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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.

  • 2026-04-08
  • Frontiers in nutrition 13
    • Yunfeng Cao
    • Yan Zheng
    • Yaling Chen
    • Qihua Chen
    • Xinbin Xia
    • Ziyi Yuan
    • Honghui Li

Study Design

Type
Systematic Review
Sample size
n = 867
Population
children with nutritional rickets
Methods
systematic search of PubMed, Embase, the Cochrane Library, Web of Science, CNKI, Wanfang, and VIP databases, followed by a Bayesian network meta-analysis
Funding
Unclear

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.

Research Insights

Adverse Events Reported

  • Vitamin D→Overall tolerability

    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.

    Finding
    No significant difference
    Significant
    No
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