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

2. 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

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

4. 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

5. 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

6. 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

7. 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

8. 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?

9. 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

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

11. 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)

12. Images courtesy of ISBE Manchester
pQCT
Images courtesy of ISBE Manchester

13. CHANGES ALONG THE TIBIA SHAFT
Healthy Boy Age 11y
Non-ambulant DMD Boy Age 11y
4% % % %

14. 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.

15. 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

16. Fractures and DMD

17. 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

18. 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

19. 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 ( 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

20. 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

21. 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

22. Research on Bone density & geometry

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

24. 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.

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

26. Lumbar Spine - Mobile

27. Lumbar Spine – Loss of Mobility

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

29. Vertebral fracture assessment

30. Vertebral Fracture Assessment - DXA

31. 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

32. 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

33. 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

34. 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

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

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

37. Reshaping of compressed vertebrae
Nov 2010
Jan 2009

38. 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:

39. 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

40. 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

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

42. 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