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

ABSTRACT

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.

1. Introduction

Transfusion‐dependent thalassemia (TDT) is a life‐threatening congenital anemia characterized by ineffective erythropoiesis and chronic tissue hypoxia, necessitating lifelong blood transfusions [1]. While transfusions ameliorate anemia, they inevitably lead to iron overload, which progressively damages vital organs, including the heart, liver, and endocrine systems [2, 3, 4].

Among the multifaceted complications of TDT, vitamin D deficiency (VDD) stands out as a highly prevalent yet understudied comorbidity, affecting up to 90% of patients [5]; Despite its high prevalence, the clinical implications of VDD in TDT extend beyond skeletal health, with emerging evidence suggesting roles in cardiac dysfunction, immune dysregulation, and metabolic disturbances [5, 6, 7, 8, 9].

The relationship between ferritin, VDD, and cardiac pathology in TDT remains contentious. While some studies report an inverse correlation between ferritin and vitamin D levels (e.g., hepatic iron impairing 25‐hydroxylation [10]), others paradoxically note elevated ferritin in vitamin d‐replete patients, suggesting fibroblast growth factor 23 (FGF23)‐mediated crosstalk [11]. Similarly, cardiac iron deposition—a hallmark of TDT cardiomyopathy—has been linked to VDD via l‐type calcium channel (LTCC)‐mediated iron uptake [12], yet other studies found no direct association between cardiac T2* MRI and vitamin D status [13]. These discrepancies have been attributed to confounding factors, including (1) Methodological heterogeneity: Studies used varying VDD thresholds (e.g., <15 ng/mL vs. <20 ng/mL), cardiac iron assessment tools (T2* MRI vs. echocardiography), and statistical adjustments for covariates. Shaykhbaygloo et al. [13] utilized cardiac T2* MRI (gold standard), whereas Yozgat et al. [12] relied solely on LVEF measurements via speckle‐tracking echocardiography—a less sensitive metric for early dysfunction. (2) Population heterogeneity: Cohorts differed in age distributions (pediatric [12] vs. adult [10]), iron chelation regimens (deferasirox vs. deferoxamine), and endocrine comorbidities (e.g., hypoparathyroidism prevalence in Saki et al. [11]). 3) Geographic and genetic modifiers: Iranian cohorts [10, 11] had higher baseline VDD prevalence (latitude, cultural sun‐avoidance) than Mediterranean studies [14], potentially amplifying ferritin‐VDD relationships. Recent evidence confirms VDR‐FokI/ff genotype frequency varies by ethnicity, altering vitamin D bioavailability independently of iron status [15, 16].

Future studies should standardize VDD definitions, stratify analyses by chelator type/genotype, and employ multivariable modeling to isolate iron‐specific effects.

By critically appraising these conflicts, this review highlights the need for standardized biomarkers and prospective studies to clarify VDD's role in TDT outcomes, also this narrative review aims to synthesize current evidence on the pathophysiology and risk factors of VDD in TDT, with emphasis on the controversial role of ferritin and hepatic iron overload, evaluate the conflicting data on the association between VDD, ferritin levels, and cardiac complications (e.g., iron deposition, ventricular dysfunction) and discuss clinical management gaps and propose strategies for optimizing vitamin D supplementation in TDT. VDD is a highly prevalent phenomenon… especially bones and the skeletal system, as well as other tissues and organs (Figure 1). Table 1 summarizes key clinical studies highlighting these controversies, including population characteristics, VDD definitions, and divergent findings on ferritin‐VDD relationships and cardiac outcomes.

Figure 1.

Absorption, biogenesis and function of Vitamin D. The requirement for vitamin D is fulfilled through exposure to sunlight, dietary sources, and supplementation. Vitamin D, once absorbed in the liver, is enzymatically converted by 25‐hydroxylase into 25‐OH‐D (calcidiol), which serves as the storage and circulating form of vitamin D. This metabolite is subsequently transformed in the kidneys by the enzyme 1‐alpha‐hydroxylase, along with the influence of parathyroid hormone (PTH), into 1,25‐OH‐D (calcitriol), the biologically active variant of vitamin D. Calcitriol is instrumental in modulating immune responses, controlling pathogen entry, and mitigating the development of autoimmune disorders by influencing immune cell function. Furthermore, this compound is pivotal in regulating cellular growth and differentiation across diverse bodily tissues. Within the kidneys, calcitriol executes multiple roles, including the modulation of the immune system, the preservation of bone and muscle integrity, and the regulation of blood pressure, among other functions.

Table 1.

Conflicting evidence on vitamin D deficiency in transfusion‐dependent thalassemia: Key clinical studies.

Study (Reference)	Population	VDD definition	Key findings on ferritin‐VDD relationship	Cardiac iron/function findings
Darvishi‐Khezri et al. [10]	Iran, 180 TDT patients, mean age 25.5 years	< 20 ng/mL (severe: <10)	Inverse correlation (ferritin ↑ =VDD ↑)	Not assessed
Saki et al. [11]	Iran, 60 thalassemia patients (30 with hypoparathyroidism, 30 without)	< 20 ng/mL	Positive correlation (ferritin ↑ =VDD ↓)	Not assessed
Yozgat et al. [12]	Turkey, 40 children with beta‐thalassemia	< 20 ng/mL	Not reported	VDD associated with ↓ LVEF (r = 0.40, p < 0.05)
Shaykhbaygloo et al. [13]	Iran, 50 thalassemia major patients	< 20 ng/mL	No significant correlation	No correlation with cardiac T2* MRI
Dimitriadou et al. [14]	Greece, 62 beta‐thalassemia major patients	< 15 ng/mL	Not reported	PTH predicts cardiac iron (p < 0.001)
Pala et al. [6]	Italy, 112 TDT patients, mean age 30.2 years	< 20 ng/mL	Ferritin >1000 ng/mL linked to VDD (OR 3.1)	VDD associated with ↓ LVEF (r = 0.38, p = 0.01)

2. Vitamin D Functional Pathways in TM

Two hydroxylation processes, the first one in the liver and the second in the kidney, result in the production of the metabolically active form of vitamin D, known as 1,25‐dihydroxyvitamin D3. The product of the first hydroxylation reaction in the liver, 25 OHD, constitutes the main form of vitamin D in circulation and more accurately reflects the reserves of this vitamin in the body. The main functional role of vitamin D is known to be the facilitation of calcium retention by various mechanisms [17]. Reduced vitamin d‐dependent intestinal calcium absorption contributes to disturbed calcium metabolism and osteopenia in thalassemic mice [18]. In hemizygous β‐globin knockout mice, impaired duodenal calcium absorption could be corrected by vitamin D and hepcidin supplementation [19]. Another function of vitamin D, along with other contributors such as calcium, is to preserve the bone mineral density (BMD) in BTM patients [20]; nevertheless, regardless of efforts to supplement sufficient vitamin D levels, these patients seem to finally develop low BMD, opposing an independent role for vitamin D in maintaining adequate bone mass in TM patients [21], a process that is profoundly affected by a thread of complications such as hypogonadism, iron‐chelator toxicity, endocrinopathies, and imbalanced bone turn over [22].

Beyond bone demineralization, VDD significantly contributes to musculoskeletal complications in thalassemia. Proximal muscle weakness and myopathy are common manifestations, resulting from impaired calcium signaling in skeletal muscle fibers [23]. This manifests clinically as reduced muscle strength, fatigue, and increased fall risk—particularly concerning in osteoporotic patients where falls may precipitate fractures. Studies report diminished physical performance scores and reduced activity tolerance in thalassemia patients with VDD compared to sufficient peers [24]. Mechanistically, VDD disrupts vitamin D receptor (VDR)‐mediated transcription of myogenic factors like MyoD and myogenin, compromising muscle regeneration [25]. This process is exacerbated by iron overload‐induced mitochondrial dysfunction in myocytes, creating a cycle of muscle wasting and weakness that further limits mobility and rehabilitation potential [26].

3. Risk Factors of VDD in TDT Patients

Generally, patients with 25(OH)D levels below 20 ng/mL are considered deficient, and those with levels between 20 and 30 ng/mL are in the borderline zone [27]. A possible risk factor for VDD in TDT patients is malnutrition [28, 29], but the role of nutritional status is controversial, given that even taking vitamin D supplementations has been able to rebound the levels of this vitamin to sufficient levels only in some, but not all, BTM patients [10, 30]. In fact, a large number of patients would remain in the deficiency or borderline zones after receiving such supplements regardless of the dose and route of administration [30, 31, 32]. Even taking sufficient amounts of nutrients through diet in BTM patients cannot guarantee maintaining of sufficient levels of vitamins and micronutrients, suggesting roles for other contributory factors such as excessive loss or consumption [33]. The development of VDD in BTM patients seems to be independent of some previously thought important demographic features, such as sex, ethnicity, living environment, sunlight exposure, etc.; however, age seems to invariably and inversely correlate with vitamin D levels in these patients [34]. The likelihood of VDD in BTM patients substantially increases with age [34, 35], and age seems to be a main predictor of VDD, with older BTM patients retaining lower levels of vitamin D compared to their younger counterparts [34]. This phenomenon correlates with an increase in hepatic iron overload with advancing age [36]. Consistently, elevated ferritin, higher hepatic iron load, and elevated serum ALT were suggested as independent predictors of VDD in patients with TDT [37]. In line, serum ferritin was observed to be a negative predictor of 25(OH)D levels in TM patients [34]. The metabolism of vitamin D, including its hydroxylation and synthesis, is disrupted following the accumulation of iron in the liver and skin, predisposing TM patients to VDD. In fact, VDD in TM has been suggested to be less related to dietary condition or sun exposure, but more to metabolic disturbances caused by deposited iron [38]. Contradictory to this observation, a positive correlation was reported between ferritin level and vitamin D levels in BTM patients, suggesting that FGF23 could role as a mediator exerting the stimulating effects of ferritin on vitamin D levels [39]. Compared to healthy individuals with VDD, BTM patients suffering from this condition revealed lower PTH and ALP levels [32]. Another study reported significantly higher PTH levels (p < 0.05) in thalassemia patients with VDD compared to peers who had normal vitamin D levels [34]. On the other hand, BTM patients who are deficient in vitamin D circulating levels (i.e., 25‐OH‐D3), may have normal or even elevated concentration of metabolically active vitamin D (1‐25‐OH‐D3), which may be explained by secondary hyperparathyroidism. Following a drop in 25‐OH‐D3 levels, compensatory elevation in PTH occurs to ensure the bioavailability of the metabolically active form of this vitamin (Table 2) [40, 46].

Table 2.

Expanded risk factors for vitamin D deficiency in transfusion‐dependent thalassemia (TDT) patients.

Risk factor	Details	Mechanism of impact	Clinical outcomes	Ref.
Malnutrition	Poor dietary intake of vitamin D precursors worsens deficiency.	Reduced intestinal absorption of vitamin D	Increased risk of deficiency, reduced bone mineral density	[2, 5, 7]
Malnutrition	Poor dietary intake contributes to inadequate vitamin D precursors.	Reduced intestinal absorption due to impaired fat metabolism	Persistent deficiency despite supplementation	[28, 30]
Transfusion dependence	Frequent transfusions may affect micronutrient balance.	Altered iron metabolism and inflammatory states	Increased risk of cardiac and skeletal complications	[31, 34]
Age	Older patients experience lower vitamin D levels due to hepatic iron overload and metabolic changes.	Impaired hydroxylation and decreased physical activity	Reduced bone mineral density (BMD), fractures	[34, 36]
Iron chelation therapy	Possible interference with micronutrient metabolism.	Reduction in vitamin D reserves due to chelator interactions	Mild vitamin D deficiency	[20, 37]
Hepatic iron overload	Excess iron in the liver disrupts vitamin D metabolism and activation.	Reduced the hydroxylation of vitamin D in the liver	Low vitamin D, increased risk of osteoporosis	[37, 38]
Endocrine disorders	Hypogonadism and secondary hyperparathyroidism impair vitamin D metabolism.	Hormonal disruptions and PTH elevation	Aggravated bone demineralization	[14, 22, 40]
Genetic polymorphisms	Variants in VDR (e.g., FokI, Bsml) are associated with lower vitamin D levels.	Altered receptor binding efficiency and vitamin bioavailability	Reduced BMD, increased osteoporosis risk	[15, 41, 42]
HCV infection	Independent risk factor for VDD and osteoporosis in thalassemia	Liver damage impairs 25‐hydroxylation of vitamin D	Reduced BMD, increased fracture risk	[43]
HIV infection	Transfusion‐related exposure; linked to VDD and bone loss	Chronic inflammation, malabsorption, ART effects	Accelerated osteoporosis, VDD severity	[44, 45]

Another contributor to VDD in BTM may be genetic signatures. The homozygote state for the Bsml polymorphism of VDR was reported to correlate with lower vitamin D and calcium levels in BTM patients [41]. Another VDR polymorphism known as FokI was also reported to be a potential contributor to VDD in thalassemic patients [47]. The mutant allele of FokI polymorphism (either in heterozygote (Ff) or homozygote (ff) states) could predict reduced levels of vitamin D [15] and lower bone mineral density (BMD) Z‐scores [48] in thalassemic patients. The role of variants in vitamin D binding protein [16] and VDR [42, 49] in vitamin D bioavailability in BTM patients merit more investigations. In addition, non‐transfusion‐dependent beta‐thalassemia patients have been reported to be more likely to develop VDD compared to their transfusion‐dependent counterparts [31, 50]; however, the possible role of transfusion in the development of VDD in BTM patients is not understood. As BTM is associated with chronic hemolysis, the relationship between vitamin D levels and hemolysis indices (lactate dehydrogenase, etc.) remains unclear and requires further investigation [51]. In a large multi‐center study in Iran in which both transfusion‐dependent and transfusion‐independent thalassemia patients participated, the main predictors of VDD were hepatic siderosis and elevated AST (ORs of 2.31 and 2.62, respectively) [10]. Also, disturbance in lipid metabolism may be a risk factor for VDD in thalassemic individuals [52]. Overall, it seems that we cannot blame a specific contributor as the main culprit of VDD in thalassemia; however, one cannot ignore the necessity of vitamin D supplementation in these patients, even in those who have apparently sufficient levels of this micronutrient.

4. Vitamin D and Bone Complications in TDT

Beta‐thalassemia patients, when they reach puberty, are exposed to a variety of transfusion‐dependent complications, including osteoporosis (which can reach up to 80%), growth impairment, rickets, and osteomalacia [53]. Similar to other sequelae of BTM, the relative contributions of different pathogenic mechanisms remain incompletely defined. Evidence supports a multifaceted phenomenon, comprising marrow expansion, hemosiderosis, hormonal disturbance, lower physical activity, reduced hepatic production of 25OH‐D (calcifediol), and genetic determinants, contributing to bone problems in BTM patients [54]. In children, VDD manifests as rickets (defective mineralization of growth plates) and growth retardation, characterized by delayed height velocity, bowing deformities, and widened metaphyse [55]. Adolescents and adults develop osteomalacia (impaired bone mineralization), leading to bone pain, proximal muscle weakness, and pathologic fractures [56]. These complications coexist with osteoporosis and are exacerbated by chronic anemia, endocrine dysfunctions (e.g., hypogonadism), and chelator toxicity [57].

Growth impairment affects 30%–50% of pediatric thalassemia patients [58]. VDD contributes to reduced insulin‐like growth factor 1 (IGF‐1) synthesis, disrupting chondrocyte differentiation in growth plates [17]. Hepatic iron overload further impairs the conversion of vitamin D to 25(OH)D, worsening rickets risk [33]. A 2020 study noted that 68% of thalassemic children with VDD had radiologic evidence of rickets, correlating with serum ferritin >1500 ng/mL (p = 0.01) [59].

The pathogenesis of bone disorders in BTM exhibits site‐specific complexity, with evidence suggesting distinct underlying mechanisms for bone resorption in different skeletal regions (e.g., femoral vs. lumbar). For example, a study noted that the FokI genetic variation of VDR was only associated with femoral, but not lumbar BMD [60]. In contrast, another study declared that FokI and Bsml polymorphisms of VDR were only associated with lumbar BMD in BTM patients [42]. In fact, despite efforts dedicated to identify the predictors of bone disease in BT patients, there are currently no reliable biological markers that can predict BMD and risk of bone fractures in these patients. The link between various bone resorption and bone formation markers and BMD has been noted to be inconclusive, warranting further studies in this area [54].

Osteomalacia in adults often presents insidiously. A 2023 study found that 41% of adult thalassemia patients with VDD (25(OH)D < 12 ng/mL) had elevated bone‐specific alkaline phosphatase (bALP > 20 μg/L), indicating mineralization defects [61]. Coexisting hypocalcemia and secondary hyperparathyroidism further drive bone demineralization [11].

While vitamin D is essential for calcium homeostasis and osteoblast function [17], its role in reversing osteoporosis in TDT is complex. Supplementation consistently improves biochemical markers (e.g., osteocalcin, PTH) [62, 63], yet fails to normalize BMD long‐term in >60% of patients [21]. This apparent contradiction arises because VDD‐induced bone loss is compounded by non‐vitamin D factors: iron‐mediated suppression of osteoblasts, hypogonadism, chelator toxicity (e.g., deferoxamine impairing collagen cross‐linking), and bone marrow expansion [22]. Vitamin D repletion alone cannot overcome established skeletal damage (e.g., trabecular microarchitecture defects) [64]. Thus, while VDD contributes to low BMD, its correction is necessary but insufficient for full skeletal recovery in TDT, necessitating adjunct therapies (e.g., bisphosphonates, hormone replacement) [64]. Recent prospective data confirm that combined vitamin D‐bisphosphonate regimens increase lumbar BMD by 8%–12% (p < 0.001 vs. vitamin D alone) [65].

The association between vitamin D levels, calcium turnover, and BMD is well‐established in BTM patients, evidenced by the elevation of BMD after receiving supplements containing these compounds [63], especially in patients who have not reached puberty yet [66]. However, with regard to the association between vitamin D levels and overall bone health in these patients, the results of studies indicate considerable discrepancy [67]. A study suggested that simultaneous supplementation with vitamin D and calcium, even in the long‐term, was insufficient to desirably boost BMD in thalassemia patients; however, enforcement with bisphosphonate could improve this parameter [68]. Patients with BTM and osteoporosis under treatment with vitamin D and calcium supplements showed reduced levels of OPG and higher levels of sRNAKL, as well as bone formation [osteocalcin (OC) and bone‐specific alkaline phosphatase (bALP)] and bone resorption [tartrate‐resistant acid phosphatase isoform‐5b (TRACP‐5b), N‐telopeptide of collagen type‐I (NTX), and deoxypyrydinoline (d‐PYR),] markers, among which only TRACP‐5b and NTX correlated with lumbar BMD [54]. For rickets/osteomalacia, high‐dose cholecalciferol (300,000 IU/month) combined with calcium (1000 mg/day) significantly improved radiographic healing and pain scores in VDD‐thalassemia patients (p < 0.001) [69].

In a study on transfusion‐dependent BTM patients, OC levels were elevated in 36% of the patients, and 62% of them were vitamin D deficient [53]. Abnormal activity of osteoclasts and osteoblasts can be a result of VDD, predisposing to bone disorders in BTM. The expression levels of the genes encoding Runx2, bALP, and OC were noted to be modulated by vitamin D supplementation in thalassemic patients (Table 3) [62]. A low serum calcium level in patients with BTM was reported to correlate with reduced levels of α‐Klotho protein [73], a vitamin D metabolism activation marker [74]. Another noteworthy point pertaining to BTM is the coincidence of multiple comorbidities, proposing a possible association between these events and vitamin D metabolism. For example, hepatitis C virus (HCV) infection was suggested as an independent event predisposing to VDD and osteoporosis, accompanied by reduced levels of OC in thalassemic patients with chronic HCV [43]. Similarly, human immunodeficiency virus (HIV) infection is linked to VDD and bone loss in BTM patients. Transfusion‐dependent individuals face an elevated risk of HIV acquisition due to frequent blood exposure. HIV exacerbates VDD through mechanisms including chronic inflammation, malabsorption, and altered vitamin D metabolism. Furthermore, HIV and certain antiretroviral therapies (ART) accelerate bone resorption and reduce bone mineral density, compounding thalassemia‐related osteoporosis. This synergy necessitates vigilant monitoring of vitamin D status and bone health in HIV‐positive BTM patients [44]. Despite advances in thalassemia management approaches and extensive supplementation with calcium and vitamin D, multifaceted bone complications remain a challenging issue in thalassemia, supporting the multifactorial pathogenesis of this condition in these patients, ranging from disease‐ and treatment‐related mediators to environmental factors [75, 76]. This notion is supported by the results of clinical trials noting the beneficial effects of the coadministration of vitamin D with compounds with somehow independent mechanisms of action, for example, strontium ranelate [77] and vitamin K [66], on boosting BMD in thalassemia patients.

Table 3.

Detailed clinical implications of vitamin D deficiency in transfusion‐dependent thalassemia.

Implication	Details	Biological mechanism	Impact on quality of life	Severity level	Proposed solutions	Ref.
Immunomodulatory effects	Deficiency leads to elevated pro‐inflammatory cytokines and reduced immune tolerance.	Dysregulated IL‐10 and TNF‐α pathways	Increased susceptibility to infections	Moderate	Anti‐inflammatory therapies and vitamin D optimization	[6, 70]
Muscle weakness	Muscle fatigue and reduced coordination increase fall risk.	Impaired calcium influx in muscle fibers	Higher injury and fracture rates	Moderate	Physiotherapy and vitamin D repletion	[10, 18]
Growth delays in children	Deficiency in vitamin D contributes to stunted skeletal development in younger patients.	Altered expression of osteocalcin and Runx2	Delayed height and poor bone strength	Moderate to High	Early intervention with calcitriol and nutritional support	[54, 62, 66]
Bone disorders	Increased fracture risk and low BMD, particularly in load‐bearing bones like spine and femur.	Reduced calcium absorption and impaired osteoblast function	Chronic pain and immobility	High	Vitamin D supplementation, calcium intake, bisphosphonates	[21, 63, 68]
Cardiac dysfunction	Linked to impaired myocardial contractility and ventricular hypertrophy	Altered calcium signaling in cardiac muscle cells	Fatigue, reduced exercise tolerance	Moderate to High	Cardiac rehabilitation and LVDCC blockers	[6, 71, 72]
Hyperparathyroidism	Elevated PTH levels disrupt calcium‐phosphorus balance, exacerbating bone loss.	Increased osteoclast activity and calcium efflux	Accelerated osteoporosis and renal calculi	High	Monitor PTH levels and optimize vitamin D supplementation	[14, 40]
Rickets/osteomalacia	Defective bone mineralization; rickets (children): growth plate deformities, bowing; osteomalacia (adults): bone pain, fractures	Impaired calcium‐phosphate homeostasis, reduced hydroxyapatite deposition	Skeletal deformities, mobility restrictions, chronic pain	High	High‐dose vitamin D3 (300,000 IU/month), calcium, phosphate supplements	[55, 61]
Growth impairment	Delayed linear growth, short stature, delayed puberty	Reduced IGF‐1, disrupted chondrogenesis, iron‐induced GH resistance	Reduced final adult height, psychosocial distress	Moderate‐High	Early vitamin D repletion, GH therapy, chelation optimization	[17, 58]

Pediatric thalassemia patients with VDD face significant growth impairments. Longitudinal studies indicate lower height‐for‐age Z‐scores (–2.1 ± 0.8 vs. –1.3 ± 0.6; p < 0.01) and delayed pubertal onset (Tanner stage delays ≥2 years in 42% vs. 18%; p = 0.003) compared to vitamin d‐sufficient counterparts [64]. VDD exacerbates growth failure through multiple pathways: (1) Direct inhibition of chondrocyte maturation and mineralization in growth plates via dysregulated FGF23‐klotho axis [78]; (2) Suppression of IGF‐1 synthesis and growth hormone (GH) sensitivity, already compromised by thalassemia‐related pituitary iron deposition [58]; and (3) Reduced calcium availability for skeletal mineralization, worsening rickets‐like changes in weight‐bearing bones [79]. Early intervention with high‐dose cholecalciferol (2000–4000 IU/day) during prepubertal stages has shown partial catch‐up growth (height velocity increase ≥0.5 SD/year) in 68% of patients, underscoring the critical window for nutritional correction [80].

5. Vitamin D and Cardiac Function

Traditional cardiovascular risk factors (e.g., diabetes, hypertension, dyslipidemia) synergize with cardiac hemosiderosis in the pathogenesis of cardiomyopathy in BTM patients. However, emerging evidence highlights the role of novel factors such as vitamin D in this pathway. In fact, VDD has been suggested as a worth‐noting parameter in predicting heart function in TM patients, in whom low levels of vitamin D have shown strong correlation with cardiac hemosiderosis and dysfunctional ventricles [6, 81, 82]. Vitamin D level has been noted to be positively associated with ejection fraction (EF) and fractional shortening (FS) in TDT patients [6, 83]. Also, lower vitamin D levels could predict mild systolic and diastolic dysfunction in adolescents with BTM [84]. In another study on 81 patients with BTM, vitamin D level also showed a positive correlation with EF (r = 0.33, p = 0.003) but not with diastolic function [85]. Moreover, TDT patients with cardiac siderosis were reported to have lower vitamin D levels (p = 0.06), but cardiac functional parameters, including LVEF or cardiac T2* score, were independent of vitamin D levels [86]. In another study on TM patients, LVEF showed a significant correlation with vitamin D levels (r = 0.33, p = 0.003) [85], a correlation that was reproduce in yet another similar study as well (r = 0.399, p = 0.019) [38].

On the other hand, there are also studies on BTM patients noting that vitamin D levels are not associated with cardiac T2* MRI [13] or LVEF [86]. Despite the assumed relationship between vitamin D level and cardiac siderosis, this relationship seems to be more correlated with the ratio of 25‐OH‐D3 to 1‐25‐(OH)‐D3 (the former being the storage form and the latter being the active metabolic form of vitamin D) [46]. In studies on TDT patients, vitamin D level was inversely associated with N‐terminal pro‐brain natriuretic peptide (NT‐proBNP) [38, 84], the amino terminal fragment of proBNP released following cardiac wall damage [8, 9] [38]. The binding of the metabolically active form of vitamin D (1, 25 (OH) D3) to its nuclear receptor inhibits the expression of atrial natriuretic peptide (ANP) and BNP in cardiac myocytes [87], which suggest a protective role for the administration of vitamin D in thalassemia patients against cardiac systolic and diastolic dysfunction [88]. In animals, vitamin D treatment has been associated with the improvement of cardiac structural (hypertrophy), functional (myocardial performance), and molecular (inhibition of natriuretic peptides and renin secretion) functions [71].

Secondary hyperparathyroidism due to VDD can also exaggerate the impact of reduced levels of vitamin D on cardiac function. The activation of l‐type voltage‐dependent calcium channels (LVDCC) is a result of the action of parathyroid hormone (PTH) on cardiomyocytes [72]. These calcium channels constitute the main entry route of Ca²⁺ into cardiomyocytes and have acquired attention in recent years for their possible role in the co‐transporting of iron into cardiac cells [71, 89]. It has been reported that the elevated levels of PTH correlate with cardiac hemosiderosis in BTM patients [14], a relationship proposed to be mediated by LVDCC‐triggered entry of non‐transferrin bound iron (NTBI) into cardiomyocytes [90]. Consistently, the overexpression of LVDCC on cardiac muscles has been declared in cardiomyocytes exposed to 1‐25‐OH‐D3 and PTH [46]. In this manner, VDD can indirectly predispose cardiac cells to more iron deposition via the mediating action of PTH [71, 72]. In fact, PTH was reported as the main predictor of cardiac iron overload in a study on 62 BTM patients, of whom 37 (60%) had severely low vitamin D level, and 7 (11%) had borderline vitamin D levels [14]. Moreover, VDD may exaggerate the activity of LVDCCs to transport calcium across cardiomyocytes, leading to the co‐transportation of NTBI into cardiac muscles. The close proximity of iron and calcium concentrations in heart muscles is another evidence supporting a role for LVDCCs in cardiac iron‐overload. Interestingly, this close correlation persisted after blocking LVDCCs, suggesting the existence of an additional, independent route for iron and calcium entry into cardiac cells [46]. Subsequently, iron deposited in cardiac cells triggers a series of oxidative stress‐mediated reactions exacerbating cardiac damage and disturbing the function of ion channels, possibly LVDCCs, in a vicious cycle.

The role of LVDCCs in cardiac siderosis remains debated. Observations in vitamin d‐deficient hemojuvelin‐knockout mice showed no change in cardiac iron; however, VDD led to an elevation in hepatic iron deposition. On the other hand, the most prominent predictor of cardiac iron level was cardiac calcium level (r (2) = 0.6; p < 0.0001). A correlation between cardiac and hepatic iron load in the animal models treated with LVDCC blockers suggests that these blockers may prevent cardiac iron deposition by mechanisms beside suppressing calcium channels on cardiac cells [46]. Verapamil, a LVDCC inhibitor, induced a concomitant reduction in both cardiac and liver iron [46], suggesting mechanisms beyond direct LVDCC blockade, potentially involving modulation of DMT1 activity [6]. In another study, verapamil led to a reduction in only cardiac, but not hepatic, iron, suggesting the specific suppression of iron entry through LVGCCs [91]. An explanation provided for this discrepancy is that in the recent study, iron dextran was utilized to create iron‐overload mice, leading to iron accumulation in hepatic macrophages rather than parenchyma, and the DMT1‐modulating effects of verapamil could only reduce the iron load in hepatocytes, where this transporter is expressed, but not in macrophages, which do not express this channel [92].

Other mechanisms implicated in the association between VDD and cardiomyopathy in BTM patients include an increase in iron absorption [46] and reducing cardiac muscles' contractility [38, 72]. Furthermore, the immunomodulatory effects of VDD likely contribute to cardiomyopathy in BTM patients. VDD promotes TNF‐α expression, implicated in inflammation and atherosclerosis, while vitamin D exerts anti‐inflammatory effects, partly mediated by IL‐10 induction [6].

6. Conclusion

Most TM patients are susceptible to develop VDD, and in some population, this condition may be even encountered in all patients reaching adulthood. Regarding the contribution of vitamin D in maintaining bone health, and its emerging role in preserving cardiac function, it is suggested to expand studies on the risk factors of VDD in these patients and consider long‐term and even lifelong supplementation with vitamin D and other micronutrients to prevent vitamin D levels falling below critical thresholds. Besides, regarding that VDD may develop even in adequately supplemented patients, studies are advisable to identify other unknown causes of vitamin D loss or consumption in TM patients.

Author Contributions

Ali Bazi: investigation, writing – original draft. Mahdieh Poodineh Moghadam: data curation, writing – original draft. Jafar Baranipour: data curation, investigation. Hajar Noori Sanchooli: writing – original draft, data curation, investigation. Hamed Soleimani Samarkhazan: writing – original draft, validation. Omolbanin Sargazi Aval: conceptualization, writing – original draft, writing – review and editing. Mojtaba Aghaei: writing – review and editing, supervision, conceptualization, investigation, project administration.

Ethics Statement

The authors have nothing to report.

Consent

The authors have nothing to report.

Conflicts of Interest

The authors declare no conflicts of interest.

Transparency Statement

The lead author, Omolbanin Sargazi Aval, Mojtaba Aghaei, affirms that this manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained.

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.