, like the synovial thickening, is
visualized as an hypointense signal in T1-weighted sequen-
ces and hyperintense signal in T2-weighted, without the use
of the contrast that, moreover, in the BME would show a
signal enhancement.
The “rheumatoid arthritis magnetic resonance image
scoring system” (RAMRIS) considers the inflammatory and
destructive aspects of the joints. The BME is considered the
most indicative early-stage RA factor (5). BE and synovitis
are independent factors of progression of joint damage that
can be used as markers of therapeutic treatment evaluation
(6).
The BME has the same characteristics within all forms
of spondylarthritis. It is evident even in the absence of
lumbar inflammatory pain. BME reflects the phenome-
non of osteitis. It is necessary to distinguish the finding of
inflammatory BME, related to hyperemia and edema from
BME-like signals such as the “fatty lesions”, late expression
of an involution of the bone marrow itself.
There is an infiltrate of T lymphocytes, macrophages and
B lymphocytes, although in a limited number. According to
some authors, the intensity of MRI signal correlates with
the number of inflammatory cells in the site. There is an
increased number of cells in the sacroiliitis compared to
patients with a low radiological signal (7).
The BME would have a prognostic role in the genesis
of the radiologically visible sacroiliitis, but it is not enough.
Even the severity is an important factor. In patients with seve-
re sacroiliitis and HLA-B27 positive, bone edema predicts the
435
development of ankylosing spondylitis at 8 years (8), while
moderate or mild osteitis characterizes patient with low risk.
In addition, BME correlates with an increased development
of syndesmophytes (9). The severity is directly proportional
to the extension of BME which will therefore be responsible
for the development of osteoporosis (10). It is clear that a
timely and aggressive treatment in SpA, already at the onset
of BME, would limit the effects of bone inflammation.
It is therefore hypothesized, on the one hand, that there is
a dissociated trend between inflammation and the appearance
of structural damage and, on the other hand, that there is a
non-sequential model in which the inflammatory and neo-
deposition of bone tissue would act in parallel triggered by
the same stress at the level of the enthesis (11), the primary
site of pathology in the SpA. The functional connection
between tendon and bone would generate micro-damage,
bone remodeling and local inflammation with hypervascu-
larization and radiological evidence of BME adjacent to the
enthesitis (12).
Bone Marrow Lesions and Osteoarthtitis
Osteoarthritis (OA) has to be considered a disease of the
osteochondral unit (13). The subchondral bone is therefore
an active part in the pathogenesis of the OA. BMLs and pain
are associated with moderate evidence (14) given origin to a
multifactorial pain (15). The severity of pain is also corre-
lated with the presence and the volume of cyst-like lesions
within the BMLs themselves (16). The risk factor of the
progression of these lesions would be the male sex, the high
BMI and the severity of the clinical signs. There is a lack
of knowledge about the pathophysiological mechanisms.
BMLs could be the results a joint overload. Especially in
the varus knees, the malalignment determines an overload
on the medial compartment (17).
The role of micro-traumatism is more likely to be assu-
med, as demonstrated in a healthy population study, where
hyper-pronation of the foot caused a widespread increase in
BMLs of the homolateral knee (18). This study confirmed the
data obtained in an experimental model on rabbits. Inducing
microlesions on the trabecular bone resulting in BMLs and
increased remodeling and angiogenesis (19).
The joint load pours on the osteochondral unit genera-
ting a cascade of reparative events and osteo-cartilaginous
remodeling, which often lead to OA. It has also been hypo-
thesized that BMLs could origin from bone hypoperfusion
and hypoxia resulting from intraosseous hypertension due to
venous stasis (18). This aspect agrees with the vascular me-
chanism in pathogenesis of the OA where pro-inflammatory
and pro-coagulating cytokines promote hypercoagulability
and edema, resulting in focal osteonecrosis. Since the struc-
tures are in communication, these cytokines will also act on
the cartilage inducing degradation, release of antigens and
sustain of synovitis (20).
At the medullary side, in a first phase, there is necrosis
and in later stages the development of edema with increased
pressure, venous stasis and further hypoxia and ischemia.
Increased vascularization would represent a dysregulation
and chronic healing process secondary to repeated micro-
trauma (21).
436
BMLs can be considered predictors of cartilaginous
thinning.
The lesion can go in regression or total remission in
variable time (22). The MOST study evaluated subjects
with high risk or with actual radiographic manifestations of
primary OA of the knee. One third of the patients without
BMLs from the baseline developed the lesion over time, 66%
with BMLs varied in size and 50% went into regression or
resolution (23).
Alterations of the subchondral bone are the key in the
onset of OA as well as a marker of disease progression.
BMLs represent a great risk factor of evolution but at the
same time, in the early stage of disease, potentially reversi-
ble. Therefore, BMLs represent an evolutionary stage prior
to the development of bone cysts or geodes and a risk factor
of knee prosthetic replacement at 4 years (24). There is no
clear convergence between BMLs and evolutionary stages
of the OA. In 1997 an initial classification was proposed: I)
BML and medullary degeneration and early osteosclerosis;
II) BML and moderate osteosclerosis with evident reduction
of the medullary space; III) BML and severe osteosclerosis
and reduction of medullary space; IV) BML and cystic
degeneration with perifocal sclerosis. This model was
obtained from resection of the anterior cruciate ligament
(ACL) in dogs and performed a post-surgery evaluation
via MRI (25).
The pattern of BMLs associated with OA, therefore,
would correspond to a set of different reliefs representing
both active and chronic remodeling, including medullary
necrosis, fibrosis, microfractures and fibrovascular ingrow-
th (17). In fact, the so-called “bone marrow edema pattern
zone” was identified. That is composed by healthy tissue,
11% of medullary necrosis, 8% of remodeled or necrotic
trabecular bone, 4% of medullary fibrosis, 4% of edema
and 2% of medullary bleeding (26).
Inside the BMLs, therefore, the presence of “pure ede-
ma” is controversial, it is not particularly expressed, but
still considered important (27). As a consequence, this data
alone is not enough to justify the marked hyperintensity in
the T2-weighted sequences. We can identify the fibrovascu-
lar ingrowth as a cause of the imaging evidence (15) or the
substitution of the medullary adipose tissue with materials
characterized by a higher presence of water (28).
Referring to signal abnormality, two types of lesions
were also identified: “edema-like lesions” with an accumu-
lation of extracellular eosinophilic fluid within the trabecular
spaces and “necrosis-like lesions” located at the periphery.
The necrosis-like lesions, instead, show prevalent fibrosis
and less necrosis. The edema-like lesions may be a pre-
necrosis-like stage (29). BMLs present a well-defined area of
hyperintensity in the fluid-sensitive sequences, histologically
corresponding to mucinous material and necrotic fragments
within a layer of fibrous connective tissue, defined cyst-like,
due to the poor evidence of epithelial tissue (30).
From the point of view of the qualitative bone changes,
microtrauma results in microfractures, especially in trabe-
cular bone and abnormalities of the cells and vessels with
focal necrosis. The tissue is then replaced but the process
is not always efficient, and often hesitates in the collapse
of the articular surface. The bone marrow is also altered
with collagen infiltration, especially type I, which create a
L. Molfetta, et al.
network predisposing to fibrosis. Since the mineralization
and the matrix in the BMLs area is reduced, the mineral to
matrix ratio that correlates with the hardness and stiffness
of the bone is altered. The stiffness decreases considerably
(31).
About imaging diagnostics, using MRI, the main sequen-
ce that has to be used is the T2-weighted but also STIR, that
showed a high sensitivity. The fluid-sensitive sequences are
better for the lesion evaluation after treatment, during the
follow up. BMLs appear at MRI as well-defined lesions
of increased T2-weighted signal in the subchondral bone,
distinguishing themselves from bone cysts with which they
share hyperintensity at the trabecular bone, below joint
cartilage (32).
Trauma-induced BMLs result from direct or indirect
acute trauma such as bone contusions and chronic overload
as stress fractures from microtrauma during physical activity,
a direct correlation with the mechanism and intensity of
the trauma. Paradigmatic is the lesion of the ACL in which
the BML is located at the lateral femoral condyle or in the
posterior and lateral portion of the tibial plateau.
Histologically, the subchondral lesions secondary to
trauma have peculiar characteristics: microfractures of the
sub-articular spongiosa, necrosis of the osteocytes and empty
gaps, bleeding and edema up to depression and collapse of
cartilage due to a high-energy subchondral fracture. Fractu-
res of the osteochondral unit will therefore present a BMLs
pattern. The cartilage damage will not resolve spontaneously
while at the subchondral level hypervascularization and mi-
gration of stem cells that will differentiate in chondrocytes
and osteoblasts will repair the subchondral bone. A wide
variability about the evolution of BMLs always persisting.
Bone Marrow Edema Syndromes (BMES)
The Bone Marrow Edema Syndromes (BMEs) are
a group of metabolic bone diseases characterized by the
bone edema and a peculiar clinical aspect in which pain
dominates with others related symptoms and a generally
favorable prognosis.
BMES include Transient Regional Osteoporosis (OTR),
which are Transient Osteoporosis of the Hip (TOH) and
Regional Migratory Osteoporosis (RMO), considered by
some Authors to be the same clinical entity in the isolated
and multifocal form. The Complex Regional Pain Syndrome
(CRPS type 1), despite the characteristic clinical presenta-
tion, prognostic and therapeutic features, can be included
in this chapter, because it shares with the diseases above a
common imaging (often due to misinterpretation), patho-
physiology and therapeutic response to bisphosphonates
(BPs) (33).
Each of them has widespread and poorly defined periarti-
cular involvement associated with edema and a characteristic
conservation of the articular surface. Sometimes it is difficult
to differentiate between these diseases and must take into
consideration the thorough medical history, the age, the
gender and the clinical picture.
TOH tends to affect the proximal region of the femur
with prevalence in the middle-aged male or pregnant or
postpartum women. It can become a migrant in a good
Bone Marrow Edema: pathogenetic features
percentage of cases. RMO affects more extensively the
hip, the knee, the metatarsals but retains the characteristic
of migration from one site to another.
The CRPS Type 1 is a regional painful condition, multi-
symptomatic, more often localized in the distal segments of
the limbs (hand-wrist, ankle-foot), with local signs such as
edema, vasomotor alterations, stiffness and damage to bone
metabolism, with dystrophic and atrophic outcomes. It is
nearly always secondary to trauma and presents, as the main
feature of suspicion, pain disproportionate to the magnitude
of the trigger itself.
Transient Osteoporosis of the Hip
TOH represents a self-limiting disorder that is mani-
fested by arthralgia and late osteopenia visible at RX. It
frequently affects the hip but also the knee, the ankle and
the joints of the foot. It was first described in a case of 3
pregnant women with hip pain and radiological evidence of
significant demineralization which spontaneously resolved
after childbirth (34). It is a rare and benign disease that ma-
nifests itself radiologically with osteopenia associated with
bone marrow edema at the proximal femur and that tends
to spontaneous resolution within a few months. It mainly
affects middle-aged men and women around the 3 month of
pregnancy or in the immediate post-partum, although cases
have been reported in non-pregnant women (35).
The clinical picture can arise suddenly or gradually with
non-traumatic pain that increases with articular load, and it
is reduced with rest and worsens in the night; the range of
motion is maintained in almost all patients. The BME appears
to come from alteration of venous drainage due to increased
intramedullary pressure, capillary thrombosis, into possible
alteration of the medullary vasomotor response and micro-
trauma. Venous congestion, similar to OA-related BMLs,
leads to a capillary rupture and interstitial fluid accumulation.
This hypothesis is supported by the fact that the edema is
greater in those locations where there is plenty of capillaries,
such as the metaphysis of long bones, in the vertebral bodies
and at the level of the carpal and tarsal bones. This pathoge-
netic mechanism concerns osteonecrosis; therefore, ischemic
insult of different severity could induce hypoxia leading to
transient BME or hesitate in irreversible anoxia of the me-
dulla generating osteonecrosis (36). The BE corresponds
to interstitial edema, alteration of fat cells, alteration of the
fibrovascular component and increase of non-mineralized
bone tissue without osteoclastic activity. The increase of the
osteoid deposition would be justified as an attempt to repair
which slows down the process of vascular necrosis suggesting
reversibility, unlike osteonecrosis (37). At the MRI scan,
patients would already have early abnormality of the signal or
a well-defined area of hypointensity in the T1-weighted and
hyperintensity in the T2-weighted or STIR sequences located
at the femoral head, potentially extended to the neck or to
the intertrochanteric region. Sometimes edema also extends
to the acetabulum. The absence of hypointense areas in the
subchondral bone suggest even more the reversibility. The
dimensions greater than 4 mm would represent a predictor
of irreversibility. In fact, osteonecrosis occurs with MRI
findings such as subchondral lesions (crescent sign), single
437
line sign with edema in T1-weighted or double line sign with
edema in T2-weighted (38). The pathognomonic sign of the
osteonecrosis is the presence of a reactive interface between
the necrotic portion and the surrounding healthy region of
the femoral head.
Regional Migratory Osteoporosis
The RMO is manifested by arthralgia initially localized
in a single location and then move to another neighboring
or, more rarely, have additive character. Patients will tend
to suffer from quite similar and recurrent manifestations of
pain elsewhere. The typical course of the disorder is proxi-
mal to distal and hardly remains confined. The time interval
between episodes varies from 2 to 12 months.
The radiological evidence is the same as the TOH with
obviously the migratory characteristic that is diagnostic of
RMO. In terms of pathogenetic features it is totally similar
to the TOH.
Complex regional pain syndrome (type 1)
CRPS type 1 is a syndrome characterized by pain with
regional distribution, allodynia, hyperpathia, hyperalgesia
and so on district swelling with vasomotor alterations and
functional limitation. It is a transversal disease. The epide-
miological profile is not well clarified due to the difficulties
of diagnostic framing and often because of the diagnostic
delay that can generate a secondary disability. Precipitating
causes are predominantly fractures (45%), sprains (18%)
and surgery (12%).
The “neuro-phlogosis” is the cornerstone of pathogene-
sis. It is characterized by the storming of pro-inflammatory
mediators with primary localization near the peripheral nerve
endings, then tending to centralize. It is related to BME
but, over time, could evolve into fibrous tissue, correlating
with chronic pain in synergy with a central sensibilization
process. The inflammation affects the soft tissues but also
extends to the bone as can be witnessed by the finding of
spotted osteoporosis, which is not always present.
The cytokines determine capillary permeability leading
to edema and secondarily to hypoxia with acidosis. This
finding is present in BME as well as in osteonecrosis despite
the increased blood supply documented at the scintigraphy is
not correlating with an increase in tissue oxygenation. Since
the first evaluation the CRPS is not sympathetic mediated.
This possibility will be hypothesized only in the forms re-
sistant to first-line therapy (especially in the shoulder-hand
syndrome).
The etiology of multifocal and migrant forms would be
from microfractures. The fact that BME is sometimes very
extensive, however, would not correlate much with this
etiological hypothesis. The role of imaging in the context
of CPRS would be limited to differentiating and excluding
other pathologies in order to confirm the clinical suspicion.
The scintigraphy seems to have a high sensitivity. The
most striking pattern shows increased angiographic flow
and widespread uptake in the late stages. The latter factor
would give the necessary sensitivity for diagnostic purposes.
438
It should be noted that the findings at the scintigraphy do
not always agree with MRI (39,40). In fact, the MRI shows
hyperintensity in T2-weighted and enhancement of contrast
in the periarticular soft tissues in the early stage of patholo-
gy; sometimes joint effusion is present. Evidence of BME
is very frequent in the early hot phase, but it is not typical
of dystrophic or atrophic (41).
Conclusions
The subject we dealt with is a scientific reality of great
relevance, although it dates back to the first evidence in
1988, the time of its primitive definition of “bone edema”.
Wilson, in fact, described in MRI a variation in the appe-
arance of specific skeletal areas, coming to the name of
bone edema, without an etiopathogenetic correlation with
specific diseases. Over the years, new aspects have been
acquired of both instrumental, like increasing the sensitivity
of MRI devices, as well as of pathogenetic features, due to
the correlations gradually emerged with the different areas
of osteoarticular diseases.
To this day, the bone edema, within each specific patho-
logy, appears clearer in terms of the diagnostic procedure
and especially the specific therapy. The most important role
is played by Bisphosphonates and in particular by Neridro-
nate (registered for CRPS type 1) and Clodronate( 42.43).
The BE fully belongs today to the diseases described by us,
representing, for example, for OA an important pathogenetic
sign in the starting and evolution of the disease.
It is hoped that further work will be done to study and
implement, above all, the treatment strategies.
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