What do we know about VITAMIN D?

1. What do we know aboutVITAMIN D? New Mexico ACP Annual Meeting Steve Urban, MD 27 October 2012

2. Outline • A brief history of vitamins • Physiology of vitamin D • Normal and abnormal vitamin D levels • Vitamin D and disease: associations • Vitamin D and disease: treatment studies • When should we measure vitamin D levels? • How should you treat Vitamin D deficiency? • Who should take vitamin D supplements?

3. A disclaimer • I am not an expert on Vitamin D. • I am not a “believer” in vitamin supplements for most healthy people. • OK, maybe I’ll relent on folic acid in pregnancy • I have a generally skeptical attitude toward received information. • I am not making any money from this talk.

4. Vitamins: a brief history • Scurvy described by Hippocrates • 1630-1750: rickets, beriberi, pellagra described • 1747: Lind and scurvy • 1860: Cod liver oil used for rickets • 1884: TakakiKanahiro and beriberi • 1897: Eijkman experiments • 1912: Casimir Frank “vital amine”

5. Vitamins: Nobel prizes 1929: Eijkman and Hopkins: “accessory factors” 1934: Minot, Murphy, Whipple: liver therapy of pernicious anemia 1937: Szent-Gyorgyi: vitamin C 1938: Karrer: structure of riboflavin, A, and E 1943: Doisy and Dam: Vitamin K 1965: Woodward, Todd, Hodgkin: structure of B12 1967: Wald: Vitamin A and retinols

6. Vitamin D • 1915 McCollum: fat-soluble A and water soluble B. • 1922: McCollum and Davis isolate Vitamin D as the “anti-rachitic factor” • 1930s: Windaus determines structure of Vitamin D to be a sterol • 1970: Fraser discovers calcitriol in kidney • 1984: Immunomodulatory effects described

7. Welcome to the nuthouse • 1930s and 40s: Synthesis and mass production • 1970: Linus Pauling shows that even a genius can become confused. Billions of dollars are wasted on vitamin supplements. • Lesson: vitamins are defined as trace elements that treat deficiency diseases. Use of vitamins for any other purpose is pharmacotherapy and can be studies like any other substance.

9. Vitamin D3 and D2

10. Vitamin D: physiology • Upregulates epithelial Ca channel • Upregulates Na/PO4 cotransporter 2b • Increases Fibroblast Growth Factor 23 • Increases RANKL expression • Suppresses renin production • Increases insulin sensitivity

11. Nuclear effects of calcitriol • Calcitriol enters the cell • Binds to VDR (vitamin D receptor) • VDR dimerizes with the retinoid X receptor • VDR-RXR complex binds to VDREs • Expression of over 200 genes affected

12. In vitro effects of calcitriol • Suppresses cellular proliferation • Decreases beta-catenin induced proliferation • Suppresses cyclin-dependent kinases • Enhances apoptotic pathways • Antiangiogenic properties • Immunomodulatory effects • Stimulates innate immunity • Modulates self-tolerance • Enhances killing of Mycobacteria

13. Definitions of normal • Population based norms: • 10-55 ng/mL • Rickets and osteomalacia never occur >10 • “Physiologic” norms • <20 ng/mL: deficient • 20-30 ng/mL: insufficient • >30 ng/mL: good enough for the government • >150 ng/mL: risk of intoxication

14. Definitions of normal

15. If this is normal… • 40-90% of US community dwelling elderly • 50% of premenopausal women • 50% of Hispanic and black adolescents • 48% of French preteens • 30-50 % of adults in Saudi Arabia and UAE • 73 % of pregnant women taking prenatal vitamins …are DEFICIENT

16. Epidemiological associations • Osteopenia and osteoporosis • Hip and vertebral fractures • Falls and gait instability • Hypertension • Congestive heart failure • Colon, prostate, and breast cancer • Type 1 and type 2 diabetes • Multiple sclerosis • Autoimmune diseases • Schizophrenia and depression

17. Interventional studies:Fractures • Chapuy MC NEJM 1992 327:1637

18. Interventional studies:Women’s Health Initiative

19. Interventional studies: Meta-analyses

20. Interventional studies:Falls

21. Interventional studies:Cardiovascular outcomes

22. Should we measure Vitamin D levels? • Technical problems • Cost • Population-wide screening ? • NOBODY recommends this (even the illuminati) • High risk groups??? • Malabsorption syndromes • High-risk medications • Anti-epileptic drugs • HAART • Corticosteroids • Certain chronic kidney diseases (espnephrotics)

23. Should we measure Vitamin D levels? • Other “high risk groups” ?????????? • Elderly • Obese • Dark-skinned • Anybody with insurance

24. Should we treat low Vitamin D?The evidence

25. If you choose to treat… • 100 IU/d raises level by about 1 ng/mL • Sunlight 3000 IU/10 minutes • Oily fish 300 IU/3 oz • Salmon, sardines, mackerel, tuna • Mushrooms 100 IU/3 oz • Fortified drinks 100 IU/8 oz • Milk, orange juice, yogurt, cereals

26. If you choose to treat… • Deficiency • 50,000 IU weekly for 8 weeks • Higher doses for malabsorption, hi-risk medications, nephrotic syndrome • Followup levels in 8 weeks • Maintenance • 800-1000 IU daily • Up to 4000 IU/day is usually safe

27. Should you take vitamin D? • IOM recommends • 600 IU/day below age 70 • 800 IU/day after age 70 • They think you can do it with diet and sunlight • USPSTF recommends • Age above 65 • Increased fall risk • Community dwellers • Endocrine society recommends • 1000-2000 IU/day • Everybody and his/her dog • Remember: THEY ARE TRUE BELIEVERS

28. Dr. Urban’s advice • If you don’t know what you’re doing… DON’T DO ANYTHING.

29. Final thoughtsWho to test? • High risk of Vitamin D deficiency PLUS high risk of fractures PLUS wouldn’t otherwise be treated: • 1. Malabsorption • 2. High risk medications • Antiepileptic drugs • Antiretroviral treatment • Corticosteroids • 3. Nephrotic syndrome

30. Final thoughtsWho should take a supplement? • People at high risk of falls and fractures: • That is to say, the frail elderly. • I would use 800 IU a day.