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ScOT-DMD
Shuko Joseph
Glasgow Neurosciences Research Group /
Developmental Endocrinology Research Group
The Royal Hospital for Children Glasgow
ScOT-DMD
SeCondary Osteoporosis & its Therapy
in Duchenne Muscular Dystrophy (ScOT–DMD)
Funded by
CSO, Action Duchenne and Muscular Dystrophy UK
Acknowledgements
Scottish Muscle Network
North Star Network
Chief Scientist Office
Muscular Dystrophy UK
Action Duchenne
Developmental Endocrinology
Research Group
The Royal Hospital for Sick Children
Glasgow
- F Ahmed
- J Wong
- A Kriyakou
- S Shephard
- M McMillan
University of Glasgow
- C McComb
Research MRI scientist
- John Foster
- Pauline hallbarrientos
Glasgow Neuromuscular Team
Glasgow Neurosciences
Research Group
- Iain Horrocks
- Marina Di Marco
- Sara Brown
- Rachel Mochrie
- Wilma Stewart
- Jennifer Dunne
Collaborators
The Royal Hospital for Sick
Children Edinburgh
- Kenneth McWilliam
- Alex Baxter
Department of Radiology The
Royal Hospital for Sick
Children Glasgow
- Ruth Allen
Introduction
• Importance & complexity of secondary osteoporosis in DMD
• Current bone imaging method & its limitations
• Novel methods of bone imaging
• ScOT- DMD Study
Background
Secondary Osteoporosis & Fracture in DMD
•Fragility fractures can occur in
40%
•Long bone fractures are
reported up to 25% (Larson et al)
•Vertebral fractures can occur
in 74% after 100 months of
steroid therapy
(Bothwell et al)
•Bone health in DMD deserves
a high priority for further
research.
Bothwell JE et al Clin Pediatr 2003
A retrospective review of bone morbidity in a
contemporary Glasgow cohort of boys with DMD
12/47 (26%) boys had sustained a total of
15 symptomatic fracture events.
Steroid And Impact On Bone Health
There is an increasing
concern regarding the
cumulative effect of
prolonged steroid
treatment on bone health
of DMD boys.
Mushtaq T , Ahmed SF Arch Dis Child 2002
Pathogenesis of Secondary Osteoporosis
Determinants Of Bone Mass
•Pathogenesis is poorly
understood.
•Likely to be multifactorial
and complex.
•Secondary osteoporosis in
DMD is unique
EMEA international bone health experts
• There is a need for a natural history study characterising
secondary osteoporosis in DMD prior to embarking on
therapeutic clinical trials on bone protective therapy
Definition of Osteoporosis
ISCD Official Position 2013
Skeletal Health Assessment In
Children and Adolescents
(Males and Females ages 5-19)
The diagnosis of osteoporosis should NOT be made on DXA measurement
But
Vertebral compression fracture (independent of DXA)
OR
a clinically significant fracture and low BMC/BMD<-2SD
clinically significant fracture history is:
• ≥2 long bone fractures by 10 yrs
• ≥3 long bone fractures at any age up to 16 yrs
Determinants of Bone Strength
1. Bone density / mass (DXA)
2. Bone Geometry
Bone size (pQCT)
Bone shape (pQCT, MRI)
3. Bone material properties (bone biopsy, MRI)
4. Forces applied to bone – weightbearing, muscle contraction
Dual X-ray Absorptiometry(DXA)
Only give
quantitative
rather than
qualitative
assessment of
bone.
Vertebral Fracture Assessment
Vertebral Fracture Assessment
Grade 0
Grade 1
Grade 2
Grade 3
Normal vertebra
20-25% - Mild Fracture
25-40% - Moderate Fracture
>40% - Severe Fracture
Detection of VF using DXA
The assessment of lateral spine images
acquired by DXA can be used to detect
vertebral fractures
• Less radiation exposure (<1/10th)
• Convenient for the patient
• Less expensive
Vertebral Fracture Assessment by DXA could be used as
complement to BMD measurement
asymptomatic vertebral fractures.
for the identification of
Agreement of DXA and Spinal XR
vertebral fracture assessment
Vertebral fracture
assessment by DXA is
both a reproducible
and accurate method
for detecting VF
Determinants of Bone Strength
1. Bone density / mass (DXA)
1. Bone Geometry
Bone size (pQCT)
Bone shape (pQCT, MRI)
3. Bone material properties (bone biopsy, MRI)
4. Forces applied to bones
High resolution MRI
(Bone microarchitecture)
& MRS (Bone marrow adiposity)
assessment
MicroMRI For assessment Of Bone Microarchitecture
B
F
A
C
E
D
Control
Osteogenesis Imperfecta
GH Deficiency
MicroMRI Bone- A Virtual Bone Biopsy
McComb et al Clin Endocrinol 2014
Determinants of Bone Strength
1. Bone density / mass (DXA)
2. Bone Geometry
Bone size (pQCT)
Bone shape (pQCT, MRI)
3. Bone material properties (bone biopsy, MRI)
4. Forces applied to bones
Muscle MRI
Magnetic imaging muscle biomarkers
Most useful MR parameters:
• Muscle cross-sectional area
• Quantatitive T2 imaging
(T1 imaging) Cross sectional
contractile area
Available online at www.sciencedirect.com
• Fat fraction (% of muscle replace
by fat) Fatty infiltration
ScienceDirect
Neuromuscular Disorders 24 (2014) 393–401
Assess
against
clinical
Longitudinal me
asure
ments
of MRI-T
muscle function assessment
Duchenne muscular dystrophy:
Effects of age a
to evaluate relationship of
a
bone
R.J. Willcocksa,⇑, I.A. Arpanmuscle
, S.C.condition
Forbesato
, D.J
. Lott a, C
J. Deol a, W.T. Triplett b, C. Ba
ligand b, M.J. Danielsc, H.L
health.
a
K. Vandenborne
a
b
Department of Physical Therapy, University of Florida,
Department of Physiology and Functional Genomics, University o
ScOT-DMD study
Overall aim
To characterise the prevalence, pathophysiology and
progression of bone morbidity in Scottish DMD boys
In order to:
1) improve the bone surveillance programme
2) better inform future clinical trials involving bone
protective therapy.
Study design
• 2 year prospective longitudinal study
( Bone imaging & biomarkers)
• Cross-sectional MRI and MRS study
(Bone & Muscle)
Recruitment
Inclusion Criteria
All boys with DMD managed in SMN that can attend Glasgow
Age 5-16years
Age >10 for MRI study
Exclusion Criteria
Boys in FOR-DMD trial
Objectives
a) To assess prevalence of vertebral fractures in DMD
over a 2 year follow-up using spinal x rays in all
patients
b) To assess the reliability of DXA based vertebral
fracture assessment for detection of vertebral
fractures
c) To evaluate relationship of bone morbidity to clinical
risk factors, markers of gonadal function, bone
turnover and growth hormone axis
d) To evaluate bone microarchitecture, bone marrow
adiposity & muscle quality using MRI and MRS
Timeline of study
Recruitment
Oct 2015June2016
Bone imaging & biomarkers
Data analysis
October 2015June-2018
>June 2018
Study Visits
6 monthly
Anthromopometry & Pubertal assessment
North Star assessment (NSAA & EK2)
DXA (TB/LS/FN/LVM)
12 monthly
Lateral spine XR, Bone age
Blood tests
-Bone turnover (VitD, PTH, osteocalcin, Bone ALP, CTX)
-Gonadal function (LH, FSH, testosterone)
-Growth hormone axis (IGF-1, IGFBP-3, ALS)
MRI study of bone microarchitecture and bone marrow adiposity
MRI study of muscle area and fatty infiltration
Summary
Prospective, systematic and standardized approach to
evaluation of bone pathology using bone imaging and bone
biomarkers.
Validate and assess clinical application of VFA by DXA
Novel MRI technique will provide new information on bone
and muscle quality and greater understanding of pathological
state of secondary osteoporosis in DMD.
Better inform bone health surveillance programme and
provide foundation for future bone protective therapy trial.