Transcript Disorders of Calcium & Phosphate Metabolism

Pediatric Metabolic
Bone Disease
Bryce Nelson, MD/PhD
Pediatric Endocrinology
Greenville Hospital System
SEACSM 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
Infancy
Mid-Childhood
Adolescence
Over 30 years
Rate of Aquisition
Rapid
Slow
Rapid
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
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Primary Conditions
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Idiopathic Juvenile Osteoporosis
Hypogonadism, GH deficiency,
Cushing, Hyperthyroidism, Diabetes
Nutritional
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Vitamin D Deficiency, celiac disease,
cystic fibrosis, anorexia
Chronic Inflammatory
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Osteogenesis Imperfecta
Endocrine
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Genetic Disorders
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SLE
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Inflammatory Bowel Disease
Immobilization
Renal
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Iatrogenic
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Infiltrative
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Leukemia
Chronic Kidney Disease
Glucocorticoids, anticonvulsants,
methotrexate, radiation, antiretroviral
To make the issue more
complicated…
•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
Greer, FR et. al Pediatrics. 117. 2006. 578585
NHANES
Vitamin D Metabolism
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7-dehydrocholesterol
converted to Vitamin D3 by
UV
Converted to 25-OH-VitD3 in
liver
Active form 1,25OH-Vitamin
D3 in kidney
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http://www.mja.com.au
1-alpha-hydroxylase
PTH
Circulates in blood bound to
either DBP or albumin
Little free form in blood
Vitamin D: Is it our new snake oil?
…more than just rickets
• Vitamin D deficiency or insufficiency often seen
in post-menopausal women and older
Americans with osteoporosis
• May be protective against some cancers
• Asthma
• Multiple Sclerosis
• Crohn’s Disease
• Ulcerative Colitis
Risk Factors for Vitamin D
Deficient Rickets
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Poor sunlight exposure
Poor dietary intake of
Vitamin D
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No vitamin supplementation
Breast fed infants,
particularly non-Caucasians
Females
Low Socioeconomic Status
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Low BMI or high BMI
Elderly
African American, Hispanic,
or Middle Eastern descent
Chronic illness,
malabsorption, renal or liver
disease
Living during the winter!
Vitamin D Levels
Wagner, CL, et al. Pediatrics. 2008. 1142.
Evaluation
History & Physical
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Breast fed
Race
Metaphyseal cupping
and fraying
Genu valgum or varum
Rachitic rosary
Frontal bossing
Lab evaluation
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First Tier Labs
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CBC, diff, platelets
CMP (alkaline
phosphatase)
Sed rate
PTH
Ca, Mg, PO4
Spot urine Ca/Cr ratio
25 OH vitamin D
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Second Tier Labs
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Bone Turnover Markers
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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
7-12 mo
1-3 yr
4-8 yr
9-18 yr
19-50 yr
50 to >70 yr
210
270
500
800
1300
1000
1200
Institute of Medicine, Food and Nutrition Board, Dietary References for Intakes for Calcium, Phosphorus,
Magnesium, Vitamin D, and Fluoride. National Academy Press. 1997
AAP Recommendations
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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 Dmilk per day should also take vit D supp (400
IU/d)
Premature infants to be started on 400-800
IU/day at birth
Misra, M et. al Pediatrics. 122. 2008. 398-417
Endocrine Society Guidelines
Vitamin D Deficiency Replacement
Group
Maintenance
(U/day)
Max Dose
(U/day)
Vitamin D deficiency
<6 mo
400
1000
2,000U/day or
50,000U 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 or
50,000U 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 antiretrovirals
Holick, et al. JCEM. 2011. 1911
Nutritional Rickets
6 Months
Post-Treatment
_____________________
Pre-Treatment
Pearl:
6 weeks to biochemical resolution
6 months to radiographic resolution
Misra, M et. al Pediatrics. 122. 2008. 398-417
Advanced Treatment
• Bisphosphonates
• Teriparatide
• Denosumab
Bisphosphonates in Pediatrics
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Primary Osteoporosis (OI)
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Well established literature supporting use
Increases BMD, decrease fractures, improved
bone pain
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Not FDA approved in kid
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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