ORIGINAL ARTICLE: GASTROENTEROLOGY
Single High-Dose Oral Vitamin D3 Therapy (Stoss): A Solution to Vitamin D Deficiency in Children With Inflammatory Bowel Disease?
Darren Shepherd, zAndrew S. Day, ySteven T. Leach, zRobert Lopez, Rachel Messenger, § Helen J. Woodhead, jjOren Ledder, and Daniel A. Lemberg
ABSTRACT Objectives: Vitamin D deficiency is common in children with inflammatory bowel disease (IBD). The aim of this study was to determine the safety and efficacy of stoss therapy on vitamin D levels during a period of 6 months in children with IBD and vitamin D deficiency (50 nmol/L at 1 month, whereas this level was seen in 96.6% at 3 months and 76.4% at 6 months. In addition, a 25-OHD level >75 nmol/L at 1 month was seen after 97 of 99 (98%) doses, with 63% of the children having a level >75 nmol/L at 3 months. Mean 25-OHD levels at 6 months remained elevated at 69.2 (31.3) nmol/L compared with pretreatment levels (P 0.05, Fig. 1). www.jpgn.org
Copyright 2015 by ESPGHAN and NASPGHAN. Unauthorized reproduction of this article is prohibited.
JPGN
Volume 61, Number 4, October 2015
Single High-Dose Oral Vitamin D3 Therapy (Stoss) was a trend for those who were deficient after 6 months to have higher pretreatment CRP (P ¼ 0.06) and lower albumin values (P ¼ 0.08).
25 OHD, nmol/L
300
200
DISCUSSION
100
0 Baseline
Month 1
Month 3
Month 6
FIGURE 1. Serum 25-OHD levels in paediatric patients with IBD following stoss therapy. Paediatric patients with IBD with serum 25OHD levels 75 nmol/L indicating sufficiency. The optimal level to enhance the other benefits of vitamin D (eg, innate immune roles) is not known. Standard vitamin D replacement dosage recommendations are also variable. The recent Australian guideline recommends 1000 to 4000 IU daily for the treatment for mild to moderate hypovitaminosis D with subsequent maintenance daily dose of 400 IU daily (15). In contrast, Pappa et al (13) suggest a cumulative dose of 140,000 to 600,000 IU of vitamin D during a 12-week period for children with IBD, with a maintenance dose of 800 to 1000 IU of vitamin D thereafter. In contrast to these regimens, Vitamin D was provided as a single dose in the present study, with the advantage that it is a single, directly observed oral dose, which achieves optimal adherence. Oral cholecalciferol as stoss therapy has been shown to be safe in children with vitamin D rickets (4), kidney disease (6), and cystic fibrosis (9,10). Similarly, a single high dose (600,000 IU) intramuscularly, followed by oral maintenance has been shown to be safe and effective in adults with osteoporosis (11). This study is unique in demonstrating the safety and efficacy of high-dose oral cholecalciferol given as a single dose (stoss therapy) and also that these increases were maintained during a
413
Copyright 2015 by ESPGHAN and NASPGHAN. Unauthorized reproduction of this article is prohibited.
Lemberg et al
JPGN
6-month period. It also demonstrates it is possible to maintain a 25-OHD level >75 nmol/L with stoss therapy. A randomised control trial in children with IBD showed that supplementation with high-dose ergocalciferol (50,000 IU/wk) is more efficacious with increased serum 25-OHD levels than lowdose ergocalciferol (2000 IU/day) during a 6-week study period (16). Pappa et al (17) showed high-dose ergocalciferol and low-dose cholecalciferol regimens increased the 25-OHD levels >50 nmol/L in 95% of patients; however, 25% and 62% of the patients did not achieve a 25-OHD level >75 nmol/L. This is in contrast to the present study, in which all of the subjects had a 25-OHD level >50 nmol/L at 1 month, and 98% of children had a 25-OHD level >75 nmol/L at this time. Furthermore, these benefits were maintained by >60% of the patients by 3 months. This would allow a clinician to assess 25-OHD levels every 3 months to ensure children with IBD remain vitamin D sufficient. Interestingly, the present study demonstrated increased 25-OHD levels at each time point despite the half-life of 25-OHD in serum being 22 to 28 days (18). It is hypothesised that vitamin D, when given as stoss therapy is stored in fat and muscle before release during several months. Ilahi et al (19) showed that a single dose of 100,000 IU of vitamin D3 in healthy adults had a halflife of >50 days, compared with 20 to 30 days at lower doses. One key rationale of improving vitamin D status in IBD is to optimise bone health and to thereby prevent or minimise future fracture risk. There is debate whether there is an increased fracture risk in children with IBD. A North American study involving 1221 children with IBD did not show an increased fracture risk compared with 3287 matched controls (20). There was, however, a nonsignificant trend toward an increased rate of vertebral fractures in the children with CD. In contrast, a significant increase in vertebral fractures has been noted in adults diagnosed as having IBD, with these fractures occurring at younger ages than in matched controls (21). Based upon these data, it seems logical to optimise vitamin D status in children with IBD to optimise their BMD and thereby prevent fractures in subsequent years. Normalisation of vitamin D may also have other potential benefits, such as innate immune function or improved disease activity. These aspects could not be delineated in the present study. The present study did not include a control group or group receiving an alternative treatment regimen. Dietary vitamin D intake was not quantitated, and estimates of bone health were not available in these children. The strengths of this study are that it was based within 1 IBD clinic population, with consistent care provided throughout, and reflects standard clinical practice. Patients lived within a similar geographical area with similar sunshine exposures. In conclusion, this study indicated that stoss therapy was a safe and effective way to normalise serum 25-OHD levels in these children with IBD. Prospective studies are now required to further ascertain the potential benefits of normalising 25-OHD status by stoss therapy in IBD.
REFERENCES 1. Day AS, Ledder O, Leach ST, et al. Crohn’s and colitis in children and adolescents. World J Gastroenterol 2012;18:5862–9.
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Volume 61, Number 4, October 2015
2. Rufo PA, Denson LA, Sylvester FA, et al. Health supervision in the management of children and adolescents with IBD: NASPGHAN recommendations. J Pediatr Gastroenterol Nutr 2012;55:93–108. 3. Green D, Carson K, Leonard A, et al. Current treatment recommendations for correcting vitamin D deficiency in pediatric patients with cystic fibrosis are inadequate. J Pediatr 2008;153:554–9. 4. Cesur Y, Caksen H, Gundem A, et al. Comparison of low and high dose vitamin D treatment in nutritional vitamin D deficient rickets. J Pediatr Endocrinol Metab 2003;16:1105–9. 5. Pappa HM, Gordon CM, Saslowsky TM, et al. Vitamin D status in children and young adults with inflammatory bowel disease. Pediatrics 2006;118:1950–61. 6. Belostotsky V, Mughal Z. A single high dose of ergocalciferol can be used to boost 25-hydroxyvitamin D levels in children. Pediatr Nephrol 2009;24:625–6. 7. Bordelon P, Ghetu M, Langan R. Recognition and management of vitamin D deficiency. Am Fam Physician 2009;80:841–6. 8. Zhao H, Zhang H, Wu H, et al. Protective role of 1,25(OH)2 vitamin D3 in the mucosal injury and epithelial barrier disruption in DSS-induced acute colitis in mice. BMC Gastroenterol 2012;12:57. 9. Shepherd DP, Belessis Y, Katz T, et al. Single high-dose oral vitamin D3 (stoss) therapy—a solution to vitamin D deficiency in children with cystic fibrosis? J Cyst Fibros 2013;12:177–82. 10. Khazai N, Judd S, Jeng L, et al. Treatment and prevention of vitamin D insufficiency in cystic fibrosis patients: comparative efficacy of ergocalciferol, cholecalciferol and UV light. J Clin Endocrinol Metab 2009;94:2037–43. 11. Diamond T, Ho K, Rohl P, et al. Annual intramuscular injection of megadose of cholecalciferol for treatment of vitamin D deficiency: efficacy and safety data. Med J Aust 2005;183:10–2. 12. Harms HK, Blomer R, Bertele-Harms RM, et al. A paediatric Crohn’s disease activity index (PCDAI). Is it useful? Study Group on Crohn’s Disease in Children and Adolescents. Acta Paediatr Suppl 1994;395: 22–6. 13. Pappa HM, Langereis EJ, Grand RJ, et al. Prevalence and risk factors for hypovitaminosis D in young patients with inflammatory bowel disease. J Pediatr Gastroenterol Nutr 2011;53:361–4. 14. Levin AD, Wadhera V, Leach ST, et al. Vitamin D deficiency in children with inflammatory bowel disease. Dig Dis Sci 2011;56:830–6. 15. Paxton GA, Teale GR, Nowson CA, et al. Vitamin D and health in pregnancy, infants, children and adolescents in Australia and New Zealand: a position statement. Med J Aust 2013;198:142–3. 16. Heaney RP. Functional indices of vitamin D status and ramifications of vitamin D deficiency. Am J Clin Nutr 2004;80 (6 suppl):1706S–9. 17. Pappa HM, Mitchell PD, Jiang H, et al. Treatment of vitamin D insufficiency in children and adolescents with inflammatory bowel disease: a randomised control trial comparing three regimes. J Clin Endocrinol Metab 2012;97:2134–42. 18. Heaney RP, Armas LA, Shary JR, et al. 25-Hydroxylation of vitamin D3: relation to circulating vitamin D3 under various input conditions. Am J Clin Nutr 2008;87:1738–42. 19. Ilahi M, Armas LA, Heaney RP. Pharmacokinetics of a single, large dose of cholecalciferol. Am J Clin Nutr 2008;87:688–91. 20. Kappelman MD, Galanko JA, Porter CQ, et al. Risk of diagnosed fractures in children with inflammatory bowel disease. Inflamm Bowel Dis 2011;17:1125–30. 21. Vazquez MA, Lopez E, Montoya MJ, et al. Vertebral fractures in patients with inflammatory bowel disease compared with a healthy population: a prospective case-control study. BMC Gastroenterol 2012; 12:47.
www.jpgn.org
Copyright 2015 by ESPGHAN and NASPGHAN. Unauthorized reproduction of this article is prohibited.
Single High-Dose Oral Vitamin D3 Therapy (Stoss): A Solution to Vitamin D Deficiency in Children With Inflammatory Bowel Disease?
Darren Shepherd, zAndrew S. Day, ySteven T. Leach, zRobert Lopez, Rachel Messenger, § Helen J. Woodhead, jjOren Ledder, and Daniel A. Lemberg
ABSTRACT Objectives: Vitamin D deficiency is common in children with inflammatory bowel disease (IBD). The aim of this study was to determine the safety and efficacy of stoss therapy on vitamin D levels during a period of 6 months in children with IBD and vitamin D deficiency (50 nmol/L at 1 month, whereas this level was seen in 96.6% at 3 months and 76.4% at 6 months. In addition, a 25-OHD level >75 nmol/L at 1 month was seen after 97 of 99 (98%) doses, with 63% of the children having a level >75 nmol/L at 3 months. Mean 25-OHD levels at 6 months remained elevated at 69.2 (31.3) nmol/L compared with pretreatment levels (P 0.05, Fig. 1). www.jpgn.org
Copyright 2015 by ESPGHAN and NASPGHAN. Unauthorized reproduction of this article is prohibited.
JPGN
Volume 61, Number 4, October 2015
Single High-Dose Oral Vitamin D3 Therapy (Stoss) was a trend for those who were deficient after 6 months to have higher pretreatment CRP (P ¼ 0.06) and lower albumin values (P ¼ 0.08).
25 OHD, nmol/L
300
200
DISCUSSION
100
0 Baseline
Month 1
Month 3
Month 6
FIGURE 1. Serum 25-OHD levels in paediatric patients with IBD following stoss therapy. Paediatric patients with IBD with serum 25OHD levels 75 nmol/L indicating sufficiency. The optimal level to enhance the other benefits of vitamin D (eg, innate immune roles) is not known. Standard vitamin D replacement dosage recommendations are also variable. The recent Australian guideline recommends 1000 to 4000 IU daily for the treatment for mild to moderate hypovitaminosis D with subsequent maintenance daily dose of 400 IU daily (15). In contrast, Pappa et al (13) suggest a cumulative dose of 140,000 to 600,000 IU of vitamin D during a 12-week period for children with IBD, with a maintenance dose of 800 to 1000 IU of vitamin D thereafter. In contrast to these regimens, Vitamin D was provided as a single dose in the present study, with the advantage that it is a single, directly observed oral dose, which achieves optimal adherence. Oral cholecalciferol as stoss therapy has been shown to be safe in children with vitamin D rickets (4), kidney disease (6), and cystic fibrosis (9,10). Similarly, a single high dose (600,000 IU) intramuscularly, followed by oral maintenance has been shown to be safe and effective in adults with osteoporosis (11). This study is unique in demonstrating the safety and efficacy of high-dose oral cholecalciferol given as a single dose (stoss therapy) and also that these increases were maintained during a
413
Copyright 2015 by ESPGHAN and NASPGHAN. Unauthorized reproduction of this article is prohibited.
Lemberg et al
JPGN
6-month period. It also demonstrates it is possible to maintain a 25-OHD level >75 nmol/L with stoss therapy. A randomised control trial in children with IBD showed that supplementation with high-dose ergocalciferol (50,000 IU/wk) is more efficacious with increased serum 25-OHD levels than lowdose ergocalciferol (2000 IU/day) during a 6-week study period (16). Pappa et al (17) showed high-dose ergocalciferol and low-dose cholecalciferol regimens increased the 25-OHD levels >50 nmol/L in 95% of patients; however, 25% and 62% of the patients did not achieve a 25-OHD level >75 nmol/L. This is in contrast to the present study, in which all of the subjects had a 25-OHD level >50 nmol/L at 1 month, and 98% of children had a 25-OHD level >75 nmol/L at this time. Furthermore, these benefits were maintained by >60% of the patients by 3 months. This would allow a clinician to assess 25-OHD levels every 3 months to ensure children with IBD remain vitamin D sufficient. Interestingly, the present study demonstrated increased 25-OHD levels at each time point despite the half-life of 25-OHD in serum being 22 to 28 days (18). It is hypothesised that vitamin D, when given as stoss therapy is stored in fat and muscle before release during several months. Ilahi et al (19) showed that a single dose of 100,000 IU of vitamin D3 in healthy adults had a halflife of >50 days, compared with 20 to 30 days at lower doses. One key rationale of improving vitamin D status in IBD is to optimise bone health and to thereby prevent or minimise future fracture risk. There is debate whether there is an increased fracture risk in children with IBD. A North American study involving 1221 children with IBD did not show an increased fracture risk compared with 3287 matched controls (20). There was, however, a nonsignificant trend toward an increased rate of vertebral fractures in the children with CD. In contrast, a significant increase in vertebral fractures has been noted in adults diagnosed as having IBD, with these fractures occurring at younger ages than in matched controls (21). Based upon these data, it seems logical to optimise vitamin D status in children with IBD to optimise their BMD and thereby prevent fractures in subsequent years. Normalisation of vitamin D may also have other potential benefits, such as innate immune function or improved disease activity. These aspects could not be delineated in the present study. The present study did not include a control group or group receiving an alternative treatment regimen. Dietary vitamin D intake was not quantitated, and estimates of bone health were not available in these children. The strengths of this study are that it was based within 1 IBD clinic population, with consistent care provided throughout, and reflects standard clinical practice. Patients lived within a similar geographical area with similar sunshine exposures. In conclusion, this study indicated that stoss therapy was a safe and effective way to normalise serum 25-OHD levels in these children with IBD. Prospective studies are now required to further ascertain the potential benefits of normalising 25-OHD status by stoss therapy in IBD.
REFERENCES 1. Day AS, Ledder O, Leach ST, et al. Crohn’s and colitis in children and adolescents. World J Gastroenterol 2012;18:5862–9.
414
Volume 61, Number 4, October 2015
2. Rufo PA, Denson LA, Sylvester FA, et al. Health supervision in the management of children and adolescents with IBD: NASPGHAN recommendations. J Pediatr Gastroenterol Nutr 2012;55:93–108. 3. Green D, Carson K, Leonard A, et al. Current treatment recommendations for correcting vitamin D deficiency in pediatric patients with cystic fibrosis are inadequate. J Pediatr 2008;153:554–9. 4. Cesur Y, Caksen H, Gundem A, et al. Comparison of low and high dose vitamin D treatment in nutritional vitamin D deficient rickets. J Pediatr Endocrinol Metab 2003;16:1105–9. 5. Pappa HM, Gordon CM, Saslowsky TM, et al. Vitamin D status in children and young adults with inflammatory bowel disease. Pediatrics 2006;118:1950–61. 6. Belostotsky V, Mughal Z. A single high dose of ergocalciferol can be used to boost 25-hydroxyvitamin D levels in children. Pediatr Nephrol 2009;24:625–6. 7. Bordelon P, Ghetu M, Langan R. Recognition and management of vitamin D deficiency. Am Fam Physician 2009;80:841–6. 8. Zhao H, Zhang H, Wu H, et al. Protective role of 1,25(OH)2 vitamin D3 in the mucosal injury and epithelial barrier disruption in DSS-induced acute colitis in mice. BMC Gastroenterol 2012;12:57. 9. Shepherd DP, Belessis Y, Katz T, et al. Single high-dose oral vitamin D3 (stoss) therapy—a solution to vitamin D deficiency in children with cystic fibrosis? J Cyst Fibros 2013;12:177–82. 10. Khazai N, Judd S, Jeng L, et al. Treatment and prevention of vitamin D insufficiency in cystic fibrosis patients: comparative efficacy of ergocalciferol, cholecalciferol and UV light. J Clin Endocrinol Metab 2009;94:2037–43. 11. Diamond T, Ho K, Rohl P, et al. Annual intramuscular injection of megadose of cholecalciferol for treatment of vitamin D deficiency: efficacy and safety data. Med J Aust 2005;183:10–2. 12. Harms HK, Blomer R, Bertele-Harms RM, et al. A paediatric Crohn’s disease activity index (PCDAI). Is it useful? Study Group on Crohn’s Disease in Children and Adolescents. Acta Paediatr Suppl 1994;395: 22–6. 13. Pappa HM, Langereis EJ, Grand RJ, et al. Prevalence and risk factors for hypovitaminosis D in young patients with inflammatory bowel disease. J Pediatr Gastroenterol Nutr 2011;53:361–4. 14. Levin AD, Wadhera V, Leach ST, et al. Vitamin D deficiency in children with inflammatory bowel disease. Dig Dis Sci 2011;56:830–6. 15. Paxton GA, Teale GR, Nowson CA, et al. Vitamin D and health in pregnancy, infants, children and adolescents in Australia and New Zealand: a position statement. Med J Aust 2013;198:142–3. 16. Heaney RP. Functional indices of vitamin D status and ramifications of vitamin D deficiency. Am J Clin Nutr 2004;80 (6 suppl):1706S–9. 17. Pappa HM, Mitchell PD, Jiang H, et al. Treatment of vitamin D insufficiency in children and adolescents with inflammatory bowel disease: a randomised control trial comparing three regimes. J Clin Endocrinol Metab 2012;97:2134–42. 18. Heaney RP, Armas LA, Shary JR, et al. 25-Hydroxylation of vitamin D3: relation to circulating vitamin D3 under various input conditions. Am J Clin Nutr 2008;87:1738–42. 19. Ilahi M, Armas LA, Heaney RP. Pharmacokinetics of a single, large dose of cholecalciferol. Am J Clin Nutr 2008;87:688–91. 20. Kappelman MD, Galanko JA, Porter CQ, et al. Risk of diagnosed fractures in children with inflammatory bowel disease. Inflamm Bowel Dis 2011;17:1125–30. 21. Vazquez MA, Lopez E, Montoya MJ, et al. Vertebral fractures in patients with inflammatory bowel disease compared with a healthy population: a prospective case-control study. BMC Gastroenterol 2012; 12:47.
www.jpgn.org
Copyright 2015 by ESPGHAN and NASPGHAN. Unauthorized reproduction of this article is prohibited.
