Vitamin D Deficiency as a Debatable Modulator of Outcomes in Transfusion-Dependent Thalassemia; An Overview of the Latest Findings: A Narrative Review.

Background and Aims: Vitamin D deficiency (VDD) is highly prevalent in transfusion-dependent thalassemia (TDT), yet its clinical implications beyond bone health remain controversial. This review explores the risk factors and clinical outcomes of VDD in TDT, with particular focus on its potential roles in cardiac iron deposition, osteoporosis, and musculoskeletal growth disturbances. Methods: We conducted a comprehensive narrative review of 72 eligible studies published between 2003 and 2024, including observational, interventional, and genetic association studies. Databases searched were PubMed, Google Scholar (top 100 records), ScienceDirect, Cochrane Library, Springer, Web of Science, and Wiley Online Library, using keywords such as "thalassemia," "vitamin D," "siderosis," "osteoporosis," and "cardiac dysfunction." Results: VDD in TDT is multifactorial, with key drivers including aging, hepatic iron overload (ferritin > 1000 ng/mL; OR 2.31-2.62), endocrine dysfunction, and VDR polymorphisms (e.g., FokI/ff). More than 60% of TDT patients remain vitamin D deficient despite supplementation. VDD is associated with reduced bone mineral density, impaired growth and development, rickets, osteomalacia, and musculoskeletal weakness. Cardiovascularly, VDD independently correlates with cardiac iron deposition (via l-type calcium channels), elevated PTH, and NT-proBNP, contributing to left ventricular dysfunction (ejection fraction r = 0.33-0.40, p < 0.05). Conclusion: VDD is a critical and underappreciated modulator of cardiac and skeletal complications in TDT. While vitamin D supplementation improves calcium metabolism and reduces secondary hyperparathyroidism, its ability to reverse osteoporosis and cardiac changes is limited unless combined with targeted treatments addressing other contributors, such as hypogonadism and iron overload. Further research is needed to clarify persistent VDD mechanisms in TDT.