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Efficacy of daily and monthly high-dose calciferol in vitamin D–deficient nulliparous and lactating women^1,2,3

¹ From the Departments of Internal Medicine (HFS and SB) and Community Medicine (NN), Faculty of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates (UAE); the Department of Internal Medicine, Tawam Hospital, Al Ain, UAE (BOA); the Department of Preventive Medicine, General Authority for Health Services for Abu Dhabi, Al Ain, UAE (RZ); and the International Health Program Center for Epidemiology and Biostatistics, Cincinnati Children's Medical Center, Cincinnati, OH (AD)

² Supported by the Sheikh Hamdan Bin Rashid Al Maktoum Award for Medical Sciences.

³ Reprints not available. Address correspondence to HF Saadi, Department of Internal Medicine, Faculty of Medicine and Health Sciences, United Arab Emirates University, PO Box 17666, Al Ain, UAE. E-mail: saadih{at}uaeu.ac.ae.

	ABSTRACT

TOP ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Background: We previously found a high prevalence of vitamin D deficiency and low medication regimen compliance in Arab and East Indian women residing in the United Arab Emirates (UAE). The appropriate dosing regimen for improving vitamin D status in this population is not known.

Objective: We aimed to determine the efficacy of daily and monthly supplementation with vitamin D₂, the only high-dose calciferol available in the UAE, in lactating and nulliparous women.

Design: Healthy lactating (n = 90) and nulliparous (n = 88) women were randomly assigned to consume 2000 IU vitamin D₂/d or 60 000 IU vitamin D₂/mo for 3 mo. Serum 25-hydroxyvitamin D [25(OH)D] concentrations were measured by radioimmunoassay at baseline and every month.

Results: Most women had vitamin D deficiency [ie, 25(OH)D < 50 nmol/L] at study entry. Mean ± SD 25(OH)D concentrations at 3 mo were significantly higher than baseline in both lactating (39.8 ± 12.4 and 25.2 ± 10.7 nmol/L, respectively) and nulliparous (40.4 ± 23.4 and 19.3 ± 12.2 nmol/L, respectively) women (P < 0.001 for both). In total, vitamin D supplementation was effective in achieving serum 25(OH)D concentrations of 50 nmol/L in 21 (30%) of 71 women at endpoint.

Conclusions: Oral vitamin D₂ supplementation with 2000 IU/d or 60 000 IU/mo for 3 mo was safe, and it increased serum 25(OH)D concentrations significantly; however, only a small proportion of the women studied achieved concentrations of 50 nmol/L. This suggests that, when sunlight exposure is limited, doses of vitamin D₂ higher than those currently studied may be needed. Monthly dosing appears to be a safe and effective alternative to daily dosing.

Key Words: Vitamin D deficiency • 25-hydroxyvitamin D • 25(OH)D • lactating women • nulliparous women • Arab women

	INTRODUCTION

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Several studies have shown that women from the Middle East and women from the Indian subcontinent generally have low serum concentrations of 25-hydroxyvitamin D [25(OH)D], mostly as a result of low vitamin D intake and inadequate sunlight exposure (1–8). Infantile vitamin D deficiency rickets also is common in many Middle Eastern and Asian countries (9, 10). Exclusively breastfed infants who lack adequate sunshine exposure and whose mothers have low vitamin D stores are frequently vitamin D deficient and thus at high risk of nutritional rickets (11, 12). Measures to prevent vitamin D deficiency include greater exposure of skin to sunlight, greater fortification of food items with vitamin D, and vitamin D supplementation. Many Middle Eastern and East Indian women residing in the United Arab Emirates (UAE) maintain a very conservative style of dress that covers most of the body when they are outside, which limits sunlight exposure. In addition, vitamin D fortification of food is not mandatory in the UAE and many other Middle Eastern countries, and the current dietary intake of vitamin D is relatively low (8). Vitamin D supplementation currently remains the most appropriate mode for improving the vitamin D status of this high-risk population.

There is mounting evidence that, in the absence of adequate exposure to sunlight, 1000 IU dietary or supplemental vitamin D/d is required in adults to prevent vitamin D deficiency (13–17). However, a critical factor affecting the outcome of such treatment is adherence to medication. Our clinical experience indicates a low compliance with vitamin D supplement use in women in the UAE. In a survey of prenatal multivitamin supplement use in the UAE, only 40% of Middle Eastern women who delivered at term in a maternity hospital reported using their prescribed prenatal vitamins in the last trimester of pregnancy (18). Intermittent high-dose regimens could overcome low compliance. A dose of 50 000 IU vitamin D₂/d has been suggested as effective in maintaining acceptable vitamin D status (19). Because the biological half-life of 25(OH)D is effectively 1–2 mo (15), dosing less than once every 2 mo may generate large fluctuations in 25(OH)D concentrations that may not be desirable or effective (20). Our objective was to determine the effectiveness and safety of 2 vitamin D supplementation regimens (a daily dose of 2000 IU or a monthly dose of 60 000 IU oral vitamin D₂) in improving the vitamin D status of a convenience sample of lactating and nulliparous women residing in the UAE. We chose to study this relatively high dose of vitamin D because our previous studies showed a high prevalence of severe vitamin D deficiency in this population (8, 11). Furthermore, daily dietary intake of 2000 IU of vitamin D₃ or of a combination of vitamin D₂ and vitamin D₃ was previously reported to be safe and effective in improving vitamin D status in lactating women (21, 22). In the present study, we used vitamin D₂, rather than the more potent vitamin D₃, because the former is the only high-dose calciferol available in the UAE. We are not aware of any studies of this dose in nonlactating women of childbearing age. For ethical reasons, we did not want to use vitamin D doses > 2000 IU/d so as not to exceed the current upper tolerable safe intake level for healthy adults recommended by the Institute of Medicine's Food and Nutrition Board (23), especially when baseline serum 25(OH)D concentration results would not be available until the supplementation dose had been administered. Our hypothesis was that the monthly regimen of vitamin D supplementation would be as effective as the daily regimen in improving vitamin D status and that it would therefore be a reasonable alternative strategy, especially for patients from whom poor compliance is anticipated.

	SUBJECTS AND METHODS

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Subjects
We recruited 88 generally healthy, nulliparous Emirati women of reproductive age (many of whom were medical students and interns working at Tawam Hospital in Al Ain, UAE) and 90 lactating women (15 Emirati, 61 other Middle Eastern, and 14 East Indian) at the time of their first postnatal visit to the Maternal and Child Health Center in Al Ain (latitude 24°N and longitude 55°E). Lactating women were eligible if they planned to continue breastfeeding for the next 3 mo. Exclusion criteria included current pregnancy, history of metabolic bone disease or calcium disorder, and treatment with vitamin D (other than multivitamins) within the past 1 y. Enrollment began in September 2005 and ended in February 2006.

Subjects received both oral and written information and gave written informed consent. The study protocol was approved by the Human Research Ethics Committee of the Al Ain Medical District.

Study design
The study was an open-label, randomized, parallel-group clinical trial of lactating and nulliparous women. Subjects in each group were randomly allocated to a dose of either 2000 IU vitamin D₂/d (daily regimen) or 60 000 IU vitamin D₂/mo (monthly regimen) in a 1:1 ratio within permuted blocks of size 10. A sample size of 40 subjects per regimen (daily or monthly) was estimated to provide sufficient power (80%) to detect a 10-nmol/L difference in the increase in 25(OH)D concentrations between the 2 regimens. This estimated sample size allowed for a maximum attrition rate of 40%, and Bonferroni's correction for multiple comparisons was applied to the 2-tailed nominal level of 0.05 when appropriate. The 60 000-IU vitamin D₂ dose was ingested at the time of each visit under direct observation to ensure compliance and prevent accidental ingestion by small children at home. The 2000-IU vitamin D₂ dose was provided in a tamper-resistant container of 90 capsules containing 2000 IU vitamin D₂ each. At 0, 1, 2, and 3 mo of daily vitamin D₂ supplementation and just before the administration of the next monthly vitamin D₂ dose, a nonfasting random urine sample was collected; 10 mL of blood also was collected at the visit, and the serum was separated and frozen at –80 °C until biochemical testing was performed. At the time of each subsequent visit, the vitamin D₂ capsules that remained in the container were counted to monitor compliance. Compliance was based on data collected at the time of last follow-up. All subjects also received supplemental calcium (600 mg elemental Ca/d). Subjects were free to withdraw from the study at any time. A few subjects returned for follow-up visits but declined laboratory tests; their data were not used in the analysis.

Questionnaire
After providing written informed consent, eligible women were interviewed in person at each of the 2 study sites (Tawam Hospital or the Maternal and Child Health Center) by 1 observer who used a questionnaire regarding medical history and reproductive, nutritional, and lifestyle factors, including the average amount (in time) of sunlight exposure per day during the 6 wk preceding the visit and the body parts usually directly exposed to the sun while outdoors. A dietary recall using a food-frequency questionnaire estimated daily dietary calcium and vitamin D intake in each subject as described previously (8). Clinical symptoms that have been associated with vitamin D deficiency—muscle pain, muscle cramps, difficulty in ascending a staircase or rising from a chair, gait disturbance, and paresthesia of the hands and feet—were evaluated at the beginning and end of the study.

Materials
Capsules containing 2000 IU vitamin D₂ each were purchased from Tishcon Corp (Westbury, NY). Vitamin D₂ tablets containing 10 000 IU vitamin D₂ each were purchased from Celltech Manufacturing Services Ltd (Ashton-under-Lyne, United Kingdom), and vitamin D₂ gelatin capsules containing 50 000 IU vitamin D₂ each were purchased from Pliva, Inc (East Hanover, NJ). Because the 2000-IU vitamin D₂ preparation was not a marketed product, we asked the supplier to provide a certificate of analysis. The product was assayed on 1 April 2005 and found to contain 2367.6 IU vitamin D₂/capsule.

Tests
Serum calcium and urinary calcium and creatinine were measured with the use of an autoanalyzer (Beckman Coulter DXC800; Beckman Instruments, Inc, Fullerton, CA) immediately after sample collection at the laboratories of the 2 study sites. Urinary calcium excretion was assessed as the ratio of urinary calcium to creatinine concentrations (urinary Ca:Cr, in mmol/mmol); a ratio of >1.0 was considered to represent hypercalciuria (24). Serum 25(OH)D concentrations were measured by radioimmunoassay (DiaSorin, Stillwater, MN). The intrassay and interassay CVs were 8.3% and 3.2%, respectively. Serum 25(OH)D concentrations <50 nmol/L (20 ng/mL) were considered to indicate vitamin D deficiency according to published reports in the literature (19, 25). For quality control, 10 baseline serum samples were shipped on dry ice to the General Clinical Research Center at the Medical University of South Carolina, where 25(OH)D concentrations were measured with the use of HPLC. Serum intact parathyroid hormone (PTH) was measured by using an immunoradiometric assay (Diagnostic Products Corporation, Los Angeles, CA). The intra- and interassay CVs were 6% and 5.1%, respectively.

Statistical analysis
Data were analyzed by using both SPSS (version 13; SPSS Inc, Chicago, IL) and SAS (version 8.01; SAS Institute, Cary, NC) statistical software. Methods used were Student's t test, chi-square test, analysis of variance (ANOVA), and analysis of covariance (ANCOVA). Adjustments for multiple comparisons were carried out with Tukey's test for post hoc pairwise comparisons. A 2-tailed P < 0.05 was considered significant. Paired binomial observations were analyzed by using McNemar's test. To compare the effects of regimen and reproductive status on follow-up serum 25(OH)D concentrations, a mixed-model ANCOVA was employed by using SAS PROC MIXED, with "individual" specified as a repeated effect and with time, regimen, and reproductive status as categorical (class) covariates; baseline 25(OH)D concentrations and body weight were used as covariates to adjust for baseline differences.

	RESULTS

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Of the 90 lactating women enrolled initially, 69 completed 1 mo of the study, 58 completed 2 mo of the study, and 48 completed the 3-mo study. Reasons for withdrawal included pregnancy (1 subject), diarrhea in the breastfed infant (1 subject), leaving the country (3 subjects), and no specific reason (the remainder of those who withdrew). Of the 88 nulliparous women enrolled initially, 55 completed 1 mo of the study, 27 completed 2 mo of the study, and 23 completed the 3-mo study. Most subjects who withdrew from the study were contacted, and none gave any specific reason for withdrawal. Comparison of the baseline characteristics of the women who completed the study and those who dropped out found no significant differences in age, ethnicity profile, number of pregnancies, vitamin D intake, and baseline 25(OH)D concentrations between the 2 groups (data not shown). Serum concentrations of 25(OH)D were measured by both radioimmunoassay and HPLC in 10 baseline samples. The measurement by radioimmunoassay (18.7 ± 11.6 nmol/L) did not differ significantly (P = 0.12, t test) from that by HPLC (14.8 ± 16.7 nmol/L). The 2 measurements were strongly positively correlated (r = 0.93, P < 0.01).

Lactating women
Forty-five lactating women were allocated to each of the 2 regimens. No significant differences in baseline characteristics were seen, which indicated effective randomization (Table 1). All women who were assigned daily vitamin D took more than two-thirds of the prescribed capsules (median: 100%; range: 67–100%). Overall mean baseline serum 25(OH)D concentrations were 25.2 ± 10.7 nmol/L. All women except one had 25(OH)D concentrations <50 nmol/L, and one-third had concentrations <20 nmol/L. The mean baseline serum 25(OH)D concentration in Emirati women was lower than that in other Middle Eastern and East Indian women, but these differences were not significant (21.7 ± 12.4, 26.0 ± 10.1, and 25.7 ± 11.6 nmol/L, respectively; P = 0.6).

Table 2

Nulliparous women
Forty-three nulliparous women were allocated to the daily regimen, and 45 nulliparous women were allocated to the monthly regimen. The baseline characteristics of nulliparous women by treatment regimen are shown in Table 3. No significant differences in baseline characteristics were seen, which indicated effective randomization. All but 1 of the women assigned to the daily vitamin D regimen took more than two-thirds of the prescribed capsules (median: 100%; range: 50–100%). The overall mean baseline serum 25(OH)D concentration was 19.3 ± 12.2 nmol/L. All but 1 of the women had 25(OH)D concentrations <50 nmol/L, and two-thirds had concentrations <20 nmol/L.

Table 4

Comparisons between lactating and nulliparous women
The mean baseline serum 25(OH)D concentration was significantly lower in nulliparous than in lactating women (19.3 ± 12.2 and 25.2 ± 10.7 nmol/L, respectively; P < 0.001). Almost one-third of nulliparous women and one-half of lactating women dressed to cover the whole body, including hands and face, while outside of their homes, and only a few exposed more than their face and hands. A small proportion of the nulliparous women reported intake of multivitamin (6.9%) or calcium (4.7%) supplements. In contrast, 46% of lactating women reported multivitamin intake, and 27% reported supplemental calcium intake. Dietary vitamin D and calcium intakes also were significantly (P < 0.05, t test) higher in lactating women. In nulliparous women, muscle pain was reported in 33%, muscle cramps in 30%, difficulty in ascending a staircase or rising from a chair in 13%, gait disturbance in 1%, and paresthesia of hands and feet in 25% at study entry. In contrast, the reported rates for the above symptoms in lactating women were much lower: 16%, 9%, 13%, 1%, and 8%, respectively. A total of 25 nulliparous and lactating women completed a questionnaire on clinical symptoms at the end of the study. The reported frequency of clinical symptoms decreased significantly only for muscle cramps (66% compared with 4%; P < 0.05, McNemar's test). Overall, 50% of women felt better at the end of the study, 50% felt the same, and none felt worse. The improvement in symptoms corresponded with a significant increase in serum 25(OH)D concentrations (from 21.0 ± 12.3 to 40.2 ± 23.0 nmol/L; P < 0.01).

To compare the effects of regimen and reproductive status (nulliparous or lactating) on follow-up 25(OH)D concentration, we used SAS PROC MIXED as described in Methods, in which baseline 25(OH)D concentrations and body weight were used as covariates to adjust for baseline differences (Table 5). Overall, the daily regimen resulted in higher mean follow-up 25(OH)D concentrations than did the monthly regimen (estimated difference ± SE: 4.8 ± 1.8 nmol/L; P < 0.01). Lactating women had slightly lower mean follow-up 25(OH)D concentrations than did nulliparous women (estimated difference ± SE: –3.6 ± 1.9 nmol/L; P = 0.064).

	DISCUSSION

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Currently, no increase in the vitamin D intake of lactating women is recommended by the Food and Nutrition Board (23) except when milk and other foods fortified with vitamin D are avoided, in which case a daily supplement of 10 µg (400 IU) vitamin D₃ is recommended (32). Our results in lactating women are in agreement with those of others (21, 22, 33), which indicates that a much higher vitamin D intake than currently recommended is needed in lactating women. We are not aware of any studies comparing vitamin D requirements in lactating and nonlactating women. However, the higher incremental change observed in nulliparous women in the present study even after adjustment for body weight and baseline 25(OH)D concentration leads us to suggest that lactating women need a higher dose of vitamin D to obtain a similar increase in serum 25(OH)D concentration.

The increases from baseline serum 25(OH)D concentration at 3 mo in lactating and nulliparous women did not differ significantly between the daily and monthly regimens. However, when lactating and nulliparous women were considered together, the daily regimen resulted in significantly higher serum 25(OH)D concentrations than did the monthly regimen in the multiple regression model after adjustment for baseline 25(OH)D concentration. We are not aware of any previous randomized studies addressing this issue. The observed difference between daily and monthly dosing could be related to different clearance patterns and could be influenced by differences in blood sampling time. Because we drew blood samples just before the next dose, the reported measurements for serum concentrations of 25(OH)D in the monthly regimen group were trough values that may not be truly representative of the average 25(OH)D concentrations typically present during the month after each dose. For example, after the administration of a single 50 000-IU dose of vitamin D₂, Armas et al (31) found that the peak serum 25(OH)D concentration occurred on day 3; the concentration then began to fall until, by day 14, it did not differ significantly from baseline. Thus, the actual concentration achieved by the monthly regimen may be higher than that which we reported, which suggests that the observed differences between daily and monthly dosing regimens may be smaller. Although the median rate of compliance with the daily dose in the present study was high, in our clinical experience, compliance rates are much lower (18). Compliance rates are known to be high (90–100%) in clinical trials because of patient selection and the special attention given to the study patients to encourage their adherence to the medication regimens (34). The special attention to compliance in our study may have encouraged adherence to medication. However, if poor compliance is anticipated, monthly supplementation could be a safe and effective alternative option.

Vitamin D deficiency was significantly more severe in the nulliparous than in the lactating women. This difference could be attributed, in part, to higher intakes of vitamin D and multivitamin supplement in the lactating women. Vitamin D deficiency causes osteomalacia, which is associated with nonspecific bone pain, muscle aches, and weakness. These symptoms were highly prevalent, especially in nulliparous women, in the present study, and they tended to improve with treatment. Similar findings were reported in Danish women of Middle Eastern descent who presented with muscle pains and weakness and who were found to have severe vitamin D deficiency (mean serum 25(OH)D concentration: 6.7 nmol/L) and osteomalacia (13). In addition, all isometric muscle-strength measurements in that group of vitamin D–deficient Danish women of Middle Eastern background were significantly lower than those in healthy Danish control subjects with mean serum 25(OH)D concentrations of 47 nmol/L (35). After 3 mo of vitamin D treatment, all muscle-related variables improved significantly in the Middle Eastern women in that study.

Some limitations of the present study deserve comment. First, the dropout rates were very high. This is unlikely to have affected our results because the baseline characteristics of the subjects who dropped out did not differ significantly from the characteristics of those who completed the study. Second, we used vitamin D₂, which could have contributed to the lower increments in serum 25(OH)D concentrations than are likely to be seen with vitamin D₃ supplementation. In addition, not all of the doses of vitamin D₂ used in the present study were independently tested for their true vitamin D content, and therefore the differences between the responses to the daily and monthly regimens may not be accurate. Third, the study included neither a control group taking the current recommended Dietary Reference Intake of 400 IU vitamin D₃ nor a reference group to account for temporal changes in serum 25(OH)D concentrations related to season. Our previous studies show no significant seasonal variation in 25(OH)D concentrations between September and May in the UAE, where there is abundant sunshine year-round (8). Despite the above limitations, we believe that our results are valid and that they provide important information with which to address appropriate dosing regimens to improve the vitamin D status of women of childbearing age and lactating mothers.

In conclusion, vitamin D₂ supplementation with 2000 IU/d or 60 000 IU/mo for 3 mo increased serum 25(OH)D concentrations significantly, but these concentrations became acceptable (50 nmol/L) in only a small proportion of the women studied. In the absence of adequate sunlight exposure and if the more potent vitamin D₃ preparation is not available, higher doses of vitamin D₂ than currently studied may be needed. Monthly dosing appears to be a safe and an effective alternative to daily dosing, especially in patients from whom poor compliance is anticipated.

	ACKNOWLEDGMENTS

 
We thank Bruce Hollis, Medical University of South Carolina, for measuring the 25(OH)D concentrations with HPLC; Hussein Qazaq for calculating vitamin D intake; Mona Helmy and Hanan Abu Taimeh for data collection; and Awad Al Essa, Lina Sejaan, Javed Yasin, and Shaikha Al Marar for technical assistance. We also thank Salah Gariballa for critiquing the manuscript.

The authors' responsibilities were as follows—HS (principal investigator): overall design, administration and coordination of the project; analysis of results; and writing of the manuscript; AD: direction of the project and participation in the study design, analysis of results, and writing of the manuscript; BA: coordination of the selection and enrollment of the nulliparous women for the study and participation in analysis of results and writing of the manuscript; RZ: coordination of the selection and enrollment of the pregnant women for the study and participation in analysis of results; NN (biostatistician): participation in sample size calculation, monitoring of data quality, analysis of results, and writing of the manuscript; and SB: sample preparation and biochemical analysis. None of the authors had a personal or financial conflict of interest.

	REFERENCES

TOP ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS DISCUSSION REFERENCES

 

1. Ghannam NN, Hammami MM, Bakheet SM, Khan BA. Bone mineral density of the spine and femur in healthy Saudi females: relation to vitamin D status, pregnancy, and lactation. Calcif Tissue Int 1999;65:23–8.[Medline]
2. Gannage-Yared MH, Chemali R, Yaacoub N, Halaby G. Hypovitaminosis D in a sunny country: relation to lifestyle and bone markers. J Bone Miner Res 2000;15:1856–62.[Medline]
3. El-Hajj Fuleihan G, Deeb M. Hypovitaminosis D in a sunny country. N Engl J Med 1999;340:1840–1.[Free Full Text]
4. el-Sonbaty MR, Abdul-Ghaffar NU. Vitamin D deficiency in veiled Kuwaiti women. Eur J Clin Nutr 1996;50:315–8.[Medline]
5. Dawodu A, Absood G, Patel M, et al. Biosocial factors affecting vitamin D status of women of child-bearing age in the United Arab Emirates. J Biosoc Sci 1998;30:431–7.[Medline]
6. Mishal AA. Effects of different dress styles on vitamin D levels in healthy young Jordanian women. Osteoporos Int 2001;12:931–5.[Medline]
7. Sedrani SH, Elidrissy AW, El Arabi KM. Sunlight and vitamin D status in normal Saudi subjects. Am J Clin Nutr 1983;38:129–32.[Abstract/Free Full Text]
8. Saadi H, Nagelkerke N, Benedict S, et al. Predictors and relationships of serum 25 hydroxyvitamin D concentration with bone turnover markers, bone mineral density, and vitamin D receptor genotype in Emirati women. Bone 2006;39:1136–43. Epub 2006 Jun 30.[Medline]
9. Majid Molla A, Badawi MH, al-Yaish S, Sharma P, el-Salam RS, Molla AM. Risk factors for nutritional rickets among children in Kuwait. Pediatr Int 2000;42:280–4.[Medline]
10. Dawodu A, Khadir A, Hardy DJ, Varady E. Nutritional rickets in UAE: an unresolved cause of childhood morbidity. Middle E Paediatr 2002;7:12–4.
11. Dawodu A, Agarwal M, Moshaddeque H, Kochiyil J, Zayed R. Hypovitaminosis D and vitamin D deficiency in exclusively breast-feeding infants and their mothers in summer: a justification for vitamin D supplementation of breast-feeding infants. J Pediatr 2003;142:169–73.[Medline]
12. Specker BL. Do North American women need supplemental vitamin D during pregnancy or lactation? Am J Clin Nutr. 1994;59(suppl):484S–90S.[Abstract/Free Full Text]
13. Glerup H, Mikkelsen K, Poulsen L, et al. Commonly recommended daily intake of vitamin D is not sufficient if sunlight exposure is limited. J Intern Med 2000;247:260–8.[Medline]
14. Harris SS, Dawson-Hughes B, Perrone GA. Plasma 25-hydroxyvitamin D responses of younger and older men to three weeks of supplementation with 1800 IU/day of vitamin D. J Am Coll Nutr 1999;18:470–4.[Abstract/Free Full Text]
15. Vieth R. Vitamin D supplementation, 25-hydroxyvitamin D concentrations, and safety. Am J Clin Nutr 1999;69:842–56.[Abstract/Free Full Text]
16. Holick MF. Too little vitamin D in premenopausal women: why should we care? Am J Clin Nutr 2002;76:3–4.[Free Full Text]
17. Holick MF. Vitamin D: importance in the prevention of cancers, type 1 diabetes, heart disease, and osteoporosis. Am J Clin Nutr 2004;79:362–71.[Abstract/Free Full Text]
18. Dawodu A, Agarwal M, Patel M, Ezimokhai M. Serum 25-OHD and calcium homeostasis in UAE mothers and neonates: a preliminary report. Middle East Paediatr 1997;2:9–12.
19. Holick MF. Sunlight and vitamin D: both good for cardiovascular health. J Gen Int Med 2002;17:733–5.[Medline]
20. Veith R. The pharmacology of vitamin D, including fortification strategies. In: Feldman D, ed. Vitamin D. 2nd ed. London, United Kingdom: Elsevier Academic Press, 2005:995–1015.
21. Hollis BW, Wagner CL. Vitamin D requirements during lactation: high-dose maternal supplementation as therapy to prevent hypovitaminosis D for both the mother and the nursing infant. Am J Clin Nutr 2004;80(suppl):1752S–8S.[Abstract/Free Full Text]
22. Ala-Houhala M, Koskinen T, Terho A, Koivula T, Visakorpi J. Maternal compared with infant vitamin D supplementation. Arch Dis Child 1986;61:1159–63.[Abstract]
23. Food and Nutrition Board, Institute of Medicine. Dietary reference intakes. A risk assessment model for establishing upper intake levels for nutrients. Washington, DC: National Academy Press, 1998.
24. Vieth R, Chan PC, MacFarlane GD. Efficacy and safety of vitamin D(3) intake exceeding the lowest observed adverse effect level. Am J Clin Nutr 2001;73:288–94.[Abstract/Free Full Text]
25. Malabanan A, Veronikis IE, Holick MF. Redefining vitamin D insufficiency. Lancet 1998;351:805–6.[Medline]
26. Cooper L, Clifton-Bligh PB, Nery ML, et al. Vitamin D supplementation and bone mineral density in early postmenopausal women. Am J Clin Nutr 2003;77:1324–9.[Abstract/Free Full Text]
27. Barger-Lux MJ, Heaney RP, Dowell S, Chen TC, Holick MF. Vitamin D and its major metabolites: serum levels after graded oral dosing in healthy men. Osteoporos Int 1998;8:222–30.[Medline]
28. Hunter D, Major P, Arden N, et al. A randomized controlled trial of vitamin D supplementation on preventing postmenopausal bone loss and modifying bone metabolism using identical twin pairs. J Bone Miner Res 2000;15:2276–83.[Medline]
29. Heaney RP, Davies KM, Chen TC, Holick MF, Barger-Lux MJ. Human serum 25-hydroxycholecalciferol response to extended oral dosing with cholecalciferol. Am J Clin Nutr 2003;77:204–10. Erratum published in Am J Clin Nutr 2003;78:1047.[Free Full Text]
30. Trang HM, Cole DE, Rubin LA, Pierratos A, Siu S, Vieth R. Evidence that vitamin D3 increases serum 25-hydroxyvitamin D more efficiently than does vitamin D2. Am J Clin Nutr 1998;68:854–8.[Abstract]
31. Armas LA, Hollis BW, Heaney RP. Vitamin D2 is much less effective than vitamin D3 in humans. J Clin Endocrinol Metab 2004;89:5387–91.[Abstract/Free Full Text]
32. Picciano MF. Pregnancy and lactation: physiological adjustments, nutritional requirements and the role of dietary supplements. J Nutr 2003;133:1997S–2002S.[Abstract/Free Full Text]
33. Hollis BW, Wagner CL. Assessment of dietary vitamin D requirements during pregnancy and lactation. Am J Clin Nutr 2004;79:717–26.[Abstract/Free Full Text]
34. Osterberg L, Blaschke T. Adherence to medication. N Engl J Med 2005;353:487–97.[Free Full Text]
35. Glerup H, Mikkelsen K, Poulsen L, Hass E, Overbeck S, Andersen H, Charles P, Eriksen EF. Hypovitaminosis D myopathy without biochemical signs of osteomalacic bone involvement. Calcif Tissue Int 2000;66:419–24.[Medline]

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