The discovery of the vitamin D endocrine system in 1970 sparked a new interest in the relationship between vitamin D and metabolic bone disease. In particular, the identification of the vitamin D receptor in tissues not related to calcium and bone has led to the investigation of vitamin D and its action in a number of other medical areas.
Many studies evaluating the effects of high-dose vitamin D in supplemental form in suppressing a wide range of diseases have been conducted, and many clinical investigators have interpreted that vitamin D does have a beneficial effect.
In metabolic bone disease, vitamin D cures rickets in children and osteomalacia in adults. However, in vitamin D-dependency type I and type II rickets, treatment with the vitamin D hormone, 1α,25-dihydroxyvitamin D3, offers more benefits. For osteoporosis, vitamin D does have a role; however, the development of oral vitamin D analogues that have anabolic properties would fulfil an unmet need.
Several vitamin D analogues have been marketed for the treatment of secondary hyperthyroidism associated with chronic renal failure, and are successful as they provide a wider therapeutic window compared with 1α,25-dihydroxyvitamin D3 and its synthetic precursor 1α-hydroxyvitamin D3. They have also proved successful in treating psoriasis.
Vitamin D and sunlight exposure has also been associated with various immune disorders (for example, multiple sclerosis and type 1 diabetes) and numerous cancers; however, the role of vitamin D-based therapies for these indications remains to be evaluated in large-scale studies.
Toxic effects of vitamin D and hypercalcaemia can occur when vitamin D is taken in doses above 25,000 IU per day (625 μg per day) or when the vitamin D endocrine system is dysregulated, such as in granuloma-forming disease or in various malignancies, such as Hodgkin's lymphoma.
Future development of vitamin D-based therapeutics will probably target specific aspects of vitamin D function, which will be aided by the identification of key specific genes responsible for the various functions of vitamin D.
It is likely that more efficacious vitamin D analogues selective for bone formation or resorption will be developed, and analogues selective for intestinal calcium absorption will also be developed. However, with the current status of knowledge, it seems that development of vitamin D analogues specific for components of the immune system is less promising.
The discovery of the vitamin D endocrine system and a receptor for the hormonal form, 1α,25-dihydroxyvitamin D3, has brought a new understanding of the relationship between vitamin D and metabolic bone diseases, and has also established the functions of vitamin D beyond the skeleton. This has ushered in many investigations into the possible roles of vitamin D in autoimmune diseases, cardiovascular disorders, infectious diseases, cancers and granuloma-forming diseases. This article presents an evaluation of the possible roles of vitamin D in these diseases. The potential of vitamin D-based therapies in treating diseases for which the evidence is most compelling is also discussed.
This is a preview of subscription content, access via your institution
Open Access articles citing this article.
Robust osteogenic efficacy of 2α-heteroarylalkyl vitamin D analogue AH-1 in VDR (R270L) hereditary vitamin D-dependent rickets model rats
Scientific Reports Open Access 22 July 2022
Current Oncology Reports Open Access 20 November 2020
Generation of novel genetically modified rats to reveal the molecular mechanisms of vitamin D actions
Scientific Reports Open Access 30 March 2020
Subscribe to Journal
Get full journal access for 1 year
only $6.58 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Get time limited or full article access on ReadCube.
All prices are NET prices.
Reed, C. I., Struck, H. C. & Steck, I. E. (eds) Vitamin D: Chemistry, Physiology, Pharmacology Pathology, Experimental and Clinical Investigations 1–389 (The University of Chicago Press, Chicago, 1939).
British Pediatric Association, Committee on Hypercalcaemia. Hypercalcemia in infants and vitamin D. BMJ 2, 149 (1956).
DeLuca, H. F. in Vitamin D 2nd edn (eds Feldman, D., Glorieux, F. H. & Pike, J. W.) 3–11 (Academic Press, San Diego, 2005).
Jones, G., Strugnell, S. A. & DeLuca, H. F. Current understanding of the molecular actions of vitamin D. Physiol. Rev. 78, 1193–1231 (1998). This is a critical and comprehensive review that provides an accurate description of vitamin D discoveries in the twentieth century.
Haussler, M. R. & McCain, T. A. Basic and clinical concepts related to vitamin D metabolism and action. N. Engl. J. Med. 297, 974–983; 1041–1050 (1977).
Christakos, S et al. Vitamin D. Molecular mechanism of action. Ann. NY Acad. Sci. 1116, 340–348 (2007).
Demay, M. B. Mechanism of vitamin D receptor action. Ann. NY Acad. Sci. 1068, 204–213 (2006).
Velluz, L. & Amiard, G. Chimie organique-nourveau précurseur de la vitamin D3 . Compt. Rend. 228, 1037–1038 (1949) (in French).
Cheng, J. B., Motola, D. L., Mangelsdorf, D. J. & Russell, D. W. De-orphanization of cytochrome P450 2R1: a microsomal vitamin D 25-hydroxylase. J. Biol. Chem. 278, 38084–38093 (2003).
Brunette, M. G., Chan, M., Ferriere, C. & Roberts, K. K. Site of 1,25-dihydroxyvitamin D3 synthesis in the kidney. Nature 276, 287–289 (1978).
DeLuca, H. F. Vitamin D: the vitamin and the hormone. Fed. Proc. 33, 2211–2219 (1974).
Aubin, J. E. & Bonnelye, E. Osteoprotegerin and its ligand: a new paradigm for regulation of osteoclastogenesis and bone resorption. Osteoporosis Int. 11, 905–913 (2000).
Plum, L. A. & DeLuca, H. F. The functional metabolism and molecular biology of vitamin D action. Clin. Rev. Bone Miner. Metab. 7, 20–41 (2009).
Fukumoto, S. Physiological regulation and disorders of phosphate metabolism — pivotal role of fibroblast growth factor 23. Inter. Med. 47, 337–343 (2008).
Quarles, L. D. Endocrine functions of bone in mineral metabolism regulation. J. Clin. Invest. 118, 3820–3828 (2008).
Omdahl, J. L., Morris, H. A. & May, B. K. Hydroxylase enzymes of the vitamin D pathway: expression, function and regulation. Ann. Rev. Nutr. 22, 139–166 (2002).
Onisko, B. L., Esvelt, R. P., Schnoes, H. K. & DeLuca, H. F. Metabolites of 1α,25-dihydroxyvitamin D3 in rat bile. Biochemistry 19, 4124–4130 (1980).
Norman, A. W. in Vitamin D 2nd edn (Feldman, D., Pike, J. W. & Glorieux, F. H. eds) 381–411 (Elsevier, San Diego, 2005).
Brumbaugh, P. F. & Haussler, M. R. Nuclear and cytoplasmic binding components for vitamin D metabolites. Life Sci. 16, 353–362 (1975). This is the first solid evidence for the vitamin D receptor.
Kream, B. E., Reynolds, R. D., Knutson, J. C. Eisman, J. A. & DeLuca, H. F. Intestinal cytosol binders of 1,25-dihydroxyvitamin D and 25-hydroxyvitamin D. Arch. Biochem. Biophys. 176, 779–787 (1976).
Baker, A. R. et al. Cloning and expression of full-length cDNA encoding human vitamin D receptor. Proc. Natl Acad. Sci. USA 85, 3294–3298 (1988).
Burmester, J. K., Maeda, N. & DeLuca, H. F. Isolation and expression of rat 1,25-dihydroxyvitamin D3 receptor cDNA. Proc. Natl Acad. Sci. USA 85, 1005–1009 (1988).
Takeda, E., Yamamoto, H., Taketani, Y. & Miyamoto, K. Vitamin D-dependent rickets type I and type II. Acta Paediatr. Jpn. 39, 508–513 (1997).
Balsan, S. et al. Rickets and alopecia with resistance to 1,25-dihydroxyvitamin D: two different clinical courses with two different cellular defects. J. Clin. Endocrinol. Metab. 57, 803–811 (1983). The first description of different mutants of the vitamin D receptor that result in differential responses to 1,25-(OH) 2 D 3.
Lieberman, U. A., Eil, C. & Marx, S. J. Clinical features of hereditary resistance to 1,25-dihydroxyvitamin D (hereditary hypocalcemic vitamin D resistant ricket type II). Adv. Exp. Med. Biol. 196, 391–406 (1986).
Bouillon, R. et al. Vitamin D and human health: lessons from vitamin D receptor null mice. Endocr. Rev. 29, 726–776 (2008).
Vanhooke, J. L. et al. CYP27B1 null mice with LacZ reporter gene display no 25-hydroxyvitamin D3-1α-hydroxylase promoter activity in the skin. Proc. Natl Acad. Sci. USA 103, 75–80 (2006).
Steenbock, H. & Herting, D. C. Vitamin D and growth. J. Nutr. 57, 449–468 (1955).
Horst, R. L., Goff, J. P. & Reinhardt, T. A. Advancing age results in reduction of intestinal and bone 1,25-dihydroxyvitamin D receptor. Endocrinology 126, 1053–1057 (1990).
Adami, S. et al. Insulin-like growth factor 1 is associated with bone formation markers, PTH and bone mineral density in healthy premenopausal women. Bone 46, 244–247 (2010).
Gallagher. et al. Intestinal calcium absorption and serum vitamin D metabolites in normal subjects and osteoporotic patients. Effect of age and dietary calcium. J. Clin. Invest. 64, 719–726 (1979).
Slovik, D. M., Adams, J. S., Neer, R. M., Holick, M. F. & Potts, Jr J. T. Deficient production of 1,25-dihydroxyvitamin D in elderly osteoporotic patients. N. Engl. J. Med. 305, 372–374 (1981).
Chen, C., Noland, K. A. & Kalu, D. N. Modulation of intestinal vitamin D receptor by ovariectomy, estrogen and growth hormone. Mech. Ageing Dev. 99, 109–122 (1997).
Xue, Y., Karaplis, A. C., Hendy, G. N., Goltzman, D. & Miao, D. Exogenous 1,25-dihydroxyvitamin D3 exerts a skeletal anabolic effect and improves mineral ion homeostasis in mice that are homozygous for both the 1α-hydroxylase and parathyroid hormone null alleles. Endocrinology 147, 4801–4810 (2006). The first clear demonstration of anabolic bone activity of 1,25-(OH) 2 D 3.
Shevde, N. K. et al. A potent analog of 1α,25-dihydroxyvitamin D3 selectively induces bone formation. Proc. Natl Acad. Sci. USA 99, 13487–13491 (2002).
Ke, H. Z. et al. A new vitamin D analog, 2MD, restores trabecular and cortical bone mass and strength in ovariectomized rats with established osteopenia. J. Bone Miner. Res. 20, 1742–1755 (2005).
Plum, L. A. et al. 2MD, a new anabolic agent for osteoporosis treatment. Osteoporosis Int. 17, 704–715 (2006).
DeLuca, H. F et al. The vitamin D analog 2MD increases bone turnover but not BMD in postmenopausal women with osteopenia: results of a 1-year, phase 2, double-blind, placebo-controlled, randomized clinical trial. J. Bone Min. Res. 1 Oct 2010 (doi:10.1002/jbmr.256).
Kubodera, N. D-hormone derivatives for the treatment of osteoporosis: from alfacalcidol to eldecalcitol. Mini Rev. Med. Chem. 9, 1416–1422 (2009).
Nishii, Y. Active vitamin D and its analogs as drugs for the treatment of osteoporosis: advantages and problems. J. Bone Miner. Metab. 20, 57–65 (2002).
Tilyard, M. W., Spears, G. F. S., Thomson, J. & Dovey, S. Treatment of postmenopausal osteoporosis with calcitriol or calcium. N. Engl. J. Med. 326, 357–362 (1992). An important clinical study that shows that 1,25-(OH) 2 D 3 reduces the fracture rate in postmenopausal women.
Matsumoto, T. & Kubodera, N. ED-71, a new active vitamin D3, increases bone mineral density regardless of serum 25(OH)D levels in osteoporotic subjects. J. Steroid Biochem. Mol. Biol. 103, 584–586 (2007).
Thacher, T. D., Obadofin, M. O., O'Brien, K. O. & Abrams, S. A. The effect of vitamin D2 and vitamin D3 on intestinal calcium absorption in Nigerian children with rickets. J. Clin. Endocrinol. Metab. 94, 3314–3321 (2009).
Levine, B. S., Kleeman, C. R. & Felsenfeld, A. J. The journey from vitamin D-resistant rickets to the regulation of renal phosphate transport. Clin. J. Am. Soc. Nephrol. 4, 1866–1877 (2009).
de Menezes Filho, H., de Castro, L. C. G. & Damiani, D. Original article. Hypophosphatemic rickets and osteomalacia. Arq. Bras. Endocrinol. Metab. 50/4, 802–813 (2006).
Martin, K. J. et al. Diagnosis, assessment, and treatment of bone turnover abnormalities in renal osteodystrophy. Am. J. Kidney Dis. 43, 558–565 (2004).
DeLuca, H. F. The biochemical basis of renal osteodystrophy and post-menopausal osteoporosis: a view from the vitamin D system. Curr. Med. Res. Opin. 7, 279–293 (1981).
Stumpf, W. E., Sar, M., Reid, F. A., Tanaka, Y. & DeLuca, H. F. Target cells for 1,25-dihydroxyvitamin D3 in intestinal tract, stomach, kidney, skin, pituitary and parathyroid. Science 206, 1188–1190 (1979). The first clear demonstration of nuclear localization of 1,25-(OH) 2 D 3 in target tissues. It also shows that vitamin D acts beyond the intestine, kidney and bone.
Haussler, P. F., Hughes, M. R. & Haussler, M. R. Cytoplasmic and nuclear binding components for 1α,25-dihydroxyvitamin D3 in chick parathyroid glands. Proc. Natl Acad. Sci. USA 72, 4871–4875 (1975).
Silver, J., Naveh-Many, T., Mayer, H., Schmeizer, H. J. & Popvtzer, M. M. Regulation by vitamin D metabolites of parathyroid hormone gene transcription in vivo in the rat. J. Clin. Invest. 78, 1296–1301 (1986). This paper demonstrates the first non-calcaemic action of 1,25-(OH) 2 D 3.
Brown, A. J. & Slatopolsky, E. Drug insight: vitamin D analogs in the treatment of secondary hyperparathyroidism in patients with chronic kidney disease. Nature Clin. Pract. Endocrinol. Metab. 3, 134–144 (2007).
Brown, A. J., Finch, J. & Slatopolsky, E. Differential effects of 19-nor-1,25-dihydroxyvitamin D3 and 1,25-dihydroxyvitamin D3 on intestinal calcium and phosphate transport. J. Lab. Clin. Med. 139, 279–284 (2002).
Sjoden, G., Smith, C., Lindgren, U. & DeLuca, H. F. 1α-Hydroxyvitamin D2 is less toxic than 1α-hydroxyvitamin D3 in the rat. Proc. Soc. Exp. Biol. Med. 178, 432–436 (1985).
Brown, A. J. & Coyne, D. W. Vitamin D analogs: new therapeutic agents for secondary hyperparathyroidism. Treat Endocrinol. 1, 313–327 (2002).
Doorenbos, C. R. C., van den Born, J., Navis, G. & de Borst, M. H. Possible renoprotection by vitamin D in chronic renal disease: beyond mineral metabolism. Nature Rev. Nephrol. 5, 691–700 (2009).
Thadhani, R. Is calcitriol life-protective for patients with chronic kidney disease? J. Am. Soc. Nephrol. 20, 2285–2290 (2009). An important study of the importance of 1,25-(OH) 2 D 3 and analogue therapy for patients with renal failure.
Fishbane, S. et al. Oral paricalcitrol in the treatment of patients with CKD and proteinuria: a randomized trial. Am. J. Kidney Dis. 54, 647–652 (2009).
Szeto. et al. Oral calcitriol for the treatment of persistent proteinuria in immunoglobulin A nephropathy: an uncontrolled trial. Am. J. Kidney Dis. 52, 724–731 (2008).
Alborzi, P. et al. Paricalcitol reduces albuminuria and inflammation in chronic kidney disease: a randomized double-blind pilot trial. Hypertension 52, 249–255 (2008).
Mizobuchi, M., Towler, D. & Slatopolsky, E. Vascular calcification: the killer of patients with chronic kidney disease. J. Am. Soc. Nephrol. 20, 1453–1464 (2009).
Mizobuchi, M. et al. Myocardial effects of VDR activators in renal failure. J. Steroid Biochem. Mol. Biol. 121, 188–192 (2010).
Zhou, C. et al. Calcium-independent and 1,25(OH)2D3-dependent regulation of the rennin-angiotensin system in 1α-hydroxylase knockout mice. Kidney Int. 74, 170–179 (2008).
Giovannucci, E., Liu, Y., Hollis, B. W. & Rimm, E. B. 25-Hydroxyvitamin D and risk of myocardial infarction in men. Arch. Intern. Med. 168, 1174–1180 (2008). A paper that highlights the importance of vitamin D in cardiovascular health.
Buell, J. S. et al. 25-Hydroxyvitamin D, dementia, and cerebrovascular pathology in elders receiving home services. Neurology 74, 18–26 (2010).
Feneis, J. F. & Arora, R. R. Role of vitamin D in blood pressure homeostasis. Am. J. Ther. 5 Mar 2010 (doi:10.1097/MJT.0b013e3181d16999).
Krämer, C. et al. Characterization of the vitamin D endocrine system in human sebocytes in vitro. J. Steroid Biochem. Mol. Biol. 113, 9–16 (2009).
Reichrath, J., Muller, S. M., Kerber, A., Baum, H. P. & Bahmer, F. A. Biologic effects of topical calcipotriol (M903) treatment in psoriatic skin. J. Am. Acad. Dermatol. 36, 19–28 (1997).
Simpson, R. U. & DeLuca, H. F. Characterization of a receptor-like protein for 1,25-dihydroxyvitamin D3 in rat skin. Proc. Natl Acad. Sci. USA 77, 5822–5826 (1980).
Hosomi, J., Hosoi, J., Abe, E., Suda, T. & Kuroki, T. Regulation of terminal differentiation of cultured mouse epidermal cells by 1α,25-dihydroxyvitamin D3 . Endocrinology 113, 1950–1957 (1983).
Abe, E. et al. Differentiation of mouse myeloid leukemia cells induced by 1α,25-dihydroxyvitamin D3 . Proc. Natl Acad. Sci. USA 78, 4990–4994 (1981). A classical paper that indicates the possible anticancer and differentiative activity of 1,25-(OH) 2 D 3.
Holick, M. F. 1,25-Dihydroxyvitamin D3 and the skin: a unique application for the treatment of psoriasis. Proc. Soc. Exp. Biol. Med. 191, 246–257 (1989).
Kragballe, K. Calcipotriol: a new drug for topical psoriasis treatment. Pharmacol. Toxicol. 77, 242–246 (1995).
Barker, J. N. W. N., Ashton, R. E., Marks, R., Harris, R. I. & Berth-Jones, J. Topical maxacalcitrol for the treatment of psoriasis vulgaris: a placebo-controlled, double-blind, dose-finding study with active comparator. Br. J. Dermatol. 141, 274–278 (1999).
Degitz, K. & Ochsendorf, F. Pharmacology of acne. Expert Opin. Pharmacother. 9, 955–971 (2008).
Nieves, N., Ahrens, J., Plum, L., DeLuca, H. & Clagett-Dame, M. Identification of a unique subset of 2-methylene-19-nor analogs of vitamin D with comedolytic activity in the rhino mouse. J. Invest. Dermatol. 130, 2359–2367 (2010).
Bhalla, A. K., Amento, E. P., Clemens, T. L., Holick, M. F. & Krane, S. M. Specific high-affinity receptors for 1,25-dihydroxyvitamin D3 in human peripheral blood mononuclear cells: presence in monocytes and induction in T lymphocytes following activation. J. Clin. Endocrinol. Metab. 57, 1308–1310 (1983).
Provvedini, D. M., Tsoukas, C. D., Deftos, L. J. & Manolagas, S. D. 1,25-Dihydroxyvitamin D3 receptors in human leukocytes. Science 221, 1181–1183 (1983).
Veldman, C. M., Cantorna, M. T. & DeLuca, H. F. Expression of 1,25-dihydroxyvitain D3 receptor in the immune system. Arch. Biochem. Biophys. 374, 334–338 (2000).
Adorini, L. & Penna, G. Control of autoimmune diseases by the vitamin D endocrine system. Nature Clin. Pract. Rheumatol. 4, 404–412 (2008).
Yang, S., Smith, C. & DeLuca, H. F. 1α,25-Dihydroxyvitamin D3 and 19-nor-1α, 25-dihydroxyvitamin D2 suppress immunoglobulin production and thymic lymphocyte proliferation in vivo. Biochim. Biophys. Acta 1158, 279–286 (1993).
Agranoff, B. W. & Goldberg, D. Diet and the geographical distribution of multiple sclerosis. Lancet 2, 1061–1066 (1974). This paper draws attention to ultraviolet irradiation and a reduction in the incidence of multiple sclerosis.
Lemire, J. M. & Archer, D. C. 1,25-Dihydroxyvitamin D3 prevents the in vivo induction of murine experimental autoimmune encephalomyelitis. J. Clin. Invest. 87, 1103–1107 (1991).
Branisteanu, D. D. et al. Prevention of murine experimental allergic encephalomyelitis: cooperative effects of cyclosporine and 1α,25-(OH)2D3 . J. Neuroimmunol. 61, 151–160 (1995).
Cantorna, M. T., Hayes, C. E. & DeLuca, H. F. 1,25-Dihydroxyvitamin D3 reversibly blocks the progression of relapsing encephalomyelitis, a model of multiple sclerosis. Proc. Natl Acad. Sci. USA 93, 7861–7864 (1996).
Meehan, T. F., Vanhooke, J., Prahl, J. & DeLuca, H. F. Hypercalcemia produced by parathyroid hormone suppresses experimental autoimmune encephalomyelitis in female but not male mice. Arch. Biochem. Biophys. 442, 214–221 (2005).
Cantorna, M. T., Humpal-Winter, J. & DeLuca, H. F. Dietary calcium is a major factor in 1,25-dihydroxycholecalciferol suppression of experimental autoimmune encephalomyelitis in mice. J. Nutr. 129, 1966–1971 (1999).
Becklund, B. R., Severson, K. S., Vang, S. V. & DeLuca, H. F. UV radiation suppresses experimental autoimmune encephalomyelitis independent of vitamin D production. Proc. Natl Acad. Sci. USA 107, 6418–6423 (2010).
Wingerchuk, D. M., Lesaux, J., Rice, A. P. A., Kremenchutzky, M. N. & Ebers, G. C. A pilot study of oral calcitriol (1,25-dihydroxyvitamin D3) for relapsing–remitting multiple sclerosis. J. Neurol. Neurosurg. Psychiatry 76, 1294–1296 (2005).
Fleming, J. O. et al. Vitamin D treatment of relapsing–remitting multiple sclerosis (RRMS): a MRI-based pilot study. Neurology 54, A338 (2000).
Zella, J. B. & DeLuca, H. F. Vitamin D and autoimmune diabetes. J. Cell. Biochem. 88, 216–222 (2003).
Zella, J. B., McCary, L. C. & DeLuca, H. F. Oral administration of 1,25-dihydroxyvtiamin D3 completely protects NOD mice from insulin-dependent diabetes mellitus. Arch. Biochem. Bioiphys. 417, 77–80 (2003).
Diabetes Epidemiology Research International Group. Geographic patterns of childhood insulin-dependent diabetes mellitus. Diabetes 37, 1113–1119 (1988).
Harris, S. S. Symposium: vitamin D insufficiency: a significant risk factor in chronic diseases and potential disease-specific biomarkers of vitamin D sufficiency. J. Nutr. 135, 323–325 (2005).
Zhu, Y., Mahon, B. D., Froicu, M. & Cantorna, M. T. Calcium and 1α,25-dihydroxyvitamin D3 target the TNF-α pathway to suppress experimental inflammatory bowel disease. Eur. J. Immunol. 35, 217–224 (2005).
Laverny, G. et al. Efficacy of a potent and safe vitamin D receptor agonist for the treatment of inflammatory bowel disease. Immunol. Lett. 131, 49–58 (2010).
Cantorna, M. T. Vitamin D and its role in immunology: multiple sclerosis, and inflammatory bowel disease. Prog. Biophys. Mol. Biol. 92, 60–64 (2006).
Kim, J. Effects of 1α,25-dihydroxyvitamin D3 on the MRL/MpJ-Fas/lpr model of systemic lupus erythematosus. Thesis, Univ. Wisconsin-Madison (2009).
Cutolo, M. Editorial. Vitamin D and autoimmune rheumatic diseases. Rheumatology 48, 210–212 (2009).
Cantorna, M. T., Hayes, C. E. & DeLuca, H. F. 1,25-Dihydroxycholecalciferol inhibits the progression of arthritis in murine models of human arthritis. J. Nutr. 128, 68–72 (1998).
Andjelkovic, Z. et al. Disease modifying and immunomodulatory effects of high dose 1α(OH)D3 in rheumatoid arthritis patients. Clin. Exp. Rheumatol. 17, 453–456 (1999).
Abrams, W. R. & Bauer, W. Treatment of rheumatoid arthritis with large doses of vitamin D. J. Am. Med. Assoc. 11, 1632–1639 (1938).
Wagner, L. C. Evaluation of arthritic cases treated with vitamin D. Ann. Int. Med. 19, 126–131 (1943).
Cantorna, M. T., Zhu, Y., Froicu, M. & Wittke, A. Vitamin D status, 1,25-.dihydroxyvitamin D3, and the immune system. Am. J. Clin. Nutr. 80, 1717S–1720S (2004).
Clark, S. A., Stumpf, W. E., Sar, M., DeLuca, H. F. & Tanaka, Y. Target cells for 1,25 dihydroxyvitamin D3 in the pancreas. Cell Tissue Res. 209, 515–520 (1980).
Colston, K., Colston, M. J. & Feldman, D. 1,25-Dihydroxyvitamin D3 and malignant melanoma: the presence of receptors and inhibition of cell growth in culture. Endocrinology 108, 1083–1086 (1981).
Rheem, D. S., Baylink, D. J., Olafsson, S., Jackson, C. S. & Walter, M. H. Prevention of colorectal cancer with vitamin D. Scand. J. Gastroenterol. 45, 775–784 (2010).
Giovannucci, E. The epidemiology of vitamin D and cancer incidence and mortality: a review (United States). Cancer Causes Control 16, 83–95 (2005).
Schwartz, G. G. Vitamin D and intervention trials in prostate cancer: from theory to therapy. Ann. Epidemiol. 19, 96–102 (2009).
Bertone-Johnson, E. R. Vitamin D and breast cancer. Ann. Epidemiol. 19, 462–466 (2009).
Grant, W. B. & Mohr, S. B. Ecological studies of ultraviolet B, vitamin D and cancer since 2000. Ann. Epidemiol. 19, 446–454 (2009).
Garland, C. F. et al. The role of vitamin D in cancer prevention. Am. J. Public Health 96, 252–261 (2006). One of many reviews suggesting a role of vitamin D in cancer prevention.
Masuda, S. & Jones, G. Promise of vitamin D analogues in the treatment of hyperproliferative conditions. Mol. Cancer Ther. 5, 797–808 (2006).
Ordonez-Moran, P. et al. Vitamin D and cancer: an update of in vitro and in vivo data. Front. Biosci. 10, 2723–2749 (2005).
Zinser, G. M., Suckow, M. & Welsh, J. Vitamin D receptor (VDR) ablation alters carcinogen-induced tumorigenesis in mammary gland, epidermis and lymphoid tissues. J. Steroid Biochem. Mol. Biol. 97, 153–164 (2005).
Deeb, K. K., Trump, D. L. & Johnson, C. S. Vitamin D signaling pathways in cancer: potential for anticancer therapeutics. Nature Rev. Cancer 7, 684–700 (2007).
Galsky, M. D. & Vogelzang, N. J. Docetaxel-based combination therapy for castration-resistant prostate cancer. Ann. Oncol. 29 Mar 2010 (doi:10.1093/annonc/mdq050).
Lappe, J. M., Travers-Gustafson, D., Davies, K. M., Recker, R. R. & Heaney, R. P. Vitamin D and calcium supplementation reduces cancer risk: results of a randomized trial. Am. J. Clin. Nutr. 85, 1586–1591 (2007).
Wactawski-Wende, J. et al. Calcium plus vitamin D supplementation and the risk of colorectal cancer. N. Engl. J. Med. 354, 684–696 (2006).
Chlebowski, R. T. et al. Calcium plus vitamin D supplementation and the risk of breast cancer. J. Natl Cancer Inst. 100, 1581–1591 (2007).
Chiang, K.-C. & Chen, T. C. Vitamin D for the prevention and treatment of pancreatic cancer. World J. Gastroenterol. 15, 3349–3354 (2009).
Bao, Y. et al. Predicted vitamin D status and pancreatic cancer risk in two prospective cohort studies. Br. J. Cancer 102, 1422–1427 (2010).
Edlich, R. F. et al. Scientific documentation of the relationship of vitamin D deficiency and the development of cancer. J. Environ. Pathol. Toxicol. Oncol. 28, 133–141 (2009).
Erber, E., Maskarinec, G., Lim, U. & Kolonel, L. N. Dietary vitamin D and risk of non-Hodgkin lymphoma: the multiethnic cohort. Br. J. Nutr. 103, 581–584 (2010).
Evans, T. R. J. et al. A phase II trial of the vitamin D analogue seocalcitol (EB1089) in patients with inoperable pancreatic cancer. Br. J. Cancer 86, 680–685 (2002).
Cunningham, D. et al. Alfacalcidol as a modulator of growth of low grade non-Hodgkin's lymphomas. BMJ 291, 1153–1155 (1985).
Raina, V., Cunningham, D., Gilchrist, N. & Soukop, M. Alfacalcidol is a nontoxic, effective treatment of follicular small-cleaved cell lymphoma. Br. J. Cancer 63, 463–465 (1991).
Dalhoff, K. et al. A phase II study of the vitamin D analogue seocalcitrol in patients with inoperable hepatocellular carcinoma. Br. J. Cancer 89, 252–257 (2003).
Binkley, N. et al. Assay variation confounds the diagnosis of hypovitaminosis D: a call for standardization. J. Clin. Endocrinol. Metab. 89, 3152–3157 (2004).
Carter, G. D., Carter, R., Jones, J. & Berry, J. How accurate are assays for 25-hydroxyvitamin D? Data from the International Vitamin D External Quality Assessment Scheme. Clin. Chem. 51, 1071–1074 (2005).
de Jong, M. & Maina, T. Of mice and humans: are they the same? Implications in cancer translational research. J. Nucl. Med. 51, 501–504 (2010).
Horváth, H. C. et al. The candidate oncogene CYP24A1: a potential biomarker for colorectal tumorigensis. J. Histochem. Cytochem. 58, 277–285 (2010).
Wang, Y., Becklund, B. R. & DeLuca, H. F. Identification of a highly specific and versatile vitamin D receptor antibody. Arch. Biochem. Biophys. 494, 166–177 (2010).
Chesney, R. W. Vitamin D and the magic mountain: the anti-infectious role of the vitamin. J. Ped. 156, 698–703 (2010).
Wang, T.-T. et al. Cutting edge: 1,25-Dihydroxyvitamin D3 is a direct inducer of antimicrobialpeptide gene expression. J. Immunol. 173, 2909–2912 (2004).
Li-Ng, M. et al. A randomized controlled trial of vitamin D3 supplementation for the prevention of symptomatic upper respiratory tract infections. Epidemiol. Infect. 137, 1396–1401 (2009).
Talat, N., Perry, S., Parsonnet, J., Dawood, G. & Hussain, R. Vitamin D deficiency and tuberculosis progression. Emerg. Infect. Dis. 16, 853–855 (2010).
Kramer, B. & Kanof, A. B. in The Vitamins Vol. 2 (eds Sebrell, W. H. Jr & Harris, R. S.) (Academic Press, New York, 1954).
Narang, N. K., Gupta, R. C., Jain, M. K. Role of vitamin D in pulmonary tuberculosis. J. Assoc. Physicians India 32, 185–188 (1984).
Jones, G. Pharmacokinetics of vitamin D toxicity. Am. J. Clin. Nutr. 99, 582S–586S (2008).
Vieth, R. Vitamin D supplementation, 25-hydroxyvitamin D concentrations, and safety. Am. J. Clin. Nutr. 69, 842–856 (1999).
Shephard, R. M. & DeLuca, H. F. Plasma concentrations of vitamin D3 and its metabolites in the rat as influenced by vitamin D3 or 25-hydroxyvitamin D3 intakes. Arch. Biochem. Biophys. 202, 43–53 (1980). A comprehensive paper showing vitamin D metabolite levels during vitamin D intoxication, suggesting that 1,25-(OH) 2 D 3 is not responsible.
DeLuca, H. F., Prahl, J. M. & Plum, L. A. 1,25-Dihydroxyvitamin D is not responsible for toxicity caused by vitamin D or 25-hydroxyvitamin, D. Arch. Biochem. Biophys. (in the press).
Eisman, J. A. & DeLuca, H. F. Intestinal 1,25-dihydroxyvitamin D3 binding protein: specificity of binding. Steroids 30, 245–257 (1977).
Adams, J. S. in Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism 2nd edn (ed. Favus, M. J.) 178–181 (Raven Press, New York, 1993)
Barbour, G. L., Coburn, J. W., Slatopolsky, E., Norman, A. W. & Horst, R. L. Hypercalcemia in an anephric patient with sarcoidosis: evidence for extrarenal generation of 1,25-dihydroxyvitamin D. N. Engl. J. Med. 305, 440–443 (1981). This paper shows that hypercalcaemia of sarcoidosis is caused by an extrarenal production of 1,25-(OH) 2 D 3 . This shows for the first time clear evidence of extrarenal expression of the 1α-hydroxylase in disease.
Hewison, M. & Adams, J. S. in Vitamin D 2nd edn (eds Feldman, D., Pike, J. W. & Glorieux, F. H.) 1379–1400 (Elsevier, San Diego, CA, 2005).
Kallas, M., Green, F., Hewison, M., White, C. & Kline, G. Rare causes of calcitriol mediated hypercalcemia: a case report and literature review. J. Clin. Endocrinol. Metab. 95, 3111–3117 (2010).
Shane, E. in Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism 2nd edn (ed. Favus, M. J.) 153–155 (Raven Press, New York, 1993)
Stewart, A. F. in Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism 2nd edn (ed. Favus, M. J.) 169–173 (Raven Press, New York, 1993)
Breslau, N. A., McGuire, J. L., Zerwekh, J. E. et al. Hypercalcemia associated with increased serum calcitriol levels in three patients with lymphoma. Ann. Intern. Med. 100, 1–7 (1984).
Tanaka, Y., DeLuca, H. F., Kobayashi, Y. & Ikekawa, N. 26,26,26,27,27,27-Hexafluoro-1,25-dihydroxyvitamin D3: a highly potent, long-lasting analog of 1,25-dihydroxyvitamin D3 . Arch. Biochem. Biophys. 229, 348–354 (1984).
Sinishtaj, S., Jeon, H. B., Dolan, P., Kensler, T. W. & Posner, G. H. Highly antiproliferative, low-calcemic, side-chain amide and hydroxamate analogs of the hormone 1α,25-dihydroxyvitamin D3 . Bioorg. Med. Chem. 14, 6341–6348 (2006).
Usera, A. R., Dolan, P., Kensler, T. W., Posner, G. H. Novel alkyl side chain sulfone 1α,25-dihydroxyvitamin D3 analogs: a comparison of in vitro antiproliferative activities and in vivo calcemic activities. Bioorg. Med. Chem. 17, 5627–5631 (2009).
Ordentlich, P. & Heyman, R. A. Nonsteroidal analogs in Vitamin D 2nd edn (eds Feldman, D., Glorieux, F. H. & Pike, J. W.) 1558–1567 (Academic Press, San Diego, 2005).
Plum, L. A. et al. Biologically active noncalcemic analogs of 1α,25-dihydroxyvitamin D with an abbreviated side chain containing no hydroxyl. Proc. Natl Acad. Sci. USA 101, 6900–6904 (2004).
Tocchini-Valentini, G., Rochel, N. Wurtz, J. M., Mitschler, A. & Moras, D. Crystal structures of the vitamin D receptor complexed to superagonist 20-epi ligands. Proc. Natl Acad. Sci. USA 98, 5491–5496 (2001).
Vanhooke, J. L., Benning, M. M., Bauer, C. B., Pike, J. W. & DeLuca, H. F. Molecular structure of the rat vitamin D receptor ligand binding domain complexed with 2-carbon-substituted vitamin D3 hormone analogues and a LXXLL-containing coactivator peptide. Biochemistry 43, 4101–4110 (2004).
Vanhooke, J. L., Tadi, B. P., Benning, M. M., Plum, L. A. & DeLuca, H. F. New analogs of 2-methylene-19-nor-(20S)-1,25-dihydroxyvitamin D3 with conformationally restricted side chains: valuation of biological activity and structural determination of VDR-bound conformations. Arch. Biochem. Biophys. 460, 161–165 (2007).
Bower, M. et al. Topical calcipotriol treatment in advanced breast cancer. Lancet 337, 701–702 (1991).
Gulliford, T. et al. A phase I study of the vitamin D analogue EB 1089 in patients with advanced breast and colorectal cancer. Br. J. Cancer 78, 6–13 (1998).
Lathers, D. M. R., Clark, J. I., Achille, N. J. & Young, M. R. I. Phase IB study of 25-hydroxyvitamin D3 treatment to diminish suppressor cells in head and neck cancer patients. Human Immunol. 62, 1281–1293 (2001).
Slapak, C. A., Desforges, J. F., Fogaren, T. & Miller, K. B. Treatment of acute myeloid leukemia in the elderly with low-dose cytarabine, hydroxyurea, and calcitriol. Am. J. Hematol. 41, 178–183 (1992).
Wieder, R. et al. Pharmacokinetics and safety of ILX23–7553, a non-calcemic-vitamin D3 analogue, in a phase I study of patients with advanced malignancies. Invest. New Drugs 21, 445–452 (2003).
Fakih, M. G. et al. A phase I pharmacokinetic and pharmacodynamic study of intravenous calcitriol in combination with oral gefitinib in patients with advanced solid tumors. Clin. Cancer Res. 13, 1216–1223 (2007).
Muindi, J. R. et al. A phase I and pharmacokinetics study of intravenous calcitriol in combination with oral dexamethasone and gefitinib in patients with advanced solid tumors. Cancer Chemother. Pharmacol. 65, 22–30 (2009).
Osborn, J. L. et al. Phase II trial of oral 1,25-dihydroxyvitamin D (calcitriol) in hormone refractory prostate cancer. Urol. Oncol. 1, 195–198 (1995).
Gross, C., Stamey, T., Hancock, S. & Feldman, D. Treatment of early recurrent prostate cancer with 1,25-dihydroxyvitamin D3 (calcitriol). J. Urol. 159, 2035–2039 (1998).
Liu, G. et al. Phase I trial of 1α-hydroxyvitamin D2 in patients with hormone refractory prostate cancer. Clin. Cancer Res. 8, 2820–2827 (2002).
Beer, T. M., Lemmon, D., Lowe, B. A. & Henner, W. D. High-dose weekly oral calcitriol in patients with a rising PA after prostatectomy or radiation for prostate carcinoma. Cancer 97, 1217–1224 (2003).
Liu, G. et al. Phase II study of 1α-hydroxyvitamin D2 in the treatment of advanced androgen-independent prostate cancer. Clin. Cancer Res. 9, 4077–4083 (2003).
Beer, T. M. et al. Weekly high-dose calcitriol and docetaxel in metastatic androgen-independent prostate cancer. J. Clin. Oncol. 21, 123–128 (2003).
Beer, T. M., Garzotto, M. & Katovic, N. M. High-dose calcitriol and carboplatin in metastatic androgen-independent prostate cancer. Am. J. Clin. Oncol. 27, 535–541 (2004).
Schwartz, G. G. et al. Phase I/II study of 19-nor-1α-25-dihydroxyvitamin D2 (paricalcitol) in advanced, androgen-insensitive prostate cancer. Clin. Cancer Res. 11, 8680–8685 (2005).
Tiffany, N. M., Ryan, C. W., Garzotto, M., Wersinger, E. M. & Beer, T. M. High dose pulse calcitriol, docetaxel and estramustine for androgen independent prostate cancer: a phase I/II study. J. Urol. 174, 888–892 (2005).
Trump, D. L., Potter, D. M., Muindi, J., Brufsky, A. & Johnson, C. S. Phase II trial of high-dose, intermittent calcitriol (1,25 dihydroxyvitamin D3) and dexamethasone in androgen-independent prostate cancer. Cancer 106, 2136–2142 (2006).
Beer, T. M. et al. Double-blinded randomized study of high-dose calcitriol plus docetaxel compared with placebo pus docetaxel in androgen-independent prostate cancer: a report from the ASCENT investigators. J. Clin. Oncol. 25, 669–674 (2007).
Wang, Y. & DeLuca, H. F. Is the vitamin D receptor found in muscle? Endocrinology (in the press).
Matusiak, D., Murillo, G., Carroll, R. E., Mehta, R. G. & Benya R. V. Expression of vitamin D receptor and 25-hydroxyvitamin D3-1α-hydroxylase in normal and malignant human colon. Cancer Epidemiol. Biomarkers Prev. 14, 2370–2376 (2005).
This work was supported by a fund from the Wisconsin Alumni Research Foundation.
Hector F. DeLuca is a founder of Deltanoid Pharmaceuticals, and Lori A. Plum is the Director of Research and Development at Deltanoid Pharmaceuticals, a company involved in the development of vitamin D analogues.
About this article
Cite this article
Plum, L., DeLuca, H. Vitamin D, disease and therapeutic opportunities. Nat Rev Drug Discov 9, 941–955 (2010). https://doi.org/10.1038/nrd3318
This article is cited by
Robust osteogenic efficacy of 2α-heteroarylalkyl vitamin D analogue AH-1 in VDR (R270L) hereditary vitamin D-dependent rickets model rats
Scientific Reports (2022)
Current Oncology Reports (2021)
Generation of novel genetically modified rats to reveal the molecular mechanisms of vitamin D actions
Scientific Reports (2020)
The synergistic effect between adult weight changes and CYP24A1 polymorphisms is associated with pre- and postmenopausal breast cancer risk
Breast Cancer Research and Treatment (2020)
Cell Biochemistry and Biophysics (2020)