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 Glasgow Neuromuscular Team Scottish Muscle Network 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 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

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. Amongst the complications that may occur in boys with DMD, there is increasing concern regarding development of osteoporosis. It is reported that Fragility fractures can occur up to 40% and these can have a significant effect on quality of life. Long bone fractures are reported in up to 25% and these Fractures not only causes significant pain but also lead to premature loss of walking in up to 27%. (Larson) High dose steroid therapy is known to increase the risk of Vertebral fractures. Bothwell has reported that 74%developed VF after 100 M Rx steroid therapy. Therefore, secondary osteoporosis is a significant problem & 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. A retrospective review of our current cohort of DMD boys in Glasgow has shown a similar prevelance of fractures.

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. Without effective curative therapy, currently steroids form the mainstay of treatment & there is a recent trend towards prolongation of steroid therapy well beyond the time at which ambulation is lost. However, Steroid therapy is known to affect bone health. Therefore, there is an increasing concern regarding the cumulative effect of such prolonged steroid treatment on bone health as DMD boys live longer. 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 There are a number of risk factors for osteoporosis such as reduced mobility & weight bearing, insufficient vitamin D level, delayed puberty, muscle inflammation in addition to the effect of steroid therapy, therefore the pathogenesis is complex.

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 Until now, the natural history of osteoporosis in DMD has not been studied throughly and therefore the European Medicines Agency has prioritised research into better understanding the development of osteoporosis in DMD before embarking on clinical trials involving bone protective therapy.

Definition of Osteoporosis The definition of osteoporosis differs in children compared to adults

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 In comparison to adults, the diagnosis of osteoporosis should NOT be made solely on densitometry In the absence of vertebral compression fractures, the diagnosis of osteoporosis is indicated by the presence of a clinically significant fracture and low BMC/BMD

Determinants of Bone Strength Bone density / mass (DXA) Bone Geometry Bone size (pQCT) Bone shape (pQCT, MRI) 3. Bone material properties (bone biopsy, MRI) 4. Forces applied to bone – weightbearing, muscle contraction There are several factors that affect bone strength as shown.

Dual X-ray Absorptiometry(DXA) Only give quantitative rather than qualitative assessment of bone. We are familiar with the use DXA to monitor BMD in DMD as part of the standard of care. However it has its limitations. In particular, it can only provide information on Bone mineral content but does not provide any information on the quality of the bone itself.

Vertebral Fracture Assessment The finding of vertebral fractures (VFs) is indicative of severe bone fragility irrespective of the reported bone mineral density (BMD) As these fractures can be asymptomatic we believe they are often missed and as a result the opportunity for secondary prevention may be missed.

Vertebral Fracture Assessment Grade 0 Normal vertebra 20-25% - Mild Fracture Grade 1 Currently we perform lateral spinal XR to look for vertebral fracture. We assess the shape and size of vertebral body on theses films. 25-40% - Moderate Fracture Grade 2 Grade 3 >40% - Severe Fracture

Detection of VF using DXA Vertebral Fracture Assessment by DXA could be used as complement to BMD measurement for the identification of asymptomatic vertebral fractures. 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 With advancement of DXA technology, we are able to obtain lateral spine images similar to those of a standard lateral spinal XR. ( as you can see in this slide) This technique has significantly reduced radiation dose compared to plain XR. Another advantage is that it can be done at the same time as routine DXA scans. Therefore we believe vertebral fracture assessment by DXA could be implemented as part of the bone sureveillance programme.

Agreement of DXA and Spinal XR vertebral fracture assessment Vertebral fracture assessment by DXA is both a reproducible and accurate method for detecting VF Our ED Research group has recently conducted a study using DXA for VFA in children with various chronic diseases and aassessment of lateral spine images acquired by DXA showed good inter observer agreement. We therefore hope to validate this technique in children with DMD.

Determinants of Bone Strength Bone density / mass (DXA) Bone Geometry Bone size (pQCT) Bone shape (pQCT, MRI) 3. Bone material properties (bone biopsy, MRI) 4. Forces applied to bones High resolution MRI is a technique that is being developed by our research group. This can provide information on bone quality.

(Bone microarchitecture) & MRS (Bone marrow adiposity) assessment High resolution MRI (Bone microarchitecture) & MRS (Bone marrow adiposity) assessment In ScOT DMD study we will be performing high resolution MRI to assess bone microarchitecture and Magnetic resonance spectroscopy looking at bone marrow adiposity.

MicroMRI For assessment Of Bone Microarchitecture D E F Our ED research group has pioneered this novel MRI bone imaging technique looking at changes in patients with GH deficiency and OI. This Novel MRI technique is almost like a virtual bone biopsy providing new information on bone quality that is not addressed by DXA . This has not been done in the DMD population before and we hope to use this imaging technique in our study to provide a greater understanding of pathological state of secondary osteoporosis in DMD. Control Osteogenesis Imperfecta GH Deficiency MicroMRI Bone- A Virtual Bone Biopsy McComb et al Clin Endocrinol 2014

Determinants of Bone Strength Bone density / mass (DXA) Bone Geometry Bone size (pQCT) Bone shape (pQCT, MRI) 3. Bone material properties (bone biopsy, MRI) 4. Forces applied to bones Bone strength is also determined by the forces applied to bones through weight bearing and muscle contraction.

Muscle MRI There is an increasing interest in Muscle MRI in neuromuscular disorders and we will be performing High resolution Muscle MRI along side bone MRI imaging as part of our study.

Magnetic imaging muscle biomarkers Most useful MR parameters: Muscle cross-sectional area (T1 imaging) Cross sectional contractile area Fat fraction (% of muscle replace by fat) Fatty infiltration Quantatitive T2 imaging Most useful MR parameters in DMD are thought to be T1 weighted imaging looking at cross sectional muscle area Degree of Fatty infiltration of muscle Quantative T2 imaging. We hope to asses muscle strength clinically and explore the relationship of muscle health and bone health in DMD. Assess against clinical muscle function assessment to evaluate relationship of muscle condition to bone health.

ScOT-DMD study Finally I would like to talk about the study

Overall aim To characterise the prevalence, pathophysiology and progression of bone morbidity in Scottish DMD boys In order to: improve the bone surveillance programme better inform future clinical trials involving bone protective therapy.

2 year prospective longitudinal study ( Bone imaging & biomarkers) Study design 2 year prospective longitudinal study ( Bone imaging & biomarkers) Cross-sectional MRI and MRS study (Bone & Muscle) The boys will be recruited into 2 year prospective longituidinal study. Subset of older boys are reruited into cross sectional MRI study.

Recruitment Inclusion Criteria Exclusion 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 To assess prevalence of vertebral fractures in DMD over a 2 year follow-up using spinal x rays in all patients To assess the reliability of DXA based vertebral fracture assessment for detection of vertebral fractures To evaluate relationship of bone morbidity to clinical risk factors, markers of gonadal function, bone turnover and growth hormone axis To evaluate bone microarchitecture, bone marrow adiposity & muscle quality using MRI and MRS To assess prevalence of vertebral fractures in DMD over a 2 year follow-up using spinal x rays in all patients To assess the reliability of DXA based vertebral fracture assessment for detection of vertebral fractures To evaluate relationship of bone morbidity to clinical risk factors, markers of gonadal function, bone turnover and growth hormone axis To evaluate bone microarchitecture and bone marrow adiposity using MRI and MRS

Timeline of study Recruitment Bone imaging & biomarkers Oct 2015-June2016 Bone imaging & biomarkers October 2015-June-2018 Data analysis >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 EK2 Egan Klassification Score

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.