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  1. Definition. Prematurity affects bone mineralization and bone growth. Normal bone is formed by the deposition of minerals, predominantly calcium (Ca+2) and phosphorus (P) onto an organic matrix (osteoid) secreted by the osteoblasts. Osteoclasts play an important role in bone remodelling.

      1. Osteopenia refers to a decrease in the amount of organic bone matrix (osteoid) due to a decrease in the thickness or number of trabeculae and/or decreased thickness of the bone cortex. These can be due to either insufficient deposition or increased resorption of the organic bone matrix.

      1. Osteomalacia refers to the lack of mineralization of the organic bone matrix resulting in softening of bones. When involving the growth plate, it results in rickets. Bone density and bone mineral content (BMC) are both decreased.

      1. Osteoporosis refers to a decrease in bone mineral density <2.5 standard deviations from the norm (adults). There is no accepted definition of osteoporosis in infants.

  2. Incidence. Due to improvements in nutritional management such as initiation of early feedings, changes in nutritional formulas, and other clinical practices, the current incidence of osteopenia is difficult to estimate. It is now more commonly seen in extreme prematurity and preterm infants with chronic illnesses like bronchopulmonary dysplasia and necrotizing enterocolitis.

    Previously, osteopenia has been reported in 23% of very low birthweight infants (VLBW) and in 55–60% in extremely low birthweight infants <1000 g. It was more commonly reported in breast-fed (40%) compared to formula-fed (16%) infants. Fractures have been reported in up to 10% of VLBW infants but are likely to be less common now.

  3. Pathophysiology

      1. An increase in trabecular thickness and bone volume occurs faster in utero compared to ex utero. After birth, bone growth is due to cyclical bone formation and resorption. In the first year, bone growth occurs by increases in length and diameter but with a decrease in cortical thickness; however, there is an overall threefold increase in bone strength. This adaptation occurs earlier in preterm infants than in term infants. Mineral retention is affected more than linear growth, contributing to a reduction in bone density following preterm birth. In preterm infants, the bone mineral content remains lower at term-equivalent than for full-term infants.

      1. Approximately 99% of body Ca+2 and 80% of P is in the skeleton at a term birth, and nearly 80% of this transfer occurs between 25 weeks' gestation and term. Fetal accretion rate for Ca+2 and P cannot be met ex utero. Further, inadequate intake (Ca+2 and P) in the face of increased growth demands result in nutrient deficiency.

      1. Vitamin D hydroxylation is fully functional at 24 weeks' gestation, and preterm infants can form 1,25 dihydroxy vitamin D.

      1. Genetics and bone disease. In adults and in VLBW infants, osteoporosis is associated with polymorphisms involving VDR, ER, and COLIA1 genes. In VLBW infants, homozygous allelic variants of ERα genotype with low number of thymidine-adenine repeat [(TA)n] were correlated with high urinary pyridinoline crosslink levels (indicating increased bone resorption) and with the development of metabolic bone disease. The locus interaction between VDR and COLIA1 was found to be protective in the development of bone disease.

  4. Risk factors

      1. Fetal and neonatal causes

          1. Prematurity and birthweight. Preterm birth results in Ca+2 and P deficiency. The frequency of osteopenia is inversely related to gestational age and birthweight. Both conditions ...

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