Dr. Pamela Leventis

Consultant Rheumatologist

Epsom & St. Helier NHS Trust

Vitamin D

Vitamin D - Outline

Vitamin D physiology in briefVitamin D – a cure for all ills?What is optimal?When to measure serum 25-OHDTreatment of vitamin D deficiency/insufficiency

Vitamin D formulationsRoute of replacement

Principles for supplementation

Vitamin D physiology

Holick, M. (2006)

Vitamin D insufficiency is prevalent

Vitamin D in the spotlightEmerging associations with onset and propagation

of range of cancers, autoimmune, and infectious diseases…and all cause mortality

Global AttentionMedia Scientific community

Explosion of epidemiological studiesOngoing research

www.clinicaltrials.gov 1488 studies relating to vitamin D registered in US509 open interventional studies

Vitamin D in the newsScientists reverse stance on sun and cancer: Now they admit sunlight can prevent skin cancer

Low vitamin D levels linked to more aggressive breast cancers

Vitamin D deficiency linked to childhood obesity

Conventional medicine finally admits MS caused by vitamin D deficiency Scientists say higher

vitamin D intake will slash cancer, MS, and diabetes risk by half

Vitamin D grows hair, prevents the flu and reduces arthritis pain

Vitamin D 'key to healthy brain'

Vitamin D intake in pregnancy prevents RSV infections in infants

Supporting evidenceBiochemistry

In vitro studies suggest that 1,25D may regulate a very large number of genes (0.8–5% of the total genome) (Bouillon et al., 2008)growth regulation and differentiationDNA repair and apoptosisMetabolism, oxidative stress

1α hydroxylase and Vitamin D receptor expressed in almost all tissues (Zitterman,2003)

Pleiotropic effects postulated, eg.Vit D down regulates inflammatory cytokines (IL-12, IL-2 and

IFN) and upregulates anti-inflamm (IL-10, IL-4)Inhibits rate of colonic epithelial cell proliferation and promotes cell

differentiationStimulates immune responses to APCs eg. Cathelicidin production

Macrophages - ?TB

Endocrine, autocrine and paracrine effects of vitamin D

Holick, M. (2006)

Supporting evidenceClinical Trials

EpidemiologicalClose relationship between latitude and serum 25 OH D levels

1 degree of latitude corresponds to 1 ng/mL of 25-hydroxyvitamin D3Lower incidence of MS, Type 1 DM, Cancers (Br, Col, pros)

closer to equator (Garland et al., 2006)

Seasonal variations most pronounced for UV-B than UV-A radiation

Cancer survival rates greatest if diagnosed in Summer (Lim et al., 2006)

Seasonality of cardiovascular disease mortality (Scragg,1981)

Vitamin D supplementation associated with lower all cause mortality rates in a meta-analysis of RCTs (Autier and Gandini, 2007)

Inconsistent follow up periods – 12-60mthsInconsistent dosing and serum 25OHD not always known

Limitations of dataCaution in interpreting observational studies

Range of confounders – higher latitudes deficient in range of other photo-chemicals, obesity, exercising outdoors, smoking, diet, healthy behaviours etc

No causal evidence currently

Short prospective studies thus far investigating cancer risk <5yrs

No large RCTs documenting role for vitamin D therapy for any organ system outside MSK system

Most evidence for effects of vitamin D on bone health, fractures and falls

Vitamin D, falls and fracturesHigher fracture incidence in vitamin D deficient patients Modest BMD changes with vitamin D replacement insufficient to

explain observation?change in bone qualityOr a reduced propensity to fall

72% patients attending falls clinic are vitamin D deficient (Dhesi et al., 2002)

Type II muscle fibre atrophy common to sarcopenia of ageing and osteomalacic myopathy

Vitamin D supplementation shown to improve muscle strength and balance reduce falls risk (Bischoff et al., 2003)

Most marked in patients with very low baseline vitamin D levels

What is the optimal serum 25OH vitamin D level?

Optimal Serum 25-hydroxyvitamin D levels for Bone Health

Associated with greatest calcium absorption, reduced rates of bone loss, falls and fractures (Dawson-Hughes et al., 2005)

Complex ‘curvi-linear’ relationship between 25(OH)D and PTH

Estimates for maximal PTH suppression now cluster in range of 70-80nmol/l

Physiological deficiency The 25(OH)D concentration below which PTH levels increase in a population

Thomas et al., 1998

Factors promoting vitamin D deficiencyIncreasing ageSkin melaninInstitutionalised/Limited sun exposure/Strict sunscreen useMalabsorption, Renal or liver diseaseMedications eg. anticonvulsants, rifampicin, glucocorticoids,

cholestyramine, HAARTObesityExclusive breast feeding beyond 6 months in infants

But deficiency/insufficiency v. widespread50% healthy adults – insufficient in winter/spring (serum 25OHD

25-50nmol/l) (Hypponen and Power, 2007)

When to measure 25OHD levelsClinical features - osteomalacia

Insidious onset widespread or localised bone pain and tenderness

Proximal muscle weaknessFallsFracturesNon specific myalgia

Biochemical osteomalaciaLow vitamin DHypocalcemia - occasional Alkaline phosphatase may be elevatedSecondary hyperparathyroidism (80%)

Vitamin D Replacement

Most widely used dose 800IU vitamin D3 or D2 +/- 1000mg calcium

In a study of 100 patients attending an osteoporosis clinic (Ryan, 2007) Mean baseline 25(OH)D 26nmol/lSupplemented for 3 months (800IU D3/d)Mean post-treatment level 58nmol/l<60nmol/l in 55% Compliance unknown Risk of renal stones

Optimal FormulationVitamin D3 versus vitamin D2

3 groups of 10 healthy

male volunteers given

single oral dose of: 50,000IU oral vitamin D2

50,000IU oral vitamin D3

placebo

Change in serum 25(OH)D after a single oral dose of 50,000 IU of vitamin D3 or vitamin D2 (Armas et al.,2004)

However daily vitamin D2 is as effective as equimolar D3(Holick et al., 2008)

Optimal RouteOral versus IM

4 groups of 8 elderly patients received:300,000IU vitamin D2 im300,000IU vitamin D2 po300,000IU vitamin D3 im300,000IU vitamin D3 po

Serum samples taken at 3, 7, 30 and 60 days

Romagnoli et al. 2008

D3po

D3im

D2po

D2im

Bolus po D3 – 3x AUC

Vitamin D replacement

No single effective regimenVarious plausible approachesRegimen should be tailored to formulation and route of

administration

Bolus oral dosingRapid and sustained rise in serum 25OHDReliable adherenceHowever high dose D3 preparations not readily available in

the community

Vitamin D Replacement Local Practice

Every 1000IU Vitamin D3 ingested increases serum 25OHD levels by ~10ng/ml (25mmol/l) (Holick et al., 2008)

Recheck serum 25OHD at 12 weeksTherapeutic goal is to achieve serum 25OHD levels

>75nmol/l compatible with biochemical repletionCalcium added only in osteoporosis

Baseline Serum 25OHD

level

Initial dosing (12 weeks)

Maintenance dosing

<25nmol/l 6000IU/day 2000IU/day

25-50nmol/l 4000IU/day 2000IU/day

Vitamin D Replacement Local Practice – Vitamin D preparations

OTCSunvite vitamin D3 400iu/1000iu tablets (Holland & Barrett)Vitamin D3 1000iu Nature’s Remedy (vegetarian option available)Biolife Vitamin D3 1000iu Lifestyle Natural Health (vegetarian)

PrescribedLamberts® Vitamin D3 1000iuIf Calcium required – Adcal D3 (calcium carbonate 1.5g/

colecalciferol 400iu) 1 tablet bdBolus oral/im vitamin D3 dosing in secondary care

Contraindications: Hypercalcaemia, metastatic Ca, primary hyperPTH.

Cautions in sarcoidosis, renal stones/hypercalciuria

Iatrogenic vitamin D toxicityVery unusual. No recorded toxicity in studies of healthy men treated with:

10,000IU vitamin D3 per day for 20 weeks (Heaney et al., 2003)

50,000IU vitamin D3 per day for 8 weeks (Barger-Lux et al., 1998)

Case report of Vitamin D toxicity in healthy 42 yr old male •using improperly diluted OTC supplement•156,000-2,604,000IU D3/day ! (Koutkia et al., 2001)

Vitamin D & Calcium supplementationand Cardiovascular risk

Re-analysis of WHI trial data and further meta-analysis of trials of calcium +/-vitamin D versus placebo (Bolland et al 2011)

Excluded patients on additional calcium supplements at randomisation

Composite risk of MI/Stroke appeared higher in patients on Calcium +/- vitamin D versus placebo (3.5 vs 2.9/1000 pt yrs)

No increased risk all cause mortalityUnexplained ↓ risk in women taking calcium supplements at baseline

Multiple limitations to study: exclusion of 56% original WHI trial patients, ?over-interpreted subgroup

analysisOverall CV risk not increased in WHI study?alternative explanations – misclassification bias

Advice for healthcare professionals (Drug Safety Update – Oct 2011) Continue to offer calcium and Vitamin D supplements to postmenopausal

women receiving treatment for osteoporosis Increasing dietary intake is preferable to supplementation where possible

Principles of vitamin D assessment and replacement

Asymptomatic suboptimal vitamin D levels are very common

Ensure clear rationale for measuring 25OHD

Extraskeletal health benefits of vitamin D not proven

Aim for a target 25(OH)D level >75nmol/l for bone health

Vitamin D3 achieves higher and more sustained 25(OH)D levels

If using Vitamin D2 aim to replace more frequently to compensate for rapid clearance

Oral dosing achieves more rapid increases in 25(OH)D

References Armas LAG, Hollis BW, Heaney RP. Vitamin D2 is much less effective than vitamin D3 in humans. J Clin Endocrinol Metab 2004;

89:5387-5391.

Autier P, Gandini S. Vitamin D supplementation and total mortality. Arch Intern Med 2007;167:1730-1737.

Barger-Lux MJ, Heaney RP, Dowell S. et al. Vitamin D and its major metabolites: serum levels after graded oral dosing in healthy men. Osteoporosis Int. 1998; 8:222-230

Bischoff HA, Stahelin HB, Dick W et al. Effects of vitamin D and calcium supplementation on falls: A randomized controlled trial. J Bone Mineral Research 2003;18:343-351.

Bolland MJ, Grey A, Avenell A et al. Calcium supplements with or without vitamin D and risk f cardiovascular events: reanalysis of the Women’s Health Initiative limited access dataset and meta-analysis. BMJ 2011;342:962

Dawson-Hughes B, Heaney RP, Holick MF et al. Estimates of optimal vitamin D status. Osteoporosis Int. 2005;16:713-716.

Dhesi JK, Bearne LM, Moniz C et al. Neuromuscular and psychomotor function in elderly subjects who fall and the relationship with vitamin D status. J Bone Mineral Research 2002;17:891-897.

Garland CF, Garland FC, Gorham ED et al. The role of vitamin D in cancer prevention. Am J Public Health 2006;96:252-261.

Heaney RP, Davies KM, Chen TC et al. Human serum 25-hydroxycholecalciferol response to extended oral dosing with cholecalciferol. Am J Clin Nutr 2003;77:204-210.

Holick MF, Biancuzzo RM, Chen TC et al. Vitamin D2 is as effective as vitamin D3 in maintaining circulating concentrations of 25-hydroxyvitamin D. J. Clin Endocrinol Metab 2008; 93:677-81

Hollis BW, Wagner CL. Normal serum vitamin D levels. N Eng J Med. Feb 3 2005;352:515-6

Koutkia P, Chen TC,Holick M. Vitamin D intoxication associated with an over-the-counter supplement. N Eng J Med 2001;345:66-67

Lim HS, Roychoudhuri R, Peto J et al. Cancer survival is dependent on season of diagnosis and sunlight exposure. Int J Cancer 2006;119:1530-1536.

Romagnoli E, Mascia ML, Cipriani C et al. Short and long term variation in serum calciotrophic hormones following a single very large dose of ergocalciferol or colecalciferol in the elderly. J Clin Endocrin Metab 2008;93:3015-3020.

Scragg R. Seasonality of cardiovascular disease mortality and the possible protective effect of ultraviolet radiation. Int J Epidemiol 1981;10:337-341.

Thomas MK, Lloyd-Jones DM, Thadhani RI et al. Hypovitaminosis D in Medical Inpatients. N Eng J Med 1998;338:777-783

Zittermann A. Vitamin D in preventative medicine: are we ignoring the evidence? Br J Nutrition 2003;89:552-572.