Building and Maintaining a
Healthy Skeleton
Lisa D. Madison, MD
Clinical Associate Professor
Pediatric Endocrinology
March 11, 2014
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Objectives
• Briefly review basic bone biology and metabolism
• Discuss the determinants of peak bone mass and timing of its
acquisition
• Explore the effects of vitamin D deficiency on the pediatric
skeleton
• Focus on vitamin D requirements in children and conditions
that affect the ability to meet these requirements
• Consider calcium intake, absorption and excretion throughout
childhood
• Touch on appropriate methods to assess bone density in
children
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Bone Biology
• Bone Structure
– Extracellular matrix
– Osteoid (type 1 collagen)
– Mineral crystals
• Bone Architecture
– Cortical bone
– Trabecular (cancellous)
bone
• Cells in Bone
– Osteoblasts
– Osteoclasts
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Bone Metabolism: The Players
•
•
•
•
Vitamin D - from dietary sources or manufactured in skin
Calcium - 99% of total body stores reside in bone
Phosphorous - 85% of total body stores reside in bone
PTH - secreted by parathyroid gland
– Primary regulator is serum iCa++ concentration
– Effects include:
• Increased Ca++/decreased phos reabsorption in kidney
• Activation of osteoclasts to release Ca++ from bone
• Stimulation of 1-alpha hydroxylase to produce activated vitamin D
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7-dehydrocholesterol
Half-life 2-3 wks
2 of 3
pathways of
Ca absorption
are vit-D
dependent
-Fortified dairy
products
-Egg yolks
-Fish oils
-Fortified
cereals
Half-life 6-8 hrs
5
Noble: Textbook of Primary Care Medicine, 3rd ed., Copyright © 2001 Mosby, Inc.
Attaining Peak Bone Mass
www.mrc-hnr.cam.ac.uk
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Attaining Peak Bone Mass
• Total skeletal calcium
– 25 g at birth
900-1200 g in adults
• 25% of peak bone mass acquired during the 2 years
surrounding peak height velocity (11.5 years in girls, 13.5
years in boys)
• 60% acquired during peripubertal years
• 90% of peak bone mass acquired by age 18
• Lifetime risk of fracture declines by an estimated 40% for each
5% gain in peak bone mass
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Hereditary Factors
• Account for 60-80% of the variability in peak bone mass
• Much of the variability is due to differences in body size, bone
size and bone geometry
– Most studies show increased BMC, BMD, bone size and
volumetric density in black vs. white youth
– Differences between Hispanic and Asian vs. white youth mostly
due to body and bone size
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Body Weight
• Direct, positive correlation between BMI and BMD
• Malnutrition associated with decreased BMD, but….
• Obese children also at increased risk for fracture
–
–
–
–
Lower bone mass and area relative to body weight
Lower calcium intake
Higher sodium intake (and therefore obligatory calcium losses)
Decreased physical activity
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Body Weight and Bone Mass/Area
• Cross-sectional study of children age 3-19 years with no
history of fracture
• 200 girls, 136 boys in New Zealand, all Caucasian
• Total body bone mineral content (BMC) and bone area (BA),
as well as body composition measured by DEXA
• Results suggest a mismatch between rate of gain in adiposity
and rate of gain in bone mass
• May accentuate the known mismatch between linear growth
and bone mineral accrual in adolescents, further increasing
the risk for fracture
• Not known whether this relative deficit persists into
adulthood
Goulding A et al. Int J Obesity. 24:627-632, 2000.
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Exercise and BMD
• Intensive weight-bearing activity in childhood increases BMD over
that seen in inactive controls
• Nature of the activity determines degree of BMD increase
– Gymnasts > Distance runners
– Swimmers = non-athletic controls
• Effects are also site-specific
– Tennis players - dominant vs. non-dominant arm
• Timing matters
– Effects of activity are greater before and during puberty than in
adulthood
• Gains are sustained for the long term
– Former gymnasts, runners, dancers have BMD values 8-12% greater
than age-matched controls years after retiring from sports
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Activity Intervention Trials
Bachrach 2001
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Vitamin D - Historical Perspective
• 1898 - Infants Hospital, Boston - 80% of infants <2 years of age
showed physical stigmata of rickets
• 1918 - Mellanby showed antirachitic effect of cod liver oil antirachitic factor assumed to be a vitamin, letter “D”
assigned
• 1919 - Huldschinsky observed prevention and cure of rickets
with exposure to sunlight
• 1925 - study by Eliot - only 4.3% of infants receiving cod liver
oil and sun exposure developed “moderate” rickets versus
33% of control infants with “moderate” or “marked” rickets
• 1930’s - Formula supplementation and provision of vitamin D
supplements to breast-fed infants nearly universal
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Rickets Returns
• Late 1970’s - Reappearance of hundreds of vitamin Ddeficiency rickets cases, primarily in dark-skinned infants
receiving “long-term breast feeding”
• Current incidence difficult to pinpoint
• Roughly 1-2 severe cases at OHSU annually
• Far higher incidence of vitamin D deficiency without stigmata
of rickets
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Why is Vitamin D Deficiency on the Rise?
• Increasing percentage of women breastfeeding and for longer
periods (human milk contains 0.25 - 6 IU/100 cc)
• Increasing percentage of minority women breastfeeding
• Lack of awareness of need for Vitamin D supplementation
• Decreased sun exposure – how much would we need?
– 30 minutes/week whole body exposure
– 2 hours/week head-only exposure
– Counter to our recommendations about sunscreen and
protective clothing
– Difficult to achieve in the Pacific Northwest at certain times of
year
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Recommended Vitamin D Intake
• AAP Position Statement 2006
– “The diet of all infants (including those who are breastfeeding),
children and adolescents should include the recommended
adequate intakes of vitamin D (200 IU [5 mcg] or 500 mL of
vitamin D-fortified formula or milk per day) as well as fruits and
vegetables that are sources of potassium and bicarbonate,
which may improve calcium absorption.”
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Recommended Vitamin D Intake
• Updated AAP Guidelines 2008
– “Breast-fed and partially breast-fed infants should be
supplemented with 400 IU/day of vitamin D beginning in
the first few days of life. Supplementation should be
continued unless the infant is weaned to at least 1L/day or
1 quart/day of vitamin D-fortified formula or whole milk.
All non breast-fed infants, as well as older children who are
ingesting less than 1000 mL/day of vitamin D-fortified
formula or milk should receive a vitamin D supplement of
400 IU/day.”
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Recommended Vitamin D Intake
•
•
•
•
Institute of Medicine –400-600 IU/day (2011 recs)
Canadian Pediatric Society – 400 IU/day
Australia and New Zealand – 400 IU/day
ESPE Bone Club – 200-800 IU/day with higher end
recommended for those with dark skin complexion and where
sun exposure is limited
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Vitamin D: Why 200 vs. 400 vs. 600 IU?
• 200 IU based on 1997 recommendations by the National
Academy of Sciences
• Supported by data from US, China and Norway
• 200 IU vitamin D daily prevents physical signs of vitamin D
deficiency and maintains serum 25(OH)D level at or above 11
ng/mL
• 400 IU maintains 25(OH)D level >28 ng/mL according to older
literature
• 600 IU maintains 25(OH)D level >20 ng/mL in 97.5% of
children over age 1 with minimal sun exposure (400 IU for
children <age 1)
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Vitamin D: Why 200 vs. 400 vs. 600 IU?
• What are “normal” levels in children?
• Are levels above 11 ng/mL truly sufficient to prevent rickets?
• Are there any bone mineral content (BMC) data available to
support a dosing recommendation?
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Vitamin D Levels in Rickets
• Recent review summarized 11 studies
• 5 studies showed mean serum 25(OH)D level <27.5 nmol/L
(11 ng/mL) in patients with rickets
• 6 studies showed mean serum 25(OH)D levels 30-50 nmol/L
(12-20 ng/mL)
• One US study showed mean serum 25(OH)D level in mild
rickets 46.7 +/- 17.5 nmol/L (18.7 +/- 7 ng/mL) – only 3 infants
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Vitamin D and PTH Levels
78 nmol/L equals 31 ng/mL (CF 2.5)
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Recommended Vitamin D Intake
JCEM January 2011, p. 53-58
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How Common is Vitamin D Deficiency?
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Vitamin D and BMC in Children
• Prospective, double-blind RCT of vitamin D supplementation
in the context of adequate dietary calcium intake
• 212 adolescent girls (mean age 11.4) recruited in Helsinki,
Finland
– No chronic medical problems
– No meds known to affect calcium metabolism
– Homogenous population - all white
• Followed for one year with biochemical markers and DEXA
Viljakainen HT et al. JBMR 21(6):836-844. 2006
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Vitamin D and BMC in Children
• BMC accrual - femur
–  14.3% w/200 IU Vit D
–  17.2% w/400 IU Vit D
• BMC accrual - spine
– No  w/200 IU Vit D
–  12.5% w/400 IU Vit D
Lifetime risk of fracture declines
by an estimated 40% for each 5%
gain in peak bone mass
Viljakainen et al. 2006
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What Does It All Mean?
• The available data appear to support a recommendation to
supplement all infants and children with 400-600 IU vitamin D
per day if they are not receiving at least this much in their
diets.
• Prior to the current IOM recommendations, only 1 study from
1932 directly addressed the question of how much is too
much – daily intakes of 1800-6300 IU inhibited linear growth
in normal infants.
• New IOM recommendations set tolerable upper limit intake
levels based on the U-shaped relationship between vitamin D
levels and all-cause mortality (adult data extrapolated to
children).
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2011 IOM Guidelines
• Tolerable upper intake levels are based on evidence regarding
toxicities and all-cause mortality
• Toxicities evaluated include:
–
–
–
–
Hypercalcemia
Hypercalciuria
Vascular and soft tissue calcification
Nephrolithiasis
• Emerging data also suggest that excess intake may result in an
increase in all-cause mortality – 25(OH)D levels greater than
50 ng/mL (125 nmol/L) may be cause for concern
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2011 IOM Guidelines
• Bone health was the only outcome for which causality
between vitamin D and improved outcomes could be
established
• For extra-skeletal conditions including cancer, cardiovascular
disease, diabetes, autoimmune disorders and mental health
conditions evidence was:
– Inconsistent
– Inconclusive as to causality
– Insufficient to form the basis for dietary intake
recommendations
– Randomized clinical trials were very sparse
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Laboratory Abnormalities
• Vitamin D-Deficiency
–
–
–
–
Initial - Ca++, normal phos
Established - PTH, low normal Ca++, phos
Advanced - Ca++, phos
Hallmark - 25(OH)D, normal 1,25(OH)2D
• Vitamin D-Dependent Rickets Type 1
– Normal 25(OH)D, 1,25(OH)2D
• Vitamin D-Dependent Rickets Type 2
– Normal 25(OH)D, 1,25(OH)2D
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Treatment
• Vitamin D Deficiency
– High dose Vitamin D repletion x 8 weeks (range 6-12 weeks)
•
•
•
•
Infants 1,000-1,500 IU/day
Toddlers 2,000 IU/day
School age 2,000-3,000 IU/day
Adolescents 4,000 IU/day or 50,000 IU/7-10 days
– With severe deficiency, monitor serum Ca++ during repletion
– After repletion, decrease to 400-600 IU/day
• Prevention
– 400 IU Vitamin D/day in infants - Poly-Vi-Sol, Vi-Daylin, Tri-ViSol, ADEK
– 400-600 IU Vitamin D day in children over age 1
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Who Else is At Risk for Decreased Bone
Accrual?
• Hepatic disease and anti-epileptic drug use: impaired
synthesis of 25(OH)D
• Renal disease: impaired conversion of 25(OH)D to
1,25(OH)2D
• Malabsorption: cystic fibrosis, celiac disease
• Inherited disorders of vitamin D metabolism or action
• Children with limited mobility/weightbearing
• Children with inadequate calcium intake
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Calcium Availability
• Intake
• Absorption
• Excretion
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Recommended Calcium Intake
JCEM January 2011, p. 53-58
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Achievement of Recommended Calcium
Intake
AAP Position Statement 2006
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Achievement of Recommended Calcium
Intake
AAP Position Statement 2006
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Calcium Availability
• Intake
• Absorption – dependent upon:
–
–
–
–
–
–
age and pubertal status
calcium load consumed
food source
form of calcium salt
inhibitory factors (i.e. phytates, oxalates)
vitamin D status
• Excretion
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Calcium Availability
• Intake
• Absorption
• Excretion
– obligatory losses increase with age – 40 mg/day in infancy to
160 mg/day in adulthood
– increases with increasing dietary protein load
– increases with increasing dietary sodium load (80 mg calcium
excreted for every 2300 mg sodium excreted)
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Assessment of Pediatric Bone Health
• Nutritional intake and supplements
• Vitamin D, calcium, alkaline phosphatase and PTH levels
• DEXA
– Advantages – readily available, low radiation exposure,
increasing availability of pediatric algorithms
– Disadvantages – 2-dimensional measurement strongly
influenced by bone shape and size
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Assessment of Pediatric Bone Health
• Quantitative Computed Tomography
– Advantages – can measure bone mass, size, geometry and
architecture then utilize algorithms to estimate bone strength
– Disadvantages – moderately high radiation dose, limited
availability of pediatric software, high cost
• Quantitative Ultrasound
– Advantages – no radiation, office-based assessment
– Disadvantages – no pediatric normative data
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Guidance on Dual-Energy X-ray Absorptiometry Interpretation in
Children and Adolescents Younger Than 20 Years*
Loud, K. J. et al. Arch Pediatr Adolesc Med 2006;160:1026-1032.
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Summary
• Adequate vitamin D is essential to pediatric bone health
• Maintaining a 25(OH)D level at least above 20 ng/mL is
justifiable based on available data
• Consider maintaining a 25(OH)D level >30 ng/mL in those at
high risk of bone disease, but this may not be fully supported
by the evidence
• No evidence that 25(OH) D>50 ng/mL is beneficial and may be
harmful
• Supplementation with 400-600 IU vitamin D per day for all
children not consuming at least this much in their diets is
advised
• Keep an eye on calcium intake as well – dietary sources are
better than supplements
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Questions?
madisonl@ohsu.edu
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