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Vitamin D: Bones and Beyond Julie Freedman June 2009

Vitamin D: Bones and Beyond Julie Freedman June 2009. Runner-up Titles. A. Sun and sardines B. Bones, groans, and Crohn’s C. Change your attitude, or change your latitude. Objectives. Review basic physiology and epidemiology of vitamin D

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Vitamin D: Bones and Beyond Julie Freedman June 2009

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  1. Vitamin D: Bones and Beyond Julie Freedman June 2009

  2. Runner-up Titles A. Sun and sardines B. Bones, groans, and Crohn’sC. Change your attitude, or change your latitude

  3. Objectives • Review basic physiology and epidemiology of vitamin D • Consider changing definitions of deficiency, and of optimal vitamin D levels • Review evidence for skeletal health • Review evidence for extraskeletal health • Develop a strategy for assessment of vitamin D levels, treatment of deficiency, and supplementation.

  4. Where does it come from? • Sources: • Sun exposure • Oily fish • Dietary supplements

  5. Physiology • Vitamin D from skin and diet metabolized in liver to 25-hydroxyvitamin D (25-OH D) • Kidney metabolizes 25-OH D to its active form: 1,25-OH D. • Renal production is tightly regulated by PTH, calcium, and phosphorous • Low vitamin D levels raise PTH which leads to osteoclast activation.

  6. Classic Target Tissues • Bone • Intestine • Kidney • (We’ll miss you, Anthony)

  7. Non-Classical Target Tissues • Parathyroid glands, pancreas, immune tissues, keratinocytes • Over 200 identified genes have vitamin D response elements. • Calcium economy • Proliferation, differentiation, apoptosis • Primary and acquired immunity

  8. Definition of deficiency • Historically, less than 20 ng/ml of 25-OH-D • Many advocate for a “physiologic” definition of normal as > 30 ng/ml • PTH levels level off at 30 or above • Increased intestinal transport when raising level from 20 to 32

  9. Prevalence • 1 billion people worldwide have deficiency or insufficiency, defined as < 20 ng/ml • 48% of white preadolescent girls in Maine • 36% of 18-20 year-olds at the end of a Boston winter • 42% of 15-49 yo Black girls and women at the end of winter • 25-54% of patients over 65 years of age • > 50% of postmenopausal women on treatment for osteoporosis. • 40% of US/European community-dwelling elderly. • 32% of healthy medical students, doctors and residents in a Boston hospital. • Serum levels of < 30 ng/ml: • 80% of Europeans and half the world’s population are deficient.

  10. Mechanisms of Deficiency • Decreased dietary intake • Decreased absorption • Reduced sun exposure • Increased hepatic catabolism (liver disease) • Decreased endogenous synthesis (renal disease) • End-organ resistance (rare)

  11. Risk factors for deficiency • Extreme latitudes • Advanced age • Institutionalization • Darker complexion • Renal failure • Liver failure • Obesity (vit D accumulates in fat stores) • Malabsorption (Celiac dz, IBD, bariatric surgery) • Medication interactions (rifampin, dilantin, carbamazepine)

  12. Skeletal health • Without vitamin D, only 10-15% of dietary Ca is absorbed; only 60% of phosphorous • Vitamin D deficiency causes hyperparathyroidism, leading to demineralization of bone, leading to rickets and osteomalacia.

  13. Vitamin D supplementation and fracture risk • Fracture risk: • Prospective study of 3300 French women: • 800IU vitamin D daily, 1200 mg calcium • reduced hip fracture by 43% and nonvertebral fracture by 32% however WHI study of women on 400 IU reported no benefit for hip fracture and increased kidney stones. • 390 women and men: • 700 IU, 500 mg calcium led to 58% reduction in nonvertebral fracture. • WHI: 36,000 women: • 400 IU vitamin D, 1000 calcium • No benefit for hip fracture, but more kidney stones

  14. Vitamin D supplementation and fracture risk • Meta-analysis of 7 trials – • little benefit with 400IU for either hip or nonvertebral fractures • Studies using 700-800IU demonstrated fracture reduction of 23% for nonvertebral fractures and 26% for hip fractures.

  15. Vitamin D supplementation and fracture risk • Is there a threshold serum level? • WHI demonstrated little effect on fracture risk for levels < 26 ng/ml • Optimal prevention trials gave 700-800 IU and raised baseline vitamin D levels from < 17 to 40 ng/ml.

  16. Falls in the Elderly • Meta-analysis of 5 RCTs demonstrated 22% reduction in falls with 800 IU as the most effective dose. 400 IU was not effective. • Subsequent study of 124 nursing home residents (average age 89): 800 IU group had 72% reduction in falls vs. placebo. No dose-response curve was seen. • Threshold level for response?

  17. Extraskeletal Hypotheses • Vitamin D can improve chronic pain! • Vitamin D helps fight infection! • Vitamin D prevents autoimmune disease! • Vitamin D prevents cancer! • (Vitamin D improves blood pressure!)

  18. Change your attitude, or change your latitude? Epidemiology: • Higher latitudes increase risk for Hodgkin’s lymphoma, colon, pancreatic, breast, and ovarian cancer. • Higher latitude increases risk of type 1 DM, multiple sclerosis, and Crohn’s disease.

  19. Pain and vitamin D • Osteomalacia patients complain of dull ache in their bones which can be tender to the touch. • Plotnikoff and Quigley, 2003 • Minneapolis, Minnesota (45°N) • 150 primary care patients with nonspecific musculoskeletal pain • Immigrants and native-born, very multiracial sample • Non-elderly, non-homebound

  20. Pain and vitamin D • 93% of patient had vitamin D level < 20 (Mean of 12). • Younger patients fared worse: • Age < 30 - mean level 9 • Age > 50 - mean level 13 • Levels lower in African-Americans - mean of 9 • Conclusion: “Patients with non-specific skeleto-muscular pain should have vitamin D levels checked.” • Caution: No evidence that raising vitamin D levels improves pain.

  21. Immune function and vitamin D • Vitamin D as immunomodulator • May enhance innate immunity while controlling the excesses of adaptive immunity (autoimmune disease). • In vitro: 25-OH D levels control generation of cathelicidin by monocytes and macrophages in response to Mycobacterium Tb challenge.

  22. Autoimmunity and vitamin D • Multiple sclerosis has a multifold increase in prevalence with increasing latitude. • Multiple sclerosis risk also changes with migration of populations - suggests environmental link.

  23. Autoimmunity and vitamin D Multiple Sclerosis: Prospective, case-control study of US military personnel - bank of stored serum samples prior to diagnosis. Caucasians - inverse correlation with vitamin D levels: highest quintile has 51% lower incidence. Among African-Americans and Hipanics, the association was not significant.

  24. Autoimmunity and vitamin D Type 1 DM: Finnish birth-cohort study: infants who received vitamin D supplementation in year 1 of life had 80% reduced risk of type 1 DM.

  25. Vitamin D and cancer risk • Normal colon, breast, and prostate cells have vitamin D receptors. • Vitamin D metabolites may inhibit angiogenesis, promote differentiation, inhibit cell proliferation. • Longstanding observation of higher breast, colon and prostate cancer risks at higher latitudes.

  26. Vitamin D and cancer risk • 30 studies of colon cancer or adenomatous polyps - 20 found a statistically significant benefit of vitamin D. • 4 Prospective studies: • Two studies showed 2x risk of colon cancer for level < 30. • One showed 2x risk for level < 20. • A fourth showed favorable, but non-significant trend.

  27. Vitamin D and cancer risk • Breast cancer: • 13 studies of breast cancer, 9 reported a favorable association. • NHANES women with high intake or sun exposure (self-reported) had reduced lifetime risk.

  28. Vitamin D and cancer risk • Prostate cancer: 13/26 studies showed significant favorable association. • One study of 19,000 men in Finland found 70% higher incidence in men with levels < 16.

  29. Treatment • Sunlight • Oily fish (salmon, mackerel, sardines) and cod liver oil. • Fortified foods (milk, cereals, margarine) • Supplements

  30. Supplementation • Vitamin D2 - ergocalciferol • Vitamin D3 - cholecalciferol • FDA recommends 400 IU daily - all ages • Current recommendations from IOM: • 200 IU daily for children/adults < 51 • 400 IU daily for age 51 - 70 • 600 IU daily for age > 70 • Doses of 1000 IU needed for level > 30

  31. Treatment of Deficiency For deficiency (<20), (or insufficieny < 30): • 50,000 IU weekly for 8 weeks, then recheck. • Follow with 1,000 IU daily maintenance. • Some studies suggest cholecalciferol increases levels more efficiently than ergocalciferol For patients with chronic renal disease or severe liver disease, calcitriol is preferable. However, 25-OH D levels will not reflect clinical status.

  32. Too much of a good thing? • Hypervitaminosis D: • Hypercalcemia. • Can lead to calcification of bones, soft tissues, heart and kidneys. • Kidney stones • Hypertension However, no evidence of excess at doses below 10,000 IU daily.

  33. How much sunlight is enough? • Exposure of arms, shoulders and back for 15 minutes in summer, 20 minutes in spring or fall, between 11 am and 2 pm, 2 - 3 times per week. • If you have dark skin, you need up to twice as long.

  34. Concluding Thoughts • Vitamin D appears to have effects far beyond the calcium economy - not just for bones anymore…. • Defining optimal vitamin D status will be difficult in chronic disease and malignancy - long latency and multifactorial causation make them difficult to study. • Although current definition of deficiency is < 20, study outcomes for fractures, falls, and cancer prevention suggest optimal level > 30. • Current recommendations for supplementation may be insufficient. Consider 800 - 1000 IU.

  35. Higher latitude increases risk of type 1 DM, multiple sclerosis, and Crohn’s disease. • Risk of MS decreases by 41% for every increase of 20 ng/ml above 24. • Finnish study of >10,000 children who received 2000IU from birth to 1 – had 80% less risk of DM 1 over 31 years.

  36. Bring a bottle of vitamin D Beach pictures The power pill: statin, ace, fish oil, green tea, dark chocolate, almonds, vitamin D? • Other tissues with vitamin D receptors: brain, prostate, breast, colon, immune cells • 1/25 OH-D controls >200 genes, some of which regulate apoptosis, proliferation, angiogenesis. • Immunomodulator – can increase synthesis of cathelicidin – fights M. tuberculosis • 25-OH levels < 20 associated with 30-50% increased risk of incident colon, prostate, breast cancer • WHI participants with level < 12 had 253% increased colorectal cancer risk over 8 years. • Higher vitamin D intake correllated with 50% less risk of breast cancer

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