Rickets

LTC Karen S. VogtPediatric Endocrinology, WRNMMCBMarch 2013

PREP 2013 Content Specifications

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

PREP 2013 Content Specifications

Understand the mechanism of rickets in children with hepatic disease

Plan the treatment of a child with familial hypophosphatemic rickets

Outline

Case Nutritional rickets and Vitamin D

deficiecy Prevention Other types of rickets PREP Questions

Case

9 month old female presents in January for her well baby visit

History

Birth: C-section at 34 weeks for placental

abruption Required PRBC transfusion x2 PDA - closed after indomethacin x 1 18 day NICU stay

PMH: healthy

Immunizations: up-to-date

More History

Diet: exclusively breastfed until 6 months of age, now taking stage 2 baby foods and soft table foods

Meds: Poly-vi-sol in first 3 months of life, no current meds

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

History and Physical Exam

Family History: parents healthy, mom no longer taking prenatal vitamins, mom is Filipino, dad is half caucasian/half Filipino

Physical Exam : Unremarkable

Plan….

Weight check in one month

Mom comes back in 2 weeks for concern for difficulty feeding

Less appetite for solids than previously and no weight gain from well visit

Labs

TSH, CRP, Celiac Panel – unremarkable

Fecal fat, reducing substances and alpha-1-antitrypsin – normal

Sweat test – normal

CMP- Alk Phos 736 U/L(150-420) Calcium 9.2 mg/dl (8.7-

10.4) Albumin 4.0 g/dl (3.5-5)

Labs

CBC - WBC 12.6 Hgb 10.8 Hct 34.7 Plt 547 MCV 64.6 (70-86)

Pediatric Endocrinology Consult More History: Mom drinks no milk,

occasional cheese, doesn’t like yogurt

Infant light skinned and born in early spring

Minimal time in the sun per mom – spent most of summer indoors

PE: subtle wrist widening, slight concavity of lateral chest walls, mild generalized low tone

More Labs….

Alk Phos: 568 U/L (150-420)

Calcium: 8.8 mg/dl (8.7-10.4)

Albumin: 4.7 g/dl (3.5-5)

Corrected Ca: 8.24 mg/dl (8.7-10.4)

Phosphorus: 2.5 mg/dl (2.7-4.5)

PTH: 346.1 pg/ml (13-75)

25 OH Vit D: < 4.0 ng/ml

Diagnosis

Rickets due to vitamin D deficiency

Treatment: Ergocalciferol (Drisdol® 8000 IU/ml)

2000 IU daily Calcium carbonate 40 mg/kg/day div bid

Pediatrics Aug 2008:122:398-417

Rickets - Definition

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

Definitions

Osteomalacia – equivalent in mature bone

Contrast to osteoporosis Low bone mass due to decreased

mineralization and decreased bone matrix

Vitamin D Synthesis

Vitamin D - Sources

Dietary Ergocalciferol (D2) – plant source Cholecalciferol (D3) – animal source

UVB exposure Promotes conversion of 7-

dehydrocholesterol to cholecalciferol (D3) in the skin

Vitamin D Metabolism

Vitamin D is converted to 25(OH)D by 25-hydroxylase in the liver

25(OH)D A.k.a calcidiol Inactive form Reflects total body stores (2-3 week ½

life)

Vitamin D Metabolism

25(OH)D is converted to 1,25(OH)2 D by 1α-hydroxylase in the kidney

1,25-OH2 D A.k.a calcitriol Active form More tightly regulated (4-6 hour ½ life)

1α-hydroxylase (kidney)

Stimulated by PTH Low phosphorous levels

1,25-OH2 Vitamin D

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

Parathyroid Hormone (PTH) Actions: keep serum calcium normal

Bone – stimulates reabsorption Kidney:▪ Stimulates 1α-hydroxylase▪ Increases calcium reabsorption▪ Increases phosphate excretion

Stimulated by decreased serum calcium levels

Hypomagnesemia impairs its secretion

Alkaline Phosphatase

Produced by active osteoblasts, which form unmineralized matrix

Levels increase with increased osteoblast activity

Pathophysiology

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

Pathophysiology

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 Bones become “soft” and less rigid

Increasing Prevalence of Vitamin D Deficiency Rickets

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

Patient Risk Factors

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

Other Risk Factors – Vit D deficiency

Nutritional Dark skin Malabsorption Obesity (sequestration in body fat) Liver or kidney disease

Drugs

Anticonvulsants Glucocorticoids HIV medications Rifampin Isoniazide Ketoconazole

Clinical Presentation - Rickets 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

Frontal Bossing

Rachitic Rosary

Chest Deformity

Leg Bowing - genu varus

Wide Wrists

Wide Ankles

Physical Exam Findings

Poor growth or weight gain Delayed anterior fontanelle closure Teeth: delayed eruption, enamel

defects Generalized muscular

weakness/hypotonia

Radiographic Findings

Wrist and/or knee films usually Metaphyseal fraying, widening,

flaring, cupping Periosteum separated from the

diaphysis Generalized osteopenia

Associated Lab Findings

Iron deficiency anemia Renal Fanconi syndrome

Vitamin D Deficiency Screening Who?

Nonspecific symptoms: poor growth, gross motor 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 BMDPediatrics 2008;122:398-417

Vitamin D Deficiency Screening

How? Serum Alkaline Phosphatase (ALP) If elevated: 25 OH Vitamin D, PTH,

Calcium and Phosphorus Films: ▪ Wrist▪ Knee

Pediatrics 2008;122:398-417

Treatment of Vitamin D Insufficiency or Deficiency

< 1 month of age: 1000 IU/day

1-12 months of age: 1000-5000 IU/ day

> 12 months of age: >5000 IU/day

Teens/adults: 50,ooo IU/week x 8 weeks

Consider Stoss therapy if compliance a concern (100,000 – 600,000 IU over 1-5 days)

Pediatrics 2008;122:398-417

Vitamin D Preparations

Ergocalciferol = D2 (Drisdol®, Calciferol®) Drops (8000 IU/mL) Capsules (50,000 IU) Injection (500,000 IU) – no longer

available

Cholecalciferol = D3 Capsules (5000 IU)

What about Calcium??

Simultaneous calcium supplementation necessary

Concern for “Hungry Bone” hypocalcemia

30-75 mg/kg/day divided TID – elemental calcium

Symptomatic hypocalcemia requires parenteral calcium replacement

Calcitriol (Rocaltrol®) can help treat hypocalcemia associated with rickets but does NOT build up vitamin D stores

Pediatrics 2008;122:398-417

Treatment Caveats

Vitamin D is fat soluble so must not overtreat Hypercalcemia▪ Weakness▪ Polyuria▪ Nephrocalcinosis

Monitoring Therapy

1 Month: Calcium, Phosphorus, ALP

3 Months: Calcium, Phosphorus, ALP

PTH, 25 OH Vit D, Urine

calcium/creatinine ratio Recheck films

Check 25 OH Vit D at one year and then annually

Pediatrics 2008;122:398-417

Rickets Follow-up

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)

Reported Associations with Vit D Deficiency

Cardiovascular disease, BMI, Insulin resistance

Autoimmune disease Cancers – breast, prostate, colon Asthma Schizophrenia, Mood disorders Tuberculosis Analogs used to treat psoriasis

What is a normal 25(OH)D level?

No established reference range in children

2008 AAP Review > 20 ng/ml IOM Report 2012 > 20 ng/ml Endocrine Society 2011 CPG

Deficiency < 20 ng/ml Insufficiency < 30 ng/ml

Prevention

Adequate dietary intake of calcium and vitamin D

Adequate sunlight exposure

AAP Clinical Report (2008)

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)

IOM Nov 2010 recommends 600 IU for children and adolescents (RDA)

Pediatrics 2008;122:1142-1152

Vitamin D Content

Breastmilk 15-50 IU/L Vit D sufficient mother

Infant formula 400 IU/L Prenatal vitamins 400 IU

IOM Report: Dietary Reference Intakes for Calcium and Vitamin D

Released Nov 2010 Supplementation for healthy infants,

children, and adults Prevention Not treatment recommendations Assumed little to no sun exposure

IOM – Vitamin D RDA

Infants (0-12 months) 400 IUChildren/Adolescents 600 IU Adults (19-70 years) 600 IU

Upper level intakes 0-6 months 1000 IU 6-12 months 1500 IU 1-3 y/o 2500 IU 4-8 y/o 3000 IU 9-70 y/o 4000 IU

IOM Report Nov 2010

IOM – Calcium per Day

AGE RDA UPPER INTAKE LEVEL

0-6 months 200 mg (AI) 1000 mg6-12 months 260 mg (AI) 1500 mg1-3 years 700 mg 2500 mg4-8 years 1000 mg 2500 mg9-18 years 1300 mg 3000 mgAdults 19-50 years

1000 mg 2500 mg

IOM Report Nov 2010

Dietary Sources of Vitamin D 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

Dietary Sources of CalciumSOURCE MG CALCIUMMilk (2%) 285 Per cupPlain low-fat yogurt 415 Per cupCheese 220 Per ozTofu 163 Per ¼ firm blockSardines 325 Per 3 ozSalmon 181 Per 3 ozSpinach 250 Per cupAlmonds 126 Per 1/3 cup

Sunlight Exposure – Vit D

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

Vitamin D Preparations

Formulary Cholecalciferol = D3 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

Calcium Preparations - Formulary

Calcium Carbonate – with food Oral suspension (500 mg/5 mL) 500 mg tab 600 mg/tab + 400 IU D3

Calcium Citrate – absorbed with/without food 200 mg tab Citracal® (315 mg/tab + 250 IU vit D3)

Calcium Preparations

Tums® Reg 500 mg/tab Extra Strength 750 mg/tab

Viactiv® chews (500 mg + 500 IU vit D3)

Other Types of Rickets

1α-hydroxylase deficiency Vitamin D receptor mutation

Associated alopecia totalis X-linked hypophosphatemic rickets Other inherited hypophosphatemic

rickets

X-linked Hypophosphatemic Rickets

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®)

Key Points - Vitamin D

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

PREP Question 1

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).

PREP Question 1

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:

PREP Question 1

A. Ionized calciumB. Serum 1,25-dihydroxyvitamin DC. Serum 25-hydroxyvitamin DD. Serum parathyroid hormoneE. Urine N-telopeptide

PREP Question 2

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.

PREP Question 2

Serum calcium measures 7.9 mg/dL, serum phosphorous measures 2.7 mg/dL, and 25-hydroxyvitamin D measures 55 ng/mL (normal 30-80).

Of the following, the most appropriate recommendation for this boy is to increase his:

PREP Question 2

A. Calcium and phosphorous intake to 1300 mg/day

B. Calcium and phosphorous intake to 2000 mg/day

C. Calcium intake to 1000 mg/dayD. Phosphorous intake to 1000 mg/dayE. Vitamin D supplementation to 2000

IU/day

PREP Question 3

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.

PREP Question 3

The MOST appropriate laboratory studies to obtain next are:

A. Calcium, phosphorous, bone densitometry (DEXA scan)

B. Calcium, phosphorous, urinary calcium-to-creatinine ratio

C. Calcium, phosphorous, 25-hydroxyvitamin D

D. Calcium, phosphorous, magnesiumE. Magnesium, phosphorous, parathyroid

hormone

PREP Question 4

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:

PREP Question 4

A. Daily injections of human growth hormone and oral calcium twice daily

B. Oral calcitriol once dailyC. Oral calcium twice daily with oral

cholecalciferol once dailyD. Oral neutral phosphate salts every

6 hours with calcitriol once or twice daily

E. Oral neutral phosphate salts once daily

References

* 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.