Vitamin D deficiency is common worldwide and can cause many health issues. It is involved in calcium absorption and bone health. Deficiency leads to osteomalacia and rickets in children, and increases risk of fractures in adults. It may also play roles in cardiovascular disease, diabetes, cancer prevention, autoimmune disease, pregnancy complications, muscle weakness, and mortality. Treatment involves dietary sources of vitamin D, supplementation, and sunlight exposure.

1. VITAMIN D DEFICIENCY
26th November 2015 Jeddah Clinic Hospital

2. History
Sources
Physiology & metabolism
Deficiency & resistance
Requirements & Treatment
Extra-skeletal effects
Vit. D intoxications
Home messages
Leading Points

3. History
1600 1st description of rickets by Whistler & Glisson
1918 Rickets linked with a fat- soluble substance
nutrient
1923 Goldblatt & Soames demonstrated that exposure to to
sunlight or UV light produced a substance that
Is linked to racket.
1936 Identification of Vitamin D by Windaus

4. Prevalence of Vitamin D Deficiency
U.S. and European elderly: 40 to 100%
Postmenopausal women Rx for osteoporosis > 50%. *
Geriatric population : 45/80 (56.2%) **
In Saudi Arabia :30-50 % of general population ***
(* Holick et al. J Clin Endocrinol Metab 2005)
(** VandeGriend et al. J Am Pharm Assoc 2008)
(*** Sedrani SH et al .Nutre. Metabo 1984)

5. Vitamin D
‘Calciferol’ A steroid hormone that primarily acts to
increase transcription of vitamin D responsive genes
primarily in the gut
These genes mediate increased absorption of
calcium and phosphorous
It plays a role in maintaining normal neuromuscular
function and immunity
There is some evidence that vitamin D regulates
apoptosis, cell proliferation and inflammation as well

6. Absorption & Metabolism
Affected by fat malabsorption :
 Pancreatic insufficiency
 CF
 Cholestastic liver disease
 Coeliac disease
 Cohn's disease

7. Medications That Increase Catabolism of
Vitamin D via P450 Enzyme Activity
Phenytoin
Phenobarbital
Carbamazepine
Isoniazid
Theophylline
Rifampin
Glucocorticoids
HAART

8. 1,25 OH Vitamin D Effects
Calcium absorption in the gut
PTH mediated bone resorption
Bone calcification
Renal calcium and phosphorus excretion
PTH secretion

9. 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.

10. 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

11. PTH Effects
Increases tubular reabsorption of calcium .
Stimulates the kidney to produce 1,25 OH vita. 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

12. Consequences of Vitamin D Deficiency
Reduced intestinal absorption of calcium &
phosphorus
Hypophosphatemia precedes hypocalcaemia
Secondary hyperparathyroidism
Bone demineralization
Osteomalacia / rickets

14. Sources of Vitamin D
Exposure to sunlight
Dietary Sources
Dietary Supplements

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

17. Exposure to Sunlight
5-10 minutes of direct exposure to the arms
and legs = 3000 IU of vitamin D3
Vitamin D def. common in sunny areas when
most of the skin is shielded from the sun (by
Hijab)(Saudi Arabia, United Arab Emirates,
Turkey, India and Lebanon)

18. Vitamin D Metabolism

20. Risk Groups

21. Elderly:
 Stores decline with age
 Winter
 House-bound or institutionalized
 Poor nutritional intake
 Impaired absorption
 CKD
At-Risk Groups

22. At-Risk Groups
Children
 Exclusively breast-fed infants
 Variable dietary intake
Vegetarian or fish-free diet
Ethnic background
Women treated for osteoporosis

23. At-Risk Groups
Hospitalized patients :
 Age
 Sun exposure
 Intake
 Renal injury
 Burns victims
 22-42% prevalence in US studies

24. Clinical Syndromes

25. 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)

26. Osteomalacia
After closure of epiphyseal plates
Impaired mineralization
Fractures
Lab tests
 Low calcium & phosphate
 High ALP
X-rays
 Diffuse bone lucencies

27. 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)

28. Vitamin D and Falls
Deficiency causes muscle weakness because
skeletal muscle has a vit. D receptor and may
require vitamin D for maximal function.
A meta-analysis of 5 RCT state that increased
vit. D intake reduced the risk of falls by 22%.
RCT, residents receiving 800 IU of vit. D3 per
day plus calcium had a 72% reduction in the
risk of falls compared with placebo.
(Broe, J Am Geriatr Soc, 2007)
(Bischoff-Ferrari, Am J Clin Nutr 2006)

29. Vit. 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, the RR
of hip fracture and non-vertebral fracture
were reduced by 26% and 23%
respectively compared to calcium and
placebo.
(Bischoff-Ferrari, Am J Clin Nutr 2006)

30. Role of Vit. 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.

31. 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

32. 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
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

33. 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

34. 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

35. Deficiency & Resistance
Impaired availability of Vit D
 Lack of sun exposure, can be seasonal
 Fat malabsorptive states
Impaired liver hydroxylation to 25-OHD
Impaired renal hydroxylation to 1,25-OHD
End-organ insensitivity to Vit D metabolites
 Hereditary Vit D resistant rickets
 Glucocorticoids – inhibit intestinal Vit D dependent
calcium absorption

36. 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

37. 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)

38. 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.

39. Vit. D Deficiency and
Other Conditions
Linked to increased incidence of :
Schizophrenia
Depression
Reactive Airway Disease

40. Associated Clinical Conditions
Bone Density and Fractures
 Risk of osteoporosis may be reduced with
adequate intake of vitamin D and calcium.
 Studies support the concept that vitamin D at
doses between 700 and 800 IU/d with calcium
supplementation effectively increase hip bone
density and reduced fracture risk, whereas
lower vitamin D doses may have less effect.

41. Role in Cancer Prevention
 Low intake of vitamin D and calcium has been
associated with an increased risk of non-
Hodgkin lymphomas, colon, ovarian, breast,
prostate, and other cancers.
 The anti-cancer activity of vitamin D
 a nuclear transcription factor that regulates
cell growth, differentiation, & apoptosis,
central to the development of cancer
 Vitamin D is not currently recommended for
reducing cancer risk
Associated Clinical Conditions

42. Associated Clinical Conditions
Autoimmune Disease
 Vitamin D supplementation is associated with a lower
risk of autoimmune diseases.
 In a Finnish birth cohort study of 10,821 children,
supplementation with vitamin D at 2000 IU/d reduced
the risk of type 1 diabetes by approximately 78%,
whereas children who were at risk for rickets had a 3-
fold higher risk for type 1 diabetes.
 In a case-control study of 7 million US military
personnel, high circulating levels of vitamin D were
associated with a lower risk of multiple sclerosis.
 Similar associations have also been described for
vitamin D levels and rheumatoid arthritis.

43. Vitamin D and Cancer
Vit. D level below 20 ng/ml is associated with a
30-50% increased risk of incident of :
 Colon, prostate and breast cancer,
 Along with higher mortality from these cancers
The mechanism?? High doe for cancer ttt
Low mortality with normal level.

44. Role in Cardiovascular Diseases
 Vit. D deficiency activates the renin-angiotensin-
aldosterone system and can predispose to
hypertension and left ventricular hypertrophy.
 increase in PTH, which increases insulin
resistance secondary to down regulation of
insulin receptors and is associated with
diabetes, hypertension, inflammation, and
increased cardiovascular risk.
Associated Clinical Conditions

45.  Vitamin D deficiency early in pregnancy is
associated with a five-fold increased risk of
preeclampsia.
 Role in All Cause Mortality
 Researchers concluded that having low
levels (<17.8 ng/mL) was independently
associated with an increase in all-cause
mortality in the general population.
Role in Reproductive Health

46. Associated Clinical Conditions
Muscle Weakness and Falls
 Proximal muscle weakness
 Chronic muscle aches
 Myopathy
 Increase in falls
 Dailly 700 and 800 IU/d in a vitamin D-deficient elderly
population can significantly reduce the incidence of falls.

47. Work up

48. Assessment

49. Screening

50. Vitamin D Basics
Units
ng/mL vs. nmol/L
2.5 nmol/L = 1 ng/mL
Rule of thumb
 For every 100 IU D3 ingested, blood level of 25-
OH-D increases by 1 ng/mL

51. Who Should Be Screened ?
Elderly
Home bound or institutionalized patients
Patients with known or suspected malabsorption
Patients with osteoporosis or osteopenia
CKD and chronic liver disease patients
Patients with nonspecific musculoskeletal pain
On medications that induce P-450 enzyme activity
Obese and pregnant women

52. Investigations

53. Diagnosis

54. Vitamin D Measurements
Interpretation Level (nmol/l) Action
Deficiency < 25 Replace Vit D
Loading dose followed by maintenance
Insufficient 25-50 Consider replacement if:
• Glucocorticoids
• Osteopenia/osteoporosis
• 2° HPTH
• Hypocalcaemia
• CKD
Maintenance dose
Replete >50 No need for replacement or continue
dose
Toxic >150 Check calcium
Stop treatment

56. Preventive Measures
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

59. Variations of sun exposure
Reduced skin synthesis:
 Sunscreen use (reduces vitamin D3 synthesis by 99%)
 Skin pigmentation
 Patients with skin grafts for burns
 Aging (reduction of 7 dehydrocholesterol reduces
vitamin D3 synthesis by 75% in a 70 year old)
 Season, latitude and time of day

60. 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 30-50% 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

61. Vitamin D preparations

62. Current recommended of vitamin D levels
Vitamin D level Health Status
>20-25 ng/ml Currently considered to be sufficient in
otherwise healthy people
>30 ng/ml New recommendations based on new
studies suggesting improved health
outcomes at higher levels
Current vitamin D intake recommendations
Age Daily Intake
Under 50 600 IU
50-70 and pregnant 600IU
Over 71 800 IU

63. Current vitamin D intake recommendations
Institute of Medicine, December 2010

64. D3 ≠ D2 ≠ 1,25-di(OH)-D3
*From 7-dehydrocholesterol **From ergosterol
Name D name Details
*Cholecalciferol D 3 Animal origin and from sun
exposure not active
** Ergocalciferol D2 Plant origin , only 1/3 as active
as D3
Calcitriol 1,25-di(OH)-D3 is converted in the kidney and
other tissues - biologically active
“Vitamin D”

65. Vitamin D Supplementation
Deficiency (<25 nmol/l or 10 mcg/l)
Oral Therapy
 1st line agent:
D3 800 iu capsules x4/d
D3 3200 iu daily for 8-12 weeks.
 2nd line:
D3 20,000 units / week for 8-12 weeks.
Injection therapy
Ergocalciferol(D2) 300,000 (or 600,000) iu
single dose by intramuscular injection Every 3
months .

67. Combined calcium & Vit. D supplements
unnecessary in primary vitamin D deficiency
 Less palatable ? affects compliance
Dual replacement if severe deficiency accompanied
by hypocalcaemia leading to secondary
hyperparathyroidism
Appropriate for the management of osteoporosis
and in the frail elderly.

68. Monitoring
afte1 month
 Bone and renal profile
After 3 months
 Bone and renal profile,
 vitamin D, and plasma parathyroid hormone.
Once vitamin D replacement is optimised no further
measurement of vitamin D is necessary.

71. Vitamin D Intoxication
Common symptoms:
 Anorexia, nausea and vomiting.
 Polyuria, polydipsia, weakness and pruritus
Lab abnormalities:
 AKI, hypocalcaemia .
 Hyperphosphatemia
Treatment:
 Stop vitamin D, low calcium diet
 Acidify the urine and steroids

72. Take Home Points
Vit. D deficiency is so common
25 OH vitamin D is a predictor of bone health
Vit. D is . potentially an independent predictor of risk of
CVD,HTN, cancer,DM, all cause mortality, and URI
At least 800 IU of vitamin D3 per day
Sensible sun exposure is a great way to maintain
vitamin D sufficiency

73. Take Home Points
• A strong evidence to support vit. D deficiency screening
• Supplementation IS NESSARY in elderly individuals.
• Controversy remains as to whether new vitamin D goals
• New recommendations regarding vitamin D testing and
supplementation are likely in the coming years.