Response of Vitamin D Concentration to Vitamin D3 Administration in Older Adults without Sun Exposure: A Randomized Double-Blind Trial.

OBJECTIVES: To determine the dose-response relationship between 25-hydroxyvitamin D (25(OH)D) and supplemental vitamin D3 in elderly nursing home residents. DESIGN: Randomized double-blind investigation. SETTING: Nursing home. PARTICIPANTS: Of 81 women (n=51) and men (n=30) (mean age 87.4±8) enrolled, 72 completed the study. INTERVENTION: Sixteen weeks of oral vitamin D3 at 800, 2,000, or 4,000 IU/d or 50,000 IU/wk. MEASUREMENTS: The main outcome was 25(OH)D concentrations (tandem mass spectrometry) after 16 weeks. Free 25(OH)D and intact parathyroid hormone (iPTH) were also analyzed. Safety monitoring of calcium and estimated glomerular filtration rate was performed, and adherence and clinical status were measured. RESULTS: 25(OH)D concentrations increased with dose (P<.001) and were higher with 50,000 IU/wk (P<.001) than other doses and with 4,000 IU/d than 800 or 2,000 IU/d, but 800 IU and 2,000 IU/d did not differ. One subject receiving 800 IU/d had concentrations less than 20 ng/mL. All subjects receiving more than 2000 IU/d had concentrations of 20 ng/mL and greater. Free 25(OH)D concentrations rose with total 25(OH) vitamin D. Total and free 25(OH)D were related to calcium concentrations; only free 25(OH)D was related to iPTH. CONCLUSION: 25(OH)D increased linearly with 800 to 4,000 IU/d and 50,000 IU/wk of vitamin D3, without a ceiling effect. Data suggest that some elderly adults will require more than 800 IU/d of vitamin D3 to ensure adequate vitamin D levels. Changes in 25(OH)D with vitamin D3 were related to starting concentrations (greatest with the lowest concentrations and unchanged with 800 and 2,000 IU/d if 20-40 ng/mL). Relationships between serum calcium and iPTH and free 25(OH)D suggest the potential for free 25(OH)D in defining optimal 25(OH)D concentrations.

Vitamin D3 effects on lipids differ in statin and non-statin-treated humans: superiority of free 25-OH D levels in detecting relationships.

CONTEXT: Inverse associations between 25-OH vitamin D levels and cardiovascular morbidity and mortality have been reported. OBJECTIVES: Our goals were to 1) investigate effects of correcting inadequate D status on lipids, 2) determine whether free 25-OH D is better correlated with lipids than total 25-OH D. DESIGN: A randomized, double-blind placebo-controlled trial was performed. SETTING: Participants resided in the general community. PARTICIPANTS: Adults with inadequate D status were randomized to D3: 14 men, 12 women, age 60 ± 8 years (mean ± SD) or placebo: 12 men, 11 women: 59 ±12 years. INTERVENTION: Responses to 12-week oral vitamin D3 titrated (1000-3000 IU/d) to achieve 25-OH D levels ≥25 ng/mL were compared to placebo. MAIN OUTCOME MEASURES: Measurements were 25-OH D (tandem mass spectometry), free 25-OH D (direct immunoassay), lipids (directly measured triglyceride, cholesterol, and subfractions; plant sterols and cholesterol synthesis precursors), and safety labs before and after 6 and 12 weeks D3 or placebo. Data were analyzed by repeated measures ANOVA and linear regression. RESULTS: Vitamin D3 was titrated to 1000 IU/d in 15/26 (58%), to 2000 IU/d in 10, and 3000 IU/d in one patient. D3 had no effect on cholesterol or cholesterol subfractions except for trends for decreases in atorvastatin-treated patients (cholesterol, P = .08; low-density lipoprotein [LDL] cholesterol, P = .05). Decreased campesterol concentrations (P = .05) were seen with D3 but not placebo in statin-treated patients. Relationships between total 25-OH D and lipids were not detected, but inverse linear relationships were detected between free 25-OH D and triglycerides (P = .03 for all participants [n = 49], P = .03 in all statin-treated [n = 19], and P = .0009 in atorvastatin-treated [n = 11]), and between free 25-OH D and LDL cholesterol (P = .08 overall, P = .02 in all statin-treated, and P = .03 for atorvastatin-treated), and total cholesterol (P = .09 overall; P = .04 for all statin-treated, and P = .05 for atorvastatin-treated). CONCLUSIONS: Vitamin D lipid-lowering effects appear limited to statin-treated patients and are likely due to decreased cholesterol absorption. Relationships between lipids and D metabolites were only detected when free 25-OH D was measured, suggesting the superiority of determining free 25-OH D levels compared to total 25-OH vitamin D levels when analyzing biologic responses.

Failure of pharmacogenetic-based dosing algorithms to identify older patients requiring low daily doses of warfarin.

INTRODUCTION: Warfarin doses vary greatly among patients and warfarin administration is accompanied by risk of bleeding. Genes responsible for its metabolism (CYP2C9) and effect on clotting (VKORC1) have been identified. It has been suggested that genotyping for variants in these genes can improve warfarin dosing and decrease bleeding complications. We evaluated performance of pharmacogenetic-based warfarin dosing estimation algorithms in old and very old patients. METHODS: Cross-sectional study of stable patients older than 65 years receiving warfarin with therapeutic International Normalized Ratio (INR) anticoagulation. Medical and laboratory data were reviewed and genotyping for CYP2C9 and VKORC1 performed. Warfarin dose estimates with and without genotype information were compared to clinically established therapeutic doses. RESULTS: Sixty-nine patients (32 men, 37 women; 41 nursing home residents; 28 senior care community residents) aged 81.4 ± 8.3 (mean ± S.D) years; ethnicity: Caucasian in 53, Asian in 10, Hispanic in 4, and African American in 2, received 3.3 ± 1.7 mg/d (range 0.7-9) warfarin achieving target INRs of 2.5 ± 0.2. Pharmacogenetic-based dose estimates (in combination with age, weight, height, smoking history, ethnicity/race, history of liver disease, selected co-medications such as amiodarone and enzyme inducers, baseline INR, clinical indication, and target INR), explained 50% of variability (P < .0001) compared with 12% without genetic data (P = .003). However, doses were overestimated in 15 of 16 patients requiring less than 2 mg/d (2.6 ± 0.9 mg/d compared with observed 1.5 ± 0.3 mg/d, P = .0001). Renal disease was a potential variable contributing to low warfarin requirements. DISCUSSION: The role of pharmacogenetic testing in the management of warfarin administration in patients is undergoing evaluation. Currently available pharmacogenetic- based warfarin dose estimation algorithms reduce variability in estimates for groups of older patients but consistently overestimate doses for older patients requiring the lowest doses of warfarin. CONCLUSIONS: Pharmacogenetic data add to our understanding of variability in warfarin dosing requirements but do not accurately identify older patients requiring the lowest warfarin doses. Therefore, the most prudent approach to warfarin therapy in older patients should include low initial doses in the absence of genotype variants associated with very low warfarin sensitivity and careful monitoring of INR responses.