# Interventions for metabolic bone disease of prematurity: A systematic review and meta-analysis

## TL;DR

This study reviews interventions to prevent and treat metabolic bone disease in premature infants, finding that nutritional and mechanical approaches significantly reduce disease incidence and improve bone health.

## Contribution

The study provides conclusive evidence that nutritional prophylaxis and mechanical interventions effectively prevent and treat metabolic bone disease of prematurity.

## Key findings

- Nutritional prophylaxis reduced MBDP incidence by 54%, with early calcium/phosphorus supplementation achieving 74–84% risk reduction.
- Mechanical interventions improved bone mineral content by 28% and increased weight gain in preterm infants.
- Both interventions showed favorable safety profiles, with no adverse events reported for mechanical protocols.

## Abstract

Metabolic bone disease of prematurity (MBDP) affects up to 30 % of very low birth weight infants; however, evidence regarding prevention and treatment strategies remains limited. We aimed to evaluate the efficacy and safety of nutritional, mechanical, and pharmacological interventions for MBDP.

Following PRISMA 2020 guidelines, we searched five databases from inception to May 5, 2025, for studies evaluating interventions for MBDP in preterm infants (<37 weeks or <1500g). Primary outcomes included MBDP incidence, bone mineral density, and safety profiles. Random-effects meta-analyses, trial sequential analysis (TSA), and GRADE assessments were conducted.

Eighteen studies (1577 infants) from ten countries met inclusion criteria. Nutritional prophylaxis significantly reduced MBDP incidence by 54 % (risk ratio [RR] = 0.46, 95 % confidence interval [CI] 0.30–0.68, P-value<0.001), with early calcium/phosphorus supplementation achieving 74–84 % risk reduction. TSA confirmed conclusive evidence, with cumulative Z-score (−5.99) crossing the O'Brien-Fleming boundary at 270.9 % of required information size. Number needed to treat was five at 40 % baseline risk. Mechanical interventions improved bone mineral content by 28 % (P-value<0.01), quantitative ultrasound speed-of-sound (mean difference [MD] = 75.3 m/s, 95 % CI 45.2–105.4), and weight gain (MD = 5.11 g/kg/day, 95 % CI 3.95–6.27). Both interventions demonstrated favorable safety profiles, with mechanical protocols reporting no adverse events.

Nutritional prophylaxis conclusively reduces MBDP incidence, while mechanical interventions effectively improve bone mineralization. Although no studies directly evaluated combined approaches, the complementary mechanisms of nutritional and mechanical interventions suggest that optimal prevention may involve integrating both strategies. Critical gaps persist in orthopedic management, necessitating future research on fracture protocols and surgical interventions.