Join Us | Latest Articles | Contact

Journal Home

Editorial Board

Recent Articles

Submit to this journal

Special Issues

Current issue

Journal of Clinical Nephrology and Renal Care

A Review on the Potential Role of Vitamin D and Mineral Metabolism on Chronic Fatigue Illnesses

Anna Dorothea Höck*

Internal Medicine, 50935 Cologne, Germany

*Corresponding author: Anna Dorothea Hoeck, MD, Internal Medicine, Mariawaldstraße 7, 50935 Köln, Germany, E-mail:
J Clin Nephrol Ren Care, JCNRC-2-008, (Volume 2, Issue 1), Review Article
Received: February 29, 2016: Accepted: May 12, 2016: Published: May 14, 2016
Citation: Höck AD (2016) A Review on the Potential Role of Vitamin D and Mineral Metabolism on Chronic Fatigue Illnesses. J Clin Nephrol Ren Care 2:008.
Copyright: © 2016 Höck AD. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


The aim of this report is to review the effects of vitamin D-deficiency on chronic mineral deregulation and its clinical consequences. Recent research data are presented including the effects of vitamin D3-induced calcium sensing receptor (CaSR), fibroblast growth factor 23 (FGF23), the cofactor of FGF1-receptor α-klotho (αKl) and the interplay with each other and with vitamin D3-repressed parathormone (PTH). The importance of persistent calcium- and phosphate deregulation following long-standing vitamin D3-deficiency for cellular functions and resistance to vitamin D3 treatment is discussed. It is proposed that chronic fatiguing illnesses might be result from mineral deregulations that are barely detected by routine laboratory workups because of compensatory changes in bone mineral stores.


Vitamin D3-deficiency, Mineral regulation, Calcium-sensing receptor, Fibroblast-growth-factor-23, Alpha-klotho, Parathormone, Chronic fatigue


The metabolite of vitamin D3, 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], regulates bone minerals calcium and phosphate [1-6]. Less well known, however, are the mechanisms by which 1,25(OH)2D3 regulates many minerals and ion channels. More recent research data add to the understanding how mineral deregulation induced by vitamin D3-deficiency could be responsible for chronic symptomatic chronic fatigue and the accompanying functional and depression-like symptoms. The objective is to attempt shedding some light on such possible interactions of calcium metabolism and uncommon clinical features, and thus adding to a potential differential diagnosis of chronic fatigue disorders, depression, and others.

Vitamin D3 regulates most parts of mineral metabolism in a highly complex manner

Well-known is that 1,25(OH)2D3 induces gene expression of its own nuclear receptor, called vitamin D receptor (VDR), and its own deactivating enzyme, named 1,25-dihydroxyvitamin D3 24-hydroxylase (CYP24A1) [7,8]. It also down-regulates the gene expression of its own activating enzyme, 1-alpha-hydroxylase (alternatively, cytochrome 27B1; CYP27B1) in renal tubular cells [7]. In contrast, gene expression of CYP27B1 in many other cells occurs by any kind of cell stress as long as sufficient 25-hydroxyvitamin D3 (25OHD3) is available [8-11].

1,25(OH)2D3 induces in addition the gene expression of following important mineral regulators such as calcium-sensing-receptor (CaSR), Fibroblast Growth Factor-23 (FGF23) and its co-receptor α-Klotho (αKL, also FGF23/αKL in this paper), yet represses the gene expression of parathormone (PTH) [2,6,12-16]. These mineral regulators, like 1,25(OH)2D3 itself, act not only via gene expression, but also modulate cell functions directly by rapid non-genomic actions. This contributes substantially to the high complexity and adaptability of mineral regulation [2,6,12,17-21].

Low vitamin D3, low dietary calcium and high phosphate intake occur frequently

Vitamin D3-insufficiency/deficiency is a common condition arising from prevalent indoor activities and use of sunscreens with high protection factor. Lacking sunlight is frequent in patients suffering from chronic fatigue syndrome (CFS), fibromyalgia (FMS), and myalgic encephalopathy (ME) probably because of fatigue-related reduction of outdoor activity, high premorbid engagement in professional or caring activities, and preceding stressful life events [22]. Vitamin D3-deficiency may develop also as side effect of certain drugs (anti-epileptics, phenobarbital, hyperforin, carbamazepine, and rifampin) and is due to induction of the CYP3A4 gene [23].

As enteral calcium absorption is enhanced by 1,25(OH)2D3, and calcium, like 1,25(OH)2D3, is engaged in gene expression and cell signaling, knowledge about the impact of calcium deficiency on global mineral balance is important as well. Western diets commonly are poor in milk and milk products, nuts and calcium-rich vegetables, but are rich in phosphate supply (soft drinks, processed foods). They thus favor calcium deficiency and deficient bone mineralization [16,24-27], as well as "phosphate toxicity" [16,26-29]. Calcium deficiency is also promoted by long-standing therapy with proton-pump inhibitors by reducing enteral calcium absorption substantially [30].

Impact of 1,25(OH)2D3 on enteral mineral absorption and renal reabsorption

Binding of 1,25(OH)2D3 to VDR induces gene expression of calcium transporting channels, pumps, exchangers and binding proteins such as transient potential protein, type 6 or type 5, calbindin 9 and calbindin 28, ATP-dependent plasma membrane calcium-ATPase, Na+/Ca2+ exchanger, and the intercellular proteins claudin 2 and 12 [2-6,16,30,31]. In addition, enteral and renal phosphate transporters are also induced by 1,25(OH)2D3 [2,6], as are enteral magnesium uptake proteins [32-35].

However, renal magnesium re-uptake is inhibited by claudin 16 which is induced by both 1,25(OH)2D3 and CaSR [33-36]. Such a potent 1,25(OH)2D3-induced antagonism against mineral overload is not only know with respect to magnesium, but exists also for calcium and phosphate. Such 1,25(OH)2D3-induced antagonists are CaSR which regulates calcium transport [6,37-40], and FGF23/αKL which regulates phosphate transport [2,6,12,15,16].

CaSR prevents calcium overload, and in addition, modifies cellular signal transduction

CaSR is ubiquitously expressed and is a nutrient sensing, G protein-coupled receptor, activated by extracellular calcium binding [3,37-40]. Transcription of CaSR and VDR genes is enhanced by Ca2+ and 1,25(OH)2D3 [37,40], and by the pro-inflammatory cytokines interleukin 1β and interleukin 6 [38,40]. In addition to calcium, CaSR becomes activated by other di- and trivalent ions, such as magnesium, strontium, gadolinium, and by organic poly-cations like polyamines and neomycine, as well as by amino acids. In contrast, protons and high sodium concentrations rather suppress CaSR activity [27,38,39]. Thus, depending upon the given biological and metabolic status, CaSR activity may vary substantially. This is further complicated as activating and deactivating antibodies may interfere in this balance [37,41], and different CaSR ligands can elicit different cell responses, called biased agonism [42,43].

Activated CaSR reduces enteral and renal transport of calcium, Na+ and Mg2+, as well as protons and water. It thus serves as a potent vitamin D3 antagonist with respect to mineral metabolism [13,15,16]. On the other hand, CaSR co-localizes and cooperates with many cell membrane and intracellular receptors, translating extracellular calcium levels into intracellular signal modulation [37-39,44,45]. Thus it also serves as a cellular calcium agonist.

In the parathyroid glands, activated CaSR represses excessive parathyroid hormone synthesis and secretion when serum calcium is above its set-point [37-40]. It also supports bone mineralization in osteocyte cells by a feed forward mechanism with enhancement of VDR and CaSR expression, while inhibiting osteoclast activity [16,37].

FGF23/αKl prevents phosphate overload, and controls calcium x phosphate product

Binding of αKl, which is a co-receptor for FGF23, mediates effective FGF23 signaling which represses 1,25(OH)2D3-synthesis and increases renal phosphate excretion. The latter is mediated by reduced gene expression and augmented membrane internalization of renal sodium-phosphate co-transporters [16,25,27,46,47]. FGF23 gene expression in osteoblasts and osteocytes is induced by 1,25(OH)2D3, and by a rise in the calcium x phosphate product. Conversely, a decrease of either calcium or phosphate inhibits the effectiveness of FGF23 levels [16,27]. With FGF23/αKl also promoting calcium re-uptake in the distal renal tubule [16,48,49], a delicate build-in control system appears in line for a balanced metabolic activity.

As αKl also interferes with the function of other transport proteins, such as, for instance, various ion channels, carriers and pumps, it as well serves as a key protein for mineral transport in general and for cell function [50].

It is worth mentioning at this place that a high phosphate diet decreases enteral calcium absorption, and, vice versa, high dietetic calcium contents inhibit enteral phosphate uptake. This mutual absorption inhibition becomes mitigated by PTH and CaSR which both assist in keeping a physiological mineral balance in spite of enteric uptake variations [27].

Because FGF23, αKl and FGFR1 must cooperate to induce FGF23 signaling, reduced αKl gene expression is expected to compromise FGF23 signaling. It is reported that already in early stages of chronic kidney disease reduced αKl might occur, whereas in advanced renal insufficiency increased FGF23 levels were found consisting of truncated proteins with reduced biologic activity [16,17,25,27,46,47].

Low serum calcium induces PTH rise and represses FGF23

Persistently low serum calcium fails to activate CaSR resulting in inhibition of repression of PTH gene and parathormone secretion, and also resulting in inhibition of FGF23 gene expression [1,6,14,51]. Both events have negative effects on bone mineralization [27,46]. A persistent PTH elevation enhances calcium transport in gut and kidney, thus mitigating serum calcium deficits secondary of vitamin D3-deficiency or low calcium intake, on the one hand, but compromises bone mineral content on the other hand [1,6,14,51]. Yet, PTH elevation may be blunted by magnesium deficiency, resulting in inadequately low PTH compared to serum calcium [52]. While transient PTH surges are essential for normal bone turnover, a persistent PTH elevation induces inflammatory cytokines and rather increases bone resorption [19,53]. This increased bone resorption keeps serum calcium and phosphate at normal levels for longer times, although bone stores become reduced; in fact, serum levels of bone minerals and phosphate may be even temporarily increased [19] with transient activation of CaSR, thus aggravating global mineral loss.

In addition, persistent PTH elevations will cause renal phosphate wasting [14,29], secondary to PTH-mediated gene induction of FGF23 [54], and also through PTH-enhanced internalization of renal sodium/phosphate co-transporters [2,6]. The resulting high renal phosphate loss will impair bone formation and renal tubular function in its own way [2,29,55,56].

Interestingly, a set-point shift of the Ca2+/PTH curve in aged calcium-deficient mice prevented excessive PTH rise, as long as CaSR activity and gene expression remained intact, possibly pointing to an adaptive phosphate-saving mechanism [57].

Bone health depends also on sufficient dietary supply of minerals and energy sources

Bone turnover and mineral balance are important for bone health by providing bone tissue renewal, repair and physical stability. Vitamin D3 sufficiency and the correct functional interplay of all known factors which regulate mineral metabolism clearly are essential for bone health, but the optimal enteral uptake of calcium, phosphate, other minerals, proteins, and other essential nutrients, and in addition, sufficient mitochondrial ATP production are important as well [1,5,14,15,27-29,31,52,55,58-69]. Due to mineral deregulation not only bone metabolism becomes negatively affected, but energy and cell metabolism as well [70-77].

Mineral regulation influences intracellular function and signaling

Although extra- and intracellular calcium and phosphate levels are regulated by different mechanisms, extra- and intracellular compartments of these ions are bound to each other by multiple complex mechanisms [69,75,77-83]. The role of CaSR in connecting extra- with intracellular calcium events has been already mentioned. Another mechanism is mediated by connexin hemichannnels [80,83,84]. Furthermore, cell signaling cascades use preferentially calcium signaling cascades. These cascades are modified by the amount of primary calcium inflow from the extracellular milieu. Signaling depends upon the cellular membrane potential and transmembrane physicochemical conditions such as voltage, pH, and gradients in extracellular and intracellular concentrations of ions [85]. Functions of intracellular proteins depend widely upon calcium and phosphate binding, whereas persistent and excessive elevation of free calcium and phosphate is toxic to cells [30,69,75,77,78,81,86-95].

Distinct intracellular organelles need distinct levels of calcium concentration for proper functioning; they then contribute to storage, signaling, and homeostasis of calcium [95]. Mitochondrial energy production [87-90,96,97], endoplasmic reticulum stress-response [76,86,91,94,95,97,98], and proteasome and autophagolysosome functions [92,94] depend upon optimal calcium binding conditions which are also essential for both cell structure and function [79,80,82,85].

Low serum calcium initiates a α-Klotho-mediated compensatory mechanism

When serum calcium drops below a critical threshold, neuro-muscular hyper-excitability will occur with muscle spasms and tetany [81,99-101]. The reduced transmembrane calcium gradient affects all membrane receptors, channels, transporters, exchangers and pumps by a sodium dependent mechanism, and finally results in cellular calcium overload [79,80,82,85,102].

Due to low serum calcium, CaSR activity should be reduced resulting in attenuation or failing of the modulating interaction between CaSR and intracellular cell signaling [44]. However, since multiple additional activators of CaSR are known, the real in-vivo effects of CaSR in hypocalcemia still need elucidation.

A particular αKl-dependent compensatory process is active in hypocalcemia. Low serum calcium levels induces αKl gene expression. Binding of αKl to the intracellular Na+/K+-ATPase enhances recruitment of the complex to the cell membrane where its ATPase activity becomes substantially enhanced. This results in membrane hyperpolarization [25,58,102]. This hyperpolarization enhances the calcium transport across renal tubular cells, and across epithelia of the plexus chorioideus and of the parathyroid gland, thus protecting renal calcium re-uptake, liquor calcium levels, and parathyroid response. However, this only occurs at the expense of ATP production [25,58,102]. This implies that in case of failing mitochondrial calcium optimum, this compensatory mechanism might become compromised due to blunted ATP production.

Intracellular calcium and phosphate deregulation induces endoplasmic reticulum stress

The endoplasmic reticulum (ER) is the key organelle when it comes to calcium storage, release and re-uptake. Most of its effector proteins are calcium-binding, some with low affinity, but with high capacity, while others show high affinity and low capacity [76,87,94,95,98]. Deregulated calcium balance will affect ER-resident proteins which in particular act as sensors for extra- and intracellular stress [95]. Such a condition will initiate a cellular rescue response, but only if optimal calcium re-uptake in the ER is available [76,87,103]. Otherwise, compromised function and stability of ER effector proteins such as chaperones will ensue followed by premature and augmented protein decay, interrupted new protein synthesis, and augmented protein malformations [103]. Calcium re-uptake into ER is dependent upon ATP-consuming ATPase activity, while ATP synthesis is thought to be compromised by a suboptimal level of mitochondrial calcium [96]. This failure, though, may be compensated by augmented gene expression of the Na+/Ca2+ exchanger [104]. This exchanger does not consume ATP and may partly alleviate the problems in calcium re-uptake. At this place it must be taken into account, though, that a process called "store-operated calcium entry" replenishing ER calcium stores by calcium inflow from the extracellular compartment will be negatively affected by low extracellular calcium, as well [93,105,106]. In addition, in cell stress, ER-chaperones such as calreticulin are leaking into the extracellular compartment [107] which appears to be linked to the activation of pro-inflammatory reactions by mediators such as the interleukins-1, -6, -12, -23 and tumor necrosis factor -alpha [76]. This underpins the close link between Ca metabolism, ER-stress response and inflammatory reactions.


Common vitamin D3 deficiency with unbalanced calcium and phosphate metabolism are easily overlooked since progressive bone resorption quasi "normalizes" serum mineral levels. Routine medical check-ups thus remain inconclusive at this stage. Only at late stages, pathological calcium levels become evident as being too low or too high. Therefore, in early stages of calcium metabolic derangements only clinical signs such as chronic fatigue, post-exertional malaise and wide-spread organ dysfunctions without detectable structural damage should prompt the care-taking physician to also check vitamin D3 levels and respective mineral changes.

Symptoms of generalized muscle weakness and widespread pain, severe headaches, intolerance of drugs, nutrients, pollutions, and generalized stress intolerance, besides non-refreshing sleep or other sleeping disorders, and failing recovery after rest are some of the most prominent symptoms. In general, patients complain of symptoms mimicking a viral infection. They report clear deterioration after physical and mental stress. Due to cognitive and emotional impairment physicians are poised to diagnose a depression. But the symptoms differ substantially from major depression.

All these dysfunctional symptoms could arise from endoplasmic reticulum stress and reduced endo- and sarcoplasmic calcium- re-uptake. Additionally, the inflammatory response induced by derangement of mineral metabolism would fit well to the few research reports about measurable inflammatory changes in chronic fatiguing illnesses [108-114].

Four stages in the respective development of clinical disease are observed corresponding to the key events in metabolic derangement. These are summarized in table 1.

Table 1: Summary of observed disease stages, the corresponding key events, expected markers, presumed pathophysiology and distinct clinical diagnoses of chronic fatiguing illnesses. View Table 1

It is important to consider that calcium and phosphate deficiency with resulting endocrine, metabolic and mineral disorders will persist in spite of vitamin D3-substitution, if calcium, phosphate and multi-minerals are not substituted at the same time. Even then, a transient phase of low normal calcium with inadequate low PTH levels might occur due to a set-point shift of the Ca2+/PTH curve. This might arise as compensation for excessive renal phosphate loss. In addition, concurrent magnesium deficiency can also induce inadequate low PTH levels. The inadequate PTH level will then compromise PTH-dependent calcium rescue mechanisms resulting in additional reduction of calcium stores. Inadequate renal calcium loss in spite of low serum calcium might be caused by low PTH, by inappropriately augmented CaSR activity, presumably due to aberrant polyamine synthesis, or by inflammatory cytokines. Another cause of inadequate renal calcium loss is tubular damage induced by continuously impaired mineral regulation and accompanying vitamin D-deficiency. In particular severe phosphate deficiency is linked to tubular damage with secondary renal calcium leak.

Disordered mineral regulation can be suspected if 1,25(OH)2D3 levels are inadequately high compared to low 25OHD3 levels. This suggests low stores of calcium and/or phosphate. In severe phosphate depletion, no renal phosphate excretion should be detectable. In contrast, a certain amount of urinary calcium is lost inevitably and physiologically.

Deficiencies of vitamin D3, as well as deficiency of calcium and phosphate, induce renal tubular epithelial damage which then affects also renal reabsorption of all minerals. These deficiencies induce compromised tubular sodium re-uptake which is followed by a compromised countercurrent mechanism. Decreased α-Klotho expression and function, as well as lowered expression of vitamin D-dependent proteins like claudins which manage passive calcium transport contribute to reduced enteral uptake and renal re-uptake of minerals. All these events can explain the generalized mineral disturbance following vitamin D-deficiency. Plasma mineral overflow due to increased global bone mineral release will contribute as well.

A scientific pilot study of coincident testing of 25OHD3, 1,25(OH)2D3, PTHi, αKl and FGF23, possibly also CaSR gene expression, might promise clarification. However, disturbance of these parameters are not supposed to be specific for chronic fatigue syndrome and related disorders. Yet, pathologic results would help to convince that real disease is going on in these patients.

Routine screening in everyday clinical setting should be restricted to investigation of 25OHD3 and PTHi, as well as calcium/creatinine (Ca2+/Crea) ratio in the second fasting morning urine. Only in special cases, such as increased urinary calcium and/or phophate loss, and inappropriate PTHi levels, or in obvious resistance against vitamin D3-treatment, investigation of 1,25(OH)2D3 is indicated. Inadequately high levels suggest deficiency of calcium and/or phosphate. As long-standing vitamin D-deficiency is reported to affect tubular phosphate reabsorption earlier than calcium reabsorption, investigation of the phosphate/creatinine (Pi/Crea) ratio might be indicated as well.

Specific and early therapy with calcium and other bone minerals, combined with vitamin D2 or D3 compounds presumably might prevent progression from chronic fatigue and functional disorder to more debilitating stages of fatiguing illnesses such as CFS, FMS, and ME.

Interestingly, a subgroup of patients with progressive chronic fatigue syndrome and obvious vitamin D3 resistance showed abnormal laboratory results suggesting indeed underlying mineral derangement. They showed low normal serum calcium, inadequately augmented Ca2+/Crea ratios, sometimes low serum phosphate, lowered or low normal 25OHD3, high normal or elevated 1,25(OH)D3, inappropriately low PTH, and urinary anion gap results suggestive of reduced renal ammonium excretion (unpublished clinical observations of the author).


I am indebted very much to Gerhard Krueger PHD and very grateful for his generous help in text revision.

  1. Bringhurst FR, Demay MB, Krane SM, Kronenberg HM (2012) Bone and mineral metabolism in health and disease. In: Longo DL, Anthony S Fauci, E Dennis L Kasper, Stephen L Hauser, J Larry Jameson, et al. Harrison’s Principles of Internal Medicine. McGraw-Hill Company, New York, 3082-3095.

  2. DeLuca HF (2014) Triennial Growth Symposium-Vitamin D: bones and beyond. J Anim Sci 92: 917-929.

  3. Hoenderop JG, Nilius B, Bindels RJ (2005) Calcium absorption across epithelia. Physiol Rev 85: 373-422.

  4. Kido S, Kaneko I, Tatsumi S, Segawa H, Miyamoto K (2013) Vitamin D and type II sodium-dependent phosphate cotransporters. Contrib Nephrol 180: 86-97.

  5. Lieben L, Benn BS, Ajibade D, Stockmans I, Moermans K, et al. (2010) Trpv6 mediates intestinal calcium absorption during calcium restriction and contributes to bone homeostasis. Bone 47: 301-308.

  6. Bouillon R, Carmeliet G, Verlinden L, van Etten E, Verstuyf A, et al. (2008) Vitamin D and human health: lessons from vitamin D receptor null mice. Endocr Rev 29: 726-776.

  7. Theodoropoulos C, Demers C, Delvin E, Ménard D, Gascon-Barré M (2003) Calcitriol regulates the expression of the genes encoding the three key vitamin D3 hydroxylases and the drug-metabolizing enzyme CYP3A4 in the human fetal intestine. Clin Endocrinol (Oxf) 58: 489-499.

  8. Jones G (2013) Extrarenal vitamin D activation and interactions between vitamin D2, vitamin D3, and vitamin D analogs. Annu Rev Nutr 33: 23-44.

  9. Ceglia L, Harris SS (2013) Vitamin D and its role in skeletal muscle. Calcif Tissue Int 92: 151-162.

  10. van der Meijden K, Bakker AD, van Essen HW, Heijboer AC, Schulten EA, et al. (2016) Mechanical loading and the synthesis of 1,25(OH)2D in primary human osteoblasts. J Steroid Biochem Mol Biol 156: 32-39.

  11. Xu G, Wang J, Gao GF, Liu CH (2014) Insights into battles between Mycobacterium tuberculosis and macrophages. Protein Cell 5: 728-736.

  12. Bikle DD (2014) Vitamin D metabolism mechanism of action and clinical applications. Chem Biol 21: 319-329.

  13. Huang C, Miller RT (2007) Regulation of renal ion transport by the calcium-sensing receptor: an update. Curr Opin Nephrol Hypertens 16: 437-443.

  14. Kumar R, Thompson JR (2011) The regulation of parathyroid hormone secretion and synthesis. J Am Soc Nephrol 22: 216-224.

  15. Tyler Miller R (2013) Control of renal calcium, phosphate, electrolyte, and water excretion by the calcium-sensing receptor. Best Pract Res Clin Endocrinol Metab 27: 345-358.

  16. Tejwani V, Qian Q (2013) Calcium regulation and bone mineral metabolism in elderly patients with chronic kidney disease. Nutrients 5: 1913-1936.

  17. Haussler MR, Whitfield GK, Haussler CA, Sabir MS, Khan Z, et al. (2016) 1,25-Dihydroxyvitamin D and Klotho: A Tale of Two Renal Hormones Coming of Age. Vitam Horm 100: 165-230.

  18. Larriba MJ, González-Sancho JM, Bonilla F, Muñoz A (2014) Interaction of vitamin D with membrane-based signaling pathways. Front Physiol 5: 60.

  19. Lips P (2006) Vitamin D physiology. Prog Biophys Mol Biol 92: 4-8.

  20. Morris HA (2014) Vitamin D activities for health outcomes. Ann Lab Med 34: 181-186.

  21. Ryan JW, Anderson PH, Morris HA (2015) Pleiotropic Activities of Vitamin D Receptors - Adequate Activation for Multiple Health Outcomes. Clin Biochem Rev 36: 53-61.

  22. Shoenfeld Y, Socha P, Solnica B, Szalecki M, Talalaj M, et al. (2013) Practical guidelines for the supplementation of vitamin D and the treatment of deficits in Central Europe - recommended vitamin D intakes in the general population and groups at risk of vitamin D deficiency. Endokrynol Pol 64: 319-327.

  23. Wang Z, Lin YS, Dickmann LJ, Poulton EJ, Eaton DL, et al. (2013) Enhancement of hepatic 4-hydroxylation of 25-hydroxyvitamin D3 through CYP3A4 induction in vitro and in vivo: implications for drug-induced osteomalacia. J Bone Miner Res 28: 1101-1116.

  24. Lou-Arnal LM, Arnaudas-Casanova L, Caverni-Muñoz A, Vercet-Tormo A, Caramelo-Gutiérrez R, et al. (2014) Hidden sources of phosphorus: presence of phosphorus-containing additives in processed foods. Nefrologia 34: 498-506.

  25. Nabeshima Y (2009) Discovery of alpha-Klotho unveiled new insights into calcium and phosphate homeostasis. Proc Jpn Acad Ser B Phys Biol Sci 85: 125-141.

  26. Pludowski P, Karczmarewicz E, Bayer M, Carter G, Razzaque MS (2013) Phosphate toxicity and vascular mineralization. Contrib Nephrol 180: 74-85.

  27. Quinn SJ, Thomsen AR, Pang JL, Kantham L, Bräuner-Osborne H, et al. (2013) Interactions between calcium and phosphorus in the regulation of the production of fibroblast growth factor 23 in vivo. Am J Physiol Endocrinol Metab 304: E310-320.

  28. Calvo MS, Tucker KL (2013) Is phosphorus intake that exceeds dietary requirements a risk factor in bone health? Ann N Y Acad Sci 1301: 29-35.

  29. Fukumoto S (2014) Phosphate metabolism and vitamin D. Bonekey Rep 3: 497.

  30. Kopic S, Geibel JP (2013) Gastric acid, calcium absorption, and their impact on bone health. Physiol Rev 93: 189-268.

  31. Bouillon R, Suda T (2014) Vitamin D: calcium and bone homeostasis during evolution. Bonekey Rep 3: 480.

  32. Allgrove J (2015) Physiology of Calcium, Phosphate, Magnesium and Vitamin D. Endocr Dev 28: 7-32.

  33. Lameris AL, Nevalainen PI, Reijnen D, Simons E, Eygensteyn J, et al. (2015) Segmental transport of Ca2+ and Mg2+ along the gastrointestinal tract. Am J Physiol Gastrointest Liver Physiol 308: G206-216.

  34. Ritchie G, Kerstan D, Dai LJ, Kang HS, Canaff L, et al. (2001) 1,25(OH)(2)D(3) stimulates Mg2+ uptake into MDCT cells: modulation by extracellular Ca2+ and Mg2+. Am J Physiol Renal Physiol 280: F868-878.

  35. Zittermann A (2013) Magnesium deficit ? overlooked cause of low vitamin D status? BMC Med 11: 229.

  36. Kladnitsky O, Rozenfeld J, Azulay-Debby H, Efrati E, Zelikovic I, et al. (2015) The claudin-16 channel gene is transcriptionally inhibited by 1,25-dihydroxyvitamin D. Exp Physiol 100: 79-94.

  37. Brown EM (2013) Role of the calcium-sensing receptor in extracellular calcium homeostasis. Best Pract Res Clin Endocrinol Metab 27: 333-343.

  38. Chakravarti B, Chattopadhyay N, Brown EM (2012) Signaling through the extracellular calcium-sensing receptor (CaSR). Adv Exp Med Biol 740: 103-142.

  39. Conigrave AD, Ward DT (2013) Calcium-sensing receptor (CaSR): pharmacological properties and signaling pathways. Best Pract Res Clin Endocrinol Metab 27: 315-331.

  40. Hendy GN, Canaff L, Cole DE (2013) The CASR gene: alternative splicing and transcriptional control, and calcium-sensing receptor (CaSR) protein: structure and ligand binding sites. Best Pract Res Clin Endocrinol Metab 27: 285-301.

  41. D'Souza-Li L (2006) The calcium-sensing receptor and related diseases. Arq Bras Endocrinol Metabol 50: 628-639.

  42. Thomsen AR, Hvidtfeldt M, Bräuner-Osborne H (2012) Biased agonism of the calcium-sensing receptor. Cell Calcium 51: 107-116.

  43. Wisler JW, Xiao K, Thomsen AR, Lefkowitz RJ (2014) Recent developments in biased agonism. Curr Opin Cell Biol 27: 18-24.

  44. Brennan SC, Mun HC, Leach K, Kuchel PW, Christopoulos A, et al. (2015) Receptor expression modulates calcium-sensing receptor mediated intracellular Ca2+ mobilization. Endocrinology 156: 1330-1342.

  45. Tuohimaa P, Keisala T, Minasyan A, Cachat J, Kalueff A (2009) Vitamin D, nervous system and aging. Psychoneuroendocrinology 34 Suppl 1: S278-286.

  46. Hu MC, Shiizaki K, Kuro-o M, Moe OW (2013) Fibroblast growth factor 23 and Klotho: physiology and pathophysiology of an endocrine network of mineral metabolism. Annu Rev Physiol 75: 503-533.

  47. Prié D; Groupe de Travail Mixte SFBC SN Biomarqueurs des Calcifications Vasculaires Au Cours de L'insuffisance Rénale Chronique (2015) The couple fibroblast growth factor 23 (FGF23)/Klotho. Ann Biol Clin (Paris) 73: 299-304.

  48. Erben RG, Andrukhova O (2015) FGF23 regulation of renal tubular solute transport. Curr Opin Nephrol Hypertens 24: 450-456.

  49. Han X, Yang J, Li L, Huang J, King G, et al. (2016) Conditional Deletion of Fgfr1 in the Proximal and Distal Tubule Identifies Distinct Roles in Phosphate and Calcium Transport. PLoS One 11: e0147845.

  50. Sopjani M, Rinnerthaler M, Almilaji A, Ahmeti S, Dermaku-Sopjani M (2014) Regulation of cellular transport by klotho protein. Curr Protein Pept Sci 15: 828-835.

  51. Goltzman D, Hendy GN (2015) The calcium-sensing receptor in bone--mechanistic and therapeutic insights. Nat Rev Endocrinol 11: 298-307.

  52. Rodríguez-Ortiz ME, Canalejo A, Herencia C, Martínez-Moreno JM, Peralta-Ramírez A, et al. (2014) Magnesium modulates parathyroid hormone secretion and upregulates parathyroid receptor expression at moderately low calcium concentration. Nephrol Dial Transplant 29: 282-289.

  53. Pacifici R (2013) Osteoimmunology and its implications for transplantation. Am J Transplant 13: 2245-2254.

  54. Fan Y, Bi R, Densmore MJ, Sato T, Kobayashi T, et al. (2016) Parathyroid hormone 1 receptor is essential to induce FGF23 production and maintain systemic mineral ion homeostasis. FASEB J 30: 428-440.

  55. Knochel JP (1981) Hypophosphatemia. West J Med 134: 15-26.

  56. Prasad N, Bhadauria D (2013) Renal phosphate handling: Physiology. Indian J Endocrinol Metab 17: 620-627.

  57. Cheng Z, Liang N, Chen TH, Li A, Santa Maria C, et al. (2013) Sex and age modify biochemical and skeletal manifestations of chronic hyperparathyroidism by altering target organ responses to Ca2+ and parathyroid hormone in mice. J Bone Miner Res 28: 1087-1100.

  58. Imura A, Tsuji Y, Murata M, Maeda R, Kubota K, et al. (2007) alpha-Klotho as a regulator of calcium homeostasis. Science 316: 1615-1618.

  59. Kogawa M, Findlay DM, Anderson PH, Ormsby R, Vincent C, et al. (2010) Osteoclastic metabolism of 25(OH)-vitamin D3: a potential mechanism for optimization of bone resorption. Endocrinology 151: 4613-4625.

  60. Lau WL, Leaf EM, Hu MC, Takeno MM, Kuro-o M, et al. (2012) Vitamin D receptor agonists increase klotho and osteopontin while decreasing aortic calcification in mice with chronic kidney disease fed a high phosphate diet. Kidney Int 82: 1261-1270.

  61. Lee AM, Sawyer RK, Moore AJ, Morris HA, O'Loughlin PD, et al. (2014) Adequate dietary vitamin D and calcium are both required to reduce bone turnover and increased bone mineral volume. J Steroid Biochem Mol Biol 144 Pt A: 159-162.

  62. Murali SK, Roschger P, Zeitz U, Klaushofer K, Andrukhova O, et al. (2016) FGF23 Regulates Bone Mineralization in a 1,25(OH)2 D3 and Klotho-Independent Manner. J Bone Miner Res 31: 129-142.

  63. Ormsby RT, Findlay DM, Kogawa M, Anderson PH, Morris HA, et al. (2014) Analysis of vitamin D metabolism gene expression in human bone: evidence for autocrine control of bone remodelling. J Steroid Biochem Mol Biol 144 Pt A: 110-113.

  64. Pike JW, Lee SM, Meyer MB (2014) Regulation of gene expression by 1,25-dihydroxyvitamin D3 in bone cells: exploiting new approaches and defining new mechanisms. Bonekey Rep 3: 482.

  65. Ryan JW, Reinke D, Kogawa M, Turner AG, Atkins GJ, et al. (2013) Novel targets of vitamin D activity in bone: action of the vitamin D receptor in osteoblasts, osteocytes and osteoclasts. Curr Drug Targets 14: 1683-1688.

  66. Turner AG, Hanrath MA, Morris HA, Atkins GJ, Anderson PH (2014) The local production of 1,25(OH)2D3 promotes osteoblast and osteocyte maturation. J Steroid Biochem Mol Biol 144 Pt A: 114-118.

  67. Viti F, Landini M, Mezzelani A, Petecchia L, Milanesi L, et al. (2016) Osteogenic Differentiation of MSC through Calcium Signaling Activation: Transcriptomics and Functional Analysis. PLoS One 11: e0148173.

  68. Wijenayaka AR, Yang D, Prideaux M, Ito N, Kogawa M, et al. (2015) 1α,25-dihydroxyvitamin D3 stimulates human SOST gene expression and sclerostin secretion. Mol Cell Endocrinol 413: 157-167.

  69. Yang D, Turner AG, Wijenayaka AR, Anderson PH, Morris HA, et al. (2015) 1,25-Dihydroxyvitamin D3 and extracellular calcium promote mineral deposition via NPP1 activity in a mature osteoblast cell line MLO-A5. Mol Cell Endocrinol 412: 140-147.

  70. Karsenty G, Oury F (2012) Biology without walls: the novel endocrinology of bone. Annu Rev Physiol 74: 87-105.

  71. Kawai M, Devlin MJ, Rosen CJ (2009) Fat targets for skeletal health. Nat Rev Rheumatol 5: 365-372.

  72. Lee NK (2010) An evolving integrative physiology: skeleton and energy metabolism. BMB Rep 43: 579-583.

  73. Pi M, Quarles LD (2013) Novel bone endocrine networks integrating mineral and energy metabolism. Curr Osteoporos Rep 11: 391-399.

  74. Rosen CJ (2008) Bone remodeling, energy metabolism, and the molecular clock. Cell Metab 7: 7-10.

  75. Alberts B, Johnson A, Lewis J, Raff M, Roberts K, et al. (2008) Mechanisms of cell communication. In: Molecular Biology of the Cell. Garland Science, Taylor & Francis Group, New York, 879-964.

  76. Peters LR, Raghavan M (2011) Endoplasmic reticulum calcium depletion impacts chaperone secretion, innate immunity, and phagocytic uptake of cells. J Immunol 187: 919-931.

  77. Skupin A, Thurley K (2012) Calcium signaling: from single channels to pathways. Adv Exp Med Biol 740: 531-551.

  78. Aihara E, Hentz CL, Korman AM, Perry NP, Prasad V, et al. (2013) In vivo epithelial wound repair requires mobilization of endogenous intracellular and extracellular calcium. J Biol Chem 288: 33585-33597.

  79. Docampo R (2015) The origin and evolution of the acidocalcisome and its interactions with other organelles. Mol Biochem Parasitol .

  80. Orellana JA, Sánchez HA, Schalper KA, Figueroa V, Sáez JC (2012) Regulation of intercellular calcium signaling through calcium interactions with connexin-based channels. Adv Exp Med Biol 740: 777-794.

  81. Zanotti S, Charles A (1997) Extracellular calcium sensing by glial cells: low extracellular calcium induces intracellular calcium release and intercellular signaling. J Neurochem 69: 594-602.

  82. Bhosale G, Sharpe JA, Sundier SY, Duchen MR (2015) Calcium signaling as a mediator of cell energy demand and a trigger to cell death. Ann N Y Acad Sci 1350: 107-116.

  83. Bergwitz C, Jüppner H (2011) Phosphate sensing. Adv Chronic Kidney Dis 18: 132-144.

  84. Hofer AM, Lefkimmiatis K, (2007) Extracellular calcium and cAMP: second messengers as "third messengers". Physiology 22: 320-327.

  85. Campbell AK (2015) Intracellular Calcium. In: Chichester, Volume 1 and 2 John Wiley & Sons, Ltd, UK.

  86. Berna-Erro A, Woodard GE, Rosado JA (2012) Orais and STIMs: physiological mechanisms and disease. J Cell Mol Med 16: 407-424.

  87. Brown MK, Naidoo N (2012) The endoplasmic reticulum stress response in aging and age-related diseases. Front Physiol 3: 263.

  88. East DA, Campanella M (2013) Ca2+ in quality control: an unresolved riddle critical to autophagy and mitophagy. Autophagy 9: 1710-1719.

  89. Glancy B, Willis WT, Chess DJ, Balaban RS (2013) Effect of calcium on the oxidative phosphorylation cascade in skeletal muscle mitochondria. Biochemistry 52: 2793-2809.

  90. Hopper RK, Carroll S, Aponte AM, Johnson DT, French S, et al. (2006) Mitochondrial matrix phosphoproteome: effect of extra mitochondrial calcium. Biochemistry 45: 2524-2536.

  91. López E, Salido GM, Rosado JA, Berna-Erro A (2012) Unraveling STIM2 function. J Physiol Biochem 68: 619-633.

  92. Park JY, Jang SY, Shin YK, Suh DJ, Park HT, et al. (2013) Calcium-dependent proteasome activation is required for axonal neurofilament degradation. Neural Regen Res 8: 3401-3409.

  93. Wei-Lapierre L, Carrell EM, Boncompagni S, Protasi F, Dirksen RT (2013) Orai1-dependent calcium entry promotes skeletal muscle growth and limits fatigue. Nat Commun 4: 2805.

  94. Williams JA, Hou Y, Ni HM, Ding WX (2013) Role of intracellular calcium in proteasome inhibitor-induced endoplasmic reticulum stress, autophagy, and cell death. Pharm Res 30: 2279-2289.

  95. Su J, Zhou L, Kong X, Yang X, Xiang X, et al. (2013) Endoplasmic reticulum is at the crossroads of autophagy, inflammation, and apoptosis signaling pathways and participates in the pathogenesis of diabetes mellitus. J Diabetes Res 2013: 193461.

  96. Balaban RS (2009) The role of Ca(2+) signaling in the coordination of mitochondrial ATP production with cardiac work. Biochim Biophys Acta 1787: 1334-1341.

  97. Bononi A, Missiroli S, Poletti F, Suski JM, Agnoletto C, et al. (2012) Mitochondria-associated membranes (MAMs) as hotspot Ca(2+) signaling units. Adv Exp Med Biol 740: 411-437.

  98. Morito D, Nagata K (2012) ER Stress Proteins in Autoimmune and Inflammatory Diseases. Front Immunol 3: 48.

  99. Cecchi E, Grossi F, Rossi M, Giglioli C, De Feo ML, et al. (2015) Severe hypocalcemia and life-threatening ventricular arrhytmias: case report and proposal of a diagnostic and therapeutic algorithm. Clin Cases Miner Bone Metab 12: 265-268.

  100. Nardone R, Brigo F, Trinka E (2016) Acute Symptomatic Seizures Caused by Electrolyte Disturbances. J Clin Neurol 12: 21-33.

  101. Policepatil SM, Caplan RH, Dolan M (2012) Hypocalcemic myopathy secondary to hypoparathyroidism. WMJ 111: 173-175.

  102. Friedman PA (1998) Codependence of renal calcium and sodium transport. Annu Rev Physiol 60: 179-197.

  103. Mei Y, Thompson MD, Cohen RA, Tong X (2013) Endoplasmic Reticulum Stress and Related Pathological Processes. J Pharmacol Biomed Anal 1: 1000107.

  104. Studer R, Reinecke H, Bilger J, Eschenhagen T, Böhm M, et al. (1994) Gene expression of the cardiac Na(+)-Ca2+ exchanger in end-stage human heart failure. Circ Res 75: 443-453.

  105. Endo Y, Noguchi S, Hara Y, Hayashi YK, Motomura K, et al. (2015) Dominant mutations in ORAI1 cause tubular aggregate myopathy with hypocalcemia via constitutive activation of store-operated Ca2+ channels. Hum Mol Genet 24: 637-648.

  106. Vasauskas AA, Chem H, Wu S, Cioffi DL (2014) The serine-threonine phosphatase calcineurin is a regulator of endothelial store-operated calcium entry. Pulm Circ 4: 116-127.

  107. Gold LI, Eggleton P, Sweetwyne MT, Van Duyn LB, Greives MR, et al. (2010) Calreticulin: non-endoplasmic reticulum functions in physiology and disease. FASEB J 24: 665-683.

  108. Rajeevan MS, Dimulescu I, Murray J, Falkenberg VR, Unger ER (2015) Pathway-focused genetic evaluation of immune and inflammation related genes with chronic fatigue syndrome. Hum Immunol 76: 553-560.

  109. Peterson D, Brenu EW, Gottschalk G, Ramos S, Nguyen T, et al. (2015) Cytokines in the cerebrospinal fluids of patients with chronic fatigue syndrome/myalgic encephalomyelitis. Mediators Inflamm 2015: 929720.

  110. Stringer EA, Baker KS, Carroll IR, Montoya JG, Chu L, et al. (2013) Daily cytokine fluctuations, driven by leptin, are associated with fatigue severity in chronic fatigue syndrome: evidence of inflammatory pathology. J Transl Med 11: 93.

  111. Maes M, Twisk FN, Kubera M, Ringel K (2012) Evidence for inflammation and activation of cell-mediated immunity in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): increased interleukin-1, tumor necrosis factor-a, PMN-elastase, lysozyme and neopterin. J Affect Disord 136: 933-939.

  112. Fletcher MA, Zeng XR, Barnes Z, Levis S, Klimas NG (2009) Plasma cytokines in women with chronic fatigue syndrome. J Transl Med 7: 96.

  113. Raison CL, Lin JM, Reeves WC (2009) Association of peripheral inflammatory markers with chronic fatigue in a population-based sample. Brain Behav Immun 23: 327-337.

  114. Aspler AL, Bolshin C, Vernon SD, Broderick G (2008) Evidence of inflammatory immune signaling in chronic fatigue syndrome: A pilot study of gene expression in peripheral blood. Behav Brain Funct 4: 44.

International Journal of Anesthetics and Anesthesiology (ISSN: 2377-4630)
International Journal of Blood Research and Disorders   (ISSN: 2469-5696)
International Journal of Brain Disorders and Treatment (ISSN: 2469-5866)
International Journal of Cancer and Clinical Research (ISSN: 2378-3419)
International Journal of Clinical Cardiology (ISSN: 2469-5696)
Journal of Clinical Gastroenterology and Treatment (ISSN: 2469-584X)
Clinical Medical Reviews and Case Reports (ISSN: 2378-3656)
Journal of Dermatology Research and Therapy (ISSN: 2469-5750)
International Journal of Diabetes and Clinical Research (ISSN: 2377-3634)
Journal of Family Medicine and Disease Prevention (ISSN: 2469-5793)
Journal of Genetics and Genome Research (ISSN: 2378-3648)
Journal of Geriatric Medicine and Gerontology (ISSN: 2469-5858)
International Journal of Immunology and Immunotherapy (ISSN: 2378-3672)
International Journal of Medical Nano Research (ISSN: 2378-3664)
International Journal of Neurology and Neurotherapy (ISSN: 2378-3001)
International Archives of Nursing and Health Care (ISSN: 2469-5823)
International Journal of Ophthalmology and Clinical Research (ISSN: 2378-346X)
International Journal of Oral and Dental Health (ISSN: 2469-5734)
International Journal of Pathology and Clinical Research (ISSN: 2469-5807)
International Journal of Pediatric Research (ISSN: 2469-5769)
International Journal of Respiratory and Pulmonary Medicine (ISSN: 2378-3516)
Journal of Rheumatic Diseases and Treatment (ISSN: 2469-5726)
International Journal of Sports and Exercise Medicine (ISSN: 2469-5718)
International Journal of Stem Cell Research & Therapy (ISSN: 2469-570X)
International Journal of Surgery Research and Practice (ISSN: 2378-3397)
Trauma Cases and Reviews (ISSN: 2469-5777)
International Archives of Urology and Complications (ISSN: 2469-5742)
International Journal of Virology and AIDS (ISSN: 2469-567X)
More Journals

Contact Us

ClinMed International Library | Science Resource Online LLC
3511 Silverside Road, Suite 105, Wilmington, DE 19810, USA


Get Email alerts
Creative Commons License
Open Access
by ClinMed International Library is licensed under a Creative Commons Attribution 4.0 International License based on a work at
Copyright © 2017 ClinMed International Library. All Rights Reserved.