What is calcitriol

Calcitriol is vitamin D3 also known as cholecalciferol or 1,25-dihydroxyvitamin D [1,25(OH)₂D], a physiologically-active analog of vitamin D. Calcitriol (1,25(OH)₂D) is the principal hormonal form of vitamin D, responsible for most of its biologic actions. Vitamin D is important for the absorption of calcium from the stomach and for the functioning of calcium in your body. Calcitriol (1,25-dihydroxyvitamin D) is used to treat hyperparathyroidism (overactive parathyroid glands) and metabolic bone disease in people who have chronic kidney failure and are not receiving dialysis.

Calcitriol is also used to treat calcium deficiency (hypocalcemia) and metabolic bone disease in people who are receiving dialysis.

Calcitriol is also used to treat calcium deficiency in people with hypoparathyroidism (underactive parathyroid glands) caused by surgery, disease, or other conditions.

Calcitriol regulates calcium in vivo by promoting absorption in the intestine, reabsorption in the kidneys, and, along with parathyroid hormone, regulation of bone growth. A calcitriol receptor-binding protein appears to exist in the mucosa of human intestine. Calcitriol also induces cell cycle arrest at G0/G1 phase of the cell cycle, cell differentiation, and apoptosis, resulting in inhibition of proliferation of some tumor cell types. This agent may be chemopreventive for colon and prostate cancers.

Calcitriol is formed primarily in the kidney by the enzyme CYP27B1, by enzymatic hydroxylation of 25-hydroxycholecalciferol (calcifediol). Calcitriol (1,25(OH)₂D) production is stimulated by low blood calcium levels and parathyroid hormone. Calcitriol increases intestinal absorption of calcium and phosphorus, and in concert with parathyroid hormone increases bone resorption.

The two major forms of vitamin D are vitamin D₂ (ergocalciferol) and vitamin D₃ (calcitriol or cholecalciferol). Vitamin D₂ (ergocalciferol) is largely human-made and added to foods, whereas vitamin D₃ (calcitriol or 1,25-dihydroxyvitamin D [1,25(OH)₂D]) is synthesized in the skin of humans from 7-dehydrocholesterol and is also consumed in the diet via the intake of animal-based foods. Both calcitriol (vitamin D₃) and ergocalciferol (vitamin D₂) are synthesized commercially and found in dietary supplements or fortified foods. The calcitriol (vitamin D₃) and ergocalciferol (vitamin D₂) forms differ only in their side chain structure. The differences do not affect metabolism (i.e., activation), and both forms function as prohormones. When activated, the calcitriol (vitamin D₃) and ergocalciferol (vitamin D₂) forms have been reported to exhibit identical responses in the body, and the potency related to the ability to cure vitamin D–deficiency rickets is the same ¹. Experimental animal studies have indicated that vitamin D₂ (ergocalciferol) is less toxic than vitamin D₃ (calcitriol or 1,25-dihydroxyvitamin D [1,25(OH)₂D]), but this has not been demonstrated in humans.

The activation steps involved in converting vitamin D from the diet and cutaneous synthesis are illustrated in Figure 1. In human, vitamin D₃ (calcitriol or 1,25-dihydroxyvitamin D [1,25(OH)₂D]) is the predominant form of vitamin D, which is synthesized from 7-dehydrocholesterol upon sunlight ultraviolet-B irradiation, which breaks the B ring to form pre-D₃ ². Vitamin D may also be obtained from dietary sources or supplements as either vitamin D₂ (ergocalciferol) or vitamin D₃ (calcitriol or 1,25-dihydroxyvitamin D [1,25(OH)₂D]).

There is no doubt that the kidney is physiologically the overwhelming site of production of calcitriol for the circulation, as chronic kidney disease or nephrectomy results in a significant fall in the serum calcitriol level ³. The production of calcitriol (1,25(OH)₂D) in the kidney is tightly controlled by two counter-acting hormones, being stimulated by parathyroid hormone (PTH), and inhibited by calcium, phosphate and fibroblast-like growth factor-23 (FGF23) ⁴. Low serum phosphorus levels stimulate calcitriol synthesis, whereas high serum phosphorus levels inhibit it. Extrarenal production of calcitriol (1,25(OH)₂D) as in keratinocytes and macrophages is under different control, being stimulated primarily by cytokines such as tumor necrosis factor alfa (TNFa) and interferon gamma (IFNg). Calcitriol (1,25(OH)₂D) reduces calcitriol levels in cells primarily by stimulating its catabolism through the induction of CYP24A1, the 24-hydroxylase. 25OHD and calcitriol (1,25(OH)₂D) are hydroxylated in the 24 position by this enzyme to form 24,25(OH)₂D and 1,24,25(OH)₃D, respectively. This 24-hydroxylation is generally the first step in the catabolism of these active metabolites to the final end product of calcitroic acid, although 24,25(OH)₂D and 1,24,25(OH)₃D have their own biologic activities. CYP24A1 also has 23-hydroxylase activity that leads to a different end product. Different species differ in their ratio of 23-hydroxylase/24-hydroxyase activity in their CYP24A1 enzyme, but in humans the 24-hydroxyase activity predominates. CYP24A1 is induced by 1,25(OH)₂D, which serves as an important feedback mechanism to avoid vitamin D toxicity. In macrophages, CYP24A1 is either missing or defective, so in situations such as granulomatous diseases like sarcoidosis in which macrophage production of calcitriol (1,25(OH)₂D) is increased, hypercalcemia and hypercalciuria due to elevated calcitriol (1,25(OH)₂D) can occur.

Following its synthesis in the kidney, calcitriol binds to vitamin D binding protein to be transported to target organs. The vitamin D metabolites, vitamin D₂ (ergocalciferol) and vitamin D₃ (calcitriol or cholecalciferol), are transported in blood bound primarily to vitamin D binding protein (85-88%) and albumin (12-15%) ⁵. Vitamin D binding protein concentrations are normally 4-8mM, well above the concentrations of the vitamin D metabolites, such that vitamin D binding protein is only about 2% saturated. The biological actions of calcitriol, involve regulation of gene expression at the transcriptional level, and are mediated through binding to a vitamin D receptor, located primarily in the nuclei of target cells ¹. Additional hydroxylation reactions, such as that mediated by CYP24A1, as shown in Figure 1, result in more polar metabolites with greatly reduced or no apparent biological activity.

Figure 1. Overview of calcitriol synthesis, intake, and activation

What does calcitriol do?

The dominant function of vitamin D in its hormonal form (calcitriol or 1,25-dihydroxyvitamin D) is the elevation of plasma calcium and phosphate levels, which are required for mineralization of bone ⁶. Furthermore, the elevation of plasma calcium to normal levels is also required for the functioning of the neuromuscular junction as well as vasodilatation, nerve transmission, and hormonal secretion.

Calcitriol increases blood calcium levels (Ca2+) by:

• Promoting absorption of dietary calcium from the gastrointestinal tract.
• Increasing renal tubular reabsorption of calcium, thus reducing the loss of calcium in the urine.
• Stimulating release of calcium from bone. For this it acts on the specific type of bone cells referred to as osteoblasts, causing them to release nuclear factor κ B (RANK) ligand, which in turn activates osteoclasts.

Calcitriol (1,25(OH)₂D) is the most powerful physiological agent that stimulates active transport of calcium, and to a lesser degree phosphorus and magnesium, across the small intestine ⁷. Calcitriol effects are mediated via a high-affinity intracellular vitamin D receptor. Vitamin D receptor acts as a ligand-modulated transcription factor that belongs to the steroid, thyroid, and retinoic acid receptors gene family ⁸. Vitamin D receptors were demonstrated in many tissues, leading to the increased recognition of multiple target organs and actions of the hormone. However, it seems that most calcitriol effects of clinical importance are associated with mineral homeostasis, though effects on muscle function and coordination, as well as on additional systems, may have clinical relevance ⁹.

Calcitriol—functioning as part of the endocrine system for maintaining serum calcium levels—elevates plasma ionized calcium levels to the normal range by three different mechanisms. The first mechanism, which does not require PTH (parathyroid hormone), is the well-established role of calcitriol in stimulating intestinal calcium absorption throughout the entire length of the intestine, although its greatest activity is in the duodenum and jejunum. It is clear that calcitriol directly stimulates intestinal calcium and, independently, phosphate absorption.

In the second mechanism, calcitriol plays an essential role in the mobilization of calcium from bone, a process requiring parathyroid hormone ¹⁰. Calcitriol induces the formation and activation of the osteoclast to function in the mobilization of calcium from bone. In short, calcitriol facilitates the formation of osteoclasts by stimulating the secretion of a protein called receptor activator for nuclear factor κ B (RANK) ligand, which, in turn, is responsible for osteoclastogenesis and bone resorption ¹¹.

In the third mechanism, calcitriol together with PTH (parathyroid hormone) stimulates the renal distal tubule reabsorption of calcium, ensuring retention of calcium by the kidney when calcium is needed ¹². These well-known functions dominate vitamin D physiology and many of the functional proteins involved in these processes have been identified, although the exact molecular mechanisms of all of these systems have yet to be elucidated ¹³.

Thus, overall, calcitriol acts on the intestine, bone, and kidney as described above to elevate serum calcium levels, closing the calcium loop. As serum calcium levels rise, PTH (parathyroid hormone) secretion drops. If serum calcium levels become too high, the parafollicular cells (“C” cells) of the thyroid secrete calcitonin, which blocks calcium resorption from bone and helps to keep calcium levels in the normal range. Calcitriol, through its receptor, the vitamin D receptor, suppresses parathyroid gene expression and parathyroid cell proliferation, providing important feedback loops that reinforce the direct action of increased serum calcium levels ¹⁴.

The mechanism of action of vitamin D in regulating serum phosphorus levels, certain aspects of which remain obscure. What is known is that (1) a deficiency of phosphate stimulates CYP27B1 to produce more calcitriol, which in turn stimulates phosphate absorption in the small intestine; and (2) calcitriol can also induce the secretion of fibroblast-like growth factor-23 (FGF23) by osteocytes in bone, which results in phosphate excretion in the kidney ¹⁴, as well as feedback on vitamin D metabolism.

Calcitriol other actions

It is noteworthy that the vitamin D receptor is present in the nucleus of many tissues that are not involved in the regulation of calcium and phosphate metabolism ¹³. For example, the vitamin D receptor has been clearly described in epidermal keratinocytes, in activated T cells of the immune system, in antigen-presenting cells, in macrophages and monocytes, and in cytotoxic T cells ¹³. Gene array studies in many cells and tissues show that calcitriol regulates several hundred genes throughout the body or as much as 5 percent of the human genome ¹⁵. However, exactly how calcitriol functions in these tissues and the physiological consequences are not clearly known.

Likewise, the importance of the paracrine or autocrine synthesis of calcitriol under non-disease conditions is unclear. The 1α-hydroxylase (CYP27B1) gene has been reported to be expressed in many extra-renal tissues ¹⁶. In some cases, this is based upon in vitro production of calcitriol by cell lines as a consequence of culture conditions, but it also includes detection of the messenger ribonucleic acid (mRNA) transcript or protein for CYP27B1 in tissues in vivo ¹⁶. The contribution of calcitriol to the maternal circulation stemming from production by the placenta is not clearly known; based on a case report for an anephric (without kidney) patient, it appears that the placenta produces calcitriol, but its contribution to the maternal circulation is low ¹⁷. The pregnancy-related rise in calcitriol is due to up-regulation of the enzymes in the maternal kidney ¹⁸. However, there may be other extra-renal 1α-hydroxylation sites that can act as intracrine systems primarily involved in regulation of cell or tissue growth: skin, gastrointestinal tract, or glandular tissue, such as prostate and breast ¹⁹. In mice missing the Vdr gene (Vdr-null), calcitriol and the vitamin D receptor play a role in lactational physiology; there is accelerated mammary development during pregnancy, but delayed involution of the mammary tissue after lactation ²⁰. Extra-renal CYP27B1 may be up-regulated during inflammation ²¹ or down-regulated in cancerous tissue proliferation ²². Furthermore, extra-renal production of calcitriol is clearly found in certain pathological diseases, including granulomatous conditions such as sarcoidosis, lymphoma, and tuberculosis ²³, which can be associated with hypercalcemia. If sarcoidosis is left untreated, the extra-renally produced calcitriol can enter the circulation, resulting in hypercalciuria and eventually hypercalcemia.

There is emerging evidence that calcitriol plays a role in the immune system that has not yet been clearly described. Exogenous calcitriol can suppress autoimmune diseases, but with hypercalcemia as an important side effect ²⁴. It has been shown that the local conversion of 25OHD into calcitriol in monocytes or macrophages results in an increase in cellular immunity by stimulating the production of cathelicidin, an anti-microbial peptide capable of killing bacteria, particularly Mycobacterium tuberculosis ²⁵. Recently, Stubbs et al. ²⁶ showed that renal dialysis patients treated with high-dose calcitriol (vitamin D3) develop a population of immune cells with increased CYP27B1, vitamin D receptor, and cathelicidin expression, although the role of these cells in vivo is unknown. Ironically, calcitriol has an opposite effect on the adaptive immune (B and T cell function) response. Calcitriol generally inhibits T helper cell proliferation and B cell immunoglobulin production. In contrast, calcitriol promotes the proliferation of immunosuppressive regulatory T cells and their accumulation at sites of inflammation ²⁷.

A role for vitamin D in carcinogenesis evolved initially from in vitro studies as cell culture approaches became more widely available for the evaluation of the mechanisms of action of vitamin D and its metabolites ²⁸. The active hormone, calcitriol, was shown to consistently inhibit the growth of cancer cells and promote differentiation in vitro by regulating multiple pathways ²⁹. Additional studies documented the presence of the vitamin D receptor in a wide array of cancer cell types. Vitamin D orchestrates cell cycle progression via alterations in key regulators such as cyclin-dependent kinases, retinoblastoma protein phosphorylation, and repression of the proto-oncogene myc as well as by modulating growth factor receptor-mediated signaling pathways ³⁰. In addition, calcitriol restores or enhances pro-apoptotic effects in cancer cells by several possible pathways, including repression of several pro-survival proteins such as Bc12 and telomerase reverse transcriptase and by activating pro-apoptotic proteins Bax and μ-calpain ³¹. Evidence also supports an anti-angiogenic effect of vitamin D. Vascular endothelial growth factor (VEGF) expression by cancer cells is suppressed and endothelial cell responses to vascular endothelial growth factor (VEGF) are inhibited by vitamin D, an observation supported by in vivo xenograft studies ³². The immunoregulatory effects of vitamin D may also have an impact on cancer biology. Inflammation is a critical early step in the carcinogenesis cascade for many cancers, and the ability of vitamin D to exhibit anti-inflammatory effects on cancer cells by down-regulating the pro-inflammatory pathways, such as cyclooxygenase-2, may contribute to cancer inhibition ³³. In contrast, the role of vitamin D in cancer immunosurveillance of nascent or established cancers remains to be defined.

The encouraging in vitro findings, tempered with concerns about hypercalcemia, led to the development of many vitamin D analogues in the hope of retaining anti-cancer activity, but without increasing serum calcium, for the pharmacological therapy of cancer, as recently reviewed ³⁴.

What is calcitriol used for?

Calcitriol is used to treat and prevent low levels of calcium and bone disease in patients whose kidneys or parathyroid glands (glands in the neck that release natural substances to control the amount of calcium in the blood) are not working normally. It is also used to treat secondary hyperparathyroidism (a condition in which the body produces too much parathyroid hormone [PTH; a natural substance needed to control the amount of calcium in the blood]) and metabolic bone disease in people with kidney disease. Calcitriol is in a class of medications called vitamin D analogs. It works by helping the body to use more of the calcium found in foods or supplements and regulating the body’s production of parathyroid hormone.

Calcitriol is also sometimes used to treat rickets (softening and weakening of bones in children caused by lack of vitamin D), osteomalacia (softening and weakening of bones in adults caused by lack of vitamin D), and familial hypophosphatemia (rickets or osteomalacia caused by decreased ability to break down vitamin D in the body). Calcitriol is also sometimes used to increase the amount of calcium in the blood of premature babies. Talk to your doctor about the risks of using this medication for your condition.

Calcitriol may be prescribed for other uses; ask your doctor or pharmacist for more information.

Calcitriol medication

Calcitriol medication comes as a capsule and a solution (liquid) to take by mouth. It usually is taken once a day or once every other day in the morning with or without food. Follow the directions on your prescription label carefully, and ask your doctor or pharmacist to explain any part you do not understand. Take calcitriol exactly as directed. Do not take more or less of it or take it more often than prescribed by your doctor.

Your doctor will probably start you on a low dose of calcitriol and may gradually increase your dose depending on your body’s response to calcitriol.

Important information

You should not use this medication if you have high levels of calcium or vitamin D in your blood, or if you have ever had an allergic reaction to calcitriol or other forms of vitamin D.

Drink plenty of fluids unless your doctor has told you to restrict your fluid intake.

Call your doctor if you have ongoing vomiting or diarrhea, or if you are sweating more than usual. You can easily become dehydrated while taking this medication, which can lead to a serious electrolyte imbalance.

Do not take other vitamin or mineral supplements unless your doctor has told you to.

Avoid using antacids without your doctor’s advice. Use only the type of antacid your doctor recommends. Some antacids can make it harder for your body to absorb calcitriol.

To be sure this medication is helping your condition, your blood will need to be tested on a regular basis. Do not miss any scheduled appointments.

Calcitriol is only part of a complete program of treatment that may also include a special diet. Follow your diet and medication routines very closely. You should become very familiar with the list of foods you must eat or avoid to help control your condition.

You should not use this medication if you have high levels of calcium or vitamin D in your blood, or if you have ever had an allergic reaction to calcitriol or other forms of vitamin D.

To make sure you can safely take calcitriol, tell your doctor about all of your medical conditions.

FDA pregnancy category C. This medication may be harmful to an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant during treatment.

Calcitriol can pass into breast milk and may harm a nursing baby. Do not use this medication without telling your doctor if you are breast-feeding a baby.

Before taking calcitriol:

• tell your doctor and pharmacist what prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products you are taking, especially calcium or magnesium-containing antacids; calcium supplements; cholestyramine (Cholybar, Prevalite, Questran); digoxin (Lanoxin); diuretics (‘water pills’); ketoconazole; lanthanum (Fosrenol); magnesium-containing laxatives; oral steroids such as dexamethasone, methylprednisolone (Medrol), and prednisone (Rayos); other forms of vitamin D; phenobarbital; phenytoin (Dilantin, Phenytek); and sevelamer (Renagel, Renvela). Also tell your doctor or pharmacist if you are taking ergocalciferol (Deltalin, Drisdol) or have stopped taking it in the past few months.Your doctor may need to change the doses of your medications or monitor you carefully for side effects.
• tell your doctor if you have high levels of calcium. Your doctor will probably tell you not to take calcitriol.
• tell your doctor if you have recently had surgery or are unable to move around for any reason and if you have or have ever had kidney or liver disease.
• tell your doctor if you are pregnant, plan to become pregnant, or are breastfeeding. If you become pregnant while taking calcitriol, call your doctor. You
• should not breastfeed while you are taking calcitriol.

What special dietary instructions should I follow?

Calcitriol will work only if you get the right amount of calcium from the foods you eat. If you get too much calcium from foods, you may experience serious side effects of calcitriol, and if you do not get enough calcium from foods, calcitriol will not control your condition. Your doctor will tell you which foods are good sources of these nutrients and how many servings you need each day. If you find it difficult to eat enough of these foods, tell your doctor. In that case, your doctor can prescribe or recommend a supplement.

If you are being treated with dialysis (process of cleaning the blood by passing it through a machine), your doctor may also prescribe a low-phosphate diet. Follow these directions carefully.

If you do not have kidney disease, you should drink plenty of fluids while taking calcitriol. If you have kidney disease, talk to your doctor about how much fluid you should drink each day.

Calcitriol dose

• To treat diseases in which calcium is not used properly by the body or to treat bone disease in kidney patients undergoing kidney dialysis:
  • For oral dosage form (capsules):
    • Adults, teenagers, and children over 10 years of age—At first, 300 to 350 micrograms (mcg) a week, taken in divided doses either once a day or every other day. Your doctor may change your dose if needed.
    • Children 2 to 10 years of age—50 mcg a day.
    • Children up to 2 years of age—20 to 50 mcg a day.
• To treat diseases in which calcium is not used properly by the body or to treat bone disease in kidney patients undergoing kidney dialysis:
  • For oral dosage forms (capsules and solution):
    • Adults, teenagers, and children—At first, 0.25 micrograms (mcg) a day. Your doctor may change your dose if needed.
  • For parenteral dosage forms (injection):
    • Adults and teenagers—At first, 0.5 mcg injected into a vein three times a week. Your doctor may change your dose if needed.
    • Children—Use and dose must be determined by your doctor.

Precautions

For individuals taking vitamin D without a prescription:

• Vitamin D is stored in the body; therefore, when you take more than the body needs, it will build up in the body. This may lead to poisoning. Problems are more likely to occur in:
  • Adults taking 20,000 to 80,000 Units a day and more for several weeks or months.
  • Children taking 2,000 to 4,000 Units a day for several months.

If you are taking this medicine for a reason other than as a dietary supplement, your doctor should check your progress at regular visits to make sure that it does not cause unwanted effects.

Do not take any nonprescription (over-the-counter [OTC]) medicine or dietary supplement that contains calcium, phosphorus, or vitamin D while you are taking any of these dietary supplements unless you have been told to do so by your health care professional. The extra calcium, phosphorus, or vitamin D may increase the chance of side effects.

Do not take antacids or other medicines containing magnesium while you are taking any of these medicines. Taking these medicines together may cause unwanted effects.

What happens if I miss a dose?

Take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

Calcitriol side effects

Some side effects can be serious. The following symptoms are uncommon, but if you experience any of them, call your doctor immediately:

• feeling tired, difficulty thinking clearly, loss of appetite, nausea, vomiting, constipation, increased thirst, increased urination, or weight loss
• weakness
• headache
• upset stomach
• dry mouth
• muscle pain
• bone pain
• metallic taste in mouth
• difficult or painful urination
• changes in vision
• lack of interest in the things around you
• hallucination (seeing things or hearing voices that do not exist)
• fever or chills
• stomach pain
• pale, fatty stools
• yellowing of the skin or eyes
• runny nose
• decreased sexual desire
• irregular heartbeat
• rash
• hives
• itching
• difficulty breathing or swallowing

Symptoms of overdose may include the following:

• feeling tired, difficulty thinking clearly, loss of appetite, nausea, vomiting, constipation, increased thirst, increased urination, or weight loss
• weakness
• headache
• upset stomach
• dry mouth
• muscle or bone pain
• metallic taste in mouth
• difficult or painful urination
• changes in vision
• hallucination (seeing things or hearing voices that do not exist)
• fever or chills
• stomach pain
• pale, fatty stools
• yellowing of the skin or eyes
• runny nose
• decreased sexual desire
• irregular heartbeat

Early symptoms of overdose:

• bone pain
• constipation (especially in children or adolescents)
• diarrhea
• drowsiness
• dryness of mouth
• headache (continuing)
• increased thirst
• increase in frequency of urination, especially at night, or in amount of urine
• irregular heartbeat
• itching skin
• loss of appetite
• metallic taste
• muscle pain
• nausea or vomiting (especially in children or adolescents)
• unusual tiredness or weakness

Late symptoms of overdose:

• bone pain
• calcium deposits (hard lumps) in tissues outside of the bone
• cloudy urine
• drowsiness
• increased sensitivity of eyes to light or irritation of eyes
• itching of skin
• loss of appetite
• loss of sex drive
• mood or mental changes
• muscle pain
• nausea or vomiting
• protein in the urine
• redness or discharge of the eye, eyelid, or lining of the eyelid
• runny nose
• weight loss

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

1. Jurutka PW, Whitfield GK, Hsieh JC, Thompson PD, Haussler CA, Haussler MR. Molecular nature of the vitamin D receptor and its role in regulation of gene expression. Reviews in Endocrinology and Metabloic Disorders. 2001;2(2):203–16.[↩][↩]
2. Aksnes L, Aarskog D. Plasma concentrations of vitamin D metabolites in puberty: effect of sexual maturation and implications for growth. Journal of Clinical Endocrinology and Metabolism. 1982;55(1):94–101[↩]
3. Martinez ME, Del Campo MT, Sanchez-Cabezudo MJ, Balaguer G, Rodriguez-Carmona A, Selgas R. Effect of oral calcidiol treatment on its serum levels and peritoneal losses. Peritoneal Dialysis International. 1995;15(1):65–70.[↩]
4. Bergwitz C, Juppner H. Regulation of phosphate homeostasis by PTH, vitamin D, and FGF23. Annual Review of Medicine. 2010;61:91–104.[↩]
5. Nguyen, T.M., Adiceam, P., Kottler, M.L., Guillozo, M., Rizk-Rabin, F., Brouillard, F., Lagier, P., Palix, C., Garnier, J.M., and Garabedian, M. (2002). Tryptophan missense mutation in the ligand-binding domain of the vitamin D receptor causes severe resistance to 1,25-dihyroxyvitamin D. J. Bone Miner. Res. 17, 1728-1737.[↩]
6. Holick MF. Vitamin D: photobiology, metabolism, mechanism of action, and clinical application, Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism. 3rd. Favus MJ, editor. Philadelphia, PA: Lippincott-Raven; 1996. pp. 74–81.[↩]
7. DeLuca, H. F. (1984). The metabolism, physiology and function of vitamin D. In: “Vitamin D: Basic and Clinical Aspects” (R. Kumar, ed.), pp. 1. Martinus Nijhoff, Boston.[↩]
8. Ozur, K., Sone, T., and Pike, J. W. (1991). The genomic mechanism of action of 1,25-dihydroxyvitamin D3. J. Bone Miner. Res. 6, 1021-1027.[↩]
9. Liberman UA. Disorders in Vitamin D Action. [Updated 2014 Jan 1]. In: De Groot LJ, Chrousos G, Dungan K, et al., editors. Endotext [Internet]. South Dartmouth (MA): MDText.com, Inc.; 2000-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK279150[↩]
10. Lips P. Vitamin D physiology. Progress in Biophysics and Molecular Biology. 2006;92(1):4–8.[↩]
11. Yasuda H, Higashio K, Suda T. Vitamin D and osteoclastogenesis, Vitamin D. Feldman D, Pike JW, Glorieux FH, editors. Vol. 1. San Diego, CA: Elsevier Academic Press; 2005. pp. 665–85.[↩]
12. Yamamoto M, Kawanobe Y, Takahashi H, Shimazawa E, Kimura S, Ogata E. Vitamin D deficiency and renal calcium transport in the rat. Journal of Clinical Investigation. 1984;74(2):507–13[↩]
13. Institute of Medicine (US) Committee to Review Dietary Reference Intakes for Vitamin D and Calcium; Ross AC, Taylor CL, Yaktine AL, et al., editors. Dietary Reference Intakes for Calcium and Vitamin D. Washington (DC): National Academies Press (US); 2011. 3, Overview of Vitamin D. Available from: https://www.ncbi.nlm.nih.gov/books/NBK56061/[↩][↩][↩]
14. Liu N, Nguyen L, Chun RF, Lagishetty V, Ren S, Wu S, Hollis B, DeLuca HF, Adams JS, Hewison M. Altered endocrine and autocrine metabolism of vitamin D in a mouse model of gastrointestinal inflammation. Endocrinology. 2008;149(10):4799–808[↩][↩]
15. Pike JW, Shevde NK, Hollis BW, Cooke NE, Zella LA. Vitamin D—binding protein influences total circulating levels of 1,25-dihydroxyvitamin D-3 but does not directly modulate the bioactive levels of the hormone in vivo. Endocrinology. 2008;149(7):3656–67.[↩]
16. Hewison M, Burke F, Evans KN, Lammas DA, Sansom DM, Liu P, Modlin RL, Adams JS. Extra-renal 25-hydroxyvitamin D3-1alpha-hydroxylase in human health and disease. Journal of Steroid Biochemistry and Molecular Biology. 2007;103(3-5):316–21.[↩][↩]
17. Turner M, Barre PE, Benjamin A, Goltzman D, Gascon-Barre M. Does the maternal kidney contribute to the increased circulating 1,25-dihydroxyvitamin D concentrations during pregnancy? Mineral and Electrolyte Metabolism. 1988;14(4):246–52[↩]
18. Kovacs CS, Kronenberg HM. Maternal-fetal calcium and bone metabolism during pregnancy, puerperium, and lactation. Endocrine Reviews. 1997;18(6):832–72.[↩]
19. Diesing D, Cordes T, Fischer D, Diedrich K, Friedrich M. Vitamin D—metabolism in the human breast cancer cell line MCF-7. Anticancer Research. 2006;26(4A):2755–9.[↩]
20. Zinser GM, Welsh J. Accelerated mammary gland development during pregnancy and delayed postlactational involution in vitamin D3 receptor null mice. Molecular Endocrinology. 2004;18(9):2208–23[↩]
21. Liu N, Nguyen L, Chun RF, Lagishetty V, Ren S, Wu S, Hollis B, DeLuca HF, Adams JS, Hewison M. Altered endocrine and autocrine metabolism of vitamin D in a mouse model of gastrointestinal inflammation. Endocrinology. 2008;149(10):4799–808.[↩]
22. Bises G, Kallay E, Weiland T, Wrba F, Wenzl E, Bonner E, Kriwanek S, Obrist P, Cross HS. 25-hydroxyvitamin D3-1alpha-hydroxylase expression in normal and malignant human colon. Journal of Histochemistry and Cytochemistry. 2004;52(7):985–9.[↩]
23. Adams JS, Modlin RL, Diz MM, Barnes PF. Potentiation of the macrophage 25-hydroxyvitamin D-1-hydroxylation reaction by human tuberculous pleural effusion fluid. Journal of Clinical Endocrinology and Metabolism. 1989;69(2):457–60.[↩]
24. DeLuca HF, Cantorna MT. Vitamin D: its role and uses in immunology. FASEB Journal. 2001;15(14):2579–85.[↩]
25. Liu PT, Stenger S, Li H, Wenzel L, Tan BH, Krutzik SR, Ochoa MT, Schauber J, Wu K, Meinken C, Kamen DL, Wagner M, Bals R, Steinmeyer A, Zugel U, Gallo RL, Eisenberg D, Hewison M, Hollis BW, Adams JS, Bloom BR, Modlin RL. Toll-like receptor triggering of a vitamin D-mediated human antimicrobial response. Science. 2006;311(5768):1770–3.[↩]
26. Stubbs JR, Idiculla A, Slusser J, Menard R, Quarles LD. Cholecalciferol supplementation alters calcitriol-responsive monocyte proteins and decreases inflammatory cytokines in ESRD. Journal of the American Society of Nephrology. 2010;21(2):353–61[↩]
27. Penna G, Amuchastegui S, Giarratana N, Daniel KC, Vulcano M, Sozzani S, Adorini L. 1,25-Dihydroxyvitamin D3 selectively modulates tolerogenic properties in myeloid but not plasmacytoid dendritic cells. Journal of Immunology. 2007;178(1):145–53.[↩]
28. Masuda S, Jones G. Promise of vitamin D analogues in the treatment of hyper-proliferative conditions. Molecular Cancer Therapeutics. 2006;5(4):797–808[↩]
29. Kovalenko PL, Zhang Z, Cui M, Clinton SK, Fleet JC. 1,25 dihydroxyvitamin D-mediated orchestration of anticancer, transcript-level effects in the immortalized, non-transformed prostate epithelial cell line, RWPE1. BMC Genomics. 2010;11:26.[↩]
30. Li P, Li C, Zhao X, Zhang X, Nicosia SV, Bai W. p27(Kip1) stabilization and G(1) arrest by 1,25-dihydroxyvitamin D(3) in ovarian cancer cells mediated through down-regulation of cyclin E/cyclin-dependent kinase 2 and Skp1-Cullin-F-box protein/Skp2 ubiquitin ligase. Journal of Biological Chemistry. 2004;279(24):25260–7.[↩]
31. Kumagai T, Shih LY, Hughes SV, Desmond JC, O’Kelly J, Hewison M, Koeffler HP. 19-Nor-l,25(OH)2D2 (a novel, noncalcemic vitamin D analogue), combined with arsenic trioxide, has potent antitumor activity against myeloid leukemia. Cancer Research. 2005;65(6):2488–97[↩]
32. Bao BY, Yao J, Lee YF. 1alpha, 25-dihydroxyvitamin D3 suppresses interleukin-8-mediated prostate cancer cell angiogenesis. Carcinogenesis. 2006;27(9):1883–93.[↩]
33. Moreno J, Krishnan AV, Swami S, Nonn L, Peehl DM, Feldman D. Regulation of prostaglandin metabolism by calcitriol attenuates growth stimulation in prostate cancer cells. Cancer Research. 2005;65(17):7917–25.[↩]
34. Trump DL, Deeb KK, Johnson CS. Vitamin D: considerations in the continued development as an agent for cancer prevention and therapy. Cancer Journal. 2010;16(1):1–9.[↩]