Disorders of Neonatal Mineral Metabolism and Metabolic Bone Disease

KEY POINTS

• 1.

  Disorders of mineral homeostasis in the neonatal period are often exaggerated responses to the normal physiologic transition. Parathyroid hormone (PTH) is the principal regulator of postnatal calcium metabolism, with vitamin D and its metabolites involved in the regulation of serum calcium levels.

• 2.

  Neonatal hypercalcemia is uncommon and often asymptomatic; calcium concentrations need to be interpreted based on age-related norms, which are higher in neonates, and in concert with serum phosphorus and PTH levels.

• 3.

  Hypocalcemia is common in the neonatal intensive care unit and is transient in most infants; congenital hypoparathyroidism should be considered in the setting of prolonged hypocalcemia.

• 4.

  Metabolic bone disease of prematurity (MBD) results from interrupted maternal–fetal mineral transfer during the third trimester and is exacerbated by inadequate postnatal nutritional mineral intake and pharmacologic exposures.

• 5.

  No single biochemical marker is sufficient for diagnosis of MBD, but common screening approaches include measurements of alkaline phosphatase, PTH, calcium, phosphorus, and 25-hydroxyvitamin D (25(OH)D).

• 6.

  Prevention and treatment of MBD are often the same and include nutritional optimization, targeted enteral calcium and phosphorus supplementation, limiting bone active medications, and physical therapy interventions.

• 7.

  MBD slowly self-resolves over time, although long-term follow-up in former preterm infants suggests negative impacts on overall growth and bone mineralization in childhood and adulthood.

Background

Neonatal calcium and phosphorus metabolism are influenced by fetal and maternal factors and are postnatally controlled by complex parathyroid-renal hormonal interactions. Homeostasis of calcium and phosphorus is critical for physiologic stability (with roles in signal transduction, neurotransmitter release, and muscle contraction) and for postnatal growth and skeletal development. Preterm infants are at particular risk for disordered mineral metabolism, resulting from interrupted maternal–fetal mineral transfer in the third trimester and exacerbated by inadequate postnatal mineral intake in the setting of rapid growth. Metabolic bone disease (MBD), or osteopenia of prematurity, primarily occurs in very low birth weight (VLBW) infants with birth weight <1500 g, although extremely low birth weight (ELBW) infants <1000 g are disproportionately affected. MBD rates were as high as 50% among ELBWs in the 1980s, although with advancements in overall neonatal care, MBD rates have declined, and 10% to 40% of ELBW infants are affected in more contemporary reports. ^, In this chapter, we review fetal and postnatal mineral physiology and discuss disorders of neonatal mineral metabolism, including calcium derangements and metabolic bone disease of prematurity.

Fetal Bone Development

Fetal bone mineralization primarily occurs during the third trimester and is reliant on active transport of calcium and phosphorus across the placenta. Eighty percent of total gestational calcium accretion occurs during the third trimester, during which time the fetus is supplied (approximately 120–150 mg/kg/day of calcium), with phosphorus accretion of approximately half that amount (70 mg/kg/day). It is thus unsurprising that perinatal conditions of decreased placental efficiency (preeclampsia, intrauterine growth restriction) in preterm infants are associated with MBD postnatally. Rapid fetal bone length growth in the third trimester (about 1.2 cm/week) is supported by these nutrients as well as bone remodeling via mechanical forces between the fetal skeleton and the uterine wall.

The fetus exists in a state of relative hypercalcemia, which is mediated by the calcium-sensing receptor (CaSR) and suppresses fetal parathyroid hormone (PTH). In addition to promoting fetal bone mineralization, fetal hypercalcemia may also buffer the physiologic drop in serum calcium that occurs after birth. Calcium binding to albumin is dependent on pH—as the neonate initiates breathing, the serum pH rises, albumin is increasingly able to bind calcium, and the free ionized calcium level falls. Active ATP-mediated transport of minerals from mother to fetus appears to be primarily mediated by elevations in fetal PTH-related peptide (PTHrP). Fetal calcitonin is also elevated and enhances bone mineral absorption; PTH and calcitriol are suppressed. ^{, ,} PTHrP is expressed in the placenta and is instrumental in regulation of active placental calcium transport from mother to fetus as well as in modulating chondrocyte differentiation and osteoblast development. However, PTHrP is not routinely measured in clinical practice because it is transiently present in serum, technically difficult to assay, and challenging to interpret given the lack of reference ranges for age.

The role of vitamin D in placental mineral transport is unclear; 25(OH)D crosses the placenta, but calcitriol does not. Fetal calcitriol levels are less than half of maternal levels, and some authorities assert that maternal 25(OH)D levels do not significantly influence fetal bone development. However, lower maternal 25(OH)D levels at 34 weeks’ gestation were associated with greater femoral metaphyseal cross-sectional area and femoral splaying at both 19 and 34 weeks’ gestation. Maternal vitamin D status does correlate with neonatal serum vitamin D levels postnatally, and additional evidence suggests that maternal 25(OH)D status influences later bone mineralization. Higher maternal serum 25(OH)D levels in late gestation were associated with increased bone area and bone mineral content as measured by dual energy x-ray absorptiometry (DXA) in female infants at 2 weeks of life. Lower maternal 25(OH)D stores in the third trimester have been associated with lower bone mineral content in offspring at 9 years of age.

The mechanisms for placental phosphorus transfer are less understood, but they also appear to be governed by PTHrP-mediated active transport. Phosphorus is also essential for fetal bone development; it mediates apoptosis of chondrocytes and is subsequently incorporated into newly formed osteoid matrix.

Postnatal Mineral and Hormone Physiology

Upon umbilical cord clamping, previously high rates of placental-fetal mineral transfer abruptly cease. In the first 12 to 24 hours of life, both serum total and ionized calcium concentrations drop by 20% to 30% (with deeper nadirs in preterm than term infants), while serum phosphorus concentrations rise, both returning to normal values within the first few days of life. In the neonate, calcium is almost entirely (99%) located in bone matrix, where it is complexed to phosphorus. In the remaining 1% of circulating calcium, 50% is ionized and biologically active, 40% is protein-bound (mostly to albumin) and biologically inactive, and the remainder is complexed to organic and inorganic acids. ^, Phosphorus is primarily (85%) stored in the skeleton, with the remainder circulating in the serum either in ionized form (55%), complexed to cations (35%), or protein-bound (10%).

Postnatal control of calcium and phosphorus metabolism is governed primarily by PTH, calcitonin, and vitamin D ( Fig. 28.1 ). PTH is the primary hormone governing calcium homeostasis after birth. Suppressed in the fetus due to relative hypercalcemia, PTH is secreted by the parathyroid gland in the setting of hypocalcemia and induced two- to five-fold in both preterm and term infants after the postnatal calcium drop. Although an acute increase in PTH has anabolic effects on the neonatal skeleton and promotes bone formation, prolonged elevation in PTH promotes osteoclast proliferation and differentiation, leading to bone resorption and release of calcium and phosphorus. In the kidney, PTH promotes calcium reabsorption and phosphorus excretion at the distal convoluted tubule and stimulates production of calcitriol in the proximal tubule by activation of renal 1-hydroxylase. Calcitonin is produced by parafollicular cells of the thyroid gland and acts in opposition to PTH, decreasing serum calcium by inhibition of osteoclasts and increasing renal excretion of calcium and phosphate.

Vitamin D is either ingested or synthesized in skin after UV exposure. In the neonatal intensive care unit (NICU), vitamin D comes almost exclusively from dietary intake. It is first hydroxylated to 25(OH)D in the liver, and given its long half-life, 25(OH)D is most reflective of overall vitamin D status. PTH mediates hydroxylation of 25(OH)D in the kidney, to produce 1,25(OH) ₂ D (calcitriol). Calcitriol has multiple effects via binding of the vitamin D receptor, including increased intestinal absorption of calcium and phosphorus, promotion of bone formation by mineralization of osteoid, and negative feedback over PTH via transcriptional downregulation. Calcitriol levels are low at birth but increase to adult levels in the first day of life. Postnatal mineral and hormone kinetics change rapidly in the first several postnatal days and are summarized in Fig. 28.2 .

Hypercalcemia

Hypercalcemia is far less common than hypocalcemia in the neonatal and infantile periods. Interpretation of an elevated serum total calcium level with suspected hypercalcemia requires measurement of the either the ionized calcium level or determination of the serum albumin concentration, with appropriate adjustment of the serum calcium level if the albumin level is abnormal. The effects of acid-base status must be considered as well, with acidosis resulting in decreased calcium binding to albumin and an increase in the ionized calcium, whereas alkalosis increases protein binding of calcium and a decrease in ionized calcium. In addition, the reference range for neonates is higher than at other ages, with the upper limit of normal at 11.3 mg/dL. Initial biochemical testing must also include determination of the serum phosphorus level, because hypophosphatemia can cause hypercalcemia, particularly in premature or low birth weight infants who receive inadequate dietary phosphorus.

Symptoms of hypercalcemia are highly variable and depend on the age of the patient, the degree of hypercalcemia, and the clinical disorder. For cases of mild to moderate hypercalcemia, usually up to 13 mg/dL, patients may be without symptoms or with nonspecific symptoms such as anorexia, feeding intolerance, irritability, or constipation. Chronic hypercalcemia can present as failure to thrive, but the vague nature of symptoms can lead to delayed diagnosis and increase the risk for morbidity and mortality. Hypercalcemia can also lead to shortened ST segment and heart block, polyuria secondary to renal resistance to vasopressin leading to nephrogenic diabetes insipidus with associated dehydration, and hypertension due to the direct vasoconstriction from elevated serum calcium levels. Renal complications such as hematuria, nephrocalcinosis, and nephrolithiasis can be early manifestations of hypercalcemia. Severe hypercalcemia can directly affect the nervous system, leading to lethargy and seizures, with rare progression to coma.

The differential diagnosis of neonatal hypercalcemia can be broadly divided into PTH-dependent and independent causes ( Table 28.1 ). Iatrogenic causes of hypercalcemia can be seen with hypophosphatemia, excessive administration of calcium and/or vitamin D, and the use of thiazide diuretics, which lead to decreased urinary calcium excretion.

PTH-Dependent Hypercalcemia

Neonatal hyperparathyroidism is characterized by high serum calcium levels with inappropriately elevated PTH levels, with low levels of serum phosphorus, normal or elevated alkaline phosphatase (ALP) levels, and relative hypocalciuria.

Neonatal transient primary hyperparathyroidism can occur in response to low in utero maternal calcium concentrations. This more commonly occurs in lower birth weight infants but otherwise comes without clinical signs. Thorough investigation of the infant’s mother will disclose previously known but inadequately treated hypoparathyroidism or clinically unsuspected hypocalcemia. Decreased calcium transport from the hypocalcemic mother to the fetus leads to fetal hypocalcemia, with secondary increased secretion of fetal PTH, stimulating mobilization of calcium from the fetal skeleton and causing bone demineralization and subperiosteal resorption. This hyperfunction of the developing parathyroid glands may persist after birth, resulting in postnatal hyperparathyroidism with resulting transient moderate hypercalcemia. Postnatally, the skeleton avidly takes up calcium, and the bone lesions heal spontaneously within 4 to 6 months. Careful management of the plasma calcium concentration in hypoparathyroid women during pregnancy will prevent the development of functional hyperparathyroidism in the fetus.

Neonatal Severe Hyperparathyroidism and Familial Hypocalciuric Hypercalcemia

Inactivating mutations of the CaSR result in altered calcium sensing with inappropriate PTH production with respect to the serum calcium level. Hypercalcemia results from this altered set point, with higher calcium levels required to suppress PTH release, resulting in higher serum calcium levels. Most cases of neonatal severe hyperparathyroidism (NSHPT) and familial hypocalciuric hypercalcemia (FHH) are homozygous and heterozygous manifestations, respectively, of the same genetic defect in the CASR gene at 3q13.3–21 that inactivates the CaSR. ^, Despite this relationship, the clinical presentations of NSHPT and FHH are distinct. NSHPT is a severe and life-threatening disorder and usually presents in the first week of life. It likely begins in the fetal period, as suggested by the finding of generalized skeletal demineralization and localized erosions at the ends of long bones and subperiosteal resorption along the shafts of tubular bones. Parathyroid glands are enlarged and biochemical findings include markedly elevated serums levels of PTH and 1,25(OH) ₂ D, low-to-normal serum phosphorus, normal-to-high serum magnesium, elevated ALP, and inappropriately normal or low urinary calcium excretion. A family history of NSHPT or FHH in a sibling can provide strong confirmation of the diagnosis. Genetic testing is available for evaluation of CASR gene mutations and the less common AP2S1 and GNA11 gene mutations, which can cause NSHPT/FHH in some families. By contrast, FHH is characterized by a relatively benign course and is generally asymptomatic despite mild-to-moderate hypercalcemia. It is most commonly discovered as an incidental finding or during the evaluation of relatives of patients with hypercalcemia. The hypercalcemia may be present at birth, or the diagnosis may be made during infancy and childhood. Circulating levels of PTH are normal or high-normal, but in the presence of hypercalcemia, they are inappropriately high, reflecting the higher set point of the parathyroid calciostat.

The treatment of hypercalcemia depends on the severity of the presentation. Hypercalcemia seen in newborns exposed to maternal hypocalcemia is often mild, transient, and self-limiting and responds to conservative management. Most patients with FHH lack symptoms and treatment is not required. By contrast, cases of severe hypercalcemia such as with life-threatening hypercalcemia of NSHPT require more aggressive treatments. In NSHPT, traditional management has involved subtotal parathyroidectomy, but appropriate medical treatments can preclude the need for surgical intervention in select cases. Initial therapies include maintenance of adequate hydration and avoiding excessive vitamin D and calcium. Intravenous isotonic fluids are the primary treatment for hypercalcemia, with the goal of increasing the urinary excretion of sodium because sodium and calcium clearance are closely linked during osmotic diuresis. Loop diuretics such as furosemide have traditionally been used to enhance calciuresis once hydration has been optimized. However, such agents must be used with caution because they may induce dehydration, which can actually worsen hypercalcemia through reduction in the glomerular filtration rate. In cases of NSHPT, hypercalcemia is often life-threatening and requires urgent medical intervention. Glucocorticoids are ineffective in the treatment of NSHPT-associated hypercalcemia. Calcitonin (2-4 U/kg every 6–12 hours) can be given by subcutaneous injection and can directly reduce osteoclastic bone resorption and lower serum calcium levels. However, calcitonin typically only works for a short time because tachyphylaxis develops quite rapidly. Nitrogen-containing bisphosphonates (e.g., pamidronate 0.5–1.5 mg/kg/dose × 3 days, zoledronic acid 0.015–0.05 mg/kg/dose), are analogs of inorganic pyrophosphate that adsorb to the hydroxyapatite matrix and can provide a more sustained inhibition of bone resorption and effectively lower serum and urinary calcium in NSHPT. Calcimimetics such as cinacalcet could be potential therapeutic options in NSHPT because they increase CaSR sensitivity to calcium and can lower serum calcium levels. Although a trial of cinacalcet may be considered in infants with severe hypercalcemia related to CASR mutations, this approach must be pursued with caution because only limited information is available regarding its safety and efficacy in children with primary hyperparathyroidism.