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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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Cceb

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


Skeletal remodeling
Skeletal Remodeling


Skeletal modeling during growth
Skeletal Modeling during Growth

W.S. Jee


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


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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 with Controls

  • 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


Hip structural analysis
Hip Structural Analysis with Controls

T. Beck


Femoral shaft z scores in crohn disease and nephrotic syndrome

1.00 with Controls

***

***

***

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


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Peripheral Quantitative CT with Controls

Muscle CSA

Cortical Dimensions

Trabecular Density


Treatment options
Treatment Options with Controls

  • Treat the underlying disease!

  • Calcium and Vitamin D supplements

  • Osteoporosis medications?

    • Antiresorptive agents

    • Anabolic agents

  • Weight bearing physical activity


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High Impact Physical Activity in Childhood with Controls

Increases Bone Density and Dimensions


Athlete studies
Athlete Studies with Controls

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?” with Controls

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 with Controls

  • 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


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anabolic with Controls

maintain

resorb

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

Qin et. al., 1998



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control with Controls

experimental

45% increase in trabecular bone volume

12% increase in stiffness

27% increase in strength

Rubin et. al.,Nature 2001


But wait there s more to the story
But, wait! with ControlsThere’s more to the story….



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Control with Controls

  • Adipogenesis

  • Mesenchymal stem cell differentiation into adipocytes

LMMS



Acknowledgements
Acknowledgements with Controls

  • 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