Vitamin D at large, single annual doses in elderly may increase fall/fracture risk

Many studies have been done on the effect of vitamin D on reducing fall and fracture risk in elderly populations, which is important as these increase mortality risk for a number of reasons.  Though some have been positive, negative results are also common; a Cochrane review and meta-analysis do not support vitamin D per se for fracture reduction, but adding calcium seems to help.  It does seem to reduce falls, however.  It is a very complicated area and some populations may respond better than others, institutionalized subjects for example, as meta-analyses fail to distinguish.

Two previous large trials have found that a dose of 100,000 IU of D3 every 4 months reduces fracture risk in a population, however a 300,000 IU D2 annual injection actually increased fracture risk in women but found no effect on men.

A study just published, Vital D (1), finds again that a high, single annual D dose increases fracture risk.  The study was performed because adherence is often low in trials with D and calcium, so doing it once per year under supervision would ensure treatment.  It would be convenient if it was equally effective as consistent low dosing.

This population consisted of 2,317 women of average age ~76.  Subjects received a single annual dose of 500,000 IU D3 for 3 to 5 years, or a matching placebo.  Falls and fractions (radiologically confirmed) were recorded, and a subset of the subjects had 25-OHD and PTH measured at baseline and 12 months.

5,404 falls over 6,925 person-years were recorded, with 74% of women in the D group and 68% in the placebo having at least 1 fall.  Relative risk for fractures was 1.26 in the D compared to placebo group, and 1.28 for nonvertebral relative risk.  In percentages, this was 15% more falls and 26% more fractures in the group taking vitamin D group. A greater fall (& trend toward significance in fracture) frequency was seen in the first 3 months after dosing than during the remaining 9.  The median 25-OHD concentration was 49 nmol/L at baseline, and at 12 months, it ranged from 55 nmol/L to 74 nmol/L, with substantial individual variation from 25 nmol/L to 120 nmol/L.

Other studies suggest that a threshold may be apparent and doses of 700-1000 IU daily, or 25-OHD levels of over 60 nmol/L may be needed.  Though this study reached these (annual average), it suggests that high serum concentrations (our bodies do not synthesize such high amounts in response to UV exposure), or the sharp subsequent decrease in concentrations, or for other reasons discussed below, 1 annual dose of D may increase fracture and fall risk.

What do we make of this data?

In an editorial in the same issue of JAMA, Bess Dawson-Hughes and Susan Harris speculate further on why this happened.  First, supported by a high dose rat study, they suggest an upregulation in CYP24, an enzyme that breaks down the active form of D, which would result in a decreased blood and tissue levels of the active form (which was not measured).  This may be supported by the fact that fall (& slightly, fracture) risk was increased the most in the first 3 months after high dosing.

They also suggest that vitamin D treated subjects may have increased mobility because of its positive effects on physical performance, pain reduction, and mood improvements, and ironically increased falls simply because they were moving around more.  Also, winter infections could have been increased in the placebo group, resulting in an increased sickness time and less activity.

Of importance, they highlight that vitamin D deficiency must still be corrected.  However these evidence suggest that infrequent, large dosing may be neutral or harmful on falls and fractures.  Future studies are needed to elucidate precisely why this may be.

Reference

1. Sanders, K., Stuart, A., Williamson, E., Simpson, J., Kotowicz, M., Young, D., & Nicholson, G. (2010). Annual High-Dose Oral Vitamin D and Falls and Fractures in Older Women: A Randomized Controlled Trial JAMA: The Journal of the American Medical Association, 303 (18), 1815-1822 DOI: 10.1001/jama.2010.594

  • DrFlinton

    The results are very clear and they do not come as a surprise. As our body gets older, the metabolism changes a lot for the worse and the intake of vitamin D is not absorbed as it used to be. Calcium is said to help, but falling is not due to the fact that you take or not calcium, but mainly because of the deterioration of cognitive functions.