Etienne Cavalier

Vitamin D and musculoskeletal health, cardiovascular disease, autoimmunity and cancer: Recommendations for clinical practice

BACKGROUNDnThere is increasing evidence that, in addition to the well-known effects on musculoskeletal health, vitamin D status may be related to a number of non-skeletal diseases. An international expert panel formulated recommendations on vitamin D for clinical practice, taking into consideration the best evidence available based on published literature today. In addition, where data were limited to smaller clinical trials or epidemiologic studies, the panel made expert-opinion based recommendations.nnnMETHODSnTwenty-five experts from various disciplines (classical clinical applications, cardiology, autoimmunity, and cancer) established draft recommendations during a 2-day meeting. Thereafter, representatives of all disciplines refined the recommendations and related texts, subsequently reviewed by all panelists. For all recommendations, panelists expressed the extent of agreement using a 5-point scale.nnnRESULTS AND CONCLUSIONnRecommendations were restricted to clinical practice and concern adult patients with or at risk for fractures, falls, cardiovascular or autoimmune diseases, and cancer. The panel reached substantial agreement about the need for vitamin D supplementation in specific groups of patients in these clinical areas and the need for assessing their 25-hydroxyvitamin D (25(OH)D) serum levels for optimal clinical care. A target range of at least 30 to 40 ng/mL was recommended. As response to treatment varies by environmental factors and starting levels of 25(OH)D, testing may be warranted after at least 3 months of supplementation. An assay measuring both 25(OH)D(2) and 25(OH)D(3) is recommended. Dark-skinned or veiled individuals not exposed much to the sun, elderly and institutionalized individuals may be supplemented (800 IU/day) without baseline testing.

Vitamin D: current status and perspectives.

Abstract The role of vitamin D in maintaining bone health has been known for decades. Recently, however, the discovery that many tissues expressed the vitamin D receptor and were able to transform the 25-OH vitamin D into its most active metabolite, 1,25-(OH)2 vitamin D, has led to a very promising future for this “old” molecule. Indeed, observational studies, and more and more interventional studies, are raising the importance of a significant vitamin D supplementation for not-only skeletal benefits. Among them, 25-OH vitamin D has been found to play an important role in prevention of cancers, auto-immune diseases, cardiovascular diseases, diabetes, and infections. Vitamin D deficiency, defined as serum 25-OH vitamin D levels <30 ng/mL, is very common in our population. The cost/benefit ratio and some recently published studies are clearly now in favor of a controlled and efficient vitamin D supplementation in these patients presenting a 25-OH vitamin D level <30 ng/mL. More attention should also be focused on pregnant and lactating women, as well as children and adolescents. Clin Chem Lab Med 2009;47:120–7.

Measurement uncertainty of 25-OH vitamin D determination with different commercially available kits: impact on the clinical cut offs

SummaryDue to “measurement uncertainty”, the “true” 25-OH vitamin D (25(OH)D) of a patient (whatever the commercially available assay tested) will be >80xa0nmol/L if its measured concentration is >100xa0nmol/L. Thus, if a physician considers that a normal VTD status is a 25(OH)D level ≥80xa0nmol/L, he should ensure that the patient’s results are ≥100xa0nmol/L.IntroductionMany experts recommend that serum levels of 25(OH)D should be above a lower normal limit of 75–80xa0nmol/L. However, the value delivered by laboratories is only an estimation of the “true” value due to “measurement uncertainty.” When using a cut off, measurement uncertainty around the cut off is important because therapeutic actions may differ if the measured value is below or above the limit. We aimed to establish the “measurement uncertainty” at different levels of concentration for several commercially available 25(OH)D analytical techniques.MethodsWe constituted three pools of serum with different 25(OH)D concentrations. Each pool was assayed in triplicate during 5xa0days with the DiaSorin RIA, Liaison, Elecsys, and Chromsystems-HPLC assays.ResultsWe report a relatively high “measurement uncertainty” for the measurement of 25(OH)D for the four different techniques: the mean relative uncertainties, all techniques confounded were 19.4%, 16.0%, and 11.3% for pool 1 (35.3xa0nmol/L), pool 2 (79.5xa0nmol/L), and pool 3 (126.1xa0nmol/L), respectively.ConclusionsOur results show that, whatever the assay, the “true” 25(OH)D of a patient will be >80xa0nmol/L if its measured concentration is >100xa0nmol/L. In other words, if a physician considers that a normal VTD status is defined by a 25(OH)D level ≥80xa0nmol/L, he should ensure that the patients present a 25(OH)D ≥100xa0nmol/L.

Serum vitamin D measurement may not reflect what you give to your patients.

The recognized index of vitamin D (VTD) status is the measurement of circulating concentrations of 25-OH VTD (25VTD). A concentration of 30 ng/ml 25VTD (75 nM) is considered by many experts as the minimum optimal concentration. There is currently a growing interest in VTD far beyond bone and calcium metabolism, including cancer, immunology, and hypertension, which has caused a recent upsurge in requests for 25VTD evaluation, necessitating the need for accurate measurement. We report here the case of a 60-yr-old woman diagnosed as having VTD deficiency (serum 25VTD measured with the automated Roche Elecsys method at 12 ng/ml). She was given a single 600,000U VTD2 oral dose. Because serum 25VTD measured with the same assay 2 wk later was still low (11 ng/ml), she was referred to our unit for extensive laboratory testing. All biochemical parameters were normal, including 25VTD (50 ng/ml), but this time the Diasorin radioimmunoassay (RIA) was used to quantify 25VTD. To study the cause for these discrepant results further, we conducted measurements of 25VTD by a specific liquid chromatography-mass spectrometry (LC/MS/MS) method. The LC/MS/MS method separates and quantifies 25hydroxylated metabolites of both VTD2 and VTD3, which are summed to get the total 25VTD concentration. The LC/MS/MS is considered by many as the candidate reference method for 25(OH)D measurement, although drawbacks because of the recognition of other compounds such as epimers have been highlighted, especially in pediatric subjects. In addition to the index case, all three methods were used to measure 25VTD in serum collected from 11 healthy subjects (5 men and 6 women; age, 21–62 yr) before (D0) and 7 and 28 days after a single 600,000U VTD2 dose to mimic the above-mentioned case. Pooling the results from the three time-points, we found that the LC/MS/MS results were highly correlated with the RIA values (Spearman’s 0.94; p < 0.0001) but not with the Elecsys values ( 0.16; not significant). On day 0, the mean concentration [SD] was similar with the three assays (Diasorin RIA: 29.3 [6.8] ng/ml; Roche Elecsys: 30.2 [6.0] ng/ml; LC/MS/MS: 27.8 [6.0] ng/liter). At day 7, 25VTD increased similarly when measured by the Diasorin RIA and LC/MS/MS assays (77.5 [22.2] and 78.4 [22.8] ng/ml, respectively) but decreased (to 27.4 [5.4] ng/ ml) with the Roche Elecsys assay. All subjects had a 25VTD concentration >30 ng/ml with LC/MS/MS and the Diasorin RIA, whereas this was the case in only two of them with the Elecsys. At day 28, 25VTD remained >30 ng/ml in all subjects when measurements were conducted by Diasorin RIA (52.0 [20.3] ng/ml) and LC/MS/MS (52.8 [8.5] ng/ml), whereas it was <30 ng/ml (21.4 [4.9] ng/ml) in all subjects with the Elecsys assay (Fig. 1). The LC/MS/MS data confirmed that the increases observed were solely caused by an increase in the 25VTD2 metabolite. The supplementation with 600,000 IU of VTD2 did not produce a significant rise in calcium and phosphorus levels (2.35, 2.35, and 2.39 mM, respectively, for day 0, 7, and 28 median calcium levels and 1.07, 1.05, and 1.06 mM, respectively, for phosphorus concentrations at the same times). We did not observe any significant variation in parathormone levels (41 versus 44 pg/ml before and after 28 days, respectively). Whereas skin exposure to UVB produces VTD3 and the food sources of VTD are mainly VTD3, supplementation is still often made with VTD2, especially in the United States. Several experts recommend exclusive use of VTD3, (7) because it has been reported that VTD3 maintains an adequate 25VTD concentration for a longer period than VTD2. (8) This recommendation has been recently challenged, and the choice of the best vitamin D supplement requires further study. Thus, as long as VTD2 is available (and prescribed), it is mandatory to measure 25VTD with a method that recognizes both 25VTD2 and 25VTD3. This is the situation if LC/MS/MS or the Diasorin RIA is used, whereas the Roche Elecsys assay exclusively measures 25VTD3. The case briefly described above shows that measuring 25VTD with an assay exclusively specific for 25VTD3, such as the Roche Elecsys assay, underestimates VTD status in patients supplemented with VTD2. This can potentially cause overtreatment, leading to further expensive and stressful studies. The authors state that they have no conflicts of interest.