Treatment of Vitamin D Deficiency with Calcifediol
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Calcifediol (25-OH-vitamin D3) is the prohormone of the vitamin D endocrine system. It is used to prevent and treat vitamin D deficiency. Calcifediol, as well as cholecalciferol (vitamin D3), is efficient and safe in the general population, although calcifediol has certain advantages over cholecalciferol, such as its rapid onset of action and greater potency. 

calcifediol cholecalciferol vitamin D deficiency efficacy toxicity predictability

1. Introduction

Vitamin D3 is the nutrient of the vitamin D endocrine system (VDES). It is derived from the steroid group that is synthesized endogenously from 7-dehydrocholesterol (provitamin D3), which is converted into 7-dehydrocholecalciferol in the upper layers of the skin by the action of ultraviolet radiation [1]. Vitamin D is also derived from diet and may be of animal origin (D3; cholecalciferol) or vegetable origin (D2; ergocalciferol). Cholecalciferol is bound to a transport protein (vitamin D binding protein [DBP]) and reaches the liver, where it is metabolized by 25-hydroxylases (mainly microsomal CYP2R1, mitochondrial CYP27R1) to 25-hydroxycholecalciferol (calcifediol; calcidiol; 25OHD3), the prohormone and cornerstone of the VDES [2]. Calcifediol binds to DBP and is transported mainly to the kidneys, where it is metabolized by the effect of 1α-hydroxylase (CYP27B1) or 24-hydroxylase (CYP24A1) [3]. The active metabolite of vitamin D3 is 1,25 dihydroxycholecalciferol, or calcitriol, whose synthesis is endocrinologically controlled, stimulated by parathyroid hormone (PTH), and inhibited by fibroblast growth factor 23 (FGF23) [4]. 24,25-dihydroxycholecalciferol production is inhibited by PTH and increased by FGF23 [1][4].
Vitamin D deficiency—measured as levels of 25OHD—is common worldwide. The potential adverse effects of poor vitamin D status are of concern for public health [5]. Dietary and pharmacological supplementation probably have no additional effects when ultraviolet radiation maintains vitamin D status within an adequate range through its endogenous component [6]. The administration of fortified foods in persons with low 25OHD levels is an alternative for achieving recommended and/or desirable levels [7]. However, the most commonly used options involve supplementation with vitamin D2 (ergocalciferol), vitamin D3 (cholecalciferol), and treatment with calcifediol, while calcitriol is indicated in chronic kidney failure and hypo- and pseudohypoparathyroidism [8]. While both cholecalciferol and calcifediol increase 25OHD levels, calcifediol is more potent, rapidly reaching desirable values [9]. In the long term, both drugs behave similarly, although calcifediol, given its pharmacokinetic properties, is preferred in situations such as liver failure, chronic kidney failure, malabsorption, and obesity. This is due to its greater solubility, decreased entrapment in adipose tissue, smaller volume of distribution, avoidance of hepatic metabolism, different mechanism of absorption. The mean half-life is different (Calcidediol, 10–22 days, cholecalciferol 14 days, calcitriol 9–10 h). In addition, it has a greater affinity for the transport protein, which enables more efficient internalization within the megalin-cubilin system [10].

2. Short-Term Efficacy

Two studies on calcifediol lack a cholecalciferol control arm. In their prospective study, Russo et al. [11] administered a dose of 500 µg per month in 18 healthy females aged 24–72 years. The follow-up period was 120 days, and the results showed an increase in 25OHD levels at 7 days, with subsequent stabilization always remaining above baseline values (18.1 ± 12.5 ng/mL, 45.1 ± 31.1 nmol/L) and, in most cases, above 30 ng/mL (74.8 nmol/L). This was associated with a decrease in PTH and bone alkaline phosphatase and unchanged type 1 collagen. In a multicenter, randomized, open-label, 3-arm, parallel-group, comparative phase III study, Minisola et al. [8] assessed the effect of 3 different doses (20 µg/day, 40 µg/day, 125 µg/week) in 87 postmenopausal females with vitamin D deficiency (baseline 25-vitamin D 16.5 ± 7.5 ng/mL, 41.1 ± 18.7 nmol/L). A linear increase in 25OHD concentrations was observed at 14 days and was maintained at 90 days, with a dose-dependent effect. Patients maintained sufficiency (30 ng/mL, 74.8 nmol/L)) with all doses used, which, in no case, exceeded 90 ng/mL (224.6 nmol/L) and were accompanied by reductions in PTH and FGF-23 at 90 days.
Other studies included a control group with cholecalciferol at variable doses. Cashman et al. [12] assessed the effect of 20 µg/day of cholecalciferol versus 7 µg/day or 20 µg/day of calcifediol in 56 patients (31 female and 25 male) aged ≥50 years for 10 weeks in winter. The increase observed was greater for calcifediol than for cholecalciferol, and calcifediol appeared to be 5 times more potent than cholecalciferol. PTH levels decreased in all cases. Bischoff-Ferrari et al. [13] analyzed 20 healthy postmenopausal females in whom 20 µg/day or 140 µg/week of calcifediol was compared with 20 µg/day or 140 µg/week of cholecalciferol. The primary objective was to assess the lower extremity response, blood pressure, and markers of innate immunity. Vitamin D status increased more rapidly and with higher values in patients receiving calcifediol than in those receiving cholecalciferol (69.5 ng/mL (173.4 nmol/L) vs 31 ng/mL (77.3 nmol/L), p < 0.0001). PTH values did not differ significantly, probably due to the small sample size. Jetter et al. [14] analyzed the pharmacokinetics of cholecalciferol and calcifediol in 35 healthy women aged 50–70 years divided into 4 arms with different doses (20 µg/day of calcifediol and 20 µg/day of cholecalciferol, 140 µg/week of calcifediol, and 140 µg/week cholecalciferol). Three other arms consisted of a single 140-µg dose of calcifediol and cholecalciferol or a combination of both. All women treated with calcifediol achieved values above 30 ng/mL (74.8 nmol/L), compared with 70% of those treated with cholecalciferol, who also took longer to achieve these values (64.8 days vs 16.8 days). The difference in potency between the 2 treatments was 2- to 3-fold.
Shieh et al. [15] compared the effect of cholecalciferol 60 µg/day versus calcifediol 20 µg/day in 35 patients with vitamin D deficiency. The study lasted 16 weeks. The results were similar to those of previous studies, with a higher increase in 25OHD serum levels (25.5 (63.6 nmol/L) vs 13.8 ng/mL (34.4 nmol/L), p < 0.001) and free 25OHD levels (6.6 vs 3.5 pg/mL, p < 0.03) in the calcifediol group than in the cholecalciferol group. Vitamin D levels normalized (≥30 ng/mL, 74.8 nmol/L) at 1 month in 87.5% of patients receiving calcifediol compared with 23.1% of those receiving cholecalciferol.
Perez-Castrillón et al. [16] conducted a study whose sample size provided sufficient statistical power to observe differences. The study population comprised 298 postmenopausal women with vitamin D deficiency who received 266 µg /month of calcifediol versus 625 µg /month of cholecalciferol, that is, a 2.5-fold greater dose. The authors reported the results at 1 and 4 months. At 1 month, 13.5% of those who received calcifediol achieved vitamin D sufficiency (30 ng/mL, 74.8 nmol/L) compared with 0% in the cholecalciferol group. At 4 months, the differences were maintained (35% vs 8.2%, p < 0.0001). At 16 weeks, the increase in 25OHD was 14.9 ± 8.1 ng/mL (37.1 ± 20.2 nmol/L) vs 9.9 ± 5.7 ng/mL (24.7 ± 14.2 nmol/L) (p < 0.0001) for the calcifediol and cholecalciferol groups, respectively. It could be concluded that the difference in potency observed in this research was 3.8 times greater in favor of calcifediol vs cholecalciferol. There were no changes in PTH or markers of bone remodeling.
All short-term studies that compared different doses of calcifediol and cholecalciferol showed that the former increased 25OHD levels faster and by greater amounts [17]. The responses of PTH and markers of bone remodeling were variable, probably because of differences in sample size and variations in the percentages of patients with values >30 ng/mL (74.8 nmol/L). In the only research with sufficient statistical power to observe differences, doses of calcifediol and cholecalciferol were small and may not have been sufficient to inhibit PTH and bone remodeling [16]. Table 1 describes the main studies.

References

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