Review Article

Indian J Med Res 127, March 2008, pp 256-262

The physiology of vitamin D : Current concepts

N. Kochupillai

M.S. Ramaiah Medical College & Hospitals, Bangalore , India

Received January 7, 2008

The vitamin D endocrine system, besides playing pivotal roles in calcium homeostasis & bone mineral
metabolism, is now recognized to subserve a wide range of fundamental biological functions in cell
differentiation, inhibition of cell growth as well as immuno modulation. Vitamin D is a prohormone
which is converted into its active hormonal form 1, 25 (OH) D2 D, 1, 25 (OH) D2 D activates its cellular
receptor (VDR) which activate target genes to engender its biological actions. This review provides a
summary of recent understanding of the complex actions of the vitamin D hormone 1, 25 (OH)2 D
α hydroxylation in the proximal tubular cells of kidneys. Emerging evidence
which is a final product of 1α
also indicates both 1, 25 (OH)2 D3 independent as well as depended action of vitamin D receptor (VDR).
Thus, the vitamin D system action may involve more than one single receptor and legand. The presence
α hydroxylase in many target cells other than proximal renal tubular cells indicates autocrine and
of 1α
paracrine functions for 1, 25 (OH)2 D3 in the control of cell proliferation and differentiation. Vitamin
D and related molecules belong to a elaborate endocrine system that acts on target genomic receptors
in several organ systems to control cell proliferation and differentiation.

Key words Bone mineral metabolism - calcium - vitamin D - vitamin D receptor

“Calcium supplementation, alone or in combination elaborated in human `skin organ’ nudged by the
with vitamin D, is effective in the preventive treatment primordial power of the sun. Known traditionally as anti
of osteoporotic fracture”. ricketic factor or sunshine vitamin, presently it is no more
identified a vitamin, but rather as a steroid hormone that
The above front page promotion in a recent issue regulates an astonishingly complex system of genomic
of the Lancet1 underscore the continuing importance of functions that are relevant to such diverse and
vitamin D supplements in global bone-mineral fundamental bio-activities as inhibition of cell growth
metabolic health promotion. The authors of the meta- and promotion of cell differentiation, immune regulation
analysis recommended 1200 mg calcium and 800 IU and prevention of neoplastic transformation!
of vitamin D daily to people above 50 yr to prevent
bone loss and fractures1. In this review some current concepts have been
summarized in the evolving body of knowledge on
Currently vitamin D can be called the ‘sunlight genomic action of 1, 25 (OH)2 D, (the hormone) and
hormone’ on the basis of the emerging knowledge of its also on the impact of its ‘deficit’ on the clinical biology
all important role as a key regulatory substance that is of human bone-mineral health in our subcontinent.
256
 KOCHUPILLAI: PHYSIOLOGY OF VITAMIN D 257

Molecular evolution & action of vitamin D hormone (OH)2D3 synthesis and degradation are under control
of local factors like cytokines and growth factors5.
The ultraviolet (UV) spectrum of sunlight (wave
length 290-310 nm) impinges on human skin and The strong bio-efficacy of 1, 25 (OH) 2D 3 is
facilitates the conversion of 7-dehydrocholesterol controlled by countervailing its biological and clinical
present in the subcutaneous fat to pro-vitamin D, which action by an equally powerful steroidal hormone 24,
undergo thermal isomerization to vitamin D3 and 25 (OH)2 D3. 24 hydroxylation of vitamin D is brought
vitamin D2. Vitamin D3 and D2 are not naturally about by the enzyme 24 hydroxylase, whose gene
present in the food consumed by the vast majority of expression is enhanced by increasing PO4 level and
people of the Indian sub-continent. Besides, the decreasing PTH levels6. Thus the 24 hydroxylase gene
pigmented skin bestowed on us by solar energy to is regulated in a reciprocal manner to the gene
protect us from its cancerous insults, simultaneously expression of 1 α hydroxylase7.
deprive us of our dermal ability to synthesize vitamin
D with the help of the same celestial power. Vitamin D transport

Liver, kidney and vitamin D Vitamin D is poorly soluble in aqueous media and
highly soluble in lipids. Therefore it is transported in
Hydroxylation of 7, 8 dehydrocholesterol to 25(OH) blood with the help of a binding carrier protein called
D3 in the liver and subsequently to 1, 25 (OH)2 D3 in the vitamin D binding protein (DBP). DBP binds vitamin
proximal tubular cells of the kidneys, and several other D related molecules with the following sequence of
vitamin D responsive organ systems are well known affinity: 25 (OH) D = 24, 25(OH)2 D> 1,25(OH)2D >
facts of vitamin D physiology. 1 α-hydroxylase enzyme Vitamin D8. Plasma concentration of DBP is 20 times
activity is tightly regulated in view of the important higher than the total amount of vitamin D metabolites
biological role of 1, 25 (OH) 2 D 3 in calcium and 99 per cent of them are protein bound. Protein bound
homeostasis. Thus detary calcium (Ca++) regulates the vitamin D metabolites have limited access to target cells
enzyme directly through changes in serum calcium and and hence increased half-life in circulation. The
indirectly by altering parathyroid hormone (PTH) resultant protection from exposure to cell metabolic
levels. The stimulation of 1 α-hydroxylase by process, makes vitamin D less susceptible to hepatic
hypocalcaemia is markedly blunted by metabolism and exertion through biliary channels.
parathyroidectomy. However 1 α-hydroxylase activity Thus, vitamin D and metabolities have high half life in
as well as its mRNA activity can be altered by direct circulation. Only free fractions of vitamin D are
action of calcium in cell lines of human renal proximal metabolized and tissue availability of vitamin D is
tubules 2 . Besides, PTH, stimulated by calcium determined by the free fraction like most other
deficiency, also stimulateS 1α-hydroxylase as well as hormones. Thus DBP protects the tissues from toxic
its mRNA in proximal renal tubular cells. However PTH levels of vitamin D. Therefore when DBP concentration
stimulation of 1 α-hydroxylase mRNA has been shown is reduced, as happens in chronic liver diseases,
to be mediated by CAMP3, which stimulateS 1 α- nephrotic syndrome and malnutrition, the susceptibility
hydroxylase gene transcription . to vitamin D intoxication is high. The reverse is true in
Dietary PO4 restriction also has been shown to conditions like pregnancy and oestrogene therapy,
stimulate renal 1 α-hydroxylase activity as well as its where the DPB concentrations increase .
messenger (mRNA). This action of PO4 is independent Free 1, 25 (OH)2 D concentration remains constant
of PTH and is believed to be through a systemic even as DBP levels change as a result of the tight self-
hormone which is yet to be identified. However, it is regulation of vitamin D metabolism. DBP linked vitamin
conjuctured that it may be one of the several newly D is actively transported by receptor mediated uptake in
discovered phosphaturic factors known collectively as the brush border of the renal proximal convoluted tubular
phosphotonins. Phosphotonins are currently thought to cells and not by diffusion through its baso-lateral surface9.
be regulators of circulating 1, 25 (OH)2D3, through their Because of this, DBP deficient rats do not face vitamin
action on 1 α-hydroxylase gene4. D intoxication. Nor do DPB deficient rats face vitamin
In organs and tissues other than kidney where 1 α D deficiency because DBP independent uptake of vitamin
hydroxylase activity related 1, 25 (OH)2D3 production D occurs through endocytosis – a megalin facilitated
is shown to occur, it acts locally in autocrine or process. (Megalin is a part of a set of complex proteins
paracrine fashion. In such extra-renal organs 1,25 that facilitate endocytosis.
258 INDIAN J MED RES, MARCH 2008

Inside the renal tubular cells, DBP is degraded and membrane-lipid turnover, prostaglandin production and
25 (OH) D is released for metabolism by 1 α or 24 protease activity that lead to bone matrix modification
hydroxylases. There are many intracellular D binding and calcification 11. At least two distinct types of
proteins (DBP) which bind vitamin D and regulate their receptors are presumably involved in these actions,
intracellular metabolism8. IDBPs are homoogues of heat known as 1, 25 D3 MARRS (membrane associated rapid
shock proteins (HSP) that bind both 25(OH) D response steroid binding proteins) isolated from chick
compound, as well as oestrogens, to serve diverse roles. intestinal basolateral membrane, which is a thiol
Overexpression of IDBP-3 in cells expressing the dependent oxo-reductase ERp57. VDR is also thought
megalin increases the movement of 25 (OH) D into the to play an important role in engendering to rapid action
mitochondria for hydroxylation. Indeed, IDBP-3 of 1, 25 (OH)2 D312.
interacts directly with 1 α-hydroxylase. On the other
Regulation of VDR-1, 25 (OH)2D3 action
hand, overexpression of IDBP-1 enhances the
movement of 1 α-hydroxylase to VDR. Megalin has 1,25 (OH) 2D3 action is determined by the net
also been shown to bind the VDR to co-activate SKI balance between the rate of uptake of the ligand into
interacting protein (SKIP), providing another means of the cell and rate of its inactivation within the cell.
regulating vitamin D action. Experiments show that intracellular ligand (vitamin D)
inactivation plays critical role in the in situ control of
Megalin levels are increased by 1, 25 (OH)2 D3,
response to vitamin D. Also, the actual content (Cone)
providing a feed–forward mechanism for 1, 25 (OH)2
of (IDBP3) may modulate ligand-VDR association -
D3 production. Partial nephrectomy may lead to gradual
disassociation rates and therefore ligand depended VDR
fall in megalin expression in the remnant kidney,
activation in a cell specific manner depending on the
beginning within two weeks – followed later by increase
relative concentrations of the reactants.
in 1 α-hydroxylase in mRNA levels. This compensates
for reduced megalin levels and decreased synthetic VDR gene in chromosome 12 is present in allelic
capacity due to loss of renal mass7. This fact justifies variants13. Substantial variations of the polymorphic
the role of vitamin D supplementation in patients with allele occur in different races and ethnic groups. Their
early renal failure. expression associates with decreased bone density,
propensity to hyperparathyroidism, resistance to
1, 25 (OH)2 D3 action
vitamin D 14 therapy, susceptibility to infections,
Genomic action of vitamin D: VDR is a member autoimmune disorders and cancers. Therefore,
of the superfamily of nuclear receptors for steroid systematic assessment of VDR-gene polymorphism in
hormones, which can be categorized as a ligand population groups, should find clinical application in
activated transcription factor9. Details of the macro- disease prevention as well as in predicting the response
molecular interactions between genomic elements to vitamin D therapy.
and ligands that bring about transcription of vitamin
Post-translational modification of VDR
D response genes are not relevant to the present
context. Suffice it to realize the complex and subtle Ligand binding to VDR promote serine
nature of the inter- and intra-macromolecular phosphorylation of the receptor. VDR phosphorylates in
interactions that form the basis for the genomic action different loci. Phosphorylation of different loci are
of vitamin D and related expression of vitamin D mediated by various kinases including casein kinase II,
responsive genes. (at serine 208), PKC (at serine 51) and PKA with diverse
effects on the transcriptional activity. Nuclear action of
Non genomic action of vitamin D: There exist rapid-
VDR could also be modulated by other hormone systems
response non-genomic actions of vitamin D, which are
acting at cell surface to activate protein kinase cascades
mediated through cell surface receptors. Vitamin D
as demonstrated by inhibition of osteocalcium gene
induction of phosphoinositide metabolism shift the
expression through 1,25 (OH)2D3 1,25 (OH)2D3 also can
cytosolic calcium levels, cyclic GMP levels, Mitrogen-
cause rapid and sustained activation of PKC on bone cells
activated protein (MAP) kinase levels, protein kinase
that result in specific activation or inhibition of VDR15.
C (PKC) levels, opening of chloride channel, etc.10,
which are examples of such rapid action of vitamin D Post-translational VDR modification is induced by
without genomic involvement. In chondrocytes, such substances from uremic plasma ultrafiltrate that reacts
rapid action of vitamin D results in an increase in covalently with VDR at or near the DNA binding
 KOCHUPILLAI: PHYSIOLOGY OF VITAMIN D 259

domain and thus disrupting VDR-RXR binding of DNA. enterocyte plasma membrane that increases the fluidity
Kidney diseases related vitamin D resistance may be and PO4 uptake16.
related to the above phenomenon.
Skeleton: Vitamin D is essential for the development
Vitamin D endocrine system: Role of 1, 25 (OH)2D3 and maintenance of mineralized skeleton. However,
in calcium homeostasis administration of a rescue diet (high Ca, high P & high
lactose diet) can make vitamin D non-essential for the
The vitamin D endocrine system helps maintain
maintenance of mineralized skeleton. So also in type II
extracellular Ca++ levels through its action in kidneys, vitamin D deficient rickets, abnormalities of bone
bones, parathyroids and intestine. 1, 25 (OH) 2D 3 mineralization were completely resolved by calcium
produced in the kidney (proximal tubules) induces infusion17. However, only a combination of high calcium
intestinal calcium absorption, controls bone- 1,25(OH)2D3 could normalize chondrolyte growth.
remodelling and suppresses PTH function (hormone
production and cell growth)11. These effects of vitamin Growth plate development requires co-ordinated
D hormone help attain calcium homeostasis. calcium and 1, 25 (OH)2D3 actions and VDR, whereas
optimal osteoblastic bone formation and osteoclastic
Bioactions of vitamin D bone resorption demand both 1,25(OH)2D3 and VDR.
Iintestine: 1, 25 (OH)2D3 enhances the efficacy of However, chonodrocyte growth and development of
small intestine to absorb calcium and phosphorus. Both growth plate are both dependent on 1, 25 (OH) 2D3.
1, 25 (OH)2 D3 and VDR are required for optimal Moreover it has been demonstrated that the 1, 25(OH)
intestinal absorption of calcium. 1, 25 (OH)2D3 induces D 3 VDR system is critical in PTH induced
active cellular calcium uptake and transport osteoclastogenesis.
mechanisms. Calcium uptake requires epithelial 1,25(OH) 2 D 3 regulates osteoclastogenesis in
calcium channel TRPV6 and to a lesser extent epithelial reciprocal regulation of receptor activation of NF-kB
calcium channel TRPV5 calbindin D transport calcium (RANK) ligand (RANKL) and osteoproteregin(OPG).
across the cell and plasma membrane Ca+channels, 1,25(OH) 2 D 3- VDR increased the expression of
prealbumin and NA+, Ca++ exchanger mediate the final RANKL on the surface of osteoblasts. RANK
delivery of Calcium to the blood stream12. interactions with its receptor RANKL promotes
Initial calcium uptake is the rate limiting step in maturation of osteoclast progenitor cells and mature
intestinal Ca++ absorption, which is highly dependent osteoclasts, the bone resorbing cells. 1,25(OH)2 D3-
on vitamin D12. The expression of TRPV5 and TRPV6 VDR complex also represses the expression of OPG, a
channels is reduced in the VDR null mice. In contrast, decoy receptor that binds RANKL and prevents RANK
the messenger RNA level of both channels are mediated osteoclastogenesis.
upregulated on calcitrol supplementation in wild type Interactions between osteoblasts and osteoclasts
mice. The higher potency of calcitriol compared with integrate bone remodelling. The binding of RANKL to
the analogue 19-nor-1,25 (OH)2D2 in upregulating the RANK induces a signaling cascade that results in
expression of the channels could account for the differentiation of maturation of osteoclasts. 1.25(OH)2
reduced calcaemic action of the latter in the intestine12. D3 as well as PTH and prostaglandins stimulate RANKL
Intestinal TRPV 5 and TRPV 6 expression confers expression, 18 but 1,25(OH) 2 D 3 also inhibits OPG
calcium influx with properties identical to those production with corresponding increase in
observed in native distal renal tubular cells including osteoclastognesis and osteclast activity.
high Ca++ selectivity and negative feedback regulation
to prevent Ca++ overload during transepithelial Ca++ 1,25(OH)2 D3 VDR & parathyroids
transport 13. Calcium transporting protein TRPV6, The 1,25(OH)2 D3-VDR system appears necessary
calbindin D9K and (PMCA lb) are increased by high for maximal PTH induced osteoclast production. The
dietary Ca++ in the duodenum of 1 α hydrolase null vitamin D endocrine system is a potent modulator of
mice, thus demonstrating a 1, 25 (OH)2 D3 independent parathyroid function. Vitamin D deficiency results in
upregulation. parathyroid hyperplasia and increased PTH synthesis
1, 25 (OH)2D3 also increases active PO4 transport and secretion. However, 1, 25 (OH)2 D3 administration
through stimulation of the expression of the Na-P1 co- inhibits PTH synthesis and parathyroid cell growth,
transporter 15 and changes the composition of the making 1, 25 D3 therapy effective in treating secondary
260 INDIAN J MED RES, MARCH 2008

hyperparathyroidism of chronic kidney disease 19. In Other nongenomic action of 1, 25 (OH)2 D3 include,
addition to direct transrepression of PTH gene by the antiproliferative properties on keratinocytes in skin
1, 25 (OH)2 D 3-VDR complex, the vitamin also diseases like psoriasis, immuno suppressive properties
regulates both parathyroid levels VDR and the response on autoimmune destruction of Langerhans cells to
of the parathyroid gland to calcium. 1, 25 (OH)2 D3 prevent type I diabetes mellitus, etc. Such immune
induced increase in parathyroid VDR results from suppressive effects of 1, 25 (OH) 2 D 3 may prove
increases in its mRNA levels, possibly secondary to valuable in the treatment of autoimmune disorders such
increase in serum calcium as well as through ligand as psoriasis, melanoma and scleroderma and type I
dependent protection of proteosomal VDR degradation. diabetes mellitus23.
In rats with kidney failure, a strong direct correlation Epidemiological observations suggest strong
has been shown to exist between serum 1, 25 (OH)2D3 association between inadequate sunlight exposure
levels and parathyroid VDR protein content. Further, related low 1, 25 (OH)2D3 levels and high BP and/or
prophylactic 1, 25 (OH)2 D3 prevents the decrease in high plasma rennin activity22. It would appear that the
parathyroid VDR expression that accompanies the 1, 25 (OH)2 D3 acts as a negative regulator of the renin-
progression of kidney disease 20. angiotensin endocrine system. In VDR null mice,
The PTH gene is directly transrepressed by marked increases in renin expression and plasma
1,25(OH)2 D3-VDR complex. Besides, 1,25(OH)2 D3 angiotensin II production caused hypertension, cardiac
regulates both the parathyroid levels of VDR and the hypertophy and increased water intake25. In such
response of the parathyroids to calcium 1,25(OH)2 D3 animals intake of 1, 25 (OH)2 D3 suppressed renin
induced increases in parathyroid VDR and its mRNA. production through a VDR medicated mechanism. In
experimental animals, vitamin D deficiency is
1, 25(OH) D3 has several renoprotective effects. associated with an earlier and more aggressive form of
They include attenuation of the development of diabetes, probably related to abnormalities in immune
glomerulosclerosis and retarding the progression of function and impaired glucose tolerance that can be
albuminuria. relieved by calcitriol25. 1, 25 (OH)2 D3 through a VDR
Non classical actions of vitamin D mediated modulation of calbindin expression, appears
to control intra-cellular calcium flux in islet cells, which
Wide range of evidences from genetic, nutritional in turn affects insulin secretion.
and epidemiological studies link vitamin D endocrine
system with diseases like hypertension, myopathic 1, 25 (OH)2 D3 deficiency, in chronic renal failure
disorders, proneness to infection, autoimmune disorders results in abnormal insulin secretion, and blunted
and cancer. Thus clonal proliferation of lukaemic cells response of the pancreatic b cells, independent of
has been shown to be inhibited and their differentiation alterations in VDR levels in pancreatic cells. Also 1,
promoted by 1, 25 (OH)2 D321. Strong epidemiological 25 (OH)2 D3 administration corrects abnormal insulin
evidence show linkages of prostate, breast & colon secretion independently of changes in serum levels of
cancer with vitamin D deficiency22. Cell biological calcium or PTH. The findings of 1 a-hydroxylase
studies show that 1,25 (OH)2 D3 - VDR system arrests activity in pancreatic cells, raises the possibility of an
cancerous cell cycle at G1- GO transition through autocrine control of insulin secretion by 1, 25
multiple mechanisms 23. 1,25 (OH) 2D 3 production (OH)2D325.
decreases in the progression of malignancy in prostate Evidences supporting direct action of 1, 25 (OH) 2D3
cancer cells. 1, 25 (OH) 2 D 3 induced apoptosis on skeletal muscles growth and differentiation exist.
contribute significantly to growth suppression Thus skeletal muscle weakeness and atrophy with
properties of sterols in hyperproliferative disorders. In electrophysiological abnormalities in muscle
breast cancer cells24. 1, 25 (OH)2 D3 induces apoptosis contraction and relaxation occur in chronic kidney
through reciprocal modulation in Bc12 and Bax disease related 1, 25 (OH)2D3 deficiency. It also occurs
content21. It also increases intracellular calcium which in prolonged anticonvulsant treatment related low
activates the calcium dependent proapoptopic proteases, 1.25(OH)2D3 levels23.
microcalpain and capsase 12. It also enhances
Vitamin D deficiency in India
antitumoral properties of ionizing radiation. Thus, in
general vitamin D has anti-cancer properties that are of Ever since the publication of Hodgkin and
potential clinical utility23. colleagues26 on uncommon prevalence of vitamin D
 KOCHUPILLAI: PHYSIOLOGY OF VITAMIN D 261

deficient rickets / osteomalacia among Punjabis in India, calcium in a human proximal tubule cell line (Abstract).
no studies appeared assessing the vitamin D status of Bone 1998; 23 : S260.
subjects living in tropical and sub tropical latitudes of 3. Rost CR, Bikle DD, Kaplan RA. In vitro stimulation of
25-hydroxycholecalciferol 1 _-hydroxylation by
the India till 1995. Also there has been a prevailing parathyroid hormone in chick kidney slices: evidence for a
impression among medical professionals that role for adenosine 3_,5_-monophosphate. Endocrinology
abundance of sunlight prevent vitamin D deficiency in 1981; 108 : 1002-6.
India. However between 1995 and 2000 27,28, we 4. Schiavi SC, Kumar R. The phosphatonin pathway: new
published evidence to show that even doctors and nurses insights in phosphate homeostasis. Kidney Int 2004; 65 :
1-14.
from northern latitudes of India have vitamin D
deficiency. These observations are confirmed by other 5. Rowe PSN, Kumagai Y, Garrett R, Blacher R, Escobada
A, Mundy GR. CHO-cells expressing MEPE, PHEX and
authors for Southern part of the country29. These reports co-expressing MEPE/PHEX cause major changes in BMD,
thus scientifically establish evidence for prevalence of Pi and serum alkaline phosphatase in nude mice (Abstract).
vitamin D deficiency in the sub-continent, despite J Bone Miner Res 2002; 17 : S211.
abundant sunlight. Meanwhile there is emerging 6. Sylvia VL, Schwartz Z, Ellis EB, Helm SH, Gomez R, Dean
evidence of wide prevalence of fluoride ingestion DD, et al. Nongenomic regulation of protein kinase C
isoforms by the vitamin D metabolites 1 _,25-(OH)2D3
through drinking water in the sub-continent30. There are and 24R,25-(OH)2D3. J Cell Physiol 1996; 167 : 380-93.
also reports that scientifically show fluoride ingestion
7. Henry HL, Norman AW. Vitamin D: metabolism and
related renal tubular damage and related dysfunctions biological actions. Annu Rev Nutr 1984; 4 : 493-520.
in the sub-continent31. Thus it would appear that despite 8. Tanaka Y, Deluca HF. The control of 25-hydroxyvitamin
abundance of sunlight the people of the sub-continent D metabolism by inorganic phosphorus. Arch Biochem
are subjected to a variety of biologically (skin Biophys 1973; 154 : 566-74.
pigmentation) and environmentally (hydric fluorosis) 9. Cooke NE, Haddad JG. Vitamin D binding protein (Gc-
induced dysfunctions that cause wide prevalence of globulin). Endocr Rev 1989; 10 : 294-307.
bone mineral metabolic diseases, both sub-clinical and 10. Boyan BD, Dean DD, Sylvia VL, Schwartz Z. Nongenomic
clinically overt, causing musculo-skeletal dysfunctions regulation of extracellular matrix events by vitamin D
metabolites. J Cell Biochem 1994; 56 : 331-9.
on the one hand and overt musculo-skeletal disorders
on the other, due to vitamin D deficiency. Besides, 11. Boyle WJ, Simonet WS, Lacey DL. Osteoclast
differentiation and activation. Nature 2003; 423 : 337-42.
practically the entire sub-continent has been mapped
12. Brown AJ, Dusso A, Slatopolsky E. Vitamin D. Am J
to have endemic fluorosis 30 . Emerging scientific Physiol Renal Physiol 1999; 277 : 157-75.
evidence also unfold variety of disorder affecting bones,
13. Koshiyama H, Sone T, Nakao K. Vitamin-D-receptor-gene
muscles, kidneys and GI system to cause disorders of polymorphism and bone loss. Lancet 1995; 345 : 990-1.
bone mineral metabolism, affecting millions living far 14. Eisman JA. Genetics of osteoporosis. Endocr Rev 1999;
and wide in the Indian sub-continent27,28,30. Fortunately 20 : 788-804.
most of these are preventable and therefore appropriate 15. Carling T, Kindmark A, Hellman P, Lundgren E, Ljunghall
measures like defluoridation of drinking water should S, Rastad J, et al. Vitamin D receptor genotypes in primary
be adopted countrywide expeditiously to prevent such hyperparathyroidism. Nat Med 1995; 1 : 1309-11.
disabling bone mineral metabolic diseases in India. 16. Kontula K, Valimaki S, Kainulainen K, Viitanen AM,
Country-wide preventive intervention, in the form of Keski-Oja J. Vitamin D receptor polymorphism and
treatment of psoriasis with calcipotriol. Br J Dermatol
milk and edible oil fortification with vitamin D would 1997; 136 : 977-8.
further enhance bone mineral metabolic health in India.
17. Uitterlinden AG, Fang Y, van Meurs JB, van Leeuwen H,
Considering the magnitude and country-wide spread of Pols HA. Vitamin D receptor gene polymorphisms in
such dysfunction and disorders, preventive measures relation to vitamin D-related disease states. J Steroid
of the type sighted are of urgent national need. Biochem Mol Biol 2004; 89 : 187-93.
18. Khosla S. Minireview: the OPG/RANKL/RANK system.
References Endocrinology 2001; 142 : 5050-5.
1. Tang BMP, Eslick GD, Nowson C, Smith C, Bensoussan 19. Dusso AS, Thadhani R, Slatopolsky E. Vitamin D receptor
A. Use of calcium or calcium in combination with vitamin and analogs. Semin Nephrol 2004; 24 : 10-6.
D supplementation to prevent fractures and bone loss in
people aged 50 year and older : a meta-analysis. Lancet 20. Denda M, Finch J, Brown AJ, Nishii Y, Kubodera N,
2007; 370 : 657-66. Slatopolsky E. 1,25-Dihydroxyvitamin D3 and 22-
oxacalcitriol prevent the decrease in vitamin D receptor
2. Bland R, Hughes SV, Stewart PM, Hewison M. Direct content in the parathyroid glands of uremic rats. Kidney
regulation of 25-hydroxyvitamin D3 1_-hydroxylase by Int 1996; 50 : 34-9.
262 INDIAN J MED RES, MARCH 2008

21. Abe E, Miyaura C, Sakagami H, Takeda M, Konno K, 27. Harinarayan CV, Gupta N, Kochupillai N. Vitamin D status
Yamazaki T, et al. Differentiation of mouse myeloid in primary hyperparathyroidism. Clin Endocrinol (oxf)
leukemia cells induced by 1_,25-dihydroxyvitamin D3. 1995; 43 : 351-8.
Proc Natl Acad Sci USA 1981; 78 : 4990-4. 28. Goswami R, Gupta N, Goswami D, Marwaha RK, Tandon
22. Zittermann A. Vitamin D in preventive medicine: are we N, Kochupillai N. Prevalence and significance of low 25-
hydroxyvitamin D concentrations in healthy subjects in
ignoring the evidence? Br J Nutr 2003; 89 : 552-72.
Delhi. Am J Clin Nutr 2000; 72 : 472-5.
23. Adriana S. Dusso, Alex J. Brown, Eduardo Slatopolsky.
29. Harinarayan CV, Ramalakshmi T, Prasad UV, Sudhakar
Am J Physiol Renal Physiol 2005; 289 : 8-28. D, Srinivasarao PVLN, Sarma KVS, et al. High prevalence
24. Schwartz GG, Whitlatch LW, Chen TC, Lokeshwar BL, of low dietary calcium, high phytate consumption and
Holick MF. Human prostate cells synthesize 1,25- vitamin D deficiency in healthy south Indians. Am J Clin
dihydroxyvitamin D3 from 25-hydroxyvitamin D3. Cancer Nutr 2007; 85 : 1062-7.
Epidemiol Biomarkers Prev 1998; 7 : 391-5. 30. Susheela AK. Fluorosis : A doctor’s handbook. New Delhi:
25. Holick MF. Vitamin D: importance in the prevention of Fluorosis Research & Rural Development Foundation
sponsored by Ministry of Health & Family Welfare (Govt.
cancers, type 1 diabetes, heart disease, and osteoporosis.
of India) & WHO (SEARO), 2005.
Am J Clin Nutr 2004; 79 : 362-71.
31. Harinaryan CV, Kochupillai N, Madhu SV, Gupta N,
26. Hodgkin P, Kay GH, Hine PM, Lumb GA, Stanbury SW. Meunier PJ. Fluorotoxic metabolic bone disease: An osteo-
Vitamin D deficiency in Asians at home and in Britain. renal syndrome caused by excess fluoride ingestion in the
Lancet 1973; 2 : 167-72. tropics. Bone 2006; 39 : 907-14.

Reprint requests: Dr N. Kochupillai, Director, M.S. Ramaiah Medical College & Hospitals, MSRIT Post
MSR Nagar, Bangalore 560 054, India
e-mail: kochupillai@gmail.com