CCEB

1. 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

3. 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

5. 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

6. Cortical and Trabecular Bone Rperi Rendo

7. Trabecular Architecture

8. Cortical Dimensions & Strength Cross-Sectional Moment of Inertia p(RP4 - RE4) Remove 30 mm2 Add 100 mm2 D. Burr and C. Turner. ASBMR Primer

10. Skeletal Remodeling

11. Skeletal Modeling during Growth W.S. Jee

12. 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.

13. 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

14. 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

15. 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

16. Models of Glucocorticoid-Induced Osteoporosis in Children • Crohn Disease • Steroid Dependent Nephrotic Syndrome • Juvenile Idiopathic Arthritis • Renal Transplant

17. 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

18. 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

19. Standard Deviation Scores (Z-Scores)

20. Whole Body Bone Mineral Content in Crohn Disease Compared with Controls Burnham, et al. J Bone Miner Res 2004

21. 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

22. Hip Structural Analysis T. Beck

23. 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

24. Peripheral Quantitative CT Muscle CSA Cortical Dimensions Trabecular Density

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

28. High Impact Physical Activity in Childhood Increases Bone Density and Dimensions

29. Athlete Studies Control Triple Jumper Midshaft Area +30% Distal Density +67% Rachel Wetzsteon Heinonen et al. Bone, 2003

30. 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.

31. 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

32. anabolic maintain resorb Bone can be maintained with a few large loading cycles, or thousands of extremely small ones Qin et. al., 1998

33. Low Magnitude Mechanical Stimuli are Anabolic to Bone

34. control experimental 45% increase in trabecular bone volume 12% increase in stiffness 27% increase in strength Rubin et. al.,Nature 2001

36. But, wait!There’s more to the story….

37. “Low Buzz May Give Mice Better Bones and Less Fat”

38. Control • Adipogenesis • Mesenchymal stem cell differentiation into adipocytes LMMS

39. “I’ve got him on vibrate”

40. 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