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

“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.

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“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.

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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

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Conclusion

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

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.

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ACL injury + extensive BB

CKC MRI 110206 CKC MRI 110206 CKC MRI 190906

7 months later

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: the articular surface is intact, but there is marked pallor of the superficial zone, indicating loss of matrix proteoglycans. (toluidine blue)

Higher magnification of the chondrocytes and matrix in the superficial zone of the image on the left, showing marked degeneration of chondrocytes. (toluidine blue)

Johnson D, et al. AJSM 26(3)1998 CKC UK

“Chronic” BME and Cartilage Delamination

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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?

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

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

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.

The Role of Subchondral Bone (1986)

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

Articular cartilage + Subchondral plate + Trabecualar bone are biologically and functionally inseparable OsteoChondral unit which absorbs and distributes loads across the joint.

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We can not think and act in monolayer terms. Add better art cart + SCB image + Carl’s slide here

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.”

Unedited MRI report David Ritchie, Glasgow, UK

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“Normal” Bone Marrow Oedema 6/12 after MFC ACI

25% PMF ACI defect 12/12, with increased BME

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Subchondral Activity Following ACI Surgery

Satisfactory MFC ACI but new MTC lesion

Subchondral Activity Following ACI Surgery

Progressive subchondral activity and late failure (graft delamination) 2 years after MFC ACI with

PD PD fat sat

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Subchondral Activity Following ACI Surgery

Subchondral Cysts Following ACI Surgery

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ACI MRI FU: 3/12: Bone marrow edema, 12/12: Subcortical cyst

Subchondral Cysts Following ACI Surgery

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.

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.

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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.

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SONK (Spontaneous Osteonecrosis)

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Spontaneous Osteonecrosis (SONK) and Beyond

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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.

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.

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).

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.

CKC UK Lecouvet FE, et al.:

“ 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?

JBJS B June 2006

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.

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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.

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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

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

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 …

  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?

ABM: An Essential Ingredient for Octeochondral Repair?

JBJS A August 2010

  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.

Summary:

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.

Transient Osteoporosis

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  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.

Transient Osteoporosis (TO and TRMO)

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  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

Transient Osteoporosis (TO and TRMO)

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  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.

Lateral Femoral Trochlea: a source of good cancellous bone and bone marrow, even in advanced OA?

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MFC AVN

Subchondral MR Imaging

Source: Dr Carl Winalski, Cleveland, USA

Source: Dr Carl Winalski, Cleveland, USA

Subchondral Marrow Signal

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

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)

Failed MFC OATS repair after 4 years:

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the graft survived and it looks great but …