High-Dose Vitamin D2 Supplementation for 1 Year Does not Cause Serious Adverse Events Such as Emergency Room Visits and Hospitalizations in African American Men with a High Burden of Chronic Disease

The observational studies of vitamin D supplements had been associated with improved health outcomes without significant adverse consequences (1,2). The randomized controlled trials (RCT), however, had been inconclusive and vitamin D combined with calcium supplementsincreased the risk of nephrolithiasis (1,2). The Institute of Medicine warned about using high doses of vitamin D and suggested 25(OH)D serum level >50 ng/ml as possibly associated with higher health risks (2). There had been no detail reports of serious adverse events (SAE) from a long-term (≥a year) RCT using high dose (≥50,000 IU/week) vitamin D (1). The present study examined SAE from a high dose vitamin D supplement in African American men (AAM). This sub-study was ancillary to “D vitamin Intervention in Veteran Administration ( DIVA)” trial described elsewhere (3). Briefly, the double blind RCT tested the effect of 12-month high dose vitamin D on glycemic control in 35–85 year-old AAM with dysglycemia (A1C 5.7–6.4%) and hypovitaminosisD (25(OH)D 5.0–29 ng/ml). All subjects received cholecalciferol(D3) 400 IU/day and either weekly ergocalciferol(D2) 50,000 IU (Pliva Co) or placebo. The dose of D2 was adjusted in a blinded manner by the research pharmacist at 3, 6, and 9-month visits to keep 25(OH)D in 40–100 ng/ml range. The SAE including emergency room (ER) visits and hospitalizations were collected from Computerized Patient Record System (CPRS) at three time points: a year prior to the trial (T0), a year of the trial (T1) and a year after the trial (T2). To account for all possible vitamin D-related SAE we designated the main outcome as total SAE including combined number of ER visits and hospitalizations during and after the trial (T1+T2). The mean dose of D2 was 62,762 (range 50,000 – 88,460 IU/week) (Table 1) and calcium (combined dietary and supplemental) intake was ≤1000 mg/day. Disease burden was high with average number of 4 medical conditions (range 0 – 8) and 6.5 medications (range 0 – 17) per person. A total of 373 SAE over a 3-year period were equally distributed among T0 (N=141), T1 (N=110) and T2 (N=122) (Table 1). On average, there were 19 hospitalizations and 42 emergency room visits per 100 subjects per year. There were no differences in SAE between placebo vs vitamin D groups including comparison of the number of subjects with SAE or the number of SAE events per group (Table 1). The most common SAE were musculoskeletal (26%), psychiatric (21%), respiratory (13%) and cardiovascular (10%) conditions. There were no incidental kidney stones. Correlation analysis for the main outcome (SAE of T1+T2) showed association with T0 hospitalizations (r=0.43, p<0.001) and T0 ER visits (r=0.53, p<0.001). Regression analysis showed that the only significant predictors for the main outcome were T0 hospitalizations (coefficient estimate 0.677, 95% CI 0.543 – 0.812, p<0.0001) and T0 ER visits (coefficient estimate 0.629, 95% CI 0.458 – 0.801, p<0.0001). Therefore, high dose vitamin D supplementation for a year did not cause an increase in kidney stones or serious adverse events in African American men with high burden of chronic disease. Table 1 Serious Adverse Events over 3-year period in the subjects from the double-blind randomized controlled trial (RCT) of a year-long high dose vitamin D supplements in African American male veterans with hypovitaminosisD and prediabetes*