Samantha M. Kimball

A phase I/II dose-escalation trial of vitamin D3 and calcium in multiple sclerosis.

Objective: Low vitamin D status has been associated with multiple sclerosis (MS) prevalence and risk, but the therapeutic potential of vitamin D in established MS has not been explored. Our aim was to assess the tolerability of high-dose oral vitamin D and its impact on biochemical, immunologic, and clinical outcomes in patients with MS prospectively. Methods: An open-label randomized prospective controlled 52-week trial matched patients with MS for demographic and disease characteristics, with randomization to treatment or control groups. Treatment patients received escalating vitamin D doses up to 40,000 IU/day over 28 weeks to raise serum 25-hydroxyvitamin D [25(OH)D] rapidly and assess tolerability, followed by 10,000 IU/day (12 weeks), and further downtitrated to 0 IU/day. Calcium (1,200 mg/day) was given throughout the trial. Primary endpoints were mean change in serum calcium at each vitamin D dose and a comparison of serum calcium between groups. Secondary endpoints included 25(OH)D and other biochemical measures, immunologic biomarkers, relapse events, and Expanded Disability Status Scale (EDSS) score. Results: Forty-nine patients (25 treatment, 24 control) were enrolled [mean age 40.5 years, EDSS 1.34, and 25(OH)D 78 nmol/L]. All calcium-related measures within and between groups were normal. Despite a mean peak 25(OH)D of 413nmol/L, no significant adverse events occurred. Although there may have been confounding variables in clinical outcomes, treatment group patients appeared to have fewer relapse events and a persistent reduction in T-cell proliferation compared to controls. Conclusions: High-dose vitamin D (∼10,000 IU/day) in multiple sclerosis is safe, with evidence of immunomodulatory effects. Classification of evidence: This trial provides Class II evidence that high-dose vitamin D use for 52 weeks in patients with multiple sclerosis does not significantly increase serum calcium levels when compared to patients not on high-dose supplementation. The trial, however, lacked statistical precision and the design requirements to adequately assess changes in clinical disease measures (relapses and Expanded Disability Status Scale scores), providing only Class level IV evidence for these outcomes.

Randomized comparison of the effects of the vitamin D 3 adequate intake versus 100 mcg (4000 IU) per day on biochemical responses and the wellbeing of patients

BackgroundFor adults, vitamin D intake of 100 mcg (4000 IU)/day is physiologic and safe. The adequate intake (AI) for older adults is 15 mcg (600 IU)/day, but there has been no report focusing on use of this dose.MethodsWe compared effects of these doses on biochemical responses and sense of wellbeing in a blinded, randomized trial. In Study 1, 64 outpatients (recruited if summer 2001 25(OH)D <61 nmol/L) were given 15 or 100 mcg/day vitamin D in December 2001. Biochemical responses were followed at subsequent visits that were part of clinical care; 37 patients completed a wellbeing questionnaire in December 2001 and February 2002. Subjects for Study 2 were recruited if their 25(OH)D was <51 nmol/L in summer 2001. 66 outpatients were given vitamin D; 51 completed a wellbeing questionnaire in both December 2002 and February 2003.ResultsIn Study 1, basal summer 25-hydroxyvitamin D [25(OH)D] averaged 48 ± 9 (SD) nmol/L. Supplementation for more than 6 months produced mean 25(OH)D levels of 79 ± 30 nmol/L for the 15 mcg/day group, and 112 ± 41 nmol/L for the 100 mcg/day group. Both doses lowered plasma parathyroid hormone with no effect on plasma calcium. Between December and February, wellbeing score improved more for the 100-mcg/day group than for the lower-dosed group (1-tail Mann-Whitney p = 0.036). In Study 2, 25(OH)D averaged 39 ± 9 nmol/L, and winter wellbeing scores improved with both doses of vitamin D (two-tail p < 0.001).ConclusionThe highest AI for vitamin D brought summertime 25(OH)D to >40 nmol/L, lowered PTH, and its use was associated with improved wellbeing. The 100 mcg/day dose produced greater responses. Since it was ethically necessary to provide a meaningful dose of vitamin D to these insufficient patients, we cannot rule out a placebo wellbeing response, particularly for those on the lower dose. This work confirms the safety and efficacy of both 15 and 100 mcg/day vitamin D3 in patients who needed additional vitamin D.

Short- and Long-Term Safety of Weekly High-Dose Vitamin D3 Supplementation in School Children

BACKGROUND Hypovitaminosis D is prevalent in youth worldwide, but the safety of vitamin D at doses exceeding 200 IU/d is unknown in this age group. We assessed the safety of high doses of vitamin D(3) administered to apparently healthy schoolchildren. METHODS To assess short-term safety, 25 subjects randomly received placebo or vitamin D(3) at doses of 14,000 IU/wk for 8 wk. To assess long-term safety, 340 subjects randomly received placebo, vitamin D(3) as 1,400 IU/wk or 14,000 IU/wk for 1 yr. Biochemical variables were monitored at 0, 2, 4, 6, and 8 wk and 8 wk off therapy in the short-term study and at 0, 6, and 12 months in the long-term study. RESULTS In both the short- and long-term studies, mean serum calcium and 1,25-hydroxyvitamin levels did not change in any group. In the short-term study, mean 25-hydroxyvitamin concentrations increased from 44 (+/- 11) to 54 (+/- 19) ng/ml in the treated groups (P = 0.033). In the long-term study, mean 25-hydroxyvitamin D levels increased from 15 +/- 8 to 19 +/- 7 ng/ml (P < 0.0001) in subjects receiving 1,400 IU/wk and from 15 +/- 7 to 36 +/- 22 ng/ml (P < 0.0001) in the group receiving 14,000 IU/wk. No subject developed vitamin D intoxication. CONCLUSION Vitamin D(3) at doses equivalent to 2000 IU/d for 1 yr is safe in adolescents and results in desirable vitamin D levels.

The ratio of serum 24,25-dihydroxyvitamin D3 to 25-hydroxyvitamin D3 is predictive of 25-hydroxyvitamin D3 response to vitamin D3 supplementation

24,25-Dihydroxyvitamin D (24,25VD) is a major catabolite of 25-hydroxyvitamin D (25VD) metabolism, and may be physiologically active. Our objectives were to: (1) characterize the response of serum 24,25VD(3) to vitamin D(3) (VD(3)) supplementation; (2) test the hypothesis that a higher 24,25VD(3) to 25VD(3) ratio (24,25:25VD(3)) predicts 25VD(3) response. Serum samples (n=160) from wk 2 and wk 6 of a placebo-controlled, randomized clinical trial of VD(3) (28,000IU/wk) were analyzed for serum 24,25VD(3) and 25VD(3) by mass spectrometry. Serum 24,25VD(3) was highly correlated with 25VD(3) in placebo- and VD(3)-treated subjects at each time point (p<0.0001). At wk 2, the 24,25:25VD(3) ratio was lower with VD(3) than with placebo (p=0.035). From wk 2 to wk 6, the 24,25:25VD(3) ratio increased with the VD(3) supplement (p<0.001) but not with placebo, such that at wk 6 this ratio did not significantly differ between groups. After correcting for potential confounders, we found that 24,25:25VD(3) at wk 2 was inversely correlated to the 25VD(3) increment by wk 6 in the supplemented group (r=-0.32, p=0.02) but not the controls. There is a strong correlation between 24,25VD(3) and 25VD(3) that is only modestly affected by VD(3) supplementation. This indicates that the catabolism of 25VD(3) to 24,25VD(3) rises with increasing 25VD(3). Furthermore, the initial ratio of serum 24,25VD(3) to 25VD(3) predicted the increase in 25VD(3). The 24,25:25VD(3) ratio may therefore have clinical utility as a marker for VD(3) catabolism and a predictor of serum 25VD(3) response to VD(3) supplementation.

Self-prescribed high-dose vitamin D3: effects on biochemical parameters in two men

Abstract The lowest observed adverse effect level for vitamin D, said to cause hypercalcaemia in normal adults, is officially 95 µg/day. Serum 25-hydroxyvitamin D (25[OH]D) concentrations associated with hypervitaminosis D remain undefined. Reported 25(OH)D concentrations resulting from prolonged excessive vitamin D3 intakes have exceeded 700 nmol/L. We report self-prescribed high dose of vitamin D3 over 5–6 years by two men. Subject 1 had been taking 100 μg/day for 3 years followed by 3 years of 200 μg/day. Serum 25(OH)D concentrations averaged 130 nmol/L while taking 100 μg/day of vitamin D3. While taking 200 μg/day of vitamin D3, mean serum 25(OH)D concentrations were 260 nmol/L with no hypercalcaemia or hypercalcuria over the 6 years of vitamin D3 intake. Subject 2 was a 39-year-old man diagnosed with multiple sclerosis. He initiated his own dose-escalation schedule. His vitamin D3 intake increased from 200 to 2200 μg/day over 4 years. The first evidence of a potential adverse effect was that urinary calcium:creatinine ratios showed an increasing trend, which preceded serum calcium concentrations above the reference range (2.2–2.6 mmol/L). His serum 25(OH)D concentration was 1126 nmol/L when total serum calcium reached 2.63 mmol/L. He stopped vitamin D3 supplementation at this point. Two months later, all biochemistry values were within reference ranges; serum 25(OH)D concentrations fell by about one-half, to 656 nmol/L. These results help to clarify the human response to higher intakes of vitamin D3. Close monitoring of biochemical responses confirmed that an increase in urinary calcium:creatinine ratio precedes hypercalcaemia as serum 25(OH)D concentrations rise.

Sunbeds with UVB radiation can produce physiological levels of serum 25-Hydroxyvitamin D in healthy volunteers

ABSTRACT Vitamin D3 is produced in the skin in response to UVB irradiation, from either sun exposure or UVB sunbeds. The objective of the current study was to characterize serum 25(OH)D response to regular sunbed use from several lamp outputs following their respective time exposure recommendations. There were three groups that tanned over 12 weeks during the winter months in dedicated sunbeds based on lamp outputs (100 W and 160 W low pressure fluorescent and 700 W high pressure filtered metal halide lamps) and a control group provided serum 25(OH)D samples at baseline and end-of-study. Tanning session lengths were calculated based on Health Canada guidelines to stay below the erythema levels. Mean 25(OH)D were increased by an average of 42 nmol/L in the sunbeds that used 100 W and 160 W fluorescents. Change in 25(OH)D was dependent on baseline 25(OH)D levels and sunbed (p = 0.003) and age (p = 0.03), but was not affected by gender, BMI, Fitzpatrick type or cumulative length of tanning sessions. There was no significant increase in 25(OH)D levels in participants using the 700 W filtered metal halide lamp sunbed or in the control participants. Skin pigmentation, , was markedly increased in all tanners and skin lightness, L*, significantly decreased at 12 weeks. Both L* and were significantly correlated with 25(OH)D concentrations for the sunbeds with fluorescent lamps emitting UVB (100 W and 160W). Participants following standardized exposure schedules meeting Health Canada regulations in sunbeds irradiating adequate UVB showed continuous increases of 25(OH)D to physiological levels even after producing a tan in a controlled manner. ClinicalTrials.gov Registration: NCT02334592

Clinical utility of serum 25-hydroxyvitamin D in the diagnosis of insulin resistance and estimation of optimal 25-hydroxyvitamin D in U.S. adults

AIMS To assess the clinical utility of measuring serum 25-hydroxyvitamin-D [25(OH)D] along with traditional risk factors in the diagnosis of insulin resistance (IR) and to estimate the optimal 25(OH)D level associated with normal glucose and insulin homeostasis. METHODS A cross-sectional analysis of 6868 adults aged≥20years without diagnosed diabetes in the National Health and Nutrition Examination Survey, with available standardized 25(OH)D data (2001-2010). IR was defined by the homeostatic-model-assessment of insulin resistance (HOMA-IR; ≥75th percentile, sex-specific: 3.9 in men or 3.6 in women). Using logistic regression, two risk models were developed to estimate the risk of IR: Model 1 included established risk factors, and Model 2 additionally included serum 25(OH)D. Predictiveness curves and decision-curve analysis were used to assess differences in IR detection among models. Receiver-operating-characteristic curves were used to estimate the lower threshold for 25(OH)D. Results were validated in a testing sample. RESULTS Model 2 marginally improved detection of IR: at a risk threshold of 0.2, adding 25(OH)D would identify an additional 2 to 4 cases per 1000 people. Overall, the lower 25(OH)D threshold was estimated at 60nmol/L, however, the threshold differed by ethnicity (Mexican-Americans: 54nmo/L, non-Hispanic whites: 68nmol/L, and non-Hispanic blacks: 41nmol/L). CONCLUSION Addition of serum 25(OH)D to traditional risk factors provided small incremental improvement in detection of IR in asymptomatic adults. The optimal 25(OH)D threshold was estimated to be at least 60nmol/L, however, the threshold may differ by ethnic-background. Further research is needed to validate these results in other populations.