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Division of Adolescent Medicine (C.M.G., A.L.W., J.M., L.S.), Division of Endocrinology (C.M.G., H.A.F.), Clinical Research Program (H.A.F.), and Division of General Pediatrics (J.E.C.), Children’s Hospital Boston, Boston, Massachusetts 02115; and Biotics Research Corp. (A.V.), Rosenberg, Texas 77471
Address all correspondence and requests for reprints to: Catherine M. Gordon, M.D., M.Sc., Divisions of Adolescent Medicine and Endocrinology, Children’s Hospital Boston, 300 Longwood Avenue, Boston, Massachusetts 02115. E-mail: catherine.gordon{at}childrens.harvard.edu.
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Abstract |
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Objective: The objective of the study was to compare the safety and efficacy of vitamin D2 daily, vitamin D2 weekly, and vitamin D3 daily, combined with supplemental calcium, in raising serum 25-hydroxyvitamin D [25(OH)D] and lowering PTH concentrations.
Design: This was a 6-wk randomized controlled trial.
Setting: The study was conducted at an urban pediatric clinic in Boston.
Subjects: Forty otherwise healthy infants and toddlers with hypovitaminosis D [25(OH)D < 20 ng/ml] participated in the study.
Interventions: Participants were assigned to one of three regimens: 2,000 IU oral vitamin D2 daily, 50,000 IU vitamin D2 weekly, or 2,000 IU vitamin D3 daily. Each was also prescribed elemental calcium (50 mg/kg·d). Infants received treatment for 6 wk.
Main Outcome Measures: Before and after treatment, serum measurements of 25(OH)D, PTH, calcium, and alkaline phosphatase were taken.
Results: All treatments approximately tripled the 25(OH)D concentration. Preplanned comparisons were nonsignificant: daily vitamin D2 vs. weekly vitamin D2 (12% difference in effect, P = 0.66) and daily D2 vs. daily D3 (7%, P = 0.82). The mean serum calcium change was small and similar in the three groups. There was no significant difference in PTH suppression.
Conclusions: Short-term vitamin D2 2,000 IU daily, vitamin D2 50,000 IU weekly, or vitamin D3 2,000 IU daily yield equivalent outcomes in the treatment of hypovitaminosis D among young children. Therefore, pediatric providers can individualize the treatment regimen for a given patient to ensure compliance, given that no difference in efficacy or safety was noted among these three common treatment regimens.
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Introduction |
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Multiple treatment regimens have been proposed to treat hypovitaminosis D in young children, including daily or weekly dosing for varying periods of time. Common recommendations include 200,000 IU vitamin D3 every 3 months (12), 1,000–2,000 IU vitamin D2 or vitamin D3 daily for several weeks (13), or the administration of a single im injection of 600,000 IU of vitamin D2, repeated after 12 wk (14, 15, 16). A regimen that has been used commonly in treating adults is 5,000–15,000 IU of vitamin D2 weekly for 4–8 wk (17, 18). Another effective method for treating hypovitaminosis D in adult patients is an oral dose of 50,000 IU of vitamin D2 weekly for 8 wk, with subsequent increases in serum 25-hydroxyvitamin D [25(OH)D] and decreases in PTH concentrations noted (19). Little information currently exists regarding the safety or efficacy of these vitamin D treatment doses in a pediatric population. The form of vitamin D administered during treatment also remains as an area of debate, and again little information is available in children. Recent reports citing data in adults suggest that vitamin D3 may provide a more efficacious treatment regimen than vitamin D2, in both terms of potency and duration of action (20, 21, 22). However, there is controversy surrounding this point because one recent study in adults noted the two treatment methods to be equally effective (23). Additionally, a study of infants and their mothers showed that vitamin D2 and vitamin D3 accounted for a similar proportion of total 25(OH)D concentration in neonates (cord blood) and maternal serum (24).
The aim of the present study was to examine prospectively three common treatment short-term regimens for correction of hypovitaminosis D in infants and toddlers. We conducted a randomized clinical trial, treating participants with either a daily low dose of vitamin D2, a higher dose of vitamin D2 once weekly, or a low dose of vitamin D3 once daily. This study examined: 1) the efficacy of each treatment in raising serum 25(OH)D and lowering PTH concentrations; and 2) the safety and tolerance of each regimen in infants and toddlers, as evaluated through documentation of hypo- or hypercalcemia and reported symptoms.
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Subjects and Methods |
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A complete description of the referral sample for this treatment trial has been published previously (25). Briefly, during the cross-sectional screening portion of the study, 380 infants and toddlers, aged 8–24 months, were enrolled consecutively throughout the calendar year from the Children’s Hospital Boston Primary Care Center between October 2005 and June 2007. Subjects completed a nutritional survey, and serum measurements of 25(OH)D, alkaline phosphatase, PTH, calcium, phosphorus, and magnesium were obtained. Skin pigmentation and sun sensitivity were evaluated by a research assistant using established methods (26, 27). Exclusion criteria for the study included having a chronic disease (e.g. asthma, seizure disorder, sickle cell disease), the use of oral glucocorticoid over the previous 3 months, or other therapy known to affect vitamin D metabolism. Patients found to be vitamin D deficient [25(OH)D 
20 ng/ml (50 nmol/liter)] were invited to participate in the randomized clinical trial, which included randomization to one of three vitamin D treatment regimens. The Committee on Clinical Investigation, Children’s Hospital Boston, approved the study protocol, and parents or guardians of all participants provided written informed consent.
Treatment protocol
Patients identified to have hypovitaminosis D were randomly assigned to one treatment protocol. The randomization list was stratified by age at screening (9 or 18 months) and blocked in randomly permuted sequences of 3 or 6, ensuring that no treatment would be disproportionately represented in any season or age group. The vitamin D treatments included one of three regimens: 2,000 IU oral ergocalciferol (vitamin D2) daily, 50,000 IU vitamin D2 weekly, or 2,000 IU cholecalciferol (vitamin D3) daily. Each group was also prescribed 50 mg/kg·d of elemental calcium to prevent hypocalcemia associated with hungry bone syndrome (14). Infants received the combined vitamin D and calcium treatment for a course of 6 wk.
Vitamin D and calcium supplements were each provided in a liquid suspension that was administered orally from a vial directly onto the tongue. Parents were instructed to shake the vial before administration. The vitamin D2 preparation (200 IU per drop or 0.025 ml) was manufactured by Sanofi-Synthelabo Inc. (Bridgewater, NJ), and doses were provided as 10 drops or 0.25 ml daily for the 2,000 IU dose and 6.25 ml weekly for the 50,000 IU dose; for each vitamin D2 dose, the suspension was administered via a provided dropper onto the tongue. The vitamin D3 (2000 IU per drop, oil and water emulsion) was provided by Biotics Research Corp. (Rosenberg, TX), and one drop or 0.025 ml was administered daily from the vial directly onto the child’s tongue. Assays of products ensured potency. The administration of the vitamin and mineral preparations in liquid form prevented problems with swallowing pills that may have presented a choking or compliance risk in our young patient population.
After approximately 3 wk of treatment, a research assistant contacted each family to ensure that the child was receiving both the calcium and vitamin D without difficulty. Within 1 wk after completing the treatment regimen, repeat serum 25(OH)D concentrations along with PTH, calcium, magnesium, phosphorus, and alkaline phosphatase were measured. To assess compliance, the amount of vitamin D and calcium syrups remaining in the respective bottles was measured by a technician in the Central Pharmacy at Children’s Hospital Boston. Outcome measures included changes in serum 25(OH)D, PTH, and alkaline phosphatase levels between baseline and follow-up. Two comparisons were formally designated as being of primary interest: daily vitamin D2 vs. weekly vitamin D2 and daily vitamin D2 vs. daily vitamin D3.
Laboratory measurements
During the baseline and follow-up visits, one blood sample (15 ml) was obtained from each subject. Laboratory samples were processed immediately at both Children’s Hospital Boston and ARUP Laboratories (Salt Lake City, UT). Serum 25(OH)D levels were measured at ARUP Laboratories, using a Diasorin chemiluminescent assay (LIAISON; DiaSorin Inc., Stillwater, MN). This assay accurately quantifies the sum of both 25(OH)D3 and 25(OH)D2. A multichannel analyzer (Roche Diagnostics, Indianapolis, IN) was used to measure serum calcium, phosphorus, magnesium, and alkaline phosphatase levels on site. Intact PTH was measured by a two-site chemiluminescence immunoassay (Nichols Institute, San Clemente, CA).
Interassay coefficients of variation were 5.4–7% for PTH, 8.6–10.0% for 25(OH)D, 0.67% for alkaline phosphatase, and 1.5–2.2% for the cations. The definition of hypovitaminosis D correlated with the lowest end of the normal reference range as provided by the manufacturer (Diasorin). Identification of severe hypovitaminosis D was consistent with the 25(OH)D Diasorin LIAISON assay sensitivity (7 ng/ml).
Statistics
We conducted an intention-to-treat analysis, attributing the assigned treatment to all randomized subjects regardless of compliance. To compare baseline characteristics among the three trial arms, we used Fisher’s extract test for dichotomous variables and one-way ANOVA for continuous measures, the latter corroborated in cases of skewed distribution by the Kruskal-Wallis test.
Changes in 25(OH)D, PTH, alkaline phosphatase, and cation levels were assessed and compared among trial arms by repeated-measures analysis of covariance (ANCOVA), adjusted for age, weight, sex, skin tone, and sun sensitivity. All concentrations showed mildly skewed distributions and were log transformed for analysis. For reporting, levels were retransformed to concentration units. Mean changes on the log scale were constructed from parameters of the fitted ANCOVA and expressed as percentages, e.g. 100% x [exp(
logPTH) – 1]. The two contrasts of primary interest, daily D2-weekly D2 and daily D2-daily D3, were constructed from parameters of the ANCOVA and compared with zero with a two-sided model, Bonferroni-adjusted critical P value of 0.025.
Pretrial power calculations for the two primary comparisons indicated that a sample of 15 subjects per arm would provide 80% power to detect a difference between treatments on the order of 60% for the 6-wk change in 25(OH)D. These calculations were based on cross-sectional data from our adolescent clinic (28) and an estimated intraclass correlation of 0.5 (not obtainable from the cross-sectional data).
Statistical computations and generation of the randomization list were performed with SAS software version 9.1 (SAS Institute, Cary, NC).
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Results |
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Within our clinical sample of 380 infants and toddlers (25), we identified 40 infants and toddlers to have hypovitaminosis D [25(OH)D 20 ng/ml (50 nmol/liter)]. Within this sample of 40 participants, 35 completed the course of therapy (87.5%). The baseline characteristics of participants in the three treatment arms are illustrated in Table 1
. There were no significant differences between groups with respect to gender, skin pigmentation, skin sensitivity, or season of year at baseline, before randomization. Biochemically, participants were also similar, and weight and age did not significantly differ across treatment groups.
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All three treatments virtually tripled the 25(OH)D concentration in these vitamin D-deficient children (Fig. 1; Table 2). The greatest effect was attained with weekly vitamin D2: from 13.8 to 44.0 ng/ml, an increase of 220%. The next greatest was the effect of D3 (13.7–41.2 ng/ml, 202%), followed by daily vitamin D2 (15.7–43.9 ng/ml, 182%). The preplanned comparisons were nonsignificant: daily vitamin D2 vs. weekly vitamin D2 (12% differences in effect, P = 0.66) and daily D2 vs. daily D3 (7%, P = 0.82). All participants achieved 25(OH)D concentrations of 20 ng/ml or greater except for three participants. Within this subgroup, one participant was receiving vitamin D3 daily, the other two, vitamin D2 weekly. For each case, the compliance of the family had been questioned at the follow-up visit.
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We examined serum calcium concentrations from the larger cross-sectional sample of healthy infants and toddlers from which the trial participants were derived. Baseline calcium concentrations were compared with the current trial participants, each with hypovitaminosis D, to 329 vitamin D replete subjects. The median calcium level was slightly higher in the vitamin D replete subjects (10.50 vs. 10.35, P = 0.04 by Wilcoxon test).
The mean change in serum calcium levels was small and similar in the three treatment groups (–3% for vitamin D2 daily, +3% vitamin D2 weekly, +1% vitamin D3 daily).
PTH
Eight participants (20%) presented with elevated PTH at baseline (reference range 10–65 pg/ml). All cases returned to normal limits after treatment (Table 2
). As illustrated in Fig. 1, the largest change in PTH was observed in the group receiving vitamin D2 weekly (down 40%, from 32.1 to 19.2 pg/ml, adjusted for covariates), compared with patients in the other treatment arms (vitamin D2 daily, down 20% from 38.5 to 30.8 pg/ml, and vitamin D3 daily, down 36% from 40.9 to 26.3 pg/ml). There was no significant difference in PTH suppression among the three groups (P = 0.74).
Alkaline phosphatase
There was no significant impact of treatment on alkaline phosphatase concentrations (Fig. 1).
Compliance
To assess compliance, we submitted vials containing the remaining vitamin D and calcium liquid preparations to the Children’s Hospital Boston Central Pharmacy. The amount remaining in the vials was compared with the expected amount consumed. No appreciable difference was noted in compliance among the three treatment groups.
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Discussion |
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Three previous reports citing data from adults have advocated strongly for supplementation with vitamin D3 (cholecalciferol) over D2 (ergocalciferol) as the preferred treatment method for vitamin D deficiency (20, 21, 22). However, our study showed that each treatment regimen was equally effective as well as safe. These data are reassuring to providers because vitamin D2 daily or weekly, or vitamin D3 daily, combined with elemental calcium, appears to provide an effective and well-tolerated treatment for correcting hypovitaminosis D in infants and toddlers. Furthermore, the consistency of these data across the treatment arms will allow practitioners to tailor their specific treatment regimens to meet an individual patient’s needs, preferences, and probability of compliance.
In this study, we sought to examine the differences between PTH at baseline and after replacement therapy in each treatment group because suboptimal serum 25(OH)D levels can be associated with a secondary or compensatory hyperparathyroidism. Interestingly, the largest change in PTH between baseline and 7 wk was observed in the group receiving vitamin D2 weekly. At baseline, we found elevated PTH concentrations in eight subjects among the cohort, and all participants’ levels decreased to the normal range after treatment. These findings further support the similarities among these three treatment arms in reversing the secondary effects that associated biochemical markers may have on vitamin D homeostasis.
Our data provide clinical guidance regarding the appropriate dosage range of vitamin D to treat deficiency in this young population. Among infants, hypercalcemia has been reported with the administration of single high-dose therapy of 300,000 IU (29) or 600,000 IU (30) as well as daily doses exceeding 10,000 IU daily (31). Whereas a single 600,000 IU dose has been strongly advocated by one group as a safe regimen and one that eliminates the problem of noncompliance (12), this recommendation has been met with controversy and, specifically, concerns about hypercalcemia (29, 32), especially in an outpatient setting. In our study, we report a surprising higher overall incidence of mild hypercalcemia at baseline in contrast to after treatment. All subjects were asymptomatic. There was no statistically significant correlation between the presence of hypercalcemia at baseline and after each tested course of treatment. Therefore, these more conservative regimens of vitamin D2 daily, vitamin D2 weekly, or vitamin D3 daily may provide the necessary treatment without the increased risk of hypercalcemia commonly associated with single large dose therapies (also known as stosstherapy) (12). The potential toxicity associated with stosstherapy is further underscored by a recent report that showed hypercalcemia in an infant treated with the equivalent of four daily stosstherapy doses (33).
Limitations of this study deserve acknowledgment and consideration. First, the sample size was small and power limited. The observed differences among the three treatment regimens in improvement of 25(OH)D level, although consistently small in comparison with the gross change achieved by treatment, were not precisely determined and thus admit the possibility of larger underlying effects. Our negative finding may therefore be due to the small sample size, although likely not to variability in age or weight, for which we controlled in our analyses. Second, it is more difficult to assess compliance among young infants and toddlers because they are unable to swallow pills, necessitating administration of a liquid vitamin preparation. Therefore, measurements of the exact amount of remaining vitamin D suspension administered during treatment were more difficult to assess, compared with pill counts that would be possible in an older patient population. To standardize our data acquisition, a single pharmacy technician completed all measurements throughout the course of the study. However, the potential inaccuracy of viscous liquid (vs. pill) measurement deserves acknowledgment, including the fact that the measurement involved extraction of the suspension from a vial. Lastly, it is possible that the participants’ parents provided increased amounts of dietary vitamin D (e.g. vitamin D-fortified milk, salmon, eggs) in addition to the supplementation upon hearing of their child’s deficiency. However, such low-potency dietary modification is not likely to have significantly affected one treatment group’s results, compared with another, and not in a way that would change the observed consistency noted among the treatment groups.
In summary, we demonstrate that 2,000 IU daily vitamin D2, 50,000 IU vitamin D2 weekly, or 2,000 IU daily vitamin D3 yield equivalent outcomes in the short-term treatment of hypovitaminosis D among otherwise healthy infants and toddlers. These results indicate that pediatric providers can determine the appropriate method of treatment for a given patient or family to ensure compliance, given that no difference in efficacy or safety was noted. The argument favoring large-dose depot therapies for correcting hypovitaminosis D must be reevaluated because more conservative lower dose therapies may provide a safer method of treatment, especially in the outpatient setting, without the associated risk of hypercalcemia. In addition, the case for vitamin D3 as the most effective treatment method must be reconsidered for young children because a weekly dose of vitamin D2 may yield a similar outcome without the inconvenience of a daily treatment. We recommend early treatment with one of these three treatment regimens, or subtle variations to the dosages studied, to prevent the potential skeletal and extraskeletal problems associated with hypovitaminosis D. Lastly, we do not endorse the use of the current relatively high doses of vitamin D for the long-term prevention of hypovitaminosis D in infants and young children. Further research is needed to clarify the appropriate daily vitamin D supplementation dose for the pediatric age group.
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Acknowledgments |
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Footnotes |
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Disclosure Summary: All authors have nothing to disclose.
First Published Online April 15, 2008
Abbreviations: ANCOVA, Analysis of covariance; 25(OH)D, 25-hydroxyvitamin D.
Received December 20, 2007.
Accepted April 9, 2008.
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