Treatment of vitamin D deficiency in transfusion-dependent thalassemia.

The survival of patients with thalassemia major has progressively improved with advances in therapy; however, osteoporosis remains a frequent, unresolved issue [1]. Adequate circulating levels of vitamin D are essential for optimal skeletal health and reducing fracture risk [2]. Vitamin D insufficiency is reported in the majority of patients with thalassemia in the USA [3] and elsewhere [4–10], despite routine prescription of 400–1,000 IU vitamin D per day. In this study, assessment of serum 25-hydroxy vitamin D (25-OH D) levels in 96 patients with thalassemia revealed that 70 (73%) were either deficient (<20 ng/ml, 43%) or insufficient (20–29 ng/ml, 30%). Significantly more transfusion-independent patients were deficient compared with the transfusiondependent group (60% versus 33%, P 5 0.014). Supervised administration of high-dose (50,000 IU) oral vitamin D2 every 3 weeks during transfusion visits in 32 transfusion-dependent patients increased the 25-OH D level from 18.4 to 24.2 ng/ml (P < 0.001) over a 4-month period. Each dose of vitamin D2, given at 3-week intervals, increased 25-OH D levels by 1.4 ± 2.0 ng/ml. These results show that vitamin D deficiency remains widespread despite daily low-dose supplementation. Supervised high-dose oral vitamin D supplementation is a safe and noninvasive method for predictable improvement of vitamin D status in thalassemia. The risk of vitamin D deficiency in thalassemia increases with age [9,10], and older patients with thalassemia have significantly worse vitamin D status compared with age-matched healthy controls [10]. One-third of healthy adults consuming vitamin D-fortified milk and multivitamin supplementation remain vitamin D-deficient [11]. Similarly, despite greater awareness and routine prescription of daily vitamin D, the problem of vitamin D deficiency in thalassemia remains intractable. The alternative to daily supplementation is intermittent supervised therapy with high-dose vitamin D [12]. Oral therapy is desirable to maintain long term acceptance of the therapy. The objective of this study was to evaluate the effect of high-dose (50,000 IU) oral vitamin D2 administered at the time of transfusion on serum levels of 25-OH D. We screened 96 patients between 3.6 and 57.5 years of age (mean ± SD: 25.2 ± 12.9 years; Table I-online material) with various types of thalassemia for vitamin D status. Exactly half of this sample was male and 61 (64%) of the patients were transfusion-dependent. There were significantly more patients with Asian ethnic background in the transfusion-independent than in the transfusion-dependent category (80% vs. 62.3%, P 5 0.002). Serum 25OH D levels were sufficient in only 26 (27%) patients, whereas 41 (43%) were deficient and 29 (30%) were insufficient. There were no significant differences in age, gender, or season of sample collection between those with deficient and sufficient levels of 25-OH D. The mean parathyroid hormone level in patients with 25-OH D<20 ng/ml was 38.6 ± 21.4 pg/ml compared with 27.3 ± 12.6 pg/ml in those with 25-OH D 20 ng/ml (P < 0.001). There was a trend toward a lower mean 25-OH D level among patients with Asian ethnic background (mean 22.4 ± 12.3 ng/ml) compared with Caucasian ethnic background (26.8 ± 9.7 ng/ml, P 5 0.12). Additionally, deficient vitamin D status was significantly more prevalent in patients with Asian ethnic background than the Caucasian ethnic group (56% vs. 9.7%, P 5 0.002). There was no difference in the mean 25-OH D level among patients with Hemoglobin H or Hemoglobin H Constant Spring disease (mean 22.2 ± 12.9 ng/ml), and those with other types of nontransfusion-dependent thalassemia (23.2 ± 12.9 ng/ml, P 5 0.82), or transfusion-dependent thalassemia (24.6 ± 10.8 ng/ml, P 5 0.39). However, a majority (60%) of the nontransfused group had deficient levels of 25-OH D compared with the transfusiondependent group (32.8%, P 5 0.014, Fig. 1). Thirty-two transfusion-dependent patients with 25-OH D <30 ng/ml were placed on intermittent high-dose oral vitamin D2 supplementation for a total of 66 unique supplementation periods. These patients received a mean of 5 (1–15) doses of 50,000 IU vitamin D2 over 129 (14–521) days. The mean daily dose of vitamin D2 delivered according to this protocol was 2,118 IU/ day. The baseline 25-OH D level increased from 18.4 ± 5.9 ng/ml to 24.3 ± 8.8 ng/ml following supplementation (P < 0.001, Fig. 2). Administration of each dose of 50,000 IU vitamin D2 increased serum 25-OH vitamin D by 1.4 ± 2.0 ng/ml. Regardless of the baseline vitamin D level or the duration of the supplement regimen, no 25-OH D level >80 ng/ml was observed over the course of the observation period. There were 18 individuals who attained a 25-OH D level >30 ng/ml at the end of their supplementation period and continued daily supplementation of 400–1,000 IU vitamin D thereafter. When retested at an average of 8 months (1–21 months) later, the serum 25-OH D had dropped significantly and collectively for all but two of them, from a mean of 34.4 ± 3.7 to 26.9 ± 6.8 ng/ml (P < 0.001). The rate of decline was on an average 1.5 ng/ml per month. Hence, patients who had inadequate vitamin D status on screening were likely to require ongoing high-dose supplementation. In contrast, the