Vitamin D3 and calcidiol are not equipotent

doi:10.1016/j.jsbmb.2016.01.014

The Journal of Steroid Biochemistry and Molecular Biology

Volume 164, November 2016, Pages 205-208

https://doi.org/10.1016/j.jsbmb.2016.01.014 Get rights and content

Highlights

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It is recommended, as endorsed by international clinical guides, to use Vitamin D₃ to treat vitamin D deficiency.
•
In several parts of the world, the use of calcidiol at the same dose than Vitamin D₃ is an extended prescription.
•
Our data confirm the available evidence stating that they are not equipotent. This may lead to over-dosage.
•
Calcifediol is faster and 3–6 times more powerful to obtain adequate serum levels of 25(OH)D in the medium-long term.
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This circumstance must be assessed and included in the therapeutic prescription guides of Osteoporosis.

Abstract

Despite the discussion on the optimal threshold of 25-hydroxyvitamin D serum level continues, there is now consensus on the fact that post-menopausal and elderly populations have inadequate Vitamin D serum levels worldwide. The adjustment of these levels is necessary to improve both bone and general health, as it is to optimize bone response to antiresortive treatments. It is recommended, as endorsed by international clinical guides, to use Vitamin D₃, the physiological form of Vitamin D, in a dose range between 600–2000 IU. It should be administered on a daily basis or on its weekly or monthly equivalents. In Spain, the use of calcidiol (25(OH)D₃) at the same dose than Vitamin D₃ is the most extended prescription, notwithstanding the available evidence stating that they are not equipotent. This may lead to over-dosage.

In order to provide evidence on this circumstance, a convenience study was performed. Four groups of ten post-menopausal osteoporotic women each (average age 67), deficient in Vitamin D ((25(OH)D 37.5 ± 10 nmol/L)) were enrolled. Each group followed a different treatment regimen: (G1) vitamin D₃ 20 μg/day [800 IU/day]; (G2) 25 (OH)D₃ 20 μg/day; (G3) 25(OH)D₃ 266 μg/week and (G4) 25(OH)D₃ 0.266 mg every two weeks. 25(OH)D levels were measured for each group at 0, 6 and 12 months, with the following results: G1 (40.5 ± 4.7;80.0 ± 2; 86.2 ± 23.7), G2 (37,2 ± 4.2; 161 ± 21.7;188.0 ± 24.0), G3 (38 ± 3.7;213.5 ± 80.0; 233.0 ± 81.2), G4 (39.5 ± 4;164.5 ± 41,7;210.5 ± 22.2).

These data reveal that both metabolites are not equipotent. Calcidiol is faster and 3–6 times more potent to obtain serum levels of 25(OH)D in the medium to long term. This circumstance must be assessed and included in the therapeutic prescription guides for Osteoporosis, since it should be of concern when planning and prescribing treatments to normalize serum levels of 25(OH)D₃ and avoid potential adverse impacts.

Introduction

Despite the discussion on the optimal serum threshold of 25-hydroxyvitamin D continues, between 50 nmol/L [1] and 75 nmol/L [2], [3], there is now a general consensus on the fact that post-menopausal and elderly populations have inadequate vitamin D serum levels worldwide [4], [5].

The adjustment of these levels is necessary to improve both bone and general health [6], [7], as it is to optimize bone response to antiresortive treatments [8], [9]. It is recommended, as endorsed by international clinical guidelines, to use Vitamin D₃ (cholecalciferol) – the physiological form of Vitamin D – in a dose range between 600–2000 IU. The biological potency of Vitamin D is established as international units (IU), so that 1 μg of cholecalciferol is equivalent to 40 IU [1]. In that context, vitamin D should be administered on a daily basis or on its weekly or monthly equivalents [10].

In some parts of the world, such as Spain, other vitamin D metabolites like calcidiol (25 hydroxyvitamin D₃) are available for use in the treatment of osteoporosis [11], [12]. Nevertheless, this metabolite is not an equipotent substitute for adequate vitamin D replacement because all the recommendations have been done with cholecalciferol (Vitamin D₃) [13]. Calcidiol compared with cholecalciferol is more hydrophilic, has a shorter half-life, and causes more rapid and sustained increase in serum 25(OH)D concentrations [14], [15].

In Spain, the use of calcidiol at a dose similar to Vitamin D₃ is the most extended prescription, notwithstanding the consistent evidence stating that they are not equipotent [16], [17]. This fact may lead to over-dosage and risk of hypervitaminosis D and hypercalcemia induced by calcidiol [18], as evidenced by a review of cases reported to the Spanish Pharmacovigilance System [19].

Based upon the foregoing, in this study we have evaluated the efficacy of calcidiol vs. Vitamin D₃ in increasing 25-hydroxyvitamin D -25(OH)D- serum levels, a convenience study in order to provide evidence of the differences between both metabolites prescribed in the common practice posology.

Section snippets

Patients and methods

This convenience study was conducted, after receiving the informed consent, at the Mineral Metabolism Unit-IMIBIC of the Hospital Universitario “Reina Sofía”, Córdoba (Spain), latitude 36.7°. Forty post-menopausal osteopenic women with general good health, average age 67 years, and deficient in Vitamin D (37.5 ± 5 nmol/L) were studied. The patients were randomized for treatment with vitamin D₃ in four groups comparable to each other with respect to all the evaluated characteristics. Each group

Results

Baseline levels, general anthropometrics and biochemical characteristics of the postmenopausal women (PM) enrolled in the study are shown in Table 1. All the PM (100%) had levels of vitamin D below 50 nmol/L at the beginning of the study.

At baseline, there was an inverse correlation between calcium and alkaline phosphatase levels (r: −0.392; p: 0.012). An inverse correlation was also found when levels of PTH were compared to phosphate (r: −0.388; p: 0.013) and 25(OH)D₃ (r: −0.768; p: 0.000).

Discussion

Vitamin D status in humans is determined by measuring serum 25(OH)D concentration (2,7). Based upon the increase induced in 25(OH)D levels by calcidiol and cholecalciferol, our data do not support either the proposal stating that both metabolites are equipotent. Contrarily, our data confirm previous reports claiming that they are different molecules with different pharmacological mechanisms, which must be dosed differently to achieve the same target.

Calcidiol is a more polar metabolite than

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Cited by (39)

Calcifediol as a therapeutic
2023, Feldman and Pike's Vitamin D: Volume Two: Disease and Therapeutics
Calcifediol (calcidiol or 25-hydroxyvitamin D₃) and ercalcidiol (25-hydroxyvitamin D₂), referred to collectively as 25(OH)D, are the dominant substrates for production of 1,25-dihydroxyvitamin D₃ (calcitriol) and 1,25-dihydroxyvitamin D₂. Widespread use of parent vitamins D₃ (cholecalciferol) and D₂ (ergocalciferol) to treat vitamin D insufficiency is hampered by their accumulation in fat depots, limited conversion to 25(OH)D, and slow onset of action. The use of calcitriol as a therapeutic is hampered by its increased risk of hypercalcemia. Immediate-release calcifediol (IRC) and extended-release calcifediol (ERC) are new options for treating vitamin D-responsive disorders. ERC's slow-release formulation substantially reduces calcemic safety concerns. Both IRC and ERC normalize circulating 25(OH)D levels within hours, not weeks or months required by vitamin D supplements. Owing to its avidity for the serum vitamin D binding protein, calcifediol avoids substantial accumulation in fat, facilitating access to CYP27B1in endocrine- and intracrine-acting tissues like the kidney and activated immune cells, respectively.
The vitamin D endocrine system: physiology and clinical significance
2022, Revista Espanola de Cardiologia Suplementos
El sistema endocrino de la vitamina D es esencial para mantener la homeostasis del calcio y el fósforo y para prevenir el raquitismo y la osteomalacia. La mayor parte de la vitamina D circulante procede de la síntesis cutánea, por acción de la radiación ultravioleta en el 7-dehidrocolesterol. Solo un 10–20% de la requerida procede de la dieta. Tras una primera hidroxilación hepática, la vitamina D sintetizada en la piel o provista por la dieta se transforma en 25-hidroxivitamina D, compuesto de vida media larga que se utiliza en la clínica como estimador de los depósitos corporales de esta vitamina. Posteriormente, una segunda hidroxilación en el túbulo renal lo transforma en un compuesto activo, el 1,25-dihidroxivitamina D, que se une al receptor intracelular de vitamina D y es capaz de regular la expresión de un gran número de genes. Desde hace años se conocen múltiples efectos extraesqueléticos de la vitamina D, como son la regulación de la función muscular, el crecimiento celular, el sistema inmunitario y la defensa contra las infecciones. Estudios clínicos han relacionado los trastornos de la vitamina D con la aparición de diabetes mellitus, cáncer, enfermedades autoinmunitarias, trastornos metabólicos y enfermedad cardiovascular. La deficiencia de vitamina D es un serio problema de salud pública, dado que su prevalencia alcanza proporciones pandémicas. Por ello, diversas sociedades científicas han definido criterios de insuficiencia y deficiencia de esta vitamina y han emitido recomendaciones para prevenir y tratar esta deficiencia y sus consecuencias clínicas.
The vitamin D endocrine system plays an essential role in maintaining calcium and phosphorus homeostasis and in preventing rickets and osteomalacia. Most circulating vitamin D is synthesized in the skin through the action of ultraviolet radiation on 7-dehydrocholesterol. Dietary intake provides only 1020% of requirements. After initial hydroxylation in the liver, the vitamin D synthesized in the skin or derived from the diet is transformed into 25-hydroxyvitamin D, a compound with a long half-life that is used clinically to estimate vitamin D storage in the body. Subsequently, hydroxylation occurs for a second time in the renal tubules to produce the active compound, 1,25-dihydroxyvitamin D, which binds to the intracellular vitamin D receptor and has the ability to regulate the expression of a large number of genes. The numerous extraskeletal effects of vitamin D have been recognized for many years, such as regulation of muscle function, cell growth, the immune system, and defense against infections. Clinical studies have associated vitamin D deficiency with the development of diabetes, cancer, autoimmune diseases, metabolic disorders, and cardiovascular disease. Vitamin D deficiency is a serious public health problem because its prevalence can reach pandemic levels. Therefore, various scientific societies have produced definitions of vitamin D insufficiency and deficiency and have issued guidelines on the prevention and treatment of vitamin D deficiency and its clinical consequences.
Treatment With 25-Hydroxyvitamin D<inf>3</inf> (Calcifediol) Is Associated With a Reduction in the Blood Neutrophil-to-Lymphocyte Ratio Marker of Disease Severity in Hospitalized Patients With COVID-19: A Pilot Multicenter, Randomized, Placebo-Controlled, Double-Blinded Clinical Trial
2021, Endocrine Practice
Citation Excerpt :
Therefore, oral 25(OH)D3 is able to correct vitamin D deficiency more rapidly and consistently than oral vitamin D3.21,22 Based on vitamin D biologic potency, 1 IU of vitamin D3 is equivalent to 0.025 μg; proportionally, 25 μg = 1000 IU of vitamin D3.23 However, there is no gold standard for the equivalence between IUs and molecular mass with 25(OH)D3.
The goal of this randomized, double-blinded, placebo-controlled clinical trial was to investigate the therapeutic efficacy of oral 25-hydroxyvitamin D₃ (25(OH)D₃) in improving vitamin D status in vitamin D–deficient/vitamin D–insufficient patients infected with the SARS-CoV-2 (COVID-19) virus.
This is a multicenter, randomized, double-blinded, placebo-controlled clinical trial. Participants were recruited from 3 hospitals that are affiliated to [Institution Blinded for Review] and [Institution Blinded for Review].
A total 106 hospitalized patients who had a circulating 25(OH)D₃ concentration of <30 ng/mL were enrolled in this study. Within 30 and 60 days, 76.4% (26 of 34) and 100% (24 of 24) of the patients who received 25(OH)D₃ had a sufficient circulating 25(OH)D₃ concentration, whereas ≤12.5% of the patients in the placebo group had a sufficient circulating 25(OH)D₃ concentration during the 2-month follow-up.
We observed an overall lower trend for hospitalization, intensive care unit duration, need for ventilator assistance, and mortality in the 25(OH)D₃ group compared with that in the placebo group, but differences were not statistically significant. Treatment with oral 25(OH)D₃ was associated with a significant increase in the lymphocyte percentage and decrease in the neutrophil-to-lymphocyte ratio in the patients. The lower neutrophil-to-lymphocyte ratio was significantly associated with reduced intensive care unit admission days and mortality.
Our analysis indicated that oral 25(OH)D₃ was able to correct vitamin D deficiency/insufficiency in patients with COVID-19 that resulted in improved immune function by increasing blood lymphocyte percentage. Randomized controlled trials with a larger sample size and higher dose of 25(OH)D₃ may be needed to confirm the potential effect of 25(OH)D₃ on reducing clinical outcomes in patients with COVID-19.
Vitamin D and Calcium Deficiency in the Elderly
2020, Endocrinology of Aging: Clinical Aspects in Diagrams and Images
Vitamin D is a pleitropic hormone that regulates Ca-P, bone metabolism, and many other functions. The main source is cutaneous synthesis from solar radiation.
Vitamin D deficiency (VDD) is common in advanced age, mostly due to insufficient sunlight exposure. VDD represents the essential cause of secondary hyperparathyroidism (SHT), which affects a variable proportion of older adults, has a multifactorial pathogenesis, and is associated with increased frequency of fractures, falls, loss of muscle strength, and frailty.
The criteria to define optimal serum levels of 25(OH)D (≥ 30 ng/mL) and the clinical manifestations and evaluation depending on the severity and duration of VDD are detailed. Severe VDD (25(OH)D < 10 ng/mL), is more prevalent in institutionalized older individuals and can cause osteomalacia, whose known manifestations are low BMD, increased fragility fractures, myopathy, and hypocalcemic syndrome.
The relationships among the extraskeletal action of vitamin D, mortality, and VDD are described. Nowadays, no causal relationship has been established between VDD and frequent nonskeletal diseases of advanced age.
The preventive recommended doses of vitamin D2 or D3 and a calcium element are outlined as well as considerations on dietary and supplemental calcium.
Vitamin D3 is the most recommended form of vitamin D for oral administration, in clinical practice guidelines. Vitamin D3 is the one that has demonstrated to improve the final treatment goals, namely, the intestinal absorption of calcium, bone fractures and falls. Vitamin D3 doses are quite variable depending on multiple individual factors. Repletion and maintenance doses of Vitamin D3, for vitamin D insufficiency and deficiency in the elderly, are also detailed. Controversy about dosage, and monitoring and the safety of vitamin D3 treatment are also described. Treatment with oral calcidiol and calcitriol should be limited to special clinical settings that we specify.
Supplemental 25-Hydroxycholecalciferol Is More Effective than Cholecalciferol in Raising Serum 25-Hydroxyvitamin D Concentrations in Older Adults
2020, Journal of Nutrition
There are few studies directly comparing the pharmacokinetics of 25-hydroxycholecalciferol [25(OH)D3] to cholecalciferol (D3).
The primary objectives were to compare the effectiveness of D3 and 25(OH)D3 in raising 25-hydroxyvitamin D [25(OH)D] serum concentrations and achieving steady state.
This was a randomized, double-blind, active comparator trial of 91 participants (53 females, 38 males), aged 63.3 ± 7.9 y. 25(OH)D3 (10, 15, and 20 µg) and D3 (20 µg) were dosed daily for 6 mo followed by 6 mo of washout. Frequent measurements of serum 25(OH)D were performed. Pharmacokinetic parameters were fitted for each individual and the treatment average was modeled with linear regression using the individual baseline level, sex, and gender as covariates.
Mean baseline 25(OH)D was similar in all groups (47.1–49.5 nmol/L). Increases in 25(OH)D to steady state were higher in the 25(OH)D3 groups than in the D3 group [least squares (LS) means (95% CI): 50.1 (43.3–58.0), 72.5 (64.3–81.7), 97.4 (86.6–109.6) nmol/L in 10, 15, and 20 µg/d and 38.7 (33.1–45.2) nmol/L in the D3 group; P = 0.0173, P < 0.0001, P < 0.0001]. The rate to reach steady state was similar in all groups, but the time to reach 25(OH)D concentrations of 75 nmol/L was faster in the higher-dosed 25(OH)D3 groups than in the D3 group (7 and 10 d compared with 40 d, P < 0.0001 and P < 0.0001 for 15 and 20 µg/d). The rate of elimination was 59–109% higher in the 25(OH)D3 groups than in the D3 group. The area under the curve (AUC)/µg dose demonstrated that 25(OH)D3 was 3 times as effective as D3 at raising 25(OH)D concentrations.
25(OH)D3 is ~3 times as effective as D3 at raising 25(OH)D concentrations. Once supplementation is discontinued, the elimination rate of 25(OH)D3 is faster than D3. This trial was registered at clinicaltrials.gov as NCT02333682.
Efficacy and Safety of Calcifediol in Young Adults with Vitamin D Deficiency: A Phase I, Multicentre, Clinical Trial—POSCAL Study
2024, Nutrients

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ReviewVitamin D3 and calcidiol are not equipotent

Highlights

Abstract

Introduction

Section snippets

Patients and methods

Results

Discussion

Best Pract. Res. Clin. Endocrinol. Metab.

Bone

Lancet (London, England)

Bone

Med. Clin. (Barc.)

Clin. Chim. Acta

Med .

J. Nutr.

Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline

J. Clin. Endocrinol. Metab.

IOF position statement: vitamin D recommendations for older adults

Osteoporos. Int.

A systematic review of vitamin D status in populations worldwide

Br. J. Nutr.

Vitamin D deficiency

N. Engl. J. Med.

Vitamin D and human health: lessons from vitamin D receptor null mice

Endocr. Rev.

Risk factors for prediction of inadequate response to antiresorptives

J. Bone Miner. Res.

Benefit-risk assessment of vitamin D supplementation

Osteoporos. Int.

Review
Vitamin D₃ and calcidiol are not equipotent