Vitamin D

M Kassim JavaidNorman Collisson Senior Research Fellow, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford

Oxfordshire Osteoporosis Metabolic Bone Disease ServiceNuffield Orthopaedic Centre, Oxford

Declaration

• These views are my own

• Oxfordshire PCT do not commission the use of high dose vitamin D

Why vitamin D

• Biology• Clinical implications• Rationale for therapy• Cost implications• Next steps

Declarations

• No pharmaceutical funding support for this talk

• In last five years received honoraria, travel and subsistence expenses from: – Proctor and Gamble, Servier, Eli Lilly and Novartis

Sunshine vitamin Sunshine vitamin

The past

1885 bone histology by Pommer

1918 Cod liver oil by Mellenby

1919 Artifical UV cure Huldschinsky

• First recognized in 1650 by Frances Glisson

Provitamin DUV 290 – 315 nm (297 peak)Converts provitamin D to previtamin DWarmth converts previtamin D to cholecalciferol

IF too much pre-vit d then uv breaks down to lumisterol4 and tachysterol3

vitamin D

25 vitamin D

1,25 vitamin D

Action

Cholecalciferol (D3)

Ergocalciferol (D2)

1 ng/ml = 2.5 nM & 10 mcg = 400 IU< 25 nM = deficiency 25 – 50 nM = insufficiency

Clinical consequencesOsteomalacia

– variable

– proximal myopathy, hypotonia

– bone tender and pain

– bowing

– fracture (groin pain)

Bone and vitamin D: Osteomalacia

• 675 iliac crest biopsies tested for osteomalacia• Autopsy• Diasorin assay to measure 25OHD threshold….

Priemel JBMR 2010

Is there a bone threshold?

• Stable high calcium intake

• Raised D deficient till 10 weeks

• Re- fed various D diets for 10 -30 wks

Anderson JBMR 2008

0 nM > 100 nM

Vitamin D and bone

RicketsSecondary

hyperparathyroidismImpaired intestinal calcium absorption

Reduced bone volume with normal mineralization

Osteopenia

Population studies of D and bone

Kuchuk JBMR 2009

N = 7441 PMOcorrected for age, BMI, serum creatinine, and season

Vitamin D and fracture

LeBoff 2000 JAMA

Local scale of the problem: NOF

0%

10%

20%

30%

Percentage

25 50 75Serum 25(OH) D (nM)

N=47

42% < 25 nM42% 25- 50 nM15% > 50 nM

15%85%

Vitamin D deficiency predicts future hip fracture

800 women from WHI (7.1yr)

Cauley AIM 2008

P for trend = 0.03

1665 men from MrOS (5.3yr)

HR 1.6 (1.18- 2.17) per sd decrease in 25OHD

Cauley JBMR 2009

OR

Vitamin D prevents fracture

• 100,000 IU D3 4mthly• British Doctors study • Ipswich GP practice• 5 yr Postal study

• 74.3 nM vs 53.4 nM

Trivedi BMJ 2003

Normal trabecular bone Osteoporotic Fragile bone

Why and when?

In pregnancy:

Life course perspective

A stimulus at a sensitive of development has lasting effect on structure and function

‘Cradle’ ‘Grave’

Birth weight

Childhood growthAdult Bone Loss

Hip Fracture

Peak bone mass

Nine ages of man by R Johnston

Maternal effects on offspring’s bone mass

Neonatal Bone mass

SGA

‘Cradle’PregnancyPre -pregnancy

Childhood Bone mass

Asthma

Diabetes

Vitamin D statusPre-eclampsiaGestational DM

Maternal Vitamin D in Osteoporosis Study

Chief Investigator:C Cooper, Norman Collisson Chair of Musculoskeletal Sciences The Botnar Research Centre

Principal Investigators: N Harvey, University of SouthamptonS Kennedy, University of OxfordN Bishop, University of Sheffield

Maternal vitamin D supplementation in pregnancy

Down’s Screeni

ng (12/40)

Not eligible

Placebo

Birth

14/40

34/40

25D >100 nmol/l

25nmol/l< 25D <100nmol/l

n = 60 each arm

25D <25 nmol/l

Vitamin D supplements

19/40

Mothers recruited

Randomisation

Anthropometry, DXA

Check 25D,

PTH,ALP, Ca, Albumin

Repeat 25D, ALP, Ca, albumin

D3 9000 iu/wk

3D Scan

To inform the management of vitamin D insufficiency in pregnant women in the UK/World

Improve Baby bone mass

Improve Maternal Vitamin D

Reduce elderly risk of fracture

The emerging roles for 25(OH)-vitamin D: both programming and adult:

25(OH)-Vitamin D

Bone metabolism

Calcium/ phosphate

balance

Immune function

Oncology

Atherosclerosis and heart failure

Osteoarthritis

Vitamin D deficiency

1 ng/ml = 2.5 nM & 10 mcg = 400 IU< 25 nM = deficiency 25 – 50 nM = insufficiency

Effect of daily vitamin D replacement

SevereDeficient

Replete

Toxic

Is it the dose or peak level ?

Ideal

Toxicity

Deficient

How to replace D: Synthesis of Vitamin D

• UV light on skin– Latitude, season, clothing, skin

pigmentation,ageing and sun-blocks

• Approx 10 % from diet– fatty fish and supplemented dairy

products

Dietary replacement of D -1000 IUFood IUs per serving* Percent DV**

Cod liver oil, 1 tablespoon 1,360 340

Salmon, cooked, 3.5 ounces

360 90

Milk, nonfat, reduced fat, and whole, vitamin D-fortified, 1 cup

98 25

Margarine, fortified, 1 tablespoon

60 15

Egg, 1 whole (vitamin D is found in yolk)

20 6

FSA 2007

3 portions of salmon per day

8 cups of milk per day

13 tablespoons per day

40 eggs per day

Vitamin D Toxicity

• Hypercalcaemia (> 2.75 mM)

• Hypercalcuria (> 10mmol or mM: Uca/Ucr >1)• Renal stones WHI 1g + 400 IU D - OR 1.17 significant but

• 5.6 per 10,000 years risk of renal stones

• Upper reference limit = 150- 200nM; TUL 2000 IU/D• Toxicity > 500 nM• Extra skeletal toxicity?• Dose related toxicity?

Vitamin D toxicity – fiction

Vitamin D toxicity - FACT

Sanders JAMA 2010

Vitamin D toxicity - FACT

• Vital D RCT Southern Australia March - August

• 2317 > 70yr women • 500,000 IU PO D3 annually

(x10 50,000 tablets)• Included: Maternal NOF/ Past #/

faller• Excluded: Cogn impaired; no

falls/# info; high level care home; >400 IU D /day; antifracture therapy; Ca >2.65;

Assessments:• Mail/ telephone contact• Falls / fracture (F) / No daily

calender• Telephone questionaire• Falls – active/ non active• Calcium intake• 150 had bloods• ITT• Solid statistics

Sanders JAMA 2010

500,000 in unselected population

• 2317 women: 76y• 40% faller• 37% fracture• 10% maternal history• 25% walking aid• 33% < 800 mg

• Median D 53 nM• 8% started anti-fracture therapy

• More Falls (5404): 74% VD/ 68% PL (15% increase)– 83.4 vs 72.7 per 100 yrs treatment– More with fracture– More with soft tissue injury

• Fracture (306): 4.9 vs. 3.9 / 100yr: (+1 per 100 yr treat)

• x1 extra fracture per 100 years of treatment• Higher rate in first 3 months in years 2-5 • Hosp/Death: 22% VD vs. 18% (p=0.06)• Death: 3.5% VD vs. 4%

Sanders JAMA 2010

500,000 in unselected population?

Who are we giving 500,000 IU to?• Baseline VitD in 10%:

– 1.5% had > 100 nM @BL

– 50% < 50 nM

– <3% < 25 nM

Sanders JAMA 2010

?

Local scale of the problem: NOF

0%

10%

20%

30%

Percentage

25 50 75Serum 25(OH) D (nM)

N=47

42% < 25 nM42% 25- 50 nM15% > 50 nM

15%85%

Vitamin D Toxicity: published cases• Hypercalcaemia (> 2.75 mM)

– 77yr Renal failure patient took 50,000 IU D2 long term at unspecified rate (355nM) = Ca 3.3 mM

– 42yr Focal segmental glomerulosclerosis with nephrotic syndrome with vitamin D 12.5nM, took 50,000 IU D2 weekly x6 + thiazide + CaCO3

• Ca 2.86 mM

– 68yr with steroid sensitive Evan’s syndrome + fracture + diuretic, • started 50,000 IU D2per day + 1g Ca• Six weeks later (2.1 million IU D): Ca = 3.7 mM• Peak D = 805 nM• Required mithramyacin, peritoneal dialysis with irreversible CRF

– 76 COPD + steroids + fracture + diuretics• 50,000 IU x2/wk + 1 g Ca for 5 yrs (5.2 million IU/year)• 25OHD = 635 nM• Reversible ARF

Schwartzamn 1987 AJM

Hyperparathyroidism

PTH stimulates activation of vitamin D and potentially increases risk of hypercalcaemia

• 25 hypercalcaemic PHPT + < 50 nM 25OHD • Intervention:• 50,000 IU D3 weekly x4 then monthly x 12• Outcome:

6 months / 12 months• No significant change in serum calcium

1Grey JCEM 2005

What did we use to do?

• Adcal D3 (400 IU)• 50,000 D2 po • 150,000; 300,000 D3 IM

D2 (Ergo)- vs D3 (chole)

IM vs po

Daily vsIntermittent

+/- Calcium

Loading vs. Maintenance

?

Treatment principles

• Patient group • Daily vs intermittent dosing• D2 (Ergo-) vs D3 (chole-) calciferol• IM vs po administration• Co-administration with Calcium

Persistance to vitamin D is key• 311 patients post NOF• 1.0g Ca + 800 IU Vitamin D od on discharge• 6 month compliance?

Giusti JBMM2009

Predictors1.Bisphosphonate use2.Preplanned visit3.No dementia4.< 7 co meds

36.7%

Effectiveness to vitamin D is key• 122 50 -90 yr post NOF• 1.2g Ca + 800 IU Vitamin D• 6 monthly clinic visits to improve compliance for 1 year

• 56% drop out rate by 12 months

•Of those still in study:

•61% adherent

•8% > 75nM 25OHD

Segal Arch Ger & Ger 2009

Dosing frequency

• 48 Women (age 80)

• Cholecalciferol po– 1,500 IU daily– 10,500 IU weekly– 45,000 IU / 28 days

• No difference in 25OHD or PTH suppression

• One episode hypercalcaemia in daily dose

• Only 50% of < 25nM at baseline had > 70nM at 8 weeks

Ish-Shalom JCEM 2008

Can use intermittent dosing

Is Intermittent dosing biological effective?

• 100,000 IU PO D3 4mthly• British Doctors study • Ipswich GP practice• 5 yr Postal study

• 74.3 nM vs 53.4 nM

Trivedi BMJ 2003

Yes with D3

Is Intermittent dosing biological effective?

• 300,000 IU IM D2 annually x3• 9440 > 75 yr attending flu vaccine• 585 incident fractures• No effect on falls

Smith Rheumatology 2007

HR 1.09 (0.93 – 1.28) HR 1.49 (1.02 – 2.18)

Intermittent D2 is not effective

Why Is Intermittent dosing dangerous?

Who are we giving 500,000 IU to?• Baseline VitD:

– 1.5% had > 100 nM @BL– 50% <> 50 nM– <3% < 25 nM

• Treatment1 mth: 82% > 100nM; 24% > 150 nM

Where now?– Our aim is to treat deficiency <50 nM

– Not answered by this study.– Balance adherence vs. potential

toxicity– Focus on dose vs. peak level

– ? Oral same as UV vitamin D

Sanders JAMA 2010

Intra-muscular route better?

• 90 female > 65yrs• Acute admissions• 72 vs 13 (ca/vitd obs)• Diasorin RIA

• How many controls on ca/D• By baseline D?

• 11% still <50 nM at 3month

Nugent Ir J Med Sci 2009

How much is needed in vitamin D deficient patients

• 100,000 cholecalciferol po

• Needs to be repeated every 2 months

• No toxicity• Not sufficient for those with

levels < 20ng/ml

Ilahi Am J Cl Nut 2008

Need more than 100,000 IU

Intermittent dose amount 300,000 iu

D3 oral

D3 IM

D2 oral

D2 IM

Romagnoli JCEM 2008

PTH suppression with 300,000 iu

D3 IM

D3 po

300,000 iu & Oral & D3 best choice

D2 IM

D2 po

How much: 300,000 vs 800 IU per day

N= 26 > 65yrs with PTH > 48pg/mlPremaor JBMR 2008

300,000 lasts about 3 months

50 n

M

After loading?

Bacon OI 2008500,000 IU D3 safe in those with 25(OH)D > 50nM

• 32 inpatients (<50nM and >50nM)• Loading = 500,00 IU D3• Maintenance = 50,000 IU per month• Both

Why measure baseline 25(OH)D?• Relatively expensive (£15) and time consuming to measure (send to liverpool)• Safe in high doses

• Safety in high doses in question

• Only offer treatment to those who need it• Titrate doses of replacement• Baseline figure to compare response

• Unlicensed treatment that is red listed as hospital consultant only

Stratify by calcium intake

• Unnecessary to give calcium if dietary replete

• Intolerance common with calcium component

• Lower compliance with daily regimes1

• Toxicity if high calcium intake?

1Rossini OI 2006

Potential risks of calcium over replacement

• 1471 Postmenopausal • > 25 nM 25OHD• 1g Ca vs placebo• 5yr follow-up• Improved HDL/LDL

0

2.5

5

7.5

10

All Vascular MI

Placebo

1g Ca

P=0.008

P=0.01

1Bolland BMJ 2008

Avoid supplementing those with high dietary calcium intakes

Treatment principles for those with low vitamin D levels

• Ergo- vs chole- calciferol

• IM vs po administration

• Daily vs intermittent dosing

• Dose amount

• Co-administration with Calcium

Cholecalciferol

Po

Intermittent

300,000 iu load

Separate

Cost implications?

AdCal D3 (600mg Ca/400iu D3); £52/ yr

Calcichew D3 forte (500mg Ca/ 400iu D3): £55/ yr

Calcit D3 (500mg Ca/ 440iu D3): £105/ yr

Calfovit D3 (1.2g/ 800iu D3): £55/ yr

Calcium and Ergot (450mg/ 400 iu D2): £37/ yr

Comparing vitamin D therapies

Comparing vitamin D therapies

800 IU 50,000 IU 300,000 IU

Comparing vitamin D therapies

800 IU bd

50,000 IUmonthly

300,000 IU4- 6 mths

Comparing vitamin D therapies

800 IU bd

£52.00/ yr

50,000 IUmonthly

£ 2.00/ yr

300,000 IU4 -6 mths£ 3.00/ yr

Oxford solution...

• IDIS Dekristol 20,000 IU D3 23p each• Biotech 50,000 IU D3 18.5 p each

– £2.22 / yr for maintenance and £1.11 for loading– Unlicensed in UK– FDA approval for over the counter use in USA– MHRA approval for import and use in the UK

• Shared guidance for adverse event/ efficacy monitoring...

Sun advice

• Aim is sun exposure without well before burning• Sun exposure 5-15 minutes twice a week from 1100 to 1500

exposed face and arms without sun-cream (Note from Nov- Feb no benefit from sun exposure)

• EXCEPT IF : a history of skin cancer, porphyrias, xeroderma pigmentosum, SLE

• albinism, sulphonamides, phenothiazines, tetracyclines, psoralens,

• granulomatous disease (Sarcoid but not TB) and lymphoma

Does it work?

0

50

100

150

200

250

300

Pos

t lo

adin

g c

once

ntra

tion

of 2

5(O

H)D

(nM

)

0 12.5 25 17.5 50

Pre loading concentration of 25(OH)D (nM)

Effect of High dose oral loading of 25(OH)D

Local data 2009

Is it safe?

PreloadingDeficiency:

Post Loading

Frequency 25OHD (IQR) % replete1 Mean Ca2+ Hyper-calcaemia (%)

Moderate (10-20 ng/ml)

44.8% 36.3 (28.7, 40.9)

90.1% 2.37 (0.1) 2% (1) 2

Severe (<10ng/ml)

55.2% 40.4 (32,6, 47.9)

96.8% 2.35 (0.08) 0 %

1Of the 5 patients who were not replete on their post loading 25OHD check, 3 had dates on their blood tests indicating that they had it done before loading and 1 had rise in D from 3.5 to 17.9 ng/ml.

2Already identified with primary hyperparathyroidism (Ca(adj) 2.64 mM)

Oxford journey• Jun 2008 Guidance produced• Nov 2008 ORH pharmacy approval• Mar 2009 MAC Approval – Black light• May 2009 MHRA import approval• Aug 2009 MAC Approval – Red light• May 2009 OxPF applied– needs PH review first – deferred• Aug 2009 PH Review delayed because of H1N1• Nov 2009 OxPF presentation…rejected needs PH review• Feb 2010 submitted TRF review to board…rejected no demand from other

PCTs• Apr 2010: PCT refuse to commisison high dose vitamin D...• await confirmation of next step.......draft specification:

Draft PCT specification

Can test in: • Premenopausal / men under 60

y with OP• Diagnosis of secondary OP:

– genetic (congenital); – hypogonadal states; – endocrine; – inflammatory diseases; – hematologic and neoplastic; – drug-induced osteoporosis; – eating disorders, – alcoholism, – transplant

• Severe osteoporosis– Lowest T score <-3

• Fracture with normal or osteopenia

• Fracture on treatment or unable to tolerate treatment

• Retest in <25nM with severe and complex deficiency

Draft PCT specification• As vitamin D deficiency can be assumed in these patients, NHS

Oxfordshire will not commission serum vitamin D testing for

• Type I osteoporosis (postmenopausal osteoporosis) (Women aged 50-70 years, disease characterised by accelerated bone loss)

• Type II (age-associated) osteoporosis (Women and men 70+ years - bone loss associated with ageing), regardless of previous fragility fracture

• As a measure of compliance with osteoporosis treatment • (see NICE Clinical Guideline 76 Medicines Adherence (2009) -

http://www.nice.org.uk/nicemedia/live/11766/42971/42971.pdf•

Summary of PCT guidance:• We will be able to test in:

– all men and women with a t score of <-3 or– if they are >-2.5 with a fracture, or– premenopausal women/men <60y with osteoporosis.

• We won’t currently be able to test 25OHD in postmenopausal women and men over 60yr with a tscore of -2.5 to -3 except if they have:– genetic (congenital); hypogonadal states; endocrine;

inflammatorydiseases; hematologic and neoplastic; drug-induced osteoporosis; eatingdisorders, alcoholism, transplant

Why are the PCT concerned?

• Testing costs (40 – 15 pounds)

• Prescribing costs– 20 pence per 50,000 capsule (hospital cost)– pack 100 capsules = £31 [£ 12 = P&P!]– Equates to 31p/caps– If buy 10 not 100 then £10 per capsule!– ‘Profit’ of £9.69 per capsule (3100%)

– Adcal costs £52

• Oxford first…

Summary• Vitamin D deficiency is common• Associated with many diseases but evidence for treating improving clinical

outcomes in only a few: • Test for it: 1) osteoporosis/ osteomalacia 2) fallers 3) ethnic minority with symptoms of osteomalacia or are planning or are

pregnant • Serious issues with persistence with daily calcium/ vitamin D preparations• High dose loading and then maintenance therapy is key in those with low

levels of D

Have we been here before?

Summary• In meantime in deficient patients (< 25 nM and < 50 nM)

1. use Adcal d3 bd and encourage adherence2. Avoid the 300,000 IU D2: not vitamin D33. 1000 IU D3 oral from Boots OTC

– LOAD: x4 per day for 8 (<25nM) or 4 (25- 50 nM) weeks (112,000 IU/ month)– Maintain: x1 per day (31,000 IU/ month)

– (A day in sun = up to 20,000 IU D3)

Treatment not commissioned…but we will persist

Questions....

Draft PCT specification• Current NICE guidance suggests that clinical testing of vitamin D

status is unnecessary as it assumes that postmenopausal women who require bisphosphonates for osteoporosis have an adequate calcium intake and are vitamin D replete.

• This guidance assumes that women who receive treatment have an adequate calcium intake and are vitamin D replete. Unless clinicians are confident that women who receive treatment meet these criteria, calcium and/or vitamin D supplementation should be considered.

•

Observational studies

TB therapy

• N=365 ITT RCT double blinded New Guinea• New diagnosis TB• 20% HIV1/10% HIV2• 100,000 IU D3 or placebo at baseline, 5m 8m

• LCMS 25OHD

• DOTS ethambutol, isoniazid, rifampicin, pyrazinamide 2m then iso/etham 6m

Wejse Am J Resp care 2009

TB therapy• Safety

– 1 in treatment and 2 in placebo Ca >2.93 mM

• Efficacy– No difference in smear rates– Weight gain– Inconsistent changes in CD4 count – fall in HIV+ve

Wejse Am J Resp care 2009

Why did it not work

• But baseline VD status still predicted outcome– Why?

• Not enough given• Residual Confounding

Wejse Am J Resp care 2009

Wejse Am J Resp care 2009

100,000 IU D3: Baseline, 5m, 8m

Cyrus CooperNigel Arden

Sarah CrozierHazel InskipNick HarveyPam MahonRhodri Martin

John WassKerri RanceRachael KnightCarol WeeksJulie AstonVicky ToghillSally Hope

Steven KennedyAris Papageorghiou Christos IoannouMohammad YaqubAlison Noble

Replacing vitamin D

• 100,000 IU D3 oral 2mnthly and 1g Ca/day• 56 adolescents: 29 VD & 27 PLC

Arpadi Pediatrics 2009

Fanconi Syndrome

• Proximal tubular dysfunction– Impaired of reabs of

• Glucose• Amino acids• Uric acid• Phosphate• Bicarbonate

• Aetiology: – Inh: cysinosis, Wilsons, Lowe, Tyrosinaemia, GSD, Dents– Tetracyclines, tenofovir, Lead poisoning, MGUS

Fanconi Syndrome

• CF– Polyuria, polydipsia, dehydration– Hypophophataemic rickets / OM– Short– Acidosis– Low K Phos high CL– Hi pruria, phosuria, glycosuria, uricosuria