Far from protecting older women from falls and fractures, yearly high-dose oral vitamin D raised the risk of falls by 15% and that of fractures by 26%, according to an Australian study.
These risks were highest in the 3-month period immediately after each annual dose, said Kerrie M. Sanders, Ph.D., of the University of Melbourne and her associates.
As this study used the “largest total annual dose of vitamin D (500,000 IU) reported in any large randomized controlled trial,” it is possible that these adverse outcomes are related to the dosage, or perhaps to the once-a-year regimen. But the levels of 25-hydroxycholecalciferol achieved in these subjects can also occur with other dosing regimens, so it appears that the safety of all high-dose vitamin D supplementation warrants further examination, they noted.
Dr. Sanders and her colleagues performed their single-center study in 2,256 white women aged at least 70. They were considered at risk for hip fracture because of their family or personal histories or because they reported recent falls.
The subjects were randomly assigned to receive a single oral dose of vitamin D (cholecalciferol) or a matching placebo at the same time every year for 3-5 years. Lab studies in a subgroup of the subjects showed that the active treatment raised levels of 25-hydroxycholecalciferol an average of 41%, as expected.
There were 5,404 falls during follow-up, involving 74% of the women taking vitamin D and 68% of those taking placebo. The rate of falls was 83 per 100 person-years with vitamin D, compared with 73 per 100 person-years with placebo, a statistically significant difference.
The increase in falls with active treatment was noted in falls that produced fractures and those that didn't, and in falls that produced soft-tissue injury.
A total of 155 women taking vitamin D sustained 171 fractures during follow-up, compared with 125 women taking placebo who sustained 135 fractures. This translates to a rate of 4.9 fractures per 100 person-years with active treatment and 3.9 fractures per 100 person-years with placebo.
These risks of falls and of fractures did not change after the data were adjusted to account for subjects' calcium intake.
“Contrary to our hypothesis, participants receiving annual high-dose oral cholecalciferol experienced 15% more falls and 26% more fractures than [did] the placebo group. Women not only experienced excess fractures after more frequent falls but also experienced more fractures that were not associated with a fall,” the investigators noted (JAMA 2010;303:1815-22).
The reason for these counterproductive effects is not yet known, but it is possible that the once-a-year oral regimen—compared with either a regimen that divides the oral doses or one that uses intramuscular doses—is at fault. “It is reasonable to speculate that high serum levels of vitamin D or metabolites resulting from the large annual dose, subsequent decrease in the levels, or both might be causal,” they wrote.
In an accompanying editorial, Dr. Bess Dawson-Hughes and Susan S. Harris, D.Sc., of the Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, said that these study findings should not detract from the importance of “correcting widespread vitamin D deficiency and insufficiency.
“There is no evidence for adverse effects of more frequent, lower-dose regimens, so daily, weekly, or monthly dosing with vitamin D3 appears to be the best option for clinicians at this time,” they noted (JAMA 2010;303:1861-2).
Disclosures: This study was supported by the National Health and Medical Research Council and the Australian Government Department of Health and Ageing. No conflicts of interest were reported by Dr. Sanders and her associates, Dr. Dawson-Hughes, or Dr. Harris.