Vitamin D: Bones and Beyond
Julie Freedman
June 2009
Runner-up Titles
A. Sun and sardines B. Bones, groans, and Crohn’sC. Change your attitude, or
change your latitude
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.
Where does it come from?
• Sources:– Sun exposure– Oily fish– Dietary
supplements
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.
Classic Target Tissues
• Bone• Intestine• Kidney
• (We’ll miss you, Anthony)
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
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
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.
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)
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)
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.
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
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.
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.
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?
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!)
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.
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
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.
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.
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.
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.
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.
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.
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.
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.
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.
Treatment
• Sunlight
• Oily fish (salmon, mackerel, sardines) and cod liver oil.
• Fortified foods (milk, cereals, margarine)
• Supplements
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
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.
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.
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.
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.
• 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.
Bring a bottle of vitamin DBeach picturesThe 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