P. LafforgueCHU Sainte-Marguerite,

Marseille, France

Pathophysiology of skeletal manifestations of type 1 Gaucher’s

disease

• Main cause of pain and disability• Most are irreversible

• Most effective treatment should be prevention.

• Bone marrow infiltration• Pain• deformity• Osteonecroses– Acute bone crises /medullary infarcts– Epiphyseal osteonecroses

• Osteolysis• Osteopenia/osteoporosis• Osteomyelitis• Growth retardation• (multiple myeloma)

• Fractures

Deformities

• 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 patients

• Femoral and humeral heads mainly

• Classical presentation …

• Chronic pain• disability• Joint replacement

Crises: 20-33%Rx: 25%

• Various locations ++• Femurs• Tibiae• Pelvic bones, vertebrae …

• Osteomyelitis-like crises

Epiphyseal ON Medullary infarcts

OSTEONECROSES

Gaucher osteonecroses hallmark« classical » ON

• = idiopathic or secondary (CTC, OH,…)

• « cold »: initially asymptomatic• Occur simultaneously

• In fatty areas :• Epiphyses and metaphyses of long

bones

« rich marrow» ON• = sickle cell, Gaucher, leukemias• « hot »: pseudo-osteomyelitis• Bouts of acute crises, at any time

• In hematopoïetic/invaded areas:• anywhere, extensive

Bone vasculature

Pathophysiology

isch

eam

ia

Vessels lesions

Vessels obturation

extrinsic vessels compression

Bone

/mar

row

nec

rosi

s

Vascular lesions ?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• Especially when ON occurs during ERT

Limits!Treated patients, assessment distant from ON initiationBiological markers of disease activityNo evidence of causality

Pavlova, Blood Cells Mol Dis 2010

Vascular obturation

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 deficiencyactivated C protein resistanceProthrombin gene mutationsFactor V Leidenanti-phospholipid Ab

thrombolysis:

HyperhomocysteinemiaMTFR gene mutation lipoprotein(a) tPaiApo B

Limits:• High prevalence in general

population• High diversity of disorders

• Inconsistency across studies• Lack of appropriate control

groups

Extrinsic vascular compression

extra-vascular components vascular space

Adipocytic 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

Hématopoietic cells

Bone trabecule

capillary

adipocyte

Risk factors for ON in GDLitterature:• correlated with marrow infiltration• 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 association of ON with:• Younger age at diagnnosis • Any other bone manifestation• splenectomy Lanfranchi-Debra 2012, unpublished

Natural course of epiphyseal ON

Cell death (osteocytes, marrow cells, adipocytes)

Demarcation by a fibrovascular rim, intra-lesional remodelling

collapse

Subchondralfracture

Natural course

1) ON are definitive

2) Their volume is fixed

3) The key event is subchondral fracture

Natural course

4) Local prognosis depends on residual mechanical properties of the femoral head.

Small ON (<10%)Weight bearing areapartially preserved

Large ON (>20%)Weight bearing area

totally affected

No symptomGood prognosis

Subchondral fractureDeformity

Chronic pain

X-rayMRI +++

osteolysis

• No or few symptoms• At risk for fracture

Osteopenia

• BMD is lower in Gaucher patients Z-score ≈ - 1 SD

• However, moderately:adults: T-score < -2.5: 10/57 (18%)

• BMD diminution is associated with splenectomy, hepatomegaly, N370S genotype Pastores, JBMR 1996

Wenstrup, JBMR 2007

Javier, Osteoporosis International 2010

Pathophysiology of osteopenia:GBA1-deficient mouse model

Mistry PK et al. PNAS 2010; 107 : 19473-8

Lower BMD ↘ stromal cells proliferation ↘ OB differentiation (through PKC inhibition) Unaffected OC activity

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 patients2.Ciana, J Inherit Metab Dis 2005; 12 patients3.Drugan, Blood Cells Mol Dis 2002; 16 patients4.Van Dussen, J Clin Endocrinol Metab 20011; 40 patients

• Formation: ↘1,2,3,4

• Resorption: ↗1,2 , ↘3 or Nl4

PERIPHERAL FRACTURES

• 14-20%

• In focal osteolytic areas (pathological fractures )

Stirnemann, Rev Med Int 2006; Javier, Osteoporosis Int 2010

T6

T9

VERTEBRAL FRACTURES • 8-21% of patients

VERTEBRAL FRACTURES • Association with low BMD: logical but no firm evidence• Not associated with splenectomy• Associated with overal skeletal burden

Katz, Spine 1993; Stirnemann, Rev Med Int 2006; Javier, Osteoporosis Int 2010

Khan A, JBMR 2012 e-pub

Pathophysiology is largely unknown, but is clearly driven by medullary infiltration!

• 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 patients without prevalent ON– ERT initiated < 2 years after diagnosis : ON incidence = 8,1/1000 pts.yrs– ERT initiated > 2 years after diagnosis : ON incidence = 16,6/1000 pts.yrs– Risk x 2 when history of splenectomy

Charrow, Clin Genet 2007Sims, Clin Genet 2008Mistry, Br J Haematol 2009

• However complications may still occur under therapyStiernemann, Arthritis Res Ther 2010

• Open prospective trial• 33 patients (M=43 years) ERT-naive treated with imiglucerase

Bone pain

Lumbar BMD

ostéocalcinBALP

DPyruNTXu

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 patients with prevalent bone crises : 0 crises after2 years therapy– 440 patients 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