Vitamin D Deficiency: To D Or Not To D, That Is The Question.

Rick Padilla, MD

Denver Health

March 10, 2009

Case

Mrs. G. is a 68 yo HF with hx of metabolic syndrome and seizure disorder who comes in for routine follow up. She has no acute complaints. Her last seizure was 3 months ago and she has 3-4 seizures per year. Her rx are glucovance 5/500 mg daily, crestor 5 mg qhs, zestoretic 20/25 mg daily, aspirin 81 mg daily, OTC calcium 2 tabs per day and dilantin 300 mg qhs. BP 124/74, P 72, RR 16, BMI 30.2 Physical exam is normal.

Case continued

Pertinent studies, HgBA1C = 6.9, LDL = 88, creat cl = 60, spot UA = moderate microalbumin. No recent dilantin level. A Dexa scan done 1 year ago reveals normal BMD with a T score of –0.8.

Should you order a 25 OH vitamin D level on this patient?

DH Lab Reference RangeINTERPRETIVE guidelines for Vitamin D (25-hydroxy):          > 80 ng/mL: Potential toxicity          30-80 ng/mL: Optimum level        20-29 ng/mL: Insufficiency         < 20 ng/mL: Deficiency      

Vitamin D BasicsUnits: ng/mL vs. nmol/L 2.5 nmol/L = 1 ng/mL If data are in nmol/L, divide by 2.5 for ng/mL

Rule of thumbFor every 100 IU vitamin D3 ingested, blood

level of 25-OH-D increases by 1 ng/mL 1 g of D3 or D2 = 40 IU

Prevalence of Vitamin D Deficiency

In several studies, 40 to 100% of U.S. and European elderly men and women still living in the community are vitamin D deficientMore than 50% of postmenopausal women taking rx for osteoporosis are vitamin D deficient (Holick et al. J Clin Endocrinol Metab 2005)45/80 (56.2%) of geriatric patients in a UCDSOM study of vit. D education intervention study were vitamin D deficient. (VandeGriend et al. J Am Pharm Assoc 2008)

Vitamin D Levels in the LUCHAR Dataset

34/139 (24.5%) normal

40/139 (28.8%) insufficiency

65/139 (46.8%) deficiency

Mean 22.5 ng/mL

Range < 5 – 52 ng/mL

Yetley EA. Am J Clin Nutr 2008;88(suppl):558S-64S.

nmol/L

nmol/L

25-OH-D levels(nmol/L)decrease withage, % body fatand BMI

D3 ≠ D2 ≠ 1,25-di(OH)-D3

D3 is made in the skin* (or ingested in supplements) – not biologically active Cholecalciferol

D2 is from plants** (not humans) – only 1/3 as active as D3 Ergocalciferol

1,25-di(OH)-D3 is converted in the kidney and other tissues - biologically active “Vitamin D” Calcitriol

25-OH-D is the storage form, NOT biol. active*From 7-dehydrocholesterol **From ergosterol

Sources of Vitamin D

Exposure to sunlight

Dietary Sources

Dietary Supplements

Exposure to Sunlight

5-10 minutes of direct exposure to the arms and legs = 3000 IU of vitamin D3In a study of 69 healthy subjects age 18-29 in Boston, 36% had 25 OH vit D level < 20 ng/ml at the end of winter. The prevalence decreased to 4% by the end of summer. (Tangpricha Am J Med 2002)Multiple studies show vitamin D def. common in sunny areas when most of the skin is shielded from the sun (Saudi Arabia, United Arab Emirates, Turkey, India and Lebanon)

Holick M. NEJM 357;3:266-280.

Sources of Vitamin D

Holick M. NEJM 357;3:266-280

Synthesis and Metabolism of Vitamin D in the Regulation of Calcium, Phosphorus, and Bone Metabolism

1,25 OH Vitamin D Effects

Increased calcium absorption in the gut

Increased PTH mediated bone resorption

Decreased renal calcium and phosphorus excretion

Decreased PTH secretion

Increased bone calcification

PTH EffectsIncreases tubular reabsorption of calcium and stimulates the kidney to produce 1,25 OH vitamin DActivates osteoblasts , which then stimulates the activation of osteoclasts, which dissolve mineralized collagen matrix in the bone, causing osteopenia and osteoporosis and increasing the risk of fracture.Causes phosphaturia. A low Ca-Phos product leads to decreased mineralization of the collagen matrix= rickets in kids and osteomalacia in adults

Osteomalacia

Softening of the bone due to impaired mineralization due to low Ca-Phos product.Symptoms include isolated or generalized bone pain, muscular weakness, and weight loss93% of 150 persons 10 to 65 year old seen in an ED in Minnesota with muscle aches and bone pain were deficient (< 20 ng/ml) in vitamin D and 28% had severe deficiency (< 8 ng/ml) (Plotnikoff, Mayo Clin Proc 2003)

Non-classical Actions of Vitamin D

Suppress cell growth/proliferationRegulate apoptosisModulate immune responses Susceptibility to infections Susceptibility to autoimmune disorders – MS, T1DM Effects in transplantation immunity

Modulate keratinocyte differentiation and function Key role in psoriasis therapy

Suppress renin-angiotensin systemStimulate insulin secretionControl neuromuscular function and the brain

Dusso AS, et al. Am J Physiol–Renal Physiol 2005;289:F8-F28.

Mechanisms of Vitamin D Deficiency

Reduced skin synthesis - Sunscreen use (SPF 15 reduces vitamin D3

synthesis by 99%) - Skin pigmentation - Aging (reduction of 7 dehydrocholesterol

reduces vitamin D3 synthesis by 75% in a 70 year old)

- Season, latitude and time of day -Patients with skin grafts for burns

Mechanisms of Vitamin D Deficiency Continued

Impaired availability of vitamin D due to inadequate dietary intake, malabsorptive disorders and obesity (sequestration of vitamin D in body fat)Impaired hydroxylation by the liver due to liver diseaseIncreased hepatic catabolism due to medicationsImpaired renal production of 1,25 –OH vit. D in stage 4 and 5 CKDRenal loss of vit. D and vit. D binding proteins in nephrotic syndrome

Medications That Increase Catabolism of Vitamin D via P450 Enzyme Activity

Phenytoin

Phenobarbital

Carbamazepine

Isoniazid

Theophylline

Rifampin

Glucocorticoids

HAART

Vitamin D and Fracture Risk

Among 3270 elderly French women given 1200 mg calcium and 800 IU of vit D3 daily for 3 years, the risk of hip fracture and nonvertebral fracture decreased by 43% and 32% respectively (Chapuy, NEJM 1992)In 389 subjects over 65 years old, 700 IU of vit D3 and 500 mg per day of calcium decreased nonvertebral fracture by 58% compared to placebo. (Dawson-Hughes, NEJM 1997)

Dawson-Hughes B et al. N Engl J Med 1997;337:670-676

Number of First Nonvertebral Fractures among All Subjects, According to Skeletal Site

Vitamin D and Fracture Risk

A meta-analysis of 7 RCT’s evaluating fracture risk in pts given 400 IU of vit D3 per day revealed little benefit. In studies using 700-800 IU of of vitamin D3 per day, the RR of hip fracture and nonvertebral fracture were reduced by 26% and 23% respectively compared to calcium and placebo. (Bischoff-Ferrari, Am J Clin Nutr 2006)

Copyright ©2006 The American Society for Nutrition

Bischoff-Ferrari, H. A et al. Am J Clin Nutr 2006;84:18-28

FIGURE 2. Relative risks (RRs; {square}) of hip fracture (A) and nonvertebral fracture (B) between subjects who took vitamin D and control subjects

Vitamin D and FallsVitamin D deficiency causes muscle weakness because skeletal muscle has a vitamin D receptor and may require vitamin D for maximal function.A meta-analysis of 5 RCT with a total of 1237 subjects revealed that increased vitamin D intake reduced the risk of falls by 22%. On further evaluation, 400 IU of vitamin D per day was not as effective 800 IU vitamin D per day in reducing the risk of falls. (Bischoff-Ferrari, Am J Clin Nutr 2006)In an RCT done in a NH, residents receiving 800 IU of vitamin D2 per day plus calcium had a 72%reduction in the risk of falls compared with placebo. (Broe, J Am Geriatr Soc, 2007)

Evidence for Role of Vitamin D in CVD

Framingham Offspring Study1739 subjects (mean 59 yr, 55% F, all C)No prior CVDMean 25-OH-D 19.7 ng/mL

28% with 25-OH-D <15 ng/mL 9% with 25-OH-D <10 ng/mL

5.4 yr follow-up120 developed first CV event

Wang TJ, et al. Circulation 2008;117:503-511.

Evidence for Role of Vitamin D in CVD: Framingham Offspring

Adj. for age, sex

Adj for *covar.

Adj. for *covar., CRP

25-OH-D >15 1.00 1.00 1.00

10 to <15 2.07(1.19-3.61)

1.93(1.09-3.42)

2.07(1.16-3.69)

<10 3.19(1.70-5.99)

2.51(1.30-4.82)

2.43(1.23-4.80)

25-OH-D >15 1.00 1.00 1.00

10 to <15 1.45(0.74-2.82)

1.06(0.53-2.13)

1.05(0.52-2.13)

<10 1.66(0.64-4.28)

1.00(0.35-2.85)

1.08(0.37-3.16)

Hyp

ert

en

sio

nN

o H

TN

Wang TJ, et al. Circulation 2008;117:503-511.

Hazard ratios

ng/mL

*Covar. SBP, anti-HTN, DM, cig, total-HDL, BMI, creat

Evidence for Role of Vitamin D in CVD

Health Professionals Follow-up Study Prospective trial nested case control 18,225 M age 40-75 (mean 63.8 yr) 94% C No known CVD, baseline 25-OH-D 24.5 vs. 23 ng/mL 10 yr follow-up 454 with nonfatal MI or fatal CHD

Giovannucci E, et al. Arch Intern Med 2008;168(11):1174-1180.

Compared with 25-OH-D >30 ng/mL

<15

ng/mL

15-22.5

ng/mL

22.6-29.9

ng/mL

RR of MI after adjustment*

2.09(1.24-3.54)

1.43(0.96-2.13)

1.60(1.10-2.32)

*FHx MI, BMI, EtOH, activity, DM, HTN, ethnicity, region, marine -3 intake, LDL, HDL, TG

Vitamin D and Hypertension148 F age 75 yr with 25-OH-D level <50 nmol/L received calcium 600 mg plus 400 IU D3 BID vs. calcium 600 mg alone BID over 8 weeks

Pfeifer M, et al. J Clin Endocrinol Metab 2001;86:1633-37.

Initial Final

Ca only Vit. D + Ca Ca only Vit. D + Ca

25-OH-D (nmol/L)

24.6 25.7 44.4(17.8 ng/mL)

64.8(25.9 ng/mL)

PTH (pmol/L) 6.1 6.1 5.3 4.6

SBP (mmHg) 140.6 144.1 134.9 131.0

DBP (mmHg) 82.6 84.7 75.7 77.5

HR (mmHg) 74.1 75.4 73.9 71.3

Vitamin D and Hypertension

In a study of hypertensive patients who were exposed to ultraviolet B radiation three times per week for 3 months, 25 OH vitamin D levels increased by approximately 180% and both SBP and DBP were reduced by 6 mm Hg. (Krause, Lancet 1998)Proposed mechanism: The 1,25 OH vitamin D produced in the kidney enters the circulation and down regulates renin production in the kidney

Studies Needed of Interactions Between Vitamin D and CVD

Prospective studies to prove that vitamin D deficiency results in increased CVD events

Well-designed studies to determine mechanisms for increased risk

Prospective studies to prove that adequate vitamin D replacement decreases CVD events

Studies to determine optimal formulation, dosing, target levels

Vitamin D and DiabetesIn 10,366 children in Finland given 2000 IU of vitamin D3 per day during their first year of life and then followed for 31 years, the risk of type 1 DM was reduced by 80%. In subset analysis, among children with vitamin D deficiency, the risk was increased by 200%. (Hyponen, Lancet 2001)Combined daily intake of 1200 mg of calcium and 800 IU of vitamin D lowered the risk of type 2 diabetes by 33 % compared to daily intake of less than 600 mg calcium and less than 400 IU of vitamin D. (Pittas, Diabetes Care 2006)Proposed mechanism: The 1,25 OH vitamin D produced in the kidney enters the circulation and stimulates insulin secretion in the islet cells of the pancreas

Vitamin D and CancerBoth prospective and retrospective epidemiologic studies reveal that levels of 25 OH vitamin D below 20 ng/ml are associated with a 30-50% increased risk of incident colon, prostate and breast cancer, along with higher mortality from these cancersThe probable mechanism is that colon, prostate and breast express 25-OH vitamin D 1-alpha hydroxylase and produce 1,25 OH vitamin D locally to control genes that help prevent cancer by limiting cellular proliferation and differentiation by inhibiting angiogenesis and inducing apoptosis

Vitamin D Deficiency and All Cause MortalityRetrospective analysis of 13,331 adults 20 years or older from NHANES III testing association of low 25 OH vitamin D and all cause, cancer and cardiovascular mortalityMedian follow up was 8.7 years, during which there were 1806 deaths, including 777 from CVDIn multivariate models (adjusted for baseline demographics and traditional and novel CVD risk factors), compared with the highest quartile, being in the lowest quartile (25 OH vitamin D <17.8 ng/ml) was associated with a 26% increased rate of all cause mortality, (95% CI, 1.08-1.46. Cancer and CVD mortality was not statistically significant.Conclusion: Lowest quartile of 25 OH vitamin D (<17.8 ng/ml) is independently associated with all cause mortality in the general population. (Melamed, Arch Intern Med, 2008)

Copyright restrictions may apply.

Melamed, M. L. et al. Arch Intern Med 2008;168:1629-1637.

Restricted cubic spline showing the fully adjusted associations between serum 25-hydroxyvitamin D (25[OH]D) levels and all-cause mortality in 13 331 participants of the Third

National Health and Nutrition Examination Survey

Ginde et al, Arch Intern Med 2009

Association Between 25- OH Vitamin D and URI

Retrospective analysis of 18,883 subjects 12 and older from NHANES III The median serum 25 OH vit D was 29 ng/mL. Recent URI was reported by 24% with 25 OH vit D < 10 ng/mL, by 20% with levels of 10 to < 30 ng/mL and 17% with levels of >30 ng/mL (p<0.001).The association between 25 OH vit D and URI higher in those with asthma (OR 5.67) and COPD (OR 2.26)Conclusion: Serum 25 OH vit D levels are inversely associated with recent URI.

Copyright restrictions may apply.

Ginde, A. A. et al. Arch Intern Med 2009;169:384-390.

Participants with recent upper respiratory tract infection (URTI) stratified by serum 25-hydroxyvitamin D level (to convert to nanomoles per liter, multiply by 2.496) and season

Vitamin D Deficiency and Other Conditions

Linked to increased incidence of :

Schizophrenia

Depression

Reactive Airway Disease

Who Should Be Screened for Vitamin D Deficiency

ElderlyHome bound or institutionalized patientsPatients with known or suspected malabsorptionPatients with osteoporosis or osteopeniaCKD patientsChronic liver disease patientsPatients with nonspecific musculoskeletal painPatients on medications that induce P-450 enzyme activityObese

Treatment of Vitamin D Deficiency

50, 000 IU capsule of vitamin D2 (erogocalciferol) once per week for eight weeks, repeat for another 8 weeks if 25 OH vitamin D is < 30 ng/ml50, 000 IU capsule of vitamin D2 (erogocalciferol) once per week for eight weeks, then 50,000 IU of vitamin D2 every 2 to 4 weeks thereafter for maintenance. If malabsorption syndrome, 50,000 IU of vitamin D2 every day or qod + the use of a tanning bed for 30-50% of the time recommended for tanning until deficiency corrected, then maintenance therapyIf stage 4 or 5 CKD, 0.25-1.0 ug of 1,25 dihydroxyvitamin D3 (calcitriol) bid

Preventive and Maintenance Measures to Avoid Vitamin D Deficiency

Sensible sun exposure- 5-30 minutes of exposure of arms and legs between 10 am and 3 pm twice a week is often adequate.

50,000 IU of vitamin D2 every 1-4 weeks

1000 IU of vitamin D3 per day

100,000 IU of vitamin D3 once every 3 months maintains 25 OH vitamin D levels at > 20 ng/ml and is also effective at reducing fracture risk

Holick M. N Engl J Med 2007;357:266-281

Strategies to Prevent and Treat Vitamin D Deficiency

Vitamin D Intoxication

Common symptoms:anorexia, nausea and vomiting, polyuria, polydipsia, weakness and pruritus

Lab abnormalities: AKI, hypercalcemia and hyperphosphatemia

Treatment: stop vitamin D, low calcium diet, acidify the urine and steroids

Mrs. G.

Should you order a 25 OH vitamin D level on this patient?

Mrs. G.

Age 68

BMI 30.2

DEXA with normal BMD (T score –0.8)

On OTC calcium

On dilantin

Mrs. G.

25 OH vitamin D level = 18 ng/ml

Was started on ergocalciferol 50,000 IU per week x 8 weeks

• Repeat 25 OH vitamin D level after treatment = 35 ng/ml

• Now on maintenance therapy of ergocalciferol 50,000 IU every 4 weeks

Take Home Points• Vitamin D deficiency is common• 25 OH vitamin D is a predictor of bone health in

terms of fracture risk and risk of falls• 25 OH vitamin D is also potentially an independent

predictor of risk of cardiovascular disease, hypertension, cancer, diabetes, all cause mortality, and URI

• At least 800 IU of vitamin D3 per day is needed to maintain vitamin D sufficiency

• Sensible sun exposure is a great way to maintain vitamin D sufficiency