1. Vitamin D Dr. Pamela Leventis Consultant Rheumatologist
Epsom & St. Helier NHS Trust

2. Vitamin D - Outline Vitamin D physiology in brief
Vitamin D – a cure for all ills?
What is optimal?
When to measure serum 25-OHD
Treatment of vitamin D deficiency/insufficiency
Vitamin D formulations
Route of replacement
Principles for supplementation

3. Vitamin D physiology
Holick, M. (2006)

4. Vitamin D insufficiency is prevalent

5. Vitamin D in the spotlight
Emerging associations with onset and propagation of range of cancers, autoimmune, and infectious diseases…and all cause mortality
Global Attention
Media
Scientific community
Explosion of epidemiological studies
Ongoing research
1488 studies relating to vitamin D registered in US
509 open interventional studies

6. Vitamin D in the news Vitamin D deficiency linked to childhood obesity
Scientists reverse stance on sun and cancer: Now they admit sunlight can prevent skin cancer
Low vitamin D levels linked to more aggressive breast cancers
Conventional medicine finally admits MS caused by vitamin D deficiency
Vitamin D deficiency linked to childhood obesity
Scientists say higher vitamin D intake will slash cancer, MS, and diabetes risk by half
Vitamin D 'key to healthy brain'
Vitamin D intake in pregnancy prevents RSV infections in infants
Vitamin D grows hair, prevents the flu and reduces arthritis pain

7. Supporting evidence Biochemistry
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 differentiation
DNA repair and apoptosis
Metabolism, 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 differentiation
Stimulates immune responses to APCs eg. Cathelicidin production Macrophages - ?TB

8. Endocrine, autocrine and paracrine effects of vitamin D
Holick, M. (2006)

9. Supporting evidence Clinical Trials
Epidemiological
Close relationship between latitude and serum 25 OH D levels
1 degree of latitude corresponds to 1 ng/mL of 25-hydroxyvitamin D3
Lower 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 – 12-60mths
Inconsistent dosing and serum 25OHD not always known

10. Limitations of data Caution 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

11. Vitamin D, falls and fractures
Higher fracture incidence in vitamin D deficient patients
Modest BMD changes with vitamin D replacement insufficient to explain observation
?change in bone quality
Or 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

12. What is the optimal serum 25OH vitamin D level?

14. Optimal Serum 25-hydroxyvitamin D levels for Bone Health
Physiological deficiency
The 25(OH)D concentration below which PTH levels increase in a population
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
Thomas et al., 1998

15. Factors promoting vitamin D deficiency
Increasing age
Skin melanin
Institutionalised/Limited sun exposure/Strict sunscreen use
Malabsorption, Renal or liver disease
Medications eg. anticonvulsants, rifampicin, glucocorticoids, cholestyramine, HAART
Obesity
Exclusive breast feeding beyond 6 months in infants
But deficiency/insufficiency v. widespread
50% healthy adults – insufficient in winter/spring (serum 25OHD nmol/l) (Hypponen and Power, 2007)

16. When to measure 25OHD levels
Clinical features - osteomalacia
Insidious onset widespread or localised bone pain and tenderness
Proximal muscle weakness
Falls
Fractures
Non specific myalgia
Biochemical osteomalacia
Low vitamin D
Hypocalcemia - occasional
Alkaline phosphatase may be elevated
Secondary hyperparathyroidism (80%)

17. 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/l
Supplemented for 3 months (800IU D3/d)
Mean post-treatment level 58nmol/l
<60nmol/l in 55%
Compliance unknown
Risk of renal stones

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

19. Optimal Route Oral versus IM
4 groups of 8 elderly patients received:
300,000IU vitamin D2 im
300,000IU vitamin D2 po
300,000IU vitamin D3 im
300,000IU vitamin D3 po
Serum samples taken at 3, 7, 30 and 60 days
Romagnoli et al. 2008
D3po
D2po
Bolus po D3 – 3x AUC
D3im
D2im

20. Vitamin D replacement No single effective regimen
Various plausible approaches
Regimen should be tailored to formulation and route of administration
Bolus oral dosing
Rapid and sustained rise in serum 25OHD
Reliable adherence
However high dose D3 preparations not readily available in the community

21. 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 weeks
Therapeutic goal is to achieve serum 25OHD levels >75nmol/l compatible with biochemical repletion
Calcium 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

22. Vitamin D Replacement Local Practice – Vitamin D preparations
OTC
Sunvite vitamin D3 400iu/1000iu tablets (Holland & Barrett)
Vitamin D3 1000iu Nature’s Remedy (vegetarian option available)
Biolife Vitamin D3 1000iu Lifestyle Natural Health (vegetarian)
Prescribed
Lamberts® Vitamin D3 1000iu
If Calcium required – Adcal D3 (calcium carbonate 1.5g/ colecalciferol 400iu) 1 tablet bd
Bolus oral/im vitamin D3 dosing in secondary care
Contraindications: Hypercalcaemia, metastatic Ca, primary hyperPTH.
Cautions in sarcoidosis, renal stones/hypercalciuria

23. Iatrogenic vitamin D toxicity
Very 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)

24. Vitamin D & Calcium supplementation and 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 mortality
Unexplained ↓ risk in women taking calcium supplements at baseline Multiple limitations to study:
exclusion of 56% original WHI trial patients, ?over-interpreted subgroup analysis
Overall 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

25. 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

26. References
Armas LAG, Hollis BW, Heaney RP. Vitamin D2 is much less effective than vitamin D3 in humans. J Clin Endocrinol Metab 2004; 89:
Autier P, Gandini S. Vitamin D supplementation and total mortality. Arch Intern Med 2007;167:
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:
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:
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:
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:
Garland CF, Garland FC, Gorham ED et al. The role of vitamin D in cancer prevention. Am J Public Health 2006;96:
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:
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 ;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:
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:
Scragg R. Seasonality of cardiovascular disease mortality and the possible protective effect of ultraviolet radiation. Int J Epidemiol 1981;10:
Thomas MK, Lloyd-Jones DM, Thadhani RI et al. Hypovitaminosis D in Medical Inpatients. N Eng J Med 1998;338:
Zittermann A. Vitamin D in preventative medicine: are we ignoring the evidence? Br J Nutrition 2003;89: