Outcomes Research in Review

High-Dose Vitamin D Supplementation May Lead to Increased Risk of Falls

Bischoff-Ferrari HA, Dawson-Hughes B, Orav E, et al. Monthly high-dose vitamin D treatment for the prevention of functional decline: a randomized clinical trial. JAMA Intern Med. Published online 4 Jan 2016.



Study Overview

Objective. To determine the effectiveness of high-dose vitamin D versus low-dose vitamin D in reducing the risk of functional decline in older adults.

Design. Double-blind randomized controlled trial.

Setting and participants. This single-center study was conducted at the University of Zurich. Home-dwelling adults aged 70 and over were recruited through newspaper advertisement in Zurich from December 2009 to May 2010. Inclusion criteria included maintenance of mobility with or without a walking aid, having the ability to use public transportation to attend clinic visits, and scoring at least 27 on the Mini-Mental State Examination. Exclusion criteria include supplemental vitamin D use exceeding 800 IU per day and unwillingness to discontinue additional calcium and vitamin D supplementation, current cancer, malabsorption syndrome, heavy alcohol consumption, uncontrolled hypocalcemia, severe visual or hearing impairment, use of medications affecting calcium metabolism, diseases causing hypercalcemia, planned travel to sunny locations for longer than 2 months per year, maximum calcium supplement dose of 250 mg/day, use of medications affecting serum 25-hydroxyvitamin D (25[OH]D) level, body mass index ≥ 40, diseases predisposing to falls, hypercalcemia, kidney disease with creatinine clearance < 15, or kidney stone within 10 years prior to enrollment.

Intervention. Participants were randomized to receive either monthly supplementation of 24,000 IU of vitamin D3 per month (low-dose group), 60,000 IU of vitamin D3 once per month (high-dose group), or 24,000 IU of vitamin D3 plus 300 µg of calcifediol once per month. It was hypothesized that higher monthly doses of vitamin D or in combination with calcifediol, which is a liver metabolite approximately 2 to 3 times more potent than vitamin D3, will increase levels of 25(OH)D and reduce the risk of functional decline.

Main outcome measures. Lower extremity function using the Short Physical Performance Battery and 25(OH)D levels at 6 and 12 months. Study nurses called participants monthly to assess falls, adverse events, and adherence to study medications.

Main results . A total of 200 participants were enrolled. Average age was 78 years (SD = 5) and 67% were female; all had a history of falls in the previous year and average baseline 25(OH)D levels ranged from 18.4 to 20.9 ng/mL in the three groups. Adherence to the study medication exceeded 94% throughout the study trial in all treatment groups.

At 6 and 12 months, 25(OH)D levels increased by an average of 12.7 and 11.7 ng/mL in the low-dose group, an average of 18.3 and 19.2 ng/mL in the high-dose group, and an average of 27.6 and 25.8 ng/mL in the calcifediol-added group. The mean changes in physical performance score indicating lower extremity function did not differ significantly among treatment groups ( P = 0.26), but for one measure—the 5 successive chair stands—the 2 high-dose groups had less improvement when compared with the low-dose group. At 12 months, 66.9% of the high-dose group and 66.1% in the group with calcifediol fell during the study period, which was more than the low-dose group (47.9%, P = 0.048). The mean number of falls was also higher among the high-dose and calcifediol groups when compared with the low-dose group.

Conclusion. Higher doses of vitamin D were not better than lower doses of vitamin D in improving lower extremity function and were associated with higher risk of falls.


Vitamin D deficiency is common among older adults and is associated with sarcopenia, functional decline, falls, and fractures [1,2]. Prior meta-analysis has supported that supplementation with vitamin D may lead to improved outcomes in fracture prevention [3]. However, the US Preventive Services Task Force, using more recent evidence reviews and an updated meta-analysis [4], found evidence lacking regarding the benefit of supplementation with vitamin D in community-dwelling postmenopausal women at doses > 400 IU, found no benefit in this group for doses ≤ 400, and found evidence lacking for supplementation in men or premenopausal women at any dose [5]. At the same time, the USPSTF also recommends exercise or physical therapy and vitamin D supplementation (800 IU daily) to prevent falls in community-dwelling adults ≥ 65 years at increased risk for falls [6]. This is consistent with the Institute of Medicine’s recommendation of 800 IU per day for older adults [7].

The current study attempted to elucidate the potential impact of high-dose vitamin D supplementation, hypothesizing that higher doses will achieve improvement in vitamin D levels and better outcomes in terms of lower extremity function and falls. However, the investigators found that rather than lowering risk of falls, higher-dose vitamin D was associated with elevated risk of falls without the benefit of improving lower extremity function. This is not the first study that has demonstrated that higher doses of vitamin D supplementation may be associated with harm. A prior randomized controlled trial utilizing a different dosing strategy of annual high- dose vitamin D supplementation also found that higher doses were associated with increased risks of falls [8]. Nonetheless, it helps support the notion that in vitamin D supplementation, more is not necessarily better.

The study is not without its drawbacks. The sample size was relatively small and the trial may have been underpowered to detect whether there may be certain patients for whom high-dose vitamin D supplementation may have a role. Also, the study was based in Zurich, which has a relatively uniform population, and study results may not be generalizable to populations in other countries.

Applications for Clinical Practice

The study lends support to the current recommendation of the Institute of Medicine—800 IU a day—for fall prevention, which is equivalent in dose to the 24,000 IU per month utilized in the trial. One of the questions not answered by the study is whether high-dose supplementation for adults who have severe deficiency in vitamin D is beneficial or harmful when compared with lower-dose supplementation. In clinical practice, clinicians often check an initial level of vitamin D and aim for a target level with supplementation. Among those patients with extremely low baseline levels, a lower-dose regimen of 800 IU a day may not yield a normalized level of vitamin D. Further studies are needed to elucidate whether there may be a role for higher-dose supplementation in these individuals. Nonetheless, it is clear that the current evidence does not support the routine use of high-dose vitamin D supplementation; it does not lead to better lower extremity function and may cause harm.

—William Hung, MD, MPH

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