{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,8]],"date-time":"2026-04-08T06:08:42Z","timestamp":1775628522822,"version":"3.50.1"},"reference-count":49,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,4,8]],"date-time":"2026-04-08T00:00:00Z","timestamp":1775606400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Nutr."],"abstract":"\n Background<\/jats:title>\n 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.<\/jats:p>\n <\/jats:sec>\n \n Objective<\/jats:title>\n To systematically compare the efficacy and safety of different oral vitamin D\u2013based combination therapies for nutritional rickets in children and to provide evidence-based guidance for clinical decision-making.<\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n 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).<\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n Ten randomized controlled trials involving 867 children were included, comparing nine vitamin D\u2013based 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 (\n P<\/jats:italic>\n &lt; 0.001). Network meta-analysis revealed distinct relative advantages across outcomes among different combinations. Sensitivity analyses confirmed the robustness of the findings.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusion<\/jats:title>\n 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.<\/jats:p>\n <\/jats:sec>\n \n Systematic review registration<\/jats:title>\n \n https:\/\/www.crd.york.ac.uk\/prospero\/<\/jats:ext-link>\n , identifier CRD420251029274.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.3389\/fnut.2026.1785775","type":"journal-article","created":{"date-parts":[[2026,4,8]],"date-time":"2026-04-08T05:31:44Z","timestamp":1775626304000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["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"],"prefix":"10.3389","volume":"13","author":[{"given":"Yunfeng","family":"Cao","sequence":"first","affiliation":[{"name":"Hunan University of Chinese Medicine","place":["Changsha, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yan","family":"Zheng","sequence":"additional","affiliation":[{"name":"Hunan University of Chinese Medicine","place":["Changsha, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yaling","family":"Chen","sequence":"additional","affiliation":[{"name":"Hunan University of Chinese Medicine","place":["Changsha, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qihua","family":"Chen","sequence":"additional","affiliation":[{"name":"The First Hospital of Hunan University of Chinese Medicine","place":["Changsha, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xinbin","family":"Xia","sequence":"additional","affiliation":[{"name":"Hunan University of Chinese Medicine","place":["Changsha, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ziyi","family":"Yuan","sequence":"additional","affiliation":[{"name":"Hunan University of Chinese Medicine","place":["Changsha, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Honghui","family":"Li","sequence":"additional","affiliation":[{"name":"The First Hospital of Hunan University of Chinese Medicine","place":["Changsha, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2026,4,8]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"96","DOI":"10.1038\/s41574-021-00593-z","article-title":"The health effects of vitamin D supplementation: evidence from human studies","volume":"18","author":"Bouillon","year":"2022","journal-title":"Nat Rev Endocrinol."},{"key":"B2","doi-asserted-by":"publisher","first-page":"100032","DOI":"10.1016\/j.pharmr.2024.100032","article-title":"Vitamin D and its analogs in immune system regulation","volume":"77","author":"Artusa","year":"2025","journal-title":"Pharmacol Rev."},{"key":"B3","doi-asserted-by":"publisher","first-page":"366","DOI":"10.1038\/s41574-022-00662-x","article-title":"Interdisciplinary management of FGF23-related phosphate wasting syndromes: a Consensus Statement on the evaluation, diagnosis and care of patients with X-linked hypophosphataemia","volume":"18","author":"Trombetti","year":"2022","journal-title":"Nat Rev Endocrinol."},{"key":"B4","doi-asserted-by":"publisher","first-page":"887","DOI":"10.1016\/S0140-6736(24)01305-9","article-title":"X-linked hypophosphataemia","volume":"404","author":"Kamenicky","year":"2024","journal-title":"Lancet."},{"key":"B5","doi-asserted-by":"publisher","first-page":"44","DOI":"10.1038\/s41413-024-00343-7","article-title":"Coactivator-independent vitamin D receptor signaling causes severe rickets in mice, that is not prevented by a diet high in calcium, phosphate, and lactose","volume":"12","author":"Doms","year":"2024","journal-title":"Bone Res."},{"key":"B6","doi-asserted-by":"publisher","first-page":"44","DOI":"10.1111\/nyas.13968","article-title":"Global prevalence and disease burden of vitamin D deficiency: a roadmap for action in low- and middle-income countries","volume":"1430","author":"Roth","year":"2018","journal-title":"Ann N Y Acad Sci."},{"key":"B7","doi-asserted-by":"publisher","first-page":"100","DOI":"10.1038\/s41538-025-00460-5","article-title":"Vitamin D: recent advances, associated factors, and its role in combating non-communicable diseases","volume":"9","author":"Deepika","year":"2025","journal-title":"NPJ Sci Food"},{"key":"B8","doi-asserted-by":"publisher","first-page":"e227410","DOI":"10.1001\/jamanetworkopen.2022.7410","article-title":"Safety of high-dose vitamin D supplementation among children aged 0 to 6 years: a systematic review and meta-analysis","volume":"5","author":"Brustad","year":"2022","journal-title":"JAMA Netw Open."},{"key":"B9","doi-asserted-by":"publisher","first-page":"217","DOI":"10.1016\/j.it.2023.01.003","article-title":"Obesity and dysregulated innate immune responses: impact of micronutrient deficiencies","volume":"44","author":"Vrieling","year":"2023","journal-title":"Trends Immunol."},{"key":"B10","doi-asserted-by":"publisher","first-page":"108294","DOI":"10.1016\/j.pharmthera.2022.108294","article-title":"Comparative efficacy of different treatment modalities in the management of pediatric non-alcoholic fatty liver disease: a systematic review and network meta-analysis","volume":"240","author":"Theodoridis","year":"2022","journal-title":"Pharmacol Ther."},{"key":"B11","doi-asserted-by":"publisher","first-page":"731","DOI":"10.1016\/j.molmed.2024.12.005","article-title":"Probiotics in inflammatory bowel disease: microbial modulation and therapeutic prospects","volume":"31","author":"Vallejos","year":"2025","journal-title":"Trends Mol Med."},{"key":"B12","doi-asserted-by":"publisher","first-page":"2221429","DOI":"10.1080\/19490976.2023.2221429","article-title":"The effect of vitamin D supplementation on the gut microbiome in older Australians - results from analyses of the D-Health Trial","volume":"15","author":"Pham","year":"2023","journal-title":"Gut Microbes."},{"key":"B13","doi-asserted-by":"publisher","first-page":"1793","DOI":"10.20246\/j.cnki.issn.1001-8174.2024.12.018","article-title":"Observation on the efficacy of vitamin D calcium phosphate glucose tablets in treating vitamin D deficiency rickets in children","volume":"35","author":"Huang","year":"2024","journal-title":"Mod Diagn Treat."},{"key":"B14","doi-asserted-by":"publisher","first-page":"108","DOI":"10.19435\/j.1672-1721.2023.11.036","article-title":"Observation of the efficacy of Xinjia Yupingfeng soup combined with vitamin D in the treatment of early vitamin D deficiency rickets","volume":"27","author":"Wang","year":"2023","journal-title":"Med Forum."},{"key":"B15","doi-asserted-by":"publisher","first-page":"34","DOI":"10.3969\/j.issn.1672-0369.2022.02.014","article-title":"Effects of Saccharomyces boulardii combined with vitamin D in treatment of children with rickets","author":"Liu","year":"2022","journal-title":"Med J Chin Peoples Health"},{"key":"B16","doi-asserted-by":"publisher","first-page":"3","DOI":"10.3969\/j.issn.2097-115X.whbb202409026","article-title":"Effect of Xiao'er Siwei Pugai Granules combined with Vitamin D treating children with vitamin D deficiency rickets","author":"Xu","year":"2024","journal-title":"J Women Child Health Guide"},{"key":"B17","doi-asserted-by":"publisher","first-page":"3366","DOI":"10.3969\/j.issn.1003-6350.2024.23.005","article-title":"Effect of Sijunzi Tang combined with vitamin D in the treatment of vitamin D-deficient rickets and its influence on bone metabolism indexes","volume":"35","author":"Zhang","year":"2024","journal-title":"Hainan Med J."},{"key":"B18","doi-asserted-by":"publisher","first-page":"33","DOI":"10.13638\/j.issn.1671-4040.2020.12.015","article-title":"Clinical observation of calcium carbonate D3 granules combined with vitamin D in the treatment of rickets in children","volume":"20","author":"Meng","year":"2020","journal-title":"Pract Clin J Integr Tradit Chin West Med."},{"key":"B19","unstructured":"Clinical effect of calcium and zinc gluconates combined with vitamin D in treatment of children with vitamin D deficiency rickets\n \n 7\n 9\n \n \n Jiang\n W\n \n \n Shi\n X\n \n \n Zhu\n S\n \n \n Chin Community Doctors.\n 41\n 2025"},{"key":"B20","unstructured":"Clinical effect of calcitriol combined with Vitamin D in the treatment of rickets in children\n \n 2\n \n \n Zhang\n X\n \n \n J Women Child Health Guide\n \n 2023"},{"key":"B21","doi-asserted-by":"publisher","first-page":"13","DOI":"10.19787\/j.issn.1008-1879.2022.14.009","article-title":"Analysis of the effect of adjuvant treatment of rickets in premature infants with alfacalcidol","author":"Hu","year":"2022","journal-title":"Tradit Chin Med Rehabil"},{"key":"B22","unstructured":"Effect of calcitriol combined with vitamin D on bone growth and development in children with rickets\n \n 87\n 8\n \n \n Liu\n Y\n \n \n Pract Clin J Integr Tradit Chin West Med.\n 17\n 2017"},{"key":"B23","doi-asserted-by":"publisher","first-page":"101876","DOI":"10.1016\/j.beem.2024.101876","article-title":"Vitamin D deficiency or resistance and hypophosphatemia","volume":"38","author":"Sarathi","year":"2024","journal-title":"Best Pract Res Clin Endocrinol Metab."},{"key":"B24","doi-asserted-by":"publisher","first-page":"63","DOI":"10.1016\/j.aninu.2025.02.004","article-title":"Determination of optimal dietary calcium levels under different zinc sources in Jing Tint 6 layer chicks from hatch to day 14","volume":"21","author":"Gong","year":"2025","journal-title":"Anim Nutr."},{"key":"B25","doi-asserted-by":"publisher","first-page":"1038960","DOI":"10.3389\/fimmu.2022.1038960","article-title":"Reduced vitamin D-induced cathelicidin production and killing of Mycobacterium tuberculosis in macrophages from a patient with a non-functional vitamin D receptor: a case report","volume":"13","author":"Al-Jaberi","year":"2022","journal-title":"Front Immunol."},{"key":"B26","doi-asserted-by":"publisher","first-page":"7510","DOI":"10.1080\/10408398.2022.2047005","article-title":"The regulative effect and repercussion of probiotics and prebiotics on osteoporosis: involvement of brain-gut-bone axis","volume":"63","author":"Zhang","year":"2023","journal-title":"Crit Rev Food Sci Nutr."},{"key":"B27","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1186\/s13020-025-01291-y","article-title":"The scientific basis of synergy in traditional Chinese medicine: physicochemical, pharmacokinetic, and pharmacodynamic perspectives","volume":"21","author":"Wang","year":"2026","journal-title":"Chin Med."},{"key":"B28","unstructured":"Multi-center randomized controlled clinical trial of Longmu Zhuanggu Granule in treatment of sweating syndrome with lung and spleen qi deficiency in children (early stage of vitamin D deficiency rickets)\n \n 1351\n 6\n \n \n Li\n H\n \n \n Hu\n S\n \n \n Zhang\n Y\n \n \n China Tradit Chin Med Pharm.\n 38\n 2023"},{"key":"B29","doi-asserted-by":"publisher","first-page":"998","DOI":"10.1016\/j.ajcnut.2023.02.011","article-title":"Serum 1,25-dihydroxyvitamin D levels in the diagnosis and pathogenesis of nutritional rickets - a multivariable re-analysis of a case-control study","volume":"117","author":"Fischer","year":"2023","journal-title":"Am J Clin Nutr."},{"key":"B30","doi-asserted-by":"publisher","first-page":"1298181","DOI":"10.3389\/fphar.2024.1298181","article-title":"Modulation of the vitamin D receptor by traditional Chinese medicines and bioactive compounds: potential therapeutic applications in VDR-dependent diseases","volume":"15","author":"Yao","year":"2024","journal-title":"Front Pharmacol."},{"key":"B31","unstructured":"Mechanism of Sijunzi Tang for improving osteosarcopenia rats based on Toll-like receptor 4\/nuclear factor-\u03baB pathway\n \n 42\n 54\n \n \n Ou\n F\n \n \n Peng\n Y\n \n \n Liu\n T\n \n \n Qin\n Y\n \n \n Chin J Comp Med.\n 36\n 2026"},{"key":"B32","doi-asserted-by":"publisher","first-page":"157447","DOI":"10.1016\/j.phymed.2025.157447","article-title":"Study on the unique effects of Wubi Shanyao Pills in improving postmenopausal osteoporosis via the \u201cgut-bone\u201d axis","volume":"148","author":"Jin","year":"2025","journal-title":"Phytomedicine."},{"key":"B33","doi-asserted-by":"publisher","first-page":"288","DOI":"10.1016\/j.ijbiomac.2021.12.168","article-title":"Shell water-soluble matrix protein from oyster shells promoted proliferation, differentiation and mineralization of osteoblasts in vitro and vivo","volume":"201","author":"Feng","year":"2022","journal-title":"Int J Biol Macromol"},{"key":"B34","doi-asserted-by":"publisher","first-page":"107372","DOI":"10.1016\/j.phrs.2024.107372","article-title":"A Saccharomyces boulardii-derived antioxidant protein, thioredoxin, ameliorates intestinal inflammation through transactivating epidermal growth factor receptor","volume":"208","author":"Qin","year":"2024","journal-title":"Pharmacol Res."},{"key":"B35","doi-asserted-by":"publisher","first-page":"120616","DOI":"10.1016\/j.lfs.2022.120616","article-title":"Saccharomyces boulardii exerts renoprotection by modulating oxidative stress, renin angiotensin system and uropathogenic microbiota in a murine model of diabetes","volume":"301","author":"Abreu","year":"2022","journal-title":"Life Sci."},{"key":"B36","doi-asserted-by":"publisher","first-page":"127741","DOI":"10.1016\/j.micres.2024.127741","article-title":"Effects of fructooligosaccharides and Saccharomyces boulardii on the compositional structure and metabolism of gut microbiota in students","volume":"285","author":"Fu","year":"2024","journal-title":"Microbiol Res."},{"key":"B37","doi-asserted-by":"publisher","first-page":"340","DOI":"10.1007\/s00535-024-02183-y","article-title":"Fungal mycobiome dysbiosis in choledocholithiasis concurrent with cholangitis","volume":"60","author":"Hao","year":"2025","journal-title":"J Gastroenterol."},{"key":"B38","doi-asserted-by":"publisher","first-page":"1306","DOI":"10.1016\/j.ajcnut.2025.07.028","article-title":"Effects of weekly cholecalciferol supplementation of lactating mothers on vitamin D status, and infant growth and gross motor development: a randomized controlled trial in rural Ethiopia","volume":"122","author":"Girma","year":"2025","journal-title":"Am J Clin Nutr."},{"key":"B39","article-title":"Treatment of children and adults with X-linked hypophosphatemia with calcitriol alone: a prospective open label study","author":"Mitchell","year":"2025","journal-title":"J Clin Endocrinol Metab"},{"key":"B40","doi-asserted-by":"publisher","first-page":"1233","DOI":"10.1002\/jbmr.4566","article-title":"Safety and efficacy of PTH 1-34 and 1-84 therapy in chronic hypoparathyroidism: a meta-analysis of prospective trials","volume":"37","author":"Puliani","year":"2022","journal-title":"J Bone Miner Res."},{"key":"B41","doi-asserted-by":"publisher","first-page":"101254","DOI":"10.1016\/j.eclinm.2021.101254","article-title":"High-dose vitamin D supplementation in pregnancy and 25(OH)D sufficiency in childhood reduce the risk of fractures and improve bone mineralization in childhood: follow-up of a randomized clinical trial","volume":"43","author":"Brustad","year":"2022","journal-title":"EClinicalMedicine."},{"key":"B42","doi-asserted-by":"publisher","first-page":"1627190","DOI":"10.3389\/fped.2025.1627190","article-title":"Case report: atypical presentation of rickets with hypocalcemia-related emesis","volume":"13","author":"Francioni","year":"2025","journal-title":"Front Pediatr."},{"key":"B43","doi-asserted-by":"publisher","first-page":"2289","DOI":"10.1007\/s00467-022-05505-5","article-title":"Rickets guidance: part II-management","volume":"37","author":"Haffner","year":"2022","journal-title":"Pediatr Nephrol."},{"key":"B44","doi-asserted-by":"publisher","first-page":"114769","DOI":"10.1016\/j.colsurfb.2025.114769","article-title":"Dual-modulation of nutrient-transporter axis and functionalized carriers: a paradigm shift for precision oral vitamin D delivery","volume":"253","author":"Wang","year":"2025","journal-title":"Colloids Surf B Biointerfaces."},{"key":"B45","doi-asserted-by":"publisher","first-page":"250","DOI":"10.1186\/s12887-023-04068-0","article-title":"Analysis of risk factors for parenteral nutrition-associated cholestasis in preterm infants: a multicenter observational study","volume":"23","author":"Wang","year":"2023","journal-title":"BMC Pediatr."},{"key":"B46","doi-asserted-by":"publisher","first-page":"e71094","DOI":"10.7554\/eLife.71094","article-title":"Placental uptake and metabolism of 25(OH) vitamin D determine its activity within the fetoplacental unit","volume":"11","author":"Ashley","year":"2022","journal-title":"Elife"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1053\/j.ajkd.2024.03.025","article-title":"Vitamin D metabolites before and after kidney transplantation in patients who are anephric","author":"J\u00f8rgensen","year":"2024","journal-title":"Am J Kidney Dis"},{"key":"B48","doi-asserted-by":"publisher","first-page":"790","DOI":"10.1001\/jamapediatrics.2021.0678","article-title":"Fortification of breast milk with preterm formula powder vs human milk fortifier in preterm neonates: a randomized noninferiority trial","volume":"175","author":"Chinnappan","year":"2021","journal-title":"JAMA Pediatr."},{"key":"B49","doi-asserted-by":"publisher","first-page":"RP97830","DOI":"10.7554\/eLife.97830.3","article-title":"Altered hepatic metabolism mediates sepsis preventive effects of reduced glucose supply in infected preterm newborns","volume":"13","author":"B\u00e6k","year":"2025","journal-title":"Elife"}],"container-title":["Frontiers in Nutrition"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnut.2026.1785775\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,8]],"date-time":"2026-04-08T05:31:51Z","timestamp":1775626311000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnut.2026.1785775\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,8]]},"references-count":49,"alternative-id":["10.3389\/fnut.2026.1785775"],"URL":"https:\/\/doi.org\/10.3389\/fnut.2026.1785775","relation":{},"ISSN":["2296-861X"],"issn-type":[{"value":"2296-861X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,8]]},"article-number":"1785775"}}