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

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

Vitamin D physiology Holick, M. (2006)

Vitamin D insufficiency is prevalent

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 www.clinicaltrials.gov 1488 studies relating to vitamin D registered in US 509 open interventional studies

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

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

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

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

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

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

What is the optimal serum 25OH vitamin D level?

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

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

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%)

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

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)

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

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

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

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

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)

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

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.