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What More Should We Know About Vitamin D

Supplementation? CME / ABIM MOC / CE
News Author: Nancy A. Melville; CME Author: Charles P. Vega, MD

Posted: 2/16/2021

Clinical Context
Millions of US adults take vitamin D supplements for fracture prevention, but how effective are these supplements among
community-dwelling older adults? A systematic review and meta-analysis by Zhao and colleagues, which was published in
the December 26, 2017, issue of JAMA, addressed this issue.[1]

Thirty-three randomized controlled trials with a total of more than 50,000 ambulatory participants contributed to the study
findings. Both calcium and vitamin D were associated with nonsignificant increases in the risk for hip fracture vs placebo or
no treatment, and the combination of calcium plus vitamin D also had no significant effect on the risk for hip fracture vs
control treatment.

Moreover, the use of supplements featuring calcium, vitamin D, or both failed to improve rates of vertebral fracture or any
fracture vs control treatment. The negative results for calcium and vitamin D were similar regardless of dose, sex, fracture
history, baseline dietary calcium consumption, and baseline 25-hydroxyvitamin D (25-OH-D) level.

Some studies have found more compelling results that vitamin D supplements can prevent falls among older adults,
although other research has found no effect. The current study uses a unique design to find the potential best dose of
vitamin D to prevent falls and then compares that dose with a low-dose vitamin D supplement control group.

Study Synopsis and Perspective

Higher doses of vitamin D supplementation not only show no benefit in the prevention of falls in older adults at increased risk
of falling compared with the lowest doses but also appear to increase the risk, new research shows.

According to these findings, supplemental vitamin D above the minimum dose of 200 IU/day likely has little benefit, lead
author Lawrence J. Appel, MD, MPH, told Medscape Medical News.

"In the absence of any benefit of 1000 IU/day vs 2000 IU/day [of vitamin D supplementation] on falls, along with the potential
for harm from doses above 1000 IU/day, it is hard to recommend a dose above 200 IU/day in older aged persons unless
there is a compelling reason," asserted Dr Appel, director of the Welch Center for Prevention, Epidemiology, and Clinical
Research at Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland.

"More is not always better, and it may even be worse," when it comes to vitamin D's role in the prevention of falls, he said.

The research, published online December 7 in the Annals of Internal Medicine,[2] adds important evidence in the ongoing
struggle to prevent falls, says Bruce R. Troen, MD, in an accompanying editorial.[3]

"Falls and their deleterious consequences remain a substantial risk for older adults and a huge challenge for health care
teams," writes Dr Troen, a physician-investigator with the Veterans Affairs Western New York Healthcare System.

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However, commenting to Medscape Medical News, Dr Troen cautioned: "There are many epidemiological studies that are
correlative, not causative, that do show a likelihood for benefit [with vitamin D supplementation].

"Therefore, there's no reason for clinicians to discontinue vitamin D in individuals because of this study.

"If you're monitoring an older adult who is frail and has multiple comorbidities, you want to know what their vitamin D level is
[and] provide them an appropriate supplement if needed," he emphasized.

Some guidelines already reflect the lack of evidence of any role of vitamin D supplementation in the prevention of falls,
including those of the 2018 US Preventive Services Task Force, which, in a reversal of its 2012 recommendation, now does
not recommend vitamin D supplementation for fall prevention in older persons without osteoporosis or vitamin D deficiency,
Dr Appel and colleagues note.

No Prevention of Falls Regardless of Baseline Vitamin D

As part of the Study to Understand Fall Reduction and Vitamin D in You (STURDY), Dr Appel and colleagues enrolled 688
community-dwelling participants who had an elevated risk of falling, defined as a serum 25-hydroxyvitamin D [25(OH)D] level
of 25 to 72.5 nmol/L (10-29 ng/dL).

Participants were a mean age of 77.2 years and had a mean total 25(OH)D level of 55.3 nmol/L at time of enrollment.

They were randomly assigned to 1 of 4 doses of vitamin D3, including 200 IU/day (the control group) or 1000, 2000, or 4000
IU/day.

The highest doses were found to be associated with worse, not better, outcomes including a shorter time to hospitalization or
death compared with the 1000 IU group. The higher-dose groups were therefore switched to a dose of 1000 IU/day or lower,
and all participants were followed for up to 2 years.

Overall, according to the editorial, 63% experienced falls over the course of the study, which, although a high percentage,
was consistent with the study's criteria of the participants having an elevated fall risk.

Of the 667 participants who completed the trial, no benefit in prevention of falling was seen across any of the doses
compared with the control group dose of 200 IU/day, regardless of participants' baseline vitamin D levels.

Safety analyses showed that even in the 1000 IU group, a higher risk for first serious fall and first fall with hospitalization was
seen compared with the 200 IU/day group.

A limitation is that the study did not have a placebo group, however, "200 IU/day is a very small dose, probably
homeopathic," Dr Appel told Medscape Medical News. "It was likely close to a placebo," he said.

Caveats: Comorbidities, Subgroups

In his editorial, Dr Troen notes other studies, including the Vitamin D and Omega-3 Trial (VITAL), also found no reduction in
falls with higher vitamin D doses; however, that study did not show any significant risks with the higher doses.

He adds that the current study lacks information on subsets of participants.

"We don't have enough information about the existing comorbidities and medications that these people are on to be able to
pull back the layers. Maybe there is a subgroup that should not be getting 4000 IU, whereas another subgroup may not be
harmed and you may decide that patient can benefit," he said.

Furthermore, the trial doesn't address groups such as nursing home patients.

"I have, for instance, 85-year-olds with vitamin D levels of maybe 20 nmol/L with multiple medical issues, but levels that low
were not included in the study, so this is a tricky business, but the bottom line is first, do no harm," he said.

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"We really need trials that factor in the multiple different aspects so we can come up, hopefully, with a holistic and
interdisciplinary approach, which is usually the best way to optimize care for frail older adults," he concluded.

The study received funding from the National Institute of Aging.

Ann Intern Med. Published December 7, 2020.

Study Highlights

The study comprised 2 parts: a randomized dose-finding study of vitamin D and a comparison between the calculated
best dose of vitamin D in comparison with 200 IU/day vitamin D as control therapy.
Study participants were community-dwelling adults aged 70 years or older. All participants were at increased risk for
falls, as evidenced by previous fall or mobility problems, and all had a low 25-OH-D level at baseline. Adults who
used more than 1000 IU/day vitamin D or more than 1200 mg/day calcium at baseline were excluded from study
participation.
Participants were randomly assigned at baseline to receive vitamin D at doses of 200, 1000, 2000, or 4000 IU/day.
They were followed for up to 24 months after randomization.
The primary study outcome was the time to first fall or death. Fall outcomes were determined by monthly calendars
kept by participants, scheduled study follow-up visits, and ad hoc contacts via telephone. Researchers also measured
gait speed as a secondary outcome.
688 adults participated in the study. The mean age of participants was 77.2 years, and 56.4% were men; 18.2% of
participants were Black. The mean 25-OH-D level in the cohort was 55.3 nmol/L.
25-OH-D levels increased during vitamin D treatment across all groups, with a dose-response effect.
The median follow-up time was 21.7 months. Compared with the other dosages, 1000 IU stood out as clearly the
most effective in preventing falls during the dose-finding period.
Once 1000 IU/day was established as the most effective dose, participants in the other dosage groups received 1000
IU/day, except for the 200 IU/day cohort (control group).
The rates of the primary outcome of falls or death were 76.9 and 76.0 in the 1000 IU/day and 200 IU/day cohorts, a
nonsignificant difference. Another analysis comparing the rates of falls or death among participants receiving vitamin
D 200 IU/day and all other dosage groups also failed to demonstrate a benefit associated with higher doses of
vitamin D.
There was also no significant difference between vitamin D doses in comparing gait speed across different cohorts.
The hospitalization rate was noted to be higher with the 1000 and 2000 IU/day doses of vitamin D vs the 200 IU/day
dose during the dose-finding period of the study. However, this risk was not significant in comparing dosage groups
during the entire study period.

Clinical Implications

A previous meta-analysis found that calcium, vitamin D, and combined calcium/vitamin D supplements failed to
improve the risks for hip and other fractures among community-dwelling older adults. These results remained stable
regardless of baseline 25-OH-D levels.
The current study finds that a moderate to high dosages of vitamin D were not effective in the prevention of falls or
death vs vitamin D 200 IU/day among community-dwelling older adults. Higher doses of vitamin D were also not
associated with improvements in gait speed.
Implications for the healthcare team: The healthcare team should account for negative trials when discussing vitamin
D supplementation with patients.

Earn Credit

References

1. Zhao JG, Zeng XT, Wang J, Liu L. Association between calcium or vitamin D supplementation and fracture incidence
in community-dwelling older adults: a systematic review and meta-analysis. JAMA. 2017;318(24):2466-2482.

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https://jamanetwork.com/journals/jama/fullarticle/2667071. Accessed December 9, 2020.

2. Appel LJ, Michos ED, Mitchell CM, Blackford AL, Sternberg AL, Miller Iii ER, Juraschek SP, Schrack JA, Szanton SL,
Charleston J, Minotti M, Baksh SN, Christenson RH, Coresh J, Drye LT, Guralnik JM, Kalyani RR, Plante TB, Shade
DM, Roth DL, Tonascia J. The effects of four doses of vitamin D supplements on falls in older adults: a response-
adaptive, randomized clinical trial. Ann Intern Med. Published online December 1, 2020. https://www.acpjournals.org
/doi/10.7326/M20-3812. Accessed December 9, 2020.
3. Troen BR. Falls: To D or not to D-that is not the (only) question! Ann Intern Med. Published online December 8, 2020.
https://www.acpjournals.org/doi/10.7326/M20-7609. Accessed December 9, 2020.

This article is a CME / ABIM MOC / CE certified activity. To earn credit for this activity visit:
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