Vitamin D Deficiency: Can We Improve Diagnosis?

Use of a ratio of vitamin D metabolites to assess vitamin D status rather than total 25-hydroxyvitamin D [25(OH)D] level may provide a better index of individual susceptibility to bone damage due to deficiency, new research suggests.

The study supports previous data suggesting that a ratio cut-off of greater than 100 is associated with the development of secondary hyperparathyroidism and the need for correction with supplementation, while a level greater than 50 suggests mild-to-moderate deficiency, said Zhinous Shahidzadeh Yazdi, MD, in a poster presented at ENDO 2023: The Endocrine Society annual meeting.

Current Endocrine Society guidelines published in 2011 advise measurement of plasma circulating 25(OH)D levels to evaluate vitamin D status in patients at risk for deficiency, defined as < 20 ng/mL (50 nmol/L). Revised guidelines are due out in early 2024.

“We don’t think measuring 25 hydroxy D is optimal because of the impact of vitamin D binding protein,” Yazdi told Medscape Medical News.

“Over 99% of all metabolites are bound to vitamin D binding protein, but only the free fraction is biologically active. By measuring total plasma 25(OH)D — as we do right now in clinic — we cannot account for the impact of vitamin D binding proteins, which vary by threefold across the population,” she added.

Thus, the total 25(OH)D deficiency cut-off of < 20 mg/mL currently recommended by The Endocrine Society may signal clinically significant vitamin D deficiency in one person but not another, noted Yazdi, who is a postdoctoral fellow at the University of Maryland, Baltimore.   

Directly measuring binding protein or the free fraction would be ideal, but “there aren’t good commercial assays for those, and it’s more difficult to do. So, as an alternative, the vitamin D metabolite ratios implicitly adjust for individual differences in vitamin D binding protein,” she explained.

The ratio that Yazdi and colleagues propose to measure is that of the vitamin D metabolites 1,25(OH)2D/24,25 (OH)2D (shortened to 1,25D/24,25D), which they say reflect the body’s homeostatic response to vitamin D levels, and which rises in the setting of deficiency. It is a measurement > 100 in this ratio that they believe means the patient should receive vitamin D supplementation.

Controversial Topic, Ratio Proposal Is Very Early in the Game

The issue of vitamin D deficiency has long generated controversy, particularly since publication of findings from the VITAL study in 2022, which showed vitamin D supplements did not significantly reduce the risk of fracture among adults in midlife and older compared with placebo.

According to the senior author of the new study, Simeon I. Taylor, MD, professor of medicine at the University of Maryland, what still remains controversial after VITAL is the question: “How can you identify people who have sufficiently bad vitamin D deficiency that it’s adversely impacting their bones?”

He added that there is a suggestion that small subpopulations in VITAL really did benefit from vitamin D supplementation, but the study “wasn’t designed to look at that.”

Indeed, the authors of an editorial accompanying the publication of the VITAL study said the findings mean there is no justification for measuring 25(OH)D in the general population or for treating to a target level.

Asked to comment on Yazdi and colleagues’ ratio proposal for diagnosing vitamin D deficiency, the co-author of the VITAL study editorial, Clifford Rosen, MD, told Medscape Medical News: “I do think it’s important to point out that changes in the vitamin D binding protein can have a significant impact on the level of 25 [OH] D…People should recognize that.”

And, Rosen noted, “I like the idea that the…[ratio] is a measure of what’s happening in the body in response to vitamin D stores. So, when you supplement it comes back up…In certain individuals at high risk for fractures, for example, you might want to consider a more extensive workup like they’re suggesting.”

However, Rosen, of the Rosen Musculoskeletal Laboratory at Maine Medical Center Research Institute, Scarborough, added: “If the 25[OH]D level is below 20 [ng/mL] you’re going to treat regardless. When we think about sensitivity, a 25[OH]D level less than 20 [ng/mL] is a good screen…Those individuals need to be treated, especially if they have low bone mass or fractures.”

To validate the ratio for clinical use, Rosen said, larger numbers of individuals would need to be evaluated. Moreover, “you’d need to run a standard of vitamin D binding protein by mass spectrometry versus their assumed method using ratios. Ratios are always a little tricky to interpret. So, I think this is very early in the game.”

And measuring the ratio of 1,25D/24,25D “is quite expensive,” he added.

He also pointed out that “calcium intake is really critical. You can have a [25(OH)D] level of 18 ng/mL and not have any of those secondary changes because [you’re] taking adequate calcium…So, that always is a consideration that has to be worked into the evaluation.”

Same 25(OH)D, Different Risk Level

In their poster, Yazdi and colleagues explain that to assess vitamin D status “one needs to understand regulation of vitamin D metabolism.” 25(OH)D undergoes two alternative fates: 1α-hydroxylation in the kidney, generating 1,25D (the biologically active form) or 24-hydroxylation leading to 24,25D (a biologically inactive metabolite).

For their study, they analyzed pilot data from 11 otherwise healthy individuals who had total baseline plasma 25(OH)D levels < 20 ng/mL, and compared 25(OH)D, 1,25D, 24,25D, and parathyroid hormone before versus after treating them with vitamin D3 supplementation of 50,000 IU per week for 4-6 weeks, aiming for a total 25D level above 30 ng/mL.

They then modeled how the body maintains 1,25D in a normal range and calculated/compared two vitamin D metabolite ratios in vitamin D deficient versus sufficient states: 25(OH)D/1,25D and 1,25D/24,25D. They then evaluated the applicability of these ratios for assessment of vitamin D status.

They explain that suppression of 24-hydroxylase is the first line of defense to maintain 1,25D levels. Secondary hyperparathyroidism is the second line of defense and occurs in severe vitamin D deficiency when the first line is maximally deployed.

Overall, there was poor correlation between 25[OH]D and 1,25D, “consistent with previous evidence that in mild to moderate vitamin D deficiency, 1,25D is maintained in the normal range, and therefore not a useful index for assessing vitamin D status,” the researchers say in their poster.

Hence, they say, the need to add the ratio of 1,25D/24,25D

They present a comparison of two study participants: one with a baseline 25[OH]D of 12.3 ng/mL, the other of 11.7 ng/mL. Although both would therefore be classified as deficient according to current guidelines, their 1,25D/24,25D ratios were 20 and 110, respectively.

In the first participant, the parathyroid hormone response to vitamin D supplementation was negligible, at +5%, compared with a dramatic 34% drop in the second participant.

“We think only the one with very high 1,25D/24,25D [ratio of 110] and a significant drop in parathyroid hormone after vitamin D supplementation [-34%] was vitamin D deficient,” the researchers say.

However, Taylor told Medscape Medical News: “The diagnostic cut-offs we describe should be viewed as tentative for the time being. Additional research will be required to fully validate the optimal diagnostic criteria.”

Yazdi and Rosen have reported no relevant financial relationships. Taylor has reported being a consultant for Ionis Pharmaceuticals.  

ENDO 2023. Presented June 15, 2023.

Miriam E. Tucker is a freelance journalist based in the Washington, DC, area. She is a regular contributor to Medscape, with other work appearing in The Washington Post, NPR’s Shots blog, and Diabetes Forecast magazine. She is on Twitter: @MiriamETucker.

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