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

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

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

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.

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%.

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?

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):1694-1699

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):1892-9.

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 0.364 116.846 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

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

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. 2005 Jul 15;172(2):212-7.

Randomized controlled trial, D2 vs D3 p 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):2037-2043

D2 twice weekly vs D3 once weekly n=47, aged 6 - 21 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):234-241

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?

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. 2016 Feb 22.

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 0 1 3 6 12 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 0-2400IU 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):177-182

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):442-449.

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

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 8 week Chandra P et al. Photodermatol Photoimmunol Photomed. 2007;23(5):179-185.

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 16w 24w Gronowitz E. at al,Acta Paediatr. 2005;94(5):547-552

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):2037-2043

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 1200-1500mg daily Encourage weight bearing exercise Discussed with GYN and switched to OCPs after she had received ~ 3 years of depot medroxyprogesterone

2012 Guidelines

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

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

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!