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Pediatric Metabolic Bone Disease
Bryce Nelson, MD/PhDPediatric Endocrinology
Greenville Hospital SystemSEACSM Meeting, Clinical Track Program
2/10/12
Objectives
•Discuss contributors to pediatric bone disease
•Discuss evaluation of child with fragility fractures
•Discuss treatment options for children with bone disease
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
Fragility vs. Traumatic Fracture
•Vertebral fractures and femur fractures without significant trauma
•Infant fractures? Abuse or not?
•Immobilization
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
Bone Mass Acquisition
Age Rate of AquisitionInfancy RapidMid-Childhood SlowAdolescence RapidOver 30 years None
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
Risk Factors for Low Bone Mineral
Density•Genetics (60-80%)
•Physical Activity (10-20%)
•Environmental (calcium, vitamin D intake, drug induced)
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
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
NHANES
• 7-dehydrocholesterol 7-dehydrocholesterol converted to Vitamin D3 converted to Vitamin D3 by UVby UV
• Converted to 25-OH-VitD3 Converted to 25-OH-VitD3 in liverin liver
• Active form 1,25OH-Active form 1,25OH-Vitamin D3 in kidneyVitamin D3 in kidney
• 1-alpha-hydroxylase1-alpha-hydroxylase
• PTH PTH
• Circulates in blood bound Circulates in blood bound to either DBP or albuminto either DBP or albumin
• Little free form in bloodLittle free form in bloodhttp://www.mja.com.auhttp://www.mja.com.au
Vitamin D MetabolismVitamin D Metabolism
•Vitamin D deficiency or insufficiency Vitamin D deficiency or insufficiency often seen in post-menopausal women often seen in post-menopausal women and older Americans with osteoporosis and older Americans with osteoporosis
•May be protective against some cancersMay be protective against some cancers
•AsthmaAsthma
•Multiple SclerosisMultiple Sclerosis
•Crohn’s DiseaseCrohn’s Disease
•Ulcerative Colitis Ulcerative Colitis
Vitamin D: Is it our new snake Vitamin D: Is it our new snake oil?oil?
…more than just rickets…more than just rickets
Risk Factors for Vitamin D Risk Factors for Vitamin D Deficient RicketsDeficient Rickets
Vitamin D Levels
Wagner, CL, et al. Pediatrics. 2008. 1142.
Evaluation
History & Physical• Breast fed
• Race
• Metaphyseal cupping and fraying
• Genu valgum or varum
• Rachitic rosary
• Frontal bossing
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
Bone Densitometry in Children
•Quantitative CT (volumetric)
•Dual energy X-ray Absorptiometry (DXA, areal density)
DXA in Children
•Advantages: fast, low radiation exposure, reasonable image resolution
•Disadvantages: body composition changes, limited reference data, puberty, stature effects
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
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
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
Basic Treatment
•Identify and treat any underlying cause
•Maximize calcium and vitamin D or replete if deficient
•Weight bearing physical activity when appropriate
US Recommended Daily Ca intake
AgeCalcium Intake
(mg/dL)0-6 mo 210
7-12 mo 2701-3 yr 5004-8 yr 800
9-18 yr 130019-50 yr 1000
50 to >70 yr 1200
Institute of Medicine, Food and Nutrition Board, Dietary References for Intakes for Calcium, Phosphorus,Magnesium, Vitamin D, and Fluoride. National Academy Press. 1997
• ALL breastfed infants and formula fed ALL breastfed infants and formula fed infants taking <1L/day should take 400 infants taking <1L/day should take 400 IU vit D supp, to be started within first IU vit D supp, to be started within first few days of lifefew days of life
• Children and adolescents without Children and adolescents without appropriate sun exposure AND less than appropriate sun exposure AND less than 500 ml of vit D-milk per day should also 500 ml of vit D-milk per day should also take vit D supp (400 IU/d)take vit D supp (400 IU/d)
• Premature infants to be started on 400-Premature infants to be started on 400-800 IU/day at birth800 IU/day at birth
AAP RecommendationsAAP Recommendations
Misra, M et. al Pediatrics. 122. 2008. 398-417
Endocrine Society GuidelinesVitamin D Deficiency Replacement
Group Maintenance(U/day)
Max Dose(U/day)
Vitamin D deficiency
<6 mo 400 1000 2,000U/day or50,000U weekly X 6 weeks
6 mo – 1 year 600 1500 4,000U/day or 50,000U weekly X 6 weeks
1-3 year 600 2500 4,000U/day or 50,000U weekly X 8 weeks
4-8 year 600 3000 4,000U/day or 50,000U weekly X 8 weeks
8-19 year 600 4000 4,000U/day or50,000U weekly X 8 weeks
19-50 year 600 6000 50,000U weekly X 8 weeks
50-70 600-800 6000-10,000
50,000U weekly X 8 weeks
Pregnant/Lactating 600 6000-10,000
50,000U weekly X 8 weeks
* Special populations
2-3X higher
* Patients on anticonvulsants, glucocorticoids, antifungals, or antiretroviralsHolick, et al. JCEM. 2011. 1911
Nutritional Rickets
6 MonthsPost-Treatment
_____________________
Pre-Treatment
Misra, M et. al Pediatrics. 122. 2008. 398-417
Pearl:6 weeks to biochemical resolution
6 months to radiographic resolution
Advanced Treatment
•Bisphosphonates
•Teriparatide
•Denosumab
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
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)
Bisphosphonates in Pediatrics
•Well tolerated in short term
•hypocalcemia
•Long term effects not known
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
Unanswered Questions•Fracture risk and vitamin D
deficiency in children
•Appropriate treatments for metabolic bone disease
•Reference data for DXA
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
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