P. Lafforgue# CHUSainteMarguerite,# Marseille,France · "%tPai% Apo%B Limits: •...
Transcript of P. Lafforgue# CHUSainteMarguerite,# Marseille,France · "%tPai% Apo%B Limits: •...
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P. Lafforgue CHU Sainte-‐Marguerite,
Marseille, France
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• Main cause of pain and disability • Most are irreversible
• Most effec5ve treatment should be preven5on.
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• Bone marrow infiltra5on • Pain • deformity • Osteonecroses – Acute bone crises /medullary infarcts – Epiphyseal osteonecroses
• Osteolysis • Osteopenia/osteoporosis • Osteomyeli5s • Growth retarda5on • (mul5ple myeloma)
• Fractures
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Deformi5es
• Erlenmeyer flask
• 60-‐80% prevalence • Non specific • Impairment of modeling of dia-‐metaphyses during growth
Faden MA et al. Am J Med Genet A. 2009; 149A: 1334-‐45
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≈ 33% of pa)ents
• Femoral and humeral heads mainly
• Classical presenta5on …
• Chronic pain • disability • Joint replacement
Crises: 20-‐33% Rx: 25%
• Various loca5ons ++ • Femurs • Tibiae • Pelvic bones, vertebrae …
• Osteomyeli5s-‐like crises
Epiphyseal ON Medullary infarcts
OSTEONECROSES
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Gaucher osteonecroses hallmark « classical » ON
• = idiopathic or secondary (CTC, OH,…)
• « cold »: ini5ally asymptoma5c • Occur simultaneously
• In fady areas : • Epiphyses and metaphyses of long
bones
« rich marrow» ON • = sickle cell, Gaucher, leukemias • « hot »: pseudo-‐osteomyeli5s • Bouts of acute crises, at any 5me
• In hematopoïe5c/invaded areas: • anywhere, extensive
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Bone vasculature
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Pathophysiology
ischeamia
Vessels lesions
Vessels obtura)on
extrinsic vessels compression
Bone
/marrow necrosis
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Vascular lesions ? 100 pa5ents – CCL4/MIP-‐1β – CCL2/MCP-‐1 – CXCL8/IL-‐8 +++ – CCL18/PARC – CCL5/RANTES +++
• & in Gaucher vs controls • & in Gaucher ON vs ON free • Especially when ON occurs during
ERT
Limits! Treated pa5ents, assessment distant from ON ini5a5on Biological markers of disease ac5vity No evidence of causality
Pavlova, Blood Cells Mol Dis 2010
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Vascular obtura)on
Micro-emboli of lipidic particles: corticosteroids dyslipidemia alcoholism
thrombosis sickle cell clotting abnormalities
Gas bubbles: dysbaric ON
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Idiopathic ON • 25 à 30% of ON • 40-‐50 years-‐old males
Thrombophilia: S protein deficiency ac5vated C protein resistance Prothrombin gene muta5ons Factor V Leiden an5-‐phospholipid Ab
thrombolysis: Hyperhomocysteinemia MTFR gene muta5on & lipoprotein(a) ( tPai Apo B
Limits: • High prevalence in general
popula5on • High diversity of disorders
• Inconsistency across studies • Lack of appropriate control
groups
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Extrinsic vascular compression
Þ extra-‐vascular components ⇒ à vascular space
Adipocy5c hypertrophy CTC OH dyslipidemia
Marrow edema ischaemia: vicious circle
intra-‐medullary hemorrhages? m. de Gaucher
Medullary hypertrophy Gaucher’s disease sickle cell
Marrow gas bubbles dysbaric ON
Hématopoie5c cells
Bone trabecule
capillary
adipocyte
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Risk factors for ON in GD Liderature: • correlated with marrow infiltra5on • splenectomy ++ • male • (( with ERT
Rodrigue, Clin Orthop 2009; Mistry, BJH 2009
ICGG Registry: 544 GD with ON compared with 2008 GD without ON: • Slightly more anemia ( 21,5% vs 11,9%) • Slightly more N270S heterozygoty • Slightly more splenectomy (31% vs 24%), NS
Khan A, JBMR 2012 e-‐pub
56 type 1 GD 24 with / 32 without ON: strong associa5on of ON with: • Younger age at diagnnosis • Any other bone manifesta5on • splenectomy Lanfranchi-‐Debra 2012, unpublished
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Natural course of epiphyseal ON
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Cell death (osteocytes, marrow cells, adipocytes)
Demarca)on by a fibrovascular rim, intra-‐lesional remodelling
collapse
Subchondral fracture
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Natural course
1) ON are defini5ve
2) Their volume is fixed 3) The key event is subchondral fracture
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Natural course
4) Local prognosis depends on residual mechanical proper5es of the femoral head.
Small ON (<10%) Weight bearing area par)ally preserved
Large ON (>20%) Weight bearing area
totally affected
No symptom Good prognosis
Subchondral fracture Deformity Chronic pain
X-‐ray MRI +++
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osteolysis
• No or few symptoms • At risk for fracture
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Osteopenia
• BMD is lower in Gaucher pa5ents Z-‐score ≈ -‐ 1 SD
• However, moderately: adults: T-‐score < -‐2.5: 10/57 (18%)
• BMD diminu5on is associated with
splenectomy, hepatomegaly, N370S genotype Pastores, JBMR 1996
Wenstrup, JBMR 2007
Javier, Osteoporosis InternaLonal 2010
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Pathophysiology of osteopenia: GBA1-‐deficient mouse model
Mistry PK et al. PNAS 2010; 107 : 19473-‐8
ü Lower BMD ü ↘ stromal cells prolifera5on ü ↘ OB differen5a5on ü (through PKC inhibi5on) ü Unaffected OC ac5vity
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Pathophysiology of osteopenia:
Role of • cytokines: IL-‐1β, IL-‐6, IL-‐10, TNFα ? • Minor lipid LysoGL-‐1? • Also look for classical risk factors
Michelakakis, Biochim Biophys Acta 1996; Allen , QJM 1997; Hollack, Blood Cells Mol Dis 1997
1.Fiore, JBMR 2002; 12 paLents 2.Ciana, J Inherit Metab Dis 2005; 12 paLents 3.Drugan, Blood Cells Mol Dis 2002; 16 paLents 4.Van Dussen, J Clin Endocrinol Metab 20011; 40 paLents
• Forma)on: ↘1,2,3,4
• Resorp5on: ↗1,2 , ↘3 or Nl4
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PERIPHERAL FRACTURES
• 14-‐20%
• In focal osteoly5c areas (pathological fractures )
SLrnemann, Rev Med Int 2006; Javier, Osteoporosis Int 2010
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T6
T9
VERTEBRAL FRACTURES • 8-‐21% of pa5ents
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VERTEBRAL FRACTURES • Associa5on with low BMD: logical but no firm evidence • Not associated with splenectomy • Associated with overal skeletal burden
Katz, Spine 1993; SLrnemann, Rev Med Int 2006; Javier, Osteoporosis Int 2010
Khan A, JBMR 2012 e-‐pub
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Pathophysiology is largely unknown, but is clearly driven by medullary infiltra5on!
• Improvement with ERT or miglustat: – Of pain – Of bone crises number – Of BMD
• Few or no new ON: ICCG Registry : follow-‐up of 2700 Gaucher pa5ents without prevalent ON – ERT ini5ated < 2 years a{er diagnosis : ON incidence = 8,1/1000 pts.yrs
– ERT ini5ated > 2 years a{er diagnosis : ON incidence = 16,6/1000 pts.yrs
– Risk x 2 when history of splenectomy Charrow, Clin Genet 2007 Sims, Clin Genet 2008 Mistry, Br J Haematol 2009
• However complica5ons may s5ll occur under therapy SLernemann, ArthriLs Res Ther 2010
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• Open prospec5ve trial • 33 pa5ents (M=43 years) ERT-‐naive treated with imiglucerase
Bone pain
Lumbar BMD
ostéocalcin BALP
DPyru NTXu
Bone markers
Sims et al, Clin Genet 2008
FN BMD
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Children • ICGG Registry • 884 chidren receiving ERT , 8 years follow-‐up
– height: Z-‐score -‐1,4 " normal (-‐0,3) – 90 pa5ents with prevalent bone crises : " 0 crises a{er2 years therapy – 440 pa5ents without prevalent bone crises " 2,5% with subsequent new crises
– BMD: Z-‐score -‐0,35 " +0,29 SD
• Fig1, 6 et 7
Andersson et al. Pediatrics 2008
height
New crises
Lumbar BMD
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Velaglucerase • Open trial velaglucerase 60 U/kg/2 weeks • 12 pa5ents → 10 pa5ents with m=6,5 years follow-‐up • M=35 years (18-‐62) • Z-‐score:
– spine: -‐1,8 SD – Femur: -‐1,5 SD
• 4 under concomitant BP
Elstein, Blood Cells Mol Dis 2011
• Improvement of lumbar and femoral BMD (p<0,01) • No addi5onal effect of BP?
-‐2
-‐1,5
-‐1
-‐0,5
0 0 10 20 30 40 50 60 70
Z-‐score
months Lumbar BMD
ITT (n=10) avec BP (n=4) sans BP (N=6)
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