Bone Health and Duchenne Muscular Dystrophy Dr Nick Shaw, Dept of Endocrinology & Diabetes Birmingham Children’s Hospital

Overview Influences on bone strength Assessment of bone health Fractures and DMD Research on bone density & geometry in DMD Use of bisphosphonates – treatment and prevention

Influences on Bone Mass during growth Genetics Nutrition: Dietary calcium intake Vitamin D Fruit and vegetable intake Carbonated beverage intake Puberty Physical activity

Mechanostat: control loop of bone adaptation Adapted: Steady State H. Frost 1964 Bone Geometry Bone Repair Osteoclasts Osteoblasts Force Bone Muscle Deformation Mechanostat 1000μStr. 2000μStr. 1/4

Mechanostat: control loop of bone adaptation Adapted: Steady State H. Frost 1964 Bone Geometry Bone Repair Osteoclasts Osteoblasts Normal Force Bone Muscle Deformation Mechanostat 1000μStr. 2000μStr. 2/4

Mechanostat: control loop of bone adaptation Adapted: Steady State H. Frost 1964 Bone Geometry Bone Repair Osteoclasts Osteoblasts Normal Force Bone Muscle Deformation x Mechanostat 1000μStr. 2000μStr. 3/4

Mechanostat: control loop of bone adaptation Adapted: Steady State Hormones Nutrition Drugs H. Frost 1964 Bone Geometry Bone Repair Osteoclasts Osteoblasts Normal Force Bone Muscle Deformation x Mechanostat 1000μStr. 2000μStr. 4/4

Why measure bone density in children? To identify those with fractures who have underlying bone fragility To identify those at risk of fragility fractures - due to their condition - or treatment What is the relationship between bone density & fractures?

Determinants of Bone Strength or Fragility Amount of bone material Bone mass / Bone Density Quality of bone material Tissue Properties Distribution of bone material Bone geometry

Bending Strength Rauch, F. Pediatrics 2007;119:S137-S140 Copyright ©2007 American Academy of Pediatrics

WHAT CAN WE MEASURE WITH DXA ? UNITS Bone Mass (g) Area bone density (g/cm2) Bone Geometry (cm) ( bone width & height) Unable to measure: Material Density (g/cm3) Volumetric bone density (g/cm3) (Separate Cortical & Trabecular bone) Cortical thickness (cm) Bone Distribution (cm4)

Images courtesy of ISBE Manchester pQCT Images courtesy of ISBE Manchester

CHANGES ALONG THE TIBIA SHAFT Healthy Boy Age 11y Non-ambulant DMD Boy Age 11y 4% 14% 20% 66%

ISCD 2013 Definition of Osteoporosis The diagnosis of osteoporosis in children and adolescents should not be made on the basis of densitometric criteria alone The finding of one or more vertebral compression fractures is indicative of osteoporosis, in the absence of local disease or high energy trauma. In such children and adolescents, measuring BMD adds to the overall assessment of bone health.

ISCD 2013 Definition of Osteoporosis In the absence of vertebral compression fracture, the diagnosis of osteoporosis is indicated by the presence of both a clinically significant fracture history and BMD Z-score ≤ -2. A clinically significant fracture history is one or more of the following: Two or more long bone fractures by age 10 years Three or more long bone fractures by age 16 years

Fractures and DMD

DMD & LONG BONE FRACTURES Hsu 1979: 30 American children 20 fractures in 17 ambulatory patients 16 fractures in 13 non-ambulatory patients 5 ceased ambulation as a direct result of fracture McDonald 2002: 378 British children (1-25y) 20.9% had sustained a fracture of which 41% were in those aged 8-11y and 48% in ambulatory patients 21% lost mobility as a direct result of fracture 17

Fractures in DMD and Steroids 33 boys with DMD age 2-30 years 25 on daily steroids ( 1mg/kg/day) - median duration 4.5 years Spine X-rays if low BMD or back pain 10 (30%) sustained vertebral fractures No vertebral fractures in first 40 months 75% predicted to have vertebral fracture by 100 months Bothwell JE et al, Clin Pediatr 2003;42:353-6

UK audit of Vertebral Fractures in DMD 30 vertebral fractures in approx 200 boys 26 ambulant, 4 non-ambulant Mean steroid dose 0.56mg/kg/day Mean latency period 4.1 yrs ( 0.7-7.4 yrs) 28 were receiving daily corticosteroids 3 boys were on prophylactic bisphosphonates 4 boys on Calcium and Vitamin D supplements GOSH – 33% of those on daily steroids < 1% on intermittent steroids Manzur A et al, Neuromuscular Disorders 2010;20(Suppl 1);S8 19

Fracture Prevalence 5 years 10 years 18 years All Fractures 16.5 % 37.4% 83.3% Vertebral Fractures 4.4 % 19.1% 58.3% Buckner JL et al, Int J Endocrinol 2015; Epub June 1st

Steroids and DMD – relevant factors Corticosteroid regime – intermittent or continuous Type of corticosteroid – Prednisolone or Deflazacort Corticosteroid dose and duration Age of commencement Mobility – ambulant or non-ambulant

Research on Bone density & geometry

Longitudinal assessment of effect of corticosteroids on bone density using DXA in boys with DMD

Materials and Methods 25 ambulant boys with DMD (Aged 5-12 years Mean 7.4 years). 4 reported fractures in 3 patients (1 arm & 3 legs: 2 from RTA). Intermittent steroid therapy; 10 days on 10 days off 0.75mg/kg/day Prednisolone DXA Lumbar Spine & Whole Body Baseline Follow up: 14 and 30 Months Bone and body composition parameters were compared to a large locally collected reference data set of healthy school children.

LUMBAR SPINE BONE MASS FOR BONE AREA ∆Z= 0.5 (0.1) P<0.001 * ↑ Increase  Decrease

Lumbar Spine - Mobile

Lumbar Spine – Loss of Mobility

Duchenne Muscular Dystrophy Adapted from Mayo AL et al, Neuromuscular Disorders 2012;22:1040-5

Vertebral fracture assessment

Vertebral Fracture Assessment - DXA

VFA Versus Spine Radiograph Lower radiation dose 12 micro Sieverts versus 200 micro Sieverts Whole spine No magnification Improved thoracic visualisation Vertebra identification Available at point of care

Example: Intermediate Dystrinopathy Normal Stature No long bone fractures Spine & TBLH Bone Density within normal limits Back Pain 30mg Prednisolone / day NOT OSTEOPOROSIS ? Vertebral Fractures on LVA OSTEOPOROSIS

Example: Duchenne Muscular Dystrophy DMD + Steroids 20mg 10/10 Reg. Low Spine & TB Bone Density Very low pQCT No reported long bone fractures OSTEOPOROSIS ? Presence of vertebral fractures confirms Osteoporosis

Impact of steroid regime Comparison of 25 boys on daily steroids with 25 boys on intermittent steroids-mean age 8.5 years After 2 years 19 boys on daily still ambulant compared to 15 boys on intermittent steroids Daily boys had less height gain and greater gain in body mass index Daily boys had a greater number of vertebral fractures (12) compared to intermittent (4) Crabtree NJ et al, Abstract presented at ICCBH 2015

Treatment Bisphosphonates – Oral eg Alendronate or Risedronate Intravenous eg Pamidronate or Zoledronate Testosterone – Oral daily eg Restandol Intramuscular monthly eg Sustanon

Potential benefits of Bisphosphonates Reduction in back pain Improvement in bone density Prevention of further fractures Reshaping of vertebral compression fractures

Reshaping of compressed vertebrae Nov 2010 Jan 2009

Intravenous Bisphosphonates Seven boys with DMD ( age 8.5 – 14.3 yrs) 27 vertebral fractures at baseline Treatment with Pamidronate or Zoledronate over 2 years Back pain resolved (n=3) or improved (n=4) 17 vertebrae improved height, 10 stable 3 new vertebral fractures occurred on treatment Sbrocchi AM et al, Osteoporos Int 2012;11:2703-11

Bisphosphonates as Prevention 43 boys with DMD Median duration of steroids 33 months Oral bisphosphonate Risedronate given weekly – average duration 24 months Lumbar spine bone density remained stable Seven boys sustained long bone fractures Three boys developed vertebral fractures Srinivasan R et al, Endocrine Abstracts 2013;33:OC 1.6

Other Important Factors Puberty – delayed puberty very common in boys with DMD – recommend refer to Endocrinologist if no signs by age 13 yrs Oral daily or intramuscular monthly Vitamin D – UK guidelines would recommend maintaining a level > 50 nmol/l Oral Vitamin D supplements either daily or intermittent eg weekly

Fig. 2 ENMC Workshop 2009 Suggested care pathway for bone protection in DMD children treated with corticosteroids. Neuromuscular Disorders 2010 20, 761-769DOI: (10.1016/j.nmd.2010.07.272) Copyright © 2010 Elsevier B.V. Terms and Conditions

Summary High incidence of fractures in boys with DMD Reduced mobility & steroids combine to adversely affect the skeleton Vertebral fractures may be asymptomatic Normal bone density may coexist with vertebral fractures In addition to bone density scans boys with DMD need spinal imaging ( by X-ray or VFA) to look for vertebral fractures