A Randomized Open Label Trial to Evaluate the Efficacy of Different Dosage Forms of Vitamin D in Patients with Vitamin D Deficiency, and the Effect of Food on Vitamin D Absorption. Zeenat Ali, PGY3 Joseph Grisanti, MD June 7 th, 2012
Introduction Low vitamin D levels have been implicated in a number of diseases. Vitamin D deficiency causes rickets among children and a painful bone disease osteomalacia among adults. It also precipitates and exacerbates osteoporosis among adults. Holick MF. Sunlight and vitamin D for bone health and prevention of autoimmune diseases, cancers, and cardiovascular disease. Am J Clin Nutr; 2004; 80; 1678-1688.
Introduction contd Vitamin D deficiency has been associated with Cancers Hypertension Cardiovascular diseases Spina CS, Tangpricha V. Vitamin D and cancer. Anticancer Res. 2006; 26; 2515-2524 Pilz S, Vitamin D status and arterial hypertension. A systematic review. Nat Rev Cardiol. 2009; 6; 621-630 Giovannucci E. 25-hydroxyvitamin D and risk of myocardial infarction in men. A prospective study. Arch Intern Med; 2008; 168; 1174-1180.
Introduction contd Vitamin D deficiency has also been linked with Multiple sclerosis Rheumatoid arthritis Type 1 diabetes mellitus Munger KL. Serum 25-hydroxyvitamin D levels and risk of multiple sclerosis. JAMA. 2006; 296; 2832-2838. Patel S. Association between serum vitamin D metabolite levels and disease activity in patients with early inflammatory polyarthritis. Arthritis Rheum. 2007; 56; 2143-2149. Mohr SB. The association between ultraviolet B irradiance, vitamin D status and incidence rates of type 1 diabetes in 51 regions worldwide. Daibetologia. 2008; 51; 1391-1398.
Introduction contd It has been estimated that 1 billion people worldwide have vitamin D deficiency (25-hydroxy (OH) vitamin D< 20ng/ml) or insufficiency (25-OH vitamin D between 21-29 ng/ml). Up to 57% of general medicine inpatients in the United States have been reported to have insufficient or deficient vitamin D levels. Holick MF. High prevalence of vitamin D inadequancy and implications for health. Mayo Clin Proc 2006; 81; 353-373. Thomas MK, Lioyd-Jones DM. Hypovitaminosis D in medical inpatients. N Eng J Med. 1998; 338; 777-783.
Introduction contd A common clinical practice to treat vitamin D deficiency is with 50,000 International Units (IU) of vitamin D2 orally once weekly for 6 to 12 weeks, and then 800 to 1000 IU of vitamin D3 daily thereafter. However, the efficacy of this practice has not been rigorously established. In a study by Malabanan et al, in 35 patients with 25-OH vitamin D levels between 10ng/ml to 25ng/ml, vitamin D rose by 109% after treatment with vitamin D2 50,000 IU/week for a total of 8 weeks. Malabanan A. Redefining vitamin D insuficiency. The Lancet. 1998; 351; 805-806.
Introduction contd However, in another study by Pepper et al, only 13% of subjects achieved vitamin D sufficiency (25-OH vitamin D>30ng/ml) when treated with vitamin D2 50,000 IU/week for a total of 8 weeks. In another study, in healthy young and middle-aged adults, 100% of subjects achieved vitamin D sufficiency when treated with 1000 IU of vitamin D3/day for 12 weeks. Pepper KJ. Evaluation of vitamin D repletion regimens to correct vitamin D status in adults. Endocr Pract. 2009; 15; 95-103 Tangpricha V. Fortification of orange juice with vitamin D: a novel approach for enhancing vitamin D nutritional health. Am J Clin Nutr. 2003; 77; 1478-1483
Introduction contd Vitamin D is a fat-soluble vitamin and it has been postulated that fat increases vitamin D absorption. In a short report by Mulligan et al, in 17 patients with a mean baseline 25-OH vitamin D level of 30.5 ng/ml, administration of vitamin D with the largest meal improved absorption and resulted in higher serum levels of vitamin D compared to taking it on an empty stomach or with a small meal. Mulligan GB. Taking vitamin D with the largest meal improves absorption and results in higher serum levels of 25-hydroxyvitamin D. Journal of Bone and Mineral Research. 2010; 25; 928-930.
Introduction contd Other studies, however, have shown that fat is not required for vitamin D to be bioavailable. Pepper KJ. Evaluation of vitamin D repletion regimens to correct vitamin D status in adults. Endocr Pract. 2009; 15; 95-103 Hollander D. Vitamin D3 intestinal absorption in vivo: influence of fatty acids, bile salts, and perfusate ph on absorption. Gut. 1978; 19; 267-272.
Study This study was conducted to evaluate the efficacy of different dosage forms of vitamin D in treating patients with vitamin D deficiency or insufficiency, and also to evaluate the effect of food on vitamin D absorption.
Study Design This study was approved by the Institutional Review Board (IRB) through Mercy Hospital of Buffalo. Study took place at Buffalo Rheumatology. Subjects with 25-OH vitamin D deficiency or insufficiency (levels 10 and <30ng/ml) were recruited in this study. Approximately 240 subjects were planned to be enrolled over a period of 12-18 months (30 subjects in each group).
Study Design contd Subjects were randomly assigned to one of the following 4 treatment groups: Vitamin D3 1000 IU/day Vitamin D3 2000 IU/day Vitamin D3 4000 IU/day Vitamin D2 50,000 IU/week Each group was further divided into two subgroups with vitamin D administered either FASTING or with the LARGEST MEAL of the day.
Study Design contd Subjects had 2 visits and participation lasted 12 weeks. At the first visit (Screening/Baseline), education was given regarding the protocol. Subjects who agreed to participate signed an informed consent.
Study Design contd Demographic information was obtained along with the medical history and current medications. 12 weeks of study medication was given along with the instructions on dosing. A lab script was provided for vitamin D reassessment at 12 weeks.
Study Design contd 2nd visit (final visit) took place at the end of 12 weeks. Compliance was ascertained by pill counts at the final visit. Adverse events were captured at the final visit. Deficient subjects at the end of 12 weeks were given prescription for vitamin D treatment.
Study Design contd Study began in Jan, 2011 and 235 subjects had completed their study by the end of Jan, 2012. Out of 235 subjects 34 were lost to the follow-up or withdrew from the study. 15 patients were excluded from the study due to low compliance (<80%) and early or late labs. 186 subjects were included in this interim analysis.
End Points Primary endpoint: % increase in 25-OH vitamin D levels from baseline. Secondary end point: % of subjects achieving normal vitamin D levels ( 30ng/dl). Absolute increase in vitamin D from baseline. Results in each group were compared to each other.
Inclusion Criteria Men and women were included. Age 18. Vitamin D levels 10 and <30ng/ml.
Exclusion Criteria Vitamin D levels <10ng/ml. Malabsorption syndromes. Intestinal bypass. Uncontrolled cardiovascular, nervous system, pulmonary, renal, hepatic, endocrine, or GI disease. History of cancer within the last 5 years (except non-melanoma skin cancers and cervical carcinoma in situ)
Statistical Analysis Paired t-test was used for statistical analysis of data within each group. Analysis of Variance (ANOVA) was used to compare data across the various groups. P-value of 0.05 was deemed as statistically significant.
Demographics Total Count 186 Mean Age (Years) 53 Mean weight (Lbs) 189 Mean BMI 30.9 Mean 1 st Vitamin D levels 22.9 ng/ml
Demographics contd Population count Number of Patients 60 50 40 30 20 10 50 48 40 48 0 1000D3 2000D3 4000D3 50,000D2 Vitamin D dosage
Demographics contd Population count Number of Patients 30 25 20 15 10 5 28 22 21 27 19 21 24 24 0 1000 Meals 1000 Fasting 2000 Meals 2000 4000 Fasting Meals Sub groups 4000 Fasting 50,000 Meals 50,000 Fasting
Demographics contd Population Count Number of Patients 100 80 60 40 20 94 92 Fasting Meals Population Count Number of Patients 160 140 120 100 80 60 40 20 0 38 Male 148 Female
Five BMI groups Number of Patients 70 60 50 40 30 20 10 0 Population Count 58 50 36 23 19 <25 25-29.9 30-34.9 35-35.9 40 BMI
Six Age groups Number of Patients 60 50 40 30 20 10 0 Population Count 51 44 46 20 16 9 <30 30-39 40-49 50-59 60-69 70 Age
Four 1st Vitamin D groups Number of Patients 100 80 60 40 20 0 Population Count 87 57 33 9 <15 15-19.9 20-24.9 25-29.9 1st Vitamin D levels
Results % Increase 140% 120% 100% 80% 60% 40% 20% 0% % Increase in Vitamin D 117% 35% 40% 25% 1000D3 2000D3 4000D3 50,000D2 P P-value<0.001 Vtamin D dosage
% of subjects with 2nd Vitamin D 30 120% 100% 98% % Subjects 80% 60% 40% 34% 63% 70% 20% 0% 1000D3 2000D3 4000D3 50,000D2 Vitamin D dosage
Absolute increase in vitamin D Vitamin D levels (ng/ml) 60.0 50.0 40.0 30.0 20.0 10.0 1st Vit D Mean 2nd Vit D Mean 0.0 1000D3 2000D3 4000D3 50,000D2 Vitamin D dosage
Fasting vs Meals % Increase in vitamin D % Increase 53% 56% P-value=0.53 Fasting Meals
Subgroup Analysis 29% % Increase 21% 1000 Meals 1000 Fasting % Incresae 36% 35% 2000 Meals 2000 Fasting P-valueP-value=0.19=0.19 P- P-value=0.74=0.79
Subgroup Analysis % Increase 51% 30% 4000 Meals 4000 Fasting % Increase 111% 122% 50,000 Meals 50,000 Fasting P-value=0.003 P-value=0.27 P-value=0.27
Subgroup analysis Subgroup analysis was also done on the basis of BMI Age 1 st vitamin D levels.
BMI % Increase in Vitamin D % Increase 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% BMI < 25 BMI 25-29.9 BMI 30-34.9 BMI 35-39.9 BMI >= 40 P-value=0.003 BMI
BMI contd Using Pearson correlation, significant but weak association was noticed between BMI and 2 nd vitamin D levels (correlation coefficient -0.22), indicating that as the BMI increases vitamin D levels tend to decrease. 100 80 60 40 20 0 2nd Vit D by BMI 2nd Vit D 0.0 50.0 100.0
80% Age % Increase in Vitamin D % Increase 70% 60% 50% 40% 30% 20% 10% 0% Age <30 Age 30-39 Age 40-49 Age 50-59 Age 60-69 Age >=70 P-value=0.98 Age Groups
1st Vitamin D levels Patients with the lowest 1st vitamin D levels had the highest % increase of 183% (P-value=0.001). % increase was only 41% in patients with highest 1st vitamin D levels (P-value <0.001).
1st vitamin D levels % Increase 200% 180% 160% 140% 120% 100% 80% 60% 40% 20% 0% % Increase in Vitamin D Vit D < 15 Vit D 15-19.9 Vit D 20-24.9 Vit D 25-29.9 1st vitamin D
Conclusion In patients with vitamin D deficiency or insufficiency, 50,000 IU/week of 25-OH vitamin D2 for a period of 12 weeks was most effective in achieving vitamin D sufficiency. Food did not affect the vitamin D absorption in 1000D3, 2000D3 and 50,000D2 IU groups, however it did affect the absorption in 4000D3 IU group.
Conclusion Patients with the highest BMI achieved lowest vitamin D level, thus suggesting the need for robust treatment in this patient population. Patients with the highest 1 st vitamin D level had lowest % increase in their vitamin D after treatment; this could be due to the plateau effect that occurs as the vitamin D levels tend to increase.
Lack of placebo arm. Study was not blinded. Limitations Follow up data is not available for patients who did not achieve vitamin D sufficiency. Additional study needs to be done to evaluate the vitamin D dosage required for maintaining vitamin D sufficiency.
Acknowledgment Dr. Khalid J. Qazi Buffalo Rheumatology staff Mary Brennan, RN, MS Tammi Kirsch, LPN Jim Hatem
THANKS