2. Advances in Vitamin D Therapeutics in CF Trang Le, M. D
Advances in Vitamin D Therapeutics in CF Trang Le, M.D. Virginia Commonwealth University / Children’s Hospital of Richmond Richmond, VA

3. Presenter Disclosure
Trang Le, M.D. There are no relationships to disclose related to this presentation.

4. Objectives
Summarize the relationship between vitamin D and cystic fibrosis (CF) health status
Discuss differences between vitamin D formulations
Review recent data on alternative vitamin D treatment options and strategies

5. Case
A 23 year old African American woman with CF is seen for routine follow up of CF-related diabetes.
She has been on ergocalciferol (D2), 50,000IU weekly for the preceding 6 months.
She has no history of fractures.
Menarche was at age 13 years, and she is on contraception with depot medroxyprogesterone.

6. Case D2 was increased to twice weekly, then three times weekly.
25-hydroxyvitamin D [25(OH)D] levels improved from 8.6 to 16.0 ng/mL.
She also takes a calcium + vitamin D supplement with meals.
Regarding diabetes, her A1c typically ranges 9-11%.

7. Case Bone mineral density (BMD) results (Z-scores): L-spine -0.9
Total hip -0.3
Femoral neck -0.9
Serum calcium and creatinine are normal
How to get this patient to goal 25(OH)D ≥ 30 ng/mL?

8. Vitamin D in CF
Vitamin D deficiency 25(OH)D level <20ng/mL or insufficiency (<30ng/mL) affects 90% of patients with CF
Risk factors include:
Pancreatic insufficiency
malabsorption of fat-soluble vitamins
Insufficient sunlight exposure
Inadequate nutritional intake
Rovner AJ, et al. Am J Clin Nutr. 2007;86(6):

9. Lower Vitamin D levels are associated with lower bone density in CF
Bone Mineral Density (g/cm2)
25(OH)D ≤ 10 ng/mL
25(OH)D>10ng/mL
L-spine Total Hip Femoral Radius
Figure 3. Bone mineral density of the lumbar spine, total hip, femoral neck, and the proximal radius in patients with low serum concentrationsof 25-hydroxyvitamin D (< 10 ng/dl; black bars) and those with borderline or normal serum concentrations of 25-hydroxyvitamin D (> 10 ng/dl; white bars)
Donovan DS Jr. et al., Am J Repir Crit Care Med. 1998 Jun;157(6 Pt 1):

10. Vitamin D independently predicts low BMD
n=103 (adults + adolescents)
Osteoporosis in 9.7%, osteopenia in 35%
BMI, gender, weight, FEV1, and 25(OH)D levels were significantly correlated with Z-scores
Model r
Adusted r2
r2 change
Beta F p 1
%FEV1
0.734
0.132
0.271
16.470
<0.001 2
Gender
0.494
0.229
0.104
-0.477
16.158 3
Weight
0.581
0.318
0.094
0.364 4
25(OH)D
0.608
0.344
0.032
-0.180
15.157
Stepwise regression analysis of demographic and clinical variables that best predict bone density Z-scores.
Sheikh S. et al., J Bone Miner Metab, 2015 Mar;33(2):180-5

11. Vitamin D status is related to lung function
25(OH)D (nmol/L)
FEV1 (% predicted)
R2 = 0.30, P < 0.001, controlling for age, gender, BMI and race
Wolfenden LL et al, Clin Endocrinol (Oxf) 2008, Sep;69(3)374-81

12. Vitamin D formulations
Two main forms of oral supplementation :
Vitamin D2 (ergocalciferol)
Vitamin D3 (cholecalciferol)
Only 5% of CF patients achieved vitamin D sufficiency with the 2005 CF Foundation recommendations for D2
Boyle MP, et al. Am J Respir Crit Care Med Jul 15;172(2):212-7.

13. Randomized controlled trial, D2 vs D3p
Initial 25(OH)D, ng/mL
21.2 ± 10.18
24.4 ± 10.3
0.8
Final 25(OH)D, ng/dL
47.1 ± 20.5
32.7 ± 9.7
0.03
% sufficient (>30ng/mL)
Initial (%) 22 40
0.09
Final (%)
100 60
0.003
D3 (50,000IU weekly) vs D2 (50,000IU weekly), 12 weeks
100% of the D3-treated patients achieved goal 25(OH)D levels ≥ 30ng/ml, vs 60% of the D2-treated patients
Khazai NB, et al. J Clin Endocrinol Metab. 2009;94(6):

14. D2 twice weekly vs D3 once weekly
n=47, aged years
doubled frequency of D2 resulted in 69% of subjects reaching goal 25(OH) D2, vs 62% on D3, p = 0.59
Simoneau T, et al. J Cyst Fibros. 2016;15(2):

15. D3 vehicle
Fat malabsorption is a cardinal feature of CF with pancreatic insufficiency
How does the vehicle in which vitamin D supplements are prepared influence the effect on serum vitamin D levels?

16. Oil vs powder D3 formulations
D3 given as 100,000IU bolus, n=15 subjects:
D3 given as 100,000IU D3 bolus, serum D3 and 25(OH)D levels were higher at 12 hours for subjects given D3 in powder-based rather than oil-based vehicle.
Hermes WA, et al. JPEN J Parenter Enteral Nutr Feb 22.

17. Single High Dose D3 (Stoss Therapy)
25(OH)D nmol/L, (ng/mL)
<3 years
3-12 years
>12 years
≤25 nmol/L (10)
200,000IU
400,000IU
600,000IU
25-50 (10-20)
150,000IU
350,000IU
500,000IU
50-75 (20-30)
100,000IU
300,000IU
Time (Months)
25(OH)D (nmol/L)
110
100 90 80 70 60 50 40
n=38 high dose, 37 controls
no toxicity
maintenance doses IU D3 daily
Administration of a very high single dose of oral D3 up to 600,000IU based on age and severity of 25(OH)D deficiency, followed by maintenance dosing
n = 38 children received high-dose treatment; none of those who completed the 12 months of follow up experienced any vitamin D toxicity
The stoss therapy group maintained better 25(OH)D levels than standard-treatment controls throughout the study:
Shepherd D, et al. J Cyst Fibros. 2013;12(2):

18. Calcitriol in CF Calcitriol administration was associated with:
increased dietary calcium absorption
decreased PTH
decreased bone resorption
N=10 CF, 10 controlls
Brown SA, et al. Osteoporos Int. 2003;14(5):

19. Ultraviolet (UV) lamps
UV lamps (such as those used for tanning) emitting UVB radiation stimulate vitamin D production in the skin
May help to circumvent any CF-related malabsorption of oral Vitamin D

20. Case series: Treatment of vitamin D deficiency with UV light in patients with malabsorption syndromes
n = 8 subjects with CF
UV exposure to lower backs in a seated position for 5–10 min (depending on the skin type)
5 exposures per week for 8 weeks 29 27 25 23
Mean 25(OH)D 21 19 17 15
0 week week
Chandra P et al. Photodermatol Photoimmunol Photomed. 2007;23(5):

21. UV lamps
up to 10 minutes of whole-body UV exposure, 1-3 times per week during the fall and winter
significant  in 25(OH) D levels in the treatment group when compared with controls,
9 of 15 patients completed the 6 month study 70 60
25 (OH)D ng/mL 50 40 30 20 10
Baseline 8w w w
Gronowitz E. at al,Acta Paediatr. 2005;94(5):

22. D2 vs D3 vs UV light UV D3 D2 p
Initial 25(OH)D, ng/mL
22.6 ± 10.8
21.2 ± 10.18
24.4 ± 10.3
0.8
Final 25(OH)D, ng/dL
28.3 ± 9.2
47.1 ± 20.5
32.7 ± 9.7
0.03
% sufficient (>30ng/mL)
Initial (%) 22 40
0.09
Final (%)
100 60
0.003
portable UV indoor tanning lamp for 3–10 min (depending on skin type) five times a week, to the lower back
>50% of patients randomized to UV self-reported underusage
UV treated group did not have a significant increase in 25(OH) D levels
Khazai NB, et al. J Clin Endocrinol Metab. 2009;94(6):

23. Back to our Case
Patient was switched from D2 to D3, same dose of 50,000IU three times per week
Repeat 25(OH)D level after 3 months on D3= 33ng/mL
Recommend dietary / supplemental Ca intake for goal of mg daily
Encourage weight bearing exercise
Discussed with GYN and switched to OCPs after she had received ~ 3 years of depot medroxyprogesterone

24. 2012 Guidelines

25. Summary
Treat all individuals with with CF with D3 to maintain 25(OH)D level ≥ 30ng/ml
Measure 25(OH)D annually, preferably at end of winter
D3 is preferred over D2
Insufficient evidence for benefit of bolus vs daily supplementation, consider patient preference

26. Summary
Use age-specific, stepwise increases for treating vitamin D deficiency and deciding on referral threshold
Consider calcitriol only in consultation with an expert in vitamin D therapy
Not enough evidence to recommend for or against UV lamps

27. Acknowledgements
Cystic Fibrosis Foundation, Envision CF: Emerging Leaders in CF Endocrinology Program
Mentor: Vin Tangpricha, MD PhD
CF Center, Virginia Commonwealth University
CF Center, Children’s Hospital of Richmond at VCU
Thank you!