With Lack of Official Guidance, How to Advise on Vitamin D Supplementation

Research Triangle Park, NC—The market for vitamin D in the United States is huge and growing.

Projections from Mordor Intelligence suggest the U.S. vitamin D supplement market will grow by a compound annual growth rate of 5.8% to reach $1.3 billion by 2025.

Yet, confirmed information on the benefits or risk of screening and supplementation tends to be nonexistent or contradictory.

According to a report from the U.S. Preventive Services Task Force (USPSTF), no studies evaluated the direct benefit or harms of screening for vitamin D deficiency. Furthermore, a literature search led by RTI International researchers found that, among asymptomatic, community-dwelling populations with low vitamin D levels, “the evidence suggests that treatment with vitamin D (with or without calcium) has no effect on mortality or incidence of fractures, falls, depression, diabetes, cardiovascular disease, cancer, or adverse events.”

The authors of the report in JAMA also advise that the evidence is inconclusive about the effect of treatment on physical functioning and infection.

The review was initiated because, in at least some studies, low serum vitamin D levels have been associated with adverse clinical outcomes. Researchers posited that identifying and treating deficiency might improve outcomes.

To do that, they searched PubMed, EMBASE, the Cochrane Library, and trial registries through March 12, 2020; bibliographies from retrieved articles, outside experts, and surveillance of the literature through November. 30, 2020. The goal was to find fair- or good-quality, English-language randomized clinical trials (RCTs) of screening with serum 25-hydroxyvitamin D (25[OH]D) compared with no screening, or treatment with vitamin D (with or without calcium) compared with placebo or no treatment conducted in nonpregnant adults. Nonrandomized, controlled intervention studies were considered for harms only, the study said, and those concerning treatment were limited to those enrolling or analyzing participants with low serum vitamin D levels.

The focus was on mortality, incident fractures, falls, diabetes, cardiovascular events, cancer, depression, physical functioning, and infection. Ultimately, 46 studies involving 16,205 participants were included, but none directly evaluated the health benefits or harms of screening.

Results indicate that, among community-dwelling populations, treatment was not significantly associated with mortality (pooled absolute risk difference [ARD], 0.3% [95% CI, −0.6%-1.1%]; 8 RCTs, n = 2006), any fractures (pooled ARD, −0.3% [95% CI, −2.1%-1.6%]; 6 RCTs, n = 2186), incidence of diabetes (pooled ARD, 0.1% [95% CI, −1.3%-1.6%]; 5 RCTs, n = 3356), incidence of cardiovascular disease (2 RCTs; hazard ratio, 1.00 [95% CI, 0.74-1.35] and 1.09 [95% CI, 0.68-1.76]), incidence of cancer (2 RCTs; hazard ratio, 0.97 [95% CI, 0.68-1.39] and 1.01 [95% CI, 0.65-1.58], or depression (3 RCTs, various measures reported).

In addition, researchers report that the pooled ARD for incidence of participants with one or more falls was −4.3% (95% CI, −11.6%-2.9%; 6 RCTs). “The evidence was mixed for the effect of treatment on physical functioning (2 RCTs) and limited for the effect on infection (1 RCT),” they add. “The incidence of adverse events and kidney stones was similar between treatment and control groups.”

“No studies evaluated the direct benefits or harms of screening for vitamin D deficiency,” the authors conclude. “Among asymptomatic, community-dwelling populations with low vitamin D levels, the evidence suggests that treatment with vitamin D has no effect on mortality or the incidence of fractures, falls, depression, diabetes, cardiovascular disease, cancer, or adverse events. The evidence is inconclusive about the effect of treatment on physical functioning and infection.”

Part of the problem, according to the study, is that serum total 25(OH)D is considered the best marker of vitamin D status, but, currently, no consensus exists regarding the serum level of 25(OH)D that represents optimal health or deficiency. So, even though this report was styled as an update of 2014 recommendations, it still failed to provide clear guidance.

Compared with the 2014 review for the USPSTF on this topic, 23 new RCTs were added, and four RCTs were excluded. 

“The importance of vitamin D for maintaining musculoskeletal health is well established; vitamin D deficiency causes osteomalacia, reduces bone mineral density, and increases risk of fracture,” according to an accompanying editorial. “These effects occur because vitamin D deficiency results in decreased intestinal calcium absorption, secondary hyperparathyroidism, hypophosphatemia, and increased bone turnover. It has been challenging to demonstrate nonmusculoskeletal effects of vitamin D, which, if present, are thought to be mediated by vitamin D acting as a transcription factor.”

The commentators from Massachusetts General Hospital and Harvard Medical School, both in Boston, and from Perelman School of Medicine at the University of Pennsylvania in Philadelphia agree with the USPTF’s call for more research, especially since 25(OH)D levels vary by race/ethnicity, with 25(OH)D levels being highest in non-Hispanic White populations, intermediate in Hispanic populations, and lowest in Black populations.

“These racial/ethnic differences in circulating 25(OH)D do not appear to be due to genetic differences in vitamin D binding protein polymorphisms, although this is disputed, and instead may reflect lower vitamin D production in skin with higher levels of melanin,” they write. “There is an increasing call to reevaluate the use of race/ethnicity in clinical algorithms, and the appropriate management of differing 25(OH)D levels is unclear.”

In the meantime, they suggest that healthcare professionals might not be as concerned about screening and simply ensure that all individuals consume the age-based recommended daily allowance of vitamin D. They add that those at increased risk for vitamin D deficiency—such those with limited sun exposure, increased skin pigmentation, body mass index >30, malabsorption or altered gastrointestinal anatomy, chronic kidney disease, chronic liver disease, or who have rickets, osteomalacia, or osteoporosis—could be recommended a higher dose of vitamin D (e.g., 2000 IU/d) that is still below the upper daily limit.

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