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Vitamin D M Kassim Javaid Norman Collisson Senior Research Fellow,

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1 Vitamin D M Kassim Javaid Norman Collisson Senior Research Fellow,
Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford Oxfordshire Osteoporosis Metabolic Bone Disease Service Nuffield Orthopaedic Centre, Oxford

2 Declaration These views are my own
Oxfordshire PCT do not commission the use of high dose vitamin D

3 Why vitamin D Biology Clinical implications Rationale for therapy
Cost implications Next steps

4 Sunshine vitamin 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

5 Males: 79.5% & 97.9% and respectively
At 50 nmol/L: Private: M 50%, F 62.2%. Institutions: M 80.7%, F 81.5%

6 The past 1885 bone histology by Pommer 1918 Cod liver oil by Mellenby
First recognized in 1650 by Frances Glisson 1885 bone histology by Pommer 1918 Cod liver oil by Mellenby 1919 Artifical UV cure Huldschinsky

7 Cholecalciferol (D3) Provitamin D vitamin D 25 vitamin D
UV 290 – 315 nm (297 peak) Converts provitamin D to previtamin D Warmth converts previtamin D to cholecalciferol vitamin D IF too much pre-vit d then uv breaks down to lumisterol4 and tachysterol3 25 vitamin D Ergocalciferol (D2) 1,25 vitamin D 1 ng/ml = 2.5 nM & 10 mcg = 400 IU < 25 nM = deficiency 25 – 50 nM = insufficiency Action

8 Clinical consequences
Osteomalacia variable proximal myopathy, hypotonia bone tender and pain bowing fracture (groin pain)

9 Bone and vitamin D: Osteomalacia
675 iliac crest biopsies tested for osteomalacia Autopsy Diasorin assay to measure 25OHD threshold…. Priemel JBMR 2010

10 Is there a bone threshold?
Stable high calcium intake Raised D deficient till 10 weeks Re- fed various D diets for wks Anderson JBMR 2008

11 Vitamin D and bone 0 nM > 100 nM Osteopenia Secondary
hyperparathyroidism Impaired intestinal calcium absorption Reduced bone volume with normal mineralization Rickets Males: 79.5% & 97.9% and respectively At 50 nmol/L: Private: M 50%, F 62.2%. Institutions: M 80.7%, F 81.5% 0 nM > 100 nM Osteopenia

12 Population studies of D and bone
N = 7441 PMO corrected for age, BMI, serum creatinine, and season Kuchuk JBMR 2009

13 Vitamin D and fracture LeBoff 2000 JAMA
30 pmo admitted with a hip fracture LeBoff 2000 JAMA

14 Local scale of the problem: NOF
Percentage 85% 15% 30% 20% 10% 0% 42% < 25 nM 42% nM 15% > 50 nM 25 50 75 Serum 25(OH) D (nM)

15 Vitamin D deficiency predicts future hip fracture
800 women from WHI (7.1yr) 1665 men from MrOS (5.3yr) OR P for trend = 0.03 HR 1.6 ( ) per sd decrease in 25OHD Cauley AIM 2008 Cauley JBMR 2009

16 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

17 In pregnancy: Why and when? Normal trabecular bone
Osteoporotic Fragile bone

18 Life course perspective
‘Cradle’ ‘Grave’ Birth weight Childhood growth Adult Bone Loss Hip Fracture Peak bone mass One food stuff many active ingredients A stimulus at a sensitive of development has lasting effect on structure and function Nine ages of man by R Johnston

19 Maternal effects on offspring’s bone mass
Pre -pregnancy Pregnancy ‘Cradle’ Neonatal Bone mass SGA Vitamin D status Pre-eclampsia Gestational DM Childhood Bone mass Asthma Diabetes

20 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 Southampton S Kennedy, University of Oxford N Bishop, University of Sheffield

21 Maternal vitamin D supplementation in pregnancy
Down’s Screening (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 D iu/wk 3D Scan 1800 women To inform the management of vitamin D insufficiency in pregnant women in the UK/World

22 Improve Maternal Vitamin D
Improve Baby bone mass Reduce elderly risk of fracture

23 The emerging roles for 25(OH)-vitamin D: both programming and adult:
Bone metabolism Osteoarthritis Calcium/ phosphate balance 25(OH)-Vitamin D Atherosclerosis and heart failure Immune function Oncology

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

25 Effect of daily vitamin D replacement
Toxic Is it the dose or peak level ? Replete Toxicity Ideal Deficient Severe Deficient

26 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

27 Dietary replacement of D -1000 IU
Food 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 3 portions of salmon per day 8 cups of milk per day 13 tablespoons per day 40 eggs per day FSA 2007

28 Vitamin D Toxicity Hypercalcaemia (> 2.75 mM)
Hypercalcuria (> 10mmol or mM: Uca/Ucr >1) Renal stones WHI 1g IU D - OR 1.17 significant but 5.6 per 10,000 years risk of renal stones Upper reference limit = nM; TUL 2000 IU/D Toxicity > 500 nM Extra skeletal toxicity? Dose related toxicity?

29 Vitamin D toxicity – fiction

30 Vitamin D toxicity - FACT
Sanders JAMA 2010

31 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

32 500,000 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

33 500,000 in unselected population?
Who are we giving 500,000 IU to? Baseline VitD in 10%: 1.5% had > 100 50% < 50 nM <3% < 25 nM ? Sanders JAMA 2010

34 Local scale of the problem: NOF
Percentage 85% 15% 30% 20% 10% 0% 42% < 25 nM 42% nM 15% > 50 nM 25 50 75 Serum 25(OH) D (nM)

35 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

36 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

37 ? What did we use to do? Adcal D3 (400 IU) 50,000 D2 po
150,000; 300,000 D3 IM IM vs po +/- Calcium ? D2 (Ergo)- vs D3 (chole) Daily vs Intermittent Loading vs. Maintenance

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

39 Persistance to vitamin D is key
311 patients post NOF 1.0g Ca IU Vitamin D od on discharge 6 month compliance? Predictors Bisphosphonate use Preplanned visit No dementia < 7 co meds 36.7% Giusti JBMM2009

40 Effectiveness to vitamin D is key
yr post NOF 1.2g Ca 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

41 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 Can use intermittent dosing Ish-Shalom JCEM 2008

42 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 Yes with D3 Trivedi BMJ 2003

43 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 Intermittent D2 is not effective HR 1.09 (0.93 – 1.28) HR 1.49 (1.02 – 2.18) Smith Rheumatology 2007

44 Why Is Intermittent dosing dangerous?
Who are we giving 500,000 IU to? Baseline VitD: 1.5% had > 100 50% <> 50 nM <3% < 25 nM Treatment 1 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

45 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

46 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 Need more than 100,000 IU Ilahi Am J Cl Nut 2008

47 Intermittent dose amount 300,000 iu
D3 oral D3 IM D2 oral D2 IM Romagnoli JCEM 2008

48 PTH suppression with 300,000 iu
D3 IM D3 po 300,000 iu & Oral & D3 best choice D2 IM D2 po

49 How much: 300,000 vs 800 IU per day 300,000 lasts about 3 months
50 nM 300,000 lasts about 3 months N= 26 > 65yrs with PTH > 48pg/ml Premaor JBMR 2008

50 After loading? 32 inpatients (<50nM and >50nM)
Loading = 500,00 IU D3 Maintenance = 50,000 IU per month Both 500,000 IU D3 safe in those with 25(OH)D > 50nM Bacon OI 2008

51 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

52 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

53 Potential risks of calcium over replacement
1471 Postmenopausal > 25 nM 25OHD 1g Ca vs placebo 5yr follow-up Improved HDL/LDL P=0.008 10 7.5 P=0.01 5 Placebo 1g Ca 2.5 All Vascular MI Avoid supplementing those with high dietary calcium intakes 1Bolland BMJ 2008

54 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

55 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

56 Comparing vitamin D therapies

57 Comparing vitamin D therapies
800 IU 50,000 IU 300,000 IU

58 Comparing vitamin D therapies
800 IU bd 50,000 IU monthly 300,000 IU 4- 6 mths

59 Comparing vitamin D therapies
800 IU bd £52.00/ yr 50,000 IU monthly £ 2.00/ yr 300,000 IU 4 -6 mths £ 3.00/ yr

60 Oxford solution... IDIS Dekristol 20,000 IU D3 23p each
Biotech 50,000 IU D 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...


62 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


64 Does it work? Effect of High dose oral loading of 25(OH)D
300 250 200 Post loading concentration of 25(OH)D (nM) 150 100 50 12.5 25 17.5 50 Pre loading concentration of 25(OH)D (nM) Local data 2009

65 Is it safe? Preloading Deficiency: 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)

66 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:

67 Draft PCT specification
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 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

68 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 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) -

69 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

70 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…

71 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

72 Have we been here before?

73 Summary Treatment not commissioned…but we will persist
In meantime in deficient patients (< 25 nM and < 50 nM) 1. use Adcal d3 bd and encourage adherence 2. Avoid the 300,000 IU D2: not vitamin D3 IU D3 oral from Boots OTC LOAD: x4 per day for 8 (<25nM) or 4 ( 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

74 Questions....


76 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.

77 Observational studies

78 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

79 TB therapy Safety Efficacy
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

80 Why did it not work But baseline VD status still predicted outcome
Not enough given Residual Confounding Wejse Am J Resp care 2009

81 100,000 IU D3: Baseline, 5m, 8m Wejse Am J Resp care 2009

82 John Wass Kerri Rance Rachael Knight Carol Weeks Julie Aston Vicky Toghill Sally Hope Steven Kennedy Aris Papageorghiou Christos Ioannou Mohammad Yaqub Alison Noble Cyrus Cooper Nigel Arden Sarah Crozier Hazel Inskip Nick Harvey Pam Mahon Rhodri Martin

83 Replacing vitamin D 100,000 IU D3 oral 2mnthly and 1g Ca/day
56 adolescents: 29 VD & 27 PLC Arpadi Pediatrics 2009




87 Fanconi Syndrome Proximal tubular dysfunction Aetiology:
Impaired of reabs of Glucose Amino acids Uric acid Phosphate Bicarbonate Aetiology: Inh: cysinosis, Wilsons, Lowe, Tyrosinaemia, GSD, Dents Tetracyclines, tenofovir, Lead poisoning, MGUS

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

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