Definition

• Decreased mineralisation of bones due to deficient phosphate (PO₄), calcium (Ca) or vitamin D in preterm babies 
• Also known as osteopenia of prematurity

Causes

• Inadequate postnatal intake or absorption to match intrauterine mineral accretion rate

Risk factors

• <32 weeks’ gestation or <1500 g birth weight 
• Male gender
• Delay in establishing enteral feeds/enteral feeds with low mineral content/bioavailability [unfortified expressed breast milk (EBM), term formula]
• PO₄/Ca or vitamin D deficiency
• Prolonged parenteral nutrition (PN) (>2 weeks)
• Chronic drug use that increases mineral excretion (diuretics, steroids, sodium bicarbonate)
• Lack of mechanical stimulation e.g. sedation/paralysis
• Chronic lung disease
• Cholestatic jaundice 
• Short gut syndrome (malabsorption of vitamin D and Ca)

Symptoms and signs

• ≤6 weeks – most babies are asymptomatic and normal on examination
• Usually presents aged 6–12 weeks 
• Poor weight gain or faltering growth
• Respiratory difficulties: failure to extubate due to increased chest wall compliance
• Fractures with minor or no trauma; may manifest as pain on handling
• Craniotabes (softening of skull bones)

Later clinical consequences

• Marked dolicocephaly (long and narrow skull)
• Reduced linear growth

Serum biomarkers

• Low serum PO4 (<1.8 mmol/L) with elevated alkaline phosphatase (ALP) (>900 IU/L) is 100% sensitive and 70% specific for diagnosing low bone mineral density 
• Low serum PO4 concentrations (<1.8 mmol/L) have 96% specificity but only 50% sensitivity. Routine PO4 supplementation in high risk babies could lead to secondary hyperparathyroidism, and thus worsen MBD
• Serum Ca levels may remain normal until late in the disease despite bone losses of Ca
• In suspected MBD with elevated ALP and low PO₄, serum parathormone (PTH) measurement will help in establishing if there is underlying Ca or PO₄ deficiency to provide correct supplementation
  • Ca deficiency causes increased PTH to maintain normocalcaemia
  • in PO₄ deficiency there is no compensatory mechanism – PTH remains normal

Urinary biomarkers

• Urinary excretion of Ca >1.2 mmol/L and PO₄ >0.4 mmol/L signifies slight surplus of supply and correlates with highest bone mineral accretion rate 
  • phosphaturia can occur due to aminoglycoside, indomethacin and steroid therapy
  • calciuria can occur due to diuretics, steroids and theophylline 
• Tubular reabsorption percent (TRP) of PO₄ is also a guide to adequacy of PO₄ supplementation. TRP of >95% indicates inadequate supplementation 
  • TRP (%TRP) = [1 − (urine PO₄/urine creatinine) (plasma creatinine/plasma PO₄)] x 100

Radiological

• Low bone density on X-rays (rachitic changes, cortical thinning, periosteal elevation) or fractures of long bones or ribs
• Dual-energy X-ray absorptiometry/qualitative ultrasound to assess bone mineral density

• Optimal nutritional intake
  • early PN with optimised Ca and PO₄ content – Parenteral nutrition guideline 
  • early enteral feeds
  • optimal ratio of enteral Ca:PO₄ of 1.3:1–≤1.4:1 mmol-to-mmol basis should be targetted to avoid secondary hyperparathyroidism
  • adequate Ca (3–5.0 mmol/kg/day) and PO₄ (2.2–3.7 mmol/kg/day) intake by using fortified EBM or preterm formula. ≥140 mL/kg/day fortified EBM or preterm formula is needed to provide this
  • daily intake of ≥400–700 units/kg/day vitamin D 
• Ensure appropriate handling and position using deep boundaries to promote active bone loading

For all high risk babies, after at least one week of full enteral feeds (≥140 mL/kg/day fortified EBM or preterm formula), measure serum Ca, PO₄ and ALP levels from third week of life and follow this guidance:

• Stop additional vitamin D when vitamin D and PTH are normal 
• Adjust Ca dose based on serum Ca levels and stop only once PTH levels normalise
• Adjust PO₄ dose based on serum PO₄ levels, and ALP adjusting Ca dose to maintain ratios
• Continue treatment until biochemical indices are normal and radiographic evidence of healing, usually until term corrected gestation