Osteopenia of Prematurity

Osteopenia of prematurity is reduced bone mineral content in preterm infants, caused mainly by inadequate calcium and phosphate supply during the period of rapid foetal bone mineralisation. Severe disease produces rickets and fractures.

About 20 to 30% of infants under 1500 g are affected, and up to half of those under 1000 g. Peak incidence is between 4 and 12 weeks of age. Risk factors are gestation under 28 weeks, prolonged parenteral nutrition, unfortified human milk, long term diuretic or corticosteroid exposure, cholestasis, bronchopulmonary dysplasia, necrotising enterocolitis, immobility and late establishment of enteral feeds.

Pathophysiology.

About 80% of foetal calcium and phosphate accretion occurs in the third trimester, so preterm infants miss the main period of mineral deposition. Human milk and unsupplemented parenteral nutrition contain too little calcium and phosphate to match the intrauterine rate.

Phosphate deficiency with relative calcium sufficiency reduces osteoblast activity, while calcium deficiency raises parathyroid hormone. Loop diuretics increase urinary calcium loss, and corticosteroids and immobility reduce bone formation.

• Usually silent until radiographic or biochemical change appears.
• Fractures, most often of ribs and long bones, found incidentally or after handling.
• Wrist and costochondral widening, frontal bossing, craniotabes and chest wall softening with worse respiratory function in severe disease.

Red flags.

• Fracture after minimal handling or a swollen limb.
• Increasing oxygen requirement with a soft chest wall.
• Hypocalcaemic seizures or tetany.

• Serum alkaline phosphatase over 500 units/L raises suspicion, and a persistent value over 800 units/L with serum phosphate under 1.8 mmol/L supports the diagnosis.
• Serum phosphate, calcium, parathyroid hormone (raised with calcium deficiency), 25-hydroxyvitamin D (target over 50 nmol/L), and urine calcium and phosphate to creatinine ratios.
• Radiograph of the wrist or knees for cupping, fraying and sub-periosteal new bone, and of the chest for rib fractures. Radiographs are insensitive until bone loss is over 20 to 40%.
• Bone densitometry is used in some centres but is not routine.

Differential diagnosis. Vitamin D deficiency rickets, cholestasis, renal tubular disorders, hypophosphatasia, copper deficiency, congenital syphilis, birth injury and abusive fracture.

Prevention and nutrition.

• Target intake of calcium 120 to 140 mg/kg/day, phosphorus 60 to 90 mg/kg/day and vitamin D 400 to 1000 units daily, using human milk with a fortifier, or preterm formula.
• Provide parenteral calcium and phosphate early and in a balanced ratio, and start enteral feeds early.
• Avoid unnecessary diuretics and prolonged corticosteroids, treat cholestasis, and provide gentle passive limb movement.

Treatment of established disease.

• Phosphate 1 to 2 mmol/kg/day orally in divided doses when serum phosphate is under 1.8 mmol/L. Calcium 20 to 40 mg/kg/day of elemental calcium in divided doses when calcium is low or parathyroid hormone is raised.
• Correct vitamin D deficiency with 1000 to 2000 units daily.
• Handle gently and avoid chest compression. Fractures usually heal with minimal splinting.

Monitoring. Alkaline phosphatase, calcium and phosphate every 2 weeks from 3 to 4 weeks of age in infants under 1500 g, and urine calcium to creatinine ratio when on calcium or phosphate supplements, to detect hypercalciuria and nephrocalcinosis.

Referral and escalation. Refer to a paediatric endocrinologist or bone specialist for fractures, persistent biochemical abnormality despite supplements, or unexplained severe rickets.