LTC Karen S. Vogt
Pediatric Endocrinology, WRNMMCB
March 2013
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Understand the necessity of adequate
vitamin D intake in children and adolescents
Understand the necessity of calcium and
phosphorous intake in children and
adolescents
Know that hypocalcemia with
hypophosphatemia suggests vitamin D
deficiency
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Understand the mechanism of rickets in
children with hepatic disease
Plan the treatment of a child with familial
hypophosphatemic rickets
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Case
Nutritional rickets and Vitamin D deficiecy
Prevention
Other types of rickets
PREP Questions
 9 month old female presents in
January for her well baby visit
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Birth:
 C-section at 34 weeks for placental abruption
 Required PRBC transfusion x2
 PDA - closed after indomethacin x 1
 18 day NICU stay
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PMH: healthy
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Immunizations: up-to-date
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Diet: exclusively breastfed until 6 months of age,
now taking stage 2 baby foods and soft table
foods
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Meds: Poly-vi-sol in first 3 months of life, no
current meds
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Development: sits unsupported when placed,
pulls to stand, cannot get from lying to sitting,
immature pincer grasp, waves bye-bye, plays
peek-a-boo, consonant babbling
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Family History: parents healthy, mom no
longer taking prenatal vitamins, mom is
Filipino, dad is half caucasian/half Filipino
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Physical Exam : Unremarkable
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Weight check in one month
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Mom comes back in 2 weeks for concern for
difficulty feeding
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Less appetite for solids than previously and
no weight gain from well visit
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TSH, CRP, Celiac Panel – unremarkable
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Fecal fat, reducing substances and alpha-1antitrypsin – normal
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Sweat test – normal
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CMP-
Alk Phos 736 U/L
Calcium 9.2 mg/dl
Albumin 4.0 g/dl
(150-420)
(8.7-10.4)
(3.5-5)
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CBC -
WBC 12.6
Hgb 10.8
Hct 34.7
Plt 547
MCV 64.6
(70-86)
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More History: Mom drinks no milk, occasional
cheese, doesn’t like yogurt
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Infant light skinned and born in early spring
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Minimal time in the sun per mom – spent most
of summer indoors
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PE: subtle wrist widening, slight concavity of
lateral chest walls, mild generalized low tone
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Alk Phos:
568 U/L
(150-420)
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Calcium:
8.8 mg/dl
(8.7-10.4)
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Albumin:
4.7 g/dl
(3.5-5)
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Corrected Ca:
8.24 mg/dl (8.7-10.4)
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Phosphorus:
2.5 mg/dl
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PTH:
346.1 pg/ml (13-75)
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25 OH Vit D:
< 4.0 ng/ml
(2.7-4.5)
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Rickets due to vitamin D deficiency
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Treatment:
 Ergocalciferol (Drisdol® 8000 IU/ml) 2000 IU daily
 Calcium carbonate 40 mg/kg/day div bid
Pediatrics Aug 2008:122:398-417
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Failure in the mineralization of newly
synthesized bone matrix (osteoid) in growing
bone
Due to deficiencies in calcium, phosphorous,
or both
Most common cause is Vitamin D deficiency
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Osteomalacia – equivalent in mature bone
Contrast to osteoporosis
 Low bone mass due to decreased mineralization
and decreased bone matrix
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Dietary
 Ergocalciferol (D2) – plant source
 Cholecalciferol (D3) – animal source
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UVB exposure
 Promotes conversion of 7-dehydrocholesterol to
cholecalciferol (D3) in the skin
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Vitamin D is converted to 25(OH)D by 25hydroxylase in the liver
25(OH)D
 A.k.a calcidiol
 Inactive form
 Reflects total body stores (2-3 week ½ life)
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25(OH)D is converted to 1,25(OH)2 D by 1αhydroxylase in the kidney
1,25-OH2 D
 A.k.a calcitriol
 Active form
 More tightly regulated (4-6 hour ½ life)
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Stimulated by
 PTH
 Low phosphorous levels
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Acts on the vitamin D receptor (nuclear
receptor) at the target organs
Major effect: absorption of calcium and
phosphorous from the GI tract
Immunomodulary effects
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Actions: keep serum calcium normal
 Bone – stimulates reabsorption
 Kidney:
▪ Stimulates 1α-hydroxylase
▪ Increases calcium reabsorption
▪ Increases phosphate excretion
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Stimulated by decreased serum calcium
levels
Hypomagnesemia impairs its secretion
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Produced by active osteoblasts, which form
unmineralized matrix
Levels increase with increased osteoblast
activity
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Deficient GI absorption of :
 Calcium → hypocalcemia → ↑PTH:
▪ Release of calcium and phosphorous from bones
▪ Activation of 1α-hydroxylase → increased formation of
1,25-OH2 D
▪ Increase in renal phosphate loss
 Phosphorous
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Net effect: decreased calcium and
phosphorous available for bone
mineralization
Osteoid continues to form without
mineralization
 Expansion of the growth plate
 Metaphyseal irregularities, fraying, flaring
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Bones become “soft” and less rigid
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Reasons for increasing prevalence
 Exclusive breastfeeding
 Breastfeeding moms with insufficient vitamin D
stores
 Increasing use of sunscreen
 Less time spent outdoors
Pediatrics 2008;122:398-417
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Prematurity
Exclusive breastfeeing for 6 months
(although was on poly-vi-sol for the first 3
months)
Probable vitamin D deficient breastfeeding
mother
Winter season
Minimal sun exposure
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Nutritional
Dark skin
Malabsorption
Obesity (sequestration in body fat)
Liver or kidney disease
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Anticonvulsants
Glucocorticoids
HIV medications
Rifampin
Isoniazide
Ketoconazole
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Incidental finding
LE bowing
Delayed walking
Failure to thrive
Bone pain
Pathologic fracture
Hypocalcemia (to include seizure)
Weakness
Pneumonia, other respiratory infection
Anorexia
Restlessness/irritability
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Poor growth or weight gain
Delayed anterior fontanelle closure
Teeth: delayed eruption, enamel defects
Generalized muscular weakness/hypotonia
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Wrist and/or knee films usually
Metaphyseal fraying, widening, flaring,
cupping
Periosteum separated from the diaphysis
Generalized osteopenia
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Iron deficiency anemia
Renal Fanconi syndrome
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Who?
 Nonspecific symptoms: poor growth, gross motor
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delays, unusual irritability
Dark skin infants in higher latitudes in the winter
and spring
Children taking chronic glucocorticoids or
anticonvulsants
Chronic diseases associated with malabsorption
Frequent fractures and low BMD
Pediatrics 2008;122:398-417
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How?
 Serum Alkaline Phosphatase (ALP)
 If elevated: 25 OH Vitamin D, PTH, Calcium and
Phosphorus
 Films:
▪ Wrist
▪ Knee
Pediatrics 2008;122:398-417
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< 1 month of age:
1000 IU/day
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1-12 months of age:
1000-5000 IU/ day
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> 12 months of age:
>5000 IU/day
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Teens/adults:
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Consider Stoss therapy if compliance a concern
(100,000 – 600,000 IU over 1-5 days)
50,ooo IU/week x 8 weeks
Pediatrics 2008;122:398-417
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Ergocalciferol = D2 (Drisdol®, Calciferol®)
 Drops (8000 IU/mL)
 Capsules (50,000 IU)
 Injection (500,000 IU) – no longer available
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Cholecalciferol = D3
 Capsules (5000 IU)
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Simultaneous calcium supplementation necessary
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Concern for “Hungry Bone” hypocalcemia
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30-75 mg/kg/day divided TID – elemental calcium
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Symptomatic hypocalcemia requires parenteral
calcium replacement
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Calcitriol (Rocaltrol®) can help treat hypocalcemia
associated with rickets but does NOT build up vitamin
D stores
Pediatrics 2008;122:398-417
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Vitamin D is fat soluble so must not overtreat
 Hypercalcemia
▪ Weakness
▪ Polyuria
▪ Nephrocalcinosis
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1 Month:
Calcium, Phosphorus, ALP
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3 Months:
Calcium, Phosphorus, ALP
PTH, 25 OH Vit D,
Urine calcium/creatinine ratio
Recheck films
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Check 25 OH Vit D at one year and then
annually
Pediatrics 2008;122:398-417
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Alk phos may increase initially due to
increased bone formation
Healing is usually complete by 4 months
Lack of response to treatment may indicate a
different etiology (or lack of adherence)
Once healed, continue a maintenance dose of
at least 600 IU vitamin D daily (often more)
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Cardiovascular disease, BMI, Insulin
resistance
Autoimmune disease
Cancers – breast, prostate, colon
Asthma
Schizophrenia, Mood disorders
Tuberculosis
Analogs used to treat psoriasis
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No established reference range in children
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2008 AAP Review > 20 ng/ml
IOM Report 2012 > 20 ng/ml
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Endocrine Society 2011 CPG
 Deficiency
< 20 ng/ml
 Insufficiency < 30 ng/ml
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Adequate dietary intake of calcium and
vitamin D
Adequate sunlight exposure
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Vitamin D supplementation (400 IU) for:
 Breast-fed or partially breast-fed infants
beginning in the first few days of life
 Infants receiving <1000 ml formula/day (33 oz)
 Older children/adolescents who don’t obtain 400
IU/day of Vit D through diet (milk, other foods)
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IOM Nov 2010 recommends 600 IU for
children and adolescents (RDA)
Pediatrics 2008;122:1142-1152
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Breastmilk
15-50 IU/L
 Vit D sufficient mother
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Infant formula
Prenatal vitamins
400 IU/L
400 IU
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Released Nov 2010
Supplementation for healthy infants,
children, and adults
Prevention
Not treatment recommendations
Assumed little to no sun exposure
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Infants (0-12 months) 400 IU
Children/Adolescents 600 IU
Adults (19-70 years)
600 IU
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Upper level intakes
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0-6 months
6-12 months
1-3 y/o
4-8 y/o
9-70 y/o
1000 IU
1500 IU
2500 IU
3000 IU
4000 IU
IOM Report Nov 2010
AGE
RDA
0-6 months
6-12 months
1-3 years
4-8 years
9-18 years
Adults 19-50
years
200 mg (AI)
260 mg (AI)
700 mg
1000 mg
1300 mg
1000 mg
UPPER INTAKE
LEVEL
1000 mg
1500 mg
2500 mg
2500 mg
3000 mg
2500 mg
IOM Report Nov 2010
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Fish oils (salmon, mackerel, sardines)
Cod liver oil
Liver and organ meats
Egg yolks
20-25 IU/yolk
Fortified milk/juice
400 IU/L
Fortified cereals
40 IU/serving
SOURCE
Milk (2%)
Plain low-fat yogurt
Cheese
Tofu
Sardines
Salmon
Spinach
Almonds
MG CALCIUM
285 Per cup
415 Per cup
220 Per oz
163 Per ¼ firm block
325 Per 3 oz
181 Per 3 oz
250 Per cup
126 Per 1/3 cup
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UVB 290-315 nm – highest at 1200 noon
(1000-1500)
Minimal Erythema Dose (MED, slight pink
skin) → 10,000-20,000 IU vitamin D
40% body to ¼ MED → approx 1000 IU
vitamin D
Pediatrics 2008;122:398-417
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Formulary Cholecalciferol = D3
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D-Vi-Sol® (400 IU/ml)
Poly-Vi-Sol® (400 IU/mL)
400 IU tab
1000 IU tab
OTC
 Most standard multivitamins (400 IU)
 Viactiv® chews (500 IU D3/chew)
 Many other OTC vitamin D supplements
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Calcium Carbonate – with food
 Oral suspension (500 mg/5 mL)
 500 mg tab
 600 mg/tab + 400 IU D3
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Calcium Citrate – absorbed with/without food
 200 mg tab
 Citracal® (315 mg/tab + 250 IU vit D3)
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Tums®
 Reg 500 mg/tab
 Extra Strength 750 mg/tab
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Viactiv® chews (500 mg + 500 IU vit D3)
 1α-hydroxylase deficiency
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Vitamin D receptor mutation
 Associated alopecia totalis
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X-linked hypophosphatemic rickets
Other inherited hypophosphatemic rickets
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Renal phosphate wasting
Defective 1α-hydroxylase activity in kidney
Due to PHEX mutation  increased levels of
FGF-23
X-linked dominant
Low serum phos, low/inappropriately normal
1,25-dihydroxyvitamin D
Treatment: phosphorous replacement,
calcitriol (Rocaltrol®)
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Prevention of vitamin D deficiency is key
Don’t forget about sunlight exposure
Supplement all breast-fed infants with 400 IU
vitamin D within the first few days
Vitamin D RDA 600 IU for children and
adolescents (IOM Report)
Vitamin D may be important for more than
just bone health
If rickets is not responding to vitamin D
treatment, consider other causes
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A 12 year old boy presents to your office for
follow-up after his third wrist fracture in 3
years. As part of his evaluation in the
emergency department, a complete
metabolic panel was obtained and revealed a
low calcium (7.5 mg/dL), low phosphorous
(2.8 mg/dL), normal magnesium (1.9 mg/dL),
and normal albumin (4 g/dL).
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With the exception of his fractures, the boy
has had no other medical problems and has
not been taking any long-term medications.
His height and weight are both at the 75th
percentile. His physical exam is
unremarkable except for his casted left wrist.
Of the following, the MOST appropriate next
step in this boy’s evaluation and
management is to measure:
A.
B.
C.
D.
E.
Ionized calcium
Serum 1,25-dihydroxyvitamin D
Serum 25-hydroxyvitamin D
Serum parathyroid hormone
Urine N-telopeptide
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A 14 y/o boy suffers a nondisplaced fracture
of his left radius and ulna while playing
soccer. He had a similar injury to his radius
and ulna 9 months ago. Physical exam reveals
SMR 2 pubic hair and testicular volume of 6
ml. A thorough review of his dietary history
suggests that his daily intake of calcium and
phosphorous are 800 mg each. He takes 400
IU of vitamin D supplement daily.
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Serum calcium measures 7.9 mg/dL, serum
phosphorous measures 2.7 mg/dL, and 25hydroxyvitamin D measures 55 ng/mL
(normal 30-80).
Of the following, the most appropriate
recommendation for this boy is to increase
his:
A.
B.
C.
D.
E.
Calcium and phosphorous intake to 1300
mg/day
Calcium and phosphorous intake to 2000
mg/day
Calcium intake to 1000 mg/day
Phosphorous intake to 1000 mg/day
Vitamin D supplementation to 2000 IU/day
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A 7-month-old child presents for a follow-up
visit after undergoing a Kasai procedure for
biliary atresia at 6 weeks of age. The mother
states that the boy is irritable when his right
arm is moved. On physical exam, the infant is
jaundiced. You detect tenderness in the
anterior radial head. Radiography of the
affected region demonstrates metaphyseal
fraying and a fracture.
The MOST appropriate laboratory studies to
obtain next are:
A. Calcium, phosphorous, bone densitometry
(DEXA scan)
B. Calcium, phosphorous, urinary calcium-tocreatinine ratio
C. Calcium, phosphorous, 25-hydroxyvitamin D
D. Calcium, phosphorous, magnesium
E. Magnesium, phosphorous, parathyroid
hormone
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You diagnose familial hypophosphatemic
rickets in a boy who presents with rickets and
whose mother had rickets as a child and
required osteotomies as an adult. You explain
to the parents that treatment can help the
boy reach normal height and lessen his
rachitic bone changes.
Of the following, the most appropriate
treatment is:
A.
B.
C.
D.
E.
Daily injections of human growth hormone
and oral calcium twice daily
Oral calcitriol once daily
Oral calcium twice daily with oral
cholecalciferol once daily
Oral neutral phosphate salts every 6 hours
with calcitriol once or twice daily
Oral neutral phosphate salts once daily
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* Misra M, Pacaud D, Petryk A, Collett-Solberg PF, Kappy M.
Vitamin d deficiency in children and its management: review of
current knowledge and recommendations. Pediatrics.
2008;122:398-417.
* Wagner CL, Greer FR. Prevention of rickets and vitamin d
deficiency in infants, children, and adolescents. Pediatrics.
2008;122:1142-1152.
Institute of Medicine Report on Dietary Reference Intakes for
Calcium and Vitamin D. Released 30 Nov 2010. Available at
http://books.nap.edu/openbook.php?record_id=13050.
Holick MF. Vitamin D deficiency. N Engl J Med. 2007;357:266-281.
Adams JS, Hewison M. Update in vitamin D. J Clin Endocrinol
Metab. 2010;95:471-478.
Carpenter TO et al. A clinician’s guide to X-linked
hypophosphatemia. JBMR. July 2011;26(7):1381-1388.