P. Lafforgue# CHUSainteMarguerite,# Marseille,France · "%tPai% Apo%B Limits: •...
29
P. Lafforgue CHU SainteMarguerite, Marseille, France
Transcript of P. Lafforgue# CHUSainteMarguerite,# Marseille,France · "%tPai% Apo%B Limits: •...
P. Lafforgue CHU Sainte-‐Marguerite,
Marseille, France
• Main cause of pain and disability • Most are irreversible
• Most effec5ve treatment should be preven5on.
• Bone marrow infiltra5on • Pain • deformity • Osteonecroses – Acute bone crises /medullary infarcts – Epiphyseal osteonecroses
• Osteolysis • Osteopenia/osteoporosis • Osteomyeli5s • Growth retarda5on • (mul5ple myeloma)
• Fractures
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
≈ 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
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
Bone vasculature
Pathophysiology
ischeamia
Vessels lesions
Vessels obtura)on
extrinsic vessels compression
Bone
/marrow necrosis
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
Vascular obtura)on
Micro-emboli of lipidic particles: corticosteroids dyslipidemia alcoholism
thrombosis sickle cell clotting abnormalities
Gas bubbles: dysbaric ON
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
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
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
Natural course of epiphyseal ON
Cell death (osteocytes, marrow cells, adipocytes)
Demarca)on by a fibrovascular rim, intra-‐lesional remodelling
collapse
Subchondral fracture
Natural course
1) ON are defini5ve
2) Their volume is fixed 3) The key event is subchondral fracture
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 +++
osteolysis
• No or few symptoms • At risk for fracture
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
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
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
PERIPHERAL FRACTURES
• 14-‐20%
• In focal osteoly5c areas (pathological fractures )
SLrnemann, Rev Med Int 2006; Javier, Osteoporosis Int 2010
T6
T9
VERTEBRAL FRACTURES • 8-‐21% of pa5ents
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
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
• 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
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
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)
