100 YEARS OF VITAMIN D: Historical aspects of vitamin D.

Vitamin D has many physiological functions including upregulation of intestinal calcium and phosphate absorption, mobilization of bone resorption, renal reabsorption of calcium as well as actions on a variety of pleiotropic functions. It is believed that many of the hormonal effects of vitamin D involve a 1,25-dihydroxyvitamin D3-vitamin D receptor-mediated transcriptional mechanism involving binding to the cellular chromatin and regulating hundreds of genes in many tissues. This comprehensive historical review provides a unique perspective of the many steps of the discovery of vitamin D and its deficiency disease, rickets, stretching from 1650 until the present. The overview is divided into four distinct historical phases which cover the major developments in the field and in the process highlighting the: (a) first recognition of rickets or vitamin D deficiency; (b) discovery of the nutritional factor, vitamin D and its chemical structure; (c) elucidation of vitamin D metabolites including the hormonal form, 1,25-dihydroxyvitamin D3; (d) delineation of the vitamin D cellular machinery, functions and vitamin D-related diseases which focused on understanding the mechanism of action of vitamin D in its many target cells.

Introduction

The history of vitamin D is a rich and storied subject and is now over 350 years old. It began in the early 1600s with the first descriptions of the human deficiency disease: rickets in children and osteomalacia in adults. Of course, there were no precise medical details that distinguished it from other bone diseases, but treatises describing the symptoms and lithographs from that time showing bone deformities resembling rickets leave little doubt that it was vitamin D deficiency. It took another 250 years to define the cause of vitamin D deficiency in the 1900–1920 period when physicians and biochemists elucidated the role of sunlight and identified the chemical structure of the two main forms of the vitamin D molecule, vitamin D2 and vitamin D3.

Another 50 years elapsed before the metabolism of vitamin D was first described in 1967 and the active form of vitamin D, namely 1,25-dihydroxyvitamin D (1,25-(OH)2D), was discovered. The period of time since has witnessed the exciting realization that vitamin D has its own set of dedicated specialized machinery consisting of transport proteins, metabolic enzymes and vitamin D receptor (VDR) to mediate the actions of vitamin D, not only in bone but also in many other tissues around the body where it has a myriad of different physiological effects.

Before we get into the history of vitamin D, let us first remind the reader of the general aspects of its nomenclature, origins and principal functions. Vitamin D is a steroidal substance required by all vertebrates including humans to maintain blood calcium and phosphate within a narrow normal range and thereby support a healthy skeleton, muscle contraction, immune function and optimal cellular functions in many locations around the body (1). The name vitamin D is a term coined by nutritionists, and is not a chemical term, which is defined as ‘a substance with anti-rachitic properties that will cure rickets’.In human biology, vitamin D usually refers to two substances: vitamin D3 (usually known as cholecalciferol) of animal origin and vitamin D2 (referred to as ergocalciferol) of plant or fungal origin. These two forms have roughly equal potencies, similar metabolic patterns and identical effects in the body.

Because of the four phases of vitamin D history, this review is divided into four sections each summarizing one particular time period:

1650–1890: history of vitamin D deficiency (rickets)

1890–1930: history of the discovery of vitamin D and its structural elucidation

1930–1975: history of the discovery of vitamin D metabolites including 1,25-(OH)2D3

1975–present: history of the discovery of the vitamin D cellular machinery, functions and vitamin D-related human diseases.

Since the different facets of the history of vitamin D represent interesting topics and span many centuries, they have been reviewed by many previous historians, including the current author, and interested readers are invited to further access these because they focus on different aspects of the overall story (2, 3, 4, 5, 6, 7, 8).

1650–1890: history of vitamin D deficiency (rickets)

There is no doubt that rickets was prevalent in Europe long before it was recognized as a specific disease in the 15th century, but the earliest documentation of the word ‘rickets’ was in a domestic receipt book of an English family in 1632 and the earliest printed record of rickets as a disease causing death in the London Bill of Mortality in 1634 (reviewed by (2, 3, 4)). The term rickets is thought to have its origins in the verb in the Dorset dialect to ‘rucket,’ which means to breathe with difficulty. However, some claim the term rickets is derived from the Anglo-Saxon word ‘wrikken,’ meaning to twist. Rickets and osteomalacia were first clearly described by Daniel Whistler in the Netherlands (1645) as a condition in which the skeleton was poorly mineralized and deformed (9). Francis Glisson (1650) provided the first documented records with his book entitled De Rachitide first published in Latin in 1650 and then translated into English in 1671 (10). It features a lithograph of children with bowing of the legs and skeletal deformities which are the hallmarks of vitamin D deficiency. One of those Glisson lithographs was reproduced as a frontispiece in a landmark treatise on Rickets Including Osteomalacia and Tetany by AF Hess in 1929 (11). It is reproduced here as Fig. 1.

Figure 1

Lithograph from Glisson’s De Rachitide (1671) (10) also depicted as the frontispiece of Hess AF’s book (11) Rickets Including Osteomalacia and Tetany. Reproduced from the US National Library digital collection. Credit: Rickets, including osteomalacia and tetany / by Alfred F Hess.

A more recent definition of vitamin D deficiency has grown to include defective chondrocyte differentiation and lack of mineralization of the growth plate, but the common feature of vitamin D deficiency is insufficiently mineralized or calcified bone matrix (1, 12, 13). Rickets is characterized by a deformed and misshaped skeleton, particularly bending and bowing of the long bones and enlargement of the epiphyses of the joints of the rib cage, arms, legs and neck. Victims have painful movements of the rib cage and difficulty breathing. In China, medical texts refer to deformities of the rib cage in severe rickets as ‘chicken breast’ (5). Severe rickets is often accompanied by pneumonia. The loss of the important role of vitamin D in strengthening the immune system compounds this problem. Though rarely is rickets life-threatening, it certainly lowers the quality of life for the afflicted individual and leads to secondary problems. One of these secondary effects of rickets occurs in young women who had vitamin D deficiency in childhood causing deformities of the pelvis which result in difficulties in childbirth (14). Shorter (14) speculates that rickets in early life must have resulted in numerous deaths of women during their first delivery.

Vitamin D deficiency is partly the result of inadequate skin synthesis of vitamin D3 from 7-dehydrocholesterol compounded by a low dietary intake of vitamin D2 from plant or fungal sources or vitamin D3 from animal products. The advent of the Industrial Revolution in Western Europe heralded in massive air pollution in the form of smoke from mills and burning of fossil fuels. This dramatically reduced the amount of UV light reaching the ground. Since the workers needed for these new industrial jobs were required to move from their rural locations into dingy, poorly-lit cities, their exposure to UV light diminished and skin synthesis of vitamin D was reduced. Rickets resulted and was associated with lack of exposure to sufficient sunlight. Thus, the 18th and 19th centuries saw a higher increase in rickets in the industrialized cities of northern Europe. The Dickensian character Tiny Tim, of the novel A Christmas Carol, clearly represents a child with a deformed skeleton who must have been a common sight in the dark cities of the late 19th century (7). Rickets was particularly prevalent in the industrialized Britain of the 16th–20th centuries, and thus, it is no surprise that it was referred to in old texts as ‘the English disease’ (7, 15).

Despite the fact that rickets seemed to be associated with lack of exposure to sunlight, by the late 1700s, some, including Percival (16) in the UK, were advocating the use of cod liver oil for the treatment of rickets suggesting a nutritional aspect to vitamin D. In contrast, in the early 1800s, Sniadecki (17) in Poland was documenting the differential incidence in city-dwellers and rural-dwellers suggesting some environmental factor was involved. He speculated that sunlight or fresh air might be involved in the etiology of the disease. By the end of the 19th century, a rigorous debate roared on whether rickets was caused by the lack of some dietary substance or an environmental factor and how could these two points of view be reconciled.

1890–1930: history of the discovery of vitamin D and its structural elucidation

By the 1890s, some researchers such as Owen (18) and Palm (19), who clearly supported the environmental theory, produced evidence that there were big geographical differences in the incidence of rickets in different parts of the UK and northern and southern China. Palm, a medical missionary, went on to suggest that exposure of children to sunlight would cure rickets (19). Subsequently, researchers in Europe and the United States namely Buchholtz (1904), Raczynski (1913), Huldshinsky (1919), and later Chick (1922) and Hess & Weinstock (1924) performed experiments in which laboratory animals and children with rickets could be cured with sunlight or light from mercury arc lamps (7, 20, 21, 22, 23, 24). This clearly demonstrated that lack of exposure to UV light was one cause of rickets.

But the proponents of the theory that a dietary factor could also be involved continued with their experiments too. The early 20th century was a momentous period in nutritional research in which nutritionists showed that a diet of highly purified carbohydrates, protein, fat and salt is unable to fully support growth and life of experimental animals (25). By adding various ‘trace factors’, researchers were able to restore growth and a full range of physiological actions. The first of these trace factors was thiamin discovered by Funk (26) which cured neuritis in what Funk termed the ‘vital amine or vitamin theory.’ Thiamin was later renamed vitamin B1, but it was one of a number of vitamin substances that are defined as ‘trace compounds which are derived from the diet and are required in small amounts per day and perform an essential role critical to life.’ Vitamin D was identified as one of these substances playing a critical role in skeletal growth and calcium and phosphate homeostasis. However, strictly speaking, vitamin D has been misnamed since it can also be derived from exposure to UV light and is not required to be in the diet. In practise and for a variety of social and religious reasons, many populations around the world do not receive adequate UV light, especially during the winter months, so that a dietary intake is essential.

The discovery of the nutritional factor, later termed vitamin D by McCollum (27), came largely as the result of the work of a number of researchers: Mellanby, McCollum, Steenbock and Hart working independently. Sir Edward Mellanby (28) in the UK reasoned that rickets might be due to a dietary deficiency and managed to produce beagle dogs with severe rickets by feeding them oatmeal and then cured their rickets with cod liver oil. Since cod liver oil is a mixture of lipids and a rich source of vitamin A, it was not clear what the active ingredient might be. McCollum (29), working first at the U Wisconsin and then Johns-Hopkins, heated and bubbled oxygen through the cod liver oil to destroy the vitamin A and found that the product still cured rickets. Building on the new vitamin nomenclature, he termed the new substance vitamin D. But how was the field to reconcile the apparently unconnected findings that UV light and a nutritional substance termed vitamin D could both cure rickets? Harry Steenbock also working at the U Wisconsin-Madison performed the definitive experiment. Steenbock & Black experimented with the diets of goats and found that sunlight or UV irradiation of the animals or their diets resulted in rickets being cured in the goats (30). Steenbock traced the bioactive substance in irradiated food to the non-saponifiable fraction of lipids in the diet and showed that it cured rickets (31). Dietary vitamin D was born.

Subsequently, Steenbock was able to show that irradiated yeast contained significant amounts of vitamin D, later shown to be vitamin D2 and that the yeast could be irradiated and added to milk which formed the basis of the first food fortification with vitamin D (5). Though Steenbock and the University of Wisconsin filed a patent for milk fortification with vitamin D, the proceeds from this discovery were used to establish the Wisconsin Alumni Research Foundation (WARF) which was one of the prototypical organizations intended to allow universities to plough the benefits of their research into future research. WARF funded the research of a number of scientists inside and outside of the vitamin D field, included several Nobel laureates, with the proceeds of Steenbock’s patent. Furthermore, vitamin D fortification of a variety of foodstuffs (including milk, margarine, bread and even beer) has become a major nutritional tool in the fight to prevent rickets and osteomalacia around the world (5).

In the late 1920s, Windaus and colleagues (32) isolated the key anti-rachitic substance from a mixture of irradiated plant sterols and named it vitamin D1, although they did not identify its structure. Later, vitamin D1 was shown to be a mixture of vitamin D2 and tachysterol. A British group headed by Askew (33) successfully identified and determined the structure of the anti-rachitic, plant-derived sterol as vitamin D2 or ergocalciferol. Windaus’s group confirmed the structure of vitamin D2 (34) and also isolated and identified the animal-derived, anti-rachitic vitamin D3 or cholecalciferol and its skin precursor, 7-dehydrocholesterol (35). For his discovery of the structures of vitamin D3, 7-dehydrocholesterol and several other sterols, Adolf Windaus was awarded the 1928 Nobel Prize for Chemistry (Fig. 2).

Figure 2

Structures of vitamin D2 and D3. The two versions of vitamin D differ only in their side chains vitamin D2 possessing an additional C-22-23 double bond and a C-24 methyl group. The modifications make little significant difference in their metabolism or biological actions.

1930–1975: history of the discovery of vitamin D metabolites including 1,25-(OH)2D3

Chemically synthesized vitamin D2 and vitamin D3 have been available since the 1930s and paved the way for the study of their biological functions and metabolism. The physiological roles of vitamin D are primarily its roles in calcium and phosphate homeostasis (1) and include:

stimulation of intestinal calcium and phosphate absorption;

mobilization of calcium from bone;

renal reabsorption of calcium.

All three of these functions serve to raise blood calcium and phosphate and ensure that these ions are available to ensure health and prevent rickets. Elucidating the details of these physiological functions became the main foci during the 1930–1960 time period, and research revealed that vitamin D was intimately connected to the roles of other calcium and phosphate-related hormones including parathyroid hormone (PTH) and calcitonin. Details of these connections are beyond the scope of this chapter and are described in reviews (1) and in other articles in this special series.

In the 1960s, there was considerable debate over whether the functions of vitamin D were carried out by vitamin D itself or its possible metabolites. Consequently, intense effort was put into studying the metabolism of vitamin D by using chemically synthesized radioactive versions of vitamin D2 and vitamin D3. The pioneer in this area was Egon Kodicek at the Dunn Nutritional Laboratories, U Cambridge UK. After 10 years of work, Kodicek (36) concluded that vitamin D was active without being metabolized. In retrospect, the radioactive vitamin D that his group were using was insufficiently labeled to detect its metabolites. However, Hector DeLuca, again at the U Wisconsin-Madison, and the final graduate student of Harry Steenbock, synthesized radioactive vitamin D3 with much higher specific activity (37) and was able to demonstrate metabolism to more polar metabolites, the principal one being 25-hydroxyvitamin D3 (25-OH-D3) (38) made in the liver and the first identified natural vitamin D metabolite.

25-OH-D3 proved to be more potent biologically than vitamin D3 and was present in the bloodstream at a higher concentration (38). We now identify 25-OH-D3 as the principal circulating form of vitamin D. But that is not the extent of vitamin D metabolism. Several other groups then entered or re-entered the picture, including Dr Kodicek’s, as well as that of one of Dr DeLuca’s former graduate students Dr Anthony Norman. Among the other polar products of vitamin D3 was a metabolite even more potent than 25-OH-D3, namely 1α,25-dihydroxyvitamin D3 (1,25-(OH)2D3) which is now universally accepted as the hormonal form of vitamin D3. Several groups including Dr Kodicek’s, (39) Dr Norman’s (40) and Dr DeLuca’s (41) were credited with playing a role in the discovery and/or in the structural identification of 1,25-(OH)2D3. Kodicek’s group administered a mixture of radioactive [4-14C] and [1-3H]vitamin D3 preparations and showed that one polar metabolite lost its tritium atom during metabolism that aided in its identification as a 1-hydroxylated compound (39). Furthermore, the Cambridge group also showed that the hormone was biologically generated in the kidney (39, 42). Dr Norman’s group showed that the new metabolite was associated with the chromatin of intestinal mucosal cells and had greater biological activity than even 25-OH-D3 (40). Holick et al. (41) showed that the additional 1-hydroxyl group was in the 1α orientation and supported their identification of the metabolite as 1α,25-(OH)2D3 with mass spectrometry. Chemically synthesized 1,25-(OH)2D3 was first produced by Semmler et al. (43) and made commercially by a group headed by Dr Milan Uskokovic at Hoffmann-La Roche in the early 1970s and is known clinically by the name calcitriol (44).

The identification of the principal metabolites, 25-OH-D3 and 1,25-(OH)2D3, spawned a frenzy of research activity in the vitamin D area and the discovery of a number of other vitamin D metabolites (1). Among these are the principal metabolites of vitamin D2 including 25-OH-D2 (45), 1,25-(OH)2D2 (46) and 24,25-(OH)2D2 (47). Also identified in that mixture of metabolites arising from radioactive vitamin D3 were several compounds that are presumed to be inactive catabolites including, 24,25-(OH)2D3, 25,26-(OH)2D3, 25-OH-D3-26,23-lactone, 1,24,25-(OH)3D3 and calcitroic acid (48, 49, 50, 51, 52, 53). A summary of the main metabolites of both vitamin D3 and vitamin D2 along with their tissue source, biosynthetic enzyme, details of first reporting and biological role is presented in Table 1 and depicted in a metabolic pathway diagram (Fig. 3).

Table 1

History of the discovery of the major metabolites of vitamins D2 and D3.

Metabolite	Tissue source	Biosynthetic enzyme	Biological role	Discovery
Vitamin D3 metabolites
25-OH-D3	Liver	25-Hydroxylase (CYP2R1)	Main circulating metabolite	Blunt et al. 1968 (38)
1,25-(OH)2D3	Kidney (major)Extra-renal sites	1α-Hydroxylase (CYP27B1)	Active hormonal form	Lawson et al. 1969 (39)Myrtle et al. 1970 (40)Holick et al. 1971 (41)
24,25-(OH)2D3	Kidney (major) Extra-renal sites	24-Hydroxylase (CYP24A1)	Principal catabolite	Suda et al. 1970a (48)Holick et al. 1972 (49)
25,26-(OH)2D3	Unknown	26-Hydroxylase (?)	Catabolite	Suda et al. 1970b (50)
25-OH-D3-26,23-lactone	Kidney (major)Extra-renal sites	24-Hydroxylase (CYP24A1)	Presumed catabolite	Wichmann et al. 1979 (51)
1,24,25-(OH)3D3	Kidney (major)Extra-renal sites	24-Hydroxylase (CYP24A1)	Unknown possible catabolite	Holick et al. 1974 (52)
Calcitroic acid	Kidney (major)Extra-renal sites	24-Hydroxylase (CYP24A1)	Excretory form	Esvelt et al. 1981 (53)
Calcioic acid	Kidney (major)	24-Hydroxylase (CYP24A1)	Excretory form	Kaufmann et al. 2019 (76)
4α,25-(OH)2D3 4β,25-(OH)2D3	Liver	General cytochrome P450 (CYP3A4)	Excretory form	Wang et al. 2013 (77)
Vitamin D2 metabolites
25-OH-D2	Liver	25-Hydroxylase (CYP2R1)	Main circulating metabolite	Suda et al. 1969 (45)
1,25-(OH)2D2	Kidney (major)	1α-Hydroxylase (CYP27B1)	Active hormonal form	Jones et al. 1975 (46)
24,25-(OH)2D2	Kidney (major)	24-Hydroxylase (CYP24A1)	Principal catabolite	Jones et al. 1980 (47)
1,24,25-(OH)3D2	Kidney (major)	24-Hydroxylase (CYP24A1)	Presumed catabolite	Reddy et al. 1986 (78)

Figure 3

Metabolism and mechanism of action of vitamin D3. Skin-synthesized or dietary vitamin D3 is converted via a two-step hydroxylation process into the active hormonal form 1,25-(OH)2D3. The hormone binds to the vitamin D receptor (VDR) and regulates serum calcium (sCa2+) and serum phosphate (sPO4) levels ensuring sufficient minerals for normal cellular activity around the body including bone. Insufficient vitamin D results in insufficient 1,25-(OH)2D3 and vitamin deficiency rickets. Circled in red are the proteins in the vitamin D-specific machinery that when mutated also result in some type of rickets. Circled in blue is the enzyme CYP24A1 that when mutated results in elevated 1,25-(OH)2D3 and hypercalcemia and/or kidney stones.

1975–present: history of the discovery of the vitamin D cellular machinery, functions and vitamin D-related human diseases

The discovery of the active forms of vitamin D heralded in a search for

the signal transduction mechanisms to explain how 1,25-(OH)2D3 was able to produce its various biological effects;

identification of the enzymes responsible for the synthesis and catabolism of 1,25-(OH)2D3;

a clear understanding of the regulation of the vitamin D endocrine system.

These studies began almost as soon as metabolism was recognized in the late 1960s when Mark Haussler, in AW Norman’s laboratory, demonstrated that vitamin D metabolites were associated with the chromatin (54). Clear evidence of the protein that is now termed the vitamin D receptor (VDR) was produced by Haussler’s lab (55). The VDR protein from various species was later purified and its gene was cloned by Haussler’s group (56, 57). Study of the pure protein has led to a determination of its crystal structure (58). Parallel to these investigations of the VDR have come other studies on how it works both at the whole-body level in calcium and phosphate homeostasis and other pleiotropic functions (1, 8, 59) and at the cellular level in a classic steroid hormone super-family like process through a transcriptional mechanism (60). Over the past 30 years, Mark Haussler, Wes Pike and colleagues (61) have demonstrated that 1,25-(OH)2D3 works through a VDR-mediated mechanism that involves many coactivators and repressors to directly interact with and regulate hundreds of genes around the body. Other researchers, most notably Anthony Norman (62), have proposed that some of the actions of vitamin D occur through rapid non-genomic signaling pathways, possibly involving a plasma membrane VDR but this protein has never been fully characterized at the molecular level. Nevertheless, there remains some uncertainty that all vitamin D ligands and analogs produce their effects through a genomic VDR mechanism (63).

The history of two other components of the vitamin D machinery deserves some mention.

These are vitamin D-binding globulin (64, 65) and the cytochromes P450-containing enzymes that metabolize vitamin D into its many metabolites (66). Being a fat-soluble vitamin, vitamin D requires a protein to transport it around the body and the vitamin D-binding globulin (usually abbreviated as DBP) performs this function. DBP was first identified as Gc (group-specific component) in the 1970s, and its properties have been reviewed extensively by the father figure of the field Roger Bouillon, U Leuven, Belgium (65). DBP has a high affinity for most of the main metabolites of vitamin D, most notably 25-OH-D, and because of this, 25-OH-D is the main circulating form in the blood.

The cytochrome P450-containing enzymes (CYPs) responsible for vitamin D metabolism were first studied in the early 1970s in tissue extracts of liver and kidney (67, 68, 69) and then in tissue culture and given names based upon their hydroxylation activity: 25-hydroxylase, 1α-hydroxylase and 24-hydroxylase. In the early 1990–2005 period, all three enzymes were purified, cloned and expressed in cell culture systems, principally by Canadian group of St-Arnaud (70) as well as the Japanese groups of Kato S (71), Okuda (72) and Sakaki (73, 74) as well as Russell’s group at the U Texas (75). The three enzymes are now known as CYP2R1, CYP27B1 and CYP24A1. A review of the CYP field and how these enzymes operate and how they are regulated is provided (66). A summary of the history of the signal transduction protein machinery for vitamin D including VDR, DBP and the various CYPs is provided in Table 2.

Table 2

History of the main protein components of the specific* vitamin D signal transduction machinery.

Protein	Abbreviation	Tissue location or source	Biological function	Discovery	Gene cloning
Vitamin D-binding globulin	DBP	Liver	Transport of vitamin D and its metabolites	Daiger et al. 1975 (64)	Cooke et al. 1991 (79)
Vitamin D receptor	VDR	Most tissues except liver	Regulation of vitamin D-dependent genes	Haussler 1969 (80)Brumbaugh et al. 1975 (55)	McDonnell et al. 1987 (56)
25-Hydroxylase	CYP2R1	Liver	25-hydroxylation of vitamins D2 and D3	Cheng et al. 2003 (81)	Cheng et al. 2004 (75)
1α-Hydroxylase	CYP27B1	Kidney (major)Extra-renal sites	1α-hydroxylation of 25-OH-D2 & 25-OH-D3	Fraser et al. 1970 (42)	St-Arnaud et al. 1997 (70)Takeyama et al. 1997 (71)
24-Hydroxylase	CYP24A1	Kidney (major)Extra-renal sites	24-hydroxylation of (& 23- & 26-hydroxylation)25-OH-D2 & 25-OH-D3 Complete catabolism of vitamin D	Knutson et al. 1972 (66)	Ohyama & Okuda 1991 (72)

Other cellular proteins play a general role in vitamin D metabolism and action, for example, CYP3A4 but this degrades many other molecules and drugs.

*The specific vitamin D signal transduction machinery is specialized to transport, activate, mediate the biological effects of and catabolize vitamin D.

No review of the recent history of vitamin D would be complete without an overview of how defects in vitamin D metabolism result in human disease. It is now evident that vitamin D deficiency and rickets are caused by several genetic and acquired errors in vitamin D metabolism which involve any of the major protein components of the vitamin D machinery described above. These are compiled into Table 3 where we document the disease name, the component of the vitamin D machinery affected, as well as the publication first describing it. Besides diseases involving too little 1,25-(OH)2D3 and resulting in rickets, diseases involving too much 1,25-(OH)2D3 which cause hypercalcemia are also included in Table 3. Most of these diseases involving a shortage of 1,25-(OH)2D3 are now treated with vitamin D analogs which were developed from knowledge of the metabolism and biological actions of vitamin D. Currently approved and marketed vitamin D analogs are listed in Table 4 along with their original publications.

Table 3

History of the main vitamin D-related genetic and acquired human diseases and animal models generated to study them.

Disease	Cause	Initial report	Animal model equivalent	Generated by
Vitamin D deficiency rickets	Lack of dietary vitamin DLack of skin synthesis of D	F Glisson 1671 (10)	Beagle dog on oatmeal dietLactating goat model	Mellanby 1919 (28)Steenbock & Black 1924 (30)
Vitamin D dependency rickets type 1A	Genetic defect in CYP27B1	Fraser et al. 1972 (82)	CYP27B1 null mouse	Kato 1999 (83)Panda et al. 2001 (84)St-Arnaud et al. 2003 (85)
Vitamin D dependency rickets type 1B	Genetic defect in CYP2R1	Cheng et al. 2004 (75)	CYP2R1 null mouse	Zhu et al. 2013 (86)
Vitamin D dependency rickets type 2	Genetic defect in VDR	Rosen et al. 1979 (87)Eil et al. 1981 (88)	VDR null mouse	Yoshizawa et al. 1997 (89)Li et al. 1998 (90)
Idiopathic infantile hypercalcemia	Genetic defect in CYP24A1	Lightwood 1953 (91)Schlingmann et al. 2011 (92)	CYP24A1 null mouse	St-Arnaud et al. 2000 (93)
Chronic kidney disease	Loss of Kidney CYP27B1 enzyme activity	DeLuca & Avioli 1970 (94)Brickman et al. 1974 (95)	Dog nephrectomy models	Rutherford et al. 1977 (96)

Table 4

History of the commercially approved vitamin D drugs (vitamin D analogs) used to treat rickets and related diseases.

Vitamin D analog	Drug name	Marketed by	Field of use*	Initial report	Comments
25-OH-D3	CalderolRayaldee	OrganonOPKO Renal	Vitamin deficiencyChronic kidney disease	Blunt & DeLuca 1969 (97)	First vitamin D metaboliteLicensed by Upjohn, Kalamazoo
1,25-(OH)2D3	CalcijexGeneric	Roche	Vitamin D dependency type 1AChronic kidney disease	Semmler et al. 1972 (43)	First vitamin D active analog
1α-OH-D3	One-alphaAlfacalcidiol	Leo Pharma	Vitamin D deficiencyChronic kiidney disease	Holick et al. 1973 (98)Barton et al. 1973 (99)	1-hydroxylated prodrug not requiring activation by kidney
1α-OH-D2	HectorolDoxercalciferol	Genzyme/SanofiSandoz	Chronic kidney disease	Lam et al. 1974 (100)	1-hydroxylated prodrug not requiring activation by kidney
19-nor-1,25-(OH)2D2	Paricalcitol	Abbott	Chronic kidney disease	Takahashi F et al. 1997 (101)	Active ‘low-calcemic’ vitamin D analog
Calcipotriol	Daivonex	Leo Pharma	Psoriasis	Calverley 1987 (102)	Topical rapidly metabolized side-chain modified vitamin D analog

*Many of the vitamin D drugs used in chronic kdney disease stages 3–-4 and beyond are used to suppress secondary hyperparathyroidism, as well as having a moderate serum calcium-raising activity.

Conclusions

The history of vitamin D is indeed a rich subject which has already stretched over 350 years and involved the four phases described in this review. While the chemical entity vitamin D remained unknown for all but 100 of those years, the significant medical consequences of vitamin D deficiency were evident for the whole of that time. Many physicians, nutritionists, biochemists, chemists and molecular biologists have worked to elucidate our current knowledge of the nature of vitamin D in addition to its metabolism, mechanism of action and biological activities. That knowledge has paid dividends by providing new therapies for the treatment of deficiency and excess vitamin D action. The field of vitamin D research is arguably one of the highlights of modern medicine.

Declaration of interest

The author declares that there is no conflict of interest that could be perceived as prejudicing the impartiality of this review.

Funding

This work did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.