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 AcquisitionAge 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

Age Calcium Intake (mg/dL)

0-6 mo 2107-12 mo 2701-3 yr 5004-8 yr 8009-18 yr 1300

19-50 yr 100050 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 weeks50-70 600-800 6000-

10,00050,000U 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 antiretrovirals

Holick, 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