Doubt Over Role of Vitamin D, Even to Limit Fractures

Becky McCall

April 03, 2014

New results from extensive analyses of observational and randomized clinical trials (RCTs) suggest that vitamin D given alone does not appear to increase bone-mineral density or reduce the risk for fractures or falls in older people, contrary to many previous reports.

The research also signifies that a clear role for vitamin-D supplementation for any other indication remains to be established — no significant effect on mortality overall in RCTs was seen for any indication. However, there was a suggestion of a potential benefit for vitamin D in pregnant women, against tooth decay in children, and in patients with chronic renal disease.

The work consists of 2 papers and an editorial, published in this week's BMJ examining vitamin D and multiple health outcomes. The first paper is an umbrella review of observational studies and RCTs; the second looks at vitamin D and risk for cause-specific death by systematic review and meta-analysis of observational cohort and randomized intervention studies.

Both sets of researchers and the editorialists make the point that benefits seen with vitamin D in observational studies have failed to translate into concrete protection in randomized clinical trials of vitamin-D supplementation, as has happened so often with other vitamins.

Asked to comment on the papers by Medscape Medical News, 2 experts on osteoporosis said they would not advocate widespread use of vitamin D for the prevention of fractures but that certain vulnerable populations may still benefit.

Coadministration of the vitamin with calcium should be avoided, however, because of lingering concerns that calcium might adversely affect cardiovascular disease risk. Also clouding the issue are the identification of the dose of vitamin D that is optimal, potential confounding from sunlight in trials, and the question of vitamin D3 vs vitamin D2 — all questions that will require answers in future trials.

Vitamin D in Falls Queried, "Possible" Benefit for Some People

In the first paper, Evropi Theodoratou, PhD, from the Centre for Population Health Sciences, University of Edinburgh, Scotland, and colleagues highlight findings relating to vitamin-D supplementation with and without the addition of calcium, including meta-analyses of the effect of vitamin D on falls, fractures, and bone-mineral density.

"Whereas some meta-analyses of randomized controlled trials have identified a protective effect of vitamin-D supplementation against falls or fractures, trials that examined vitamin-D–only supplementation failed to replicate these findings," they observe.

In addition, the umbrella review examines links to a total of 137 clinical outcomes reportedly linked to vitamin D, including skeletal, malignant, cardiovascular, autoimmune, infectious, and metabolic diseases. "Some indications exist that low plasma vitamin-D concentrations might be linked to several diseases, but firm universal conclusions about its benefits cannot be drawn," said Dr. Theodoratou.

Indeed, "highly promising results identified from most of the meta-analyses of observational studies were either not tested or not replicated in meta-analyses of randomized controlled trials," the authors note.

While some "probable" associations were found, Dr. Theodoratou said highly convincing evidence of a clear role of vitamin D with highly significant results in both randomized and observational evidence does not exist for any outcome.

"We found that vitamin-D supplementation is probably linked to a decrease in dental caries in children and in parathyroid hormone concentrations in patients with chronic kidney disease requiring dialysis and to an increase in maternal vitamin-D concentrations at term and in birth weight [of resulting babies]." But these conclusions carry the proviso that further studies and better-designed trials are needed to draw firmer conclusions.

Vitamin D2 or D3 Important for Mortality Benefit?

The second review, by Rajiv Chowdhury, PhD, a cardiovascular epidemiologist from the department of public health and primary care at the University of Cambridge, United Kingdom, and colleagues looked at vitamin D and risk for cause-specific death in a systematic review and meta-analysis of 73 cohort studies and 22 RCTs of vitamin D given alone vs placebo or no treatment.

They found a moderate but significant inverse association between circulating vitamin-D concentrations and the risk for all-cause mortality in the primary-prevention cohort studies. In particular, this association was evident specifically for deaths due to coronary disease, lymphoma, upper digestive cancer, and respiratory disorders.

However, they noted that "in all randomized controlled trials combined, vitamin-D supplementation, when given alone, did not reduce overall mortality significantly among older adults."

Of particular interest was the finding that the type of vitamin-D supplementation, whether D2 or D3, given alone, affected outcomes. Vitamin D3 reduced all-cause mortality significantly by 11% (relative risk, 0.89). By contrast, supplementation with vitamin D2 alone had no overall effect on mortality (relative risk, 1.04).

Commenting on the second paper in an editorial, University of Glasgow doctors Paul Welsh, PhD, British Heart Foundation intermediate fellow, and Naveed Sattar, MD, professor of metabolic medicine at the Institute of Cardiovascular and Medical Science, cautioned against reading too much into the finding relating to D2 or D3.

"The apparent degree of benefit from D3 in the new analyses…seems remarkable, but before these results are taken as a green light for widespread-D3 supplementation, several limitations must be considered," they say. For example, just "14 trials contributed to the D3 meta-analysis, totaling only 13,637 participants, and 6 of these were scored as being at high risk of bias."

Vitamin D Dose, Role of Calcium, in Fracture Prevention

The finding of Dr. Theodoratou and colleagues' review indirectly questions the basis of new guidance from the American Geriatrics Society, published in the Journal of the American Geriatrics Society in December 2013.

That consensus statement said that older patients should receive sufficient vitamin-D intake from all sources to lower their risk for falls and fractures, including dietary sources, sunlight, and supplements.

"The notion that vitamin-D–only supplementation increases bone-mineral density or reduces the risk of fractures or falls in older people is not supported. Therefore, our overview of the evidence on vitamin-D supplementation suggests that strong recommendations cannot be made," say Dr. Theodoratou and coauthors.

Helen Macdonald, PhD, professor of nutrition and musculoskeletal health at the University of Aberdeen, Scotland, and advisor to the United Kingdom's National Osteoporosis Society (NOS), said the main problem in measuring the effectiveness of vitamin-D supplementation is the health status of the study population.

"Most are healthy and probably not deficient in vitamin D. Opinion varies on what defines deficiency. About 30% of healthy Aberdeen women have [25-hydroxyvitamin D (25OHD)] concentration of less than25 nmol/L in winter and are defined as grossly deficient by some, at risk of deficiency by others, or 'not a worry unless this low in the summer,' by still others."

She also noted that some meta-analyses argue it is the dose of vitamin D that is important for fracture prevention and that it should be greater than 800 IU daily. Others find it is the calcium along with the vitamin D that is key. "It is hard to separate the 2, as they are often given together in these studies," she notes.

By way of further explanation for the conflicting results on vitamin-D use, Dr. Macdonald pointed out that if an individual already has healthy bones, "it is not logical to extrapolate that more vitamin D will be beneficial. Or if someone's vitamin D status is adequate, it is common sense that you would not benefit from more. [But] that does not mean to say that those who have problems with bone density and are at risk would not benefit."

Observational Data Doubtful; More Nuances in Research

The editorial raises an interesting parallel with the observational epidemiology that "extolled the virtues of antioxidant vitamins, only for major trials of vitamins E and C and ß carotene to show null or even some harmful effects of supplementation on a range of outcomes."

Drs. Welsh and Sattar note that this serves to highlight "the often-underestimated problems of confounding and reverse causality that can lead to premature causal inferences in observational studies."

Take-home messages are: healthcare professionals should treat all observational data cautiously, "as existing disease and associated risk factors may cause, rather than be a consequence of, low circulating 25-hydroxyvitamin D"; new trial data are needed with a focus on potential risks as well as benefits before widespread supplementation is considered; and "further reanalysis of existing data will not suffice."

With respect to future studies, Dr. Macdonald emphasized that she believed that 25OHD might not be the best marker for research anymore.

"It used to be great for finding those who were deficient, but now that the deficiency threshold keeps moving upward and supplementation doses are much higher, other metabolites might be more important.

"There is also a huge confounder with sunlight — most studies are not well-designed to take this into account," she added. "There may be effects attributed to vitamin D that should really be attributed to light."

Premature to Advocate Widespread Vitamin D Use

Also asked to comment briefly on the papers, Roger Francis, MBChB, FRCP, from the University of Newcastle, a former consultant physician at the Metabolic Bone Clinic, Freeman Hospital, Newcastle, United Kingdom, and trustee of the UK NOS, said: "It would be premature to advocate widespread vitamin-D supplementation, either alone or in combination with calcium, not least because of concerns about the potential adverse effects of calcium on cardiovascular disease."

As to which patients might benefit from vitamin-D supplementation, Dr. Francis pointed out that "it would be more appropriate to target vitamin-D supplementation for people who would benefit most, such as those with or at high risk for vitamin-D deficiency, such as housebound and institutionalized older people and some people with osteoporosis and/or fragility fractures."

Finally, echoing Dr. Francis and reflecting the continuing lack of consensus over vitamin-D supplementation, Drs. Welsh and Sattar conclude in their editorial that "we should stick to what is proven: encourage better lifestyles in general and target established risk factors in people at elevated risk."

Drs. Theodoratou and coauthors and Chowdhury and coauthors have reported no relevant financial relationships. Dr. Sattar has received honoraria and acted as a consultant for pharmaceutical companies for work related to lipid-lowering drugs; Dr. Welsh has reported no relevant financial relationships. Dr. Macdonald recently joined a vitamin-D advisory group funded by Internis, which makes a vitamin-D capsule. She has just started a small pilot study with vitamin-D3 tablets that were provided by Pure Encapsulations, which is a vitamin-supplement manufacturer based in the United States. Her other work has been funded by the UK Department of Health. She provides voluntary advice to the National Osteoporosis Society. Dr. Francis has served as an adviser or speaker for Consilient, Internis, and Takeda, all of whom market vitamin-D supplements.

BMJ. Published online April 1, 2014. Theodoratou article, Chowdhury article, Editorial

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