Download Vitamin D Deficiency: To D or not to D, that is the question.

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 Range
INTERPRETIVE guidelines for Vitamin D (25hydroxy):
> 80 ng/mL: Potential toxicity
30-80 ng/mL: Optimum level
20-29 ng/mL: Insufficiency
< 20 ng/mL: Deficiency
Vitamin D Basics
Units: 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 thumb

For 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 deficient
More 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
nmol/L
25-OH-D levels
(nmol/L)
decrease with
age, % body fat
and BMI
nmol/L
Yetley EA. Am J Clin Nutr 2008;88(suppl):558S-64S.
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 D3
In 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)
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
Holick M. NEJM 357;3:266-280
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 Effects
Increases tubular reabsorption of calcium and
stimulates the kidney to produce 1,25 OH
vitamin D
Activates 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
loss
93% 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/proliferation
Regulate apoptosis
Modulate 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 system
Stimulate insulin secretion
Control 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 disease
Increased hepatic catabolism due to
medications
Impaired renal production of 1,25 –OH vit. D
in stage 4 and 5 CKD
Renal 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)
Number of First Nonvertebral Fractures among All Subjects, According to Skeletal Site
Dawson-Hughes B et al. N Engl J Med 1997;337:670-676
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. (BischoffFerrari, Am J Clin Nutr 2006)
FIGURE 2. Relative risks (RRs; {square}) of hip fracture (A) and nonvertebral fracture (B)
between subjects who took vitamin D and control subjects
Bischoff-Ferrari, H. A et al. Am J Clin Nutr 2006;84:18-28
Copyright ©2006 The American Society for Nutrition
Vitamin D and Falls
Vitamin 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. (BischoffFerrari, 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 Study
1739 subjects (mean 59 yr, 55% F, all C)
 No prior CVD
 Mean 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-up
 120 developed first CV event

Wang TJ, et al. Circulation 2008;117:503-511.
Evidence for Role of Vitamin D in
CVD: Framingham Offspring
No HTN
Hypertension
Hazard ratios Adj. for age,
ng/mL
sex
Adj for
*covar.
25-OH-D >15
1.00
1.00
1.00
10 to <15
2.07
1.93
2.07
(1.19-3.61)
(1.09-3.42)
(1.16-3.69)
3.19
2.51
2.43
(1.70-5.99)
(1.30-4.82)
(1.23-4.80)
25-OH-D >15
1.00
1.00
1.00
10 to <15
1.45
1.06
1.05
(0.74-2.82)
(0.53-2.13)
(0.52-2.13)
1.66
1.00
1.08
(0.35-2.85)
(0.37-3.16)
<10
<10
(0.64-4.28)
Wang TJ, et al. Circulation 2008;117:503-511.
Adj. for
*covar., CRP
*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
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
1.43
1.60
(1.24-3.54)
(0.96-2.13)
(1.10-2.32)
*FHx MI, BMI, EtOH, activity, DM, HTN, ethnicity, region, marine -3 intake, LDL, HDL, TG
Giovannucci E, et al. Arch Intern Med 2008;168(11):1174-1180.
Vitamin D and Hypertension
148 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
Initial
25-OH-D
(nmol/L)
Final
Ca only
Vit. D + Ca
Ca only
Vit. D + Ca
24.6
25.7
44.4
64.8
(17.8 ng/mL)
(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
Pfeifer M, et al. J Clin Endocrinol Metab 2001;86:1633-37.
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 Diabetes
In 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 Cancer
Both 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 cancers
The 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 Mortality
Retrospective 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 mortality
Median follow up was 8.7 years, during which there
were 1806 deaths, including 777 from CVD
In 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)
Restricted cubic spline showing the fully adjusted associations between serum 25hydroxyvitamin D (25[OH]D) levels and all-cause mortality in 13 331 participants of the Third
National Health and Nutrition Examination Survey
Melamed, M. L. et al. Arch Intern Med 2008;168:1629-1637.
Copyright restrictions may apply.
Association Between 25OH 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.
Ginde et al, Arch Intern Med 2009
Participants with recent upper respiratory tract infection (URTI) stratified by serum 25hydroxyvitamin D level (to convert to nanomoles per liter, multiply by 2.496) and season
Ginde, A. A. et al. Arch Intern Med 2009;169:384-390.
Copyright restrictions may apply.
Vitamin D Deficiency
and Other Conditions
Linked to increased incidence of :
Schizophrenia
Depression
Reactive Airway Disease
Who Should Be Screened for Vitamin D
Deficiency
Elderly
Home bound or institutionalized patients
Patients with known or suspected
malabsorption
Patients with osteoporosis or osteopenia
CKD patients
Chronic liver disease patients
Patients with nonspecific musculoskeletal
pain
Patients on medications that induce P-450
enzyme activity
Obese
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/ml
50, 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 3050% of the time recommended for tanning until
deficiency corrected, then maintenance therapy
If 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
Strategies to Prevent and Treat Vitamin D Deficiency
Holick M. N Engl J Med 2007;357:266-281
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