new vit d guidelines

 

 

 

The Endocrine Society just published new guidelines on vitamin D assessment and treatment for the general population of adults, basically negating the need to perform vitamin D monitoring or therapy (see vit d endocrine soc guidelines2024 in dropbox, or doi.org/10.1210/clinem/dgae322). This document was actually written at a “guideline communication” by the Endocrine Society’s Guideline Development Panel. quotes below are from the guidelines or the more extensive systematic reviews published to support their findings

 

Details/Commentary:

-- the new guidelines suggest the following major changes to their prior guidelines of 2011:

    -- they no longer endorse the concept of vitamin D “sufficiency”, previously defined as 25(OH)D levels at least 30 ng/mL, nor vitamin D “insufficiency” as being a 25(OH)D levels of 20-30 ng/mL, nor vitamin D “deficiency” as being a 25(OH)D <20 ng/mL, for the following reasons:

        -- this concept of vitamin D tiers is based on using surrogate markers (e.g. parathyroid hormone levels being inversely associated with 25(OH)D levels), as opposed to the actual clinical outcomes of fractures and falls. They also are concerned about the utility of other surrogate markers, including fractional intestinal calcium absorption, bone mineral content and bone mineral density, histopathologic assessment of osteomalacia, risk of nutritional rickets, and fracture risk.

            -- they further comment that patients are not interested in the surrogate markers because low bone density does not cause symptoms, neither does reduced intestinal calcium absorption nor high PTH levels, and that patients are generally interested in the actual clinical outcomes [to me, this is a pretty weird statement since patients do seem to accept the importance trying to get their hemoglobin A1c levels in range, use of PSA as a marker of increased prostate cancer risk, etc. And, patients do seem to accept that increased risk of fragility fractures is a reasonable criterion for taking bisphosphonates]

        -- the Institute of Medicine (IOM, now the National Academy of Medicine) estimated that 25(OH)D concentrations of 16 and 20 ng/mL would meet bone health needs in about 50% and 97.5% of the population, respectively. And that 25(OH)D >50 ng/mL may be associated with unacceptably increased adverse event risks [I could not find the references for these numbers, and the commonly held understanding is that vitamin D toxicity is when levels of 25(OH)D levels are >150 ng/mL, a level very difficult to achieve on standard vitamin D therapy.  Of course, some people may get higher calcium levels on vitamin D supplementation, and it is reasonable to check serum calcium levels after initiating vitamin D replacement therapy just to be sure]

        -- if one goes by the IOM criteria, one would need to do testing and treating for 25(OH)D >20 ng/mL for only 2.5% of the generally healthy population, leading to unnecessarily screening, providing unnecessary vitamin D supplementation, and doing unnecessary 25(OH)D monitoring "for the vast majority". Though I would argue that the incidence of vitamin D deficiency is clearly related to one's geography: much more common in Boston or regions more northerly than in the southern regions of the US, related to the adequacy of UV light exposure (ie, an average for the "majority" of people is a pretty useless concept since it would actually not represent the actual wide variability within the larger group); the goal of primary prevention is to take into account the actual risk of individuals and stratify interventions based on the different risks that these individuals have. And the majority of the generally healthy people in northern climates do not have adequate vitamin D levels as per the IOM comment above (over the past several decades, I have routinely checked serum 25(OH)D levels in all of my hundreds of patients in the relatively sun-deprived Boston, only about 10% have “sufficient” levels of >30 ng/mL, about 30-40% have levels between 20-30 ng/mL, about 30-40% have levels under 20 ng/mL and about 5-10% have undetectable levels), and I also recheck levels as needed to make sure the patients are taking the supplement (medication adherence overall is quite low, especially for non-symptomatic conditions)

        -- there are concerns that prior studies on bone health associated with 25(OH)D levels may have been falsely attributed to vitamin D and that other issues such as calcium intake and general nutrition status may have played a significant role in some of the outcomes assessed

        -- there are issues with the consistency of laboratories in defining the ”optimal” 25(OH)D levels

    -- they also feel that clinical trial evidence to date does not clearly support routine vitamin D supplementation beyond the RDA (recommended dietary allowance) for adults younger than 50, independent of baseline 25(OH)D levels

       -- the RDA for vitamin D is 600 IU daily until age 70, and 800 IU daily for people 70 or older

    -- for pregnant women, there should be empirical vitamin D supplementation without regard to baseline 25(OH)D levels (https://gmodestmedblogs.blogspot.com/2018/06/vitamin-d-supplementation-in-pregnancy.html reviews data showing the importance of vitamin D in reducing the risk for small-for-gestational age infants)

    -- these 2024 guidelines were based on randomized controlled trials to assess data on subgroups with low 25(OH)D concentrations. There did seem to be a small but important mortality benefit in those over 75 years old with vitamin D supplementation when the 25(OH)D levels were below 20-24 ng/mL (relative risk, 0.96 (0.93–1.00) in a meta-analysis), however there was no evident benefit from studies assessing fracture risk, cardiovascular disease, MI, stroke, cancer, nephrolithiasis, renal disease or failure, or respiratory tract infections. The panel did recommend empirical vitamin D supplementation in those at least 75 years and older, beyond the vitamin D intake suggested in the RDA

        -- although the vast majority of these recommendations rely on the role of vitamin D in bone health, they do comment that, based on the IOM 2011 report, there was insufficient evidence for vitamin D intake for the other potential vitamin D related issues including cancer, cardiovascular disease, falls, and infections.

 

-- of note, the guideline authors do note that “a limitation of this systematic review is the frequent absence of baseline and postsupplementation 25(OH)D levels in many included studies. In those trials that did report baseline 25(OH)D levels, most were in ranges considered sufficient for many outcomes” [ie, there was minimal information showing that vitamin D supplementation was not important, since the studies often compared cohorts both of which were in the vitamin D "sufficient" range, or did not include essential information on the baseline serum vitamin D levels]

-- the guidelines then proceed to comment that since the “available clinical trial evidence did not clearly indicate 25(OH)D thresholds that specifically predict net benefit with vitamin D supplementation beyond the IOM-determined RDAs”, then there is no benefit “specifically predicted by 25(OH)D concentrations  below 20 to 24 ng/ml” (ie, per their own admission, the “available evidence is incomplete” and not does necessarily prove ineffectiveness of assessing vitamin D levels and providing supplementation when low: see vit d guidelines systematic review JClinEndo2024 in dropbox or https://doi.org/10.1210/clinem/dgae312)

       -- so, their conclusion was that baseline screening of 25(OH)D levels and 25(OH)D monitoring “might be unnecessary” (ie, not that it is unnecessary)

-- so, they openly admit that the studies are quite lacking in actually testing whether vitamin D supplementation is beneficial or not, whether there should be a tiered-approach to treating vitamin D levels at a certain serum 25(OD)D level, and they equivocate in the document on their suggestions (though they “nevertheless”, per their abstract, support the changes noted)

 

-- the study formally referenced in detail in their document is the VITAL study (VITamin and OmegA-3 TriaL):

    -- the VITAL study assessed fracture risk, feeling that this is the most likely benefit from vitamin D supplementation. Of note the VITAL study did also assess the effects of either vitamin D supplementation or n-3 fatty acids on both cardiovascular and cancer outcomes by giving 2000 international units of vitamin D3, a dose which is expected to raise the 25(OH)D level to 40 ng/mL  But a few comments about the VITAL trial:

    -- this guideline itself noted that the overall population in the VITAL study was at “low risk for incident fractures”, and stratification found that the subgroups with low 25(OH)D levels were very small in the study

    -- the median followup of 5.2 years “may not have been long enough to identify important long-term differences” with therapy, as they also noted

    -- calcium supplementation of up to 1200 mg per day was allowed and taken by 20% of the study participants: calcium was not either required or standardized, which is important because calcium is necessary for the skeletal effects of vitamin D; also all participants (including the placebo group) were allowed to take up to 800IU of vitamin D daily, as was done by 43% of them.  all of this muddies the waters...

 

In my critique of the VITAL trial (https://gmodestmedblogs.blogspot.com/2022/08/vitamin-d-supplement-not-decrease.html ), i make the following points:

    -- this study does not answer the really basic question:  does vitamin D supplementation at an early age in those vitamin D deficient and continued for decades prevent bone demineralization and clinical outcomes of fracture risk? And does it have any utility for preventing other potential vitamin D-deficient concerns (cancer, multiple sclerosis, heart disease, immunologic dysfunction…..)?

    -- many of these potential vitamin D-deficient problems begin early in life (eg bone demineralization in women begins in their 30s), and, once established, are incompletely treated by later interventions. the issue with bones seems to be similar to that in cardiovascular disease: statins do work for secondary prevention of heart disease, with relative risk reductions for cardiovascular events of about 30%, similar to those found in primary prevention. BUT those in the secondary prevention group who already have heart disease have a much higher absolute risk of further cardiovascular disease outcomes. Similarly, once one has significant bone demineralization or fragility fractures, patients are still at higher risk of future problems with medications than if their bones were "normal"

        -- ie, preventing disease, a usual primary care imperative, does make sense: ie, identify problems early and provide preventative measures (both nonpharmacologic and pharmacologic)

    -- vitamin D receptors are present throughout the body, on pretty much every cell including the diverse components of the immunologic system (and, there is good laboratory evidence that vitamin D plays an important role in immune system function: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3166406/)

        -- per https://nyaspubs.onlinelibrary.wiley.com/doi/10.1111/nyas.13219: "The vitamin D receptor (VDR) is found in nearly all, if not all, cells in the body. The enzyme that produces the active metabolite of vitamin D and ligand for VDR, namely CYP27B1, likewise is widely expressed in many cells of the body", though not on red blood cells and a few others

    -- since these vitamin D receptors are so generally present, it raises the question of whether we actually know all of the functions of vitamin D in the body, and whether low vitamin D levels might be responsible for preventing important adverse effects that we are just unaware of. Perhaps some of these potential adverse effects are more evident in small groups of patients (eg with some minor immunologic deficiency) that might not be apparent in the majority of patients so might not be found in big studies???

    -- vitamin D supplementation is cheap, easy, and basically without significant adverse effects   

    -- so a short-term study as the VITAL trial in people 67yo who are healthy but who have likely already lost a lot of bone mineralization by that age, with the vast majority of patients having pretty appropriate baseline vitamin D levels, and assessing outcomes only on bones (in this substudy of VITAL) does not really answer the question about vitamin D supplement utility…

 

-- the above recommendations are for the general population and not specific individuals at higher risk of low vitamin D levels (e.g., by malabsorption, short gut syndrome, gastric bypass, inflammatory bowel disease, nephrotic syndrome, chronic kidney disease, other disorders of calcium metabolism, meds that interfere with vitamin D such as phenytoin which increases vitamin D breakdown): https://doi.org/10.1210/clinem/dgae290 . It is curious that vitamin D levels seem to matter for these individuals in the guidelines, but not for the general population:

    -- one could argue that living in Boston or further north is also a strong predictor of low vitamin D levels and should be considered to be "at higher risk"

    -- or being older, having darker pigmented skin, being obese also lead to lower vitamin D synthesis and lower vitamin D levels

    -- and the guidelines do promote eating foods with high vitamin D levels, though not supplements.

        -- All of this is basically contradicts their nihilist approach to diagnosing and treating vitamin D deficiency, since the only way to know if enough high vitamin D foods are consumed or there is sufficient exposure to UV light is to check a 25(OH)D level….. And treating it if it is low…

 

So, what is one to make of this new guideline communication:

-- the presupposition of this committee is: if it is not clearly beneficial, then don’t do it

    -- this is certainly reasonable for many medical interventions, especially those that are potentially dangerous, would not have clear benefit pathophysiologically, are very expensive, require long term followup to uncover potentially serious consequence, etc

    -- in fact, we in clinical practice regularly do apply nongeneralizable information from even well-done randomized clinical trials to our patients: most cardiovascular studies exclude our patients with chronic kidney disease (https://gmodestmedblogs.blogspot.com/2024/06/cardiovasc-trials-patients-with-ckd.html ). Most studies exclude elderly patients (ie, “how does the study’s result apply directly to the 95 year old Latina woman in front of me???”). Yet we decide to use the results of the study for these patients despite the dearth of unequivocal information (ie, much of what we do is not really evidence-based, despite these well-done studies)

-- but the issue with vitamin D is that it is physiologically necessary, cheap, has minimal adverse effects in all of the studies, has evolutionarily survived with receptors all over the body (almost all cells in the body, immune cells included), these vitamin D receptors might well have evolutionarily devolved if vitamin D played no role in health (the “thrifty gene” hypothesis), and there are no good long-term studies of vitamin D supplementation that could assess well both the bone and non-bone benefits (the recommendations from the Endocrine Society above freely admits that the studies are insufficient on vitamin D supplementation)

-- and if vitamin D supplementation is a reasonable intervention, that reinforces the importance of testing 25(OH)D levels initially

-- So, all of this supports checking and treating low 25(OH)D levels in people at high risk, be it by medical conditions or social situations (access to adequate UV light and exposing enough skin to that light to be adequate).  For example, my index patient was a 60 year old patient I saw many decades ago who, on my advice for his heart condition, would walk about 8 miles a day (exceeding my actual advice...) who on 25(OH)D testing had a level <10 ng/mL in the middle of the summer in Boston. Then I saw him walking on one of my trips to see inpatients at a local hospital and noticed he wore a hat, long sleeve shirt, long pants, and had essentially no exposed skin…. So, I do test all of my patients.

        -- And, by the way, the observational studies on some potential vitamin D-related problems (eg cancer) have suggested that a higher 25(OH)D level seems to be associated with lower cancer risk (the studies on vitamin D and cancer are mixed, though vitamin D does seem to have immune-modulatory effects and may decrease inflammation as mechanisms to decrease cancer incidence (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6201256/ ). The point here is that the optimal level of 25(OH)D levels may be different for bone vs other non-bone outcomes.

geoff

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