Comprehensive evaluation of the efficacy and safety of different vitamin D combination regimens based on indirect comparisons for children with rickets: a network meta-analysis.

BACKGROUND

Nutritional rickets is a major pediatric bone disorder closely associated with vitamin D deficiency. Clinical practice has gradually shifted from vitamin D monotherapy toward combination regimens aiming to enhance therapeutic efficacy through complementary mechanisms. However, head-to-head evidence comparing different vitamin D-based combinations remains limited, and their relative efficacy and safety rankings are unclear.

OBJECTIVE

To systematically compare the efficacy and safety of different oral vitamin D-based combination therapies for nutritional rickets in children and to provide evidence-based guidance for clinical decision-making.

METHODS

We conducted a systematic search of PubMed, Embase, the Cochrane Library, Web of Science, CNKI, Wanfang, and VIP databases, followed by a Bayesian network meta-analysis. The study protocol was prospectively registered in PROSPERO (CRD420251029274).

RESULTS

Ten randomized controlled trials involving 867 children were included, comparing nine vitamin D-based combination regimens with vitamin D3 monotherapy. Pairwise meta-analyses showed that combination therapies significantly improved serum 25-hydroxyvitamin D levels, reduced bone-specific alkaline phosphatase, and increased serum calcium and phosphate concentrations, without an increased risk of adverse events. Subgroup analyses indicated significantly greater benefits among term infants than preterm infants (P < 0.001). Network meta-analysis revealed distinct relative advantages across outcomes among different combinations. Sensitivity analyses confirmed the robustness of the findings.

CONCLUSION

Vitamin D-based combination therapies are overall more effective than vitamin D3 monotherapy in improving biochemical markers of bone metabolism in children with rickets, without compromising safety. Different regimens exhibit outcome-specific advantages, with clearer benefits observed in term infants. These findings support individualized, goal-oriented combination strategies, although further high-quality trials are required to strengthen the evidence base.

SYSTEMATIC REVIEW REGISTRATION: https://www.crd.york.ac.uk/prospero/, identifier CRD420251029274.