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Pathophysiology of skeletal manifestations of type 1 Gaucher’s disease

Pathophysiology of skeletal manifestations of type 1 Gaucher’s disease. P. Lafforgue CHU Sainte-Marguerite, Marseille, France. Main cause of pain and disability Most are irreversible Most effective treatment should be prevention . Bone marrow infiltration Pain deformity

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Pathophysiology of skeletal manifestations of type 1 Gaucher’s disease

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  1. Pathophysiology of skeletal manifestations of type 1 Gaucher’sdisease P. Lafforgue CHU Sainte-Marguerite, Marseille, France

  2. Main cause of pain and disability • Most are irreversible • Most effective treatmentshouldbeprevention.

  3. Bonemarrow infiltration • Pain • deformity • Osteonecroses • Acute bone crises /medullaryinfarcts • Epiphysealosteonecroses • Osteolysis • Osteopenia/osteoporosis • Osteomyelitis • Growth retardation • (multiple myeloma) • Fractures

  4. Deformities • Erlenmeyerflask • 60-80% prevalence • Non specific • Impairment of modeling of dia-metaphysesduringgrowth Faden MA et al. Am J Med Genet A. 2009; 149A: 1334-45

  5. OSTEONECROSES Epiphyseal ON Medullaryinfarcts ≈ 33% of patients • Femoral and humeralheadsmainly • Classicalpresentation … • Chronic pain • disability • Joint replacement • Crises: 20-33% • Rx: 25% • Various locations ++ • Femurs • Tibiae • Pelvicbones, vertebrae … • Osteomyelitis-like crises

  6. Gaucher osteonecroseshallmark • « richmarrow» ON • = sicklecell, Gaucher, leukemias • « hot »: pseudo-osteomyelitis • Bouts of acute crises, atany time • In hematopoïetic/invaded areas: • anywhere, extensive « classical » ON • = idiopathic or secondary (CTC, OH,…) • « cold »: initiallyasymptomatic • Occursimultaneously • In fatty areas : • Epiphyses and metaphyses of long bones

  7. Bonevasculature

  8. Pathophysiology Vesselslesions Vessels obturation ischeamia Bone/marrownecrosis extrinsicvessels compression

  9. Vascularlesions ? 100 patients • CCL4/MIP-1β • CCL2/MCP-1 • CXCL8/IL-8 +++ • CCL18/PARC • CCL5/RANTES +++ •  in Gaucher vs controls •  in Gaucher ON vs ON free • Especiallywhen ON occursduring ERT Limits! Treated patients, assessment distant from ON initiation Biological markers of diseaseactivity No evidence of causality Pavlova, Blood Cells Mol Dis 2010

  10. Vascular obturation Micro-emboli of lipidicparticles: corticosteroids dyslipidemia alcoholism Gasbubbles: dysbaric ON thrombosis sicklecell clottingabnormalities

  11. Idiopathic ON • 25 à 30% of ON • 40-50 years-old males •  thrombolysis: • Hyperhomocysteinemia • MTFR gene mutation •  lipoprotein(a) • tPai Apo B Thrombophilia: S proteindeficiency activated C proteinresistance Prothrombingene mutations Factor V Leiden anti-phospholipid Ab • Inconsistencyacrossstudies • Lack of appropriate control groups • Limits: • High prevalence in general population • High diversity of disorders

  12. capillary adipocyte Bonetrabecule Hématopoieticcells Extrinsicvascular compression  extra-vascular components   vascularspace Adipocytichypertrophy CTC OH dyslipidemia Medullaryhypertrophy Gaucher’sdisease sicklecell Marrowgasbubbles dysbaric ON intra-medullaryhemorrhages? m. de Gaucher Marrowedema ischaemia: viciouscircle

  13. Riskfactors for ON in GD • Litterature: • correlatedwithmarrow infiltration • splenectomy ++ • male •  with ERT • Rodrigue, Clin Orthop 2009; Mistry, BJH 2009 • 56 type 1 GD 24 with / 32 without ON: strong association of ON with: • Youngerageatdiagnnosis • Anyotherbone manifestation • splenectomy • ICGG Registry: 544 GD with ON comparedwith 2008 GD without ON: • Slightly more anemia ( 21,5% vs 11,9%) • Slightly more N270S heterozygoty • Slightly more splenectomy (31% vs 24%), NS • Lanfranchi-Debra 2012, unpublished • Khan A, JBMR 2012 e-pub

  14. Natural course of epiphyseal ON

  15. Celldeath (osteocytes, marrowcells, adipocytes) collapse Demarcation by a fibrovascularrim, intra-lesionalremodelling Subchondral fracture

  16. Natural course 1) ON are definitive 2) Their volume isfixed 3) The keyeventissubchondral fracture

  17. Natural course 4) Local prognosisdepends on residualmechanicalproperties of the femoralhead. Small ON (<10%) Weightbearing area partiallypreserved X-ray MRI +++ Large ON (>20%) Weightbearing area totallyaffected No symptom Good prognosis Subchondral fracture Deformity Chronic pain

  18. osteolysis • No or few symptoms • Atrisk for fracture

  19. Osteopenia • BMD islower in Gaucher patients Z-score ≈ - 1 SD • However, moderately: adults: T-score < -2.5: 10/57 (18%) • BMD diminution isassociatedwithsplenectomy, hepatomegaly, N370S genotype Javier, Osteoporosis International 2010 Pastores, JBMR 1996 Wenstrup, JBMR 2007

  20. Pathophysiology of osteopenia: GBA1-deficient mouse model • Lower BMD • ↘ stromalcellsproliferation • ↘ OB differentiation • (through PKC inhibition) • Unaffected OC activity Mistry PK et al. PNAS 2010; 107 : 19473-8

  21. Pathophysiology of osteopenia: • Formation: ↘1,2,3,4 • Resorption: ↗1,2 , ↘3 or Nl4 Role of • cytokines: IL-1β, IL-6, IL-10, TNFα ? • MinorlipidLysoGL-1? • Also look for classicalriskfactors 1.Fiore, JBMR 2002; 12 patients 2.Ciana, J InheritMetab Dis 2005; 12 patients 3.Drugan, Blood Cells Mol Dis 2002; 16 patients 4.Van Dussen, J Clin EndocrinolMetab 20011; 40 patients Michelakakis, BiochimBiophys Acta 1996; Allen , QJM 1997; Hollack, Blood Cells Mol Dis 1997

  22. PERIPHERAL FRACTURES • 14-20% • In focal osteolytic areas (pathological fractures ) Stirnemann, Rev Med Int 2006; Javier, Osteoporosis Int 2010

  23. VERTEBRAL FRACTURES • 8-21% of patients T9 T6

  24. VERTEBRAL FRACTURES • Association withlow BMD: logical but no firmevidence • Not associatedwithsplenectomy • Associatedwithoveralskeletalburden Katz, Spine 1993; Stirnemann, Rev Med Int 2006; Javier, Osteoporosis Int 2010 • Khan A, JBMR 2012 e-pub

  25. Pathophysiologyislargelyunknown, but isclearlydriven by medullary infiltration! • Improvementwith ERT or miglustat: • Of pain • Of bone crises number • Of BMD • Few or no new ON: ICCG Registry : follow-up of 2700 Gaucher patients withoutprevalent ON • ERT initiated < 2 yearsafterdiagnosis : ON incidence = 8,1/1000 pts.yrs • ERT initiated > 2 yearsafterdiagnosis : ON incidence = 16,6/1000 pts.yrs • Risk x 2 whenhistory of splenectomy • However complications maystilloccurundertherapy Charrow, Clin Genet 2007 Sims, Clin Genet 2008 Mistry, Br J Haematol 2009 Stiernemann, ArthritisResTher 2010

  26. Open prospective trial • 33 patients (M=43 years) ERT-naivetreatedwithimiglucerase Bone pain BALP ostéocalcin Bone markers FN BMD Lumbar BMD DPyru NTXu Sims et al, Clin Genet 2008

  27. Children • ICGG Registry • 884 chidrenreceiving ERT , 8 yearsfollow-up • height: Z-score -1,4  normal (-0,3) • 90 patients withprevalentbone crises :  0 crises after2 yearstherapy • 440 patients withoutprevalentbone crises  2,5% withsubsequent new crises • BMD: Z-score -0,35 +0,29 SD Fig1, 6 et 7 Andersson et al. Pediatrics 2008 height Newcrises Lumbar BMD

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