Annual Vitamin D Dose Linked to Increased Fall, Fracture Risk in Older Women

Laurie Barclay, MD

May 12, 2010

May 12, 2010 — Older, community-dwelling women who receive annual oral high-dose cholecalciferol have an increased risk for falls and fractures, according to the results of a double-blind, placebo-controlled trial reported in the May 12 issue of the Journal of the American Medical Association.

"Improving vitamin D status may be an important modifiable risk factor to reduce falls and fractures; however, adherence to daily supplementation is typically poor," write Kerrie M. Sanders, PhD, from the University of Melbourne in Geelong, Australia, and colleagues. "We hypothesized that high-dose cholecalciferol (500 000 IU) given orally once a year to community-dwelling older women would reduce falls and fractures."

From June 2003 to June 2005, a total of 2256 community-dwelling women, 70 years or older, thought to be at high risk for fracture were recruited and were randomly assigned to receive cholecalciferol (500,000 IU) or placebo each autumn to winter for 3 to 5 years until study conclusion in 2008.

Monthly calendars were used to identify falls and fractures, and telephone interview and radiography allowed confirmation of the details. Serial blood sampling for 25-hydroxycholecalciferol and parathyroid hormone levels was performed in a substudy of 137 randomly selected participants.

Fractures occurred in 171 women in the cholecalciferol (vitamin D) group and in 135 in the placebo group, yielding an incidence rate ratio (RR) for fracture of 1.26 (95% confidence interval [CI], 1.00 - 1.59; P = .047). Fracture rates per 100 person-years were 4.9 for vitamin D vs 3.9 for placebo.

In the vitamin D group, there were 2892 falls in 837 women (rate, 83.4 per 100 person-years) vs 2512 falls in 769 women in the placebo group (rate, 72.7 per 100 person-years; incidence RR, 1.15; 95% CI, 1.02 - 1.30; P = .03). A post hoc analysis of falls revealed a temporal pattern, with an incidence RR of falling in the vitamin D group vs the placebo group of 1.31 in the first 3 months after dosing and 1.13 during the following 9 months (test for homogeneity; P = .02).

Median baseline serum 25-hydroxycholecalciferol level was 49 nmol/L in participants in the substudy, and less than 3% of the substudy participants had 25-hydroxycholecalciferol levels of less than 25 nmol/L. In the vitamin D group, 25-hydroxycholecalciferol levels increased to approximately 120 nmol/L at 1 month after dosing, were approximately 90 nmol/L at 3 months, and remained higher than the placebo group at 12 months after dosing.

"Among older community-dwelling women, annual oral administration of high-dose cholecalciferol resulted in an increased risk of falls and fractures," the study authors write. "Our study used the largest total annual dose of vitamin D (500 000 IU) reported in any large randomized controlled trial, raising the possibility that the adverse outcome is dose-related."

Limitations of this study include the possibility that nonclinical vertebral fractures would have been missed, possibly missing baseline clinical information because the participants were not evaluated at the study center, and lack of biochemical assessment of all participants.

In an accompanying editorial, Bess Dawson-Hughes, MD, and Susan S. Harris, DSc, from Tufts University in Boston, Massachusetts, note the need for better understanding of basic vitamin D physiology.

"Specifically, the effect of dose size, route (intramuscular vs. oral), and dosing interval on aspects of vitamin D metabolism including CYP24 activity and on local tissue-specific 1,25-dihydroxyvitamin D levels and actions should be investigated," Drs. Dawson-Hughes and Harris write. "It may also be necessary to reevaluate the risks and benefits of the current clinical practice of providing high loading doses of cholecalciferol to patients who are vitamin D deficient. In the meantime, it is important to reiterate that although vitamin D insufficiency is widespread, it can be safely corrected with a variety of existing supplement types and regimens and it should continue to be identified and treated in clinical practice."

The National Health and Medical Research Council and the Australian Government Department of Health and Ageing supported this study. The study authors and editorialists have disclosed no relevant financial relationships.

JAMA. 2010;303:1815-1822, 1861-1862.

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