Treatment of Vitamin D Deficiency with Calcifediol

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1		Jose-Luis Pérez-Castrillón	--	2088	2022-05-18 07:07:56	\|
2	format corrected.	Beatrix Zheng	+ 6 word(s)	2094	2022-05-20 08:50:43	\|

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.

Table 1. Short-term studies.

Authors	Type of Study	Population	Design	Baseline Vitamin D ng/L/nmol/L	Methods Vitamin D	Superiority of Calcifediol	Other Data
Russo et al. ^[11]	Open	18 pre- and postmenopausal females	One arm with 500 μg of 25D_3. 16 weeks	18.1 ± 12.5 ng/mL 45.1 ± 31.1 nmol/L	RIA	NA	88% > 30 ng/mL (74.8 nmol/L)
Minisola et al. ^[8]	RCT	87 postmenopausal females	Three arms of 25D3 20μg/day,40μg/day,125μg/week. 16 weeks	16.5 ± 7.5 ng/mL 41.1 ± 18.7 nmol/L	Chemiluminiscence	NA	100% > 30 ng/mL (74.8 nmol/L)
Cashman et al. ^[12]	RCT	56 adults (25m, 31f) > 50 years	Three arms of 20μg/day D3, 7μg/day and 20μg/day 25D3. 10 weeks	17.4 ± 4.9 ng/mL 43.6 ± 122.3 nmol/L	ELISA	YES	>Dose 20μg/day 25D3
Bischoff-Ferrari et al. ^[13]	RCT	20 postmenopausal females	Two arms, 20μg/day D3 vs20μg/day 25D3. 16 weeks	13 ± 3.8 ng/mL 32.4 ± 9.4 nmol/L	HPLC-MS/MS	YES	-
Jetter et al. ^[14]	RCT	35 females aged 50–70 years	7 arms:20μg/day and 140μg/week of D3 vs 20μg/day and 140 μg/week of 25D3 and combination of both arms. 15 weeks	13 ± 5 ng/mL 32.4 ± 12.4 nmol/L	HPLC-MS/MS	YES	Long-term kinetics similar between the two supplements
Shieh et al. ^[15]	RCT	35 subjects aged >18 years	Two arms 60μg/day of D3 vs 20μg/day of 25D3. 16 weeks	<20ng/ml	HPLC-MS/MS	YES	Determination of free vitamin D with superiority of calcifediol
Perez-Castrillón et al. ^[16]	RCT	303 postmenopausal females	Two arms 625μg/month D3 vs 266μg/month 25D3. 16 weeks	13 ± 3.9 ng/mL 32.4 ± 9.7 nmol/L	Chemiluminiscence	YES	Greater efficacy at one month and four months for both total vitamin D and free vitamin D

RIA: Radioimmunoassay; HPLC: Liquid chromatography; HPLC-MS/MS: Liquid chromatography coupled to tandem mass spectrometry detection.

3. Long-Term Efficacy

Various studies have analyzed treatment with calcifediol for periods of >6 months, although these are less uniform, and follow-up times and doses are heterogeneous.

The oldest study, which did not include a control group, was a randomized study with the systematic inclusion of all patients treated for hypovitaminosis D in a rheumatology unit ^[18]. Seventy patients were included (11 male and 59 female, age 70 ± 11 years). All patients received a loading dose of 266 µg of calcifediol weekly for 4 weeks and were subsequently randomized to 3 arms: 266 µg monthly, 266 µg every 3 weeks, and 266 µg every 2 weeks. All patients achieved high 25OHD concentrations, ranging from 59.5 (145.5 nmol/L) to 69.8 ng/mL (174.2 nmol/L) at the third follow-up visit (second and third follow-up visits every 8 ± 4 months), with no associated adverse effects. Follow-up lasted 28 ± 14 months, the longest of all the studies evaluated. Following the same treatment regimen, the authors subsequently conducted a study that included an arm with cholecalciferol ^[19] in 129 patients (20 male and 109 female) who underwent loading treatment with calcifediol for 4 weeks (266 µg week). The mean 25OHD level achieved was 86 ng/mL (214.6 nmol/L). Patients were then randomized to 2 arms: cholecalciferol 20 μg /day versus calcifediol 266 µg /every 3 weeks. Higher vitamin D values were achieved at 12 months with calcifediol (70 ± 24 ng/mL (174.7 ± 59.9 nmol/L) vs 48 ± 23 ng/mL (119.8 ± 57.4 nmol/L), p = 0.001).

Rossini et al. ^[20] conducted a randomized trial that included 271 women with osteopenia or osteoporosis with associated hypovitaminosis D. Two groups were established: one received 66.5 μg of calcifediol weekly, and the other 20 µg/day of cholecalciferol, with 1 g of calcium administered in both groups. Follow-up was irregular, with a high degree of dropout in patients who received the daily supplements, probably in relation to the added calcium. The 25OHD concentration values at the end of the study were similar in both groups.

Navarro Valverde et al. ^[21] included 40 osteopenic postmenopausal women with a mean age of 67 years and hypovitaminosis D. Patients were randomized to 4 groups, with similar clinical and demographic characteristics, and received cholecalciferol at 20 µg/day, calcifediol at 20 µg/day, calcifediol at 266 µg/week or calcifediol at 266 µg/2 weeks. The follow-up period was 12 months, and PTH and markers of bone remodeling were determined. Increases in 25OHD concentrations were higher in the group receiving calcifediol, although all groups achieved sufficiency at 6 months. However, the study did not include previous measures with which to draw comparisons. The decrease in PTH was higher in patients who received calcifediol, while the behavior of remodeling markers was irregular. The difference in potency between the 2 supplements was 3- to 5-fold higher in the calcifediol group and more pronounced at higher doses.

An Italian study analyzed patients with hypovitaminosis D (60%) admitted to an acute geriatric unit (77 patients (46 females and 31 males), age ≥75 years) ^[22]. The patients were randomized to calcifediol 150 µg/week or cholecalciferol 150 µg/week. From 10 days onward, and differences in 25OHD concentrations were observed between the 2 therapies, with calcifediol proving superior, an effect that was maintained at 60 days. At the end of the study, there were no differences between the 2 drugs, although the increase in concentration was higher with calcifediol (19 ng/mL (47.4 nmol/L) vs 16 ng/mL (39.9 nmol/L), p = 0.5). PTH decreased similarly in both groups.

Vaes et al. ^[23] carried out a small, randomized, controlled, double-blind study in patients aged ≥65 years. The control group received 20 µg/day of cholecalciferol, and a further 3 arms were established (5, 10, and 15 µg/day of calcifediol). The study lasted 24 weeks. Stability was reached at 2 weeks, and only the doses of calcifediol 10 and 15 µg/day reached levels of >30 ng/mL (74.8 nmol/L), with all mean values achieved at higher calcifediol levels than in the control group.

A real-life study in 156 osteoporotic patients compared 2 doses of calcifediol—266 µg monthly versus 266 µg every 2 weeks ^[24]. Both groups received antiresorptive agents. A significant increase in 25OHD concentrations was observed with both regimens. The final level was clearly higher in patients who received the fortnightly regimen (56.2 ± 18.5 ng/mL (140.2 ± 46.1 nmol/L) vs 38.8 ± 12.5 ng/mL (96.8 ± 31.1 nmol/L); p < 0.01).

This entry is adapted from 10.3390/nu14091943

References

Suda, T.; Masuyama, R.; Bouillon, R.; Carmeliet, G. Physiological functions of vitamin D: What we have learned from global and conditional VDR knockout mouse studies. Curr. Opin. Pharmacol. 2015, 22, 87–99.
Zhu, J.G.; Ochalek, J.T.; Kaufmann, M.; Jones, G.; Deluca, H.F. CYP2R1 is a major but not exclusive contributor to 25-hydroxyvitamin D production in vivo. Proc. Natl. Acad. Sci. USA 2013, 110, 15650–15655.
Deluca, H.F. History of the discovery of vitamin D and its active metabolites. Bonekey Rep. 2014, 3, 479.
Quarles, L.D. Skeletal secretion of FGF-23 regulates phosphate and vitamin D metabolism. Nat. Rev. Endocrinol. 2012, 8, 276–286.
Bouillon, R. Comparative analysis of nutritional guidelines for vitamin D. Nat. Rev. Endocrinol. 2017, 13, 466–479.
Perez-Castrillón, J.L. Mitos en nutrición: Usos y abusos de la vitamina D. Nutr. Clin. Med. 2020, 14, 51–63.
Pilz, S.; März, W.; Cashman, K.D.; Kiely, M.E.; Whiting, S.J.; Holick, M.F.; Grant, W.B.; Pludowski, P.; Hiligsman, M.; Trummer, C.; et al. Rationale and Plan for Vitamin D Food Fortification: A Review and Guidance Paper. Front. Endocrinol. 2018, 9, 373.
Minisola, S.; Cianferotti, L.; Biondi, P.; Cipriani, C.; Fossi, C.; Franceschelli, F.; Giusti, F.; Leoncini, G.; Pepe, J.; Bischoff-Ferrari, H.A.; et al. Correction of vitamin D status by calcidiol: Pharmacokinetic profile, safety, and biochemical effects on bone and mineral metabolism of daily and weekly dosage regimens. Osteoporos. Int. 2017, 28, 3239–3249.
Bouillon, R.; Bikle, D. Vitamin D metabolism revised: Fall of dogmas. J. Bone Miner. Res. 2019, 34, 1985–1992.
Bouillon, R.; Marcocci, C.; Carmeliet, G.; Bikle, D.; White, J.H.; Dawson-Hughes, B.; Lips, P.; Munns, C.F.; Lazaretti-Castro, M.; Giustina, A.; et al. Skeletal and extraskeletal actions of vitamin D: Current evidence and outstanding questions. Endocr. Rev. 2019, 40, 1109–1151.
Russo, S.; Carlucci, L.; Cipriani, C.; Ragno, A.; Piemonte, S.; Del Fiacco, R.; Pepe, J.; Fassino, V.; Arima, S.; Romagnoli, E.; et al. Metabolic changes following 500 μg monthly administration of calcidiol: A study in normal females. Calcif. Tissue Int. 2011, 89, 252–257.
Cashman, K.D.; Seamans, K.M.; Lucey, A.J.; Stöcklin, E.; Weber, P.; Kiely, M.; Hill, T.R. Relative effectiveness of oral 25-hydroxyvitamin D3 and vitamin D3 in raising wintertime serum 25-hydroxyvitamin D in older adults. Am. J. Clin. Nutr. 2012, 95, 1350–1356.
Bischoff-Ferrari, H.A.; Dawson-Hughes, B.; Stöcklin, E.; Sidelnikov, E.; Willet, W.C.; Edel, J.O.; Stähelin, H.B.; Wolfram, S.; Jetter, A.; Schwager, J.; et al. Oral supplementation with 25(OH)D3 versus vitamin D3: Effects on 25(OH)D levels, lower extremity function, blood pressure, and markers of innate immunity. J. Bone Miner. Res. 2012, 27, 160–169.
Jetter, A.; Egli, A.; Dawson-Hughes, B.; Staehelin, H.B.; Stoecklin, E.; Goessl, R.; Henschkowski, J.; Bischoff-Ferrari, H.A. Pharmacokinetics of oral vitamin D(3) and calcifediol. Bone 2014, 59, 14–19.
Shieh, A.; Ma, C.; Chun, R.F.; Witzel, S.; Rafison, B.; Contreras, H.T.M.; Wittwer-Schegg, J.; Swinkels, L.; Huijs, T. Effects of cholecalciferol vs calcifediol on total and free 25-hydroxyvitamin D and parathyroid hormone. J. Clin. Endocrinol. Metab. 2017, 102, 1133–1140.
Pérez-Castrillón, J.L.; Dueñas-Laita, A.; Brandi, M.L.; Jódar, E.; Del Pino-Montes, J.; Quesada-Gómez, J.M.; Cereto Castro, F.; Gómez-Alonso, C.; Gallego López, L.; Olmos Martínez, J.M.; et al. Calcifediol is superior to cholecalciferol in improving vitamin D status in postmenopausal women: A randomized trial. J. Bone Miner. Res. 2021, 36, 1967–1978.
Okoye, C.; Calsolaro, V.; Niccolai, F.; Calabrese, A.M.; Franchi, R.; Rogani, S.; Coppini, G.; Morelli, V.; Caraccio, N.; Monzani, F. A Randomized, Open-Label Study to Assess Efficacy of Weekly Assumption of Cholecalciferol versus Calcifediol in Older Patients with Hypovitaminosis D. Geriatrics 2022, 7, 13.
Larrosa, M.; Gratacos, J.; Fernandez, M.E.; Berlanga, E.; Casado, E.; Gómez, A.; Real, J. Administración de calcidiol y valores séricos de 25-OH-D3. ¿Qué pauta clínica utilizar? Rev. Esp. Reumatol. 2003, 30, 548–553.
Larrosa, M.; Casado, E.; Gomez, A.; Moreno, M.; Berlanga, E.; Galisteo, C.; Gratacós, J. Colecalciferol o calcidiol ¿Qué metabolito utilizar en el déficit de vitamina D? Rev. Española Enferm. Metabólicas Óseas 2007, 16, 48–52.
Rossini, M.; Viapiana, O.; Gatti, D.; James, G. The long-term correction of vitamin D deficiency: Comparison between different treatments with vitamin D in clinical practice. Minerva Med. 2005, 96, 1–7.
Navarro-Valverde, C.; Sosa-Henríquez, M.; Alhambra-Expósito, M.R.; Quesada-Gómez, J.M. Vitamin D3 and calcidiol are not equipotent. J. Steroid Biochem. Mol. Biol. 2016, 164, 205–208.
Ruggiero, C.; Baroni, M.; Bini, V.; Brozzetti, A.; Parretti, L.; Zengarini, E.; Lapenna, M.; Antinolfi, P.; Falorni, A.; Mecocci, P.; et al. Effects of weekly supplementation of cholecalciferol and calcifediol among the oldest-old people: Findings from a randomized pragmatic clinical trial. Nutrients 2019, 11, 2778.
Vaes, A.M.M.; Tieland, M.; de Regt, M.F.; Wittwer, J.; Can Loon, L.J.C.; De Groot, L.C.P.G.M. Dose-response effects of supplementation with calcifediol on serum 25-hydroxyvitamin D status and its metabolites: A randomized controlled trial in older adults. Clin. Nutr. 2018, 37, 808–814.
Olmos, J.M.; Arnaiz, F.; Hernández, J.L.; Olmos-Martínez, J.M.; González Macías, J. Calcifediol mensual frente a calcifediol quincenal en el tratamiento de pacientes osteoporóticos. Estudio en la vida real. Rev. Osteoporos. Metab. Miner. 2018, 10, 89–95.

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Jose-Luis Pérez-Castrillón

Ricardo Usategui-Martín

Pawel Pludowski

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1. Introduction

2. Short-Term Efficacy

3. Long-Term Efficacy

References