Osteonecrosis of the Femoral Head Valérie Gangji Rheumatology and Physical Medicine Hôpital Erasme Université Libre de Bruxelles Belgium 1

Osteonecrosis of the Femoral Head

Valérie GangjiRheumatology and Physical Medicine

Hôpital ErasmeUniversité Libre de Bruxelles

Belgium

1

Cellular Therapy for osteonecrosis

Osteonecrosis of femoral head

– Painful disorder leading in its late stage to fracture and total hip replacement

– Corticosteroids and alcohol abuse are among the most widely recognized risk factor in Caucasians

– Sickle cell disease is the major risk factor for ON in African patients

– The prevalence of ON in sickle cell patients

– For symptomatic ON: 3-10%

– For asymptomatic ON : 10-40%

Cellular therapy for osteonecrosis

Osteonecrosis of the femoral head

• ON is more frequent in homozygous patient (hemoglobin SS) but ON can also be

found in heterozygous patients and in thalassemia α et β

• The risk of ON is correlated to the incidence of vaso-occlusive crisis and to high

hematocrit Painful disorder leading in its late stage to fracture and total hip

replacement

• Core decompression of the femoral head is the most widespread procedure to

treat early stages of ON

• Efficacy of core decompression remains controversial



Ostéonécrose de la tête fémoralePhysiopathogénie : Hypothèse vasculaire

Traumatisme Coagulation Embolie Hyperpression

intravasculaire intramédullaire

Interruption Thrombose Compressionvasculaire extravasculaire

Diminution du flux sanguin

Ischémie

OSTEONECROSE

Osteonecrosis - physiopathologyCellular therapy

Vascular and Bone DiseaseVascular Disease Bone disease

Fat emboli

Into capillaries

Intravascular

coagulation

Osteoblastic Cells

Therapeutic Strategies

Cellular Therapy


Core Decompression

7

Stems cells

Osteonecrosis in sickle cell anemiaCellular therapy

• Autologous bone marrow transplantation was reported for the first time in 1994 in a patient sustaining ON of the humeral head due to SS anemia

• Three months after the transplantation, MRI showed a tendancy towards normalisatio of the signal.

Osteonecrosis - cellular based therapy

Stem Cell

OsteocyteOsteoblastPreosteo-Osteo-progenitor

MesenchymalStem Cell

Hematopoietic stem cells

Adipocyte

Myocyte

Endothelial

--

l

Cartilage-tendon

9

Concentration

Expansion

Expansion and differentiation

• Bone marrow is concentrated for immediate implantation

• Bone marrow stem cells are separated and expanded for 1 to 3 weeks

• Bone marrow stem cells are separated, expanded and differentiated in a specific cell population

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Osteonecrosis-cellular based therapy

Cellular therapy for osteonecrosisBone marrow procedure

Bone marrow aspiration from the posterior iliac crest

Cobe system - bone marrow collection kit

Harvest system - bone marrow collection kit

Cellular therapy for osteonecrosisBone marrow procedure

Bone marrow is filtered to eliminate spicules and bacteria

Cellular therapy for osteonecrosisBone marrow implantation

Gangji et al. 2005, Marker et al. 2008, Mont et al. 2004, Song et al. 2007

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Less invasive surgery, small incision, 3mm core decompression, injection of the concentrated bone marrow through the trephine-lower morbidity and postoperative

complication rates


• A five year prospective controlled double blind trial on the efficacy of bone marrow implantation in osteonecrosis of the femoral head

• 19 patients suffering from stage 1 and 2 ON of the femoral head

• Patient’s hips (24 hips) were alternatively allocated to a core decompression procedure only (control group) or with autologous bone marrow grafting (bone marrow graft group)

• Primary outcomes were • safety

• clinical symptoms

• disease progression from stage 1-2 to the stage 3

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Assessment at baseline, 3, 6, 12, 24, 36, 48 and 60 months

• Clinical evaluation

visual analogue scale (VAS), algofunctionnal index of Lequesne,

WOMAC score

• Radiological evaluation

anteroposterior radiographs of the affected hip

measurement of the necrotic zone by MRI on T1-weighted scans

Cellular therapy for osteonecrosisBone marrow harvest procedure

• 400 ml of bone marrow obtained from the anterior or posterior iliac crest

• Mononuclear cells sorted on a Cobe Spectra cell separator and marrow concentrated to a final volume of ~ 50 ml

• Total injected volume was 51 1.8 ml

• Number of leukocytes 2.0 109 0.3 109

• Number of CD34+ cells 1 0.2 %

• Number of CFU-F 92 28 / 107 cells


Core decompression Bone marrow implantation

Cellular therapy for osteonecrosisHoming of bone marrow cells at 24H

Leukocytes were labeled with Indium Oxine and mixed with the injected bone marrow

Cellular therapy for osteonecrosisEfficacy on symptoms

0

10

20

30

40

50

60

70

0 3 6 12 24 36 48 60

Months

VA

S (

mm

)

Control group

Bone-marrow graftgroup

* * * * *

Gangji et al. 2004, Gangji et al. 2009 - Submitted


0

2

4

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0 3 6 12 24 36 48 60

Months

Leq

ue

sn

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Control group

Bone-marrow graftgroup

** * * *



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0 3 6 12 24 36 48 60

Months

WO

MA

C S

co

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Control group

Bone-marrow graft group


Cellular based therapy for osteonecrosis Efficacy on disease evolution

Time to Collapse - Kaplan-Meier Survivorship Analysis


3 of 13 hips in the bone marrow graft group progressed to stage III. Log-rank test; p=0.008

7 of 11 hips in the control group deteriorated to the stage III

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Cellular based therapy for osteonecrosis Efficacy on volume of the lesion

0

5

10

15

20

25

30

0 3 6 12 24 36 48 60

Months

Rat

io o

f th

e vo

lum

e o

f th

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f th

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ead

(%

)

Control group

Bone Marrow graft group

*The volume of the necrotic lesion decreased significantly in the bone marrow graft group at 24 months (p=0.041) and approached statistical significance at 60 months (p=0.066)


Cellular based therapy for osteonecrosis

Results of previous studies

• Hernigou et al. (2002)– Prospective study: 189 hips in 116 patients– Followed up from 5-10 years– Total hip replacement was needed :

• in 5/145 hips for stage 1-2• 25/44 hips for stage 3-4

– More efficient in SS patients– Efficacy related to the amount of CFU

implanted

Cellular based therapy for osteonecrosis Osteonecrosis – Hypothesis for efficacy

Vascular and Bone DiseaseVascular Disease Osteonecrosis

Fat emboli

Into capillaries

Intravascular coagulation

Mesenchymal Stem Cells

Osteoblastic Cells


Bone marrow


Core decompression

25

Cellular therapy for bone diseasesHypothesis for efficacy

• Availability of mesenchymal and endothelial stem cells endowed with osteogenic and angiogenic properties could explain the efficacy

• The efficacy of BMPs like BMP-2 and BMP-7 in treating nonunion fracture could be explained by their ability to recruit mesenchymal stem cells and to initiate their differentiation into osteoprogenitors

• Bone marrow will also provide osteogenic and angiogenic growth factors like FGF-2, TGF-β, PDGF, VEGF, angiopoietin resulting in increased osteogenesis and angiogenesis

Cellular therapy for osteonecrosisConclusions

• Pioneer trials in bone marrow implantation in osteonecrosis have shown safety and some degree of efficacy

• Larger controlled and randomized trials are needed to confirm those results

• Improvement of clinical outcome can only be possible through the optimization of the cellular product– Improvement of intra-operative bone marrow

harvest/concentration– Selection of cells

Remerciements

• L’équipe de l’unité de thérapie cellulaire de l’Hôpital Erasme

Cellular therapy for osteonecrosisConclusions

• Improvement of clinical outcome can only be possible through the optimization of the cellular product– Improvement of intra-operative bone marrow

harvest/concentration– Selection of cells

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Osteonecrosis of the Femoral Head Valérie Gangji Rheumatology and Physical Medicine Hôpital Erasme Université Libre de Bruxelles Belgium 1