Karen Jane Loechner MDPhD Associate Professor Director Bone Clinic Division Pediatric Endocrine Goals of Presentation Define osteopeniaosteoporosis in children Radiological tools Laboratory Clues blood urine ID: 932243
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Slide1
Sticks and Stones: Pediatric Osteoporosis
Karen Jane Loechner, MD/PhD
Associate Professor
Director, Bone Clinic
Division Pediatric Endocrine
Slide2Goals of Presentation
Define osteopenia/osteoporosis in children
Radiological tools
Laboratory Clues (blood, urine)
Risk factors for bone health
Identify who to screen, who to refer
Collaborative Bone Health Projects to date
Intro to Treatment Options
Referral Algorithm
Slide3Measuring Bone Strength:
DXA scans
Dual X-ray Absorptiometry
- measures X-rays at 2 photon energies
- (g/cm
2
) Hologic QDR scanner - fast scans, low irradiation exposure - multiple sites can be used
Less than a ‘day in the life’
Less than exposure during flight across country
DXA scans
Region
Area
cm
2
BMC (grams)
BMD
(
g/cm
2
)
L1
12.85
10.01
0.779
L2
13.90
11.38
0.819
L3
14.81
11.52
0.778
L4
14.88
12.71
0.854
total
56.44
45.61
0.808
Slide5What is Normal?
Z
-score: (
NOT
T-score = adults-peak mass)
Most appropriate for children Compares to appropriate age rangeMeasured BMD =Age matched mean BMD Population Standard DeviationEquals a SD!±2 SD defines a normal population
Slide6Interpretation of Z-scores
2014 Recommendations for Pediatrics
1
Osteoporosis definition:
A
Z
-score > -2.0 SD below pediatric age appropriate mean PLUS (at least one of the following)Fracture long bone lower extremities by 10 years oldVertebral compression fracture3 or more long bone fractures up to 19 years old J Clinical Densitometry: 17 (2): 275-280, 2014
Slide7Consortium Statement
2014 added
spine compression fracture
as pathologic
*Guidelines mostly for “
normal healthy kids”*High risk populations now identified
- skeletal dysplasias (OI, “brittle bone”) - immobility (CP-like) - steroids - malnutrition
Slide830% of children after 2-3 years of GCs
Can occur with conditions BEFORE GCs
1/3 symptomatic
Best imaged by AP and LAT films (not scoliosis screen)
Can occur with NORMAL spine density
Predicts other fractures
Vertebrae can “reshape” (if still growing and cause resolves) Grover and Bachrach. Curr Osteoporos Rep (2017) 15:271–282Vertebral Compression Fractures
Slide9Vertebral Compression Fractures
Indian J
Endocrinol
Metab
2014; 18(3): 295
Slide10Spine films
Multiple VCFs
(arrows)
Thoracic spine: Compression deformities of
T5, T6, T7, T8,T9, T10, and T11
. Lumbar spine: L5Individual VCF with max compression of 63% (right).
Slide11Risk Factors
Nutritional (ASD, IBD, short gut)
Medication-induced (e.g., steroids)
Hormonal Deficiency (
e.g
, E, T)
Hormonal Excess (e.g., cortisol)Immobility (e.g., CP, DMD)Genetic bone disease (e.g., OI)Hypercalciuria (“Bones No Stones”)*Combinations of above
Slide12Dietary intake assessment
Calories (kcal)
Protein (g)
Carbohydrates (g)
Fat (g)
Vitamin A - RAE (mcg)
Vitamin B12 (mcg)
Vitamin C (mg)
Vitamin D
Calcium (mg)
Vitamin E - Alpha-
Toco
(mg)
Folate, DFE (mcg DFE)
Iron
(mg)
Zinc (mg)
FSST: Analysis of 3 day food diary
Nutrient Average daily intake
Dietary Reference Intake (DRI)
% Recommended
Slide13Nutrition Unsung Heroes
B12:
GH signaling, deficiency associated with low BMD
Clemens TL N
Eng
J Med 2014; 371:963 Mg: LOW decreases PTH releaseVitamin E
: HIGH increases osteoclasts fusion that leads to increased bone massFujita K et an 2012 Nature Med. 18:589.Vitamin K: LOW: decreased BMD; unclear if supplements help BMD although increases bone formation markersIntern Med. 2016;55(15):1997-2003 Vitamin A: no effect if vitamin D replete; HIGH vitamin A may actually decrease BMDJoo, NS et al Nutrients. 2015 Mar 10;7(3):1716-27
Slide14Zinc Deficiency
1. Affect actions of IGF1
2. Decreases chondrocyte proliferation
3. Stimulates osteoblasts in culture
4. Increases osteoclasts (ZN inhibits osteoclasts
in vitro)4. Zn may block TNF alpha actions
5. LOW Zn leads to an increase in serum PTH and elevated 1,25 OHD but ? Still poor calcium absorption (rats)J Nutr Sci Vitaminol (Tokyo). 2015;61(5):382-90Ann Nutr Metab 2013; 62S:8-17
Slide15Vitamin D
Metabolism
UVB 280-305nm
Skin color
Sun exposure
SunblockLatitude > 41Screen time
Slide16PTH
and Treat
Ca
2+
PTH
:
KIDNEY actions:normal1. Stimulates 1α-OH activity2. Increases 25- to 1,25-vitamin D UCa2+ excretion ...in response to a decrease in Ca2+KIDNEY actions:1. Stimulates 1α-OH activity2. Increases 25- to 1,25-vitamin D formationBONE actions:
Increases efflux of calcium and phosphate
PTH receptors on osteoblasts and direct effect on osteoclasts
Restore Ca
2+
then inhibits
PTH and feedback loop closed
Slide171,25 (OH)
2
Vitamin D
KIDNEY actions
:
Decreases U
Ca2+ excretion (distal tubule)Increases fractional excretion (proximal tubule) UPO4GUT actions:Increase Ca2+ and PO4 absorptionSUMMARY on Ca2+ GUT: absorptionKIDNEY: reabsorption
Slide18Without vitamin D, only 10-15% of dietary calcium is absorbed!
Drink 10 glasses of milk = only 1 counts!
Bone = largest store of calcium
So if you are vitamin D deficient, where is your calcium coming from?
Slide19Soft drinks
phosphoric acid decreases Ca
2+
absorption
majority of effect is choose soda > milk
Caffeine Increases Ca2+ and Mg2+ loss in urine *2 tbsp milk in your coffee offsets Ca2+ loss Pediatrics 134(4): 1229-1243Vitamin D Fun Facts
Slide20Risk Factors
Nutritional (ASD, IBD, short gut)
Medication-induced (e.g., steroids)
Hormonal Deficiency (
e.g
, E, T)
Hormonal Excess (e.g., cortisol)Immobility (e.g., CP, DMD)Genetic bone disease (e.g., OI)HypercalciuriaOR *Combinations of above
Slide21GCs and Bone
Decrease function and lifespan osteoblasts
Increase survival of osteoclasts
Decrease intestinal calcium absorption + Increase urinary calcium loss =
increased PTH (catabolic)
Decrease anabolic hormones
GHFSH/LH (indirect) Direct inhibition of E2 (ovary) and T (testes)ACTH---leads to decrease in adrenal androgens
Slide22Mechanistic Actions of GCs
RankL
Receptor
activator
of
NFkB
Stimulates Osteoclasts growth & differentiationM-CSF Macrophage colony stim factor
Stim differentiation of Osteoclasts
PPARg2 Peroxisome
proliferator-activated
receptor gamma
Regulated
fat storage/metabolism
Inhibits Osteoblasts
Stim Osteoclasts
Wnt
Cononical
signaling pathways
Activation stimulates
Osteoblasts and INC net bone accrual
Caspase 3 Signaling
proteinase
Part of Osteoblast apoptosis
pathway; estrogen works by interfering
with this pathway
Slide23GCs and Bone
What is Excess?
exogenous > endogenous
oral (>7.5 mg daily)
Inhaled
Decrease BMD after 1 year (oral)
0.6-6%/year decease in BMD reportedSpine most sensitive (trabecular bone)
Slide24Seizure Meds
Vitamin D
Increase 25 vitamin D metabolism (variable reports)
Thyroid (examples)
Carbemazepine
/oxcarbazepine (
Trileptal) decreases Free T4; no change TSHValproic acid increases TSH with normal FT4 (subclinical hypothyroidism)
Slide25Risk Factors
Nutritional (ASD,
IBD, short gut
)
Medication-induced (e.g., steroids)
Hormonal Deficiency (
e.g, E, T)Hormonal Excess (e.g., cortisol)Immobility (e.g., CP, DMD)Genetic bone disease (e.g., OI)Hypercalciuria*Combinations of above
Slide26Osteoblast Osteoclast
Formation Resorption
The See-Saw of bone mineral densityPTH (low, intermittent)GH / IGF-1T3 (IGF1, alk
phos
)
Mechanical Load
PTH
(high, continuous)
Thyroid Hormone (T3)
Prolactin and via hypogonadism
Glucocorticoids
Estrogen, Androgens
Slide27Risk Factors
Nutritional (ASD, IBD, short gu
t
)
Medication-induced (e.g., steroids)
Hormonal Deficiency (
e.g, E, T)Hormonal Excess (e.g., cortisol)Immobility (e.g., CP, DMD)Genetic bone disease (e.g., OI)Hypercalciuria*Combinations of above
Slide28Immobility
Decrease mechanical stress (decrease osteoblast stimulation)
Decrease muscle tone (force on bone)
Model: Space Flight (no gravity)
Loss of 1-2% bone mass per
MONTH in space flightNASA.gov
Slide29Risk Factors
Nutritional (ASD, IBD, short g
ut
)
Medication-induced (e.g., steroids)
Hormonal Deficiency (
e.g, E, T)Hormonal Excess (e.g., cortisol)Immobility (e.g., CP, DMD)Genetic bone disease (e.g., OI)Hypercalciuria*Combinations of above
Slide30Osteogenesis Imperfecta
Most common
genetic
cause of osteoporosis
Clinical spectrum due to mutations in
Type 1 collagen
Type 1 collagen: bone, sclerae, organ capsules, fascia, tendons, meninges, dentin and dermis.7 main subtypes (many more)Types 1-4 account for 90% and all Autosomal DominantTypes 5-7-Autosomal Recessive Clinically these resemble Type III
Slide31Osteogenesis Imperfecta
OI type1
-
Quantitative
collagen defect –
Alpha 1 chain is a null allele with a
50% decrease in Type I collagenOI Types 2,3,4 - Qualitative collagen defectOI Types 5, 6, 7 -Autosomal Recessive
Slide32Slide33Slide34Slide35Risk Factors
Nutritional (ASD, AN, celiac, IBD)
Medication-induced (e.g., steroids)
Hormonal Deficiency (
e.g
, E, T)
Hormonal Excess (e.g., cortisol)Immobility (e.g., CP, DMD)Genetic bone disease (e.g., OI)Hypercalciuria*Combinations of above
Slide36Hypercalciuria: Bones, no Stones
Urine calcium/creatinine ratio (start with random)
Often “idiopathic
hypercalciuria
”
If
hypercalciuria present: (various ranges published)<2 yo = 0.60-0.802-8 yo= 0.408yo= < 0.20Caveat: low urine creatinine (eg, DMD, malnutrition)-falsely ‘high’ ratio
Slide37Hypercalciuria: Bones, not Stones
Consider renal ultrasound at baseline and yearly depending on indication
CHECK FAMILY
Hx
Refer to Nephrology
Increase daily fluid intake
Low salt diet Low animal protein (*often cited by patients as reason to NOT drink milk)Thiazide diuretics (e.g., diuril)*Calcium restriction can actually increase oxalate absorption (see short gut)
Slide38Caveats to DXA interpretation
Short stature
Vertebral Compression Fractures
Hip Dysplasia
Hardware
Slide39Short Stature and BMD
Chronic conditions (e.g., short gut, IBD) with short stature
DXA Z-scores will
over
-estimate BMD deficit
need to re-index for height age (HA)
Chronological Age
HA
J
Clin
Densitom
, 2005; 8: 48–56. J
Clin
Densitom
2014; 17: 225–242.
[
http://www.bcmcspublic.com
]
Slide40VCFs and Spine BMD
Vertebral Spine Compression Fractures
Loss of Height, Wedge Compression
Can be associated with NORMAL DXA spine Z-score!
Change in bone strength without density change (steroids)
DXA computes as more dense with compression
?
Slide41Caveats to DXA interpretation
Hardware
Pinning for SCFE will falsely raise Z-score at femur/hip
Use other hip if that side normal
Rods-OI
NeuromuscularScoliosis, spine fusion
Alternative DXA site: forearm siteaccommodate for contractures trabecular + cortical boneJ Clin Densitom. 2014 ; 17(4): 522–527
Slide42Cases, QI projects in progress
Vitamin D deficiency rickets
ASD (Autism Spectrum Disorder)
IBD
IROC (short gut)
DMD (Duchenne’s)
Slide43Nutritional Rickets (Vitamin D deficiency
)
- Metaphyseal broadening, cupping, widening
- Remainder of the bones of the hands are demineralized
Labs:
Ca 8.7,
phos 2.6 25Vit D <13 , 1,25 vit D= 141PTH 553 Alk phos 1201
Slide44Case: Teen with ASD
Nonverbal teen (boy)
Mom says:
“He will not walk on his leg”
Tests to do?
SCFE film
Right femoral neck fracture with a portion of the fracture line extending proximally to the growth plate in keeping with a Salter II injury. Associated coxa vara deformity. Left hip joint is intact. (SCFE)
Slide45CALCIUM
5.8
mg/
dL
PHOSPHORUS 4.5 mg/dL
MAGNESIUM 2.1 mg/dL ALBUMIN
3.3 g/dL (correct for Ca) ALKALINE PHOS 902 U/L AST (SGOT), ALT (SGPT) normal (shows likely bone origin)25-OHD <13.0 ng/mL Range: 19.9 - 79.3 VITAMIN D 1,25 OHD 157 pg/mL Range: 19.9 - 79.3 (good conversion)PTH INTACT 504.5 pg/mL Range: 8.5 - 77.1 (low Ca)Urine Ca/creatinine normalOrthopedist comments: “The bones felt funny during surgery”
Slide46Vertebral Compression Fractures (VCFs)
Multiple VCFs
(arrows)
Thoracic spine: Compression deformities of
T5, T6, T7, T8,T9, T10, and T11
Lumbar spine: L5Individual VCF with max compression of 63% (right)
Slide47Marcus Autism Feeding Program:
Dietary intake assessment: Severe restrictive eating
Nutrient
Average daily intake
Dietary Reference Intake (DRI)
Percent of DRI
Calories (kcal)
2081.33
2075
100.30%
Protein (g)
63.73
47.43
134.37%
Carbohydrates (g)
293.68
285.31
102.93%
Fat (g)
72.07
64.56
111.64%
Vitamin A - RAE (mcg)
62.72
900
6.97%
Vitamin B12 (mcg)
0.06
2.4
2.70%
Vitamin C (mg)
396.66
75
528.89%
Vitamin D
0
15
0%
Vitamin E - Alpha-Toco (mg)
1.08
15
7.17%
Folate, DFE (mcg DFE)
341.52
400
85.38%
Vitamin K (mcg)
18.91
75
25.21%
Calcium (mg)
389.57
1300
29.97%
Iron (mg)
11.39
11
103.51%
Zinc (mg)
0.81
11
7.33%
FSST: Analysis of 3 day food diary
Slide48How to Treat our Teen?
Initial Treatment
Rocaltro
l
initally
Due to low calcium Supplemental calciumCalcium carbonate (poor dietary intake)Ergocaliferol 50,000 IU weekly for 8 weeksThen vitamin D3 1000-2000 IU dailyDietary calciumChallenge with ASD (feeding program)Fortified OJCheck FHx kidney stonesMultiple DeficienciesVitamin DCalciumZincB12Vitamins A, E, K (fat soluble)
Vitamin C
Slide49Teen with ASDs
post
Rx
CALCIUM, SERUM 9.5
PHOSPHORUS, SERUM 5.5
ALBUMIN, SERUM 4.3
ALKALINE PHOSPHATASE, SERUM Range: 107 - 340 IU/L 332 Calcitriol(1,25 di- OH Vit D) Range: 19.9 - 79.3 pg/mL 138.0 VITAMIN D, 25-HYDROXY Range: 30.0 - 100.0 ng/mL 46.8 PTH INTACT Range: 15 - 65 pg/mL 91 (likely insufficient calcium intake)
Slide50DXA pre and post supplementation
BMD pre and post vitamin D and calcium supplementation results in marked improvement in BMD with 73% increase over baseline L1-L4 spine (left) BMD and 24.7% increase in TBLH BMD (right). TBLH used femur/hip site not affected by SCFE/pinning.
Slide51ASD and Bone Health:MAC Pilot Grant
(with Dr. Will Sharp, Dr. Larry Scahill)
Food Selectivity Screening Tool
(FSST) will be used to classify children with:
1. ASD with severe food selectivity (n=15)
2. ASD and mild food selectivity (n=15)3. Children without ASD (n=15). Assess the association among severity of food selectivity and vitamin D deficiency and bone density Hypothesis: Children with >5 nutrient deficiencies (e.g., severe food selectivity) will be more likely to have altered bone metabolism markers(blood, urine) and compromised BMD (DXA)Assess the risk for vertebral compression fractures (VCFs) in those children at highest risk low spine BMD (Z-score < -2.0) Hypothesis: The presence of VCFs will correlate with severity of food selectivity
Slide52IBD
Poor weight gain
Short stature
Decreased BMD
*Osteopenia can occur
BEFORE GCs*Vertebral compression fractures can be present even BEFORE GCs started
DXA obtain at diagnosis (adjust for HA given short stature)J Pediatr Gastroenterol Nutr. 2006 Jul;43(1):42-51.Osteoporos Int. 2014 Jul;25(7):1875-83. doi: 10.1007/s00198-014-2701-x. Epub 2014 Apr 24.
Slide53IBD and Bone HealthInflammation
TNF-alpha, IL-6, IL-10 and IL-12
Malnutrition
Corticosteroids (+/-)
Slide54IBD and Remicade (infliximab)
TNF-alpha
decreases bone formation
increases bone resorption (stimulates osteoclasts)
affects trabecular bone (spine) > cortical bone density (appendicular)
Remicade
(monoclonal antibody against TNF alpha)
Versus
pamidronate
(bisphosphonate)
Increases IL-6 and IL-10
Direct inhibition of osteoclasts
Minerva
Gastroenterol
Dietol
. 2010 Jun;56(2):233-43
Slide55Remicade
33 pediatric patients with inflammatory bowel disease received infliximab
Weight gain, improved height in 21/33 children
Improved 25OHD levels
No change in BMD after one year
remicadeThose with BMD Z-score < -2.0 had higher inflammatory markers, lower BMI, height and 25OHD after remicade
Acta Paediatr. 2014 Feb;103(2):e69-75.
Slide56Short GutSite-specific calcium absorption
Duodenum/upper jejunum
Active/transcellular transport
Vitamin D dependent (90%)
Calcium channel and binding protein (synthesis dependent on vitamin D; down-regulated with high calcium intake due to down-regulation of 1,25 vitamin D
Important when calcium intake LOW
Slide57Vitamin D and Ca absorption
25 vitamin D 1/100 as potent for calcium absorption as 1,25 vitamin D
Low calcium absorption results in increase in PTH
Elevated PTH drives conversion to 1,25 vitamin D
Ament, 1998 J
Peds
Slide58Short GutSite-specific calcium absorption
Throughout all of small intestine
Passive/
paracellular
Independent of vitamin D
Depends on calcium intestinal content
May be MOST effective way to increase calcium absorption but maybe NOT in this population!Bronner, F. Nutrition Reviews. 2009
Slide59B
ones, Not Stones In Short Gut
Jejunum-colon patients
Decreased bile salts (leads to increased absorption of oxalate)
Elevated calcium oxalate
25%
risk renal stones-calcium oxalateHigh oxalate foods: Spinach, broccoli, soy, nuts, strawberries TreatLow oxalate diet, dietary calcium from other sourceshydration
Slide60IROC “Bone and Renal Health Project”
Challenges in intestinal rehab population:
Calcium-phosphorus product in TPN
Inadequate calcium via gut absorption
Hypocalcemia and hyperparathyroidism
Hypercalciuria
and risk of calcium oxalate nephrolithiasis (poor bile acid absorption)Feeding/oral aversion Steroid HistoryBone and Renal Health Screening Protocol
Slide61Slide62Preliminary Findings
Annual DXA scan
if
>
3 years old
Spine/TBLH/femur
If spine Z-score <- 2.0, bone pain and/or steroids:
AP/LAT T-L spine films
BMD < -2.0
VCFs
Endocrine/Bone Referral
Bone Health
Biannual Urine Ca/Cr
if
>
1 year old
Hypercalciuria
Nutritional evaluation:
1. Assess Ca intake
2. Assess Na intake
3. Assess hydration
Persistent
hypercalciuria
/
nephrocalcinosis
Nephrology Referral
Renal Health
Annual DXA scan
if
>
3 years old
Spine/TBLH/femur
If spine Z-score <- 2.0, bone pain and/or steroids:
AP/LAT T-L spine films
BMD < -2.0
VCFs
Endocrine/Bone Referral
Bone Health
Biannual Urine Ca/Cr
if
>
1 year old
Hypercalciuria
Nutritional evaluation:
1. Assess Ca intake
2. Assess Na intake
3. Assess hydration
Persistent
hypercalciuria
/
nephrocalcinosis
Nephrology Referral
Renal Health
Annual DXA scan
if
>
3 years old
Spine/TBLH/femur
If spine Z-score <- 2.0, bone pain and/or steroids:
AP/LAT T-L spine films
BMD < -2.0
VCFs
Endocrine/Bone Referral
Bone Health
Biannual Urine Ca/Cr
if
>
1 year old
Hypercalciuria
Nutritional evaluation:
1. Assess Ca intake
2. Assess Na intake
3. Assess hydration
Persistent
hypercalciuria
/
nephrocalcinosis
Nephrology Referral
Renal Health
Nadella S, Romero R, Hofmekler T, George R Loechner, K. 2018. Pediatric Endocrine Society, 2018
Slide63DMDRisk Factors for Bone Health
DMD: X-linked severe muscular dystrophy 1/3500 (dystrophin)
Steroids
30%
of patients with
VFC
(vertebral compression fractures) after 2 years of steroidsOnly 30% of patients with VFC has symptoms of back painDeflazacort (Emflaza) or PrednisoneImmobility‘Delayed’ puberty (Consider Testosterone treatment at 14 years old if no puberty)
Slide64Goals of DMD QI
Detect and treat vitamin D deficiency
Optimize calcium intake (dietary preferred)
Detect decreased BMD (DXA)
Detect VCFs
Treat per algorithm (+/- bisphosphonate)Follow for
hypercalciuria and nephrocalcinosis KEEP BOYS WALKING!
Slide65Algorithm for DMD Bone Health
David J
Birnkrant
et. al
Lancet Neurology
2018
Slide66DMD QI
Vitamin D
increased # boys tested and treated
DXA
TBLH, spine, femur/hip (acquired hip dysplasia if wheel-chair bound)
Spine radiographsWas: If DXA spine <-2.0 (most sensitive to steroids)Now: PRE GC exposure and Yearly after GC exposure
Slide67DMD QI
Hypercalciuria
Urine calcium/
creat
ratio
(caveat: low
creat often yield falsely elevated ratio)Renal ultrasound-nephrocalcinosis (2 boys)Nephrology referralBisphosphonates (8 boys thus far)Pathological fractureVertebral compression fracturesOtto*, A., Loechner, K and Verma, S. American Academy of Neurology Meeting, 2017; Abstract #2617.
Slide68How do I get my patient to Bone Clinic?Have a low impact fracture
Have risk factors for low bone density
Get a DXA scan that is low for chronologic and height age
Get suspicious lab results including vitamin D deficiency
Use “staff inbox in EPIC”
Slide69Laboratory Leads: Blood “Wish List”
25 vitamin D
(“stores”, 25 hydroxylation at liver)
1,25 vitamin D
(
PRE rocaltrol treatment: draw and confirm in lab; otherwise = “
rocaltrol dose”)Intact PTH with Calcium Conversion of 25OHD to 1,25 OHD driven by PTH through 1 alpha hydroxylaseCMP with alk phos (bone formation marker, osteoblasts)Also made in liver, intestinePhosphorusOsteocalcin (bone formation, osteoblasts, expensive)-not get routinely
Slide70Laboratory Leads: Urine “Wish List”
Urine calcium/creatinine (random to start)
Hypercalciuria
can lead to
nephrocalcinosis
Increased risk with +FHx kidney stones Increased with immobilization
Slide71Treatment Strategies
Treat underlying condition
Nutritional
Vitamin D
Dietary calcium if possible
Aquatic therapyBisphosphonates
Slide72Vitamin D
Without vitamin D, only 10-15% of dietary calcium is absorbed!
Multiple forms of Vitamin D
25 OH Vitamin D2
Plant:
ergocalciferol
(covered by insurance)25 OH Vitamin D3Animal: cholecaliferol1,25 vitamin D (calcitriol)= active hormonePediatrics.2014;134;2014-2173
Slide73V
itamin D Replacement
Deficiency
treatment: many modalities used
50,000 IUs orally once weekly for 6-8 weeks
OR
-2,000 IU/day for 6 weeksGoal: 25-OH vitamin D level > 30 ng/mL (75 nmol/L) (AAP > 20 ng/mL)Maintenance therapy: Age 0-1 year - 400-1,000 units/day Age 1-18 years - 600-1,000 units/day Endocrin Soc recommendations/ Pediatrics 2014; 134:e1229.
Slide74Calcium and Vitamin D Dietary Reference Intakes*
Age
Calcium
Vitamin D
RDA (mg/d)
1
UL (mg/d)
2
RDA (IU/d)
1
UL (IU/d)
2
Infants
0-6
months
200
3
1000
400
3
1000
6-12 months
260
3
1500
400
3
1500
1-3 y
700
2500
600
2500
4-8 y
1000
2500
600
3000
9-13 y
1300
3000
600
4000
14-18 y
1300
3000
600
4000
1
Intake that meets needs of
≥
97.5 % of Population
2
Upper limit(UL) level above which there is risk of adverse events. The UL is not intended as a target since there is no consistent evidence of greater benefit of intake above RDA.
3
Reflects adequate intake reference value rather than RDA. RDAs not established for infants.
*
from Golden, Abrams, and Committee on Nutrition. “Optimizing Bone health
in children and adolescents”.
Pediatrics
2014;
134
:e1229.
Slide75Dose-Expected Increase in Blood 25OHD Concentration after 2 to 3 months of D2 or D3 Rx
100 IU 1 ng/mL
200 IU 2
ng
/mL
400 IU 4 ng/mL
800 IU 8 ng/mL 1,000 IU 10 ng/mL 2,000 IU 20 ng/mL Cannell JJ, Vieth R, Umhau JC, et al. Epidemic influenza and vitamin D. Epidemiol Infect. 2006;134:1129–1140. How much is needed?
Slide76Dietary Calcium
Goal: elemental calcium
Pre-teen: 1,000 mg/day
Teen: 1,200-1,500 mg/day
≥ 11 years old
BUT
: “calcium supplementation has little effect on bone mineral content or bone mineral density in healthy children”Pediatrics 2006 Jan;117(1):259; 2014 (134); 1229-1243BMJ 2006 Oct 14;333(7572):775
Slide77Dietary Sources of Calcium*
Dairy
serving
calories
calcium (mg)
Whole Milk
8
oz
149
276
Skim Milk
8
oz
83
299
Low Fat Plain Yogurt
8
oz
143
415
Low Fat Fruit
Yogurt
8 oz
232
345
Swiss cheese
1.5
oz
162
336
American cheese
2
oz
187
323
Non-dairy
Canned sardines
3
oz
177
325
Broccoli, cooked
1 cup
44
72
Broccoli, raw
1 cup
25
42
Collards, cooked
1 cup
49
226
Spinach, cooked
1 cup
41
249
Calcium-fortified foods
Orange juice
8
oz
117
500
Breakfast cereals
1 cup
100-210
250-1000
Soy Milk
1
8
oz
104
299
1
not all Soy milks are fortified
*Dietary Guidelines for Americans, 2010.
www.ndb.usda.gov
Aquatherapy
Low impact weight-bearing
Low fracture risk in water
Muscle tension and loading exercises
FUNNot as robust as gymnastics, but better suited for many patient groups
ImmobilitySevere osteoporosis
Slide79Aquatherapy
Postmenopausal women (n=108) randomized in CG versus
aquatherapy
x 24 weeks
Improved bone formation markers
Lower bone resorption markersDXA stable vs slight decrease in FN in CG
All: 1000 IU vit D + 500 mg calcium dailyFernandes Moreira• et al., 2013 Japanese Society for Bone and Mineral Research
Slide80Vibration TherapyWhole Body Vibration (WBV)
Frequency varies
Treatment varies
Increased lumbar bone density
Improved muscle mass
Improved hip bone density (other studies)
Rauch; 2009;Devel Med and Child Neurology; 51, 166-168
Slide81Bisphosphonate Therapy
Based on OI population
Inhibits osteoclasts (bone ‘chewing’ cells)
Used in multiple conditions associated with
*
clinical pathology
bone pain, fracturesTreat child not the Z-score!
Slide82Bisphosphonate AEs
Side Effects
(usually show
tachyphylaxis
)
Bone Pain (IV>po)Hypocalcemia (IV>po)
Muscle cramps (IV>po)Thrombophlebitis (IV only)Fever (IV>po)Screen for:HypothyroidismHyperlipidemiaElevated liver function testsUremiaMicrocytic anemia
Slide83Bisphosphonate AEs
Atypical fractures
Jaw necrosis (‘drug-induced osteonecrosis’)
Variable reports
Incidence: 6/100,000 women
Postmenopausal women; s/p chemotherapy
Occurs usually post dental implant/extractionZolendronate>Pamidronate>AlendronateUnknown risk in children Rx with bisphosphonatePrecautions for implants/extractions
Slide84Referral Guideline
Slide85Thanks!
Slide86Slide87Other Treatments
Forteo
(
Synthetic
hPTH)Increase bone formation
Spine > FNHypercalcemiaHypercalciuria– Black box warning (rat studies)
• Osteosarcoma (humans)– >430,000 patients– 2 cases as of 2010DenosumabRANK ligand inhibitorGrowth plate changes (rat)Atypical fractures (human)PainHypocalcemia/rebound hypercalcemiaRemicade (infliximab)TNF alpha inhibitor
Slide88Multiple tissues
Vitamin D Metabolism
heat (37ºC) and (UV) light (wavelength
280-305
nm)
Vitamin D Binding Proteins (VDBP) hepatic
microsomal
and mitochondrial
cytochrome
P450-containing vitamin D
3
25-hydroxylase enzyme
VDBP
1-
a
-hydroxylase (
cytochrome
P450) encoded on chromosome 12q14
24R,25-dihydroxy-vitamin D
3
, a relatively inactive vitamin D metabolite,
chromosome
4q11-13
Slide89Ranges with Rickets
Serap
Turan,
1
Burcu
Topcu,2 Ibrahim Gökçe,2 Tülay Güran,1 Zeynep Atay,1 Anjumanara Omar,1 Teoman Akçay,3 and Abdullah Bereket1 Serum Alkaline Phosphatase Levels in Healthy Children and Evaluation of Alkaline Phosphatasez-scores in Different Types of RicketsJ Clin Res Pediatr Endocrinol. 2011 March; 3(1): 7–11. Published online 2011 February 23. doi: 10.4274/jcrpe.v3i1.02.
Slide90Case Trends
Urine NTX TREND with
pamidronate
infusion
Inhibit bone resorption with pamidronate
(block action of osteoclasts)See TREND of decrease in NTXNote: will have ups and downs (e.g., fracture)Urine NTX in child with OI receiving PAM
N-Telopeptide, Urine nmol/L / UR Creatinine mg/dL 1,374, 825, 824, 762, 497 Two month intervals, intercurrent fractures occurredDecrease over time supports inhibition of bone resorption by osteoclasts
Slide91Hypothyroidism
Mechanisms (in bone):T4 converted to T3
Type 2
deiodinase
active T3 (
osteoblasts after fetal life)Type 3 deiodinase converts to inactive T3T3 acts at TRaT3Increases osteoblast activityIncreases alkaline phosphataseIncreases IGF1May also decrease osteoclast activityEndocrinol Metab Clin N Am 44 (2015) 171-180
Slide92Growth Hormone Excess
acromegaly
Clinical:
Increase vertebral compression fractures
- 1/3 of
acromegalic
patients- Even with normal DXA scan - Correlates with IGF1 levels, NOT BMDDXA CAVEAT:- Structural changes in spine make DXA inaccurate (osteophytes)Endocrinol Metab Clin N Am 44 (2015) 171-180
Slide93Hyperprolactinemia
Clinical
Decreased BMD
- Particularly lumbar spine
- Increased vertebral compression fractures
Increased fracture rate
Not fully restored when PRL normalizedEndocrinol Metab Clin N Am 44 (2015) 171-180
Slide94Cushing’s Disease
High ACTH
High
cortisol
levels
Inhibit
osteoblastsStimulate osteoclastsAffects Trabecular bone >cortical boneFractures occur before decreased BMD Fracture = vertebral compression30-50% of patients with Cushing’s diseaseEndocrinol Metab Clin N Am 44 (2015) 171-180