Purpose and Goal: CNEP # 2027

  • Understand bone mineral metabolism in the neonate.
  • Learn about the effects of poorly mineralized bones in the neonate.

None of the planners, faculty or content specialists has any conflict of interest or will be presenting any off-label product use. This presentation has no commercial support or sponsorship, nor is it co-sponsored.

Requirements for successful completion:

  • Successfully complete the post-test
  • Complete the evaluation form

Date

  • September 2015 – September 2017

Learning Objectives

  • Describe the physiology of bone mineral metabolism.
  • Describe the effects of bone mineral imbalances in the neonate.
  • Identify 2 approaches for the treatment of osteopenia of prematurity.

Introduction

  • Bone health is a critically important concern in the neonate
    • It is especially critical in premature infants
  • Calcium (Ca) and phosphorous (P) are essential for bone growth
    • To ensure adequate bone function
    • To ensure adequate structural integrity
  • Magnesium (Mg) is also essential for adequate bone growth
  • Because of rapid growth, neonates require higher mineral intake

Bone Mineral Metabolism

  • The physiology and metabolism of bone minerals
    • Are interrelated
    • Are influenced by other nutrients
    • Are influenced by hormones
  • Bone mineral metabolism is influenced by:
    • Maternal factors
    • Gestational factors
    • Postnatal factors
  • The daily mineral requirement is affected by:
    • Gestational age
    • Intestinal absorption
    • Urinary excretion
  • A lack of adequate mineral intake can lead to:
    • Osteopenia
    • Rickets
    • Fractures

Gestational Age

  • Bone minerals are actively transferred in utero
  • The third trimester is the period of most active transfer
  • Mineral levels reach a peak accretion rate at 32 – 36 weeks
    • Ca levels are 100 – 130 mg/kg of fetal weight
    • P levels are 60 – 70 mg/kg of fetal weight
  • The accretion rate is related to fetal bone growth
  • Daily mineral requirements with ↓ gestational age
    • To compensate for the loss of accretion
  • In ELBW infants < 1000 grams or < 28 weeks
    • There is increased risk of osteopenia
    • There is increased risk of rickets

Intestinal Absorption

  • Ca and P absorption occurs in the small intestine
    • By active transport
    • By passive diffusion
  • Vitamin D is essential for active absorption of Ca
  • Vitamin D does not ↑ Ca absorption in preterm infants
    • Most absorption is passive diffusion
  • Absorption of Ca from breast milk or formula
    • Approximates 60% of intake
  • Absorption of P from breast milk or formula
    • Approximates 90% of breast milk intake
    • Approximates 80% of formula intake
  • P retention and absorption is improved
    • With a Ca to P ratio between 1.6:1 to 1.8:1
    • A ratio of 2:1 does not improve P absorption
  • Absorption of C and P is positively affected by:
    • Postnatal age
    • Ca and P intake
    • Lactose intake
    • Fat intake
    • Vitamin D levels
  • Absorption of Ca and P is negatively affected by:
    • Glucocorticoids
      • Inhibits intestinal transfer
    • Phenytoin (Dilantin)
      • Inhibits Ca absorption
      • Interferes with Vitamin D metabolism
    • Phenobarbital
      • Inhibits Ca absorption
      • Interferes with Vitamin D metabolism

Renal Excretion and Absorption

  • All filtered Ca is reabsorbed in the renal tubule
  • Two main exceptions lead to calcium depletion:
    • Loop diuretic use
      • Enhances calcium excretion
      • May result in nephrocalcinosis
    • P deficiency
      • Enhances calcium excretion
      • Leads to ongoing calcium loss
      • May result in calcium depletion
  • In the presence of hypocalcemia
    • Parathyroid hormone (PTH) ↓ urinary Ca excretion

Calcium Homeostasis

  • 99% of the Ca is stored in bone
  • Maternal factors that influence Ca stores
    • Maternal thinness
    • Low dietary Ca intake
    • Smoking during pregnancy
  • These factors alter fetal hormone pathways
    • Which lead to ↓ fetal Ca accretion
  • Calcium is essential for:
    • Blood coagulation
    • Neuromuscular excitability
    • Cell membrane permeability
    • Normal cardiac function
    • Skeletal structure and integrity
  • Serum calcium is available in 3 forms:
    • Protein bound (40%)
    • Inactivated (10%)
    • Free ionized (50%)
  • Free ionized Ca (iCa) is the only bioavailable form
    • It is considered the active component
    • It is the most accurate measure of Ca
  • Ca balance is regulated by the parathyroid-renal hormone axis
    • PTH mobilizes Ca and P from bone
    • PTH stimulates renal synthesis of vitamin D
    • Vitamin D ↑ intestinal absorption of Ca and P
  • Ca homeostasis is also regulated by the kidneys
    • Kidneys inhibit excretion of Ca to maintain balance
  • Ca homeostasis is also regulated by calcitonin
    • Calcitonin is a regulatory hormone
    • It is secreted by the thyroid gland
    • It inhibits Ca release from bone breakdown
  • Ca freely crosses the placenta in utero
    • PTH and calcitonin do not cross the placenta
    • This results in a state of fetal hypercalcemia
    • Neonates experience a sudden ↓ in Ca at birth
      • As soon as the maternal supply stops
    • Neonates depend on stored Ca and dietary intake
  • Hypocalcemia is defined as a serum Ca < 7 and an iCa < 4.4
  • Early onset hypocalcemia occurs in the first 3 days
    • May be related to:
      • Prematurity
      • Maternal diabetes
      • Placental insufficiency
      • Perinatal asphyxia
      • Maternal anticonvulsant therapy
      • Low Ca intake
  • Late onset hypocalcemia occurs after the first week
    • May be related to:
      • Hypomagnesemia
      • Hypoparathyroidism
      • Vitamin D deficiency
      • DiGeorge syndrome
      • Hyperphosphatemia
      • Intestinal malabsorption

Phosphorous Homeostasis

  • 80% of P is stored in bone
  • Phosphorous is essential for:
    • Energy stores
    • Intracellular function
  • P homeostasis is regulated by:
    • Parathyroid hormone
    • Calcitonin
    • Vitamin D
  • P is absorbed throughout the intestine
    • Occurs by passive diffusion
    • Occurs by active sodium-phosphate transport
  • P is filtered and absorbed/excreted by the kidneys
  • Hypophosphatemia is defined as a P level < 4
  • Low P levels may be related to:
    • Prematurity
    • Aluminum in antacids
    • Renal damage

Magnesium Homeostasis

  • Magnesium (Mg) is an intracellular electrolyte
  • Maternal factors may influence Mg stores
    • IUGR status
    • Maternal diabetes
    • Hypophosphatemia
    • Hyperparathyroidism
  • Magnesium is essential for:
    • Cell regulation
    • Adenosine formation
    • PTH and Vitamin D function
    • Supporting many enzymes
  • Mg homeostasis is regulated by:
    • PTH
    • Renal function
    • GI tract function
  • Hypomagnesemia is defined as a Mg level < 1.5
  • Low levels may be related to:
    • Low Ca levels
    • Renal dysfunction
    • Intestinal malabsorption

Interrelationship Between Ca, P and Mg

  • A relationship exists between Ca, P, Mg
  • Ca, P, Mg are tightly controlled by:
    • PTH
    • Vitamin D
    • Calcitonin
  • An imbalance in one → imbalance in other two
  • The ability of the intestine to absorb Ca
    • Depends on the concentration of P
    • Increased P → decreases Ca absorption
  • The ability of the intestine to absorb P
    • Depends on the concentration of Ca
    • Increased Ca → decreases P absorption
  • A low Ca level increases PTH secretion
  • Increased PTH:
    • Releases Ca and P from bone
    • Increases urinary Ca reabsorption
    • Increases urinary P excretion
    • Increases production of Vitamin D
      • Improves intestinal absorption of Ca
      • Improves intestinal absorption of P
  • Calcitonin increases Ca excretion
  • Calcitonin inhibits bone reabsorption
  • A low Mg level decreases PTH secretion
    • Leading to low Ca levels
    • Corrected by bone breakdown

Metabolic Bone Disease

  • Dietary intake is critical for bone strength
    • Ca and P
    • Vitamin D
  • Dietary intake is the major source of Ca and P
  • Term formula is adequate for most term infants
  • Dietary requirements for preterm infants
    • Is significantly higher than term infants
    • Cannot be met by unfortified breastmilk
    • Cannot be met by term formula
  • The inability to provide adequate Ca and P
    • Increases the risk of metabolic bone disease
    • Occurs in > 30% of infants < 1500 grams
    • Occurs in > 50% of infants < 1000 grams
  • Inadequate Ca places infants at risk for osteopenia
  • Osteopenia means “deficiency of bone”
    • Results from decreased bone formation
    • Results from increased bone resorption
  • Untreated osteopenia can lead to rickets
  • Rickets is a chronic deficiency of Ca and P
    • Presents between 3 and 12 weeks
    • Presents with signs of bone demineralization
    • Presents with increased alkaline phosphatase
  • Risk factors for developing rickets:
    • Prematurity
    • Low birth weight
    • Complicated medical course
    • Long term parenteral nutrition
    • Diuretic therapy
    • Cholestasis
    • Immobility or sedation
    • Inappropriate nutrition
  • Clinical signs of bone demineralization:
    • Decreased linear growth
    • Frontal bossing
    • Craniotabes
    • Pain with handling
  • Radiographic evidence of bone disease:
    • Widened epiphyseal growth plates
    • Cupped or frayed metaphyses
    • Decreased bone density
      • Skull
      • Spine
      • Scalpula
      • Ribs
    • Bone fractures

Alkaline Phosphatase

  • Alkaline phosphatase (AP) is an enzyme
    • Active in dephosphorylation reactions
    • Removes phosphate from molecules
  • It originates in the liver and bone
  • It is an indicator of bone demineralization
    • It is also a marker for rickets
  • Serial measurements are more helpful then a single value

Management of Bone Disease

  • Prevention is the primary goal
    • To promote normal bone growth
  • Management consists of improving nutrition
    • Enteral nutrition is key to adequate treatment
    • Parenteral nutrition cannot meet requirements
      • Absorption is decreased
      • Retention is not optimal
  • Infants with bone disease require:
    • Increased calories
    • Increased Ca and P
    • Increased Vitamin D
  • Breastmilk should be fortified
    • Especially in premature infants
  • The American Academy of Pediatrics guidelines
    • Calories: ~120 kcal/kg/day
    • Calcium: 180-220 mg/kg/day
    • Phosphorous: 75-140 mg/kg/day
    • Vitamin D: 200-400 IU/day
  • Soy formula should be avoided
    • Lowers intestinal absorption of P
  • Loop diuretic use should be avoided
  • Serial monitoring of Ca, P and AP is recommended
  • Physical activity may improve bone mineralization

Physical Activity and Bone Health

  • Bone mineralization may be dependent on force
  • The fetus pushes against the uterus in utero
    • Bone minerals may ↑ to withstand the force
    • Preterm infants may experience less force
  • Therapeutic positioning that allows for movement
    • May mimic intrauterine activity
    • Encourages pushing and flexible resistance
  • Passive range of motion might also ↑ mineralization
  • Studies are looking at potential outcomes and benefits

Summary

  • Ca, Mg, P are vital to normal bone health
  • Providing early and adequate nutrition is critical
  • Monitoring these mineral levels is important
    • To recognize bone mineral disorders
    • To prevent bone mineral disorders
    • To treat bone mineral disorders

References

  1. Koo, W.W.K & Warren, L. 2003. Calcium and Bone Health in Infants. Neonatal Network, 22 (5), p. 23-37.
  2. Williford, A.L, Pare, L.M & Carlson, G.T. 2008. Bone Mineral Metabolism in the Neonate: Calcium, Phosphorous, Magnesium and Alkaline Phosphatase. Neonatal Network, 27 (1), p. 57-63.
  3. Abrams, S.A. 2015. Management of Neonatal Bone Health. Up-To-Date
  4. Stalnaker, K.A & Poskey, G.A. 2016. Osteopenia of Prematurity: Does Physical Activity Improve Bone Mineralization in Preterm Infants? Neonatal Network, 35 (2), p. 95-104.

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