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