By Usama Ragab Youssif Vitamin D Health Issues When to treat Whom to screen What is vitamin D

1. Email: usamaragab@medicine.zu.edu.eg
Slideshare: https://www.slideshare.net/dr4spring/
Mobile: 00201000035863

2. Agenda
Vitamin D a
global issue
Vitamin D 101
Vitamin D in
skeletal Health
(MBD)
How to treat
Whom to
screen
Extraskeletal
benefits (or
myths?!)
Take-home
Messages

3. Vitamin D deficiency and
insufficiency is a global health
problem
• Vitamin D deficiency is a common
global issue.
• About 1 billion people worldwide have
vitamin D deficiency
• 50% of the population has vitamin D
insufficiency.
J Pharmacol Pharmacother , 2012 Apr;3(2):118-26.

4. Status of vitamin D among Egyptian population
164
420
245
263
1092
1357
1447
544
606
3954
Severe deficiency (<10)
Moderate def. (10–20)
Insufficient (20–30)
Normal (>30)
Total
males females
30.1%
36.9 %
15.6%
17.2%
n= 5046
Endocrine Abstracts (2019) 63 P473 | DOI: 10.1530/endoabs.63.P473 Calcium and Bone 2

5. Definitions of
Vitamin D Deficiency
• No broad consensus on definition of vitamin D deficiency.
• Different organizations have slightly different definitions,
based on serum levels of 25 (OH)D.
Mayo Clin Proc 2010; 85:752-758.
IOM (Institute of Medicine). 2011 Dietary Reference Intakes for Calcium and Vitamin D.
J Clin Endocrinol Metab 2011; 96:1911-30
Endocr Pract. 2016;22(Suppl 4):1-42.

6. What is Vitamin D?
• Vitamin D is a fat-soluble vitamin
• It is involved in the regulation of
calcium homeostasis and bone
health.
• Vitamin D need various steps of
activation to be utilized

7. Sources of Vitamin D
Being exposed to the
sun.
Through the foods
you eat.
Through nutritional
supplements.

8. Daily requirements
Life Stage Recommended Amount
Birth to 12 months 10 mcg (400 IU)
Children 1–13 years 15 mcg (600 IU)
Teens 14–18 years 15 mcg (600 IU)
Adults 19–70 years 15 mcg (600 IU)
Adults 71 years and older 20 mcg (800 IU)
Pregnant and breastfeeding teens and women 15 mcg (600 IU)
https://ods.od.nih.gov/factsheets/VitaminD-Consumer/

9. Minimal amounts of vitamin D
in human breast milk
• The American Academy of Pediatrics
recommends vitamin D supplementation
starting at age 2 months for infants fed
exclusively with breast milk.
Pediatrics. 2003 Apr. 111(4 Pt 1):908-10.

10. Consequences
of Vitamin D
Deficiency
Severe and prolonged
deficiency → bone
mineralization diseases (MBD)
Vitamin D deficiency →
abnormalities in Ca, Po4, and
bone metabolism.
JAMA. 2021;325(14):1436-1442.

11. Consequences of Vitamin D Deficiency
• Vitamin D deficiency has also been associated with fractures, falls, functional
limitations, some types of cancer, diabetes, cardiovascular disease, and
depression. However, the U.S. Preventive Services Task Force notes that,
“Inadequate evidence on the benefit of treatment of asymptomatic vitamin D
deficiency on other outcomes, including falls, cancer, cardiovascular events,
depression, infection, or physical functioning.”
JAMA. 2021;325(14):1436-1442.

12. Symptoms of
vitamin D
deficiency
• Often asymptomatic.
• Severe or prolonged deficiency may
cause:
Bone Pain and tenderness
Falls and impaired physical
function
Muscle aches and weakness
Symmetric low back pain (in
women)
Bordelon P et al. Recogni7on and management of vitamin D deficiency. Am Fam Phys 2009; 80:841-846.

13. Vitamin D and
Bone Health
• Maximum calcium absorption occurs at levels of
(25[OH]D) greater than 32 ng/mL.
• Vitamin D also enhances the absorption of
phosphorus from the distal small bowel.
• Ca + Po-
4 = proper mineralization
• It is also involved in maturation of osteoclasts,
which resorb calcium from the bones.
Journal of the American College of Nutrition 2003, 22 (2): 142-6

14. Which Vitamin D
• The term vitamin D = vitamin
D2 or vitamin D3.
• Vitamin D3 = cholecalciferol
(made in the skin or obtained
in the diet from fatty fish).
• Vitamin D2 = ergocalciferol
(obtained from irradiated fungi,
such as yeast or mushroom).
• Both are used to supplement
food products or in
multivitamins.
J Clin Endocrinol Metab. 2004 Nov. 89(11):5387-91.
Am J Clin Nutr. 1998 Oct. 68(4):854-8.

15. Vitamin D2 and Vitamin D3
• Past studies suggested that vitamin D3 may be more
effective than vitamin D2 in establishing normal vitamin
D stores.
• However, a study by Holick and colleagues
demonstrated that vitamin D2 and vitamin D3 appear to
be equipotent in raising 25(OH)D concentrations when
they are given in daily doses of 1000 IU.
• Some prefer vitamin D3 over vitamin D2, it’s Ok
J Clin Endocrinol Metab. 2004 Nov. 89(11):5387-91.
Am J Clin Nutr. 1998 Oct. 68(4):854-8.

16. The main
problem is the
bone health
• Metabolic Bone disease (MBD) especially rickets
or osteomalacia

17. Metabolic bone disease (MBD)
• MBD, any of several diseases that cause various abnormalities
or deformities of bone
• Examples of MBD include osteoporosis, rickets/osteomalacia,
osteogenesis imperfecta, marble bone
disease (osteopetrosis), Paget disease of bone, and fibrous
dysplasia.

18. Osteomalacia
Several different disorders cause osteomalacia via mechanisms
that result in hypocalcemia, hypophosphatemia, or direct
inhibition of the mineralization process.
Osteomalacia is a disorder of bone, characterized by decreased
mineralization of newly formed osteoid at sites of bone turnover.

19. Poor mineralization
• Failure to replace the turnover of Ca and P in bone
matrix → bone becomes demineralized
• The bony substance becomes replaced by soft osteoid
tissue
• It is mainly a qualitative bone defect.
• There is, unlike osteoporosis, a decline in the ratio of
mineralized bone to matrix.

20. Osteomalacia vs. Osteoporosis
• osteoMalacia = ↓↓ Mineralization.
• osteoPorosis = ↓↓ Protein matrix.

21. Osteomalacia vs Osteoporosis

22. Osteomalacia
Disease of poor women

23. There are many causes
But the most important is vitamin D deficiency

24. Synthesis of Vitamin D

25. 2ry
hyperparathyroidism
• The most common
cause is vitamin D
deficiency
• It is the combination of
calcium loss from bone
and phosphate
depletion that leads to
impaired bone
mineralization.
CaSR

26. The classification of osteomalacia
1. Hypocalcemic osteomalacia
• Vitamin D deficiency = ‫موجود‬ ‫مش‬
• Pseudovitamin D deficiency = ‫شغال‬ ‫مش‬
2. Hypophosphatemic osteomalacia
3. Osteomalacia with normal bone homeostasis
= Defective mineralization

27. The
classification
of
osteomalacia
Abnormal
vitamin D
metabolism
Reduced
availability
Poor diet
Inadequate exposure to sun
Malabsorption
Defective
metabolism
Hepatobiliary disease
Chronic Kidney disease
Vitamin D-dependent rickets type I (AR)
Anticonvulsant drugs, barbiturate, rifamycin → ↑↑
metabolism
Receptor defects Vitamin D-dependent rickets type II (AR)
Altered
phosphate
homeostasis
Malabsorption Malabsorption syndromes
Renal phosphate
loss
X-linked hypophosphatemia (XLD) → Po4 loss
Oncogenic hypophosphatemia→ ↑ FGF-23 → Po4 loss
Fanconi syndrome: loss of Po4, Ca, a.a., sugar...
Defective
mineralization
Aluminum and fluoride toxicity
Bisphosphonate toxicity
Hypophosphatasia
VDDR type I: AR, ↓↓ α-hydroxylase → ↓↓ active vitamin D → treated with calcitriol
VDDR type II: AR, end organ resistance if with alopecia type IIa, if without alopecia type IIb, → treated by
supraphysiological doses of calcitriol & calcium.
Both are called pseudovitaminosis

28. Clinical
features
Osteomalacia is the adult counterpart of rickets
• Skeletal discomfort (from bone and muscle pain),
deformities; kyphosis, triradiate hip i.e., soft hip → this is
exaggerated in children → bone bowing.
• Bone tenderness
• Tetany may be manifested: rarely may be severe enough
→ dysrrhythmia + convulsions
• Muscular weakness with marked proximal myopathy with
waddling gait.
• Rickets: rachitic rosary, Harrison’s groove, delayed
dentition.

29. Workup=
Bone
Markers
Abnormal
A- Laboratory
B- Imaging
C- Biopsy

30. A- Laboratory
1. Serum Calcium and phosphorus are decreased;
but phosphorus may be increased in renal
failure.
2. Alkaline phosphatase is increased in 90% of
cases.
3. Serum FGF-23 is elevated in many people with
tumour-induced osteomalacia, x-linked
hypophosphatemic rickets.
4. Vitamin D levels (25 OH Vit D) are reduced
5. PTH is often increased

31. Serum 25(OH)D
This is the best test to determine
vitamin D status.
Intestinal calcium absorption is
optimized at levels above 30-32
ng/mL.
PTH start to rise at 25(OH)D < 31
ng/mL, which is another “indirect”
marker of vitamin D insufficiency.
N Engl J Med. 2005 Feb 3. 352(5):515-6; author reply
515-6.
J Am Coll Nutr. 2003 Apr. 22(2):142-6.
J Bone Miner Res. 2003 Jul. 18(7):1342; author reply
1343.
Clin Chem Lab Med. 2016 Jun 30.
Medscape Medical News. May 1, 2013.

32. PTH
• Not always required for the diagnosis of
vitamin D insufficiency but may help to
establish the diagnosis of vitamin D
insufficiency.
• Often, PTH is elevated = 2ry
hyperparathyroidism.
• An inverse relationship exists between PTH
and 25(OH)D levels.
• Usually, PTH levels decrease after the
correction of a vitamin D
Clin Chem Lab Med. 2016 Jun 30.
Indian Journal of Endocrinology and Medicine Page : 422-427, DOI:
10.4103/ijem.IJEM_322_19

33. A- Laboratory
(cont.)
5. Urinary phosphate and low urinary calcium
excretion
6. Levels of 1,25-dihydroxyvitamin D may be
normal and are, therefore, not helpful. If the
serum calcium and 25-hydroxyvitamin D levels
are normal as well, then the defect is likely to
be renal handling of phosphate or end-organ
resistance.

34. Biochemical findings of causes of
osteomalacia
Disorder Ca Po4 ALP 25 (OH) D3 1,25 (OH)2 D3 PTH Other
Vit. D ↓↓ ↓ ↓ ↑ ↓ ↓ ↑
CKD ↓ ↑ ↑ N ↓ ↑ ↓ GFR lead to Po4 retention
VDDR type I ↓ ↓ ↑ N ↓ ↑ As CKD but Po4 is low
VDDR type II ↓ ↓ ↑ N ↑ ↑ End organ resistance
XL-hypophosphatemia
(Vitamin D resistant
rickets)
N ↓ ↑ N N N or ↑ ↑ serum FGF-23 → + heparin
& klotho → bind to PCT →
Po4 loss
Oncogenic
hypophosphatemia
N/↓ ↓ ↑ N ↓ N May have aminoaciduria &
proteinuria, ↑ FGF-23
Phosphate depletion N ↓ ↑ N ↑ N ↑ urine Ca
Fanconi Synd ↓/N ↓ ↑ N ↑ N Aminoaciduria, glucosuria
RTA ↓/N ↓ ↑ N N/↓ N Non-anion gap MA
Toxic
(etidronate/floride)
N N N N N N Dx by biopsy

35. B- Imaging
1. X-ray
Bone rarefaction
Radiographic osteopenia
2. Bone scan: can show multiple
hot spots in the ribs and pelvis
at the site of fractures and the
appearance may be mistaken
for metastases

36. C- Bone Biopsy
Not usually done

37. Treatment
1. Treatment of the cause e.g., correct bowel disorder, tumor resection, stop offending
drug.
2. Sun exposure
3. Diet
4. Ca supplements: at doses of 800–1000 mg/day for adults.
5. Vitamin D2 (ergocalciferol), or D3 (cholecalciferol)
6. Alfacalcidol especially in cases of renal failure, vitamin D dependent rickets type I
“physiological dose” i.e., 0.5 – 1 mcg/day, vitamin D dependent rickets type II
“supraphysiological dose”, also in hypophosphatemic rickets.

38. Take Care
• Patients with CKD or hypoparathyroidism need both vitamin
D2 or D3 + calcitriol as CKD → ↓↓ 1α hydroxylase and
hypoparathyroid patients are unable to convert 25 (OH) D to
1,25 (OH)2 D in absence of PTH.
• With rapid clinical improvement, an elevation in serum
25(OH)D and a reduction in PTH.
• Serum ALP levels sometimes rise initially as mineralization of
bone increases, but eventually fall to within the reference
range as the bone disease heals.

39. Vitamin D in treatment

40. Vitamin D For All??

41. Nutrients 2022, 14, 1483.

42. Statement
regarding
treatment
of vitamin D
deficiency in
adults
It is recommended to initiate a
vitamin D deficiency treatment at a
25(OH)D concentration of <20 ng/mL.
At a concentration of <30 ng/mL a
treatment may be considered
In patients without other risk factors,
a dosage of 6000 IU/day, is
recommended.
Nutrients 2022, 14, 1483.

43. In certain individuals or conditions, higher
vitamin D dosages, up to 10,000 IU
• Malabsorption
• Chronic treatment of medications that influence vitamin
D metabolism
• Obesity
Nutrients 2022, 14, 1483.

44. Duration of treatment
• A treatment duration of 4–12
weeks is recommended
• As soon as a 25(OH)D
concentration of 30–50 ng/mL
is achieved, a maintenance
dose of 800–2000 IU/day is
recommended
Nutrients 2022, 14, 1483.

45. Endocrine society adult dosing
Adults
• 6,000 IU per day or 50,000 IU per week for 8 weeks to achieve a
blood level 25(OH)D above 30 ng/ml. Followed by maintenance
therapy of 1,500-2,000 IU/day.
Special
Cases
• Obese patients, those with malabsorption syndromes, and those
on medications affecting vitamin D metabolism should receive a
higher dose of 6,000 to 10,000 IU/day to achieve levels above 30
ng/ml. Followed by a maintenance dose of 3,000-6,000 IU/day.
The Journal of clinical endocrinology & metabolism. 2011 Jul 1;96(7):1911-30.

46. Route for treatment
• Vitamin D2 or D3 are recommended.
• For the treatment of vitamin D
deficiency in adults, oral
cholecalciferol (vitamin D3) is
preferred.
• In certain risk groups (e.g., patients
with severe malabsorption),
parenteral vitamin D treatment can
be considered.
Mayo Clin Proc 2010; 85:752-758. J Clin Endocrinol Metab 2011; 96:1911-30. Am Fam Phys 2009; 80:841-846. Ann
Intern Med 2015; 162:133-141. Nutrients 2022, 14, 1483.

47. Vitamin D2 vs Vitamin D3

48. Does it matter if the supplement is taken
on an empty stomach vs with a meal?
• Taking either vitamin D2 or D3 with the largest
meal of the day increased the average serum
25(OH)D level by 50.2%
• Mean serum 25(OH)D concentrations were
higher in those who took the supplement with a
meal that included at least 15 g of fat.
• Oil based preparation may offer this
Cleveland Clinic Journal of Medicine. 2022 Mar;89(3):155.

49. 48%

50. In a nutshell
Goal → 25 (OH) D3 > 30 ng/mL (ideally > 50 ng/mL)
Goal
After replenish → start maintenance vitamin D → 800 – 2000 IU daily of vitamin D
Replenish
Wait for 2 weeks then measure 25 (OH) vitamin D levels
Wait

51. Prevention

52. Sun
• Especially between the hours of 10:00 am
and 3:00 pm produces vitamin D = X2
compared with ingested vitamin D.
• If sun exposure produces slight pinkness,
the amount of vitamin D equivalent to
ingesting 10,000-25,000 IU.
• It is affected in increased skin
pigmentation, aging, and application of a
sunscreen.
J Clin Invest. 1993 Jun. 91(6):2552-5.
Am J Clin Nutr. 2008 Apr. 87(4):1080S-6S.

53. The following
foods contain
the indicated
amounts of
vitamin D
(cont.)
• Fortified milk (8 oz) - 100 IU
• Fortified orange juice (8 oz) - 100 IU
• Fortified cereal (1 serving) - 40-80 IU
• Pickled herring (100 g) - 680 IU ‫الرنجة‬
• Canned salmon with bones (100 g) - 624 IU ‫السلمون‬
‫المعلب‬
• Mackerel (100 g) - 360 IU ‫سمك‬
‫الماكريل‬
• Canned sardines (100 g) - 272 IU ‫المعلب‬ ‫السردين‬
• Codfish (100 g) - 44 IU
• Swiss cheese (100 g) - 44 IU
• Raw shiitake mushrooms (100 g) - 76 IU
• Most multivitamins (1 tab) - 400 IU
US Department of Agriculture's (USDA's) Nutrient Data Laboratory

54. Vitamin D
Supplement
ation
800–2000 IU/day, in winter times
In elderly: 800–2000 IU/day is
recommended throughout the year
In hospitalized/institutionalized: 800–
2000 IU/day is recommended
throughout the year.
Nutrients 2022, 14, 1483.

55. Vitamin D doses above the UL of 4000 IU/day, are
recommended for prevention in:
Malabsorption, or
using drugs impair
vitamin D
Metabolism
Obesity (BMI ≥ 30
kg/m2)
Dark skin
pigmentation
Nutrients 2022, 14, 1483.

56. Statement regarding vitamin D in musculoskeletal disorders
Nutrients 2022, 14, 1483.

57. Prevention in
childbearing periods
• As recommended for healthy
adults without other risk
factors (800–2000 IU/day).
• The vitamin D
supplementation should be
continued throughout
pregnancy and lactation.

58. The Journal of clinical endocrinology & metabolism. 2011 Jul 1;96(7):1911-30.

59. Prevention: Institute of Medicine (IOM)
Recommendations
Children and
adults aged 1-70:
600 IU per day
Adults older than
70: 800 IU per
day

60. Prevention: AACE Recommendations
Endocr Pract. 2016;22(Suppl 4):1-42.
Daily supplementation with vitamin D3 at a dose of 1,000
to 2,000 IU is typically needed to maintain an optimal
serum 25(OH)D level.
Higher doses may be necessary in the presence of
certain factors including obesity, malabsorption, and
certain ethnicities.
Transplant patients and older individuals may also need
higher doses

61. How…
It is stored in fat, so the frequency of intake (daily, weekly,
monthly) is equal
If monthly doses are not exceedingly high, choose any
Patient preference
For the prevention of vitamin D deficiency, the supplementation
of oral cholecalciferol (vitamin D3) is recommended.
Nutrients 2022, 14, 1483.

62. 2 Questions
• Screening
• Extraskeletal benefits of
vitamin D

63. Screening

65. JAMA. 2021;325(14):1436-1442., Twenty Things Physicians and Patients Should Question. American Society for Clinical Pathology. Published 2017, Clinical Preventive Service Recommendation: vitamin D
deficiency. American Academy of Family Physicians., J Clin Endocrinol Metab. 2011;96(7):1911-1930., Endocr Pract. 2016;22(suppl 4):1-42.
• Neither the Endocrine Society, the Mayo Clinic, the USPSTF, nor the AACE recommends
universal screening for vitamin D deficiency among the general population or asymptomatic
individuals. However, they do recommend screening in individuals with risk factors for vitamin
D deficiency.
• The American Society for Clinical Pathology recommends against it.

66. Nutrients 2022, 14, 1483.

67. Screening of vitamin D deficiency should be
considered in
Osteoporosis; Osteomalacia; Musculoskeletal pain;
Chronic kidney disease; Hepatic failure; Malabsorption syndromes (e.g., cystic fibrosis,
inflammatory bowel diseases, bariatric surgery, radiation enteritis);
Hyperparathyroidism;
Chronic treatment with medications that influence vitamin D metabolism (e.g., antiseizure
medications, glucocorticoids, AIDS-medications, antifungal agents, cholestyramine);
Chronic autoimmune diseases (e.g., multiple sclerosis, rheumatoid arthritis);
Nutrients 2022, 14, 1483.

68. Screening of vitamin D deficiency should be
considered in (cont.)
Pregnant and lactating women;
Institutionalized or hospitalized patients;
Older adults (>65 years) in general; Older adults with history of falls or nontraumatic fractures;
Granuloma-forming disorders (e.g., sarcoidosis, tuberculosis, etc.)
BMI ≥ 30kg/m2);
Dark skin pigmentation.
Nutrients 2022, 14, 1483.

69. Extraskeletal benefits
of Vitamin D

70. No conclusive evidence
• Vitamin D has other function rather than the metabolic one
• Remember it is a hormone, so it has roles in cell proliferation,
immune and muscle function, skin differentiation, and reproduction.
• Observational studies “just observational” found that, poor vitamin D
status is present in almost all diseases
• However, RCT, Mendelian randomization and GWAS studies draw
mixed conclusion

71. Vitamin D in
immune
modulation
Shymanskyi, Ihor, et al. "Vitamin D Deficiency and Diabetes Mellitus." Vitamin D Deficiency. IntechOpen, 2019.

72. Mechanisms
of glucose
homeostasis
deregulation
Shymanskyi, Ihor, et al. "Vitamin D Deficiency and Diabetes Mellitus." Vitamin D Deficiency. IntechOpen, 2019.

73. Final Bottom-line