The document discusses the controversies surrounding vitamin D therapy, highlighting its role as a prohormone sourced from sunlight and diet. It details the association of vitamin D deficiency with various health risks and notes that claims of its benefits beyond skeletal health have not been substantiated by significant clinical trials. Currently, vitamin D supplementation is recommended only for individuals with confirmed deficiency, focusing primarily on skeletal benefits.

1. Controversies in
Vitamin D Therapy
Nemencio A. Nicodemus Jr., MD, FPCP, FPSEDM
Professor, University of the Philippines-College of Medicine
Philippine College of Physicians
49th Annual Convention, May 7, 2019
SMX Convention Center

2. Conflicts of Interest
• None that pertain to the topic of this lecture

3. Objectives
Review Vitamin D metabolism and the
pathophysiology of Vitamin D deficiency
Clarify conundrums and controversies in
Vitamin D therapy, including different
forms of Vitamin D replacement
Apply knowledge to treatment of Vitamin
D deficiency in clinical practice

4. Sources of Vitamin D
Lockau, L., International Journal of Paleopathology (2017), https://doi.org/10.1016/j.ijpp.2017.11.005

5. The metabolic
pathway for
vitamin D
Christakos S et al. Physiol Rev 96: 365–408, 2016

6. Effects Of 1,25(OH)2D3 In The Intestine
Christakos S et al. Physiol Rev 96: 365–408, 2016

7. Vitamin D Signaling Pathways
Deeb KK et al. Nature Reviews Cancer volume 7, pages 684–700 (2007)

8. Vitamin D adequacy is determined by serum
total 25-hydroxyvitamin D concentration
25-hydroxyvitamin D3
+
25-hydroxyvitamin D2
3-epimer of 25-hydroxyvitamin D
1,25(OH)2D
24,25(OH)2D3
DBP
free 25-dihydroxyvitamin D
Bouillon R. Nat Rev Endocrinol. 2017;13(8):466–479
Holick MF, et al. J Clin Endocrinol Metab. 2011;96(7):1911–1930

9. Classification of Serum 25-OH D Concentrations
Institute of Medicine of the National Academies (2012) Dietary Reference Intakes for calcium and vitamin D.
Endocrine Society. J Clin Endoc Metab, July 2011, 96(7): 1911–1930
1 nmol/L=0.4 ng/mL

10. Risk factors for Vitamin D Deficiency
Sun/UV ray
factors
Physiologic
factors
Low intake Medications
Holick MF. Rev Endocr Metab Disord (2017) 18:153–165

11. Risk Factors Of Low Vitamin D Status
Holick MF. Rev Endocr Metab Disord (2017) 18:153–165

13. Percentage of Vitamin D insufficiency
among Filipino adults: 8th NNS, 2013
48.7
55.5
32.1
54.1
43.5
62.5
43.8
38.1
28.9
0
10
20
30
40
50
60
70
Overall Age Gender Area
20-39 40-59 ≥60 Male Female NCR Cebu Davao del sur
Angeles-Agdeppa I et al. Mal J Nutr 24(3): 395-406, 2018
Cut offs for Vitamin D levels: Deficient (<20 ng/m;), Insufficient (20 -29 nmol/l) and Sufficient was ≥30 nmol/l (Holick, 2009)

14. Predictors* of vitamin D insufficiency among
Filipino adults in the NCR, Cebu and Davao
*Using multivariate logistic regression
Angeles-Agdeppa I et al. Mal J Nutr 24(3): 395-406, 2018

15. Percentage of adults using sunscreen
by area, age and gender: 8th NNS, 2013
Angeles-Agdeppa I et al. Mal J Nutr 24(3): 395-406, 2018

16. Clinical features of Vitamin D deficiency

17. Consequences of Vitamin D Deficiency

18. HR* of death from all causes by 25-OH
Vitamin D concentrations:
Individual participant data meta-analysis
Category (nmol/L) Categorical HR (95% CI)
<30 1.50 (1.28 - 1.71)
30 - 39.99 1.24 (1.07 - 1.42)
40 - 49.99 1.12 (0.97 - 1.27)
50 - 74.99 1.05 (0.92 - 1.18)
75 - 99.99 1.0
100 - 124.99 1.07 (0.69 - 1.45)
≥125 0.87 (0.21 - 1.53)
*Adjusted for age, sex, season of blood drawing, BMI, active smoker status, diabetes mellitus,
arterial hypertension, history of CVD (myocardial infarction and/or history of stroke), and
history of cancer at baseline visit.
Adapted from Gaksch M, et al. (2017). PLoS ONE 12(2): e0170791. doi:10.1371/journal.pone.0170791

19. Dose-response trend of HRs of death
from all causes by 25-OH Vitamin D
Gaksch M, et al. (2017). PLoS ONE 12(2): e0170791. doi:10.1371/journal.pone.0170791
There is an association between low 25(OH)D and increased
risk of all-cause mortality

20. Broad Groups For Clinical Consideration
And Decision-making

21. Recommended Vitamin D Intakes
Holick MF. Rev Endocr Metab Disord (2017) 18:153–165

22. Sources of Vitamin D2 and D3
Holick MF. N Engl J Med 357:266–281, 2007
IU = 25 ng

23. Sources of Vitamin D2 and D3
Holick MF. N Engl J Med 357:266–281, 2007
IU = 25 ng

24. Effect of vitamin D on bone density in
community-dwelling older adults: RCT
P
• 452 older community-resident adults
I
• monthly doses of vitamin D3 100 000 IU vs
placebo; follow-up 2 years
O
• Change in lumbar spine BMD
• Exploratory analyses: effect of baseline 25-
OHvitamin D on BMD
Reid IR et al. J Intern Med 2017; 282: 452–460

25. Changes in BMD With Vitamin D
Reid IR et al. J Intern Med 2017; 282: 452–460
No clinically important
benefit to BMD from
untargeted vitamin D
supplementation of older,
community-dwelling adults

26. Changes in BMD at 2 years according to
baseline serum 25-OH vitamin D concentrations
Reid IR et al. J Intern Med 2017; 282: 452–460
Vitamin D supplementation benefits those with baseline
25-hydroxyvitamin D ≤ 30 nmol/L

28. N Engl J Med 2019; 380:33-44

29. The Vitamin D and Omega-3 Trial
(VITAL) Study: nationwide RCT
Population 25,871 men ≥50 years and women ≥ 55 years old
Interventions Vitamin D3 (cholecalciferol) 2000 IU/day and omega-3 fatty
acids 1 g/day in two-by-two factorial design; median follow-
up 5.3 years
Primary end
points:
Invasive cancer of any type
Major cardiovascular events (composite of MI, stroke, or CV death)
Secondary
end points:
Site-specific cancers
Death from cancer
Additional cardiovascular events
Manson JE et al. for the VITAL Research Group. N Engl J Med 2019; 380:33-44

30. Characteristics of the Participants
at Baseline: VITAL study
Manson JE et al. for the VITAL Research Group. N Engl J Med 2019; 380:33-44

31. Cumulative Incidence Rates of Invasive
Cancer of Any Type: VITAL Study
Manson JE et al. for the VITAL Research Group. N Engl J Med 2019; 380:33-44
Supplementation with vitamin D did not result in a lower
incidence of invasive cancer

32. Cumulative Incidence Rates of Major
CV Events: VITAL Study
Manson JE et al. for the VITAL Research Group. N Engl J Med 2019; 380:33-44
Supplementation with vitamin D did not result in a lower
incidence of cardiovascular events

33. HR for the Primary End Points in
Intention-To-Treat Analyses: Vital Study
Manson JE et al. for the VITAL Research Group. N Engl J Med 2019; 380:33-44

34. HR for the Secondary End Points in
Intention-To-Treat Analyses: Vital Study
Manson JE et al. for the VITAL Research Group. N Engl J Med 2019; 380:33-44

35. HR of Invasive Cancer of Any Type
According to Subgroup: Vital Study
Manson JE et al. for the VITAL Research Group. N Engl J Med 2019; 380:33-44

36. HR of Invasive Cancer of Any Type
According to Subgroup: Vital Study
Manson JE et al. for the VITAL Research Group. N Engl J Med 2019; 380:33-44

37. HR of Major CV Events According to
Subgroup: Vital Study
Manson JE et al. for the VITAL Research Group. N Engl J Med 2019; 380:33-44

38. HR of Major CV Events According to
Subgroup: Vital Study
Manson JE et al. for the VITAL Research Group. N Engl J Med 2019; 380:33-44

39. Summary:
Controversies in Vitamin D Therapy
Vitamin D is a prohormone that is obtained
either from sunlight exposure or from external
sources (e.g. food, supplements)
• Deficiency of this vitamin is associated with symptoms and
increased risk of death
Claims of the extra-skeletal benefits of Vitamin
D have not been proven in large, properly
conducted clinical trials
At present, vitamin D supplementation must only
be advised for its skeletal benefits among
people with documented deficiency