Preterm birth is a major public health challenge and the leading cause of long‑term morbidity, with lasting effects on growth, development and quality of life. In Australia, over 1,000 infants are born extremely preterm (<28 weeks’ gestation) each year, and around 40% develop osteopenia of prematurity (OFP). OFP is characterised by impaired bone mineralisation, skeletal deformities, fragility fractures and postnatal growth failure. Despite current clinical management, extremely preterm infants continue to show reduced bone mineral content and density into childhood, underscoring the need for improved understanding of OFP pathogenesis and preclinical models to support therapeutic development.

To characterise the skeletal consequences of preterm birth in a large‑animal model and evaluate the preterm piglet as a clinically relevant translational model for OFP.

Preterm piglets (delivered at 99 days’ gestation, equivalent to 28-29 human gestational weeks) were supported for 15 days to reach term-equivalent age and compared with term-born controls. Bone development was assessed using serum markers of mineralisation, whole-body CT for skeletal morphology, micro-CT for trabecular microarchitecture, and histological analysis for structural and cellular evaluation.

Preterm piglets displayed hallmark skeletal abnormalities consistent with OFP. Whole-body CT revealed open cranial sutures and widened skulls, while distal femur micro-CT showed profound trabecular deficits, including reduced trabecular bone volume (10 vs 20%, p = 0.003) and number (1700 vs 2800 1/mm, p = 0.003), with increased separation (340 vs 240 mm, p = 0.006) compared with term controls. Histomorphometry confirmed severe microarchitectural disruption and a three‑fold increase in osteoblast (35 vs 10%, p = 0.0061) and osteoclast surfaces (12 vs 4%, p = 0.006), indicating elevated but ineffective remodelling. Preterm piglets also had higher serum vitamin D (87 vs 46 nmol/L, p = 0.01) and phosphate (3.3 vs 2.3 mmol/L, p = 0.004), while ALP and PTH remained unchanged, mirroring clinical OFP where biochemical markers may appear normal despite skeletal impairment.

Preterm birth disrupts early skeletal development, producing structural, cellular and morphological abnormalities characteristic of OFP. These findings establish the preterm piglet as a clinically relevant large‑animal model for investigating OFP pathophysiology and evaluating therapeutic strategies.