Major Research Findings

Ergosterol, a precursor of vitamin D2, did not significantly affect bone mineralization in chicks receiving either cholecalciferol (vitamin D3) or ergocalciferol (vitamin D2) in their diet. 1 This study demonstrated that ergosterol did not influence growth, plasma calcium concentration, or bone ash content in chicks, suggesting that it does not interfere with the absorption of either form of vitamin D.

Vitamin D supplementation has been found to improve mood (depression and anxiety) and overall health (mental and physical) in women with type 2 diabetes mellitus (T2DM). 26

Vitamin D, a secosteroid hormone with immunomodulatory properties, plays a role in the development and activity of inflammatory bowel disease (IBD). 9 Epidemiological data suggests that vitamin D deficiency is associated with an increased risk of IBD, hospitalizations, surgery, and a decline in response to biological therapies. Conversely, IBD can also contribute to vitamin D deficiency. This bidirectional relationship emphasizes the importance of monitoring and replenishing vitamin D levels in IBD patients as needed.

A meta-analysis examining the effect of vitamin D supplementation on fracture and fall risk, considering different dosages and intervals, found that while several studies have compared various dosages and intervals, an optimal dose or interval for achieving benefits in fracture risk remains unclear. 22

The impact of vitamin D2 and D3 supplements on 25-hydroxyvitamin D levels varies depending on the dose, sex, and time elapsed since supplementation. 4 Vitamin D supplementation is crucial given the prevalence of vitamin D deficiency worldwide. However, debates persist regarding the relative potency of ergocalciferol (D2) and cholecalciferol (D3), optimal dosing schedules, and the influence of sex on 25-hydroxy D (25(OH)D) levels, which serve as the best indicator of vitamin D status.

Vitamin D deficiency is common and often severe in children and adults with chronic kidney disease (CKD). 24 While native vitamin D {25-hydroxyvitamin D [25(OH)D]} is believed to have diverse effects on numerous organ systems, its influence on bone health has been most extensively researched. 25(OH)D deficiency is linked to rickets and fractures in both healthy children and those with CKD, contributing to the CKD-mineral and bone disorder (MBD) complex. Despite the prevalence of vitamin D deficiency in CKD, limited studies provide evidence for vitamin D therapy or guidelines for its use in this population. The European Society for Paediatric Nephrology (ESPN) CKD-MBD and Dialysis working groups have developed recommendations for the evaluation, treatment, and prevention of vitamin D deficiency in children with CKD. These recommendations address the use of ergocalciferol (vitamin D2) and cholecalciferol (vitamin D3) in children with CKD Stages 2-5 and those undergoing dialysis. Active vitamin D analogue therapy recommendations are outlined in a separate document. These recommendations are based on an extensive literature review including meta-analyses, randomized controlled trials in healthy children and adults with CKD, and prospective observational studies in children with CKD. The Grading of Recommendation, Assessment, Development and Evaluation (GRADE) system was used to develop and assess these recommendations. In the absence of relevant research data, expert opinions from the ESPN CKD-MBD and Dialysis working groups are provided, but these opinions are clearly GRADE-ed and should be carefully considered by the treating physician and adapted to individual patient needs as appropriate.

Vitamin D treatment has been shown to improve levels of sexual hormones, metabolic parameters, and erectile function in middle-aged men with vitamin D deficiency. 14

Beyond its crucial role in calcium and bone metabolism, vitamin D also mediates various non-calcemic effects by modulating several biological responses. 13 It exists in two major forms: vitamin D₂, commonly known as ergocalciferol, and vitamin D₃, commonly known as cholecalciferol. Both forms bind to vitamin D-binding protein for transport to vital target organs, where they serve as natural ligands for vitamin D receptors, enabling their biological actions. Clinical reports linking vitamin D deficiency to an increase in thrombotic episodes suggest a role for vitamin D and its associated molecules in regulating thrombosis-related pathways. Thrombosis, the formation and propagation of a blood clot known as a thrombus, can occur in both the arterial and venous systems, leading to serious complications such as myocardial infarction, stroke, ischemia, and venous thromboembolism. Vitamin D, directly or indirectly, controls the expression of genes responsible for regulating cellular proliferation, differentiation, apoptosis, and angiogenesis, processes relevant to thrombotic disorders. This review explores the effects of vitamin D on pathways involved in thrombosis, including the hemostatic process, inflammatory pathways, and endothelial cell activation, focusing on the molecular mechanisms associated with them.

A double-blinded, randomized placebo-controlled trial assessed the effects of oral vitamin D supplements on vaginal health in postmenopausal women with vulvovaginal atrophy (VVA). 12 The trial, conducted for 12 weeks, investigated changes in the vaginal maturation index (VMI), vaginal pH, and the visual analog scale (VAS) for VVA symptoms. The vitamin D group received 40,000 IU of oral ergocalciferol per week, while the placebo group received an identical placebo capsule. Eighty postmenopausal women were enrolled. While there were no significant differences in baseline characteristics between the groups, an intention-to-treat analysis revealed no significant differences in VMI, vaginal pH, or VAS scores between the groups at 6 and 12 weeks. However, the mean difference in VMI between baseline and 6 weeks showed significant improvement in the vitamin D group (5.5 + 16.27, p <0.05). Furthermore, the mean vaginal pH and VAS scores of VVA patients in the vitamin D group showed significant improvement at both 6 and 12 weeks compared to baseline. Oral vitamin D supplementation for 12 weeks may potentially improve vaginal health outcomes in postmenopausal women with VVA symptoms, as demonstrated by improved mean VMI, vaginal pH, and VAS scores at 6 and 12 weeks compared to baseline, although no significant differences were observed from the placebo treatment.

This study investigated the prevalence of vitamin D [25(OH)D] deficiency, its association with nutrition-related parameters, and the effects of ergocalciferol supplementation in stage 5 chronic kidney disease (CKD). 19 Measures of interest included serum albumin, glycosylated hemoglobin (HgA1c), hemoglobin, phosphorus, corrected calcium, parathyroid hormone (iPTH), equilibrated normalized protein catabolic rate (enPCR), and quality-of life-survey physical component score (SF-36 PCS).

Residual albuminuria is associated with an increased risk of progression to end-stage kidney disease (ESKD). 6 This study examined whether native vitamin D supplementation could reduce albuminuria in stable CKD patients under maximal renin-angiotensin system (RAS) blockade.

Low vitamin D status is a global public health issue that vitamin D food fortification and biofortification may help to alleviate. 5 This study presents an updated and extended systematic review and meta-analysis of randomized controlled trials examining the effects of vitamin D food fortification and biofortification on serum 25-hydroxyvitamin D concentrations in adults and children.

Vitamin D deficiency is often reported in people with chronic liver diseases. 8 Improving vitamin D status could therefore be beneficial for individuals with chronic liver diseases.

This study systematically reviews the effects of maternal vitamin and/or mineral supplementation on the content of breast milk. 16

Two recent vitamin D supplementation (ergocalciferol) trials in stage G5D CKD patients with vitamin D insufficiency showed that ergocalciferol effectively increases serum 25-hydroxyvitamin D [25(OH)D] but fails to modify serum PTH or other clinical outcomes. 20 One perspective argues that the duration of these studies was too short for meaningful analysis based on a clinical endpoint. Additionally, this perspective points out that in the second study, the use of active forms of vitamin D, phosphate binders, and cinacalcet might have obscured the effects of ergocalciferol supplementation alone. The opposing view presents an updated meta-analysis demonstrating that inactive forms of vitamin D largely fail to reduce serum PTH and impact various relevant endpoints, including muscle strength, functional capacity, quality of life, and hospitalization. Studies suggesting an effect of inactive vitamin D forms in advanced CKD are either small, primarily based on sequential, uncontrolled observations, or inherently weak, simple pre/post studies. No biological or clinical evidence exists to suggest that 25(OH)D exerts meaningful effects in CKD patients already treated with active forms of vitamin D. Thorough etiological studies based on omics sciences, involving precise pathophysiological profiling of individual CKD patients followed by targeted interventions within a precision medicine framework, are likely to provide a definitive answer to the persistent question of whether inactive vitamin D forms possess biological effects beyond those produced by their proximate metabolite, 1,25-dihydroxyvitamin D3.

Excessive ultraviolet (UV) exposure is known to have harmful effects. However, moderate exposure to UV radiation is beneficial and essential for active vitamin D synthesis in our bodies. 17 Individuals living in the coldest regions of the Earth are unable to expose their skin to solar UV radiation; therefore, additional supplementation of Vitamin D2 is recommended. Mushrooms are a consumable macrofungi with high vitamin content and are used in various traditional medicines. Specifically, UVB-irradiated mushrooms are rich in active vitamin D content and are recommended for inclusion in the daily diets of individuals suffering from bone mineralization problems. This study evaluated the cytotoxic effects of mushroom extract (UVB-ME) (Lentinus edodes) treatment against MG-63 cells, HepG2 cells, and CCD 841 CoN cells. Furthermore, the potential of UVB-ME on Ca⁺⁺ uptake in osteoblast-like MG-63 cells was explored. Next, the response of Ca⁺⁺ uptake to the growth and development of zebrafish larvae was validated. Additionally, the anti-inflammatory and immunomodulatory potential of UVB-ME treatment against lipopolysaccharide-induced inflammatory response was analyzed in vivo. Collectively, the study suggests that dietary supplementation with UVB-irradiated mushroom is beneficial for bone calcification and could modulate the host immune system.

Phosphaturic mesenchymal tumor (PMT) is a rare neoplasm that ectopically secretes fibroblast growth factor 23, a bone cell-derived protein that regulates phosphate homeostasis. 23 Overproduction of fibroblast growth factor 23 leads to a paraneoplastic syndrome characterized by hyperphosphaturia, hypophosphatemia, hypovitaminosis D, and vitamin D refractory rickets/osteomalacia. These effects disappear upon tumor removal. PMT can occur in several anatomical regions, mainly in the limbs, usually involving both soft tissue and bone. Acral locations occur in 10% to 15% of cases, mostly in the feet, with 95 cases reported in this region to date. This study reports a case of PMT in a young adult male who presented with the classic constellation of signs and symptoms in 2007. A small soft-tissue tumor was detected in his right heel 3 years after extensive investigations using various imaging techniques at different institutions. Prior to tumor detection, attempts to manage the patient’s osteomalacia with phosphate and vitamin D (both calcitriol and ergocalciferol) supplementation were unsuccessful. Following surgical resection, the patient experienced prompt correction of the phosphaturia and gradual reconstitution of his bone mineralization. The pathological diagnosis was (benign) PMT, mixed connective tissue type. In 2019, 12 years after resection, the patient is asymptomatic, and his bone mineral homeostasis has been restored.

Hypovitaminosis D is common in most fragility hip fracture patients. 2 However, measuring 25-hydroxyvitamin D (25(OH)D) levels is costly and may not be available in some centers. Without baseline serum 25(OH)D levels, the appropriate dose of vitamin D supplementation is unknown. This study aimed to evaluate the effectiveness and safety of vitamin D supplementation in fragility hip fracture patients, comparing high- and low-dose vitamin D supplementation.

Vitamin D deficiency, a lipid-soluble vitamin and steroid hormone, affects about 24% to 40% of the population in the Western world. 18 In addition to its well-documented effects on the musculoskeletal system, vitamin D also contributes significantly to promoting and preserving cardiovascular health by modulating immune and inflammatory functions and regulating cell proliferation and migration, endothelial function, renin expression, and extracellular matrix homeostasis. This review focuses on the cardiovascular and cerebrovascular effects of vitamin D and the cellular, molecular, and functional changes that occur in the circulatory system in vitamin D deficiency (VDD). It explores the links between VDD and adverse vascular remodeling, endothelial dysfunction, vascular inflammation, and an increased risk of cardiovascular and cerebrovascular diseases. Understanding the complex role of VDD in the pathogenesis of atherosclerotic cardiovascular diseases, stroke, and vascular cognitive impairment is crucial for all cardiologists, dietitians, and geriatricians, as VDD presents an easy target for intervention.

Disrupted vitamin D metabolism is a primary trigger for secondary hyperparathyroidism (SHPT) in CKD. 10 KDIGO guidelines recommend correcting 25(OH)D deficiency through nutritional vitamin D administration to prevent and treat SHPT in CKD stage G3-G5 and G1T-G5T patients, though the evidence supporting this recommendation remains inconsistent. Nutritional vitamin D is available as cholecalciferol, ergocalciferol, or calcifediol. Calcifediol’s superior ability to increase 25(OH)D levels has been suggested due to its improved bioavailability. The safer pharmacokinetic profile of the recent modified-release (MR) formulation of calcifediol has been effective in replenishing 25(OH)D levels while minimizing impacts on vitamin D catabolism and fibroblast-growth factor-23 (FGF-23) activation. This review discusses the use of calcifediol in treating SHPT across various CKD stages, adopting a physiology-driven approach with a focus on vitamin D metabolism, guideline recommendations, and a comparison of the clinical effects of calcifediol, cholecalciferol, and ergocalciferol on SHPT. While optimal targets for 25(OH)D and parathormone remain unclear, calcifediol, particularly in its newer MR formulation, may represent a compelling option to combine effective correction of 25(OH)D deficiency and SHPT, with limited impact on vitamin D catabolism and FGF-23 activation. Further data are needed to better understand the role of MR calcifediol in treating SHPT.

Feline vitamin D status is determined by dietary intake, but the metabolism of this essential nutrient and the efficacy of supplementation forms are poorly understood in cats. 21 This study aimed to further elucidate the metabolites of vitamin D₂ in cats and compare the effectiveness of vitamin D₂ and 25(OH)D₂ in increasing feline vitamin D status. Eight adult, male, castrated domestic shorthair cats received vitamin D₂ or 25(OH)D₂ in a single crossover design. Vitamin D₂ was dosed daily at a molar equivalent dosage to the vitamin D₃ ingested in the diet, while 25(OH)D₂ was provided at a daily dose of 20% molar equivalent intake of dietary vitamin D₃, based on its expected higher potency. Plasma concentrations of 25-hydroxyvitamin D epimers were evaluated at baseline and every 2 weeks for a total of 10 weeks. Analysis of multiple vitamin D metabolite concentrations was completed at the end of each supplementation period, followed by a washout period before the second phase of the crossover trial. Results showed that supplementation with 25(OH)D₂ more effectively and rapidly raised circulating 25(OH)D₂ levels in cat plasma compared to vitamin D₂. The formation of C-3 epimers of 25(OH)D₃, 25(OH)D₂, and 24,25R(OH)₂D₃, but not 24,25(OH)₂D₂, were observed in feline plasma. The abundant concentrations of epimeric forms of vitamin D metabolites found in circulation suggest that these metabolites should be considered during vitamin D analyses in cats. Further studies using 25(OH)D and vitamin D₂ forms are needed to conclude the safety and efficacy of these vitamers for supplementation in this species.

Vitamin D deficiency is often reported in individuals with chronic liver diseases. 7 Therefore, improving vitamin D status could have a beneficial effect on people with chronic liver diseases.

In recent years, there has been a growing awareness of the role of vitamin D in non-skeletal health and its potential for preventing chronic diseases. 15 Vitamin D is an essential hormone regulating calcium/phosphorous balance and plays a role in the development of inflammation, insulin resistance, and obesity. The main forms of vitamin D, cholecalciferol (vitamin D3) and ergocalciferol (vitamin D2), are converted into the active form (1,25-dihydroxyvitamin D) through two hydroxylation steps in the liver, kidney, pancreas, and immune cells. Vitamin D promotes the production of anti-inflammatory cytokines at higher levels, while suppressing the release of pro-inflammatory cytokines. Toll-Like Receptor (TLR) expression is increased, and a pro-inflammatory state is associated with low vitamin D levels. Regardless of its impact on inflammation, various pathways suggest that vitamin D directly improves insulin sensitivity and secretion. The level of vitamin D in the body can alter the ratio of pro- to anti-inflammatory cytokines, influencing insulin action, lipid metabolism, and the development and function of adipose tissue. Many studies have demonstrated an inverse relationship between vitamin D concentrations and pro-inflammatory markers, insulin resistance, glucose intolerance, metabolic syndrome, obesity, and cardiovascular disease. Notably, several long-term studies have also revealed an inverse correlation between vitamin D levels and the occurrence of diabetes mellitus. Vitamin D supplementation in humans has controversial effects. While some studies have shown improvements in insulin sensitivity, glucose, and lipid metabolism, others have revealed no significant impact on glycemic homeostasis and inflammation. This review aims to provide insight into the molecular basis of the relationship between vitamin D, insulin resistance, metabolic syndrome, type 1 and 2 diabetes, gestational diabetes, and cardiovascular diseases.

Vitamin D supplements are prescribed to correct low circulating concentrations of 25-hydroxyvitamin D. 11 In CKD, vitamin D metabolism is complicated by a decrease in the conversion of 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D by CYP27B1 and possibly a decrease in the conversion of 25-hydroxyvitamin D to 24,25-dihydroxyvitamin D by CYP24A1. This study aimed to determine the effects of vitamin D₂ supplementation on vitamin D metabolism in both healthy individuals and those with CKD.

Vitamin D has been recognized for its involvement in mineral and bone homeostasis for many years. 25 Previously, its primary use was in treating osteoporosis and rickets. In recent years, it has been discovered that vitamin D is an immune-modulating agent and may also play a role in various diseases, including autoimmune diseases. Immune-modulating effects are believed to be mediated by the interaction of vitamin D with the vitamin D receptor (VDR), which has transcriptional effects and is expressed on various cell types, especially those of the immune system. Immunologic and rheumatologic diseases were the first to be studied, but currently, the focus is on the interactions between tumor cells and vitamin D. This review focuses on four forms of cancer that appear to benefit from vitamin D supplementation during treatment: prostate, breast, colorectal cancers, and melanoma. Several studies have reported differences between white and black patients, which are discussed in this review.

This study investigated the effect of dried and UV-C irradiated mushroom powder on lipid oxidation and vitamin D content in fish meat. 3 Flammulina velutipes, Grifola frondosa, Hypsizygus marmoreus, Lentinula edodes, Pleurotus eryngii, and Pleurotus ostreatus were dried using hot air and irradiated with UV-C to evaluate the effects of these treatments on the components. Generally, the ergothioneine content did not change significantly, the total phenolic compound content decreased with hot air drying, and the ergocalciferol content increased with UV-C irradiation. To assess the impact of mushroom powder on lipid oxidation and vitamin D content in fish meat, 5% of the hot air dried and UV-C irradiated mushroom powder was added to fish meat and subjected to oxidation. As a result, all six mushrooms prevented lipid oxidation, and the ergocalciferol content in each mushroom powder remained between 58.2% and 69.7%. Overall, P. eryngii, L. edodes, and P. ostreatus strongly prevented the formation of lipid peroxide and aldehyde.

Benefits and Risks

Benefits Summary

Vitamin D supplementation offers a range of potential benefits, including improved bone health, enhanced immunity, mood regulation, and better metabolic function. Notably, a study found that vitamin D supplementation might help improve mood (depression and anxiety) in women with type 2 diabetes. 26

Risks Summary

Excessive vitamin D intake can lead to adverse effects such as nausea, vomiting, constipation, loss of appetite, dehydration, and potentially high blood calcium levels (hypercalcemia). It is important to note that the effectiveness of vitamin D supplementation in reducing fracture and fall risk varies depending on the dosage and interval, and an optimal dose or interval has not been established. 22

Comparison of Studies

Similarities in Studies

Many studies highlight the essential role of vitamin D in bone health, immunity, and metabolic function. However, it’s crucial to acknowledge that the effects of vitamin D can vary based on the form, dosage, and interval of supplementation.

Differences in Studies

Studies differ in their focus, including the specific diseases or symptoms investigated, the form of vitamin D used, the dosage and interval of supplementation, and the characteristics of the study participants. Direct comparisons between research findings can be challenging given these variations.

Consistency and Discrepancies in Findings

Research findings exhibit both consistency and discrepancies. For instance, one study showed that ergosterol did not affect bone mineralization. 1 However, another study suggested that vitamin D might influence pathways related to thrombosis. 13 These discrepancies highlight the potential variability in vitamin D’s effects based on factors such as the form of vitamin D, the dosage, the individuals studied, and other variables.

Practical Applications and Considerations

While vitamin D plays a vital role in health, it is crucial to be aware of the potential risks of excessive intake. Vitamin D supplementation should be undertaken under the guidance of a healthcare professional. When applying research findings to individual situations, careful consideration is essential. Various factors can influence the effects of vitamin D, such as individual body composition, lifestyle habits, and other nutrient intakes.

Limitations of Current Research

Many studies have limitations, such as small sample sizes and the inability to assess long-term effects. Additionally, the variations in study populations, forms of vitamin D used, dosages, and intervals make generalizing research findings challenging.

Future Research Directions

Further research is needed to gain a deeper understanding of the impact of vitamin D on various diseases and symptoms. Specifically, research is required to identify the optimal form, dosage, interval, and personalized supplementation strategies tailored to individual characteristics.

Conclusion

Vitamin D offers a range of potential health benefits, including improved bone health, enhanced immunity, better mood, and improved metabolic function. However, the risks of excessive intake must be acknowledged. Vitamin D supplementation is best undertaken under the guidance of a healthcare professional. Further research can shed more light on the safety and efficacy of vitamin D supplementation.