Vitamin D

1. Vitamin D and
Osteoporosis
Iris Thiele Isip Tan MD, FPCP, FPSEM
Clinical Associate Professor, UP College of Medicine
Section of Endocrinology, Diabetes & Metabolism
Department of Medicine, Philippine General Hospital

2. Disclosure
Merck Sharp & Dohme (MSD)
Honoraria as RTD speaker
Travel grant for regional endocrine meeting

3. How much
vitamin D is enough?

4. How much
vitamin D is enough?

5. Should vitamin D
levels be measured?
How much
vitamin D is enough?

6. Should vitamin D
levels be measured?
How much
vitamin D is enough?

7. Should vitamin D
levels be measured?
How much
vitamin D is enough?
Does supplemental
vitamin D reduce
fractures and falls?

8. How much
vitamin D is
enough?

9. Vitamin D and Bone Metabolism
Gut
In vitamin D-
deficient state,
calcium absorption
decreases Low calcium causes
increase in PTH secretion
PTH
Low Levels of Vitamin D
Calcium reservoir of bone is depleted to
correct for low calcium absorption in gut
Mobilization of calcium
from bone
PTH
Balanced System
Calcium absorption meets metabolic demands
Normal bone mineralization is maintained
Dietary calcium
Circulation
1
2
3
Calcium
reabsorption
Renal distal
tubule
4
Vitamin D
Vitamin D
Adapted from Holick M. Curr Opin Endocrinol Diabetes. 2002;9:87–98; DeLuca HF. Am J Clin Nutr. 2004;80(suppl 1):1689S–1696S;
Lips P. Endocr Rev. 2001;22:477–501; Holick MF. J Nutr. 2005;135:2739S–2748S.
Parathyroid

10. Calcium Absorption: Threshold Effect
Heaney R. Clin J Am Soc Nephrol 2008;3:1535-41
Vitamin D
metabolic utilization
4,000 IU/day
32 ng/dL

11. Vitamin D-fortified milk (400 IU/quart)
Cereals (40-50 IU/serving)
Egg yolks
Saltwater fish
Liver
Clinician’s Guide to the Prevention & Treatment of Osteoporosis
National Osteoporosis Foundation, 2008
Chief Dietary Sources of Vitamin D

12. Vitamin D: Recommended daily intake
The Hormone Foundation 2009
Recommended
daily intake
Vitamin D Calcium
Under age 50 400-800 IU at least 1,000 mg
Over age 50 800-1,000 IU at least 1,200 mg

13. •
•
•
10/11 RCTs: ↑ serum 25(OH)D
Response depends on baseline level
‣ Greater if baseline 25(OH)D <50 nmol/L
0.7 nmol increase in serum 25(OH)D in
healthy young men for each 1 ug
(40 IU) of vitamin D
Brannon et al, Am J Nutr 2008;88:483S-90S
Response to Fortified Food

14. + 100 IU oral
vitamin D intake
= + 1 ng/mL
(2.5 nmol/L)
serum 25(OH)D
Rule of Thumb
Patient with a starting
serum 25(OH)D of 15
ng/mL would require
1,500 IU/d to bring his
level to 30 ng/mL
Heaney R. Clin J Am Soc Nephrol 2008;3:1535-41

15. Individualize requirements for
vitamin D supplementation
Skin
pigmentation
Type of vit D
supplement
(D3 is 3x
more potent
than D2)
Brown S, Alternative Medicine Review 2008

16. TOXICITY
Vitamin D supplementation
Trial characteristics
22 vitamin D trials with AE
outcomes
19 trials: adults only
Many too short to observe AEs
400-4,000 IU/d vit D3 (n=19)
5,000-10,000 IU/d vit D2 (n=2)
Most frequently reported
Hypercalcemia
Hypercalciuria
More events in vit D
group but difference with
placebo group NS
Asymptomatic
Cranney et al, Am J Clin Nutri 2008;88(suppl):513S-9S

17. TOXICITY
Vitamin D supplementation
Trial characteristics
7 trials reported kidney stone
incidence
5 trials had no cases
1 trial reported NS difference
1 reported increase in stones
(WHI)
Women’s Health Initiative
n = 36,282
400 IU vitamin D3 +
1000 mg Ca vs Ca alone
5.7 events/10,000
women-years exposure
Cranney et al, Am J Clin Nutri 2008;88(suppl):513S-9S

18. Institute of Medicine
Tolerable Upper
Intake Level (TUIL)
2,000 IU/day
No-observed-adverse-
effect-level (NOAEL)
10,000 IU/day
Heaney R. J Musculoskelet Neuronal Interact 2006:6(4):334-
Serum 25(OH)D
32 ng/mL = minimum
daily intake of
2,600 IU vitamin D
(US residents)

19. 80-90% of vitamin D is
cutaneously produced
from sunlight
Limited by
age
higher latitudes
working indoors
use of sunscreen
skin pigmentation
cultural practices
precluding skin exposure

20. Bathing suit exposure
during summer
until skin just begins
to turn pink
⇩
skin production of
10,000 - 50,000 IU of
vitamin D3
Adams et al. NEJM 1982;306:772-775

21. Effect on serum
25(OH)D
Nursing home residents
with low baseline 25(OH)D
Suberythemal UV light
exposure = 25(OH)D
28-42 nmol/L after 3 mos.
4 RCTs using artificial
UVB light source
4 RCTs using solar
exposure
Cranney et al, Am J Clin Nutri 2008;88(suppl):513S-9S

22. “Fair evidence to suggest that artificial and solar
exposure increases 25(OH)D levels in vitamin D-
deficient and replete persons, including the elderly.”
Brannon et al, Am J Nutr 2008;88:483S-90S

23. TOXICITY
Sun exposure
Cranney et al, Am J Clin Nutri 2008;88(suppl):513S-9S
“Is a specific level of sunlight
exposure sufficient to maintain
adequate vitamin D levels
without increasing the risk of
non-melanoma skin cancer or
melanoma?”
No studies!

24. Should
vitamin D
levels be
measured?

25. National Osteoporosis Foundation
Measure serum 25(OH)D in
those at risk of deficiency
elderly
malabsorption (i.e. celiac
disease)
chronic renal insufficiency
housebound
chronically ill
limited sun exposure

26. Low Vit D Status Despite Abundant Sun Exposure
University of Hawaii
A’ala Park Board Shop
Serum 25(OH)D and PTH
Skin color: reflectance colorimetry
Sun exposure index: amount of
skin exposed X reported average
sun exposure per week without
sunscreen
Convenience sample of adults
in Honolulu, Hawaii (lat 21 ̊ )
n = 93 (63 ♂, 30♀)
Mean self-reported
sun exposure without
sunscreen use
22.4 h (range 2-96)
28.9 + 1.5 h/wk
Binkley et al, JCEM 2008; 92;2130-5

27. Low Vit D Status Despite Abundant Sun Exposure
51% of subjects had low vit D status
with serum 25(OH)D cutpoint of 30 ng/mL
Evolutionary?
Genetic differences:
Optimal amount of vit D
Cytochrome P450
Inadequate D3
Inadequate cutaneous production
Enhanced cutaneous destruction
of previt D3 or D3
Downregulation of cutaneous
synthesis by sun-induced melanin
production
Abnormalities of transport from
skin to circulation
Binkley et al, JCEM 2008; 92;2130-5

28. Low Vit D Status Despite Abundant Sun Exposure
Sun exposure to the hands
and face for 15 minutes
may not be enough
Measure serum 25(OH)D?
Binkley et al, JCEM 2008; 92;2130-5

29. Measure serum 25(OH)D in otherwise
healthy women with osteoporosis?
Objective:
Identify most useful/
cost-efficient screening
tests in detecting
secondary contributors
to osteoporosis
24-h urine Ca for all
If urine Ca abn,
serum Ca and PTH
Serum TSH for all
on T4 replacement
1
4
24-h urine Ca &
serum Ca for all
If urine Ca or serum
Ca abn, serum PTH
Serum TSH for all
on T4 replacement 2
24-h urine Ca, serum
Ca & PTH for all
Serum TSH for all on
T4 replacement
3
24-h urine Ca, serum
Ca, PTH and
25(OH)D for all
Serum TSH for all on
T4 replacement
Serum Ca, PTH and
25(OH)D for all
Serum TSH for all on
T4 replacement
5
n = 173 postmenopausal women, no known
contributors to osteoporosis on past medical history
Tannenbaum et al, JCEM 2002:87;4431-7

30. Measure serum 25(OH)D in otherwise
healthy women with osteoporosis?
Disorders identified:
56/173 women
Hypercalciuria most
common (9.8%; n=17)
vitamin D deficiency
(4.1%; n=7)
24-h urine Ca ➜
serum Ca & PTH
Serum TSH for all
on T4 replacement
1 2
3 4 5
24-h urine Ca &
serum Ca ➜ PTH
Serum TSH for all
on T4 replacement
T4 replacement
24-h urine Ca,
serum Ca, PTH and
25(OH)D for all
Serum TSH for all on
T4 replacement
Serum Ca, PTH and
25(OH)D for all
Serum TSH for all on
T4 replacement
n = 173 postmenopausal women, no known
contributors to osteoporosis on past medical history
n=33 n=35
n=48
24-h urine Ca, serum
Ca & PTH
Serum TSH for all on
n=55 n=37
Tannenbaum et al, JCEM 2002:87;4431-7

31. Measure serum 25(OH)D in otherwise
healthy women with osteoporosis?
24-h urine
Ca ➜
serum Ca &
PTH
Serum TSH
if indicated
1 2
24-h urine
Ca & serum
Ca ➜ PTH
Serum TSH
if indicated
24-h urine
Ca, serum
Ca & PTH
Serum TSH
if indicated
3
n=33 (59%)
$22/patient
$116 per
diagnosis
n=35 (63%)
$30/patient
$148 per
diagnosis
n=48 (86%)
$75/patient
$272 per
diagnosis
24-h urine
Ca, serum
Ca, PTH,
25(OH)D
Serum TSH
if indicated 4
n=55 (98%)
$116/patient
$366 per
diagnosis
Serum Ca,
PTH,
25(OH)D
Serum TSH if
indicated
5
n=37 (66%)
$108/patient
$506 per
diagnosis
1999: 24h urine Ca $8, serum Ca $7, PTH $57, serum 25(OH)D $41, TSH $23
Tannenbaum et al, JCEM 2002:87;4431-7

32. Vitamin D Deficiency: A Common Occurrence in
Both High- and Low-energy Fractures
44 orthopedic
trauma in-patients
(20♂, 24♀)
Low-energy fracture
fracture from a fall of standing height
High-energy fracture
fracture from a fall greater than
standing height or motor vehicle impact
Mean 29.8
Mean 30.3
Median 27.5
0
10
20
32
30
40
Median 33.5
50
70
60
Men
25(OH)D
[ng/ml]
26/44 (59%)
vit D deficient
18/24 (75%)
Women
8/20 (40%)
Steele et al, HSSJ 2008:4;143-8

33. Vitamin D Deficiency: A Common Occurrence in
Both High- and Low-energy Fractures
Table 2 Age and 25(OH)D level vs. fracture etiology
Low-energy
fractures
High-energy p value
fractures
a. Men
d
b.
Agea
25(OH)Db
72.5±16
19.5
45.9±19
34
0.02c
0.007
Women
Agea
71.1±14 57.8±18 0.053c
25(OH)Db
28 27 0.7d
a
Mean age in years ± standard deviation
b
Median 25(OH)D ng/ml
c
p values were calculated using the t test
d
p values were calculated using the Mann–Whitney test
Steele et al, HSSJ 2008:4;143-8

34. What cut-off value defines
low vitamin D status?
Serum 25(OH)D
<25 nmol/L 25-75 nmol/L >75 nmol/L
Deficiency Insufficiency Sufficiency
Dawson-Hughes B, Am J Clin Nutr 2008:88(suppl);537S-40S
Variability of vit D concentration
by geographical location
Differences in assay methodology
Optimal level of
25(OH)D 30 ng/mL
determined in a
Caucasian population

35. Goal of vit D supplementation?
Serum 25(OH)D greater than an accepted
cutpoint (e.g. 30 ng/ml)
Upper limit of normal (a value that varies
between laboratories)
Binkley et al, JCEM 2008; 92;2130-5

36. Does
supplemental
vitamin D
reduce fractures
and falls?

37. Data Source
MEDLINE and
EMBASE from
1966 to 1999
25 trials
Meta-analysis of the Efficacy of Vitamin D
Treatment in Preventing Osteoporosis in
Postmenopausal Women
Guyatt et al, Endoc Rev 2002; 23(4);560-9

38. Meta-analysis of the Efficacy of Vitamin D
Treatment in Preventing Osteoporosis in
Postmenopausal Women
25 trials
Vitamin D (n=4017) vs
control (n=4107)
Patients with ↓bone
density (17 trials)
Standard vitamin D
(10 trials)
Hydroxylated
vitamin D (14 trials)
Both forms of
vitamin D (1 trial)
Follow-up: 1-5 y
Loss to follow-up
<10% (2 trials)
10-20% (8 trials)
>20% (13 trials)
unknown (2 trials)
Blinded (18 trials)
Unblinded (5 trials)
Blinding unclear
(2 trials)
Guyatt et al, Endoc Rev 2002; 23(4);560-9

39. Vitamin D Treatment in Preventing
Osteoporosis in Postmenopausal Women
RR with 95%CI for vertebral fractures
Guyatt et al, Endoc Rev 2002; 23(4);560-9

40. Vitamin D Treatment in Preventing
Osteoporosis in Postmenopausal Women
RR with 95%CI for nonvertebral fractures
Guyatt et al, Endoc Rev 2002; 23(4);560-9

41. Proposed Scientific and Ethical Guidelines for
Clinical Trials on Vitamin D and Fracture
Osteoporosis Education Project
Vitamin D levels
achieved should
be 32 ng/mL
Achievement of
vit D sufficiency
should be verified
by 25(OH)D
Only those with
25(OH)D >32 ng/
mL should be
included
Vit D
supplementation
must be continued
for at least 12 mos
Vit D3
(cholecalciferol)
should be used
1 3
4
2
5
Brown S, Alternative Medicine Review 2008

42. Trial
Trial Overview
(All RCTs)
Trial
Compliance
Serum Vit D
(Therapeutic
threshold is 32
ng/mL)
% Fracture
Reduction
French Decalyos
I Study
3270 ambulatory
elderly French
women
18-month trial
800 IU D3 w/ tri-
calcium phosphate
(1,200 mg elemental
Ca)
1,762 (54%)
completed the trial
Good supplement
compliance
16 ng/mL average
Vit D level at
baseline
42 ng/mL average
vit D level at
completion of trial
32% ↓ in all
non-vertebral
fractures
43% ↓ in hip
fractures
French Decalyos
I Study
Extension
3270 ambulatory
elderly French
women
18-month extension
of trial
800 IU D3 w/ tri-
calcium phosphate
(1,200 mg elemental
Ca)
Supplement
compliance unclear
but appears
adequate
16 ng/mL average
Vit D level at
baseline
42 ng/mL average
vit D level at
completion of trial
24% ↓ in all
non-vertebral
fractures
29% ↓ in hip
fractures
Vitamin D and Fracture Trials
Brown S, Alternative Medicine Review 2008

43. Trial
Trial Overview
(All RCTs)
Trial
Compliance
Serum Vit D
(Therapeutic
threshold is 32
ng/mL)
% Fracture
Reduction
French Decalyos
II Study
610 ambulatory
French women
2-year trial
800 IU of D3 with
tri-calcium
phosphate (1,200
mg elemental Ca)
422 (69%)
completed the trial
95% supplement
compliance
9 ng/mL average Vit
D level at baseline
30 ng/mL average
vit D level at
completion of trial
Non-significant
↓ in allnon-
vertebral
fractures
31-38% ↓ in hip
fractures
British study of
vit D and
osteoporotic
fracture
2,686 community
living men and
women aged 65-85
5-year trial
100,000 IU tablets
of vit D3 every 4
months
75% of participants
took the vit D at
least 80% of the
time
66% compliance for
final dose
At 4 years
29 ng/mL average
Vit D level in those
on supplements
21 ng/mL average
vit D in placebo
group
33% overall ↓ of
fractures (hip,
wriat, spine,
forearm)
Vitamin D and Fracture Trials
Brown S, Alternative Medicine Review 2008

44. Trial
Trial Overview
(All RCTs)
Trial
Compliance
Serum Vit D
(Therapeutic
threshold is 32
ng/mL)
% Fracture
Reduction
Boston area
study
389 community
dwelling men &
women (mean age
74)
3-year trial
Intervention: 700 IU
D3 and 500 mg
elemental Ca (as
citrate maleate)
318 (82%)
completed the trial
Supplement
compliance
appears good
30 ng/mL average
Vit D level at
baseline
44 ng/mL average
vit D level at
completion of trial
60% ↓ in all non-
vertebral fractures
60% ↓ inhip
fractures
Japanese study
of sunlight
exposure on
258 stroke patients
12-month trial
50% of patients
had 15 minutes/day
of sunlight exposure
to face and hands
50% were sunlight
deprived
Compliance with
sunlight exposure
appears good
6.8 ng/mL average
Vit D level at
baseline
20.8 ng/mL average
vit D level at
completion of trial
Sixfold ↓ in hip
fracture incidence
in the sunlight-
exposed group
3.1%↑ in BMD in
sunlight-exposed
3.3% ↓ in BMD in
sunlight-deprived
BMD & hip
fracture
incidence
among vit D
deficient stroke
patients
Vitamin D and Fracture Trials
Brown S, Alternative Medicine Review 2008

45. Trial
Trial Overview
(All RCTs)
Trial
Compliance
Serum Vit D
(Therapeutic
threshold is 32
ng/mL)
% Fracture
Reduction
284 Alzheimer’s
patients
12-month trial
1,200 mg elemental
calcium 2x/day to
both groups; 50%
of patients had 15
min/day of sunlight
exposure to face,
hands and forearms
(total exposed skin
area 426 +32 cm3);
50% of patients
were sunlight
deprived
Compliance with
sunlight exposure
appears good
9.6 ng/mL average
Vit D level at
baseline
4x more frequent
non-vertebral
fractures in
sunlight-deprived
group (11 vs 3)
4x more frequent
hip fractures in
sunlight deprived-
group (9 vs 2)
2.7% ↑ in BMD in
sunlight-exposed
5.6% ↓ in BMD in
sunlight-deprived
Japanese study
of hip fracture
reduction
20.8 ng/mL average
vit D level at
completion of trial
among
Alzheimer’s
patients through
sunlight
exposure
Vitamin D and Fracture Trials
Brown S, Alternative Medicine Review 2008

46. Vitamin D and Fracture Trials
Some observations
Supplementation
with 400 IU vitamin
D repeatedly found
to have no impact
on fracture
incidence
Bischoff-Ferrari et al meta-analysis
Pooling of 12 studies with 400 IU
vitamin D daily failed to influence
fracture incidence
700-800 IU daily of vitamin D
↓ hip fracture by26%
↓ all fractures by23%
Brown S, Alternative Medicine Review 2008

47. Vitamin D and Fracture Trials
Brown S, Alternative Medicine Review 2008
Vitamin D at an
800 IU daily dose
leads to 25(OH)D
levels of 32 ng/mL
in some but not
all subjects
Less than half of adults will
achieve 25(OH)D of 32 ng/mL
with 700-1,000 IU vitamin D
supplementation x 8 weeks
Some observations
British RECORD trial
800 IU vitamin D in older adults raised
vit D to an average of 24.8 ng/mL
Swiss study
Vit D levels increased from 12.3 ng/mL
to 26.2 ng/mL in ambulatory elderly
given 800 IU D3 daily x 3 months

48. Vitamin D Status and Treatment of Postmenopausal
Osteoporosis with Bisphosphonates
25 (OH) D : 93 [3.3]nmol/L 25 (OH) D : 50 [1.9]nmol/L
#
112 women
On bisphosphonate
Etidronate (n=30)
Alendronate (n=64)
Risedronate (n=38)
Serum 25(OH)D <70
nmol/L (53%)
Deane et al, Alternative BMC Musculoskeletal Disorders 2007

49. Data Source
MEDLINE,
EMBASE, BIOSIS
and Cochrane
database from Jan
1985 to June 2005
5 studies
Meta-analysis: Vitamin D and the Risk of Falls
Jackson et al, QJM 2007;100:185-192

50. All RCTs except 1
D3 used in all
D3 + Ca (4 trials)
Postmenopausal
women only (3 trials)
Mean baseline
25(OH)D were
inadequate (defined
as <76.2 nmol/L)
5 trials
Duration 18 weeks
to over 5 years
D3 dose from 300
to 800 IU except 1
trial (oral capsule of
100,000 IU vit D3 q4
months)
Meta-analysis: Vitamin D and the Risk of Falls
Jackson et al, QJM 2007;100:185-192

51. Meta-analysis: Vitamin D and the Risk of Falls
Review:
Comparison:
Outcome:
Vitamin D3 review
01 Falls
01 Falls including calcium
Study
or sub-category
Vitamin D3 (+/ Ca)
n/N
Control
n/N
RR (fixed)
95% CI
Weight
%
RR (fixed)
95% CI
Graafmans
Pfeifer
62/177
11/70
66/177
19/67
Bischoff 14/62 18/60
16.82
4.95
4.66
0.94 [0.71,
0.55 [0.29,
0.75 [0.41,
1.24]
1.08]
1.37]
Trivedi
Grant
100/270
161/1306
92/255
196/1332
24.11
49.46
1.03 [0.82, 1.29]
0.84 [0.69, 1.02]
1891 100.00 0.88 [0.78, 1.00]
Total (95% CI) 1885
Total events: 348 (Vitamin D3 (+/ Ca)), 391 (Control)
Test for heterogeneity: Chi² = 4.36, df = 4 (P = 0.36), I² = 8.3%
Test for overall effect: Z = 1.95 (P = 0.05)
0.1 0.2 0.5 1 2 5 10
Favours treatment Favours control
Pooled RR for D3 preventing falls 0.88 (95%CI 0.78-1.00)
Postmenopausal women only
Pooled RR 0.81 (95%CI 0.48-1.34)
Jackson et al, QJM 2007;100:185-192

52. Vitamin D and the Risk of Falls
Randomized controlled trials
Trial
Vit D dose/
preparation
ug (IU)/d
Duration
of trial
25(OH)D level
achieved
nmol/L
Outcome
Muscle
performance
Sato 25(1000) D2 3 y 84 +
Pfeiffer 20 (800) D3 2 mo 66 +
Bischoff 20 (800) D3 3 mo 66 +
Falls
Bischoff 17.5 (700) D3 3 y 99 +
Broe 20 (800) D2 5 mo 75 +
Flicker 20 (800) D2 2 y NA +
Grant 20 (800) D3 5 y 62 Null
Dawson-Hughes, Am J Clin Nutr 2008;88(suppl):573S-40S

53. Vitamin D and Risk of Falls
Some observations
Trials assessing
impact of vit D on
falling more likely
to have positive
results when
conducted in
institutions
Presence of nursing staff
More accurate
ascertainment of falls
Higher supplement
compliance
Dawson-Hughes, Am J Clin Nutr 2008;88(suppl):573S-40S

54. Vitamin D and Risk of Falls
Some observations
Research has not
identified the
minimum 25(OH)D
level for maximal
benefit in fall
prevention
Trials indicate mean values
of 75 nmol/L and 99 nmol/L
? higher values might confer
benefit
Dawson-Hughes, Am J Clin Nutr 2008;88(suppl):573S-40S

55. Should vitamin D
levels be measured?
How much
vitamin D is enough?
Does supplemental
vitamin D reduce
fractures and falls?

56. Thank You
http://www.endocrine-witch.info