Subchondral Activity and Treatment, Columbia 2010 Presenter: Vladimir Bobic, Chester Knee Clinic, UK

1. Department of Orthopaedic Surgery Grand Rounds
University of Missouri, Columbia, Missouri, USA
20 October 2010
OsteoChondral Unit and
Subchondral Activity
Vladimir Bobic, MD, FRCSEd
Consultant Orthopaedic Knee Surgeon
Chester Knee Clinic @ Nuffield Health, The Grosvenor Hospital Chester, United Kingdom
www.kneeclinic.info

2. “The Terminology is a bit Confusing …”
Disclaimer: Arthrex (OATS inventor) and clinical advisor for TiGenix (CCI).
This is a non-EBM (orthopaedic surgeon’s) clinical overview of subchondral events,
based on our clinical and MRI experience since 1996.
We have a problem at the outset: what are we actually talking about? How do we
treat a wide range of chondral and subchondral problems which are still poorly
defined and understood?
Bone Bruise (BB): a transient traumatic event = a series of trabecular
microfractures. No surgical treatment required.
Bone Marrow Oedema (BME): MRI evidence of increased subchondral metabolic
activity. Remodeling or reparative process, or a failure of subchondral remodeling or
repair = a degenerative process? Initially a reparative process, if persistent – a
degenerative process (often associated with initial formation of subchondral cysts,
which are a consequence of failed focal repair). No surgical treatment required, but …
Transient Osteoporosis (TOP): no history of trauma, the knee pain is spontaneous
and disabling, exacerbated on weight-bearing. Usually gets better over many
months, back to normal MRI and clinically. When multiple joints are involved (in
approx. 40% of patients) the condition is referred to as Transient Regional
Migratory Osteoporosis (TRMO). No surgical treatment required.
CKC UK

3. “The Terminology is a bit Confusing …”
Spontaneous Osteonecrosis (SONK): is the term used to describe a
subchondral insufficiency fracture that causes osteonecrosis. MRI
appearance: a thin linear hypointense subchondral focus on T1W and
T2W that blends in with overlying cortex and is typically surrounded by
diffuse BME. With or without subchondral fractures/deformity.
Avascular Necrosis (AVN): an osteonecrotic lesion, low signal rim on
T1W and double line sign on T2W, with or without BME. The necrotic
focus often extends some distance away from the articular margin and
may contain fat, blood, fluid, fibrous tissue. With or without
subchondral fractures/deformity.
Osteochondritis Dissecans (OCD): semidetached osteochondral
fragment (essentially a non-union) with fluid layer at osseous interface
and seemingly intact articulating surface. A traumatic or metabolic
event, or both?
Secondary Osteoarthrosis (not –itis): if localized, this is perhaps
the end result of more extensive progressive failure of subchondral
remodeling. Increased but unsuccessful subchondral activity (BME +
multiple cysts) seems to be a primary event, with secondary loss of
articulating surface, which fails gradually as it is not supported by
normal elastic trabecular bone. May go as far back as injury-induced
BB, with or without visible initial chondral damage.
CKC UK

4. The overall volume and
the depth of subchondral
injury seem to be very
important for the
outcome of subchondral
repair and consequent
remodelling.
Proposed MRI classification of
bone barrow oedema (BME)
following articular cartilage
repair
Source: Brittberg, Winalski, JBJS A Supp 2003

5. Conclusion
Higher grades of articular
cartilage defects are
associated with higher
prevalence and greater
depth and cross-sectional
area of subchondral bone
marrow oedema.
CKC UK

6. Conclusion:
A majority of
acutely ACL injured
knees (92%) had a
cortical depression
fracture, which was
associated with larger
BML volumes.
This indicates
strong compressive
forces to the
articular cartilage
at the time of
injury, which may
constitute an
additional risk factor
for later knee OA
development.
CKC UK

7. ACL injury + extensive BB 7 months later
CKC MRI 110206 CKC MRI 190906
CKC MRI 110206

8. Bone Bruise Histology
The most interesting information on bone bruising to date has come from Johnson et al. Biopsied bone
bruises in 10 patients undergoing ACL reconstruction consistently showed variable degrees of
articular cartilage and subchondral bone changes.
Histologic examination revealed degeneration of chondrocytes, osteocyte
necrosis, and empty lacunae, suggesting that the MRI-detectable bone
bruise represented substantial damage to normal articular cartilage
homeostasis.
Biopsy specimen of bruised area: Higher magnification of the
the articular surface is intact, but chondrocytes and matrix in the
there is marked pallor of the superficial zone of the image on the
superficial zone, indicating loss of left, showing marked degeneration
matrix proteoglycans. (toluidine of chondrocytes. (toluidine blue)
blue)
Johnson D, et al. AJSM 26(3)1998
CKC UK

9. “Chronic” BME and Cartilage Delamination
CKC UK

10. BB & BME: what is the difference?
A Bone Bruise is a post-traumatic
event (series of trabecular
microfractures) which usually
disappears within 3 to 6 months (ACL
injury, patella dislocation, etc.).
What happens to articular cartilage
initially and months later?
How do we call symptomatic
subchondral changes, which are still
present and visible after 6 or 12 months
or longer (after ACL injury, cartilage
repair)?
A Bone Bruise appears to be an
acute traumatic event while Bone
Marrow Oedema signal seems to be
a chronic one.
Is BME a remodelling process?
How does this correlate to patient’s
symptoms?

11. BME Classification:
Traumatic bone oedema is thought to relate to internal
trabecular microtrauma with secondary capillary
haemmorrhage. The pattern of bone edema described as bone
bruising is dictated by mechanism, being globular following
impaction, focal following distraction and linear following shear
injuries.
Tumorigenic oedema is thought to reflect tumor induced bone
destruction and disorganisation.
Vasogenic or hyperemic oedema is thought to reflect
increased fluid delivery to marrow spaces as a result of precapillary
dilatation induced by inflammatory mediators as occurs in bone
infection.
Congestive marrow oedema is thought to reflect impaired exit
of fluid from the marrow capillary bed as a result of capillary
venous thrombosis or cellular swelling and packing. This form is
identified following avascular necrosis and possibly transient
osteoporosis. Pain occurs secondary to disruption or irritation of
sensory nerves within marrow neurovascular bundles.
Dr Stephen Eustace, Director Of Radiology, National Orthopedic Hospital, Cappagh, Dublin, Ireland

12. No Edema in Bone Marrow Edema!
The correlation of bone marrow lesions with pain in knee OA has been
convincingly established. Here, another compelling association is established
between bone marrow (edema) lesions and risk for progression of knee OA.
What remains to be established is the cause-and-effect relationship between
the various variables.
It is interesting that, histologically, the lesions that appear as
bone marrow edema on MRI contain very little edema at all. Rather,
they demonstrate fibrosis, osteonecrosis, and extensive bony
REMODELLING and are likely the result of contusions and focal
microfractures.
Also, it is not clear, whether an initial injury to articular cartilage
leads to mechanical malalignment and subsequent subchondral
bone destruction or rather subchondral bone damage leads to
mechanical malalignment and subsequent articular cartilage
destruction.
Does bone marrow edema predict progression of knee arthritis?
A summary of Felson’s 2001 and 2003 AIM articles written by Jon Gilles, M.D., The John Hopkins Arthritis Center, 2003.
http://www.hopkins-arthritis.org/arthritis-news/2003/bone_edema_oa.html

13. The Role of Subchondral Bone (1986)
Radin et al. focused on subchondral role as an effective shock absorber. They
found shear stress in the articular cartilage always occurring whenever there is
a discontinuity or substantial gradient in stiffness of the subchondral plate. In
former studies finite element analysis showed increasing stress in the cartilage
subsequent to subchondral plate stiffening. The fact that these changes occurred
without any evidence of metabolic or inflammatory changes implied that the
latter follow the mechanical changes, first in the bone and than in the cartilage!
December 1986.
CKC UK

14. This junction is often ignored, but it is of great importance … for
maintaining a healthy and strong interface between cartilage and bone
CKC UK

15. Articular cartilage + Subchondral plate + Trabecualar bone
are biologically and functionally inseparable OsteoChondral
unit which absorbs and distributes loads across the joint.
We can not think and act in monolayer terms. Add better art cart + SCB image + Carl’s slide here
CKC UK

16. “Normal” Bone Marrow Oedema 6/12 after MFC ACI
MFC ACI, 6/12: “In the
medial compartment, the ACI
graft has been placed over
the central weight-bearing
portion of the medial femoral
condyle. Small cartilage flap
at the interface peripherally in
keeping with minor
delamination but otherwise
the graft appears good with
no cartilage overgrowth or
major defects. The
inhomogeneity of the
implant cartilage and mild
marrow oedema-like
signal beneath the graft
are expected normal
findings 6 months after
the procedure.”
CKC MRI 260906 Unedited MRI report
David Ritchie, Glasgow, UK

17. Subchondral Activity Following ACI Surgery
25% PMF ACI defect 12/12, with increased BME
CKC Chester UK

18. Subchondral Activity Following ACI Surgery
Satisfactory MFC ACI but new MTC lesion

19. Subchondral Activity Following ACI Surgery
Progressive subchondral activity
and late failure (graft delamination)
CKC Chester UK
2 years after MFC ACI with
PD PD fat sat

20. Subchondral Cysts Following ACI Surgery
CKC UK

21. Subchondral Cysts Following ACI Surgery
ACI MRI FU: 3/12: Bone marrow edema, 12/12: Subcortical cyst

22. Subchondral Cyst Formation Following ACI Surgery
Subchondral cysts are bad news as they
represent a terminal failure (trabecular necrosis
and collapse) of local subchondral remodeling.

23. BME and Insufficiency Fracture
Recent localised incomplete subarticular fracture of the outer aspect of the MFC
(15 x 5 x 3 mm) with slight depression of the overlying articular cortex and
prominent surrounding marrow and soft tissue oedema but no obvious
disruption of the overlying articular cartilage or unstable osteochondral
fragment.
CKC UK

24. Insufficiency Fracture
and SONK
Our histopathological findings
suggest that the primary
event leading to
spontaneous osteonecrosis
of the knee is a subchondral
insufficiency fracture and
that the localized osteonecrosis
seen in association with this
disease is the result of a
fracture.
CKC UK

25. SONK (Spontaneous Osteonecrosis)
CKC UK CKC UK

26. Spontaneous Osteonecrosis (SONK) and Beyond
CKC UK

27. Spontaneous Osteonecrosis of Both Femoral Condyles
Shifting Bone Marrow Oedema is a self-contained disorder involving both femoral condyles.
On MRI it exhibits vast marrow oedema and is most likely an event on the SONK timeline.

28. Transient Regional Migratory Osteoporosis: and 2nd MRI here
Shifting Bone Marrow Oedema is a self-contained disorder involving both femoral condyles.
On MRI it exhibits vast marrow oedema and is most likely an event on the SONK timeline.

29. Spontaneous Osteonecrosis (SONK)
Ahlback et al first described
spontaneous osteonecrosis of
the knee as a distinct clinical
entity in 1968.
Osteonecrosis of the knee has
also been described as a
postsurgical complication
following arthroscopic
meniscectomy (Muscolo et al.,
Prues-Latour et al.) and
following radiofrequency-
assisted arthroscopic
treatments, mainly in 50+
age groups.
The pathophysiology of
osteonecrosis following these
arthroscopic procedures is not
fully understood (vascular
isufficiency, trabecular
microfractures?), or, more
likely, a consequence of pre-
arthrosopy osteopoenia and
altered focal biomechanics
(bone density should be
looked into).

30. SONK Histology
In the early stages of the
condition a subchondral
fracture was noted in the
absence of any features of
osteonecrosis, whereas in
advanced stages,
osteonecrotic lesions were
confined to the area distal to
the site of the fracture which
showed impaired healing. In
such cases, formation of
cartilage and fibrous tissue,
occurred indicating delayed
or non-union.
These findings strongly suggest
that the histopathology at each
stage of spontaneous
osteonecrosis is characterised
by different types of repair
reaction for subchondral
fractures.

31. Lecouvet FE, et al.:
CKC UK

32. “ If progressive collapse
accompanied by severe
symptoms occurs, high
tibial osteotomy,
unicompartmental
replacement, and total
knee replacement are
therapeutic
alternatives.”
Is there anything else,
less severe, that can be
done?

34. JBJS B June 2006

36. Red Bone Marrow
Red marrow has significant haematopoietic stem cell
potential and still persists in adults in certain areas such
as the iliac crests.
The anterolateral trochlea (the usual OATS donor site) is
often spared even in advanced OA and seems to contain
reasonably good bone marrow, which can be aspirated
through the donor site.
Pluripotent haematopoietic stem cells can differentiate into any
and all of the cells of circulating blood and the immune system.
MRI studies have indicated that the conversion of red to fatty
marrow occurs prematurely in some patients with avascular
necrosis.
Osteonecrosis is associated with a decrease in progenitor cells
in the proximal femur. Bone marrow also contains osteogenic
progenitors, with a potential for effective bone regeneration.
It seems sensible to use core decompression but also to
deliver better “biologic fuel” with pluripotent cells to the
affected area.
CKC UK

37. SONK, ON and SOA
An alternative approach to the treatment of
femoral and tibial Osteonecrosis, Chronic SONK
and Secondary OA:
The knee is often not too bad or it is too early for a partial or a full
knee replacement.
Classic Microfracture and Core Decompression are probably not
deep enough.
Looking at most MRIs it seems that we need to reach at least 15
to 20 mm deep into subchondral bone, which is where any
cylindrical osteochondral harvesters are very handy.
Effectively, this is a combination of OAT and deep core
(subchondral) decompression, with a hand driven K-wire, through
the bottom of the recipient socket, with
a mixture of autologous blood + bone marrow injected into the
recipient socket,
and capped with 10 mm OATS plug, which was soaked in the
same mixture of bone marrow and blood.
This “integrated” subchondral repair concept makes sense, it gives
most people quick and durable pain relief and better knee
function, but it is based on huge assumptions.
CKC UK

38. SONK: sudden onset,
severe knee pain
MRI: “In the outer weight-
bearing portion of the medial
femoral condyle, there is an
osteochondral lesion (22mm ant-
post x 10mm med-lat x 2mm
deep), with fluid at the interface
with parent bone, mild reactive
marrow oedema and a cortical
break peripherally in keeping
with instability. Degenerative
changes in the medial
compartment with spontaneous
osteonecrosis of the medial
femoral condyle (SONK) and
unstable fragment.”
David Ritchie, Glasgow
CKC MRI 060506

39. FU MRI: “In the medial
compartment, the graft over the
central weight-bearing portion of
the medial femoral condyle has
incorporated with adjacent
bone and the overlying
articular cartilage is flush
with adjacent native
cartilage. A small focus of
marrow oedema is noted directly
beneath the graft but overall
there has been a reduction in
marrow oedema around the
graft. A small trace of
subcortical fluid in the peripheral
portion of the medial femoral
condyle is similar to the pre-
operative scan - presumably not
included in the repair.”
David Ritchie, Glasgow
CKC MRI 030307

40. SONK Before and After Subchondral Decompression
15/12/08: subarticular
insufficiency fracture and slight
flattening of the MFC and
prominent subarticular marrow
oedema more marked on the
femoral side. Since 04/04/08,
significant deterioration in the
medial compartment with SONK-
like process, progressive
degenerative changes …
11/09/09: Comparison is made
with the previous scan
15/12/2008. In the medial
compartment, following the
subchondral decompression,
there is now evidence of
articular irregularity,
deficiency and thinning of
articular cartilage, slight
increase in the subarticular
marrow oedema and early
subarticular cyst formation in
the outer aspect of the MFC …

41. ABM: An Essential Ingredient for Octeochondral Repair?
Conclusions: Delivery of
bone marrow concentrate
can result in healing of acute
full-thickness cartilage
defects that is superior to
that after microfracture
alone in an equine model.
If this is the case, looking at
osteochondral defects, is
this combination working
better because microfracture
(multiple perforations and
tunnelling) of subchondral
bone is making it less stiff
but also allows “biologic
fuel” (bone marrow, blood
and who knows what else) to
reach deeper areas, re-
establish nutrition and
facilitate local osteochondral
repair?
JBJS A August 2010

42. Summary:
VB to DR email 9 May 2006:
Subject: SONK and all that jazz (re confusing MRI
appearance of different subchondral events):
VB: “ There is something there and it seems it’s all
connected. We are probably looking at different stages of
the same thing:
It seems that subchondral repair and remodelling are a
common denominator, some of which is successful
(traumatic bone bruising, transient osteoporosis, SONK),
partially successful (persisting bone marrow oedema) or
not at all (progressive chronic bone marrow oedema,
subchondral cysts, AVN, osteonecrosis, and in the end
secondary osteoarthrosis). I don’t know, for some people
most of this is probably at various places on the same
timeline, but I am not sure if that makes sense.”
DR: “The terminology is a bit confusing … “
I would like to thank Dr David Ritchie and Dr Carl
Winalski for their unreserved help and patience over
many years.

43. Obviously, subchondral events are giving us headaches …
… but we must do a lot more work to get to the bottom of this problem. Thank you.

45. Transient Osteoporosis
The aetiology of TO and TRMO remains unclear:
One of the likely explanations for the pathogenesis of TO is
perhaps that proposed by Frost14 and others.15,16 He stated that
under noxious tissue stimuli, the ordinary biological processes,
including blood flow, cell metabolism and turnover and also
tissue modelling and remodelling, might be greatly accelerated,
called the Regional Acceleratory Phenomenon (RAP). In his
opinion a prolonged or exaggerated RAP in which a large
number of bone turnover foci are activated, is the cause of TO.
It has been hypothesized that symptoms may be related to
bone marrow edema demonstrated at MRI and to a transitory
regional arterial hyperflow observed at the early scintigraphic
analysis.17 Bone tissue micro damage is the most frequent
noxious stimulus that provokes RAP and bone tissue micro
fracture is the main consequence.
Several elements support this hypothesis. The repeatedly
observed histological findings in patients with TO showing mild
inflammatory changes and osteoporosis, associated with an
elevated bone turnover with increased bone resorption and
reactive bone formation18,19,20 are a good description of ongoing
TRMO.
CKC UK

46. Transient Osteoporosis (TO and TRMO)
Transient Osteoporosis (TO) is a rare self-limited
syndrome characterized by sudden onset of joint pain,
followed by focal osteopenia after few weeks, with
spontaneous recovery. This was first described by
Revault, et al., as a distinct clinical syndrome in French
literature and was thought to be due to neurotropic
changes, possibly secondary to minor trauma.
The first report of this disorder in the English literature
was by Curtis and Kincaid in 1959.
When multiple joints are involved (which is the case in 40% of
patients with this condition) the condition is referred to as
Transient Regional Migratory Osteoporosis (TRMO).
Regional migratory osteoporosis (RMO), first described by
Duncan et al. is a disorder manifested by arthralgia migrating to
other joints or within the same joint
In most cases, plain radiographs and bone densitometry will
reveal localized demineralization in the juxtarticular bone within
3–6 weeks after the onset of the symptoms, whereas increased
uptake of radionuclide is demonstrated by bone scintigraphy.
The pattern of symptoms migration has been reported as
typically sequential, proximal to distal with a migratory interval
of up to 9 months
CKC UK

47. Transient Osteoporosis (TO and TRMO)
Successful pamidronate treatment of severe and refractory
regional migratory osteoporosis
Schapira D, Gutierrez G, Mor M, Nahir AM. J Clin Rheumatol.
2001 Jun;7(3):188-90. The B. Shine Department of
Rheumatology, Rambam Medical Center and Faculty of Medicine,
Technion-Israel Institute of Technology, Haifa, Israel
Abstract: We report the case of a middle-aged patient with
repeated attacks of regional migratory osteoporosis of the
lower limbs, manifesting as severe pain and swelling of both
joint and periarticular areas, and marked physical disability
during a period of 2 1/2 years. After the therapeutic failure of
conservative therapy (physical therapy, rehabilitation therapy,
analgesics and nonsteroidal anti-inflammatory drugs (NSAIDs))
and after the correct diagnosis was reached, pamidronate
treatment was instituted. The results were a rapid, complete,
and long-lasting remission of the symptoms and the renewal of
the patient's previous activities. Intravenous biphosphates
are proposed as a safe and promising therapy for regional
migratory osteoporosis. To our knowledge, this is the first report
of pamidronate treatment for this condition.
CKC UK

48. Lateral Femoral Trochlea:
a source of good cancellous bone and bone marrow, even in advanced OA?
MFC AVN
CKC UK

49. Subchondral MR Imaging
Source: Dr Carl Winalski, Cleveland, USA

50. Subchondral Marrow Signal
Source: Dr Carl Winalski, Cleveland, USA

51. Bone Marrow Oedema Can Cause Pain in OA
Cartilage degeneration, although fundamental to the pathogenesis of
osteoarthritis, is not the site of origin of pain, the predominant symptom of
osteoarthritis. Peripheral nerves generally follow the path of blood vessels, and
cartilage contains no nerves or blood vessels.
Felson et al. describe oedema in the subarticular bone marrow adjacent to the knee,
detected by T2-weighted magnetic resonance imaging (MRI), in patients with painful
osteoarthritis of that joint.
Oedema of the bone marrow has also been demonstrated in patients with traumatic
bone injuries, including "bone bruises" and other forms of "overuse“
The pathologic process in the subarticular marrow of patients with osteoarthritis is
probably an analogous phenomenon.
Thinning and erosion of the cartilage in osteoarthritis decrease the
protection of the underlying bone afforded by the articular cartilage, which
loses its capacity to absorb impact stresses and minimize friction during
joint motion. The increase in physical stresses transmitted to the
subchondral bone results in cortical thickening; the increased density of the
bone further decreases the dampening of physical stresses, especially
impact stresses, which are thus transmitted more fully to the underlying
trabecular bone and bone marrow.
Oedema of the bone marrow seen on MRI reflects an inflammatory response to these
traumatic forces. Afferent nociceptive nerve fibers containing the neurotransmitter
substance P are found in periarticular tissues, including the periosteum and
subchondral bone, of patients with osteoarthritis

52. Bone Marrow Oedema Can Cause Pain in OA
The development of venous hypertension and bone marrow oedema
may also be related to the development of cysts in the subchondral
bone in osteoarthritis (next slide).
Oedematous changes in the bone marrow early in the evolution of
avascular necrosis of the femoral head have been reported (next
slide)
In view of the observation that bone marrow oedema is found in most
patients with painful osteoarthritis of the knee, as well as in other
syndromes associated with juxta-articular pain, such as bone bruises
and osteonecrosis, we can conclude that oedematous changes in the
subcortical bone marrow are one of the many sources of knee
pain.
Radin et al. focused on its role as an effective shock absorber. He found shear
stress in the articular cartilage always occuring whenever there is a discontinuity
or substantial gradient in stiffness of the subchondral plate. In former studies finite
element analysis showed increasing stress in the cartilage subsequent to
subchondral plate stiffening. The fact, that these changes occurred without any
evidence of metabolic or inflammatory changes implied that the latter follow the
mechanical changes, first in the bone and than in the cartilage.
Radin EL, Rose RM : Role of Subchondral Bone in the Initiation and Progression of Cartilage damage. Clin. Orthop.
213: 34-40, 1986)

54. Failed MFC OATS repair after 4 years:
CKC GNH UK
CKC GNH UK
the graft survived and it looks great but …