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