No full-text available
To read the full-text of this research,
you can request a copy directly from the author.
Vitamin D supplementation: cholecalciferol, calcifediol, and calcitriol
Abstract
The specific compound that is meant for use in the context of vitamin D supplementation is often ambiguous. The term “supplementation” has been used in the context of cholecalciferol, ergocalciferol, calcidiol, and calcitriol. In nature, by far the major form of vitamin D that nurtures the body is cholecalciferol. In contrast, ergocalciferol is primarily a synthetic and less stable product which is less potent per microgram dose than is cholecalciferol. Calcidol is the major circulating metabolite of cholecalciferol, while calcitriol is the hormone that upregulates the active transport of calcium from the gut, and which suppresses parathyroid hormone secretion. Nutrition policy papers and guidelines leave unstated the obvious fact that calcidiol and calcitriol are not nutrients, and that those metabolites are not pertinent to food fortification or dietary supplementation. Recent evidence shows that ergocalciferol is not stable with storage, and it is far more susceptible to breakdown with cooking and baking than is cholecalciferol. Therefore, it must be concluded that cholecalciferol is the only form of vitamin D that should be considered in the context of the nutritional functions of fortification and supplementation.
... Thus, when we talk about vitamin D, we mean a system composed of the three forms mentioned above: cholecalciferol (vitamin D 3 ) as the form of vitamin D synthesized following exposure to sunlight, calcidiol [25(OH)D] as the circulating form of vitamin D of which the dosage is made, and calcitriol [1,25(OH) 2 D] as the active form [10]. ...
... Thus, when we talk about vitamin D, we mean a system composed of the three forms mentioned above: cholecalciferol (vitamin D3) as the form of vitamin D synthesized following exposure to sunlight, calcidiol [25(OH)D] as the circulating form of vitamin D of which the dosage is made, and calcitriol [1,25(OH)2D] as the active form [10]. ...
... Exposure of almost the entire body to sunlight for an entire day can produce as much as 10,000 IU (International Units) of cholecalciferol, i.e., approximately 250 IU of 25(OH)D 3 , i.e., calcidiol [10]. Of these, only about 3% (2 IU) will become 1,25(OH) 2 D 3 , the active form. ...
Vitamin D3 deficiency and insufficiency are becoming a common global issue for us, especially in the most industrially developed countries. The only acknowledged activity of vitamin D3 in vertebrates is to promote the absorption of calcium and, therefore, allow for the mineralization of bones. Accordingly, its deficiency is associated with diseases such as rickets. Other numerous vital functions associated with vitamin D3 are yet to be considered, and the function of vitamin D2 in plants is unknown. Thus, 100 years after its discovery, the importance of vitamin D still seems to be unacknowledged (except for rickets), with little attention given to its decrease throughout the world. In this review, I suggest that vitamin D deficiency and insufficiency may be linked to the westernized lifestyle in more developed countries. Furthermore, I suggest that, rather than the calcemic activity, the main function of vitamin D is, in general, that of strengthening living organisms. I conclude with the hypothesis that vitamin D deficiency may represent a marker for a greater risk of chronic inflammatory diseases and a shorter life expectancy.
... However, as deliberate sun exposure has declined, the necessity for increased supplement intake has become unavoidable [2]. Skin exposure to ultraviolet B spectrum (290-315 nm) (UVB) causes a photolytic conversion of the 7-dehydrocholesterol (7-DHC) to pre-vitamin D 3 , which then undergoes a thermally induced isomerization to form pre-vitamin D [84] (Figure 1). ...
... For communities with a high prevalence of vitamin D deficiency, targeted food fortification is a costeffective way to alleviate it [71]. These approaches can ensure an adequate supply of vitamin D3 to maintain optimal vitamin D levels in the population-mean serum 25(OH)D concentrations above 40 ng/mL [84,91]. In individuals, maintaining levels above 50 ng/mL can bolster immunity, reduce illnesses and absenteeism, and enhance productivity. ...
... For communities with a high prevalence of vitamin D deficiency, targeted food fortification is a cost-effective way to alleviate it [71]. These approaches can ensure an adequate supply of vitamin D 3 to maintain optimal vitamin D levels in the population-mean serum 25(OH)D concentrations above 40 ng/mL [84,91]. In individuals, maintaining levels above 50 ng/mL can bolster immunity, reduce illnesses and absenteeism, and enhance productivity. ...
Vitamin D is a crucial micronutrient, critical to human health, and influences many physiological processes. Oral and skin-derived vitamin D is hydroxylated to form calcifediol (25(OH)D) in the liver, then to 1,25(OH)2D (calcitriol) in the kidney. Alongside the parathyroid hormone, calcitriol regulates neuro-musculoskeletal activities by tightly controlling blood-ionized calcium concentrations through intestinal calcium absorption, renal tubular reabsorption, and skeletal mineralization. Beyond its classical roles, evidence underscores the impact of vitamin D on the prevention and reduction of the severity of diverse conditions such as cardiovascular and metabolic diseases, autoimmune disorders, infection, and cancer. Peripheral target cells, like immune cells, obtain vitamin D and 25(OH)D through concentration-dependent diffusion from the circulation. Calcitriol is synthesized intracellularly in these cells from these precursors, which is crucial for their protective physiological actions. Its deficiency exacerbates inflammation, oxidative stress, and increased susceptibility to metabolic disorders and infections; deficiency also causes premature deaths. Thus, maintaining optimal serum levels above 40 ng/mL is vital for health and disease prevention. However, achieving it requires several times more than the government’s recommended vitamin D doses. Despite extensive published research, recommended daily intake and therapeutic serum 25(OH)D concentrations have lagged and are outdated, preventing people from benefiting. Evidence suggests that maintaining the 25(OH)D concentrations above 40 ng/mL with a range of 40–80 ng/mL in the population is optimal for disease prevention and reducing morbidities and mortality without adverse effects. The recommendation for individuals is to maintain serum 25(OH)D concentrations above 50 ng/mL (125 nmol/L) for optimal clinical outcomes. Insights from metabolomics, transcriptomics, and epigenetics offer promise for better clinical outcomes from vitamin D sufficiency. Given its broader positive impact on human health with minimal cost and little adverse effects, proactively integrating vitamin D assessment and supplementation into clinical practice promises significant benefits, including reduced healthcare costs. This review synthesized recent novel findings related to the physiology of vitamin D that have significant implications for disease prevention.
... To summarize, vitamins D 2 and D 3 are not equivalent in raising circulating 25(OH)D, and bolus dosing may have adverse effects on vitamin D metabolism and clinical outcomes. As such, it is to be expected that calls for the use of only cholecalciferol and avoidance of ergocalciferol have been and continue to be published (233,239,240) with recent osteoporosis-treatment guidance advising cholecalciferol over ergocalciferol (241) (see Table 4). Despite these recommendations, high-dose ergocalciferol remains widely prescribed in the United States. ...
... It promotes active intestinal calcium absorption and suppresses PTH secretion. Calcitriol has a short half-life of around 5 to 8 hours; therefore, it should be administered daily (or with intermittent regimens) and sometimes in lower doses distributed over a 24-hour period (240,250). As calcitriol is not an organic micronutrient, its use in clinical practice requires careful monitoring. ...
... Moreover, some studies have reported a more significant incidence of adverse events such as hypercalcemia and hypercalciuria. Thus, there is a need to monitor serum and urine calcium and phosphate (240,251,252). Because of these safety and clinical practicality issues, there is consensus that calcitriol use should be limited to hormone replacement for patients with limited/absent renal tubular 1-α-hydroxylase activity, as their capacity to produce calcitriol is severely limited (240,251,252). ...
The 6th International Conference, "Controversies in Vitamin D," was convened to discuss controversial topics, such as vitamin D metabolism, assessment, actions, and supplementation. Novel insights into vitamin D mechanisms of action suggest links with conditions that do not depend only on reduced solar exposure or diet intake and that can be detected with distinctive noncanonical vitamin D metabolites. Optimal 25-hydroxyvitamin D (25(OH)D) levels remain debated. Varying recommendations from different societies arise from evaluating different clinical or public health approaches. The lack of assay standardization also poses challenges in interpreting data from available studies, hindering rational data pooling and meta-analyses. Beyond the well-known skeletal features, interest in vitamin D's extraskeletal effects has led to clinical trials on cancer, cardiovascular risk, respiratory effects, autoimmune diseases, diabetes, and mortality. The initial negative results are likely due to enrollment of vitamin D-replete individuals. Subsequent post hoc analyses have suggested, nevertheless, potential benefits in reducing cancer incidence, autoimmune diseases, cardiovascular events, and diabetes. Oral administration of vitamin D is the preferred route. Parenteral administration is reserved for specific clinical situations. Cholecalciferol is favored due to safety and minimal monitoring requirements. Calcifediol may be used in certain conditions, while calcitriol should be limited to specific disorders in which the active metabolite is not readily produced in vivo. Further studies are needed to investigate vitamin D effects in relation to the different recommended 25(OH)D levels and the efficacy of the different supplementary formulations in achieving biochemical and clinical outcomes within the multifaced skeletal and extraskeletal potential effects of vitamin D.
... No obstante, la variedad de dosis y de posologías reportadas indica que los médicos podrían variar su pauta de elección en función del grado de deficiencia, siguiendo las recomendaciones(12,13,49,51).Se observa que, entre los especialistas que tratan la sospecha de hipovitaminosis D sin medir niveles de 25(OH)D en sangre, el uso de colecalciferol es significativamente superior al de calcifediol (p < 0,05), lo que podría justificarse dado su perfil farmacocinético y de seguridad. Los estudios farmacocinéticos han determinado que la vida media del colecalciferol es de 60 días, ya que su naturaleza lipofílica y liposoluble permite el almacenamiento de tejidos(55)(56)(57).Esta característica de colecalciferol favorecería que el 25(OH)D se genere a partir de colecalciferol tisular de acuerdo con los requisitos del organismo(55).La tasa de conversión de colecalciferol en 25(OH)D sigue un aumento no lineal, lo que da lugar a una curva plasmática de 25(OH)D que alcanza una meseta a niveles de aproximadamente 30-50 ng/ml (56,58-64). Es decir, se produce un mayor aumento (curva más pronunciada) en el 25(OH)D sérico en caso de deficiencia más grave de vitamina D y se observa una tasa de conversión más baja una vez que los niveles de 25(OH)D se acercan a un cierto umbral o en pacientes con niveles suficientes (58,59,61-64). ...
... No obstante, la variedad de dosis y de posologías reportadas indica que los médicos podrían variar su pauta de elección en función del grado de deficiencia, siguiendo las recomendaciones(12,13,49,51).Se observa que, entre los especialistas que tratan la sospecha de hipovitaminosis D sin medir niveles de 25(OH)D en sangre, el uso de colecalciferol es significativamente superior al de calcifediol (p < 0,05), lo que podría justificarse dado su perfil farmacocinético y de seguridad. Los estudios farmacocinéticos han determinado que la vida media del colecalciferol es de 60 días, ya que su naturaleza lipofílica y liposoluble permite el almacenamiento de tejidos(55)(56)(57).Esta característica de colecalciferol favorecería que el 25(OH)D se genere a partir de colecalciferol tisular de acuerdo con los requisitos del organismo(55).La tasa de conversión de colecalciferol en 25(OH)D sigue un aumento no lineal, lo que da lugar a una curva plasmática de 25(OH)D que alcanza una meseta a niveles de aproximadamente 30-50 ng/ml (56,58-64). Es decir, se produce un mayor aumento (curva más pronunciada) en el 25(OH)D sérico en caso de deficiencia más grave de vitamina D y se observa una tasa de conversión más baja una vez que los niveles de 25(OH)D se acercan a un cierto umbral o en pacientes con niveles suficientes (58,59,61-64). ...
... The prevalence of OP was significantly higher among women 60 years of age and beyond, indicating that this age range associates with a high-risk of the disease. Menopausal hormone therapy, a primary preventive measure for postmenopausal OP, reduces the incidence of all fractures, including vertebral and hip fractures, and is an effective modality to decrease fracture incidence in perimenopausal and postmenopausal women (US Preventive Services Task Force et al., 2022;The 2022 Hormone Therapy Position Statement of The North American Menopause Society Advisory Panel, 2022). The Menopause Study Group of the Chinese Medical Association of Obstetrics and Gynecology proposes that "early initiation of MHT after menopause or at any stage of estrogen deficiency yields greater benefits and achieves primary prevention of osteoporotic fractures" (Chinese Menopause Society, 2023). ...
... Calcitriol, a vitamin-like drug and an important active metabolite of vitamin D3, directly binds to receptors and promotes calcium absorption. In addition, calcitriol plays a key role in regulating the calcium balance and providing a good pharmacological basis for the treatment of OP, including the stimulation of osteoblast activity in the bones and the correction of hypocalcemia (Vieth, 2022;Tilyard et al., 1992). ...
Purpose
This study aimed to analyze the current medication treatment status for women with osteoporosis (OP) based on real-world prescription data from 2016 to 2021 in Chinese nine cities' tertiary Grade A hospital and systematically describe the medication treatment patterns in women with OP.
Methods
Prescription information for female OP patients in nine cities (Beijing, Shanghai, Guangzhou, Hangzhou, Tianjin, Zhengzhou, Chengdu, Shenyang, Harbin) was extracted from the Hospital Prescription Analysis Collaboration Project Database of the Hospital Pharmacy Professional Committee of the Chinese Pharmaceutical Association. Statistical analysis was conducted to evaluate demographic characteristics and medication treatment patterns.
Results
A total of 669,505 prescriptions for medication treatment of female OP patients were included in this study. The majority of patients were aged 60 to 99 years (69.79 %) followed by 50 to 59 years (18.81 %) and 40 to 49 years (6.69 %). Geographically, the highest concentration of patients was in North China (Beijing, Tianjin) (43.05 %) followed by East China (Shanghai, Hangzhou) (31.43 %). The top three prescribed medications were active vitamin D and its analogs (40.78 %), calcium supplements (32.51 %), and bisphosphonates (18.75 %). The prescription frequency of menopausal hormone therapy (MHT) was 0.31 %. The proportion of female OP patients receiving monotherapy and two drug combinations therapy is equivalent (about 37 %).
Conclusion
The diagnosis and treatment of female OP patients in China showed regional variations. The most commonly prescribed medications for this population were calcitriol, calcium carbonate with vitamin D3, and alendronate sodium with vitamin D3. The use of MHT was relatively limited.
... The Polish biochemist Casimir Funk (1884-1967) coined the term vitamin in 1912 for a substance that appeared to be vital to life, although it was not an amine, but the term was already enshrined and persisted without change (Latin vita + amine) [114,115,116,117]. A vitamin is an organic micronutrient existing in minute amounts in natural foodstuffs, indispensable to normal metabolism, whose lack in the diet may cause deficiency disease [114,116,117]. ...
... The Polish biochemist Casimir Funk (1884-1967) coined the term vitamin in 1912 for a substance that appeared to be vital to life, although it was not an amine, but the term was already enshrined and persisted without change (Latin vita + amine) [114,115,116,117]. A vitamin is an organic micronutrient existing in minute amounts in natural foodstuffs, indispensable to normal metabolism, whose lack in the diet may cause deficiency disease [114,116,117]. ...
Normal metabolism ensures the adequate use of nutrients. Enzymes are the most important mediators of metabolism. Vitamin C, also identified as L-ascorbic acid (or L-ascorbate), is an important enzyme cofactor, playing other significant physiological roles in the human organism. During evolution, a few species, including the Homo sapiens, lacked L-gulonolactone oxidase (recommended name), L-gulono-1,4-lactone oxidase (a synonym), i.e., the enzyme that catalyzes the last step of vitamin C biosynthesis. Hereafter, vitamin C is an essential micronutrient for humans and its deficiency (or scurvy) may be fatal. Indeed, scurvy has plagued humankind since prehistoric times. Nevertheless, the industry began producing vitamin C in the early 1930s. Scientific interest in vitamin C became popular thanks to the eminent American chemist Linus Carl Pauling (1901-1994), who helped to spread the vitamin benefits worldwide, especially toward viral infections (e.g., common cold and flu). The COVID-19 pandemic has renewed the interest in vitamin C, opening new perspectives in the vitamin research and potential therapeutic uses. New conceptual elements have emerged, allowing the elucidation of points related to the evolution, prehistory, and history of vitamin C, and motivating the present review article.
... Vitamin D refers to the different isoforms, ergocalciferol (D 2 ) and cholecalciferol (D 3 ), resulting from the non-enzymatic reaction utilising ultraviolet B (UVB) light in a thermo-sensitive process. 1 Vitamin D 2 and D 3 are derived from food, sun exposure and supplements. They remain inactive until activated by enzymatic hydroxylation in the liver and kidneys. 2 Vitamin D is a fat-soluble molecule, classified as a member of the steroid hormone family, which is dissolved in dietary fat and needs to be emulsified by bile salts before absorption. ...
... The cholecalciferol metabolite, ergocalciferol is found in substantial quantities in circulation, while the calcitriol hormone upregulates the active transport of calcium from the gut, and suppresses the secretion of the PTH. 1 Both cholecalciferol and ergocalciferol are used as supplements during vitamin D deficiency and the choice between the two depends on practical reasons and preference. Ergocalciferol is used predominantly in North America, whereas cholecalciferol is the popular choice in Europe. ...
... Vitamin D refers to the different isoforms, ergocalciferol (D 2 ) and cholecalciferol (D 3 ), resulting from the non-enzymatic reaction utilising ultraviolet B (UVB) light in a thermo-sensitive process. 1 Vitamin D 2 and D 3 are derived from food, sun exposure and supplements. They remain inactive until activated by enzymatic hydroxylation in the liver and kidneys. 2 Vitamin D is a fat-soluble molecule, classified as a member of the steroid hormone family, which is dissolved in dietary fat and needs to be emulsified by bile salts before absorption. ...
... The cholecalciferol metabolite, ergocalciferol is found in substantial quantities in circulation, while the calcitriol hormone upregulates the active transport of calcium from the gut, and suppresses the secretion of the PTH. 1 Both cholecalciferol and ergocalciferol are used as supplements during vitamin D deficiency and the choice between the two depends on practical reasons and preference. Ergocalciferol is used predominantly in North America, whereas cholecalciferol is the popular choice in Europe. ...
Vitamin D is a fat-soluble molecule referring to the different isoforms, ergocalciferol (D2) and cholecalciferol (D3). Its physiological functions include increasing calcium serum concentrations. 25-hydroxyvitamin D3 (25(OH)D) (Calcifediol), a non-active, circulating instant precursor is seen as a pre-hormone. Studies have shown that a deficiency in calcifediol is related to chronic conditions such as cardiovascular, musculoskeletal, immune system, neurological, and anti-neoplastic functions. Vitamin D supplementation has shown its benefit as prophylaxis and treatment during the coronavirus disease 2019 (COVID-19) pandemic and an increase in the prescribing of vitamin D supplementation has been observed. The intention of this review article is to provide guidance on the recommended dosage regimen as a prophylactic measure during COVID-19 and its use as a supplement in general. From this review article, it is clear that vitamin D has an important role to play not only in COVID-19 but also in various other health aspects of the human body.
Contribution
This review article highlighted the role of vitamin D in managing vitamin D deficiency and its role as a supplement in the management of respiratory tract infections, especially COVID-19. This overview can assist physicians in optimising healthcare by optimised dosing recommendations and indications.
... It is therefore not surprising that the measurement of calcifediol in serum is used to assess the nutritional status of the system [1-3], although this measurement is often expressed and erroneously described as "vitamin" D levels. In this regard, and to cause further nosological confusion, vitamin D itself, as well as calcifediol or even calcitriol, are often referred to as vitamin D [4]. ...
... It is therefore not surprising that the measurement of calcifediol in serum is used to assess the nutritional status of the system [1][2][3], although this measurement is often expressed and erroneously described as "vitamin" D levels. In this regard, and to cause further nosological confusion, vitamin D itself, as well as calcifediol or even calcitriol, are often referred to as vitamin D [4]. ...
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 [...]
... Still, this endocytosis occurs to a lesser extent than the quantities entering via diffusion from circulation [21]. The cholecalciferol (D3) synthesized in the skin indirectly regulates its own catabolic enzyme, 24-hydroxylase (transcribed from CYP24A1), through a negative feedback mechanism [22][23][24]. This catabolizes excess vitamin D into the inactive form, 24(OH)D [25], preventing high levels of vitamin D from entering the circulation and causing adverse effects. ...
Human skin is a physical and biochemical barrier that protects the internal body from the external environment. Throughout a person’s life, the skin undergoes both intrinsic and extrinsic aging, leading to microscopic and macroscopic changes in its morphology. In addition, the repair processes slow with aging, making the older population more susceptible to skin diseases. Intrinsic factors associated with advanced age gradually degrade the dermal collagen matrix, resulting in fine wrinkles and reduced elasticity; this is accelerated in post-menopausal women due to estrogen deficiency. In contrast, extrinsic factors associated with advanced age, primarily caused by exposure to ultraviolet (UV) radiation, lead to coarse wrinkles, solar elastosis, hyperkeratosis, irregular pigmentation, and skin cancers. UVB radiation, while contributing to skin photo-aging, also induces the cutaneous synthesis of vitamin D. Vitamin D, in turn, protects the skin from oxidative stress, inflammation, and DNA damage, thereby delaying both chronological and photo-aging. Moreover, research has demonstrated an association between lower vitamin D levels and a higher prevalence of certain cutaneous diseases. This review explores and summarizes the critical role of vitamin D in skin aging and age-related skin diseases. The data presented highlight the importance of maintaining vitamin D adequacy throughout life.
... In addition, in a mouse model of dry eye, esculetin significantly ameliorated dry eye symptoms [39] . Calcitriol Calcitriol [calcitriol,1α,25-(OH) 2 D3] is the active metabolite of vitamin D; its main function is to regulate calcium and phosphate homeostasis, and it also regulates cell proliferation and differentiation and plays a key role in the reactions of the immune and nervous systems [61] . The mechanism of action of calcitriol is mediated by vitamin D receptors, a subfamily of nuclear receptors that enter target cells as transcription factors after heterodimerization with retinoid X receptors. ...
Dry eye, the most common ocular surface disease, can cause ocular surface tissue damage and discomfort symptoms and seriously affect people’s quality of life. The etiology of dry eye is diverse, and its pathogenesis is complex. The oxidative stress reaction is considered to be among the important factors in the pathogenesis of dry eye. Therefore, activating the antioxidant system has a potential therapeutic effect on dry eye. Nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway is considered the most important antioxidant pathway in the body. The activation of the Nrf2 signaling pathway and its interaction with other pathways are important mechanisms to prevent the occurrence and development of dry eye. This review describes the structure and function of Nrf2, summarizes the changes in the oxidative stress response in dry eye, focuses on the potential mechanism of the Nrf2 signaling pathway in the treatment of dry eye, and, finally, summarizes the drugs that activate the Nrf2 signaling pathway in the treatment of dry eye.
... [14] The patients who had low levels of Vitamin D3 (89%) and Vitamin B12 (70%) were put on a weekly dose of 60,000 IU cholecalciferol syrup and a daily supplement of methylcobalamin 1500 µg with breakfast, respectively. [15,16] All conventional medicines, including pancreatic enzymes, were stopped for all patients from the start of the treatment. Patients suffering from diabetes (29%) and hypertension (8%) were advised to continue antidiabetic and anti-hypertensive medicines in consultation with their physicians. ...
Recurrent Acute/Chronic Pancreatitis (RA/CP) is a progressively debilitating disease with rising incidences in recent years. The limitations of conventional treatment, along with the psychological fear and financial burden associated with it, compel the patients to explore alternative options. In India, where traditional medicines are recognized as treatment options, a North India-based ayurvedic clinic has been treating RA/CP patients using an ayurvedic Herbo-Mineral Formulation (HMF) with a balanced diet and regulated lifestyle. The HMF is prepared using processed mercury, copper, and sulfur following the principles of Rasashastra. The HMF has demonstrated pancreatitis preventive properties in rat models and passed acute, subacute, and chronic toxicity assessments. This retrospective study enrolled 1750 well-diagnosed cases of RA/CP from January 1997 to July 2023. About 67% of the enrolled patients were nonalcoholics, 81% were nontobacco users, and 93% had no family history of the disease. The age group of 19–45 years represented the highest proportion of patients, with a male predominance (5:1). Nine hundred and sixteen patients with RA/CP completed 1-year ayurvedic intervention using HMF, without pancreatic enzymes. The ayurvedic treatment resulted in a significant 93% reduction in the frequency of pancreatitis attacks and a 97% decrease in emergency hospitalizations. The HMF has shown no adverse effects or toxicity in the treated patients. About 1.7% of patients experienced mortality during the treatment or follow-up period due to various reasons. The ayurvedic treatment protocol demonstrated sustainable effects, with the longest remission exceeding 26 years, and has brought a significant reduction in frequency and intensity of RA/CP attacks with an overall improvement in quality of life, warranting further randomized clinical trials to establish strong proof of efficacy.
... Among various factors (sedentary lifestyle, obesity, and Western diet), vitamin D has gained significant attention because of its potential role in cancer prevention [1]. Vitamin D (cholecalciferol), which is primarily obtained through sunlight exposure and diet, is metabolized in the liver to 25-hydroxyvitamin D (calcidiol), the main circulating form, and further converted in the kidneys to its active form, 1,25-dihydroxyvitamin D (calcitriol) [2]. Vitamin D deficiency, defined by serum calcidiol levels less than 20 ng/mL (50 nmol/L), is prevalent globally, with approximately 40% of Europeans reported to be deficient and Biomedicines 2024, 12,1922 2 of 11 13% severely deficient. ...
(1) Colorectal cancer is a major cause of cancer-related death, with colorectal adenomas (CRAs) serving as precursors. Identifying risk factors such as vitamin D deficiency and the insulin-like growth factor (IGF) axis is crucial for prevention. (2) This case–control study included 85 participants (53 CRA patients and 32 controls) who underwent colonoscopy. We measured serum vitamin D3 (cholecalciferol), calcidiol (vitamin D metabolite), calcitriol (active vitamin D metabolite), insulin-like growth factor-1 (IGF-1), and insulin-like growth factor binding protein-3 (IGFBP-3) to explore their associations with CRA risk. (3) Results: We found that lower cholecalciferol levels were a significant risk factor for CRA (OR = 4.63, p = 0.004). Although no significant differences in calcidiol and calcitriol levels were observed between CRA patients and controls, calcidiol deficiency was common in the study population. IGF-1 levels inversely correlated with age, calcitriol, and IGFBP-3 in CRA patients. (4) This study highlights the potential of lower cholecalciferol levels to detect patients at risk of CRA when calcidiol values cannot, suggesting the importance of evaluating different vitamin D metabolites in cancer prevention research. Our findings underscore the need to further investigate the interactions between calcitriol, the active form of vitamin D, and the IGF axis in colorectal cancer development.
... As both UVA and UVB rays are harmful, there is no benefit of specialized lamps over natural sun light. [51,[83][84][85][86][87][88][89][90][91][92]. ...
Vitamin D deficiency is a significant global public health issue, even in regions with all year sun exposure. Currently, the scientific community has not yet reached a unanimous agreement regarding the optimum levels of vitamin D and the precise threshold values. Additional efforts are required to standardize the evaluation of vitamin D insufficiency and deficiency and to provide uniform treatment guidelines. Epidemiological studies have identified a broad spectrum of estimated prevalences in athletes. Their performance when participating in sports. depend on their muscles, heart and lung function. It seems that athletes have significantly lower levels of vitamin D compared to the general population. However, there is a lack of comprehensive studies and systematic reviews on this subject, making it challenging to reach conclusions due to variations in laboratory techniques and cut-off values. While there is an abundant of research on the supplementation of vitamin D and its benefits, it is challenging to provide general recommendations for athletes due to the limitations of extrapolation. However, there is a rather high occurrence of Vitamin D deficiency among individuals who engage in regular physical activity. Supplementing with Vitamin D helps prevents osteoporosis, bone fractures, enhances muscle strength, avoids lung infections, heart failure, and arrhythmias. It is generally safe when used in appropriate quantities, given its wide therapeutic range. Athletes can decrease the occurrence of training dropouts caused by infection, arrhythmias, muscular weakness and potentially prevent the inability to participate in competitions through correct nutrition and vitamin D supplementation. Keywords: vitamin D; sports; muscle; heart, athletes rehabilitation, vitamin D, ventricular premature contractions, physical activity
... While calcitriol has a short half-life of 4-8 h, calcidiol, has a half-life of 2-3 weeks. This notably longer half-life makes calcidiol a reliable biomarker for serum vitamin D assessment [2,21]. Both vitamin D 2 (ergocalciferol) and D 3 (cholecalciferol) undergo analogous hydroxylation processes, yielding the same active metabolite, calcitriol (1,25(OH) 2 D). ...
Vitamin D's role extends beyond classical calcium and phosphate homeostasis to encompass a pivotal influence on immune modulation and metabolic health. The mechanisms by which vitamin D exerts these effects involve its conversion to hormonally active calcitriol, which binds intracellular vitamin D receptors, initiating various downstream cascades. In this review, we tease out the evidence showing the relationship between vitamin D deficiency and prediabetes within the context of subclinical inflammation, with a special focus on the novel monocyte-to-HDL ratio (MHR), a novel inflammatory marker reflecting subclinical inflammation. This was based on a thorough literature review using reputable databases covering the period from 1980 to 2024. In light of this, we discuss calcitriol's anti-inflammatory effects and consequently link vitamin D deficiency to both overt and subclinical inflammation. Additionally, the utility of several bio-markers, notably MHR, in investigating this association is also discussed. We further reviewed the role of vitamin D deficiency in precipitating prediabetes and type 2 diabetes mellitus (T2DM) via insulin resistance, decreased insulin synthesis and secretion, and subclinical inflammation. Taken together, this mini review highlights that vitamin D deficiency is significantly associated with subclinical inflammation, playing a critical role in the development of prediabetes and the progression to T2DM. Addressing vitamin D deficiency through appropriate interventions may serve as a preventative measure against the development of prediabetes and T2DM.
... Feedback inhibition of enzyme activity at adequate 25(OH)D amounts or intrinsic kinetic features of 25-hydroxylase have been proposed as potential mechanisms for regulation of the cholecalciferol-to-25(OH)D hepatic conversion (Quesada-Gomez and Hall, 2020). This pharmacokinetic profile also avoids 25(OH)D fluctuations in serum following individual administrations, otherwise getting sustained 25 (OH)D levels (Charoenngam et al., 2021), which was ideally suggested elsewhere (Vieth, 2020). Altogether, the hepatic hydroxylation step, together with the lack of a linear relationship in the 25(OH)D production, may prevent an indefinite increase of serum values once under treatment, presented by other metabolites such as calcifediol (Jetter et al., 2014;Bischoff-Ferrari et al., 2012;Minisola et al., 2017;Sosa Henriquez et al., 2020;Bouillon and Quesada Gomez, 2023). ...
Introduction
Treatment of calcium (Ca) and vitamin D (VD) deficiency (VDD) is crucial for health, especially in bone conditions, such as low bone mineral density (BMD) and osteoporosis. Despite updates in clinical guideline recommendations, no studies have evaluated the efficacy and safety of administering 2000 IU of cholecalciferol combined with calcium. Thus, the main objective of this study was to evaluate VD levels following treatment with Ca 600 mg/ cholecalciferol 2000 IU in real-life clinical practice.
Methods
This multicenter, retrospective, observational study included 302 adult patients receiving Ca 600 mg/D3 2000 IU orodispersible tablets, daily for ≥24 weeks. The primary outcome was 25-hydroxivitamin D [25(OH)D] serum levels following treatment. Key secondary outcomes included changes in serum 25(OH)D levels and other bone metabolism (BM) parameters, safety and tolerability. The protocol was approved by a Research Ethics Committee.
Results
285 patients were evaluated (mean age [SD]: 67.4 [12.6] years old; 88.4 % women; basal serum 25(OH)D: 20.0 [8.6] ng/mL); 80.7 % reported previous history of osteoporosis/low BMD (osteopenia) and 37.2 % had received other Ca/VD prior to start study treatment. Median treatment duration was 38.5 weeks [range 24.0–82.4]. Overall, 94.4 % of patients increased serum 25(OH)D following treatment to a mean of 36.3 [11.8] ng/mL (p < 0.001 vs. baseline). Patients with basal VDD, significantly increased serum 25(OH)D to a mean over 30 ng/mL; no significant change found in repleted patients (basal 25(OH)D level ≥ 30 ng/mL). PTH was significantly reduced after treatment, with no clinically relevant effect on serum Ca or phosphate. Three non-serious treatment-emergent adverse events were reported. A post-hoc analysis on osteoporotic patients revealed virtually identical results in this population.
Conclusion
Treatment with Ca 600 mg/cholecalciferol 2000 IU for at least 24 weeks is effective and safe, especially in osteoporosis. Patients with VDD significantly increase plasma 25(OH)D to optimal range for bone health, with no clinically relevant changes on other bone metabolism parameters other than reducing secondary hyperparathyroidism. The magnitude of 25(OH)D increase directly correlates with the severity of VDD, with no effect in basally repleted patients.
... These include the endogenous precursor cholecalciferol (D3), derived from cholesterol; its partially active hydroxylated derivative, calcidiol (25(OH)D3), synthesized by the liver; and its active dihydroxy-form, calcitriol (1,25(OH)2D3), hydroxylated in the kidneys [19,20]. Additionally, there is a plant-derived form known as ergocalciferol (D2), characterized by a worse pharmacokinetic profile, less biological activity and lower stability than its animal derived analogues [21,22]. Calcitriol's most known effect is enhancing the absorption of calcium in the intestines and controlling phosphate levels. ...
Chronic kidney disease (CKD) and cardiovascular disease (CVD) are highly prevalent conditions, each significantly contributing to the global burden of morbidity and mortality. CVD and CKD share a great number of common risk factor, such as hypertension, diabetes, obesity, and smoking among others. Their relationship extends beyond these factors, encompassing intricate interplay between the two systems. Within this complex network of pathophysiological processes, vitamin D has emerged as a potential linchpin, exerting influence over diverse physiological pathways implicated in both CKD and CVD. In recent years, scientific exploration has unveiled a close connection between these two prevalent conditions and vitamin D, a crucial hormone traditionally recognized for its role in bone health. This article aims to provide an extensive review of vitamin D's multifaceted and expanding actions concerning its involvement in CKD and CVD.
... Vitamin D (VD) incorporates a group of hormones with structural and functional similarities to progesterone [1]. Two of them are particularly relevant for the human body: calcidiol (or 25-hydroxyvitamin D 3 ), which serves as circulating storage of VD; and calcitriol (or 1,25-dihydroxyvitamin D 3 ), which is generally considered the hormonally active metabolite of VD [2], albeit all VD forms have a certain degree of affinity towards the VD receptor (VDR) [3]. Due to its relatively long half-life, calcidiol is routinely quantified within the blood to assess VD status; therefore, identifying whether a person has sufficient circulating levels of VD [4]. ...
Purpose
The study aims to demonstrate the effects of Vitamin D (VD) supplementation, prior to oocyte pick-up within IVF protocols, in women with diverse VD status at the enrollment.
Methods
A total of 204 women eligible for intra-cytoplasmatic sperm injection (ICSI) cycles were included in the study and two homogeneous groups were selected from the database. Both group of patients with normal VD baseline level (> 40 ng/ml) and patients with low VD baseline level (< 20 ng/ml) were divided into control group and treatment group. The control group followed the standard procedure. The treatment group was supplemented with vitamin D3 as cholecalciferol in combination with Myo-Inositol, folic acid, and melatonin 3 months before standard procedure, once a day in the evening.
Results
VD levels significantly increased in the study group of low baseline VD, both in serum and in the follicular fluid compared to controls. The treatment induced a significant improvement of the embryo quality in both group of patients considered.
Conclusion
Supplementation of VD in patients undergoing ICSI procedures significantly improved the number of top-quality embryos compared with the control group, either starting from VD normal baseline values or starting from low values.
Trial registration number
07/2018.
... Elevating serum 25(OH)D concentrations in acutely ill patients, such as ICU patients, will take about a week [80]. This delay is attributed to the time it takes for vitamin D to be absorbed via the intestinal lymphatic system and undergo hepatic 25-hydroxylation to produce 25(OH)D, which is a rate-limiting step [82][83][84]. In acute situations, the optimal choice is to provide partially activated vitamin D, calcifediol [25(OH)D], using a dose of 0.014 mg/kg body weight [36,56]. ...
Introduction and aim: SARS-CoV-2 outbreaks occur cyclically, aligning with winter when vitamin D levels are lowest, except after new variant outbreaks. Adequate vitamin D is crucial for robust immune function. Hypovitaminosis diminishes immune responses, increasing susceptibility to viral infections. The manuscript explores the discrepancy between increased SARS-CoV-2 hospitalizations and lower mortality.
Method: SARS-CoV-2 mutants, including Delta, BQ, and XBB Omicron lineages, developed immune evasion capabilities, reducing the effectiveness of COVID-19 vaccines and bivalent boosters. The failure of COVID-19 vaccines to prevent infections and spread to others, coupled with the immune evasion exhibited by mutant viruses, contributed to continued SARS-CoV-2 outbreaks. Interestingly, dominant new mutants, despite their increased transmissibility, have caused fewer deaths. This article scrutinizes the mentioned incongruity through an analysis of published data.
Results: Achieving herd immunity and eradicating SARS-CoV-2 has proven elusive due to ongoing mutagenesis and immune evasion, leading to recurrent viral outbreaks. The failure to approve repurposed early therapies for COVID-19 by regulators and misinformation and weak strategies undertaken by leading health authorities exacerbated the situation. Repurposed agents, including vitamin D and ivermectin, have demonstrated high efficacy against SARS-CoV-2 from the beginning and remain unaffected by mutations. Despite their cost-effectiveness and widespread availability, regulatory approval for these generic agents in COVID-19 treatment is pending.
Conclusion: Regulators hesitated to approve cost-effective, repurposed generic agents primarily to safeguard the temporary approval status of COVID-19 vaccines and anti-viral agents under Emergency Use Authorization, which persists. This reluctance overlooked the opportunity to implement an integrated approach with repurposed agents alongside COVID-19 vaccines, potentially reducing hospitalizations and fatalities and preventing outbreaks; this led to the failure to eradicate SARS-CoV-2 and becoming endemic. It is imperative that regulators now reconsider approving affordable generics for SARS-CoV-2 to effectively control future viral outbreaks. Non-technical Importance (Lay Abstract) Adequate vitamin D levels significantly bolster the human immune system-deficiency compromises immune responses and increases susceptibility, particularly to viruses. While new SARS-CoV-2 mutations like Omicron are less severe, they are more infectious and adept at evading immunity from vaccines; thus, they offer a limited spectrum of protection and duration. Primary COVID-19 vaccines have reduced disease severity but have failed to prevent viral spread, contributing to outbreaks. Booster doses had little effect on the virus but caused immune paresis, thus increasing susceptibility to infections. Regulators should consider approving generic, repurposed agents like vitamin D and ivermectin as adjunct therapies to address this challenge and better prepare for future pandemics. Proactively International Journal of Frontiers in Science and Technology Research, 2024, 06(02), 001-020 2 Integrating vitamin D supplementation to fortify the immune system can mitigate vital outbreaks, alleviate hospital burdens, and reduce healthcare costs.
... We also want to stress that we are well aware that our assumption of functional vitamin D deficiency as a condition indicating high vitamin D requirements based on the consideration that the human body reduces vitamin D catabolism reflected by low 24,25(OH)D levels according to the prevailing vitamin D demand is just a simplified hypothesis. Therefore, we stress that there exists a complex and partially unknown regulation of vitamin D metabolism, in particular of 24-hydroxylase activity, with many interacting factors [26][27][28]. Further research is warranted to better characterize vitamin D metabolism with the aim to further improve the identification of individuals who are most likely to benefit from vitamin D supplementation and to critically evaluate and eventually optimize the classification of functional vitamin D deficiency as applied in our study. ...
Circulating 25-hydroxyvitamin D (25(OH)D) is the generally accepted indicator of vitamin D status. Since hydroxylation of 25(OH)D to 24-25-dihydroxyvitamin D (24,25(OH)2D) is the first step of its catabolism, it has been suggested that a low 24,25(OH)D level and a low vitamin D metabolite ratio (VMR), i.e., 24,25(OH)2D divided by 25(OH)D, may indicate high vitamin D requirements and provide additional diagnostic information beyond serum 25(OH)D. We, therefore, evaluated whether the classification of “functional vitamin D deficiency”, i.e., 25(OH)D below 50 nmol/L, 24,25(OH)2D below 3 nmol/L and a VMR of less than 4%, identifies individuals who benefit from vitamin D supplementation. In participants of the Styrian Vitamin D Hypertension trial, a randomized controlled trial (RCT) in 200 hypertensive patients with serum 25(OH)D below 75 nmol/L, who received either 2.800 international units of vitamin D per day or placebo over 8 weeks, 51 participants had functional vitamin D deficiency. In these individuals, there was no treatment effect of vitamin D supplementation on various parameters of bone metabolism and cardiovascular risk except for a significant effect on parathyroid hormone (PTH) and expected changes in vitamin D metabolites. In conclusion, a low vitamin D metabolite profile did not identify individuals who significantly benefit from vitamin D supplementation with regard to bone markers and cardiovascular risk factors. The clinical significance of functional vitamin D deficiency requires further evaluation in large vitamin D RCTs.
... In conclusion, our study showed that idiopathic CIPO is strongly associated with low serum levels of 25-hydroxy-vitamin D. Vitamin D deficiency may negatively affect intestinal permeability and motility, gut microbiome and mucosal immunity, thus contributing to the severity of disease and risk of complications. Thus, our finding would further support to test serum level of vitamin D in all patients with CIPO and supplement vitamin D until normal levels are reached [29,30]. Prospective randomized studies with a large sample size are needed to confirm our findings and provide additional information on the causal link between CIPO and 25-hydroxy-vitamin D deficiency. ...
Idiopathic chronic intestinal pseudo-obstruction (CIPO) is associated with intestinal inflammation and malabsorption and may cause serum vitamin D deficiency. We aimed to assess whether there is an association between idiopathic CIPO and serum levels of 25-hydroxy-vitamin D. Consecutive patients with confirmed diagnosis of idiopathic CIPO were prospectively enrolled and matched with healthy controls by gender, age, and BMI. Median serum level of 25-hydroxy-vitamin D of patients with CIPO was compared with that of healthy subjects using the Wilcoxon signed-rank test for matched samples. A total of 35 patients with CIPO and 35 matched healthy subjects were enrolled. All patients with CIPO had a 25-hydroxy-vitamin D deficiency with serum levels <12 ng/ml. The median serum level of vitamin D was significantly lower in patients with CIPO than in healthy controls (5.7 vs. 29.7 ng/ml, P < 0.0001). Serum level of vitamin D was not associated with gender ( P = 0.27), age ( P = 0.22), BMI ( P = 0.95), high (>10 000 × ml) WBC count ( P = 0.08), or high (>5 mg/l) C-reactive protein ( P = 0.87) among patients with CIPO. CIPO seems to be strongly associated with low serum levels of 25-hydroxy-vitamin D.
... According to the Central and Eastern European Expert Consensus Statement published in 2022, a therapeutic dose of up to 10,000 IU of cholecalciferol daily may be used [6]. This dose also corresponds to the maximal physiologic dose rate per day (250 µg), which can be roughly acquired per day through exposure of whole-body skin to the sun for 30 min [17,18]. ...
Vitamin D deficiency and insufficiency are highly prevalent in CKD, affecting over 80% of hemodialysis (HD) patients and requiring therapeutic intervention. Nephrological societies suggest the administration of cholecalciferol according to the guidelines for the general population. The aim of the observational study was to evaluate the efficacy and safety of the therapy with a high dose of cholecalciferol in HD patients with 25(OH)D deficiency and insufficiency to reach the target serum 25(OH)D level > 30 ng/mL. A total of 22 patients (16 M), with an average age of 72.5 ± 13.03 years and 25(OH)D concentration of 13.05 (9.00–17.90) ng/mL, were administered cholecalciferol at a therapeutic dose of 70,000 IU/week (20,000 IU + 20,000 IU + 30,000 IU, immediately after each dialysis session). All patients achieved the target value > 30 ng/mL, with a mean time of 2.86 ± 1.87 weeks. In the first week, the target level of 25(OH)D (100%) was reached by 2 patients (9.09%), in the second week by 15 patients (68.18%), in the fourth week by 18 patients (81.18%), and in the ninth week by all 22 patients (100%). A significant increase in 1,25(OH)2D levels was observed during the study. However, only 2 patients (9.09%) achieved a concentration of 1,25(OH)2D above 25 ng/mL—the lower limit of the reference range. The intact PTH concentrations remained unchanged during the observation period. No episodes of hypercalcemia were detected, and one new episode of hyperphosphatemia was observed. In conclusion, our study showed that the administration of a high-therapeutic dose of cholecalciferol allowed for a quick, effective, and safe leveling of 25(OH)D concentration in HD patients.
... Among vitamin-related drugs, Calcitriol (1,25-dihydroxyvitamin D), Cholecalciferol (25-hydroxyvitamin D), and Calcifediol are distinct forms of Vitamin D, such as precursors or derivatives (Sosa Henríquez and Gómez de Tejada Romero, 2020;Vieth, 2020;Quesada-Gomez et al., 2022). Vitamin D plays a crucial role in the absorption of calcium in the intestines and maintaining appropriate serum calcium and phosphate concentrations (Khazai et al., 2008;Schafer, 2017;Fleet and Health, 2022). ...
... Therefore, our study proposes that calcitriol is more effective in HT intervention. However, due to the increased risk of hypercalcemia compared to native vitamin D, calcitriol is not recommended for the treatment of vitamin D deficiency/insufficiency. [59,60] In summary, we contend that calcitriol is more effective in managing HT; however, the safety of calcitriol in HT requires confirmation through more clinical studies. ...
Background
Hashimoto’s thyroiditis (HT) is the prevailing form of autoimmune thyroiditis and the leading cause of hypothyroidism in iodine-sufficient regions worldwide. This study aims to evaluate the efficacy of vitamin D supplementation on HT through a meta-analysis of randomized controlled trials (RCTs).
Methods
The databases searched included PubMed, and others. We included RCTs that the treatment group received vitamin D, while the control group received either a placebo or no treatment. The studies measured the baseline and endpoint levels of 25-hydroxyvitamin D [25(OH)D], thyroid-stimulating hormone (TSH), free thyroxine (FT4), free triiodothyronine (FT3), anti-thyroid peroxidase antibody (TPO-Ab), and thyroglobulin antibody (TG-Ab). We performed a meta-analysis to calculate the standardized mean difference (SMD) and 95% confidence interval (CI).
Results
A total of 12 studies involving 862 individuals were included. Vitamin D supplementation has a significant impact on reducing the titers of TPO-Ab (SMD = −1.084, 95% CI = −1.624 to −0.545) and TG-Ab (SMD = −0.996, 95% CI = −1.579 to −0.413) in patients with HT, and it also improves thyroid function by decreasing TSH level (SMD = −0.167, 95% CI = −0.302 to 0.031) and increasing FT3 (SMD = 0.549, 95% CI = 0.077–1.020) and FT4 (SMD = 0.734, 95% CI = 0.184–1.285) levels. Active vitamin D (calcitriol) significantly reduces the titer of TPO-Ab compared to naive forms of vitamin D (vitamin D 2 or D 3 ); treatment durations > 12 weeks result in a more effective reduction of TPO-Ab levels and a more significant increase in FT4 and FT3 levels in patients with HT (meta-regression P < .05).
Conclusion
Vitamin D supplementation may have beneficial effects on HT patients by modulating immune responses and improving thyroid function.
... It has the highest bioavailability (absorption, 62-77%), a high affinity for vitamin D binding protein (VDBP) (99%), and the epimer 25(OH)-3-epi-D binds and activates the VDR [26] . Calcifediol increases serum 25(OH)D₃ within 2 hours of administration and the level peaks after 4-8 hours; a 33% reduction of peak level is evident after 1 week [27] . Compared with cholecalciferol, calcifediol, due to its high polarity, has greater solubility in organic solvents such as water. ...
Vitamin D deficiency has a high prevalence in the elderly population. This condition can cause sarcopenia and osteoporomalacia, which are associated with an increased risk of falls and fractures, especially of the proximal femur. These fractures have devastating consequences in terms of mortality, disability, and healthcare and social costs. Considering that 60% of hip fracture patients have hypovitaminosis D, and a serum 25(OH)D₃ increase of 10 ng/ml reduces the risk of hip fracture by 20%, correction of vitamin D status is clearly essential. Among the available preparations of vitamin D, calcifediol is preferred in cases with liver disease, malabsorption, obesity, and concomitant use of corticosteroids. Calcifediol administration corrects vitamin D deficiency and suppresses parathyroid hormone within 1 week, reaching the serum 25(OH)D₃ threshold of 30 ng/ml in 2 weeks. Correction of hypovitaminosis D with calcifediol also improves muscle strength and physical performance, reducing the risk of falls. Evidence about the role of calcifediol in the management of hip fracture patients is still scarce. Compared with placebo, administration of calcifediol in combination with strengthening exercise led to increased overall survival in patients with hip fracture. The efficacy of calcifediol in rapidly normalizing vitamin D status might be particularly useful in patients at imminent risk of fracture, such as those with hip fracture who need to receive immediate treatment with anti-osteoporotic drugs. KEY WORDS: Hip fractures, vitamin D deficiency, calcifediol, osteoporosis.
... Some studies have reported that vitamin D is a potent endogenous suppressor of the RAS, due to its ability to inhibit renin transcription in vitro and in vivo (33). Calcitriol is the major active form of vitamin D (34). In this study, we found that calcitriol can reduce blood pressure in aged mice, accompanied by inhibiting renal AT 1 R expression and function. ...
Background
The vitamin D level in the blood is associated with the incidence of hypertension. The present study investigated whether or not calcitriol, an active form of vitamin D, reverses age-related hypertension.
Methods
Young (3-month-old) and aged (12-month-old) C57BL/6 male mice were administered with or without calcitriol at 150 ng/kg per day by oral gavage for 8 weeks. Blood pressure was measured by tail-cuff plethysmography and telemetry, and superoxide production in renal tissue was assessed by fluorescence imaging, and the protein expression of AP1/AT1R signaling pathway was examined by Western blot.
Results
We showed that 24-hour renal sodium excretion was impaired and blood pressure was increased in aged mice, which was related to the enhancement of renal AT1R expression and function. In addition, the expression of transcription factor AP1 (a dimer of c-Fos and c-Jun) and the binding of AP1 to the AT1R promoter region was significantly enhanced, accompanied by decreased nuclear translocation of Nrf2, abnormal mitochondrial function including decreased ATP production, NAD⁺/NADH ratio and mtDNA copy numbers, and increased reactive oxygen species. Calcitriol increased 24-hour urinary sodium excretion and reduced blood pressure in aged mice. Mechanically, calcitriol increased the nuclear translocation of Nrf2, improved mitochondrial function, reduced AP1 binding ability to AT1R promoter, which reversed enhanced AT1R expression and function, and lowered blood pressure in aged mice.
Conclusions
Our findings indicated that calcitriol reversed age-related hypertension via downregulating renal AP1/AT1R pathway through regulating mitochondrial function. Thus, calcitriol may be a valuable therapeutic strategy for age-related hypertension.
... According to the Central and Eastern European Expert Consensus Statement published in 2022, a therapeutic dose up to 10,000 IU of cholecalciferol daily may be used [6]. This dose also corresponds to the maximal physiologic dose rate per day (250 µg), that can be roughly acquired per day through exposure of whole body skin to sun for 30 minutes [17,18]. ...
Vitamin D deficiency and insufficiency are highly prevalent in CKD affecting over 80% of hemodialysis (HD) patients and require therapeutic intervention. Nephrological societies suggest the administration of cholecalciferol according to the guidelines for the general population. The aim of the observational study was to evaluate the efficacy and safety of the therapy with a high dose of cholecalciferol in HD patients with 25(OH)D deficiency and insufficiency to reach the target serum 25(OH)D level > 30 ng/mL. 22 patients (16 M), with an average age of 72.5 ± 13.03 years and 25(OH)D concentration of 13.05 (9.00–17.90) ng/mL were administered cholecalciferol at a therapeutic dose of 70,000 IU/week (20,000 IU + 20,000 IU + 30,000 IU, immediately after each dialysis session). All patients achieved the target value >30 ng/mL, with a mean time of 2.86 ± 1.87 weeks. In the first week, the target level of 25(OH)D (100%) was reached by 2 patients (9.09%), in the second week – by 15 patients (68.18%), in the fourth week – by 18 patients (81.18%) and in the ninth week by all 22 patients (100%). A significant increase in 1,25(OH)2D levels was observed during the study, however, only 2 patients (9.09%) achieved a concentration of 1,25(OH)2D above 25 ng/mL – the lower limit of the reference range. The intact PTH concentrations remained unchanged during the observation period. No episodes of hypercalcemia, and one new episode of hyperphosphatemia were observed. In conclusion, our study showed that the administration of a high therapeutic dose of cholecalciferol allowed for a quick, effective, and safe leveling of 25(OH)D concentration in HD patients.
... Among the other available metabolites of Vitamin D, calcifediol is the one with good potential benefits but is less studied, with limited use in clinical settings. [9] Calcifediol is a highly potent oral formulation of Vitamin D, with good oral bioavailability, leading to higher and faster elevation in serum 25(OH)D concentrations. Importantly, it has a linear dose-response curve, such that the influence of baseline 25(OH)D level on the final 25(OH)D concentrations is much less marked with its use as opposed to Vitamin D3. ...
BACKGROUND: Vitamin D deficiency (VDD) is highly prevalent across the globe. Cholecalciferol (Vitamin D3) fails to attain sufficient serum concentrations of 25‑hydroxyvitamin D (25(OH)D) in a significant proportion of supplemented individuals. Calcifediol (25‑hydroxyvitamin D3) is less studied in healthy adults and its effects on 25(OH)D, parathyroid hormone (PTH), and 1,25‑dihydroxyvitamin D (1,25(OH)2D) at higher doses are not well known.
MATERIALS AND METHODS: The study was an open‑label, interventional trial recruiting consecutive participants with VDD who were allocated to receive either 2 capsules (50 μg‑group) or
1 capsule (25 μg‑group) daily doses of calcifediol. Baseline assessment included clinicodemographic parameters, dietary calcium, calcemic (calcium, inorganic phosphate, albumin, alkaline phosphatase, urine spot calcium/creatinine), and hormonal parameters (25(OH)D, PTH, and 1,25(OH)2D). Participants
were followed up at 4 and 8 weeks with repeat assessments of calcemic and hormonal parameters.
RESULTS: There were 64 participants, 35 (50 μg‑group) and 29 (25 μg‑group), without any significant difference in any of the baseline parameters. 97.1% participants in the 50 μg‑group (at
4 and 8 weeks) and 93.1% (at 4 weeks) and 96.5% (at 8 weeks) in the 25 μg‑group attained 25(OH)D sufficiency (≥30 ng/ml) with calcifediol. The mean serum 25(OH)D was 84.0 ± 27.7 ng/ml
in the 50 μg‑group and 58.0 ± 23.6 ng/ml in the 25 μg‑group group at 4 weeks, which later rose to 94.3 ± 21.8 ng/ml and 76.0 ± 16.4 ng/ml, respectively, at 8 weeks. PTH levels decreased in both
groups at both time points. 1,25(OH)2D rose significantly in both groups at 4 and 8 weeks but was not significantly different between both groups. There was no case of incident hypercalcemia or symptomatic nephrolithiasis.
CONCLUSION: Calcifediol is a safe and efficacious alternative for oral Vitamin D supplementation in young adults. Increment in 25(OH)D levels is rapid and dose‑dependent.
... There is a growing interest in addressing the evaluation of vitamin D concentrations in specializations other than skeletal evaluation, such as, for example, in neurology, where benefits may be found for those with sclerosis or epilepsy, or in the improvement of sexual function in postmenopausal women (9)(10)(11). Given the wide range of beneficial effects that can be attributed to vitamin D supplementation (12)(13)(14)(15), the present article has the objective to provide an exhaustive review of the various effects that have been identified through clinical trials regarding vitamin D supplementation, both in terms of the organs and systems involved and the effect studied. ...
Vitamin D is supplemented in individuals with or without risk factors
for deficiency, although its effects at specific doses and frequency are
controversial. In consequence, we aimed to perform an exhaustive
review on the effects of vitamin D supplementation in randomized
clinical trials in adult patients, grouped by target system and the evaluation criteria established in the objectives,
by searching clinical trials published in the last 5
years in PubMed and EBSCO are included, with the
keywords “vitamin D supplementation” AND effect,
in English or Spanish, excluding participants <19
years. Our initial search yielded 91 results from two
databases, of which 71 were included. A total of 24
articles published a significant effect of vitamin D
supplementation. Significant effects were identified
in 3 of 4 studies in postmenopausal patients on bone
density and/or strengthening of the musculoskeletal
system. Other statistically significant effects were
observed with supplementation in patients with
high body mass index, in glucose control and
glycosylated hemoglobin levels. We conclude that
randomized clinical trials show significant effects in
different organs and systems, the effect on glycemic
control is promising, even when overrepresenting
specific human groups.
... This is because supplements can provide a higher and more consistent dose of vitamin D compared to fortified foods, which may vary in their vitamin D content and bioavailability. However, fortified foods can still be a good source of vitamin D if consumed regularly as part of a balanced diet [37,38]. ...
Vitamin D is a pleiotropic hormone that plays a vital role in regulating bone growth, maintaining calcium and phosphate homeostasis, modulating immune function, and a wide range of other pleiotrophic actions in humans, which have increased the attention for its clinical applications. Despite its importance, vitamin D deficiency is prevalent worldwide and is related to a range of pathophysiological conditions, including an increased risk of osteoporosis and chronic and autoimmune diseases. The recommended daily doses of vitamin D vary depending on genetics, age, sex, and health status, with specific doses recommended for infants, children, adults, and those at increased risk of deficiency or specific health conditions. Maintaining adequate vitamin D levels is essential for optimal health, and together with sun exposure, appropriate supplementation strategies can help achieve this goal. Vitamin D supplementation is commonly used to maintain adequate levels, and the optimal administration strategy, such as a daily dose vs. a bolus, is still being investigated. This review aims to understand vitamin D physiology and the impact of relevant vitamin D polymorphisms and to evaluate the role of a daily dose versus a bolus in maintaining optimal vitamin D levels and clinical health outcomes. It also provides suggested clinical guidelines for clinicians based on the most recent scientific evidence.
... As a result, oral Vitamin D supplements have become highly popular and constitute a promising strategy to fight VDD [14][15][16] because they are readily available, cost effective and easy to administer. Most often (and possibly most beneficial), Vitamin D is supplied in the form of Vitamin D 3 , otherwise known as cholecalciferol [17]. This form of the vitamin is used in the present study. ...
Vitamin D is an essential nutrient with important immunomodulatory properties. As a fat-soluble compound, Vitamin D (and its D3 form) is immiscible with water, which presents challenges to absorption. In an in vitro setting, the current study characterizes novel micellar formulations of Vitamin D3 designed to improve absorption. Techniques used to evaluate and compare the micellar formulations against a non-micellar formula include the following: cryo-SEM to determine morphology; laser diffraction to determine particle size and distribution; zeta potential to determine stability of the particles; solubility assays to determine solubility in water and gastrointestinal media; and Caco-2 cell monolayers to determine intestinal permeability. Results show advantageous features (particle size range in the low micrometres with an average zeta potential of −51.56 ± 2.76 mV), as well as significant improvements in intestinal permeability, in one optimized micellar formula (LipoMicel®). When introduced to Caco-2 cells, LipoMicel’s permeability was significantly better than the control (p < 0.01; ANOVA). Findings of this study suggest that the novel micellar form of Vitamin D3 (LipoMicel) has the potential to promote absorption of Vitamin D3. Thus, it can serve as a promising candidate for follow-up in vivo studies in humans.
... The findings obtained from present study demonstrated that cholecalciferol had a more positive effect on the survival rate of infected mice. This could be explained by the efficient conversion of cholecalciferol stored in adipose tissue and muscle into the active form of vitamin D (1,25 (OH)2 D3) [18]. Moreover, this study showed a greater RR for the effect of vitamin D on the survival rates of mice infected with P. berghei. ...
Abstract Background Vitamin D supplementation is recommended as an effective adjunct to counteract malaria pathogenesis, but the evidence on this point is limited and controversial. This systematic review and meta-analysis aimed to investigate the effect of vitamin D administration on the survival rate of Plasmodium-infected animals in experimentally-induced malaria on days 6 and 10 post-infection. Methods Five electronic databases were searched up to 20 December 2021. The pooled risks ratio (RR) and associated 95% confidence interval were estimated using the Restricted-maximum likelihood (REML) random-effects model. Heterogeneity was assessed by Cochran’s Q test and I2 value. Sub-group analyses were used to identify the sources of heterogeneity for several variables, such as type of vitamin D, type of intervention, and dose of vitamin D. Results Out of 248 articles found in the electronic database, six were eligible for inclusion in the meta-analysis. The current study found that the pooled random effect of risks ratio favored a statistically significant effect of vitamin D administration on survival rate in infected mice on day 6 post Plasmodium infection (RR = 1.08, 95%CI 1.03, 1.15, p
... The natural vertebrate-form of vitamin D3 (the parental vitamin D) is the desirable supplementation, preferably obtained via routine safe skin exposure to ultraviolet sun rays and/or daily or weekly supplementation or targeted food fortification programs [14]. These mentioned modes can provide sufficient amounts of vitamin D to maintain the population's vitamin D sufficiency [i.e., maintaining the mean serum 25(OH)D concentrations above 40 ng/mL) [43,137], which would enhance the population's immunity and significantly reduce illnesses and absenteeism, thus increasing productivity. A robust immunity in the population can inherently curtail the spread of pathogenic microbial infections, particularly viral epidemics, and pandemics such as SARS-CoV-2, and reduce the associated hospitalization and deaths from infections [59,138]. ...
Vitamin D is essential for life—its sufficiency improves metabolism, hormonal release, immune functions, and maintaining health. Vitamin D deficiency increases the vulnerability and severity of type 2 diabetes, metabolic syndrome, cancer, obesity, and infections. The active enzyme that generates vitamin D [calcitriol: 1,25(OH)2D], CYP27B1 (1a-hydoxylase), and its receptors (VDRs) are distributed ubiquitously in cells. Once calcitriol binds with VDRs, the complexes are translocated to the nucleus and interact with responsive elements, up- or down-regulating the expression of over 1200 genes and modulating metabolic and physiological functions. Administration of vitamin D3 or correct metabolites at proper doses and frequency for longer periods would achieve the intended benefits. While various tissues have different thresholds for 25(OH)D concentrations, levels above 50 ng/mL are necessary to mitigate conditions such as infections/sepsis, cancer, and reduce premature deaths. Cholecalciferol (D3) (not its metabolites) should be used to correct vitamin D deficiency and raise serum 25(OH)D to the target concentration. In contrast, calcifediol [25(OH)D] raises serum 25(OH)D concentrations rapidly and is the agent of choice in emergencies such as infections, for those who are in ICUs, and for insufficient hepatic 25-hydroxylase (CYP2R1) activity. In contrast, calcitriol is necessary to maintain serum-ionized calcium concentration in persons with advanced renal failure and hypoparathyroidism. Calcitriol is, however, ineffective in most other conditions, including infections, and as vitamin D replacement therapy. Considering the high costs and higher incidence of adverse effects due to narrow therapeutic margins (ED50), 1α-vitamin D analogs, such as 1α-(OH)D and 1,25(OH)2D, should not be used for other conditions. Calcifediol analogs cost 20 times more than D3—thus, they are not indicated as a routine vitamin D supplement for hypovitaminosis D, osteoporosis, or renal failure. Healthcare workers should resist accepting inappropriate promotions, such as calcifediol for chronic renal failure and calcitriol for osteoporosis or infections—there is no physiological rationale for doing so. Maintaining the population’s vitamin D sufficiency (above 40 ng/mL) with vitamin D3 supplements and/or daily sun exposure is the most cost-effective way to reduce chronic diseases and sepsis, overcome viral epidemics and pandemics, and reduce healthcare costs. Furthermore, vitamin D sufficiency improves overall health (hence reducing absenteeism), reduces the severity of chronic diseases such as metabolic and cardiovascular diseases and cancer, decreases all-cause mortality, and minimizes infection-related complications such as sepsis and COVID-19-related hospitalizations and deaths. Properly using vitamin D is the most cost-effective way to reduce chronic illnesses and healthcare costs: thus, it should be a part of routine clinical care.
... Vitamin D has several forms that are critical to the biochemical functions of cellular health and organ systems. Vitamin D compounds function as a vitamin-nutrient, cell-signaling molecule, prehormone, or hormone, depending on the molecular structure, function, and place in the life cycle of vitamin D [36][37][38]. ...
Preventable vitamin D deficiency (VDD) is a global health concern. The prevention, early detection, and treatment of vitamin D deficiency aligning with serum 25-hydroxyvitamin D concentration recommendations of 40–60 ng/mL (100–150 nmol/L), provided by an international panel of 48 vitamin D researchers, would result in significant health benefits and cost savings to individuals and society. However, research shows that healthcare professionals lack knowledge and confidence in best practices with respect to vitamin D. A vitamin D toolkit was developed that included a model for decision-making support, e-tools, and accompanying resources and was implemented using an online, asynchronous learning management system. This pre-test, post-test, and follow-up survey study design aimed to increase nurses’ and dietitians’ levels of knowledge and confidence regarding vitamin D, aid in their translation of evidence into spheres of practice and influence, and help them identify translation barriers. The completion of the toolkit increased the participants’ (n = 119) knowledge from 31% to 65% (p < 0.001) and their confidence from 2.0 to 3.3 (p < 0.001) on a scale of 1–5. Respondents reported using the model (100%) as a framework to successfully guide the translation of vitamin D knowledge into their sphere of influence or practice (94%) and identifying translation barriers. The toolkit should be included in interdisciplinary continuing education, research/quality improvement initiatives, healthcare policy, and institutions of higher learning to increase the movement of research into practice.
... A number of studies further investigated the beneficial effect of vitamin D supplementation and demonstrated its potential modulatory activity on H. pylori pathogenicity (Yang et al., 2019). Owing to its high stability, cholecalciferol (vitamin D3) is the primary supplementary form of vitamin D that more efficiently increases the serum levels of vitamin D, compared to ergocalciferol (vitamin D2) (Vieth, 2020). ...
Background
Owing to the emergence and spread of multidrug resistance mechanisms in Helicobacter pylori, achieving a successful eradication has become exceedingly difficult. Thus, this study for the first time determines the effect of a combination of vitamin D3 and probiotic on the pathogenesis and treatment of H. pylori.
Methods
We established an in vitro experimental system using AGS human gastric carcinoma cells and explored the synergistic effect of Levilactobacillus brevis IBRC-M10790 and vitamin D3 on H. pylori. Live and pasteurized L. brevis, L. brevis-derived membrane vesicles (MVs), and L. brevis cell-free supernatant (CFS), as well as their combination with vitamin D3 were used during this study. We assessed the anti-inflammatory and anti-oxidative effects of these combinations using RT-qPCR and ELISA, respectively. We further performed an adhesion assay to evaluate the influence of L. brevis and vitamin D3 on the adherence rate of H. pylori to AGS cells.
Results
Our results demonstrated that L. brevis and vitamin D3 possess anti-inflammatory and anti-oxidative effects against H. pylori infection in AGS cells. The combination of vitamin D3 with the probiotic strain (particularly live L. brevis and its CFS) can more efficiently reduce the expression of pro-inflammatory cytokines IL-6, IL-8, IFN-γ, and TNF-α in the AGS cells. Moreover, vitamin D3 and L. brevis exhibited an additive impact preserving the integrity of the epithelial barrier by increasing the expression of the tight junction protein ZO-1. Furthermore, this combination can potentially reduce H. pylori adherence to AGS cells.
Conclusions
This study indicates the advantage of combining vitamin D3 and probiotic to attenuate H. pylori-induced inflammation and oxidative stress. Consequently, probiotic and vitamin D3 co-supplementation can be considered as a novel therapeutic approach to manage and prevent H. pylori infection.
... 5 Although the active form can be measured, 25(OH)D is the first choice for screening for VitD deficiency as it is the major circulating metabolite of cholecalciferol (VitD 3 ) and has greater reliability for monitoring VitD stores. 6 The active form is primarily regulated by parathyroid hormones and may even increase with VitD deficiency, which is why screening for 1,25(OH) 2 D levels is used in specific conditions such as kidney disease, sarcoidosis, and granulomatous diseases. 5 , 7 In addition to the scientific debate to establish optimal cutoff values of circulating VitD according to specific conditions, the nuances of dosing regimens are often discussed among clinicians. ...
Background:
Low serum 25-hydroxy-vitamin D [25(OH)D] levels are prevalent worldwide. Although the benefits of vitamin D supplementation have focused on skeletal disorders (eg, rickets, osteomalacia, osteoporosis), emerging evidence for nonskeletal health merits further discussion.
Purpose:
The purpose of this review was to critically examine the vitamin D supplementation literature pertaining to nonskeletal health to help guide clinicians.
Methods:
A scoping review that included observational studies and randomized clinical trials (RCTs) was performed. Evidence from meta-analyses and individual RCTs are discussed, and controversies and future directions are considered.
Findings:
25(OH)D deficiency is a ubiquitous condition associated with multiple nonskeletal diseases, including cardiometabolic (heart disease, diabetes, and kidney disease), immune (HIV/AIDS and cancer), lung (from traditional chronic disorders to coronavirus disease 2019), and gut diseases. Vitamin D deficiency also affects health across the life span (children, pregnant, and elderly), mental illness, and reproduction in both men and women. In contrast, vitamin D supplementation does not necessarily improve major medical outcomes, even when low 25(OH)D levels are treated. Screening for 25(OH)D status remains an important practice, primarily for high-risk patients (eg, elderly, women with osteoporosis, people with low exposure to sunlight). It is reasonable to supplement with vitamin D to treat 25(OH)D deficiency, such that if beneficial nonskeletal health occurs, this may be considered as a coadjutant instead of the central tenet of the disease. Furthermore, optimizing dosing regimens is an important clinical consideration.
Implications:
Although 25(OH)D deficiency is prevalent in nonskeletal diseases, there is no uniform evidence that vitamin D supplementation improves major medical outcomes, even when low 25(OH)D levels are corrected. Findings from RCTs warrant caution due to possible selection bias. Overall, vitamin D supplementation must be guided by circulating levels as a reasonable medical practice to correct 25(OH)D deficiency.
Vitamin D (calciferol), i.e. its active metabolite calcitriol [1,25(OH)2D], apart from essential participation in calcium and phosphorus homeostasis, is an important factor in the regulation of cell proliferation, differentiation and apoptosis, angiogenesis, imine and hormonal activity and others processes in the human body. Hence, its optimal balance is extremely important for adequate prenatal and postnatal growth and development, as well as for the preservation of health in other phases of life. This article provides a brief overview of the natural source of vitamin D, its metabolism and physiological role, as well as current recommendations related to the coverage of its optimal needs.
Over the last two decades, the emergence of lethal virulent strains of coronavirus (CoV), including the severe acute respiratory syndrome CoV 2 (SARS-CoV-2), which is responsible for the coronavirus disease 2019 (COVID-19) pandemic, has become a matter of great attention to the scientific community. Despite the implementation of preventive measures throughout the world, the spread of this disease and associated co-morbidities and mortality continue in all countries, continents, and populations of all ages. COVID-19 is highly contagious. Clinical manifestations are diverse and range from asymptomatic, mild to severe, life-threatening complications in the elderly and patients with underlying conditions such as cardiovascular disease, diabetes, obesity, and asthma. In addition, viral infections can trigger asthma attacks. To date, there is no specific treatment schema to combat COVID-19 disease. Current patient care revolves around disease severity and supportive treatment of symptoms from home-rest in mild disease to anti-viral therapy, oxygen support, anti-inflammatories, and anti-coagulants in severe COVID-19. Regarding prevention, the World Health Organization recommends vaccination, social distancing, quarantine, the wearing of surgical masks, and handwashing. In many countries, vaccination is optional, and given that parents are often reluctant to vaccinate themselves and their children for fear of side effects, identifying ways to enhance or support the immune system to prevent infection or improve recovery in vulnerable populations is worth investigating. Furthermore, research has focused on the pharmacological management of COVID-19 symptoms and much less has been published on nutrition therapy. Therefore, the scope of this review is to summarize the latest evidence on the use of vitamin D to support the metabolism and the immune system of asthma patients during the COVID-19 pandemic. A brief overview of asthma and COVID-19 pathophysiology, COVID-19 treatment guidelines for asthma patients, and the role of vitamin D in lung health, including the optimal blood level required to enhance immunity, will be suggested.
Chronic kidney disease (CKD) and cardiovascular disease (CVD) are highly prevalent conditions, each significantly contributing to the global burden of morbidity and mortality. CVD and CKD share a great number of common risk factors, such as hypertension, diabetes, obesity, and smoking, among others. Their relationship extends beyond these factors, encompassing intricate interplay between the two systems. Within this complex network of pathophysiological processes, vitamin D has emerged as a potential linchpin, exerting influence over diverse physiological pathways implicated in both CKD and CVD. In recent years, scientific exploration has unveiled a close connection between these two prevalent conditions and vitamin D, a crucial hormone traditionally recognized for its role in bone health. This article aims to provide an extensive review of vitamin D’s multifaceted and expanding actions concerning its involvement in CKD and CVD.
FIP, is an abroad-spectrum phenylpyrazole insecticide, and/or its metabolites trigger the toxicity in liver via the mitochondrial respiratory chain inhibition. This work aimed to investigate the effect of vitamin D 3 against FIP-induced liver toxicity in male rats. Vit. D 3 attenuated liver markers, hepatic necrosis and inflammation, and dyslipidemia in FIP-intoxicated rats. Vit. D 3 also reduced FIP-induced oxidative stress by increasing the activities of antioxidant enzymes, such as SOD, CAT, GPx, and GSH, and inhibiting lipid peroxidation products and nitric oxide levels in rat liver. Further investigations revealed that Vit. D 3 counteracted FIP-induced increased levels of IL-6, TNF-α. Moreover, Vit. D 3 up-regulated the AMPK-α, and PPAR-γ mRNA gene expression. In addition, Vit D 3 improved the histopathological changes caused by FIP. In conclusion , Vit. D 3 prevented liver damage in FIP-treated rats via augmentation of antioxidant defense mechanisms and inhibition of inflammatory cytokines/mediators and up-regulation of AMPK-α, and PPAR-γ.
The female athlete triad (TRIAD) is a spectrum of disorders involving low energy availability (LEA), low bone mineral density, and menstrual disorders. It is increasingly common to use the term ‘relative energy deficiency in sport’ (RED), emphasising the extensive impact of LEA on the body. The aim of this narrative review was to gather original research encompassing female athletes across various sports as well as to collect findings on the potential of a nutrition-focused approach to prevent or treat the aforementioned disorders. A comprehensive search was conducted in PubMed and Scopus. Several challenges were identified regarding the adequacy of the energy availability, protein, and carbohydrate requirements in the diets of female athletes. Moreover, insufficient intake of vitamin D has been observed across all athlete groups studied. This insufficiency also extends to the average requirement for Ca, Mg, the Ca/P ratio, Zn, and Fe. To address those concerns, a nutritional approach is proposed in the latter part of this review. The factors that can improve the absorption of micronutrients have also been discussed. The TRIAD/REDs affect an ever-growing number of women and require appropriate therapeutic management, particularly through nutritional care. Therefore, cooperation within an interdisciplinary team comprising a physician, nutritionist, physiotherapist, and psychologist is crucial.
Objective:
Vitamin D (a prohormone) is an important micronutrient required by the body for skeletal homeostasis and a range of non-skeletal actions. Calcitriol, the active form of vitamin D, regulates a variety of cellular and metabolic processes through both genomic and nongenomic pathways. Often prescribed for treating rickets and osteoporosis, vitamin D deficiency can exacerbate various other medical conditions.
Significance, methods, and results:
Despite its multifunctional uses, the sensitivity of vitamin D makes formulating an efficient drug delivery system a challenging task, which is further complicated by its poor aqueous solubility. Enhancing the oral absorption of vitamin D is vital in utilizing its full efficacy. Recent developments in encapsulation and nanotechnology have shown promising results in overcoming these constraints.
Conclusion:
This review thus offers an insight to adequately comprehend the mechanistic pharmacology of vitamin D, its pathophysiological role, and justification of its medical indications, along with the benefits of utilizing nanotechnology for vitamin D delivery.
Geriatric rehabilitation inpatients are at a higher risk of 25-hydroxyvitamin D (25(OH)D) deficiency due to poor nutrition and low sunlight exposure. This study aimed to evaluate the prevalence of 25-hydroxyvitamin (25(OH)D) deficiency and supplementation and to investigate their association with adverse health outcomes in geriatric rehabilitation inpatients.
Prospective, observational and longitudinal study.
Geriatric rehabilitation inpatients admitted to geriatric rehabilitation wards at the Royal Melbourne Hospital (Melbourne, Australia) from 16th, October 2017 and discharged until 18th, March 2020 in the REStORing health of acutely unwell adulTs (RESORT) study were included.
25(OH)D levels measured close to rehabilitation admission were classified as sufficiency (>54 nmol/L), insufficiency (26–54 nmol/L), or deficiency (<26 nmol/L). The usage of vitamin D supplementation was extracted from medication records. Outcomes included incidence of institutionalization at three-month post-discharge, in-hospital mortality and post-discharge mortality.
The median age of 1328 geriatric rehabilitation inpatients was 83.9 years (IQR: 78.1–88.7, 58.6% female). 25(OH)D deficiency and insufficiency were present in 8.1% and 26.4% of inpatients, respectively; 74.2% used vitamin D supplementation. 25(OH)D deficiency was associated with higher odds of institutionalization (odds ratio (OR): 1.88, 95% confidence interval (CI): 1.14–3.11), in-hospital mortality (OR: 3.30, 95% CI: 1.54–7.07) and higher risks of one-year mortality (hazard ratio (HR): 1.77, 95% CI: 1.17–2.69) compared to 25(OH)D sufficiency but not with three-month mortality. 25(OH)D insufficiency was not associated with outcomes. Patients who did not use supplementation and had 25(OH)D insufficiency or deficiency had significantly higher in-hospital mortality compared to those who used supplementation.
Among geriatric rehabilitation inpatients, 25(OH) D deficiency was associated with institutionalization, in-hospital mortality and one-year mortality. Attention to monitor the vitamin D status is of upmost importance during hospitalization.
Background
Vitamin D deficiency is present in 40%–70% of children with intestinal failure (IF), yet there are no published guidelines for repleting and maintaining vitamin D levels in this population. The purpose of this study is to evaluate the efficacy of a standardized vitamin D algorithm in reducing the incidence of deficiency.
Methods
A retrospective chart review was performed in children with IF who had at least one serum vitamin D (25‐hydroxyvitamin D 3 ) measurement. Vitamin D levels were compared prealgorithm (2014–2016) and during active‐algorithm use (2018–2020). Vitamin D levels were classified as severe deficiency (<12.5 nmol per L), mild deficiency (12.5–39 nmol/L), insufficiency (40–74 nmol/L), optimal (75–224 nmol/L), or toxicity (>225 nmol/L). Descriptive and comparative statistics were calculated using a linear mixed‐effects model, with P < 0.05 considered significant.
Results
Twenty‐eight children with IF were enrolled, which included 157 vitamin D measurements (58 in the prealgorithm group and 98 in the active‐algorithm group). Algorithm compliance was 4% in the prealgorithm group and 61% in the active‐algorithm group. Active‐algorithm patients had improved vitamin D levels in all categories compared with those of prealgorithm patients (mild deficiency: 8% vs 9%; insufficiency: 41% vs 72%; optimal: 50% vs 19%). Algorithm use was found to have a statistically significant effect on serum vitamin D levels ( β = 21.58; 95% confidence interval, 14.11–29.05; P < 0.005).
Conclusions
Children with IF are at high risk for vitamin D deficiency. Use of a standardized vitamin D supplementation algorithm was associated with increased serum vitamin D levels.
Telomeres are major contributors to cell fate and aging through their involvement in cell cycle arrest and senescence. The accelerated attrition of telomeres is associated with aging‑related diseases, and agents able to maintain telomere length (TL) through telomerase activation may serve as potential treatment strategies. The aim of the present study was to assess the potency of a novel telomerase activator on TL and telomerase activity in vivo. The administration of a nutraceutical formulation containing Centella asiatica extract, vitamin C, zinc and vitamin D3 in 18‑month‑old rats for a period of 3 months reduced the telomere shortening rate at the lower supplement dose and increased mean the TL at the higher dose, compared to pre‑treatment levels. TL was determined using the Q‑FISH method in peripheral blood mononuclear cells collected from the tail vein of the rats and cultured with RPMI‑1640 medium. In both cases, TLs were significantly longer compared to the untreated controls (P≤0.001). In addition, telomerase activity was increased in the peripheral blood mononuclear cells of both treatment groups. On the whole, the present study demonstrates that the nutraceutical formulation can maintain or even increase TL and telomerase activity in middle‑aged rats, indicating a potential role of this formula in the prevention and treatment of aging‑related diseases.
Vitamin D deficiency can lead to musculoskeletal diseases such as rickets and osteomalacia, but vitamin D supplementation may also prevent extraskeletal diseases such as respiratory tract infections, asthma exacerbations, pregnancy complications and premature deaths. Vitamin D has a unique metabolism as it is mainly obtained through synthesis in the skin under the influence of sunlight (i.e., ultraviolet-B radiation) whereas intake by nutrition traditionally plays a relatively minor role. Dietary guidelines for vitamin D are based on a consensus that serum 25-hydroxyvitamin D (25[OH]D) concentrations are used to assess vitamin D status, with the recommended target concentrations ranging from ≥25 to ≥50 nmol/L (≥10–≥20 ng/mL), corresponding to a daily vitamin D intake of 10 to 20 μg (400–800 international units). Most populations fail to meet these recommended dietary vitamin D requirements. In Europe, 25(OH)D concentrations <30 nmol/L (12 ng/mL) and <50 nmol/L (20 ng/mL) are present in 13.0 and 40.4% of the general population, respectively. This substantial gap between officially recommended dietary reference intakes for vitamin D and the high prevalence of vitamin D deficiency in the general population requires action from health authorities. Promotion of a healthier lifestyle with more outdoor activities and optimal nutrition are definitely warranted but will not erase vitamin D deficiency and must, in the case of sunlight exposure, be well balanced with regard to potential adverse effects such as skin cancer. Intake of vitamin D supplements is limited by relatively poor adherence (in particular in individuals with low-socioeconomic status) and potential for overdosing. Systematic vitamin D food fortification is, however, an effective approach to improve vitamin D status in the general population, and this has already been introduced by countries such as the US, Canada, India, and Finland. Recent advances in our knowledge on the safety of vitamin D treatment, the dose-response relationship of vitamin D intake and 25(OH)D levels, as well as data on the effectiveness of vitamin D fortification in countries such as Finland provide a solid basis to introduce and modify vitamin D food fortification in order to improve public health with this likewise cost-effective approach.
Rationale:
Calcidiol can be employed to correct vitamin D deficiency.
Main results:
Calcidiol administered at daily and weekly regimens over a period of 3 months was able to successfully raise 25-hydroxyvitamin D levels without altering other markers related to bone and mineral metabolism.
Significance:
Calcidiol supplementation is effective and safe.
Introduction:
The correction of vitamin D status is necessary to maintain an optimal mineral and skeletal homeostasis. Despite cholecalciferol (vitamin D3) is the most commonly used drug for vitamin D supplementation, the more hydrophilic compound calcidiol (25-hydroxyvitamin D3) can be employed at daily, weekly, and monthly regimens to reach in the short term the target levels of serum 25-hydroxyvitamin D [25(OH)D]. In the administration of different doses of calcidiol pharmacokinetic study (ADDI-D study), the efficacy and safety of daily and weekly dosages of calcidiol were tested.
Methods:
A total of 87 Caucasian, community-dwelling, postmenopausal women, aged 55 years or older, with vitamin D inadequacy (serum 25(OH)D levels <30 ng/ml, with mean 25(OH)D below 20 ng/ml, namely 16.5 ± 7.5 ng/ml) were randomized to receive three different dosages of calcidiol: 20 μg/day, 40 μg/day, and 125 μg/week for 3 months. The attained level of serum 25(OH)D was selected as primary endpoint to assess efficacy, while other parameters of mineral metabolism, (serum calcium, parathyroid hormone, phosphate, FGF23, urinary calcium, and markers of bone turnover) were assessed as secondary endpoints to establish safety.
Results:
In all the three groups, serum 25(OH)D values significantly and promptly rose and plateaued above the 30 ng/ml threshold remaining within safety interval after 14 days of treatment, with similar efficacy for the similar daily and weekly dose regimens. The different dosages were also equally effective in controlling secondary hyperparathyroidism. No significant changes in calcium and phosphate metabolism and in bone turnover markers were observed for any of the treatments, confirming the safety of this compound.
Conclusions:
The results of this study demonstrate the short- and mid-term efficacy and safety on core parameters of mineral metabolism of different daily or weekly dosages of calcidiol when used to treat vitamin D inadequacy or deficiency in postmenopausal women. Further studies are needed to assess falls as primary outcome of calcidiol supplementation.
To assess the bioavailability and safety of vitamin D3 from fortified mozzarella cheese baked on pizza.
In a randomized, double-blind trial, 96 apparently healthy, ethnically diverse adults were randomized to consume 200 IU or 28 000 IU vitamin D3 fortified mozzarella cheese with pizza once weekly for a total of 8 weeks. Blood and urine samples were collected at baseline (week 1) and final (week 10) visits for serum 25-hydroxyvitamin D and other biochemical measures. The primary outcome compared serum 25-hydroxyvitamin D between groups at 10 weeks. The secondary outcome evaluated the safety of vitamin D dosing protocol as measured by serum and urine calcium, phosphate, creatinine, and serum parathyroid hormone (PTH).
Serum 25-hydroxyvitamin D increased by 5.1 ± 11 nmol/L in the low-dose group (n = 47; P = 0.003), and by 73 ± 22 nmol/L in the high-dose group (n = 49; P < 0.0001). None of the subjects in either group developed any adverse events during the supplementation protocol. Serum PTH significantly decreased in the high-dose group only (P < 0.05).
Vitamin D3 is safe and bioavailable from fortified mozzarella cheese baked on pizza.
Humans derive most vitamin D from the action of sunlight in their skin. However, in view of the current Western lifestyle with most daily activities taking place indoors, sun exposure is often not sufficient for adequate vitamin D production. For this reason, dietary intake is also of great importance. Animal foodstuffs (e.g., fish, meat, offal, egg, dairy) are the main sources for naturally occurring cholecalciferol (vitamin D-3). This paper therefore aims to provide an up-to-date overview of vitamin D-3 content in various animal foods. The focus lies on the natural vitamin D-3 content because there are many countries in which foods are not regularly fortified with vitamin D. The published data show that the highest values of vitamin D are found in fish and especially in fish liver, but offal also provides considerable amounts of vitamin D. The content in muscle meat is generally much lower. Vitamin D concentrations in egg yolks range between the values for meat and offal. If milk and dairy products are not fortified, they are normally low in vitamin D, with the exception of butter because of its high fat content. However, as recommendations for vitamin D intake have recently been increased considerably, it is difficult to cover the requirements solely by foodstuffs.
Improving vitamin D status may be an important modifiable risk factor to reduce falls and fractures; however, adherence to daily supplementation is typically poor.
To determine whether a single annual dose of 500,000 IU of cholecalciferol administered orally to older women in autumn or winter would improve adherence and reduce the risk of falls and fracture.
A double-blind, placebo-controlled trial of 2256 community-dwelling women, aged 70 years or older, considered to be at high risk of fracture were recruited from June 2003 to June 2005 and were randomly assigned to receive cholecalciferol or placebo each autumn to winter for 3 to 5 years. The study concluded in 2008.
500,000 IU of cholecalciferol or placebo.
Falls and fractures were ascertained using monthly calendars; details were confirmed by telephone interview. Fractures were radiologically confirmed. In a substudy, 137 randomly selected participants underwent serial blood sampling for 25-hydroxycholecalciferol and parathyroid hormone levels.
Women in the cholecalciferol (vitamin D) group had 171 fractures vs 135 in the placebo group; 837 women in the vitamin D group fell 2892 times (rate, 83.4 per 100 person-years) while 769 women in the placebo group fell 2512 times (rate, 72.7 per 100 person-years; incidence rate ratio [RR], 1.15; 95% confidence interval [CI], 1.02-1.30; P = .03). The incidence RR for fracture in the vitamin D group was 1.26 (95% CI, 1.00-1.59; P = .047) vs the placebo group (rates per 100 person-years, 4.9 vitamin D vs 3.9 placebo). A temporal pattern was observed in a post hoc analysis of falls. The incidence RR of falling in the vitamin D group vs the placebo group was 1.31 in the first 3 months after dosing and 1.13 during the following 9 months (test for homogeneity; P = .02). In the substudy, the median baseline serum 25-hydroxycholecalciferol was 49 nmol/L. Less than 3% of the substudy participants had 25-hydroxycholecalciferol levels lower than 25 nmol/L. In the vitamin D group, 25-hydroxycholecalciferol levels increased at 1 month after dosing to approximately 120 nmol/L, were approximately 90 nmol/L at 3 months, and remained higher than the placebo group 12 months after dosing.
Among older community-dwelling women, annual oral administration of high-dose cholecalciferol resulted in an increased risk of falls and fractures.
anzctr.org.au Identifier: ACTRN12605000658617; isrctn.org Identifier: ISRCTN83409867.
In older adults, a serum 25-hydroxyvitamin D [25(OH)D] concentration >75 nmol/L lowers the risk of fracture. An oral intake of 125 microg (5000 IU) vitamin D(3)/d may be required to achieve this target.
The objective was to characterize the safety and efficacy of fortifying bread with a biologically meaningful amount of vitamin D(3).
In a single-arm design, 45 nursing home residents consumed one bun daily that had been fortified with 125 microg (5000 IU) vitamin D(3) and 320 mg elemental calcium.
The initial mean (+/-SD) serum 25(OH)D concentration was 28.5 +/- 10.8 nmol/L. After 12 mo, the 25(OH)D concentration was 125.6 +/- 38.8 nmol/L, and it exceeded 74 nmol/L in 92% of the patients. At every 3-mo follow-up, serum parathyroid hormone was lower than at baseline (P = 0.001). No changes in serum calcium or cases of hypercalcemia were observed at the follow-up assessments. Both mean total urinary calcium and the mean urinary calcium-creatinine ratio increased from baseline at one follow-up time point (P < 0.05). Between baseline and the 12-mo visit, z scores for bone mineral density at the lumbar spine and the hip both increased significantly (P < 0.001).
Fortification of bread with much more vitamin D than used previously produced no evident adverse effects on sun-deprived nursing home residents and improved bone density measures. Fortification of bread with 5000 IU vitamin D(3)/d provided reasonable assurance that vitamin D-deficient older adults attained a serum 25(OH)D concentration greater than the desirable objective of >75 nmol/L. This trial was registered at (ClinicalTrials.gov) as: NCT00789503.
Vitamin D deficiency (serum 25-hydroxyvitamin D (25(OH)D) < 50 nmol/l or 20 ng/ml), is common in Europe and the Middle East. It occurs in < 20 % of the population in Northern Europe, in 30-60% in Western, Southern and Eastern Europe and up to 80 % in Middle East countries. Severe deficiency (serum 25(OH)D < 30 nmol/l or 12 ng/ml) is found in > 10 % of Europeans. The ECTS advises that the measurement of serum 25(OH)D be standardized e.g. by the Vitamin D Standardization Program. Risk groups include young children, adolescents, pregnant women, older people, especially the institutionalized, and non-western immigrants. Consequences of vitamin D deficiency include mineralization defects and lower bone mineral density causing fractures. Extra-skeletal consequences may be muscle weakness, falls and acute respiratory infection, and are the subject of large ongoing clinical trials. The ECTS advises to improve vitamin D status by food fortification and the use of vitamin D supplements in risk groups. Fortification of foods by adding vitamin D to dairy products, bread and cereals can improve the vitamin D status of the whole population, but quality assurance monitoring is needed to prevent intoxication. Specific risk groups such as infants and children up to 3 years, pregnant women, older persons and non-western immigrants should routinely receive vitamin D supplements. Future research should include genetic studies to better define individual vulnerability for vitamin D deficiency, and Mendelian randomization studies to address the effect of vitamin D deficiency on long term non-skeletal outcomes such as cancer.
Chronic kidney disease-mineral and bone disorder (CKD-MBD) encompasses laboratory and bone abnormalities and vascular calcification and has deleterious effects on clinical outcomes. KDOQI (Kidney Disease Outcomes Quality Initiative), an initiative of the National Kidney Foundation, addressed this issue with the publication of a clinical practice guideline for bone metabolism and disease in CKD in 2003, and 2 years later, a new definition and classification scheme for CKD-MBD was developed following a KDIGO (Kidney Disease: Improving Global Outcomes) Controversies Conference. The initial KDIGO guideline on CKD-MBD was then published in 2009. New evidence was subsequently reviewed at the 2013 KDIGO Controversies Conference, and in 2017, KDIGO issued a clinical practice guideline update for the diagnosis, evaluation, prevention, and treatment of CKD-MBD. This commentary presents the views of the KDOQI CKD-MBD work group convened by the National Kidney Foundation. The KDOQI work group agrees with most of the KDIGO guideline update recommendations, particularly the suggestions regarding bone mineral density testing, joint assessments of longitudinal trends in mineral metabolism markers, and dietary phosphate counseling focused on phosphate additives. However, the KDOQI work group has some concerns about the suggestions related to hypocalcemia and hypercalcemia, phosphate-binder choice, and treatment of abnormal parathyroid hormone concentrations. The overall goal of this commentary is to provide a broad discussion for the US nephrology community regarding CKD-MBD and its diagnosis, prevention, and treatment.
Vitamin D is essential for calcium and bone homeostasis. Humans are largely dependent on UVB-radiation-induced photosynthesis of vitamin D, as few foods contain vitamin D. However, the same radiation that produces vitamin D is also carcinogenic, albeit with a long lag time, and causes DNA damage. In view of the increasing life expectancy, avoiding excessive sun exposure is prudent. Several groups of people have a shortfall between their requirements for vitamin D and their combined endogenous synthesis and intake from natural foods, and therefore need vitamin D supplementation. Governments and scientific societies are regularly updating their recommendations for intake of vitamin D, especially for groups that should (infants) or prefer to (especially elderly individuals) avoid direct sunlight. An overview of such guidelines is presented in this Review. A fairly large consensus exists that all infants should receive 400 international units (IU) (10 μg) daily during their first year of life and that elderly individuals should have access to vitamin D supplementation (at recommended dosages varying from 400 IU to 800 IU daily in most governmental guidelines but at higher dosages in other guidelines). All guidelines unanimously agree that serum levels of 25-hydroxyvitamin D (25OHD) <25 nmol/l (10 ng/ml) should be avoided at all ages. Children and adults who have limited sun exposure should receive vitamin D supplementation, but the recommended doses vary widely (from 200 IU to 2,000 IU daily), in line with disagreement regarding the minimal desirable serum concentration of 25OHD (which varies from 25 nmol/l to >100 nmol/l).
A history of vitamin D has been provided, dating from the earliest description of rickets, the disease resulting from vitamin D deficiency, to a current understanding of vitamin D metabolism and the mechanism of action of its hormonal form in regulating gene expression in target organs. Vitamin D is produced in skin by impact of 280–310 nm light on 7-dehydrocholesterol. The vitamin D is then converted in the liver to a circulating form, 25-hydroxyvitamin D that is converted largely, if not exclusively, in the kidney to the final hormone, 1α,25-dihydroxyvitamin D. This hormone functions through a nuclear receptor that regulates expression of key genes in target organs. Among its many resulting functions are increased intestinal calcium and phosphate absorption, bone calcium mobilization, and renal reabsorption of calcium. The resultant increase in serum calcium and phosphate supports bone mineralization, curing rickets, and osteomalacia. There are many other functions of vitamin D that remain to be described that contribute to its health supporting role.
There is a need for food-based solutions for preventing vitamin D deficiency. Vitamin D
3
(D
3
) is mainly used in fortified food products, although the production of vitamin D
2
(D
2
) is more cost-effective, and thus may hold opportunities. We investigated the bioavailability of D
2
from UV-irradiated yeast present in bread in an 8-week randomised-controlled trial in healthy 20–37-year-old women (
n
33) in Helsinki (60°N) during winter (February–April) 2014. Four study groups were given different study products (placebo pill and regular bread=0 µg D
2
or D
3
/d; D
2
supplement and regular bread=25 µg D
2
/d; D
3
supplement and regular bread=25 µg D
3
/d; and placebo pill and D
2
-biofortified bread=25 µg D
2
/d). Serum 25-hydroxyvitamin D
2
(S-25(OH)D
2
) and serum 25-hydroxyvitamin D
3
(S-25(OH)D
3
) concentrations were measured at baseline, midpoint and end point. The mean baseline total serum 25-hydroxyvitamin D (S-25(OH)D=S-25(OH)D
2
+S-25(OH)D
3
) concentration was 65·1 nmol/l. In repeated-measures ANCOVA (adjusted for baseline S-25(OH)D as total/D
2
/D
3
), D
2
-bread did not affect total S-25(OH)D (
P
=0·707) or S-25(OH)D
3
(
P
=0·490), but increased S-25(OH)D
2
compared with placebo (
P
<0·001). However, the D
2
supplement was more effective than bread in increasing S-25(OH)D
2
(
P
<0·001). Both D
2
and D
3
supplementation increased total S-25(OH)D compared with placebo (
P
=0·030 and
P
=0·001, respectively), but D
2
supplementation resulted in lower S-25(OH)D
3
(
P
<0·001). Thus, D
2
from UV-irradiated yeast in bread was not bioavailable in humans. Our results support the evidence that D
2
is less potent in increasing total S-25(OH)D concentrations than D
3
, also indicating a decrease in the percentage contribution of S-25(OH)D
3
to the total vitamin D pool.
Importance
Vitamin D deficiency has been associated with poor physical performance.Objective
To determine the effectiveness of high-dose vitamin D in lowering the risk of functional decline.Design, Setting, and Participants
One-year, double-blind, randomized clinical trial conducted in Zurich, Switzerland. The screening phase was December 1, 2009, to May 31, 2010, and the last study visit was in May 2011. The dates of our analysis were June 15, 2012, to October 10, 2015. Participants were 200 community-dwelling men and women 70 years and older with a prior fall.Interventions
Three study groups with monthly treatments, including a low-dose control group receiving 24 000 IU of vitamin D3 (24 000 IU group), a group receiving 60 000 IU of vitamin D3 (60 000 IU group), and a group receiving 24 000 IU of vitamin D3 plus 300 μg of calcifediol (24 000 IU plus calcifediol group).Main Outcomes and Measures
The primary end point was improving lower extremity function (on the Short Physical Performance Battery) and achieving 25-hydroxyvitamin D levels of at least 30 ng/mL at 6 and 12 months. A secondary end point was monthly reported falls. Analyses were adjusted for age, sex, and body mass index.Results
The study cohort comprised 200 participants (men and women ≥70 years with a prior fall). Their mean age was 78 years, 67.0% (134 of 200) were female, and 58.0% (116 of 200) were vitamin D deficient (<20 ng/mL) at baseline. Intent-to-treat analyses showed that, while 60 000 IU and 24 000 IU plus calcifediol were more likely than 24 000 IU to result in 25-hydroxyvitamin D levels of at least 30 ng/mL (P = .001), they were not more effective in improving lower extremity function, which did not differ among the treatment groups (P = .26). However, over the 12-month follow-up, the incidence of falls differed significantly among the treatment groups, with higher incidences in the 60 000 IU group (66.9%; 95% CI, 54.4% to 77.5%) and the 24 000 IU plus calcifediol group (66.1%; 95% CI, 53.5%-76.8%) group compared with the 24 000 IU group (47.9%; 95% CI, 35.8%-60.3%) (P = .048). Consistent with the incidence of falls, the mean number of falls differed marginally by treatment group. The 60 000 IU group (mean, 1.47) and the 24 000 IU plus calcifediol group (mean, 1.24) had higher mean numbers of falls compared with the 24 000 IU group (mean, 0.94) (P = .09).Conclusions and Relevance
Although higher monthly doses of vitamin D were effective in reaching a threshold of at least 30 ng/mL of 25-hydroxyvitamin D, they had no benefit on lower extremity function and were associated with increased risk of falls compared with 24 000 IU.Trial Registration
clinicaltrials.gov Identifier: NCT01017354
Disorders in the synthesis of the active metabolites of vitamin D,1,2 dialysate calcium (Ca) concentration,3 dietary Ca and phosphorus (P),4 and secondary hyperparathyroidism5 have been shown to influence Ca metabolism and the severity of the bone disease associated with uremia. The present study was designed to evaluate the effects of pharmacologic doses of calcifediol (25-hydroxy vitamin D3, [25OHD3]) on total body Ca (TBCa) and the bone mineral content (BMC) of the distal radius in patients with uremia. Previous studies from our laboratory have indicated that the serial and simultaneous measurements of TBCa and BMC of the distal radius reflect long-term changes in Ca balance and calcified tissue mass, as well as the distribution of Ca between bone and soft tissue.6 Since calcifediol influences the absorption and distribution of Ca, as well as has a direct effect on bone collagen metabolism in uremic animals
Context:
There is no doubt that vitamin D must be activated to the hormonal form 1,25-dihydroxyvitamin D to achieve full biological activity or that many tissues participate in this activation process-be it endocrine or autocrine. We believe that not only is 25-hydroxyvitamin D important to tissue delivery for this activation process, but also that intact vitamin D has a pivotal role in this process.
Objective:
In this review, evidence on the vitamin D endocrine/autocrine system is presented and discussed in relation to vitamin D-binding protein affinity, circulating half-lives, and enzymatic transformations of vitamin D metabolites, and how these affect biological action in any given tissue.
Conclusions:
Circulating vitamin D, the parent compound, likely plays an important physiological role with respect to the vitamin D endocrine/autocrine system, as a substrate in many tissues, not originally thought to be important. Based on emerging data from the laboratory, clinical trials, and data on circulating 25-hydroxyvitamin D amassed during many decades, it is likely that for the optimal functioning of these systems, significant vitamin D should be available on a daily basis to ensure stable circulating concentrations, implying that variation in vitamin D dosing schedules could have profound effects on the outcomes of clinical trials because of the short circulating half-life of intact vitamin D.
This analysis assessed whether seasonal change in 25-hydroxyvitamin D concentration was associated with bone resorption, as evidenced by serum parathyroid hormone and C-terminal telopeptide concentrations. The main finding was that increased seasonal fluctuation in 25-hydroxyvitamin D was associated with increased levels of parathyroid hormone and C-terminal telopeptide.
Introduction:
It is established that adequate 25-hydroxyvitamin D (25(OH)D, vitamin D) concentration is required for healthy bone mineralisation. It is unknown whether seasonal fluctuations in 25(OH)D also impact on bone health. If large seasonal fluctuations in 25(OH)D were associated with increased bone resorption, this would suggest a detriment to bone health. Therefore, this analysis assessed whether there is an association between seasonal variation in 25(OH)D and bone resorption.
Methods:
The participants were (n = 279) Caucasian and (n = 88) South Asian women (mean (±SD); age 48.2 years (14.4)) who participated in the longitudinal Diet, Food Intake, Nutrition and Exposure to the Sun in Southern England study (2006-2007). The main outcomes were serum 25(OH)D, serum parathyroid hormone (sPTH) and serum C-terminal telopeptide of collagen (sCTX), sampled once per season for each participant.
Results:
Non-linear mixed modelling showed the (amplitude/mesor) ratio for seasonal change in log 25(OH)D to be predictive of log sPTH (estimate = 0.057, 95 % CI (0.051, 0.063), p < 0.0001). Therefore, individuals with a higher seasonal change in log 25(OH)D, adjusted for overall log 25(OH)D concentration, showed increased levels of log sPTH. There was a corresponding significant ability to predict the range of seasonal change in log 25(OH)D through the level of sCTX. Here, the corresponding parameter statistics were estimate = 0.528, 95 % CI (0.418, 0.638) and p ≤ 0.0001.
Conclusions:
These findings suggest a possible detriment to bone health via increased levels of sPTH and sCTX in individuals with a larger seasonal change in 25(OH)D concentration. Further larger cohort studies are required to further investigate these preliminary findings.
To evaluate the effects of calcium and 25-OHD in the therapy of senile osteoporosis, we studied a group of 39 women aged 69 + 7 (standard deviation, SD) years with severe osteoporosis. The group was characterized histomorphometrically by depressed bone remodeling rates without hyperosteoidosis. No subject had risk factors for osteopenia other than their age and postmenopausal status, and no subject was receiving therapy for bone disease at the onset of the study. Subjects were followed for 2 years after randomization to receive either 1200 mg/day of calcium (as calcium carbonate) and 40 μg/day of 25-OHD (calcium-25-OHD group), or 1200 mg/day of calcium plus placebo (calcium-placebo group). Calcium-25-OHD resulted in a clear increase in 25-OHD levels (p < 0.001) and an increase in calcium absorption as indicated by urinary calcium excretion. Nevertheless, there was no significant change in fasting serum calcium, phosphorus, alkaline phosphatase, PTH, or 1,25-(OH)2D in either group. Radial and phalangeal bone mineral content and trabecular bone volume in the biopsied patients remained stable in both groups over the 2 year period. Unexpectedly, repeat bone biopsies revealed a clear improvement in the rate of mineralization in both groups, presumably as a result of the calcium supplementation alone. In summary, calcium-placebo and calcium-25-OHD treatment were both associated with stable appendicular bone mineral content in women with senile osteopenia. The finding of an effect of calcium supplementation on the rate of mineralization indicates that relative calcium deficiency may impair the mineralization phase of remodeling. Calcium therapy may thus provide some benefit in the therapy of osteoporosis characterized by prolonged remodeling rates.
Currently, there is a lack of clarity in the literature as to whether there is a definitive difference between the effects of vitamins D2 and D3 in the raising of serum 25-hydroxyvitamin D [25(OH)D].
The objective of this article was to report a systematic review and meta-analysis of randomized controlled trials (RCTs) that have directly compared the effects of vitamin D2 and vitamin D3 on serum 25(OH)D concentrations in humans.
The ISI Web of Knowledge (January 1966 to July 2011) database was searched electronically for all relevant studies in adults that directly compared vitamin D3 with vitamin D2. The Cochrane Clinical Trials Registry, International Standard Randomized Controlled Trials Number register, and clinicaltrials.gov were also searched for any unpublished trials.
A meta-analysis of RCTs indicated that supplementation with vitamin D3 had a significant and positive effect in the raising of serum 25(OH)D concentrations compared with the effect of vitamin D2 (P = 0.001). When the frequency of dosage administration was compared, there was a significant response for vitamin D3 when given as a bolus dose (P = 0.0002) compared with administration of vitamin D2, but the effect was lost with daily supplementation.
This meta-analysis indicates that vitamin D3 is more efficacious at raising serum 25(OH)D concentrations than is vitamin D2, and thus vitamin D3) could potentially become the preferred choice for supplementation. However, additional research is required to examine the metabolic pathways involved in oral and intramuscular administration of vitamin D and the effects across age, sex, and ethnicity, which this review was unable to verify.
Background:
Available evidence on the effects of vitamin D on mortality has been inconclusive. In a recent systematic review, we found evidence that vitamin D3 may decrease mortality in mostly elderly women. The present systematic review updates and reassesses the benefits and harms of vitamin D supplementation used in primary and secondary prophylaxis of mortality.
Objectives:
To assess the beneficial and harmful effects of vitamin D supplementation for prevention of mortality in healthy adults and adults in a stable phase of disease.
Search methods:
We searched The Cochrane Library, MEDLINE, EMBASE, LILACS, the Science Citation Index-Expanded and Conference Proceedings Citation Index-Science (all up to February 2012). We checked references of included trials and pharmaceutical companies for unidentified relevant trials.
Selection criteria:
Randomised trials that compared any type of vitamin D in any dose with any duration and route of administration versus placebo or no intervention in adult participants. Participants could have been recruited from the general population or from patients diagnosed with a disease in a stable phase. Vitamin D could have been administered as supplemental vitamin D (vitamin D3 (cholecalciferol) or vitamin D2 (ergocalciferol)) or as an active form of vitamin D (1α-hydroxyvitamin D (alfacalcidol) or 1,25-dihydroxyvitamin D (calcitriol)).
Data collection and analysis:
Six review authors extracted data independently. Random-effects and fixed-effect meta-analyses were conducted. For dichotomous outcomes, we calculated the risk ratios (RRs). To account for trials with zero events, we performed meta-analyses of dichotomous data using risk differences (RDs) and empirical continuity corrections. We used published data and data obtained by contacting trial authors.To minimise the risk of systematic error, we assessed the risk of bias of the included trials. Trial sequential analyses controlled the risk of random errors possibly caused by cumulative meta-analyses.
Main results:
We identified 159 randomised clinical trials. Ninety-four trials reported no mortality, and nine trials reported mortality but did not report in which intervention group the mortality occurred. Accordingly, 56 randomised trials with 95,286 participants provided usable data on mortality. The age of participants ranged from 18 to 107 years. Most trials included women older than 70 years. The mean proportion of women was 77%. Forty-eight of the trials randomly assigned 94,491 healthy participants. Of these, four trials included healthy volunteers, nine trials included postmenopausal women and 35 trials included older people living on their own or in institutional care. The remaining eight trials randomly assigned 795 participants with neurological, cardiovascular, respiratory or rheumatoid diseases. Vitamin D was administered for a weighted mean of 4.4 years. More than half of the trials had a low risk of bias. All trials were conducted in high-income countries. Forty-five trials (80%) reported the baseline vitamin D status of participants based on serum 25-hydroxyvitamin D levels. Participants in 19 trials had vitamin D adequacy (at or above 20 ng/mL). Participants in the remaining 26 trials had vitamin D insufficiency (less than 20 ng/mL).Vitamin D decreased mortality in all 56 trials analysed together (5,920/47,472 (12.5%) vs 6,077/47,814 (12.7%); RR 0.97 (95% confidence interval (CI) 0.94 to 0.99); P = 0.02; I(2) = 0%). More than 8% of participants dropped out. 'Worst-best case' and 'best-worst case' scenario analyses demonstrated that vitamin D could be associated with a dramatic increase or decrease in mortality. When different forms of vitamin D were assessed in separate analyses, only vitamin D3 decreased mortality (4,153/37,817 (11.0%) vs 4,340/38,110 (11.4%); RR 0.94 (95% CI 0.91 to 0.98); P = 0.002; I(2) = 0%; 75,927 participants; 38 trials). Vitamin D2, alfacalcidol and calcitriol did not significantly affect mortality. A subgroup analysis of trials at high risk of bias suggested that vitamin D2 may even increase mortality, but this finding could be due to random errors. Trial sequential analysis supported our finding regarding vitamin D3, with the cumulative Z-score breaking the trial sequential monitoring boundary for benefit, corresponding to 150 people treated over five years to prevent one additional death. We did not observe any statistically significant differences in the effect of vitamin D on mortality in subgroup analyses of trials at low risk of bias compared with trials at high risk of bias; of trials using placebo compared with trials using no intervention in the control group; of trials with no risk of industry bias compared with trials with risk of industry bias; of trials assessing primary prevention compared with trials assessing secondary prevention; of trials including participants with vitamin D level below 20 ng/mL at entry compared with trials including participants with vitamin D levels equal to or greater than 20 ng/mL at entry; of trials including ambulatory participants compared with trials including institutionalised participants; of trials using concomitant calcium supplementation compared with trials without calcium; of trials using a dose below 800 IU per day compared with trials using doses above 800 IU per day; and of trials including only women compared with trials including both sexes or only men. Vitamin D3 statistically significantly decreased cancer mortality (RR 0.88 (95% CI 0.78 to 0.98); P = 0.02; I(2) = 0%; 44,492 participants; 4 trials). Vitamin D3 combined with calcium increased the risk of nephrolithiasis (RR 1.17 (95% CI 1.02 to 1.34); P = 0.02; I(2) = 0%; 42,876 participants; 4 trials). Alfacalcidol and calcitriol increased the risk of hypercalcaemia (RR 3.18 (95% CI 1.17 to 8.68); P = 0.02; I(2) = 17%; 710 participants; 3 trials).
Authors' conclusions:
Vitamin D3 seemed to decrease mortality in elderly people living independently or in institutional care. Vitamin D2, alfacalcidol and calcitriol had no statistically significant beneficial effects on mortality. Vitamin D3 combined with calcium increased nephrolithiasis. Both alfacalcidol and calcitriol increased hypercalcaemia. Because of risks of attrition bias originating from substantial dropout of participants and of outcome reporting bias due to a number of trials not reporting on mortality, as well as a number of other weaknesses in our evidence, further placebo-controlled randomised trials seem warranted.
The question of what makes an 'optimal' vitamin D intake is usually equivalent to, 'what serum 25-hydroxyvitamin D [25(OH)D] do we need to stay above to minimize risk of disease?'. This is a simplistic question that ignores the evidence that fluctuating concentrations of 25(OH)D may in themselves be a problem, even if concentrations do exceed a minimum desirable level. Vitamin D metabolism poses unique problems for the regulation of 1,25-dihydroxyvitamin D [1,25(OH)2D] concentrations in the tissues outside the kidney that possess 25(OH)D-1-hydroxylase [CYP27B1] and the catabolic enzyme, 1,25(OH)2D-24-hydroxylase [CYP24]. These enzymes behave according to first-order reaction kinetics. When 25(OH)D declines, the ratio of 1-hydroxylase/24-hydroxylase must increase to maintain tissue 1,25(OH)2D at its set-point level. The mechanisms that regulate this paracrine metabolism are poorly understood. I propose that delay in cellular adaptation, or lag time, in response to fluctuating 25(OH)D concentrations can explain why higher 25(OH)D in regions at high latitude or with low environmental ultraviolet light can be associated with the greater risks reported for prostate and pancreatic cancers. At temperate latitudes, higher summertime 25(OH)D levels are followed by sharper declines in 25(OH)D, causing inappropriately low 1-hydroxylase and high 24-hydroxylase, resulting in tissue 1,25(OH)2D below its ideal set-point. This hypothesis can answer concerns raised by the World Health Organization's International Agency for Research on Cancer about vitamin D and cancer risk. It also explains why higher 25(OH)D concentrations are not good if they fluctuate, and that desirable 25(OH)D concentrations are ones that are both high and stable.
Transfection of retrovirus DNA from Gardner-Arnstein strain feline sarcoma virus containing v-fes oncogene into a rat fibroblastic cell line 3Y1 caused not only cell transformation but also a remarkable change in ganglioside expression. The ganglioside phenotype of the 3Y1 cells was characterized by the exclusive expression of GM3, along with a trace amount of "A" pathway-related gangliosides (GM2-GM1a-GD1a), whereas in the transfected transformant, 3Y1-GA, sialosylparagloboside containing N-acetyl neuraminic acid (NeuAc) and novel ganglio-series gangliosides (presumably GM1b and GD1 alpha) were expressed in addition to GM3. Thus, the Gardner-Arnstein strain feline sarcoma virus DNA transfection open two new ganglioside metabolic pathways, one leading to the synthesis of neolacto-series and the other to that of ganglio-series gangliosides. These results were in striking contrast to the cases of transfection with so-called "intranuclearly expressed" transforming genes, adenovirus E1, SV40-T, and myc, with which the same 3Y1 cells newly expressed GD3 with a concomitant decrease in precursor ganglioside GM3. The difference in underlying mechanisms of ganglioside metabolism shown by these two different types of oncogenes might reflect differences in the modes of action of the oncogenes and their biological activities.
Requirements of vitamin D2, vitamin D3, 25-hydroxyvitamin D3 and 1α,25-dihydroxyvitamin D3 were studied in five patients with vitamin-D-dependent rickets, a recessively inherited form of vitamin-D-refractory rickets. Massive doses of vitamin D2 (1.25 to 2.50 mg per day), vitamin D3 (1.25 mg per day) and 25-hydroxyvitamin D3 (0.4 to 0.9 mg per day) were required to heal the rachitic lesions, but minute doses of 1α,25-dihydroxyvitamin D3. (1.0 μg per day) promptly initiated healing. The dosage of 1α,25-dihydroxyvitamin D3 was probably in the physiologic range for the human infant — evidence against target-cell unresponsiveness. Our data suggest that conversion of vitamin D to 25-hydroxyvitamin D was normal in our patients, but that a block was present in subsequent conversion to 1α,25-dihydroxyvitamin D, the active metabolite. We postulate, therefore, that vitamin-D-dependent rickets is an inborn error of vitamin D metabolism due to a genetic defect in 25-hydroxycholecalciferol-1-hydroxylase, the e...
In 1905, Cornelius Adrianus Pekelharing found that animals fed purified proteins, carbohydrates, fats, inorganic salts, and water would thrive only if small amounts of milk were added to the diet. He concluded that the milk contained some unrecognized substance that in very small quantities was necessary for normal growth and maintenance. In 1911, Casimir Funk isolated a concentrate from rice polishings that cured polyneuritis in pigeons. He named the concentrate "vitamine" because it appeared to be vital to life and because it was probably an amine. Although the concentrate and other "accessory food substances" were not amines, the name stuck, but the final "e" was dropped. In 1913 two groups discovered a "fat-soluble" accessory food substance. Initially believed to be a single vitamin, two separate factors were involved. One, effective against xerophthalmia, was named vitamin A; the other, effective against rickets, was named vitamin D. The factor that prevented scurvy was isolated in 1928. Known as "water-soluble C," it was renamed ascorbic acid.
For adults, the 5-microg (200 IU) vitamin D recommended dietary allowance may prevent osteomalacia in the absence of sunlight, but more is needed to help prevent osteoporosis and secondary hyperparathyroidism. Other benefits of vitamin D supplementation are implicated epidemiologically: prevention of some cancers, osteoarthritis progression, multiple sclerosis, and hypertension. Total-body sun exposure easily provides the equivalent of 250 microg (10000 IU) vitamin D/d, suggesting that this is a physiologic limit. Sailors in US submarines are deprived of environmentally acquired vitamin D equivalent to 20-50 microg (800-2000 IU)/d. The assembled data from many vitamin D supplementation studies reveal a curve for vitamin D dose versus serum 25-hydroxyvitamin D [25(OH)D] response that is surprisingly flat up to 250 microg (10000 IU) vitamin D/d. To ensure that serum 25(OH)D concentrations exceed 100 nmol/L, a total vitamin D supply of 100 microg (4000 IU)/d is required. Except in those with conditions causing hypersensitivity, there is no evidence of adverse effects with serum 25(OH)D concentrations <140 nmol/L, which require a total vitamin D supply of 250 microg (10000 IU)/d to attain. Published cases of vitamin D toxicity with hypercalcemia, for which the 25(OH)D concentration and vitamin D dose are known, all involve intake of > or = 1000 microg (40000 IU)/d. Because vitamin D is potentially toxic, intake of >25 microg (1000 IU)/d has been avoided even though the weight of evidence shows that the currently accepted, no observed adverse effect limit of 50 microg (2000 IU)/d is too low by at least 5-fold.
Official nutrition committee reports in both North America and Europe now state that Vitamin D is more of a hormone than a nutrient. These statements are wrong, and do not reflect the definitions of either vitamin or hormone. Researchers often compound the problem by referring to calcitriol or other deltanoids as "Vitamin D". These things have serious consequences: (1) The literature is burdened by an ongoing confusion that presumes that the reader will somehow "know" what the writer refers to by "Vitamin D". (2) Medical practitioners not familiar with the ambiguities administer Vitamin D inappropriately when calcitriol or a deltanoid analog would be correct, or vice versa. (3) Attempts to promote Vitamin D nutrition are hindered by alarmist responses justifiably associated with the widespread administration of any hormone. Vitamin D is a vitamin in the truest sense of the word, because "insufficient amounts in the diet may cause deficiency diseases". The term, prohormone, is not relevant to the Vitamin D system, but 25-hydroxy-Vitamin D (calcidiol) is appropriately described as a prehormone, i.e. a glandular secretory product, having little or no inherent biologic potency, that is converted peripherally to an active hormone.
Supplemental vitamin D is available in 2 distinct forms: ergocalciferol (vitamin D2) and cholecalciferol (vitamin D3). Pharmacopoeias have officially regarded these 2 forms as equivalent and interchangeable, yet this presumption of equivalence is based on studies of rickets prevention in infants conducted 70 y ago. The emergence of 25-hydroxyvitamin D as a measure of vitamin D status provides an objective, quantitative measure of the biological response to vitamin D administration. As a result, vitamin D3 has proven to be the more potent form of vitamin D in all primate species, including humans. Despite an emerging body of evidence suggesting several plausible explanations for the greater bioefficacy of vitamin D3, the form of vitamin D used in major preparations of prescriptions in North America is vitamin D2. The case that vitamin D2 should no longer be considered equivalent to vitamin D3 is based on differences in their efficacy at raising serum 25-hydroxyvitamin D, diminished binding of vitamin D2 metabolites to vitamin D binding protein in plasma, and a nonphysiologic metabolism and shorter shelf life of vitamin D2. Vitamin D2, or ergocalciferol, should not be regarded as a nutrient suitable for supplementation or fortification.
The serum 25-hydroxyvitamin D [25(OH)D] concentration that is the threshold for vitamin D toxicity has not been established. Hypercalcemia is the hazard criterion for vitamin D. Past policy of the Institute of Medicine has set the tolerable upper intake level (UL) for vitamin D at 50 mug (2000 IU)/d, defining this as "the highest level of daily nutrient intake that is likely to pose no risks of adverse health effects to almost all individuals in the general population." However, because sunshine can provide an adult with vitamin D in an amount equivalent to daily oral consumption of 250 mug (10,000 IU)/d, this is intuitively a safe dose. The incremental consumption of 1 mug (40 IU)/day of vitamin D(3) raises serum 25(OH)D by approximately 1 nM (0.4 ng/ml). Therefore, if sun-deprived adults are to maintain serum 25(OH)D concentrations >75 nM (30 ng/ml), they will require an intake of more than the UL for vitamin D. The mechanisms that limit vitamin D safety are the capacity of circulating vitamin D-binding protein and the ability to suppress 25(OH)D-1-alpha-hydroxylase. Vitamin D causes hypercalcemia when the "free" concentration of 1,25-dihydroxyvitamin D is inappropriately high. This displacement of 1,25(OH)(2)D becomes excessive as plasma 25(OH)D concentrations become higher than at least 600 nM (240 ng/ml). Plasma concentrations of unmetabolized vitamin D during the first days after an acute, large dose of vitamin D can reach the micromolar range and cause acute symptoms. The clinical trial evidence shows that a prolonged intake of 250 mug (10,000 IU)/d of vitamin D(3) is likely to pose no risk of adverse effects in almost all individuals in the general population; this meets the criteria for a tolerable upper intake level.
Annual high-dose oral vitamin D and falls and fractures in older women: a randomized controlled trial
- K M Sanders
- A L Stuart
- E J Williamson
- J A Simpson
- M A Kotowicz
- D Young
- KM Sanders
Institute of Medicine Committee to Review Dietary Reference Intakes for Vitamin D, Calcium. The National Academies Collection: Reports funded by National Institutes of Health