Vitamin D (calciferol) is a fat-sol-uble vitamin, the main sources

of which are dermal synthesis andfortified foods.

Few foods contain vitamin D(oily fish, cod-liver oil, supple-mented breakfast cereals, mar-garine and infant formula milk,with lesser amounts in egg yolks,liver and mushrooms) such thatthere is significant risk of deficiencyin populations with limited expo-sure to sunlight. Nutritional ricketsis diagnosed in several hundred UKchildren annually.

Deficiency in adults is com-mon1 and it often goes unrecog-nised. In addition to being thecause of nonspecific symptoms and

increased fracture risk, low levelsof vitamin D have been associatedwith an increased risk of malig-nancy.2 Relationships between vita-min D deficiency and risk ofautoimmune disease are also beingstudied.

MetabolismIn humans >80 per cent of avail-able vitamin D (in the form of D3)is synthesised in the skin from 7-dehydrocholesterol on exposureto ultraviolet radiation (UVB) insunlight.

The length of exposure to sun-light required to obtain sufficientlevels of vitamin D varies depend-ing upon skin type, time of day,

season and latitude.3 It has beenestimated that a fair-skinned per-son would generate 2000IU ofvitamin D3 following exposure ofthe face and forearms for 20–30minutes, and this two to threetimes per week would be suffi-cient. Those with pigmented skinand the elderly would requiremore exposure.

Unfortunately, for six monthsof the winter 90 per cent of the UK lies above the latitude that would allow this exposure to UVB.4

The diet provides lesseramounts of both vitamin D2 and D3.

Vitamin D from the diet andskin is biologically inactive and

www.prescriber.co.uk Prescriber 5 February 2013 29

Prescribing in practice

Vitamin D deficiency: current

approaches to managementLN Rao Bondugulapati MRCP and John Harvey MD, FRCP

Vitamin D deficiency is com-

mon in the UK, the preva-

lence may be increasing and

it often goes unrecognised.

The authors discuss current

vitamin D serum levels used

in diagnosis and the recom-

mended treatment of a range

of conditions.

Figure 1. Rickets is a sign of severe vitamin D deficiency and is diagnosed in several

hundred children in the UK every year

SP

L

requires enzymatic conversion toits active metabolites (see Figure2). It is converted to 25-hydroxyvi-tamin (25OH) D (calcidiol) that isthe major circulating form of vita-min D by the 25-hydroxylaseenzyme in the liver, and then to1,25-dihydroxy vitamin (1,25OH) D(calcitriol), the active form of vita-min D, by 1-alpha hydroxylase inrenal tubular cells.

One alpha hydroxylase isexpressed by other cell types invitro but 1,25OH-D is absent fromthe circulation in anephric sub-jects, indicating the importance ofthe kidney.

Actions1,25OH-D binds to a nuclearreceptor to activate vitamin Dresponse elements within targetgenes. It promotes enterocyte dif-ferentiation and the intestinalabsorption of calcium. It also stim-ulates intestinal phosphateabsorption, directly suppressesparathyroid hormone (PTH)release from the parathyroids andregulates osteoblast and osteoclastactivity.

These functions play a vital rolein the maintenance of normal cal-cium and phosphate concentra-tions in the blood and in the

mineralisation of newly formedbone. Vitamin D is also thought tohave a direct effect on musclewhich is relevant in the elderly (seebelow).

Diagnosis of vitamin DdeficiencyThe clinical features of vitamin Ddeficiency are nonspecific andinclude muscle and bone pain andproximal myopathy. Thus a highindex of suspicion is required tomake this diagnosis.

In practice, measurement ofvitamin D concentrations is usuallyconfined to individuals with sug-gestive biochemistry (low serumcalcium and phosphate, raisedPTH and, in advanced cases, raisedalkaline phosphatase) or thosewho fall into at-risk categories (seeTable 1).

Vitamin D levels are measuredby estimation of 25OH-D. Measure -ments of 1,25OH-D should not beused for this purpose because invitamin D deficiency one-alphahydroxylation is promoted by thesecondary hyperparathyroidismthat occurs.

There is no clear consensus onthe optimal level of 25OH-D forskeletal health. The Institute ofMedicine (IOM) recommends aserum level above 50nmol per litre(20ng per ml).

Other authorities (The Endo -crine Society, The InternationalOsteoporosis Foundation) suggestthat a minimum level of 75nmolper litre (30ng per ml) is necessaryin older adults to minimise the riskof falls and fracture.5,6

Thus, concentrations between50 and 75nmol per litre may beinsufficient. Serum levels <50nmolper litre certainly indicate defi-ciency.

Levels below 25nmol per litrerepresent severe deficiency andmay be accompanied by clinicalrickets or osteomalacia.

30 Prescriber 5 February 2013 www.prescriber.co.uk

Prescribing in practice

Figure 1. Synthesis of vitamin D from the diet and skin

Skin –

7-dehydrocholesterol

colecalciferol

(vitamin D3)

ergocalciferol

(vitamin D2)

calcidol (25-hydroxy

vitamin D)

calcitriol

(1,25-dihydroxy

vitamin D)

24,25-dihydroxy

vitamin D (inactive)

liver

kidney

Diet – animal sources Diet – plant sources

UVB sunlight

(290–320nm)

TreatmentThe elderlyIn the elderly there is a consensussupporting supplementation asstandard practice without priormeasurement of vitamin D levels.Scottish Intercollegiate GuidelinesNetwork (SIGN) guidelines recom-mend the housebound elderlyreceive 1000mg calcium and 800IUof vitamin D daily.7

There are several meta-analysesshowing the reduction in falls withtreatment in the elderly, especiallywhen baseline vitamin D levels arevery low.8 The beneficial effect ofvitamin D on muscle is likely tocontribute to this.

Long-term treatment with suchdoses of vitamin D and calcium isused for primary prevention ofosteoporotic fracture. Many of thetrials of antiresorptive therapiesalso had patients on calcium andvitamin D.

Pregnancy and breast-feedingIn pregnancy and when breast-feeding 400IU (10g) of vitamin Ddaily is now recommended asroutine.9

Mild to moderate deficiencyMild to moderate vitamin D defi-ciency can occur in many settingsand can be treated with prepara-tions containing 400–800IU vita-min D with or without calcium.

It should be noted that certaingroups of patients need higherdoses of vitamin D to achieve thesame target levels (obese individ-uals,10 patients with malabsorp-tion, use of medications affectingvitamin D metabolism: liverenzyme inducers, glucocorti-coids).

The factors causing deficiency,particularly lack of exposure tosunlight, often affect whole fami-lies, and therefore considerationshould be given to screening siblings.

Severe deficiencyIn severe deficiency (total serumvitamin D <25nmol per litre) acourse of high-dose therapy isrequired to replenish stores in areasonable timescale. EndocrineSociety guidelines recommend50 000IU per week of either vita-min D2 or D3 for eight weeks toincrease the levels of 25OH-Dabove 75nmol per litre (30ng perml).5 This should be followed by maintenance therapy of1500–2000IU per day, usuallyindefinitely.

The safety of this regimen is notsufficiently studied in pregnantand lactating women, and there isa concern that high-dose therapycan result in hypercalcaemia in theinfant. Hence, a more cautious reg-imen is adopted in these patientswith supplementation of 600–800IU per day.

Other conditionsThe management of hypoparathy-roidism and some malabsorptiveconditions, eg short bowel syn-drome following surgery, requireslarge doses of vitamin D. Mal -

absorption or chronic liver diseasemay require 40 000IU per day.The hypocalcaemia of hypo -parathyroidism will require dosesup to 100 000IU per day toachieve normocalcaemia.

One-alpha hydroxycholecalcif-erol (alfacalcidol) and calcitriol(1,25OH-D) are most useful inthose with chronic renal failure orin type 1 vitamin D-dependent rick-ets (due to an inactivating muta-tion in the 1-hydroxylase gene).Calcitriol is available in capsuleform whereas alfacalcidol can beadministered both orally and par-enterally.

Dangerous levels of hypercal-caemia can occur, particularly withalfacalcidol, if the dose is notappropriately titrated or withdeclining renal function over time.Some authorities recommend reg-ular monitoring of serum calciumlevels in patients treated with one-alpha hydroxylated vitamin Dmetabolites.

In patients with vitamin D defi-ciency and co-existing primaryhyperparathyroidism, there hasbeen no clear consensus until

www.prescriber.co.uk Prescriber 5 February 2013 31

Prescribing in practice

Table 1. Risk factors for and indicators of possible vitamin D deficiency

• individuals with limited sun exposure due to concealing clothing, particularly

if dark skinned

• obesity (BMI >30)

• vegetarian (no fish) diet

• elderly individuals with history of falls: fractures following minimal trauma are

particularly suggestive

• institutionalised individuals

• pregnant and lactating women

• exclusive breast feeding

• medications that accelerate the metabolism of vitamin D: liver enzyme

inducers (eg anticonvulsants, rifampicin, antiretroviral therapy, gluco -

corticoids)

• malabsorption due to small bowel disease: inflammatory bowel disease,

coeliac disease, radiation enteritis, bariatric surgery, short bowel syndrome

following surgery

• pancreatic disease: chronic pancreatitis, cystic fibrosis, pancreatectomy

• chronic kidney disease

• chronic liver disease

• osteoporosis

32 Prescriber 5 February 2013 www.prescriber.co.uk

Prescribing in practice

recently with regards to the replen-ishment of vitamin D.

The 3rd International Work -shop on Asymptomatic PrimaryHyperparathyroidism recom-mended measuring 25OH-D in allpatients with primary hyper-parathyroidism and repletingthose with low levels (<50nmolper litre, 20ng per ml).11 Closemonitoring of these patientswhen on vitamin D therapy isrequired.

There is no clear consensus onwhether vitamin D treatmentmight reduce cancer risk. VitaminD is antiproliferative, thus cal-citriol (Silkis), calcipotriol andtacalcitol (Curatoderm) are usedtopically in the treatment of pso-riasis.

Available preparationsRepletion of vitamin D can beachieved using either ergocalcif-erol (vitamin D2) or colecalcif-erol (vitamin D3).

Many preparations – flav -oured, effervescent, chewable –are available in which vitamin D3400–800IU is combined with cal-cium. Calcium is often notneeded and in some cases makespreparations unpalatable.

Desunin tablets and Fultium-D3capsules contain 800IU vitamin D3.Vitamin D 25µg (1000IU) tabletsare available without prescriptionfrom Boots.

For larger doses, Dekristoltablets containing 20 000IU havebeen used but are not licensed andavailable only on special order.Ergocalciferol (D2) tablets contain-ing 10 000 and 50 000IU are listedbut difficult to obtain. Parenteralergocalciferol 300 000IU per ml isavailable.

One-alpha hydroxylated vita-min D (alfacalcidol) and calcitriol,used primarily in chronic renal dis-ease, are not appropriate forpatients with simple vitamin D defi-ciency and can cause hypercal-caemia as described above.

ConclusionVitamin D deficiency is commonand the prevalence may be increas-ing. There has been controversyover what serum level indicatesdeficiency but it seems that, unlessoily fish are consumed twiceweekly or there is regular sunexposure, a majority of UK adultswill have some degree of vitaminD deficiency.

It has been suggested that thepublic health response to this hasbeen inadequate,4 although theprecise consequences of mild defi-ciency remain uncertain.

The UK national recommenda-tion of an intake of 400IU (10g)per day is sufficient to preventosteomalacia and rickets but maynot be adequate for optimumhealth.

Higher-dose therapeutic prepa-rations have been difficult toobtain but are clearly required insome clinical situations.

References1. Hypponen E, et al. Am J Clin Nutr2007;85:860–8.2. Holick MF. N Engl J Med 2007;357:266–81.3. Terushkin V, et al. J Am Acad Dermatol2010;62(6):929.4. Pearce SHS, et al. BMJ 2010;340:b5664.5. Holick MF, et al. J Clin EndocrinolMetab 2011;96(7):1911.6. Dawson-Hughes, B, et al. OsteoporosisInt 2010;21(7):1151–4.7. SIGN. Management of osteoporosis. Anational clinical guideline. www.sign.ac.uk/pdf/sign71.pdf.8. Cameron ID, et al. Cochrane DatabaseSyst Rev. 2010;CD005465.9. NICE. Antenatal care. ClinicalGuideline 62. 2010.10. Wortsman J, et al. Am J Clin Nutr2000;72:690–3.11. Eastell R, et al. Clin Endocrinol Metab2009;94(2):340.

Declaration of interestsNone to declare.

Dr Bondugulapati is specialist regis-trar in the Department ofEndocrinology and Diabetes, MaelorHospital, Wrexham, and Dr Harveyis senior lecturer in diabetes,Endocrinology and Metabolism,Bangor University, and honoraryconsultant physician, MaelorHospital, Wrexham