High-Dose Oral Vitamin D Supplementation and Risk of Falls in Older Women

To the Editor: Dr Sanders and colleagues¹ studied the effects of a single annual dose of 500 000 IU of cholecalciferol in older women and found an increase in falls and fractures. The authors suggested that such an increase may depend on the high total annual dose used in the study, but they did not present any hypothesis for the underlying mechanism of this phenomenon.

Experimental data² demonstrate that vitamin D₃ in vitro promotes the differentiation of osteoclasts from monocyte macrophage stem cell precursors and at high doses increases in vivo osteoclastic bone resorption. This latter effect depends on vitamin D₃ increasing the production in osteoblasts of RANKL (receptor activator for nuclear factor-κ B ligand), a key factor necessary for osteoclast differentiation and activation. This casts further doubt on the safety of high doses of vitamin D in patients at high risk of fractures and should be taken into account in the design of future studies.