1. Pediatric Metabolic Bone Disease Bryce Nelson, MD/PhD Pediatric Endocrinology Greenville Hospital System SEACSM Meeting, Clinical Track Program 2/10/12

2. Objectives Discuss contributors to pediatric bone disease Discuss evaluation of child with fragility fractures Discuss treatment options for children with bone disease

3. Bone Health in Children Osteoporosis in adults considered a pediatric disease (Dent, et. al. Postgrad Med J. 1973) Bone Mass achieved in adolescence is main contributor of peak bone mass which is major determinant of fracture risk

4. Fragility vs. Traumatic Fracture Vertebral fractures and femur fractures without significant trauma Infant fractures? Abuse or not? Immobilization

5. Fractures: Tansient Fragility? Fracture incidence proportional to height velocity Age 11-12 in girls Age 13-14 in boys Peak bone mass lags behind peak growth velocity by about 18 months

6. Bone Mass Acquisition AgeRate of Aquisition InfancyRapid Mid-ChildhoodSlow AdolescenceRapid Over 30 yearsNone

7. Peak Bone Mass Bone Mineral Density >95% of peak value by age 20 First at hip, then spine, then whole body Gender Difference Earlier in women then men

8. Risk Factors for Low Bone Mineral Density Genetics (60-80%) Physical Activity (10-20%) Environmental (calcium, vitamin D intake, drug induced)

9. Some Disorders Associated with Fragility Fractures Primary Conditions Genetic Disorders Osteogenesis Imperfecta Idiopathic Juvenile Osteoporosis Chronic Inflammatory SLE Inflammatory Bowel Disease Immobilization Infiltrative Leukemia Endocrine Hypogonadism, GH deficiency, Cushing, Hyperthyroidism, Diabetes Nutritional Vitamin D Deficiency, celiac disease, cystic fibrosis, anorexia Renal Chronic Kidney Disease Iatrogenic Glucocorticoids, anticonvulsants, methotrexate, radiation, antiretroviral

10. To make the issue more complicated… Greer, FR et. al Pediatrics. 117. 2006. 578- 585 Children >8 years of age do not achieve RDI of Ca Adequate intake affected by age, gender, physical activity and diet Calcium RDI varies with age

11. NHANES

12. 7-dehydrocholesterol converted to Vitamin D3 by UV 7-dehydrocholesterol converted to Vitamin D3 by UV Converted to 25-OH-VitD3 in liver Converted to 25-OH-VitD3 in liver Active form 1,25OH-Vitamin D3 in kidney Active form 1,25OH-Vitamin D3 in kidney 1-alpha-hydroxylase 1-alpha-hydroxylase PTH PTH Circulates in blood bound to either DBP or albumin Circulates in blood bound to either DBP or albumin Little free form in blood Little free form in blood http://www.mja.com.au Vitamin D Metabolism

13. Vitamin D deficiency or insufficiency often seen in post-menopausal women and older Americans with osteoporosis Vitamin D deficiency or insufficiency often seen in post-menopausal women and older Americans with osteoporosis May be protective against some cancers May be protective against some cancers Asthma Asthma Multiple Sclerosis Multiple Sclerosis Crohn’s Disease Crohn’s Disease Ulcerative Colitis Ulcerative Colitis Vitamin D: Is it our new snake oil? …more than just rickets

14. Poor sunlight exposure Poor sunlight exposure Poor dietary intake of Vitamin D Poor dietary intake of Vitamin D No vitamin supplementation No vitamin supplementation Breast fed infants, particularly non-Caucasians Breast fed infants, particularly non-Caucasians Females Females Low Socioeconomic Status Low Socioeconomic Status Low BMI or high BMI Low BMI or high BMI Elderly Elderly African American, Hispanic, or Middle Eastern descent African American, Hispanic, or Middle Eastern descent Chronic illness, malabsorption, renal or liver disease Chronic illness, malabsorption, renal or liver disease Living during the winter! Living during the winter! Risk Factors for Vitamin D Deficient Rickets

15. Vitamin D Levels Wagner, CL, et al. Pediatrics. 2008. 1142.

16. Evaluation

17. History & Physical Breast fed Race Metaphyseal cupping and fraying Genu valgum or varum Rachitic rosary Frontal bossing

18. Lab evaluation First Tier Labs CBC, diff, platelets CMP (alkaline phosphatase) Sed rate PTH Ca, Mg, PO4 Spot urine Ca/Cr ratio 25 OH vitamin D Second Tier Labs Bone Turnover Markers Osteocalcin Urine N-telo peptides Bone Marrow

19. Bone Densitometry in Children Quantitative CT (volumetric) Dual energy X-ray Absorptiometry (DXA, areal density)

20. DXA in Children Advantages: fast, low radiation exposure, reasonable image resolution Disadvantages: body composition changes, limited reference data, puberty, stature effects

21. Areal vs Volumetric BMD DXA underestimates total areal BMD in short children or overestimates in tall or “big bone” courses.washington.edu/bonephys/opBMAD.html

22. WHO Classification of Bone Mineral Density (BMD) No densitometric criteria in children for osteoporosis Z score -2.0 or less: “low BMD for age” Z score needs to be bone age and stature adjusted Spine and total body are preferred skeletal sites for measurement

23. Consideration and Controversy Osteoporosis diagnosis in children requires both clinically significant fracture history and low BMD No link between vitamin D and fracture risk in children DXA needs to be performed appropriately

24. Basic Treatment Identify and treat any underlying cause Maximize calcium and vitamin D or replete if deficient Weight bearing physical activity when appropriate

25. US Recommended Daily Ca intake AgeCalcium Intake (mg/dL) 0-6 mo210 7-12 mo270 1-3 yr500 4-8 yr800 9-18 yr1300 19-50 yr1000 50 to >70 yr1200 Institute of Medicine, Food and Nutrition Board, Dietary References for Intakes for Calcium, Phosphorus, Magnesium, Vitamin D, and Fluoride. National Academy Press. 1997

26. ALL breastfed infants and formula fed infants taking <1L/day should take 400 IU vit D supp, to be started within first few days of life ALL breastfed infants and formula fed infants taking <1L/day should take 400 IU vit D supp, to be started within first few days of life Children and adolescents without appropriate sun exposure AND less than 500 ml of vit D- milk per day should also take vit D supp (400 IU/d) Children and adolescents without appropriate sun exposure AND less than 500 ml of vit D- milk per day should also take vit D supp (400 IU/d) Premature infants to be started on 400-800 IU/day at birth Premature infants to be started on 400-800 IU/day at birth AAP Recommendations Misra, M et. al Pediatrics. 122. 2008. 398-417

27. Endocrine Society Guidelines Vitamin D Deficiency Replacement GroupMaintenance (U/day) Max Dose (U/day) Vitamin D deficiency <6 mo40010002,000U/day or 50,000U weekly X 6 weeks 6 mo – 1 year60015004,000U/day or 50,000U weekly X 6 weeks 1-3 year60025004,000U/day or 50,000U weekly X 8 weeks 4-8 year60030004,000U/day or 50,000U weekly X 8 weeks 8-19 year60040004,000U/day or 50,000U weekly X 8 weeks 19-50 year600600050,000U weekly X 8 weeks 50-70600-8006000-10,00050,000U weekly X 8 weeks Pregnant/Lactating6006000-10,00050,000U weekly X 8 weeks * Special populations2-3X higher * Patients on anticonvulsants, glucocorticoids, antifungals, or antiretrovirals Holick, et al. JCEM. 2011. 1911

28. Nutritional Rickets 6 Months Post-Treatment _____________________ Pre-Treatment Misra, M et. al Pediatrics. 122. 2008. 398-417 Pearl: 6 weeks to biochemical resolution 6 months to radiographic resolution

29. Advanced Treatment Bisphosphonates Teriparatide Denosumab

30. Bisphosphonates in Pediatrics Primary Osteoporosis (OI) Well established literature supporting use Increases BMD, decrease fractures, improved bone pain Not FDA approved in kid Cyclic pamidronate, alendronate, zolendronate

31. Bisphosphonates in Pediatrics Secondary Osteoporosis Not as well established None of the small trials have shown antifracture efficacy Cochrane Review (Ward, et al. Cochrane Reviews. 2010)

32. Bisphosphonates in Pediatrics Well tolerated in short term hypocalcemia Long term effects not known

33. Bisphosphonates in Pediatrics Bisphosphonate-Induced Osteopetrosis. Michael P. Whyte, M.D., Deborah Wenkert, M.D., Karen L. Clements, R.N., William H. McAlister, M.D., and Steven Mumm, Ph.D.N Engl J Med 2003; 349:457-463

34. Unanswered Questions Fracture risk and vitamin D deficiency in children Appropriate treatments for metabolic bone disease Reference data for DXA

35. Summary Metabolic or “secondary” pediatric bone disease is a growing problem Screen appropriate patients for vitamin D deficiency and treat accordingly Involve Pediatric Endocrinologist to consider bisphosphonate