What Is Known/What Is New
What Is Known
- Vitamin D is vital for bone mineralization and immune regulation.
- The prevalence of vitamin D deficiency in pediatric patients with inflammatory bowel disease is high.
- There are many modes of vitamin D replacement therapies.
What Is New
- A single high-dose of 300,000 IU cholecalciferol is a safe and effective replacement therapy to correct vitamin D deficiency in children with inflammatory bowel disease.
- Patients preferred stoss therapy over standard weekly therapy.
Vitamin D is instrumental to normal physiology, with a wide range of effects, from skeletal mineralization to immune regulation (1–3). Yet many children with inflammatory bowel disease (IBD), as many as 60% to 70%, are deficient (4,5). Deficiency may be associated with disease flare, nonadherence, or insufficient dietary intake. Normalization, a goal of medical care, not only improves bone mineral density in patients with IBD (3), but could also reduce the risk of relapse (6) through the inhibition of pro-inflammatory cytokines via alterations in the T-helper cell balance (1,7).
There are many strategies of vitamin D repletion. Various regimens are used, ranging from 4000 IU of cholecalciferol daily to 50,000 IU weekly for 5 to 8 weeks. The latter regimen is the standard practice at our center. An alternative therapy is a single, high-dose oral vitamin D3 at 200,000 to 800,000 IU (stoss therapy). This strategy may offer a substantial advantage as adolescents with IBD who are known to have a high rate of medication nonadherence, reportedly as high as 93% (8).
Several studies suggest that stoss therapy may be safe and highly effective in correcting hypovitaminosis D in children with chronic diseases including IBD (9,10), cystic fibrosis (CF) (11), kidney disease (12), and vitamin D deficiency rickets (13). No prospective, randomized studies have, however, compared stoss therapy to the widely used weekly vitamin D replacement therapy in a pediatric population with IBD. We hypothesized that stoss therapy is well-tolerated and noninferior to weekly vitamin D replacement therapy.
We performed a randomized, prospective, pilot study, in 44 children and adolescents (ages 6–21) with IBD and hypovitaminosis D (25-OHD level <30 ng/mL), recruited at a single-center, Nationwide Children's Hospital, in Columbus, OH. This study was approved by the Committee for the Protection of Human Subjects Institutional Review Board. Patients with a history of small bowel resection, kidney or liver disease, and anyone receiving vitamin D replacement therapy at the time of enrollment were excluded. Patients were randomized in a 1:1 ratio to receive either weekly oral dose of 50,000 IU D3 capsule for 6 weeks, which is standard of care (SOC) at our institution, or a single dose of 300,000 IU.
In accordance with the institutional standard of care, serum 25-OHD, a complete metabolic panel (CMP, including total serum calcium), and C-reactive protein (CRP) were collected at the time of enrollment (baseline). Serum parathyroid hormone (PTH) levels were additionally obtained before the initiation of stoss therapy. CMP and serum 25-OHD were repeated at weeks 4 and 12. Safety of stoss therapy was based on evaluation of PTH and serum calcium levels at week 4. Telephone calls to patients or caregivers were obtained at week 4 and week 12, inquiring for any clinical signs or symptoms of hypercalcemia or hypervitaminosis D (gastrointestinal symptoms, such as vomiting, nausea, diarrhea, constipation, and musculoskeletal symptoms, such as weakness, pain, fatigue). Upon study completion, patients were requested to complete an online survey, which included a question about preference for vitamin D replacement therapies.
Comparisons between the stoss and SOC group demographics were made using an unpaired t-test for continuous data and the Fisher exact test or Chi-square test for categorical data. A nonparametric mixed model was performed to evaluate the change in vitamin D laboratory value over 3 time points and between 2 study groups. This was performed in order to account for missing values in an intention-to-treat fashion. Differences in the stoss group safety laboratory values were assessed using an unpaired t-test. All data were analyzed using statistical software SPSS version 21 (IBM Corp, Armonk, NY) or SAS version 9.2 (SAS Institute Inc, Cary, NC) with 2-sided P values <0.05 considered statistically significant.
Patient Population and Demographics
Of all 44 enrolled, 39 patients completed the study. One patient received colectomy during the study period. Two patients were out of town and could not get to their local lab for the blood draw. We were not able to reach the last 2 patients and they did not return our phone calls. The mean age at enrollment was 15.6 ± 2.4 years and 19 (43%) were boys. The majority of patients (95%) were Caucasians and the average BMI was 22 kg/m2. There were more patients with Crohn disease (64%) than ulcerative colitis (UC)/indeterminate colitis (IC) (36%). The stoss group had 13 (54%) patients with UC/IC whereas the SOC group had only 3 (15%) patients with UC/IC (Table 1). There were no statistically significant differences between the therapy groups for age, sex, season, and BMI.
Vitamin D Levels Over Time
As anticipated, 25-OH D levels changed with time in each group (P < 0.0001) (Fig. 1). There was a significant interaction of treatment group over time when assessed using an intention-to-treat analysis (P = 0.0003). Baseline 25-OH D mean levels of SOC and stoss groups were < 30 ng/mL but without significant difference at 23.1 ± 3.6 and 20.4 ± 6.4 ng/mL, respectively. A substantial rise in serum 25-OH D levels at the 4-week time point was observed but no significant difference occurred, with SOC and stoss group 54.6 ± 17.5 and 53.6 ± 17.3 ng/mL, respectively. At week 12, serum 25-OHD levels decreased in both groups, with SOC and stoss group means significantly different at 40.4 ± 11.9 and 29.8 ± 7.1 ng/mL, respectively (P = 0.04). No patients in the stoss or SOC groups had serum 25-OHD above the level of toxicity (>150 ng/mL) when tested at week 4 or 12.
Adverse Events and Safety
Stoss therapy was well tolerated with no reports of vomiting, nausea, diarrhea, constipation, weakness, myalgia, or fatigue at week 4 and week 12. No patient in the stoss group developed hypercalcemia (serum calcium levels >10.5 mg/dL) (Fig. 2A). The mean serum calcium levels were 9.3 ± 0.4 mg/dL at baseline and 9.5 ± 0.6 mg/dL at week 4, which were not statistically significant. Patients in the stoss group also did not have suppressed PTH levels (serum PTH <10 pg/mL) at week 4 (Fig. 2B). The mean serum PTH levels were 41.6 ± 18.1 pg/mL at baseline and 34.3 ± 16.9 pg/mL at week 4, which were not statistically significant.
Thirty-five patients (17 and 18 from the stoss and the SOC groups, respectively) completed a survey at the end of the study. When both groups were described, almost 80% of all patients preferred stoss therapy to the weekly regimen. All but 1 patient from the SOC group reported that they took cholecalciferol as prescribed.
Our study demonstrated that stoss therapy with 300,000 IU of oral vitamin D3 was as effective as the weekly regimen in correcting hypovitaminosis D at week 4 in patients with IBD. We also show that this single high-dose vitamin D treatment sustained a vitamin D level close to 30 ng/mL at 12 weeks. To our knowledge, this study is the first to compare the effectiveness of these 2 treatment regimens in a randomized prospective study design. The mean 25-OHD levels of both groups at week 4 were nearly identical, at 54 ng/mL, safely below the level of toxicity (>150 ng/mL) (14).
In this study, we utilized the same vitamin D3 dose of 300,000 IU for all patients ages 6 to 21 years, rather than age-based dosing up to 600,000 to 800,000 IU used in studies by Shepherd et al.(9) and Martin et al.(10) that reported no evidence of vitamin D toxicity in any of the patients. The dose used in this study was chosen because of safety concerns reported in a recent study showing increased prevalence of hypercalcemia in stoss therapy when using 600,000 IU in young children with vitamin D deficiency (15). The lower dose used in our study may explain the lower vitamin D levels at week 12. This is not surprising, as a recent study in older children with hypovitaminosis D without rickets utilizing this same single dose of 300,000 IU vitamin D showed that serum 25-OHD levels significantly increased at week 4 but dropped to 24.6 ± 7.2 ng/mL by week 12 (16). Furthermore, the half-life of 25-OHD in serum is 28 days (17), which likely explains the drop in vitamin D levels in both groups by 12 weeks. Future studies are needed to determine whether pediatric IBD patients can tolerate a higher single dose of vitamin D to sustain an adequate level of vitamin D for longer periods.
One of the major advantages of stoss therapy is that it reduces the treatment burden and perhaps improves adherence because it is only given once. Although almost all patients who received weekly vitamin D therapy reported adherence to the treatment course during the study period, in the real world setting, treatment adherence is likely a challenge and burdensome to the patient (8). The patient survey in both groups at the conclusion of the study indicated high preference for the concept of stoss therapy over our standard weekly therapy.
Theoretical risks for stoss therapy include hypercalcemia, hypoparathyroidism, and renal calculi (18). Several studies have shown that stoss supplementation can be used safely and successfully in children with vitamin D deficiency with or without rickets (13,16), kidney disease (12), and cystic fibrosis (11). Consistent with the previous studies, our study showed no observed episodes of hypercalcemia or suppressed PTH levels. Patients also denied any clinical signs of hypervitaminosis D including gastrointestinal and musculoskeletal symptoms.
This small, pilot study has several limitations. The majority of our patients had lighter skin. A larger multicenter study will provide a more robust and representative patient population. A longitudinal study with longer follow up period, evaluating duration of optimal vitamin D levels (≥30 ng/mL) as well as assessing for association with other IBD-related health outcomes should be considered and studied. We did not collect data on other possible confounders including dietary vitamin D intake and sunlight exposure. In addition, the study was not blinded, which could have led to recall bias. Further studies may consider administering each dose in clinic under direct supervision, resulting in optimal adherence. This would, however, require additional staff and a dedicated clinical space, which can be cost-prohibitive. This would also not be reflective of “real world” conditions. The strength of this study is that it was the first prospective and randomized study comparing stoss supplementation to a commonly prescribed weekly vitamin D replacement therapy in pediatric IBD patients.
In conclusion, a single high-dose (300,000 IU) vitamin D is a safe and effective mode of therapy to correct hypovitaminosis D in children with IBD. We recognize that although we have shown stoss therapy can effectively increase vitamin D levels without any signs of hypervitaminosis D, we have not demonstrated the long-term clinical outcomes for hypovitaminosis D in children with IBD. A longitudinal study evaluating vitamin D levels with a higher dose of cholecalciferol and relevant clinical outcomes is required. The majority of patients preferred the concept of stoss therapy to weekly therapy and can be an alternative option for patients with poor compliance.
1. Ardizzone S, Cassinotti A, Trabattoni D, et al. Immunomodulatory effects of 1,25-dihydroxyvitamin D3 on TH1/TH2 cytokines in inflammatory bowel disease: an in vitro study. Int J Immunopathol Pharmacol
2. Di Rosa M, Malaguarnera G, De Gregorio C, et al. Immuno-modulatory effects of vitamin D3 in human monocyte and macrophages. Cell Immunol
3. Pappa H, Thayu M, Sylvester F, et al. Skeletal health of children and adolescents with inflammatory bowel disease. J Pediatr Gastroenterol Nutr
4. Abraham BP, Prasad P, Malaty HM. Vitamin D deficiency
and corticosteroid use are risk factors for low bone mineral density in inflammatory bowel disease patients. Dig Dis Sci
5. Farraye FA, Nimitphong H, Stucchi A, et al. Use of a novel vitamin D bioavailability test demonstrates that vitamin D absorption is decreased in patients with quiescent Crohn's disease. Inflamm Bowel Dis
6. Reich KM, Fedorak RN, Madsen K, et al. Vitamin D improves inflammatory bowel disease outcomes: basic science and clinical review. World J Gastroenterol
7. Mora JR, Iwata M, von Andrian UH. Vitamin effects on the immune system: vitamins A and D take centre stage. Nat Rev Immunol
8. Spekhorst LM, Hummel TZ, Benninga MA, et al. Adherence to oral maintenance treatment in adolescents with inflammatory bowel disease. J Pediatr Gastroenterol Nutr
9. Shepherd D, Day AS, Leach ST, et al. Single high-dose oral vitamin D3 therapy (Stoss): a solution to vitamin d deficiency
in children with inflammatory bowel disease? J Pediatr Gastroenterol Nutr
10. Martin NG, Day AS, Leach ST, et al. Single high-dose oral vitamin D3 treatment in New Zealand children with inflammatory bowel disease. Transl Pediatr
11. Shepherd D, 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
12. Belostotsky V, Mughal Z, Webb NJ. A single high dose of ergocalciferol can be used to boost 25-hydroxyvitamin D levels in children with kidney disease. Pediatr Nephrol
13. Soliman AT, El-Dabbagh M, Adel A, et al. Clinical responses to a mega-dose of vitamin D3 in infants and toddlers with vitamin D deficiency
rickets. J Trop Pediatr
14. Alshahrani F, Aljohani N. Vitamin D: deficiency, sufficiency and toxicity. Nutrients
15. Harnot J, Verma S, Singhi S, et al. Comparison of 300,000 and 600,000 IU oral vitamin-d bolus for vitamin-D deficiency in young children. Indian J Pediatr
16. Kocyigit C, Çatlı G, İnce G, et al. Can stoss therapy be used in children with vitamin D deficiency
or insufficiency without rickets? J Clin Res Pediatr Endocrinol
17. 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
18. Vogiatzi MG, Jacobson-Dickman E, DeBoer MD. Vitamin D supplementation and risk of toxicity in pediatrics: a review of current literature. J Clin Endocrinol Metab