Osteonecrosis of the Femoral Head
Valérie GangjiRheumatology and Physical Medicine
Hôpital ErasmeUniversité Libre de Bruxelles
Belgium
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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
Cellular therapy for osteonecrosis
Cellular therapy for osteonecrosis
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
Therapeutic Strategies
Core Decompression
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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
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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
Cellular therapy for osteonecrosis
• 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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Cellular therapy for osteonecrosis
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
Cellular therapy for osteonecrosis
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
Cellular therapy for osteonecrosisEfficacy on symptoms
0
2
4
6
8
10
12
0 3 6 12 24 36 48 60
Months
Leq
ue
sn
e in
dex
Control group
Bone-marrow graftgroup
** * * *
Gangji et al. 2004, Gangji et al. 2009 - Submitted
Cellular therapy for osteonecrosisEfficacy on symptoms
0
5
10
15
20
25
30
35
40
45
0 3 6 12 24 36 48 60
Months
WO
MA
C S
co
re
Control group
Bone-marrow graft group
Gangji et al. 2004, Gangji et al. 2009 - Submitted
Cellular based therapy for osteonecrosis Efficacy on disease evolution
Time to Collapse - Kaplan-Meier Survivorship Analysis
Gangji et al. 2004, Gangji et al. 2009 - Submitted
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
e n
ecro
tic
lesi
on
to
th
e vo
lum
e o
f th
e fe
mo
ral h
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)
Gangji et al. 2004, Gangji et al. 2009 - Submitted
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
Therapeutic Strategies
Bone marrow
Therapeutic Strategies
Core decompression
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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
PREOB® - BONE THERAPEUTICS