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Osteopenia of Prematurity

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Significant advances in the nutritional care of preterm babies such as the initiation of early intravenous nutrition, early enteral feeds, breastmilk fortifier and preterm formula have been associated with a declining incidence of metabolic bone disease (MBD) in preterm infants. However MBD remains a significant problem for extremely preterm and very low-birthweight (VLBW) babies, particularly those who have chronic illnesses such as chronic lung disease and necrotizing enterocolitis. Recent findings suggest that, despite large differences in neonatal mineral intake, no effect of neonatal nutrition on bone mass or bone turnover is detectable in early adult life. However, greater exposure to human milk in the neonatal period, despite its very low mineral content, is associated with higher peak bone mass1. Studies in healthy term infants suggest that suboptimal maternal vitamin D status during pregnancy has adverse effects on offspring bone health in infancy and later childhood2; however, effects in infants born preterm have not been investigated. The role and optimal dose of vitamin D for later bone health in preterm infants requires further research.1,3

Risk factors

  • <30 weeks gestation, <1000g birthweight, male gender
  • Delayed establishment of full enteral feeds, fluid restriction
  • Prolonged intravenous nutrition
  • Enteral feeds with low mineral content or bioavailability (unfortified EBM, term formula)
  • Chronic use of medications that increase mineral excretion (diuretics, dexamethasone, sodium bicarbonate)
  • Lack of mechanical stimulation e.g. sedation and paralysis
  • Phosphorus deficiency (primary nutritional reason)
  • Vitamin D deficiency
  • Cholestatic jaundice
  • Short gut syndrome (malabsorption of vitamin D and calcium)

When an infant is identified to be at risk of metabolic bone disease (MBD), measurement of urinary calcium and phosphorus and serum 25-OH D should be considered.

Clinical Presentation

MBD presents between 6 and 12 weeks of age but may remain asymptomatic for weeks until overt rickets or fractures develop.3 Symptoms may include poor weight gain, faltering growth, and respiratory difficulties or failure to wean off ventilatory support due to excessive chest wall compliance. Fractures may manifest as pain on handling.

Early recognition of MBD is important for nutritional management in preterm infants.

The diagnosis of MBD remains largely subjective because most babies do not manifest overt signs or symptoms. Diagnosis has been based on criteria that include clinical signs, biochemical markers, and measurement of bone mineral content and radiologic findings (a late sign). There are no diagnostic biochemical tests.

Markers of Bone Formation

  • Serum calcium values may remain normal until late in the course.
  • Low serum phosphate concentrations (<1 mmol/L) have low sensitivity but high specificity. Low concentrations of inorganic phosphate (<1.8 mmol/L with elevated alkaline phosphatase (>900 IU/L) may be more sensitive (100%) and specific (70%) for diagnosing inadequate intake and low bone mineral density. Concentrations of 1, 25 (OH)2 vitamin D are elevated, but routine vitamin D and parathyroid hormone measurements are not required for diagnosis.
  • Elevated alkaline phosphatase values are seen with normal growth, healing rickets, fractures, or copper deficiency; low concentrations are seen with zinc deficiency, malnutrition, and congenital hypophosphatasia.
  • ALP is correlated negatively with phosphate concentrations; high values (>1,200 units/L) have been associated with short stature in childhood.

Guidelines for the Treatment of Osteopenia of Prematurity

  1. Prescribe:
    Elemental calcium 2.5 - 4 mmol/kg/day and
    Elemental phosphate 2 - 3 mmol/kg/day to be given in divided doses.
    N.B. Calcium and phosphate must not be given at the same time (because they may precipitate), so in practice should be given at alternate feeds.

    For example:
    0600hr Calcium 1.25mmol/kg/dose
    1200hr Phosphate 1.0 mmol/kg/dose
    1800hr Calcium 1.25mmol/kg/dose
    2400hr Phosphate 1.0 mmol/kg/dose

    As intestinal obstruction has been associated with calcium supplementation of enteral feeds, incremental advancement of calcium and phosphate supplements is recommended starting at 50% of the target dose recommended above.
  2. Ensure an adequate intake of calcium and phosphate from feeds:
    If <3.5kg fortified breastmilk or preterm formula
    (N.B. This is different from the usual recommendation of 2.5kg)
    If >3.5kg unfortified EBM or post discharge preterm formula (not soy)
    Ensure a daily intake of at least 800 IU Vitamin D per day.
  3. Weekly monitoring for infants being treated with additional calcium, phosphate, or vitamin D: serum calcium, phosphate, sodium, potassium, creatinine, acid/base balance, alkaline phosphatase.
    Calcium and phosphate supplementation is not without risk. Serum mineral and electrolyte status can be affected and intestinal obstruction has been associated with calcium supplementation.6 Phosphate supplementation can cause acidosis.7

    Weekly monitoring of urinary calcium, phosphorus and creatinine is also recommended due to the risk of nephrocalcinosis.5 Treatment is continued until biochemical indices are normal and radiographic evidence of healing is present. Consider other nutritional deficiencies (for example zinc) in an infant who has faltering growth with evidence of significant bone disease.

Caution: Chronic diuretic therapy with loop diuretics (frusemide) increases urinary calcium excretion. High urinary calcium increases the risk of nephrocalcinosis.


  1. Fewtrell MS. Does early nutrition program later bone health in preterm infants? The American journal of clinical nutrition 2011.
  2. Viljakainen HT, Korhonen T, Hytinantti T, et al. Maternal vitamin D status affects bone growth in early childhood--a prospective cohort study. Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA 2011;22:883-91.
  3. Vachharajani AJ, Mathur AM, Rao R. Metabolic Bone Disease of Prematurity. NeoReviews 2009;10:e402-e11.
  4. National Women's Health Clinical Guidelines Metabolic Bone Disease/Osteopenia of Prematurity. (accessed on 2/12/2012).
  5. Krug SK. Osteopenia of Prematurity. In: Groh-Wargo S, Thompson M, Hovasi Cox J, Hartline J, eds. Nutritional Care for High-Risk Newborns. 3 ed. llinois: Precept Press; 2000:489-505.
  6. Koletzko B, Tangermann R, von Kries R, et al. Intestinal milk-bolus obstruction in formula-fed premature infants given high doses of calcium. Journal of Pediatric Gastroenterology and Nutrition 1988;7:548-53.
  7. Atkinson SA. Calcium, phosphorus and vitamin D needs of low birthweight infants on various feedings. Acta Paediatrica Scandinavica Supplement 1989;351:104-8.

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Document Control

  • Date last published: 02 April 2013
  • Document type: Clinical Guideline
  • Services responsible: Neonatology
  • Author(s): Barbara Cormack
  • Owner: Newborn Services Clinical Practice Committee
  • Editor: Sarah Bellhouse
  • Review frequency: 2 years