Prevention and management of metabolic bone disease of prematurity: a systematic review

OBJECTIVE: Metabolic Bone Disease of Prematurity (MBDP) results from disrupted third-trimester mineral accretion in preterm neonates, leading to inadequate bone mineralization. Despite adherence to standard nutritional guidelines, MBDP remains common. This systematic review assesses the effectiveness of nutritional supplementation and physiotherapy in reducing MBDP incidence and severity. STUDY DESIGN: The review was conducted under PRISMA guidelines and registered with PROSPERO. We retrieved 942 studies from PubMed and Embase. Eligible studies included RCTs/cohort studies published 2020-2025 that investigated postnatal calcium, phosphate, vitamin D supplementation, or physiotherapy in preterm infants (<37 weeks), while recognising that the highest MBDP burden occurs in infants born <32 weeks or with very low birth weight and that selected moderate-to-late preterm infants may remain vulnerable when additional nutritional or clinical risk factors are present. Studies were screened with Covidence, and relevant data were qualitatively synthesized by intervention type and outcomes. RESULTS: From a total of 942 records initially identified, sixteen studies were included (eleven supplementation, five physiotherapy). Higher-dose calcium and organic phosphate, especially when administered continuously, improved biochemical and radiological outcomes. High-dose vitamin D offered no benefit over standard dosing, but individualized monitoring improved safety. Limited evidence demonstrated that active or reflex-based physiotherapy improved bone density and growth but with some concerns for safety; passive approaches had limited effect. CONCLUSION: Continuous high-dose calcium and organic phosphate are particularly beneficial. Standardized diagnostic criteria for biochemical and radiological MBDP assessment are needed, as the absence of consensus disease definitions remains a major barrier to interstudy comparability, evidence synthesis, and the development of clinical intervention protocols. REGISTRATION: This systematic review was prospectively registered with PROSPERO (CRD420251116486).