2nd ICRS Summit: The Ageing Cartilage Zermatt, Switzerland15 and 16 January 2015

What happens with injured and ageing subchondral bone?

Thoughts on Osteochondral Unit, Subchondral Activity, OA and Ageing

Prof. Vladimir Bobic, MD, FRCSEd Consultant Orthopaedic Knee Surgeon

Chester Knee Clinic @ Nuffield Health, The Grosvenor Hospital Chester, United Kingdom

… the short answer is: we don’t really know, but this is a great opportunity to talk about this issue …

… so this is a story about normal wear and tear, injuries, repair and ageing …

… speaking of ageing, this is me at the age of two.

Ageing and OA: An inevitable Encounter?

T Huegle et al.: Aging and OA: An Inevitable Encounter? JAR 2012

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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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. Articular cartilage (surface) repair is not good enough. We have to think and act in 3D terms!

Subchondral MR Imaging

Source: Dr Carl Winalski, Cleveland, USA

” … recent studies have shown that cartilage and subchondral bone act as a single functional unit. This review highlights this novel concept.”

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…Therefore, cartilage repair is not only about restoring functional properties but also about arresting the pathological changes of degenerative arthritis that result from altered

loading due to damage to articular cartilage.

The Subchondral Unit: A New Frontier

re-drawn from Imhof et al. 1999

Henning Madry, Saarland University, Homburg/Saar, Germany

Imhof H, Breitenseher M, Kainberger F, Rand T, Trattnig S. (1999): Importance of subchondral bone to articular cartilage in health and disease. Top Magn Reson Imaging 10:180–192

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The Structure of Subchondral Bone

Redrawn from: Imhof H, Breitenseher M, Kainberger F, Rand T, Trattnig S. (1999): Importance of subchondral bone to articular cartilage in health and disease. Top Magn Reson Imaging 10:180–192

A surprisingly high number of arterial and venous vessels, as well as nerves, can be seen in the subchondral region sending tiny branches into

the calcified cartilage …

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The Structure of Subchondral Bone

•This is extremely important for cartilage repair: the tidemark is crossed by collagen fibrils extending from the articular cartilage into the calcified cartilage, while no collagen fibrils connect the calcified cartilage to the subchondral bone plate.

• Blood vessels from the subchondral region can extend into the overlying calcified cartilage through canals in the subchondral bone plate.

• Therefore, nutrients can reach chondrocytes in the calcified zone via these perforations.

• Unsurprisingly, the perforations are grouped together in the regions of subchondral plate where the stress is greatest.

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The Structure of Subchondral Bone

The changes in the thickness of the subchondral bone plate depend on the location and mechanical loads

Henning Madry, Saarland University, Homburg/Saar, Germany 15

This study presents results that conflict with previously published papers and opinions regarding subchondral bone thickness and density as related to OA.

The results of this study demonstrate decreasing subchondral bone density and thickness with increasing age, even though the incidence of OA lesions increase with age.

No correlation could be found between OA grade and increasing bone thickness or density, in fact, the opposite was found in this study.

• VB to DR email, 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 (“Vladimir, stop staring at MR images and stick to your day job.”)

Subchondral Events in a Nutshell:

The Terminology is a Bit Confusing …

• Disclaimer: Arthrex (OATS inventor), principal investigator for UK BioPoly clinical trial, former clinical advisor for TiGenix CCI.

• This is a non-EBM (orthopaedic surgeon’s) clinical overview of “subchondral events”, based on our clinical and MR imaging experience since 1996.

• We have a problem at the outset: what are we actually talking about? How do we treat a wide range of osteochondral 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. Remodelling or reparative process, or a failure of subchondral remodelling or repair = a degenerative process? Initially a reparative process, but if persistent it is probably a degenerative process (often associated with initial formation of subchondral cysts, which are a consequence of failed local 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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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

Conclusion: A majority of acutely ACL injured knees (92%) had a cortical depression fracture, which was associated with larger BME 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

7 months later

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 Dr David Ritchie, Glasgow, UK CKC MRI 260906

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

“Chronic” BME and Cartilage Delamination

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Transient Regional Migratory Osteoporosis:

MRI report: “The diffuse bone marrow oedema pattern with development of subchondral linear fractures would therefore suggest regional migratory osteoporosis rather than typical SONK lesions.”

Transient Osteoporosis – Extreme Bone Remodeling?

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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 Frost and others. • 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. 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 formation are a good description of ongoing TRMO.

The Terminology is Even More 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 remodelling. Increased but unsuccessful subchondral activity (progressive 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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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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SONK (Spontaneous Osteonecrosis)

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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).

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.

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.

Spontaneous Osteonecrosis (SONK) and Beyond

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MFC BME + Subchondral Cyst Following ACL Surgery

No problems with ACL reconstruction, good functional result, no meniscal deficiency.

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

Subchondral Cysts Following ACI Surgery

Subchondral Cysts Following ACI Surgery

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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.

Chondrogenesis and OA

• The process of chondrogenesis is relevant to osteoarthritis (OA) in two ways:

• 1st: evidence is beginning to emerge that osteoarthritic chondrocytes are quite metabolically active and reinitiate synthesis of some proteins that are characteristic of early developmental stages.

• 2nd: an understanding of cartilage differentiation and development will provide guiding principles for tissue engineering of neo-cartilage, and may, therefore, play a part in new therapies for this common disease.

• In the early phase of OA, the pathologic processes seem to indicate that mechanisms of cartilage repair, rather than degradation, are at work!

• There is substantial evidence to indicate that chondrocytes are activated in OA and potentially could be stimulated to synthesize appropriate cartilage ECM, or even recapitulate developmental patterns.

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• 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

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 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 …

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.”

Dr David Ritchie, Glasgow CKC MRI 030307

Articular Cartilage Repair or Regeneration?

• Repair refers to the restoration of a damaged articular surface with new tissue that resembles but does not duplicate the structure, composition and function of articular cartilage.

• Regeneration refers to the formation of new tissue which is indistinguishable from normal articular cartilage.

• Therefore, we are still unable to regenerate the hyaline articular cartilage.

• The best we can do at the moment is to repair the articulating surface with similar, functional tissue.

• Are we doing enough to restore osteochondral structure and function?

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• Mainly because we still do not seem to understand complex biological and mechanical interaction of articulating surface and subchondral bone.

• This is probably the reason why all mainstream cartilage repair technologies suffer from two major problems:

• insufficient peripheral chondral integration (biomechanical problem?) • insufficient longitudinal subchondral integration (nutritional and biomechanical problem?).

• We may have to accept that this is as good as it gets, at this point in time.

• However, finding a biological solution for cartilage regeneration is one of the fastest growing areas of research and development in orthopaedics and regenerative medicine in general.

So, Why is Cartilage Repair Still a Problem?

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… and this is also me, many years later, with my family (a few weeks ago)

Thank You,

Happy and Healthy Ageing