Sticks and Stones: Pediatric Osteoporosis - PowerPoint Presentation

Slide1

Sticks and Stones: Pediatric Osteoporosis

Karen Jane Loechner, MD/PhD

Associate Professor

Director, Bone Clinic

Division Pediatric Endocrine

Slide2

Goals 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

Slide3

Measuring 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

Slide4

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

Slide5

What 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

Slide6

Interpretation 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

Slide7

Consortium 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

Slide8

30% 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

Slide9

Vertebral Compression Fractures

Indian J

Endocrinol

Metab

2014; 18(3): 295

Slide10

Spine 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).

Slide11

Risk 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

Slide12

Dietary 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

Slide13

Nutrition 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

Slide14

Zinc 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

Slide15

Vitamin D

Metabolism

UVB 280-305nm

Skin color

Sun exposure

SunblockLatitude > 41Screen time

Slide16

PTH

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



Slide17

1,25 (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

Slide18

Without 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?

Slide19

Soft 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

Slide20

Risk 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

Slide21

GCs 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

Slide22

Mechanistic 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

Slide23

GCs 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)

Slide24

Seizure 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)

Slide25

Risk 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

Slide26

Osteoblast 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

Slide27

Risk 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

Slide28

Immobility

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

Slide29

Risk 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

Slide30

Osteogenesis 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

Slide31

Osteogenesis 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

Slide32

Slide33

Slide34

Slide35

Risk 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

Slide36

Hypercalciuria: 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

Slide37

Hypercalciuria: 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)

Slide38

Caveats to DXA interpretation

Short stature

Vertebral Compression Fractures

Hip Dysplasia

Hardware

Slide39

Short 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

]

Slide40

VCFs 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

?

Slide41

Caveats 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

Slide42

Cases, QI projects in progress

Vitamin D deficiency rickets

ASD (Autism Spectrum Disorder)

IBD

IROC (short gut)

DMD (Duchenne’s)

Slide43

Nutritional 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

Slide44

Case: 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)

Slide45

CALCIUM

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”

Slide46

Vertebral 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)

Slide47

Marcus 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

Slide48

How 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

Slide49

Teen 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)

Slide50

DXA 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.

Slide51

ASD 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

Slide52

IBD

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.

Slide53

IBD and Bone HealthInflammation

TNF-alpha, IL-6, IL-10 and IL-12

Malnutrition

Corticosteroids (+/-)

Slide54

IBD 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

Slide55

Remicade

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.

Slide56

Short 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

Slide57

Vitamin 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

Slide58

Short 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

Slide59

B

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

Slide60

IROC “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

Slide61

Slide62

Preliminary 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

Slide63

DMDRisk 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)

Slide64

Goals 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!

Slide65

Algorithm for DMD Bone Health

David J

Birnkrant

et. al

Lancet Neurology

2018

Slide66

DMD 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

Slide67

DMD 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.

Slide68

How 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”

Slide69

Laboratory 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

Slide70

Laboratory Leads: Urine “Wish List”

Urine calcium/creatinine (random to start)

Hypercalciuria

can lead to

nephrocalcinosis

Increased risk with +FHx kidney stones Increased with immobilization

Slide71

Treatment Strategies

Treat underlying condition

Nutritional

Vitamin D

Dietary calcium if possible

Aquatic therapyBisphosphonates

Slide72

Vitamin 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

Slide73

V

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.

Slide74

Calcium 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.

Slide75

Dose-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?

Slide76

Dietary 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

Slide77

Dietary 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

Slide78

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

Slide79

Aquatherapy

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

Slide80

Vibration 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

Slide81

Bisphosphonate 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!

Slide82

Bisphosphonate 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

Slide83

Bisphosphonate 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

Slide84

Referral Guideline

Slide85

Thanks!

Slide86

Slide87

Other 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

Slide88

Multiple 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

Slide89

Ranges 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.

Slide90

Case 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

Slide91

Hypothyroidism

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

Slide92

Growth 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

Slide93

Hyperprolactinemia

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

Slide94

Cushing’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