Effects of High Dose Bolus Cholecalciferol on Free Vitamin D Metabolites, Bone Turnover Markers and Physical Function

Abstract

High dose bolus cholecalciferol supplementation has been associated with falls and fracture, and this does not appear to be due to hypercalcaemia. The primary aim of this study was to determine the change in free vitamin D and metabolites after high dose bolus supplementation. This was a single centre, double-blinded, randomised, controlled trial of three different oral bolus doses of vitamin D₃ (50,000 IU, 150,000 IU, and 500,000 IU) in otherwise healthy, vitamin D deficient (total 25-hydroxylated vitamin 25(OH)D < 30 nmol/L) postmenopausal women. Thirty-three women were randomized to one of the three treatment groups. Twenty-seven vitamin D sufficient (25(OH)D > 50 nmol/L) postmenopausal women were recruited as a concurrent control group. Participants attended five study visits over three months. We measured total 25(OH)D₃ and free 25(OH)D, total and free 1,25(OH)₂D, parathyroid hormone, fibroblast-growth factor-23, serum calcium, ionised calcium, urinary calcium excretion, and bone turnover markers (procollagen I N-propeptide (PINP), serum C-telopeptides of type I collagen (CTX-I) and Osteocalcin (OC)). We assessed muscle strength and function with grip strength and a short physical performance battery. Postural blood pressure and aldosterone:renin ratio (ARR) was also measured. Total 25(OH)D₃ and free 25(OH)D increased in response to dose, and there were proportionate increases in total and free metabolites. Treatment did not affect serum calcium, postural blood pressure, ARR, or physical function. Bone turnover markers increased transiently one week after administration of 500,000 IU. High dose bolus cholecalciferol supplementation does not cause disproportionate increases in free vitamin D or metabolites. We did not identify any effect on blood pressure regulation or physical function that would explain increased falls after high dose treatment. A transient increase in bone turnover markers one week after a 500,000 IU bolus suggests that very high doses can have acute effects on bone metabolism, but the clinical significance of this transient increase is uncertain.

Keywords: bolus dose vitamin D; bone turnover; falls and fracture; free vitamin D; physical function; vitamin D supplementation; vitamin D toxicity.

Figure 1

Progress of phases of the study highlighted by Consort flow diagram.

Figure 2

Concentration of blood vitamin D metabolites after different bolus dose of cholecalciferol; (a) Total 25(OH)D₃ (b) Total 1,25(OH)₂D (c) Free 25(OH)D (d) Calculated free 1,25(OH)₂D. Data are presented as geometric means and 95% confidence intervals. ^a p < 0.001, 500,000 vs. 50,000; ^b p < 0.001, 500,000 vs. 150,000; ^c p < 0.001, 150,000 vs. 50,000.