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CCEB. Whole Body Vibration as an Anabolic Bone Therapy in Children. Mary B. Leonard, MD, MSCE The Children’s Hospital of Philadelphia Center for Clinical Epidemiology and Biostatistics. 2000 NIH Osteoporosis Consensus Conference Statement.

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slide1

CCEB

Whole Body Vibration as an Anabolic Bone Therapy in Children

Mary B. Leonard, MD, MSCE

The Children’s Hospital of Philadelphia

Center for Clinical Epidemiology and Biostatistics

2000 nih osteoporosis consensus conference statement
2000 NIH Osteoporosis Consensus Conference Statement
  • Peak Bone Mass is a critical determinant of life-long skeletal health
  • Maximizing peak bone mass is a priority
  • The NIH called for research strategies to identify and intervene in disorders that compromise attainment of peak bone mass in children with chronic disease
    • Especially corticosteroid therapy
rethinking osteoporosis
Rethinking Osteoporosis
  • Bone strength is a function of bone density (g/cm3) and bone quality
  • Bone quality refers to geometry, micro-architecture, turnover, micro-damage repair, and mineralization

Osteoporosis Prevention, Diagnosis & Therapy

NIH Consensus Conference 2000

cortical dimensions strength
Cortical Dimensions & Strength

Cross-Sectional Moment of Inertia

p(RP4 - RE4)

Remove 30 mm2

Add 100 mm2

D. Burr and C. Turner. ASBMR Primer

changes in cortical trabecular bone with growth
Changes in Cortical & Trabecular Bone with Growth
  • Trabecular Bone Volume Fraction
    • Increases during Tanner stages III – V
    • Increases are greater in blacks than whites
    •  trabecular thickness and material density
  • Cortical Density and Dimensions
    • Density increases with age, F > M
    • During puberty boys develop greater periosteal radius and girls develop relatively smaller endosteal radius
    • CSMI greater in blacks than whites

Gilsanz V, et al. NEJM 1991, J Clin Endo Metab 1997, J Clin Endo Metab 1998.

Seeman E. Lancet 2002. Rauch and Schoenau JBMR 2001.

threats to bone health in children with crohn diseases
Threats to Bone Health in Children with Crohn Diseases
  • Decreased muscle forces / loading
  • Malnutrition
    • Calcium, Vitamin D, Vitamin K, Zinc
  • Delayed puberty
  • Alternations in GH / IGF axis
  • Medications
    • Glucocorticoids
  • Inflammatory Cytokines
    • IL-6, TNF-a
glucocorticoid induced osteoporosis
Glucocorticoid-Induced Osteoporosis
  • Glucocorticoids are widely used in pediatrics
  • Glucocorticoids
    •   Bone formation
    •  Bone resorption then ?  Bone resorption
  • Glucocorticoids are associated with increased fracture rates in children
  • Assessment of GC effects may be confounded by
    • effects of the underlying disease
    • altered growth, maturation and body composition
    • limitations of DXA techniques
slide15

Glucocorticoid & Cytokine Effects

on Bone Cells

  • Glucocorticoid Effects
  • Decrease Bone Formation
  • Shift cellular differentiation of stem cells away from osteoblasts
  • Inhibit osteoblast production of bone matrix
  • Promote osteoblast apoptosis
  • Impair osteocytes

Increase Bone Resorption

  • Promote osteoclastogenesis by  RANKL and  OPG expression in osteoblasts
  • TNF-a Effects
  • Decrease Bone Formation
  • Shift cellular differentiation of stem cells away from osteoblasts
  • Inhibit collagen synthesis by osteoblasts
  • Promote osteoblast apoptosis
  • Impair osteocytes

Increase Bone Resorption

  • Promote osteoclastogenesis by  RANKL and  OPG expression in osteoblasts
models of glucocorticoid induced osteoporosis in children
Models of Glucocorticoid-Induced Osteoporosis in Children
  • Crohn Disease
  • Steroid Dependent Nephrotic Syndrome
  • Juvenile Idiopathic Arthritis
  • Renal Transplant
crohn disease
Crohn Disease
  • Chronic inflammatory bowel disease
  • Insidious onset
  • May result in abscesses, granulomas or fistulas
  • 85% of children present with weight loss
  • Growth failure and pubertal delay are common
  • Treated with systemic glucocorticoids, steroid enemas, 5-ASA, methotrexate and other immunomodulators
  • Associated with fractures in children and adults
crohn disease bone mineral content
Crohn Disease & Bone Mineral Content
  • DXA Scans in 104 children and young adults with CD
  • Age: 4 – 25 yr
  • CD duration: 4.0 + 3.4 yr
  • Median cumulative glucocorticoid exposure: 10,300 mg

Ln (Height)

Burnham, et al. J Bone Miner Res 2004

whole body bone mineral content in crohn disease compared with controls
Whole Body Bone Mineral Content in Crohn Disease Compared with Controls

Burnham, et al. J Bone Miner Res 2004

inflammatory cachexia
Inflammatory Cachexia
  • Lean mass deficits without fat mass deficits
  • Muscle active cytokines (TNF-a, IL-6, IL-1b)
    • inhibit myogenic differentiation
    • stimulate muscle protein degradation
    • induce myoblast apoptosis
  • Note: Glucocorticoids increase myostatin, a negative regulator of muscle mass

Burnham, et al. AJCN 2005

Thayu, et al IBD 2007

femoral shaft z scores in crohn disease and nephrotic syndrome

1.00

***

***

***

0.50

Group differences eliminated after adjustment for lean mass for height z-score

0.00

-0.50

Z Scores

-1.00

-1.50

CD

SSNS

-2.00

Subperiosteal

Cross-Sectional

Section

-2.50

Width

Area

Modulus

Femoral Shaft Z-Scores in Crohn Disease and Nephrotic Syndrome

Burnham, et al. JBMR 2007

slide24

Peripheral Quantitative CT

Muscle CSA

Cortical Dimensions

Trabecular Density

treatment options
Treatment Options
  • Treat the underlying disease!
  • Calcium and Vitamin D supplements
  • Osteoporosis medications?
    • Antiresorptive agents
    • Anabolic agents
  • Weight bearing physical activity
slide28

High Impact Physical Activity in Childhood

Increases Bone Density and Dimensions

athlete studies
Athlete Studies

Control

Triple Jumper

Midshaft

Area +30%

Distal

Density +67%

Rachel Wetzsteon Heinonen et al. Bone, 2003

is there a window of opportunity
Is there a “Window of Opportunity?”

20%

8%

BMC % Side-to-Side Diff

3%

Pre-Menarche

Post-Menarche

Slide prepared by Rachel Wetzsteon Kannus et al., 1995.

bone strain
Bone Strain
  • Osteocytes sense bone strain
  • Bone strain is the percentage change in length in response to a load.
  • If bone is deformed by 0.1%, its strain is 0.001, or 1000 mstrain.
  • In humans, peak strains are generally less than 2000-3000 mstrain, even during vigorous activities
slide32

anabolic

maintain

resorb

Bone can be maintained with a few large loading cycles, or thousands of extremely small ones

Qin et. al., 1998

slide34

control

experimental

45% increase in trabecular bone volume

12% increase in stiffness

27% increase in strength

Rubin et. al.,Nature 2001

slide38

Control

  • Adipogenesis
  • Mesenchymal stem cell differentiation into adipocytes

LMMS

acknowledgements
Acknowledgements
  • Project Staff
    • Krista Howard and Kristin Frino
  • NIH
    • NIDDK, NIDDK and NIAMS
  • CHOP IBD Center and GI Division
    • Robert Baldassano and Meena Thayu
    • Meena Thayu, MD
  • CHOP Nutrition and Growth Lab
    • Babette S. Zemel, PhD
  • SUNY and Juvent, Inc
    • Clint Rubin, PhD