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Vitamin D Endocrine System: Calcifediol for Treatment and Prevention of Infection and Disease

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A special issue of Nutrients (ISSN 2072-6643). This special issue belongs to the section "Micronutrients and Human Health".

Deadline for manuscript submissions: closed (20 February 2022) | Viewed by 43635

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Special Issue Editors

Prof. Dr. José Manuel Quesada-Gómez

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Guest Editor

Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Hospital Universitario Reina Sofía, 18 14004 Córdoba, Spain
Interests: vitamin D endocrine system; vitamin D; calcifediol

Prof. Dr. Roger Bouillon

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Guest Editor

Laboratory of Clinical and Experimental Endocrinology, Department of Chronic Diseases, Metabolism and Ageing, KU Leuven, Belgium
Interests: endocrinology; vitamin D; bone

Special Issue Information

Dear Colleagues,

The vitamin D endocrine system (VDES) is well known for its beneficial effects on calcium and bone homeostasis, especially in children, the elderly, and osteoporotic patients. In addition, it likely has extra-skeletal effects, especially on lung function and the immune system.

Vitamin D3 (cholecalciferol) is a threshold nutrient that needs to be converted to 25-hydroxyvitamin D (25OHD) in the liver, through the action of 25-hydroxylases (mainly CYP2R1 and some other P450 enzymes). 25OHD is the best biomarker of the nutritional status of VDES. 25OHD3, or calcifediol, is a substrate for the synthesis of 1,25(OH)2D3, or calcitriol, an active metabolite of the endocrine system, through the action of 1α-hydroxylase (CYP27B) in the kidney for its endocrine actions, and in multiple cells of the body for its auto/paracrine action.

Calcifediol has pharmacokinetics that differ from vitamin D due to differences in intestinal absorption, serum and tissue transport, and metabolism. Treatment with calcifediol may therefore have some advantages over vitamin D for all indications related to vitamin-D-deficiency-related diseases, including musculoskeletal disorders, infectious diseases, and lung diseases.

We invite authors to submit original research articles, reviews, mini reviews, or perspectives that address any aspect of calcifediol in the management or prevention of vitamin D deficiency or associated pathological conditions.

Prof. Dr. José Manuel Quesada-Gómez
Prof. Dr. Roger Bouillon
Guest Editors

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Keywords

Calcifediol
Vitamin D endocrine system
Vitamin D
Rickets
Osteoporosis
Osteomalacia
Infectious diseases
Immunity
Respiratory diseases
Women's health
Fertility
Musculoskeletal health
COVID-19

Published Papers (10 papers)

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Editorial

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4 pages, 217 KiB

Open AccessEditorial

Calcifediol Cornerstone of the Vitamin D Endocrine System

by Jose Manuel Quesada-Gomez and Roger Bouillon

Nutrients 2023, 15(10), 2290; https://doi.org/10.3390/nu15102290 - 12 May 2023

Cited by 1 | Viewed by 1281

Abstract

It is likely that rickets has afflicted humanity since the dawn of time, but it was first described in great detail in the mid-17th century [...] Full article

(This article belongs to the Special Issue Vitamin D Endocrine System: Calcifediol for Treatment and Prevention of Infection and Disease)

Research

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12 pages, 1315 KiB

Open AccessArticle

Effect of Calcifediol on Physical Performance and Muscle Strength Parameters: A Systematic Review and Meta-Analysis

by Mario Barbagallo, Nicola Veronese, Agnese Di Prazza, Francesco Pollicino, Luca Carruba, Anna La Carrubba and Ligia J. Dominguez

Nutrients 2022, 14(9), 1860; https://doi.org/10.3390/nu14091860 - 29 Apr 2022

Cited by 7 | Viewed by 3820

Abstract

There is general agreement that optimal vitamin D status is necessary for bones, muscles, and general health, particularly in older adults, who are at higher risk of negative consequences of vitamin D deficiency, including sarcopenia; vitamin D supplementation is proposed as a potential intervention to mitigate sarcopenia. Several RCTs have reported that calcifediol (25(OH)D) was more potent than cholecalciferol in increasing plasma 25(OH)D. The present systematic review and meta-analysis aimed to summarize the effects of calcifediol on physical performance and muscle strength. We searched databases from inception to 1 January 2022 for studies investigating calcifediol on physical performance or muscle strength parameters. We calculated the difference between the means of follow-up vs. baseline data using standardized mean differences (SMD) and their 95% confidence intervals (CIs); a random-effect model was considered for all of the analyses. Seven RCTs were included in the meta-analysis. Calcifediol significantly improved gait speed (SMD = 2.500; 95%CI = 1.768–3.223; p < 0.0001); handgrip strength (n = 5446 participants, SMD = 0.532; 95%CI: 0.305–0.758; p < 0.0001; I² = 20.2%); and leg extension (n = 4318 participants, SMD = 0.641; 95%CI: 0.346 to 0.935; p < 0.0001; I² = 18.8%;) vs. baseline values. In conclusion, in this systematic review and meta-analysis, we observed that calcifediol may have a positive effect on muscle strength parameters, with less evidence on physical performance. These data further indicate the importance of vitamin D and, in particular, of calcifediol, not only on bone metabolism but also on muscle parameters and sarcopenia. Full article

(This article belongs to the Special Issue Vitamin D Endocrine System: Calcifediol for Treatment and Prevention of Infection and Disease)

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Review

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20 pages, 3995 KiB

Open AccessReview

Vitamin D Endocrine System and COVID-19: Treatment with Calcifediol

by Jose Manuel Quesada-Gomez, José Lopez-Miranda, Marta Entrenas-Castillo, Antonio Casado-Díaz, Xavier Nogues y Solans, José Luis Mansur and Roger Bouillon

Nutrients 2022, 14(13), 2716; https://doi.org/10.3390/nu14132716 - 29 Jun 2022

Cited by 20 | Viewed by 4976

Abstract

The COVID-19 pandemic is the greatest challenge facing modern medicine and public health systems. The viral evolution of SARS-CoV-2, with the emergence of new variants with in-creased infectious potential, is a cause for concern. In addition, vaccination coverage remains in-sufficient worldwide. Therefore, there is a need to develop new therapeutic options, and/or to optimize the repositioning of drugs approved for other indications for COVID-19. This may include the use of calcifediol, the prohormone of the vitamin D endocrine system (VDES) as it may have potential useful effects for the treatment of COVID-19. We review the aspects associating COVID-19 with VDES and the potential use of calcifediol in COVID-19. VDES/VDR stimulation may enhance innate antiviral effector mechanisms, facilitating the induction of antimicrobial peptides/autophagy, with a critical modulatory role in the subsequent host reactive hyperinflammatory phase during COVID-19: By decreasing the cytokine/chemokine storm, regulating the renin–angiotensin–bradykinin system (RAAS), modulating neutrophil activity and maintaining the integrity of the pulmonary epithelial barrier, stimulating epithelial repair, and directly and indirectly decreasing the increased coagulability and prothrombotic tendency associated with severe COVID-19 and its complications. Available evidence suggests that VDES/VDR stimulation, while maintaining optimal serum 25OHD status, in patients with SARS-CoV-2 infection may significantly reduce the risk of acute respiratory distress syndrome (ARDS) and severe COVID-19, with possible beneficial effects on the need for mechanical ventilation and/or intensive care unit (ICU) admission, as well as deaths in the course of the disease. The pharmacokinetic and functional characteristics of calcifediol give it superiority in rapidly optimizing 25OHD levels in COVID-19. A pilot study and several observational intervention studies using high doses of calcifediol (0.532 mg on day 1 and 0.266 mg on days 3, 7, 14, 21, and 28) dramatically decreased the need for ICU admission and the mortality rate. We, therefore, propose to use calcifediol at the doses described for the rapid correction of 25OHD deficiency in all patients in the early stages of COVID-19, in association, if necessary, with the new oral antiviral agents. Full article

(This article belongs to the Special Issue Vitamin D Endocrine System: Calcifediol for Treatment and Prevention of Infection and Disease)

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21 pages, 1616 KiB

Open AccessReview

Calcifediol for Use in Treatment of Respiratory Disease

by Marta Entrenas-Castillo, Lourdes Salinero-González, Luis M. Entrenas-Costa and Rubén Andújar-Espinosa

Nutrients 2022, 14(12), 2447; https://doi.org/10.3390/nu14122447 - 13 Jun 2022

Cited by 2 | Viewed by 5027

Abstract

Calcifediol is the prohormone of the vitamin D endocrine system (VDES). It requires hydroxylation to move to 1,25(OH)2D3 or calcitriol, the active form that exerts its functions by activating the vitamin D receptor (VDR) that is expressed in many organs, including the lungs. Due to its rapid oral absorption and because it does not require first hepatic hydroxylation, it is a good option to replace the prevalent deficiency of vitamin D (25 hydroxyvitamin D; 25OHD), to which patients with respiratory pathologies are no strangers. Correcting 25OHD deficiency can decrease the risk of upper respiratory infections and thus improve asthma and COPD control. The same happens with other respiratory pathologies and, in particular, COVID-19. Calcifediol may be a good option for raising 25OHD serum levels quickly because the profile of inflammatory cytokines exhibited by patients with inflammatory respiratory diseases, such as asthma, COPD or COVID-19, can increase the degradation of the active metabolites of the VDES. The aim of this narrative revision is to report the current evidence on the role of calcifediol in main respiratory diseases. In conclusion, good 25OHD status may have beneficial effects on the clinical course of respiratory diseases, including COVID-19. This hypothesis should be confirmed in large, randomized trials. Otherwise, a rapid correction of 25(OH)D deficiency can be useful for patients with respiratory disease. Full article

(This article belongs to the Special Issue Vitamin D Endocrine System: Calcifediol for Treatment and Prevention of Infection and Disease)

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11 pages, 303 KiB

Open AccessReview

Treatment of Vitamin D Deficiency with Calcifediol: Efficacy and Safety Profile and Predictability of Efficacy

by Jose-Luis Pérez-Castrillon, Ricardo Usategui-Martín and Pawel Pludowski

Nutrients 2022, 14(9), 1943; https://doi.org/10.3390/nu14091943 - 05 May 2022

Cited by 7 | Viewed by 3271

Abstract

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. This review analyzed studies comparing the efficacy and safety of both calcifediol and cholecalciferol drugs in the short and long term (>6 months). Calcifediol was found to be more efficacious, with no increase in toxicity. We also assessed the predictability of both molecules. A 25OHD increase depends on the dose and frequency of calcifediol administration. In contrast, after cholecalciferol administration, 25OHD increase depends on more factors than dose and frequency of administration, also phenotypic aspects (such as obesity and malabsorption), and genotypic factors impacts in this increase. Full article

(This article belongs to the Special Issue Vitamin D Endocrine System: Calcifediol for Treatment and Prevention of Infection and Disease)

13 pages, 776 KiB

Open AccessReview

25(OH)Vitamin D Deficiency and Calcifediol Treatment in Pediatrics

by Luis Castano, Leire Madariaga, Gema Grau and Alejandro García-Castaño

Nutrients 2022, 14(9), 1854; https://doi.org/10.3390/nu14091854 - 29 Apr 2022

Cited by 9 | Viewed by 2651

Abstract

Vitamin D is essential for the normal mineralization of bones during childhood. Although diet and adequate sun exposure should provide enough of this nutrient, there is a high prevalence of vitamin D deficiency rickets worldwide. Children with certain conditions that lead to decreased vitamin D production and/or absorption are at the greatest risk of nutritional rickets. In addition, several rare genetic alterations are also associated with severe forms of vitamin-D-resistant or -dependent rickets. Although vitamin D3 is the threshold nutrient for the vitamin D endocrine system (VDES), direct measurement of circulating vitamin D3 itself is not a good marker of the nutritional status of the system. Calcifediol (or 25(OH)D) serum levels are used to assess VDES status. While there is no clear consensus among the different scientific associations on calcifediol status, many clinical trials have demonstrated the benefit of ensuring normal 25(OH)D serum levels and calcium intake for the prevention or treatment of nutritional rickets in childhood. Therefore, during the first year of life, infants should receive vitamin D treatment with at least 400 IU/day. In addition, a diet should ensure a normal calcium intake. Healthy lifestyle habits to prevent vitamin D deficiency should be encouraged during childhood. In children who develop clinical signs of rickets, adequate treatment with vitamin D and calcium should be guaranteed. Children with additional risk factors for 25(OH)D deficiency and nutritional rickets should be assessed periodically and treated promptly to prevent further bone damage. Full article

(This article belongs to the Special Issue Vitamin D Endocrine System: Calcifediol for Treatment and Prevention of Infection and Disease)

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18 pages, 351 KiB

Open AccessReview

Calcifediol (25OHD) Deficiency and Its Treatment in Women’s Health and Fertility

by Ana Arnanz, Juan A. Garcia-Velasco and José Luis Neyro

Nutrients 2022, 14(9), 1820; https://doi.org/10.3390/nu14091820 - 27 Apr 2022

Cited by 4 | Viewed by 3334

Abstract

Currently, there is abundant scientific evidence showing that the vitamin D endocrine system (VDES) is a highly complex endocrine system with multiple actions in different regions of the body. The unequivocal presence of vitamin D receptors in different tissues related to fertility, and to specific aspects of women’s health such as pregnancy, undoubtedly implies functions of this steroid hormone in both male and female fertility and establishes relationships with different outcomes of human gestation. In order to review the role of the VDES in human fertility, we evaluated the relationships established between 25-hydroxyvitamin D (calcifediol) deficiency and in vitro fertilization, as well as aspects related to ovarian reserve and fertility, and commonly diagnosed endocrinopathies such as polycystic ovary disease. Likewise, we briefly reviewed the relationships between calcifediol deficiency and uterine fibroids, as well as the role that treatment may have in improving human fertility. Finally, the best scientific evidence available on the consequences of calcifediol deficiency during pregnancy is reviewed in relation to those aspects that have accumulated the most scientific literature to date, such as the relationship with the weight of the newborn at the time of delivery, the appearance of preeclampsia, and the risk of developing gestational diabetes and its final consequences for the pregnancy. To date, there is no definitive consensus on the necessary dose for treatment of calcifediol deficiency in the therapeutic management of infertility or during pregnancy. Large prospective clinical intervention studies are needed to clarify the benefits associated with this supplementation and the optimal dose to use in each situation. Although most intervention studies to date have been conducted with cholecalciferol, due to its much longer history of use in daily care, the use of calcifediol to alleviate 25-hydroxyvitamin D deficiency seems safe, even during pregnancy. The unequivocal presence of vitamin D receptors in very different tissues related to human fertility, both male and female, as well as in structures typical of pregnancy, allows us to investigate the crucial role that this steroid hormone has in specific aspects of women’s health, such as pregnancy and the ability to conceive. Well-designed clinical studies are needed to elucidate the necessary dose and the best form of treatment to resolve the very common calcifediol deficiency in women of reproductive age. Full article

(This article belongs to the Special Issue Vitamin D Endocrine System: Calcifediol for Treatment and Prevention of Infection and Disease)

18 pages, 329 KiB

Open AccessFeature PaperReview

Calcifediol (25OH Vitamin D₃) Deficiency: A Risk Factor from Early to Old Age

by Roger Bouillon, Leen Antonio and Oscar Rosero Olarte

Nutrients 2022, 14(6), 1168; https://doi.org/10.3390/nu14061168 - 10 Mar 2022

Cited by 18 | Viewed by 6484

Abstract

Vitamin D deficiency is the main cause of nutritional rickets in children and osteomalacia in adults. There is consensus that nutritional access to vitamin D can be estimated by measuring serum concentrations of 25OHD and vitamin D deficiency can thus be considered as calcifediol deficiency. However, the threshold for vitamin D/calcifediol sufficiency remains a matter of debate. Vitamin D/calcifediol deficiency has been associated with musculoskeletal effects but also multiple adverse extra-skeletal consequences. If these consequences improve or if they can be treated with vitamin D supplementation is still unclear. Observational studies suggest a higher infection risk in people with low calcifediol levels. There is also a consistent association between serum calcifediol and cardiovascular events and deaths, but large-scale, long-term intervention studies did not show any benefit on cardiovascular outcomes from supplementation, at least not in subjects without clear vitamin D deficiency. Cancer risk also did not change with vitamin D treatment, although there are some data that higher serum calcifediol is associated with longer survival in cancer patients. In pregnant women, vitamin D supplementation decreases the risk of pre-eclampsia, gestational diabetes mellitus, and low birth weight. Although preclinical studies showed that the vitamin D endocrine system plays a role in certain neural cells as well as brain structure and function, there is no evidence to support a beneficial effect of vitamin D in neurodegenerative diseases. Vitamin D supplementation may marginally affect overall mortality risk especially in elderly subjects with low serum calcifediol concentrations. Full article

(This article belongs to the Special Issue Vitamin D Endocrine System: Calcifediol for Treatment and Prevention of Infection and Disease)

10 pages, 675 KiB

Open AccessEditor’s ChoiceReview

Emerging Roles of Vitamin D-Induced Antimicrobial Peptides in Antiviral Innate Immunity

by John H. White

Nutrients 2022, 14(2), 284; https://doi.org/10.3390/nu14020284 - 11 Jan 2022

Cited by 46 | Viewed by 7881

Abstract

Vitamin D deficiency, characterized by low circulating levels of calcifediol (25-hydroxyvitamin D, 25D) has been linked to increased risk of infections of bacterial and viral origin. Innate immune cells produce hormonal calcitriol (1,25-dihydroxyvitamin D, 1,25D) locally from circulating calcifediol in response to pathogen threat and an immune-specific cytokine network. Calcitriol regulates gene expression through its binding to the vitamin D receptor (VDR), a ligand-regulated transcription factor. The hormone-bound VDR induces the transcription of genes integral to innate immunity including pattern recognition receptors, cytokines, and most importantly antimicrobial peptides (AMPs). Transcription of the human AMP genes β-defensin 2/defensin-β4 (HBD2/DEFB4) and cathelicidin antimicrobial peptide (CAMP) is stimulated by the VDR bound to promoter-proximal vitamin D response elements. HDB2/DEFB4 and the active form of CAMP, the peptide LL-37, which form amphipathic secondary structures, were initially characterized for their antibacterial actively. Notably, calcitriol signaling induces secretion of antibacterial activity in vitro and in vivo, and low circulating levels of calcifediol are associated with diverse indications characterized by impaired antibacterial immunity such as dental caries and urinary tract infections. However, recent work has also provided evidence that the same AMPs are components of 1,25D-induced antiviral responses, including those against the etiological agent of the COVID-19 pandemic, the SARS-CoV2 coronavirus. This review surveys the evidence for 1,25D-induced antimicrobial activity in vitro and in vivo in humans and presents our current understanding of the potential mechanisms by which CAMP and HBD2/DEFB4 contribute to antiviral immunity. Full article

(This article belongs to the Special Issue Vitamin D Endocrine System: Calcifediol for Treatment and Prevention of Infection and Disease)

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Other

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12 pages, 790 KiB

Open AccessEditor’s ChoiceSystematic Review

Rapid Nontranscriptional Effects of Calcifediol and Calcitriol

by Simone Donati, Gaia Palmini, Cinzia Aurilia, Irene Falsetti, Francesca Miglietta, Teresa Iantomasi and Maria Luisa Brandi

Nutrients 2022, 14(6), 1291; https://doi.org/10.3390/nu14061291 - 18 Mar 2022

Cited by 20 | Viewed by 3128

Abstract

Classically, a secosteroid hormone, vitamin D, has been implicated in calcium and phosphate homeostasis and has been associated with the pathogenesis of rickets and osteomalacia in patients with severe nutritional vitamin D deficiency. The spectrum of known vitamin D-mediated effects has been expanded in recent years. However, the mechanisms of how exactly this hormone elicits its biological function are still not fully understood. The interaction of this metabolite with the vitamin D receptor (VDR) and, subsequently, with the vitamin D-responsive element in the region of specific target genes leading to the transcription of genes whose protein products are involved in the traditional function of calcitriol (known as genomic actions). Moreover, in addition to these transcription-dependent mechanisms, it has been recognized that the biologically active form of vitamin D₃, as well as its immediate precursor metabolite, calcifediol, initiate rapid, non-genomic actions through the membrane receptors that are bound as described for other steroid hormones. So far, among the best candidates responsible for mediating rapid membrane response to vitamin D metabolites are membrane-associated VDR (VDRm) and protein disulfide isomerase family A member 3 (Pdia3). The purpose of this paper is to provide an overview of the rapid, non-genomic effects of calcifediol and calcitriol, whose elucidation could improve the understanding of the vitamin D₃ endocrine system. This will contribute to a better recognition of the physiological acute functions of vitamin D₃, and it could lead to the identification of novel therapeutic targets able to modulate these actions. Full article

(This article belongs to the Special Issue Vitamin D Endocrine System: Calcifediol for Treatment and Prevention of Infection and Disease)

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