Vitamin D deficiency in children – 6 Interesting Facts

How common is Vitamin D deficiency in children

Interesting Facts

1. Threshold levels to define vitamin D deficiency vary by professional society but most set 20 ng/mL as cutoff for deficiency
2. 95% of cases of vitamin D deficiency are due to deficient dietary intake of cholecalciferol (D₃)/ergocalciferol(D₂), or deficient cutaneous synthesis of cholecalciferol
3. Severe and longstanding deficiency can present with hypocalcemia or physical signs suggestive of rickets, such as:
   • Short stature/delayed growth
   • Thickened wrists and ankles
   • Long bone bowing
   • Rachitic rosary (beading of the ribs)
   • Pectus carinatum (highly prominent sternum)
4. Serum 25-hydroxyvitamin D level test is the gold standard and definitive
5. Vitamin D replacement therapy on a daily or weekly regimen is appropriate for all cases of vitamin D deficiency
   • When levels are back to within reference range, replacement dose may be lowered to a maintenance dose
6. Prognosis is favorable; most children treated for vitamin D deficiency achieve reference-range levels of 25-hydroxyvitamin D with standard therapy and do not develop complications
7. Especially in black infants and breastfed infants, vitamin D malabsorption problems may occur
8. Bone pain, bowing of legs, and osteoporosis
9. Low serum 25-hydroxyvitamin D level, secondarily elevated parathyroid hormone level

Pitfalls

• Measuring the concentration of 1,25-dihydroxyvitamin D instead of 25-hydroxyvitamin D for assessment of vitamin D status can lead to erroneous conclusions because 1,25-dihydroxyvitamin D concentrations will be within reference range or even elevated in the face of vitamin D deficiency as a result of secondary hyperparathyroidism
• Diagnosis of vitamin D deficiency can be missed since mild to moderate vitamin D deficiency is often asymptomatic and lacks physical signs
• Vitamin D requirements cannot ordinarily be met by human milk alone; infants should receive 400 international units per day of supplemental vitamin D, regardless of mode of feeding, but this is especially important for breastfed infants ¹

Urgent Action

• Hypocalcemia due to reduced vitamin D–dependent calcium absorption can be life-threatening and requires prompt treatment, including calcium supplementation
  • IV calcium is necessary for signs of severe neuromuscular irritability, such as hypocalcemic tetany

Terminology

Clinical Clarification

• Vitamin D deficiency is a condition caused by low circulating levels of vitamin D ²
  • Also called hypovitaminosis D
• Serum concentration that constitutes vitamin D deficiency is controversial, especially in the pediatric population
  • Threshold levels to define vitamin D deficiency vary by professional society but most set 20 ng/mL as cutoff for deficiency ³
• Physiology
  • Vitamin D is an essential steroid hormone that exists in the body as multiple forms
    • 25-hydroxycholecalciferol (calcidiol) and 1,25-dihydroxycholecalciferol (calcitriol) are the main forms
  • Vitamin D can be obtained from any of the following:
    • Dietary sources of vegetable origin (vitamin D₂ or ergocalciferol)
    • Dietary sources of animal origin (vitamin D₃ or cholecalciferol)
    • Through conversion of 7-dehydrocholesterol, synthesized in the skin, into cholecalciferol (vitamin D₃) by UV-B exposure
      • Vitamin D that comes from the skin or diet is biologically inert and requires 2 hydroxylation steps to become active
  • In the liver, cholecalciferol is converted into 25-hydroxyvitamin D
    • 25-hydroxyvitamin D concentration depends on nutritional supply or synthesis in the skin after exposure to UV-B light
  • In the kidney, 25-hydroxyvitamin D is converted to 1,25-dihydroxyvitamin D
  • 1,25-dihydroxyvitamin D is considered to be the biologically active form, and its concentration is highly regulated
  • Units for 25-hydroxyvitamin D levels are expressed as ng/mL or nmol/L; the conversion between them is [nmol/L] = 2.5 * [ng/mL]

Classification

• Vitamin D deficiency is classified by some professional societies based on severity, which are variably categorized and used

	Institute of Medicine	Endocrine Society	American Academy of Pediatrics	Society for Adolescent Health and Medicine	Multinational Consensus Expert Panel on Rickets
Vitamin D deficiency	Less than 20 ng/mL	Less than 20 ng/mL	Less than 15 ng/mL	Less than 20 ng/mL	Less than 12 ng/mL
Severe vitamin D deficiency			Less than 5 ng/mL
Mild to moderate vitamin D deficiency			5-15 ng/mL
Vitamin D insufficiency		21-29 ng/mL	16-20 ng/mL	20-29 ng/mL	12-20 ng/mL
Vitamin D sufficiency		30 ng/mL or greater	21 ng/mL or greater	30 ng/mL or greater	20 ng/mL or greater

• Vitamin D deficiency
  • 25-hydroxyvitamin D less than 20 ng/mL: Institute of Medicine, ⁴ Endocrine Society, ⁵ and Society for Adolescent Health and Medicine ⁶
  • 25-hydroxyvitamin D less than 15 ng/mL: American Academy of Pediatrics
  • 25-hydroxyvitamin D less than 12 ng/mL: Multinational Consensus Expert Panel on Rickets
• Deficiency severity classifications
  • Severe deficiency
    • 25-hydroxyvitamin D less than 5 ng/mL: American Academy of Pediatrics ^8 7
  • Mild to moderate deficiency
    • 25-hydroxyvitamin D 5 to 15 ng/mL: American Academy of Pediatrics ^8 7
• Vitamin D insufficiency is a range of vitamin D levels between overt deficiency and the point at which parathyroid hormone levels approach or reach reference range; insufficiency classifications: ³
  • 25-hydroxyvitamin D 12 to 20 ng/mL: Multinational Consensus Expert Panel on Rickets ¹
  • 25-hydroxyvitamin D 16 to 20 ng/mL: American Academy of Pediatrics ⁷
  • 25-hydroxyvitamin D 21 to 29 ng/mL: Endocrine Society ⁵

Diagnosis

Clinical Presentation

• From Christakos S et al: Vitamin D: metabolism. Endocrinol Metab Clin North Am. 39(2):243-53, 2010, Figure 1.The metabolic pathway for vitamin D.

History

• Mild to moderate vitamin D deficiency is asymptomatic
• Severe and/or long-standing (months to years) vitamin D deficiency can produce the following: ⁹
  • Symptomatic hypocalcemia, manifested by:
    • Irritability
    • Nervousness
    • Jitteriness
    • Malaise or lethargy
    • Anorexia, poor feeding, and/or vomiting
    • Seizures (most common presentation in neonates) ¹⁰
  • Musculoskeletal complications, such as:
    • Current and/or history of myalgia or ostealgia ⁷
    • Bony deformities and stunted growth, characteristic of rickets ¹⁰
    • Nontraumatic or minimally traumatic fractures in rickets

Physical examination ¹

• Signs of hypocalcemia occur primarily with severe vitamin D deficiency
  • Fasciculations and/or tremors
  • Carpopedal spasm
  • Tetany
  • Laryngeal stridor
  • Seizure
• Skeletal signs suggestive of rickets that can occur with severe vitamin D deficiency include:
  • Slowing linear growth
  • Metaphyseal swelling at long bone ends
  • Genu varum: outward bowing of the lower legs (most common skeletal deformity in infants with untreated rickets)
  • Genu valgum: knock knees (develops at later age than genu varum)
  • Rachitic rosary (beading of the ribs)
  • Pectus carinatum (highly prominent sternum)
  • Delayed closure of the fontanelles
  • Parietal and frontal bossing
  • Craniotabes
• Nonskeletal signs suggestive of rickets, which can occur with severe vitamin D deficiency, include: ¹⁰
  • Hypotonia
  • Delayed motor milestones
  • Enamel hypoplasia and delayed dentition
  • Failure to thrive
  • Irritability in a young child

Causes and Risk Factors

Causes

• Deficient dietary intake of cholecalciferol (D₃)/ergocalciferol(D₂) or deficient cutaneous synthesis of cholecalciferol (represents approximately 95% of cases ¹¹)
  • Malnutrition
  • Simple inadequate intake as a result of exclusive breastfeeding or insufficient consumption of vitamin D–fortified dairy products
  • Deficient cutaneous synthesis of 25-hydroxyvitamin D is caused by inadequate sunlight (UV-B) exposure
• Conditions affecting intestinal absorption ¹² (approximately 5% of cases ¹¹):
  • Whipple disease
  • Cystic fibrosis
  • Celiac disease
  • Parenchymal or cholestatic liver disease
  • Inflammatory bowel disease
• Drugs that affect the absorption, metabolism, or activation of vitamin D (less than 1% of cases ¹¹):
  • Glucocorticoids ¹²
  • Rifampin ¹²
  • Highly active antiretroviral therapy ¹²
  • Antiepileptic drugs ⁷

Risk factors and/or associations

Genetics

• Hereditary vitamin D–dependent rickets (rare inherited disorders)
  • Vitamin D–dependent rickets type 1A (OMIM #264700) ¹³ results from defects in the CYP27B1 gene, coding for 25-hydroxyvitamin D₃–1α-hydroxylase
  • Vitamin D–dependent rickets type 1B (OMIM #600081) ¹⁴ results from defects in the CYP2R1 gene, coding for 25-hydroxylase
  • Vitamin D–dependent rickets type 2 (OMIM #277440) ¹⁵ results from defects in the VDR gene, coding for the vitamin D receptor

Ethnicity/race

• Ethnicities with dark pigmentation (nonwhite) are at higher risk ¹⁶
  • Melanin absorbs UV-B radiation and reduces vitamin D₃ synthesis ¹⁷
  • Require longer sun exposure than people with white skin to synthesize the same amount of vitamin D₃ ¹⁷

Other risk factors/associations

• Factors reducing exposure of skin to solar UV-B
  • Overzealous use of sunscreen with sun protection factor 30 or higher: reduces biosynthesis of vitamin D₃ by more than 95% ⁵
  • Living in high-latitude areas (latitude higher than 40° north or south) ¹⁸
  • Cultural practices that encourage covering most or all skin ¹²
• Prolonged and exclusive breastfeeding ¹
  • Breast milk is a poor source of vitamin D, and the amount contained is insufficient on its own to prevent deficiency in an infant, unless the mother is taking high doses (4000 international units daily) of vitamin D supplements
  • Infants breastfed from vitamin D–replete mothers will have vitamin D levels below reference range after 8 weeks of exclusive breastfeeding ¹⁹
• Eating disorders (eg, bulimia nervosa, anorexia nervosa)
• Picky eating in which children exclude milk and milk products, eggs, and other dietary sources of vitamin D
• Lactose intolerance causing avoidance of milk
  • Not all milk substitutes (eg, soy milk, almond milk, rice milk) are fortified with vitamin D
• Chronic kidney disease ⁷

Diagnostic Procedures

Primary diagnostic tools

• History (including sun exposure, vitamin D and calcium intake, and medication information) and presence of risk factors suggest vitamin D deficiency ¹
  • Physical examination is generally only valuable in moderate to severe cases, when physical signs of hypocalcemia or skeletal abnormalities are found ¹
• Formal diagnosis is made by laboratory testing of vitamin D levels ⁵
  • Vitamin D levels should be obtained in children with:
    • Hypocalcemia
    • Radiographic evidence of rickets or
    • At risk for vitamin D deficiency, which includes
      • Exclusively breastfed or premature infants
      • Dark-skinned infants and children
      • Children on medications that compromise vitamin D concentrations
        • Azole antifungals, corticosteroids, or cytochrome P450 3A4 inducers
        • Highly active antiretroviral therapy
        • Anticonvulsant drugs such as phenytoin, carbamazepine, oxcarbazepine, and phenobarbital
      • Children with chronic conditions such as chronic kidney disease, HIV/AIDS, cystic fibrosis, and other diseases that affect vitamin D metabolism or nutrient absorption
      • Children who reside in areas with limited-sun exposure (high latitude areas)
      • Obese children
  • 25-hydroxyvitamin D level is the gold standard and definitive test for vitamin D deficiency
  • Parathyroid hormone, serum calcium, serum phosphate, and alkaline phosphatase activity values are useful for differentiating simple deficiency of vitamin D intake or sunlight from vitamin D–resistant rickets
• Diagnosis of nutritional rickets is suspected on the basis of history, physical examination, and biochemical testing, and is confirmed by radiographs ¹
  • Typical laboratory findings
    • Low 25-hydroxyvitamin D, serum phosphorus, and urinary calcium levels
    • Low or low–reference range serum calcium level
    • Elevated serum parathyroid hormone and alkaline phosphatase levels

Laboratory

• Vitamin D levels
  • Serum 25-hydroxyvitamin D (calcidiol) level
    • Most important test for vitamin D deficiency, reflecting long-term stores of the hormone ⁷
    • Threshold levels to define vitamin D deficiency
      • 25-hydroxyvitamin D level less than 15 ng/mL, per the American Academy of Pediatrics ⁷
      • 25-hydroxyvitamin D level less than 20 ng/mL, per the Institute of Medicine ⁴ and Endocrine Society ⁵
  • Serum 1,25-dihydroxyvitamin D (calcitriol) level
    • Indicated only in cases evaluating for and monitoring certain conditions, such as inherited disorders of vitamin D metabolism ²⁰
    • Elevated in hereditary vitamin D–resistant rickets ²¹
    • Low in vitamin D–dependent rickets type 1A (1α-hydroxylase deficiency) ²¹
    • Measuring the concentration of 1,25-dihydroxyvitamin D instead of 25-hydroxyvitamin D for assessment of vitamin D status can lead to erroneous conclusions because 1,25-dihydroxyvitamin D concentrations will be within reference range or even elevated in the presence of vitamin D deficiency as a result of secondary hyperparathyroidism
• Serum calcium, phosphate, parathyroid hormone, and alkaline phosphatase levels
  • This set of tests can support a diagnosis of vitamin D deficiency or distinguish from other abnormalities of calcium and phosphorus metabolism ⁷
  • Serum calcium level ⁷
    • Most often at reference range in mild cases, but can be slightly decreased
    • Notable decreases in calcium generally occur only in severe cases
  • Serum phosphorus level
    • Test result serves as supporting information
    • Will be low with vitamin D deficiency
  • Serum parathyroid hormone level ²²
    • Inverse association between calcium level and parathyroid hormone level: parathyroid hormone begins rising as 25-hydroxyvitamin D falls below 30 ng/mL (before calcium levels become below reference range)
    • High parathyroid hormone levels reflect secondary hyperparathyroidism, resulting from vitamin D deficiency
    • Low parathyroid hormone levels occur in phosphopenic causes of rickets
  • Alkaline phosphatase level ²³
    • Result serves as supporting information
    • As serum 25-hydroxyvitamin D level decreases, alkaline phosphatase level increases, indicating bone resorption
• Biochemical findings in various disorders of vitamin D and calcium.Calcium levelPhosphorus levelParathyroid hormone level25-hydroxyvitamin D level1,25-dihydroxyvitamin D levelVitamin D deficiencyMild to normal, moderate, or severe to lowLowHighLowNormal or highVitamin D–dependent rickets type 1A (1α-hydroxylase deficiency)LowLowHighNormal or highVery lowVitamin D–dependent rickets type 1B (25-hydroxylase deficiency)LowLowHighVery lowVariableVitamin D–dependent rickets type 2 (vitamin D receptor defects)LowLowHighNormal or highHighHypophosphatemic rickets (X-linked)NormalVery lowNormal or slightly highNormal or lowLowHypophosphatemic rickets with hypercalciuriaNormalLowNormal or lowNormalHigh View full sizeCitation: Data from Elder CJ et al: Rickets. Lancet. 383(9929):1665-75, 2014.

Imaging

• Plain film radiography ¹
  • Used to assess skeletal complications of severe vitamin D deficiency and required to document skeletal abnormalities to assign a formal diagnosis of rickets
  • Imaging areas should include long bones with views at the knee and wrist (distal ulna), which are the sites where rickets initially manifests
    • Widening of the epiphyseal plate and loss of definition of the zone of calcification at the epiphyseal/metaphyseal interface are the earliest radiographic signs of rickets
  • Skeletal features characteristic of advanced rickets
    • Minimal-trauma fractures
    • Pelvic deformities including outlet narrowing (indicates risk of obstructed labor and death)
    • Rachitic rosary on anterior rib ends
    • Angular deformities in arm and leg bones
    • Splaying, fraying, cupping, and coarse trabecular pattern of metaphyses

Differential Diagnosis

Most common

• Calcium deficiency (without vitamin D deficiency) due to inadequate dietary calcium ²⁴
  • Typical scenario for this is a child who avoids milk products but gets plenty of sunlight exposure and/or eats egg yolks, fish, or liver
  • Similarities with vitamin D deficiency
    • Severe cases can also present with features of rickets ²⁵
  • Distinguished from vitamin D deficiency on the basis of laboratory testing
    • 25-hydroxyvitamin D level is at reference range if it is an isolated calcium deficiency without deficiency of vitamin D
  • Definitive diagnosis is established by serum calcium and 25-hydroxyvitamin D levels
• Hereditary resistance to vitamin D ¹⁵(OMIM #277440)
  • Rare autosomal recessive condition of vitamin D resistance that results from abnormalities in the VDR gene, which encodes the vitamin D receptor
  • Presents with rickets and alopecia within the first 2 years of life
  • Distinguished from vitamin D deficiency by 25-hydroxyvitamin D level being within reference range or high, and by the massive doses of calcitriol and calcium required to normalize serum calcium
  • Definitive diagnosis is made by genetic testing
• Hypophosphatemic rickets (2 forms) ¹⁰
  • Inherited disorders that present with rickets due to renal phosphate wasting
  • Can have a similar phenotype to severe vitamin D deficiency (bowed legs)
  • Distinguished from vitamin D deficiency–associated rickets on the basis of biochemical findings, which show 25-hydroxyvitamin D levels within reference range to low, low serum phosphorus level, and increased urinary phosphate excretion
  • X-linked hypophosphatemic rickets ²⁶
    • Caused by mutations in PHEX gene
    • Presents with short stature, leg bowing, and dental abnormalities
    • Serum FGF23 level is high and urine phosphate level is very high
  • Hypophosphatemic rickets with hypercalciuria ²⁶
    • Rare autosomal recessive disorder due to loss of function mutations in a renal sodium phosphate transporter
    • Presents with bone pain and muscular weakness
    • Serum 1,25 dihydroxyvitamin D level is elevated and FGF23 level is within reference range

Treatment

Goals

• Restore serum 25-hydroxyvitamin D to level greater than 30 ng/mL ⁷
• Treat symptoms of severe hypocalcemia (eg, seizure, tetany) if present ⁷
• Prevent complications, such as osteopenia, osteoporosis, and rickets ²⁷

Disposition

Admission criteria

• Admission is warranted in patients with symptomatic hypocalcemia manifesting with tetany ²⁸

Recommendations for specialist referral

• Gastroenterologist ⁵
  • Indicated for work-up for malabsorption (such as in Crohn disease, celiac disease, or cystic fibrosis with a gastrointestinal component) for a patient who is vitamin D deficient despite plentiful dietary vitamin D, calcium, and sunlight exposure
• Endocrinologist ²⁹
  • Indicated in any of the following settings:
    • Deficiency is established with absence of known risk factors
    • Atypical biochemistry, such as persistent hypophosphatemia or elevated creatinine level
    • Family history of rickets
    • Infants younger than 1 month with hypocalcemia (owing to seizure risk)
      • In this situation, mothers should be referred to internists for determination of vitamin D status
    • Failure to normalize vitamin D levels after 8 to 12 weeks of initial treatment

Treatment Options

Vitamin D replacement therapy on a daily or weekly regimen is appropriate for all cases of vitamin D deficiency ⁵

• Efficacy of vitamin D₂ and vitamin D₃ are equivalent when given on a daily basis ⁵
  • Most professional society (eg, Endocrine Society) guidelines do not state a preference between vitamin D₂ and vitamin D₃ ⁵

Calcitriol (1,25-dihydroxyvitamin D) is reserved for special cases, such as: ⁷

• 1α-hydroxylase deficiency (inability to convert 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D)
• Patients requiring emergency increase of 1,25-dihydroxyvitamin D activity to boost serum calcium level

Key points on vitamin D supplementation ⁵

• Vitamin D requirements cannot ordinarily be met by human milk alone
• Vitamin D supplementation is recommended in all infants
• Breastfed infants should receive vitamin D supplementation beginning in the first 3 to 5 days of life ³⁰
• Preterm infants require higher doses (400-800 international units/day)
• Children who are obese or who are on anticonvulsant medications, glucocorticoids, or antifungals should receive at least 2 to 3 times more vitamin D
• For simple vitamin D deficiency, treatment doses should be continued until 25-hydroxyvitamin D levels normalize; thereafter, use maintenance doses ¹
• For vitamin D deficiency accompanied by nutritional rickets, treatment doses should continue until vitamin D levels normalize and radiographic changes are evident, for a minimum of 3 months; some children may require longer treatment duration ¹
• If parathyroid hormone levels are elevated add elemental calcium

Drug therapy

• Vitamin D₂ (ergocalciferol) ⁵
  • Dosage for treating deficiency
    • Vitamin D (Ergocalciferol) Oral drops, solution; Neonates: 25 mcg (1000 International Units) PO once daily has been recommended to treat deficiency. Treatment may continue for 2—3 months to replete deficient stores. Individualize dose based upon 25(OH)D concentrations.
    • Vitamin D (Ergocalciferol) Oral drops, solution; Infants: 25—125 mcg (1000—5000 International Units) PO once daily has been recommended to treat deficiency. One study demonstrated that 2000 IU/day PO OR 50,000 IU PO once weekly resulted in equivalent outcomes in the short-term treatment of hypovitaminosis D among otherwise healthy infants >= 8 months, and appeared to be safe. Treatment may continue for 2—3 months to replete deficient stores, followed by maintenance dosing in accordance with RDAs. Individualize dose based upon 25(OH)D concentrations.
    • Vitamin D (Ergocalciferol) Oral capsule; Children and Adolescents: At least 125 mcg (5000 International Units) PO once daily has been recommended to treat deficiency. High doses have been used: 225—250 mcg/day (9000—10,000 IU/day) or 5—7 mcg/kg/day (200—280 IU/kg/day) PO. Also, weekly regimens (with higher doses once weekly or as a single course over 1—5 days) are occasionally used if compliance is an issue that prevents adequate repletion. One study demonstrated that 2000 IU/day PO OR 50,000 IU PO once weekly resulted in equivalent outcomes in the short-term treatment of hypovitaminosis D among otherwise healthy toddlers 12—24 months of age, and appeared to be safe. Treatment may continue for 2—3 months to replete deficient stores, followed by maintenance dosing in accordance with RDAs. Individualize dose based upon 25(OH)D concentrations.
• Vitamin D₃ (cholecalciferol) ⁵
  • Acceptable alternative to vitamin D₂
    • Vitamin D (Cholecalciferol) Oral solution; Neonates: 25 mcg (1,000 International Units) PO once daily has been recommended to treat deficiency. Treatment may continue for 2 to 3 months to replete deficient stores, followed by maintenance dosing in accordance with RDAs. Individualize dose based upon 25(OH)D concentrations.
    • Vitamin D (Cholecalciferol) Oral solution; Infants: 25 to 125 mcg (1,000 to 5,000 International Units) PO once daily has been recommended to treat deficiency. One study demonstrated that 2,000 International Units/day PO OR 50,000 International Units PO once weekly resulted in equivalent outcomes in the short-term treatment of hypovitaminosis D among otherwise healthy infants 8 months of age and older, and appeared to be safe. Treatment may continue for 2 to 3 months to replete deficient stores, followed by maintenance dosing in accordance with RDAs. Individualize dose based upon 25(OH)D concentrations.
    • Vitamin D (Cholecalciferol) Oral capsule; Children and Adolescents: At least 125 mcg (5,000 International Units) PO once daily has been recommended to treat deficiency. High doses have been used: 225 to 250 mcg/day (9,000 to 10,000 International Units/day) or 5 to 7 mcg/kg/day (200 to 280 International Units/kg/day) PO. Also, weekly regimens (with high doses once weekly or as a single course over 1 to 5 days) are occasionally used if compliance is an issue that prevents adequate repletion. One study demonstrated that 2,000 International Units/day PO OR 50,000 International Units PO once weekly resulted in equivalent outcomes in the short-term treatment of hypovitaminosis D among otherwise healthy toddlers 12 to 24 months of age, and appeared to be safe. Treatment may continue for 2 to 3 months to replete deficient stores, followed by maintenance dosing in accordance with RDAs. Individualize dose based upon 25(OH)D concentrations.
• Calcitriol (1,25-dihydroxyvitamin D)
  • Indicated for patients with chronic kidney disease (stages 2-3) or genetic deficiency of 1-α hydroxylase ⁷
  • Also indicated for patients with severe symptomatic hypocalcemia, presenting with seizure and/or tetany ⁷
  • Calcitriol Oral solution; Infants, Children, and Adolescents: 0.05 mcg/kg/day PO (Max: 0.5 mcg/day) until calcium levels normalize; give with calcium.

Nondrug and supportive care

• Nutritional counseling
  • Dietary sources of vitamin D₃ include:
    • Fatty fish, such as salmon, mackerel, and tuna
    • Beef liver, cheese, and egg yolks
  • Dietary sources of vitamin D₂ include:
    • Mushrooms
    • Phytoplankton
  • In the United States, milk and infant formula are fortified with either vitamin D₂ or D₃, depending on the particular brand ³¹

Comorbidities

• Vitamin D deficiency is often accompanied by other micronutrient deficiencies, especially other fat-soluble vitamins (particularly vitamin A and K) and calcium ³²
• Vitamin D deficiency is associated with autoimmune diseases, such as: ³³
  • Type 1 diabetes mellitus
  • Multiple sclerosis
  • Rheumatoid arthritis
  • Juvenile systemic lupus erythematosus

Special populations

• Chronic kidney disease ⁷
  • Vitamin D supplementation at 400 international units/day is standard care, but those with 25-hydroxyvitamin D level less than 30 ng/mL should receive vitamin D replacement therapy; dose based on levels as follows:
    • 25-hydroxyvitamin D level less than 5 ng/mL: Vitamin D₂ (ergocalciferol), initial 8,000 international units/day PO or 50,000 international units/week PO x 4 weeks, then 4,000 international units/day PO or 50,000 international units PO every 2 weeks x 2 months.
    • 25-hydroxyvitamin D level 5 to 15 ng/mL: Vitamin D₂ (ergocalciferol) 4,000 international units/day PO, or 50,000 international units PO every 2 weeks x 3 months.
    • 25-hydroxyvitamin D level 16 to 30 ng/mL: Vitamin D₂ (ergocalciferol) 2,000 international units PO daily, or 50,000 international units PO every 4 weeks x 3 months.
  • Resume maintenance dose of 400 international units/day once 25-hydroxyvitamin D level reaches 30 ng/mL
  • Daily doses are preferred but vitamin D can also be administered as a single oral dose of 50,000 international units once a month
  • Measure 25-hydroxyvitamin D levels after the first 3 months of therapy to assess the need for further treatment; when it is adequate, check annually
  • Assess serum corrected calcium concentrations and phosphorus level at 1 month and then every 3 months
  • If total serum corrected calcium level exceeds 10.2 mg/dL or if serum phosphate level exceeds the upper limit for age and 25-hydroxyvitamin D levels are within reference range, vitamin D may be discontinued
  • Calcitriol has utility in children with chronic kidney disease stages 2 through 5 for the treatment of secondary hyperparathyroidism
    • As kidney function continues to decline, the enzyme activity of 1α-hydroxylase decreases; therefore, calcitriol preparations may be needed rather than vitamin D₂ or D₃ preparations
• Cystic fibrosis
  • Maintaining optimal vitamin D stores in this population is especially important because severe bone disease may exclude these individuals from being qualified for lung transplant
  • Vitamin D₃ supplements should be given to maintain 25-hydroxyvitamin D concentrations; 30 ng/mL or greater ³⁴ is standard (Cystic Fibrosis Foundation Consensus Conference on Bone Health Guidelines), but 35 ng/mL can be used as cutoff level when parathyroid hormone is less than 50 pg/mL ³⁵
  • Doses up to 50,000 international units of vitamin D₃ PO daily for several months may be necessary for initial treatment ⁷
  • Maintenance therapy ³⁴
    • Infants aged up to 1 year: 400 to 500 international units vitamin D₃ PO daily.
    • Children aged 1 to 10 years: 800 to 1,000 international units vitamin D₃ PO daily.
    • Children older than 10 years: 800 to 2,000 international units vitamin D₃ PO daily.
  • Treatment doses vary depending upon child’s age and degree of vitamin D deficiency (based on the existing vitamin D level) ³⁴ and are available through the Cystic Fibrosis Foundation website ³⁶

Age	Calcium recommended dietary allowance (mg/day)	Vitamin D recommended dietary allowance for prevention (international units/day)	Prevention if risk factors for deficiency are present (international units/day)	Daily treatment doses for vitamin D deficiency (international units/day)	Alternate weekly treatment doses for vitamin D deficiency (international units/week)
Neonates	200	400	400-1000	1000	50,000
1-6 months	200	400	400-1000	1000-2000	50,000
6-12 months	260	400	400-1000	2000	50,000
1-3 years	700	600	600-1000	2000	50,000
4-8 years	1000	600	600-1000	2000	50,000
9-13 years	1300	600	600-1000	2000	50,000
14-18 years	1300	600	600-1000	2000	50,000

 View full size

Caption: May use either vitamin D2 or vitamin D3; treatment continued until there is normalization of vitamin D level and radiographic changes are evident (usually 6-8 weeks); if parathyroid hormone level is elevated, add elemental calcium 30 to 75 mg/kg per day divided in 3 doses.

Citation: Data from Munns CF et al: Global Consensus Recommendations on Prevention and Management of Nutritional Rickets. Horm Res Paediatr. 85(2):83-106, 2016; and Holick MF et al: Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 96(7):1911-30, 2011.

Monitoring

• For simple vitamin D deficiency, measure 25-hydroxyvitamin D level 1 and 3 months after beginning therapy
• For rickets due to vitamin D deficiency
  • Monitor serum calcium and phosphorus levels weekly
  • Measure 25-hydroxyvitamin D level after 2 to 3 months
  • Repeat skeletal radiography to assess healing response after 2 to 3 months
• In patients with chronic kidney disease treated for vitamin D deficiency ⁷
  • Measure 25-hydroxyvitamin D level after first 3 months of therapy to assess the need for further treatment; once adequate, measure annually
  • Serum corrected calcium concentrations and phosphorous concentrations should be assessed at 1 month and every 3 months

Complications and Prognosis

Complications

• Nutritional rickets, caused by vitamin D deficiency
  • Phosphaturia caused by secondary hyperparathyroidism results in a low–reference range or low serum phosphorus level
  • Consequently, an inadequate calcium-phosphorus product causes abnormal chondrocyte differentiation, defective mineralization of the growth plate, and defective osteoid mineralization ³⁷
  • In young children who have little mineral in their skeleton, this defect results in a variety of skeletal deformities classically known as rickets ⁷
    • Skeletal deformities include: ¹⁸
      • Scoliosis
      • Long bone bowing
      • Rachitic rosary (beading of the ribs)
      • Pectus carinatum
      • Thickened wrists and ankles
  • Can lead to any of the following:
    • Respiratory complications:
      • Obstruction and lower respiratory infections due to weakened thoracic wall ⁵
      • Pneumonia in infants ²¹
    • Risk of fracture
      • Children with radiographically confirmed rickets have an increased risk of fracture ¹
  • Infants and children are at risk with 25-hydroxyvitamin D levels lower than 10 ng/mL, particularly if calcium intake is insufficient (300-500 mg/day) or deficient (less than 300 mg/day) ¹
• Other skeletal defects
  • Untreated subclinical vitamin D deficiency affects bone acquisition, beginning in utero and extending into adolescence ³⁸
    • Osteopenia and osteoporosis ³⁹
      • Decrease in the efficiency of intestinal calcium and phosphorus absorption of dietary calcium and phosphorus, resulting in increase of parathyroid hormone levels
      • Secondary hyperparathyroidism maintains serum calcium within reference range at the expense of mobilizing calcium from the skeleton and increasing phosphorus wasting in the kidneys
      • Parathyroid hormone–mediated increase in osteoclastic activity creates local foci of bone weakness and causes a generalized decrease in bone mineral density
    • Fractures ²⁷
      • Risk of fracture is elevated in older children and adolescents with vitamin D deficiency
      • Risk of fracture is not elevated in infants and younger children with simple vitamin D deficiency (eg, no radiographic evidence of rickets) ¹
    • Osteomalacia
      • Decreased mineralization and increased action of parathyroid hormone ⁷
• Complications of treatment
  • Vitamin D toxicity
    • In children, defined as hypercalcemia and serum 25-hydroxyvitamin D level greater than 100 nd/dL, with hypercalciuria and suppressed parathyroid hormone
    • Manifests as any or all of the following: ⁷
      • Hypercalcemia
      • Serum 25-hydroxyvitamin D level greater than 150 ng/mL
      • Suppressed parathyroid hormone
      • Nephrolithiasis, when vitamin D is combined with calcium
• IV calcium is necessary for signs of severe neuromuscular irritability, such as hypocalcemic tetany

Prognosis

• Prognosis is favorable for treated vitamin D deficiency; most children treated achieve reference-range levels of 25-hydroxyvitamin D with no complications ⁵

Screening and Prevention

Screening

Screening is not recommended for the general population, but is recommended for at-risk groups

At-risk populations ⁵

• Exclusively breastfed or premature infants
• Dark-skinned infants and children
• Children on medications that compromise vitamin D concentrations
  • Azole antifungals, corticosteroids, or cytochrome P450 3A4 inducers
  • Highly active antiretroviral therapy
  • Anticonvulsant drugs such as phenytoin, carbamazepine, oxcarbazepine, and phenobarbital
• Children with chronic conditions such as chronic kidney disease, HIV/AIDS, cystic fibrosis, and other diseases that affect vitamin D metabolism or nutrient absorption
• Children who reside in areas with limited-sun exposure (high latitude areas)
• Obese children

Screening tests

• Serum 25-hydroxyvitamin D test is recommended for:
  • At-risk populations of infants and children ⁵
  • Pregnant and lactating women ⁴⁰

Prevention

• Primary prevention recommended for all children:
  • Adequate dietary intake of 400 international units/day or greater for neonates to infants aged 1 year; 600 international units/day or greater for children and adolescents aged 1 to 18 years ^1 4 5
    • Obtained via natural sources of vitamin D, fortified foods, and/or supplementation
  • Exposure to sunlight ¹²
    • Sensible exposure to sunlight is recommended for infants older than 6 months and children ¹²
      • In light-skinned children, reaching slight pinkness over the full-body (eg, while wearing a swimsuit), the amount of vitamin D produced in response to exposure of the full body is equivalent to ingesting 10,000 to 25,000 IU
    • Infants younger than 6 months should remain out of direct sunlight to reduce the risk of skin cancer ⁴¹
• Routine supplementation for at-risk populations ¹
  • Neonates to infants aged 12 months
    • 400 international units/day (10 mcg/day)
      • Breastfed and partially breastfed infants should take 400 international units/day of vitamin D supplementally beginning in first few days of life ⁴²
      • Supplementation should be continued unless the infant is weaned to at least 1 L/day or 1 qt/day of vitamin D–fortified formula or whole milk ⁴²
    • Recommended regardless of feeding method
  • Children older than 12 months and pregnant women
    • 600 international units/day or greater total, via dietary sources (eg, fortified foods) and/or supplementation
    • Supplementation in pregnant women can prevent:
      • Congenital vitamin D–deficiency rickets
      • Elevated alkaline phosphatase level
      • Neonatal hypocalcemia
      • Increased fontanelle size
  • Supplementation for at-risk populations
    • Obese children and children on anticonvulsant medications, glucocorticoids, antifungals such as ketoconazole, and HIV/AIDS medications
      • May require 2 to 3 times recommended amount of vitamin D for appropriate age group
• In all children, adequate dietary calcium should be maintained, since negative calcium balance depletes vitamin D stores: ¹
  • Recommended calcium intake
    • Neonates to infants aged 6 months
      • 200 mg/day
    • Infants aged 6 months to 12 months
      • 260 mg/day
    • Children older than 12 months
      • More than 500 mg/day
• Daily calcium requirements based on age: ⁴
  • Neonates to infants aged 6 months: 200 mg
  • Infants aged 7 to 12 months: 260 mg
  • Children aged 1 to 3 years: 700 mg
  • Children aged 4 to 8 years: 1000 mg
  • Children aged 9 years and older: 1300 mg
• Preventive measures associated with pregnancy and lactation: ⁴⁰
  • In pregnant and lactating women, especially those with darker skin or those who wear veils and other body covering, screening and treatment for maternal vitamin D deficiency is indicated
  • Breastfed infants should take vitamin D supplements for the first 12 months of life, beginning within the first 5 days of life

Sources

1: Munns CF et al: Global consensus recommendations on prevention and management of nutritional rickets. Horm Res Paediatr. 85(2):83-106, 2016 Cross Reference