Scientific and technical assistance to the evaluation of the safety of calcidiol monohydrate as a novel food.

EFSA was asked by the European Commission to provide scientific assistance with respect to the EFSA adopted scientific opinion on 'Safety of calcidiol monohydrate produced by chemical synthesis as a novel food pursuant to Regulation (EU) 2015/2283', including its bioavailability as a metabolite of vitamin D3 when added for nutritional purposes to food supplements. On 5 July 2023, EFSA adopted the 'Scientific opinion on the tolerable upper intake level for vitamin D, including the derivation of a conversion factor for calcidiol monohydrate'. This opinion concerns an updated exposure assessment for vitamin D and proposes a conversion factor for calcidiol monohydrate into vitamin D3 of 2.5 for labelling purposes. In addition, in reference to the EFSA opinion on the safety of calcidiol monohydrate, the Commission had received a letter from the pharmaceutical company EirGen Pharma Ltd requesting a revision of this opinion based on new data concerning calcidiol. Based on the information and data considered in this scientific technical report, EFSA concludes that the novel food calcidiol monohydrate proposed for use in food supplements is a bioavailable source of the biologically active metabolite of vitamin D, i.e. 1,25-dihydroxyvitamin D, that a conversion factor of 2.5 reflects the relative bioavailability of calcidiol vs vitamin D3 under the proposed conditions of use and use levels, and that it is safe under the proposed conditions of use and use levels, i.e. up to 10 µg/day for children ≥ 11 years old and adults, including pregnant and lactating women, and up to 5 µg/day for children 3-10 years of age.

Scientific opinion on the tolerable upper intake level for vitamin D, including the derivation of a conversion factor for calcidiol monohydrate.

Following two requests from the European Commission (EC), the EFSA Panel on Nutrition, Novel Foods and Food Allergens (NDA) was asked to deliver a scientific opinion on the revision of the tolerable upper intake level (UL) for vitamin D and to propose a conversion factor (CF) for calcidiol monohydrate into vitamin D3 for labelling purposes. Vitamin D refers to ergocalciferol (vitamin D2), cholecalciferol (vitamin D3), and calcidiol monohydrate. Systematic reviews of the literature were conducted to assess the relative bioavailability of calcidiol monohydrate versus vitamin D3 on serum 25(OH)D concentrations, and for priority adverse health effects of excess vitamin D intake, namely persistent hypercalcaemia/hypercalciuria and endpoints related to musculoskeletal health (i.e. falls, bone fractures, bone mass/density and indices thereof). Based on the available evidence, the Panel proposes a CF for calcidiol monohydrates of 2.5 for labelling purposes. Persistent hypercalciuria, which may be an earlier sign of excess vitamin D than persistent hypercalcaemia, is selected as the critical endpoint on which to base the UL for vitamin D. A lowest-observed-adverse-effect-level (LOAEL) of 250 µg/day is identified from two randomised controlled trials in humans, to which an uncertainty factor of 2.5 is applied to account for the absence of a no-observed-adverse-effect-level (NOAEL). A UL of 100 µg vitamin D equivalents (VDE)/day is established for adults (including pregnant and lactating women) and for adolescents aged 11-17 years, as there is no reason to believe that adolescents in the phase of rapid bone formation and growth have a lower tolerance for vitamin D compared to adults. For children aged 1-10 years, a UL of 50 µg VDE/day is established by considering their smaller body size. Based on available intake data, European populations are unlikely to exceed the UL, except for regular users of food supplements containing high doses of vitamin D.

Benefits of Vitamin D in Health and Diseases.

This Special Issue of Nutrients, titled "Benefits of Vitamin D in health and diseases", includes a total of twenty-five publications that consider different aspects of vitamin D, both at the cellular/preclinical and clinical levels, in neonates or children, in pregnant women, in adults and in elderly subjects [...].

The Potential Impact of Inducing a Restriction in Reimbursement Criteria on Vitamin D Supplementation in Osteoporotic Patients with or without Fractures.

In October 2019, the Italian Drug Agency (AIFA) restricted reimbursement criteria for vitamin D (VD) use outside the osteoporosis setting (Note 96). However, whether this restriction could also have involved patients at risk for or with osteoporotic fractures has not yet been investigated. We retrospectively analyzed databases from five Italian Local Health Units. Patients aged ≥50 years with either at least one prescription for osteoporosis treatment or with fragility fractures and evidence of osteoporosis from 2011 to 2020 were included. The proportion of subjects with an interruption in VD treatment before and after the introduction of the new reimbursement criteria and predictors of this interruption were analyzed. A total of 94,505 patients (aged 69.4 years) were included. Following the introduction of Note 96, a 2-fold (OR 1.98, 95% CI: 1.92-2.04) increased risk of VD discontinuation was observed. These findings were independent of seasonal variation, osteoporosis treatment patterns, as well as other confounding variables. However, a higher rate of interruption was observed in patients without vertebral/femur fracture (37.8%) vs. those with fracture (32.9%). Rheumatoid arthritis, dyslipidemia and previous fracture were associated with a lower risk of VD interruption, while stroke increased the risk of VD interruption. Our results highlight that a possible misinterpretation of newly introduced criteria for reimbursement restrictions in VD outside of osteoporosis have resulted in an inadequate level of VD supplementation in patients with osteoporosis. This undertreatment could reduce the effect of osteoporosis therapies leading to increased risk of negative outcome.

Effectiveness of In-Hospital Cholecalciferol Use on Clinical Outcomes in Comorbid COVID-19 Patients: A Hypothesis-Generating Study.

Little information is available on the beneficial effects of cholecalciferol treatment in comorbid patients hospitalized for COVID-19. The aim of this study was to retrospectively examine the clinical outcome of patients receiving in-hospital high-dose bolus cholecalciferol. Patients with a positive diagnosis of SARS-CoV-2 and overt COVID-19, hospitalized from 15 March to 20 April 2020, were considered. Based on clinical characteristics, they were supplemented (or not) with 400,000 IU bolus oral cholecalciferol (200,000 IU administered in two consecutive days) and the composite outcome (transfer to intensive care unit; ICU and/or death) was recorded. Ninety-one patients (aged 74 ± 13 years) with COVID-19 were included in this retrospective study. Fifty (54.9%) patients presented with two or more comorbid diseases. Based on the decision of the referring physician, 36 (39.6%) patients were treated with vitamin D. Receiver operating characteristic curve analysis revealed a significant predictive power of the four variables: (a) low (<50 nmol/L) 25(OH) vitamin D levels, (b) current cigarette smoking, (c) elevated D-dimer levels (d) and the presence of comorbid diseases, to explain the decision to administer vitamin D (area under the curve = 0.77, 95% CI: 0.67-0.87, p < 0.0001). Over the follow-up period (14 ± 10 days), 27 (29.7%) patients were transferred to the ICU and 22 (24.2%) died (16 prior to ICU and six in ICU). Overall, 43 (47.3%) patients experienced the combined endpoint of transfer to ICU and/or death. Logistic regression analyses revealed that the comorbidity burden significantly modified the effect of vitamin D treatment on the study outcome, both in crude (p = 0.033) and propensity score-adjusted analyses (p = 0.039), so the positive effect of high-dose cholecalciferol on the combined endpoint was significantly amplified with increasing comorbidity burden. This hypothesis-generating study warrants the formal evaluation (i.e., clinical trial) of the potential benefit that cholecalciferol can offer in these comorbid COVID-19 patients.

Calcium intake from different food sources in Italian women without and with non-previously diagnosed osteoporosis.

An adequate calcium and vitamin D intake may play a role in preventing osteoporosis, but the contribution of the different food sources of calcium with regards to the risk of osteoporosis been barely explored. This observational study evaluated the calcium intake through a food frequency questionnaire in 126 adult women with not previously diagnosed osteoporosis undergoing Dual-energy X-ray Absorptiometry (DXA) to screen for osteoporosis, and to correlate the calcium intake with parameters of bone density, measured by DXA. Total daily calcium intake and daily intake from food were similar among women found to have osteoporosis, osteopenia or normal condition. The main food source was milk and dairy products, while calcium supplementation was consumed by only 14% of subjects, irrespectively from osteoporosis conditions. DXA parameters were not significantly correlated with total daily calcium intake and calcium from food. The present study highlighted no qualitative and quantitative differences in the consumption of food groups contributing to calcium intakes in women with and without osteoporosis.

Claimed Effects, Outcome Variables and Methods of Measurement for Health Claims on Foods Related to Vision Proposed Under Regulation (EC) 1924/2006.

Adequate visual function has a strong impact on the quality of life of people. Several foods and food components have been hypothesized to play a role in the maintenance of normal visual function and in the prevention of eye diseases. Some of these foods/food components have been the object of a request of authorization for use of health claims under Articles 13(5) or 14 of the Regulation (EC) 1924/2006. Most of these requests have received a negative opinion from the European Food Safety Authority (EFSA) due to the choice of inappropriate outcome variables (OVs) and/or methods of measurement (MMs) applied in the studies used to substantiate the claims. This manuscript refers to the collection, collation and critical analysis of OVs and MMs related to vision. Guidance document and requests for authorization of health claims were used to collect OVs and MMs related to vision. A literature review was performed to critically analyse OVs and MMs, with the aim of defining their appropriateness in the context of a specific claimed effect related to vision. The results highlight the importance of adequate choices of OVs and MMs for an effective substantiation of claims related to visual function.

Claimed effects, outcome variables and methods of measurement for health claims on foods related to the gastrointestinal tract proposed under regulation (EC) 1924/2006.

Most of the requests of authorisation to the use of health claims pursuant to Regulation EC 1924/2006 related to the gastrointestinal (GI) tract have received a negative opinion by the European Food Safety Authority (EFSA), mainly because of an insufficient substantiation of the claimed effect (CE). The present manuscript refers to the collection, collation and critical analysis of outcome variables (OVs) and methods of measurement (MMs) related to the GI tract compliant with Regulation 1924/2006. The critical evaluation of OVs and MMs was based on the literature review, with the final aim of defining their appropriateness in the context of a specific CE. The results obtained are relevant for the choice of the best OVs and MMs to be used in randomised controlled trials aimed to substantiate the claims on the GI tract. Moreover, the results can be used by EFSA for updating the guidance for the scientific requirements of such health claims.

Claimed Effects, Outcome Variables and Methods of Measurement for Health Claims Proposed Under European Community Regulation 1924/2006 in the Framework of Maintenance of Skin Function.

Evidence suggests a protective role for several nutrients and foods in the maintenance of skin function. Nevertheless, all the requests for authorization to use health claims under Article 13(5) in the framework of maintenance of skin function presented to the European Food Safety Authority (EFSA) have received a negative opinion. Reasons for such failures are mainly due to an insufficient substantiation of the claimed effects, including the choice of inappropriate outcome variables (OVs) and methods of measurement (MMs). The present paper reports the results of an investigation aimed at collecting, collating and critically analyzing the information with relation to claimed effects (CEs), OVs and MMs related to skin health compliance with Regulation 1924/2006. CEs, OVs and MMs were collected from both the EFSA Guidance document and from the authorization requests of health claims under Article 13(5). The critical analysis of OVs and MMs was based on a literature review, and was aimed at defining their appropriateness (alone or in combination with others) in the context of a specific CE. The results highlight the importance of an adequate choice of OVs and MMs for an effective substantiation of the claims.

Calcium metabolism and vitamin D in the extreme longevity.

Skeletal remodelling is a continuous process during life and is still active also in extreme senescence. In the elderly, bone resorption often prevails over bone formation, causing bone loss and fragility. Elderly subjects are exposed to the risk of fractures, and loss of self-sufficiency, if considering that the proximal femur is the most frequently involved site. Bone remodelling can maintain circulating calcium within physiological ranges, at the expense of a substantial loss of this ion from the skeleton, particularly during senescence. Calcium metabolism is regulated at cellular/molecular level by a network of cytokines, growth factors, systemic hormones that act on bone in paracrine/autocrine/systemic fashion. Among the molecules involved in bone metabolism, parathyroid hormone (PTH) and vitamin D present some peculiar aspects during senescence. The osteometabolic features in a consistent group of centenarians have been evaluated. It results that a severe hypovitaminosis D was present in 99 out of 104 centenarians (25-OH vitamin D below 5 nmol/L), and that it plays an important role as a factor inducing a vicious circle involving hypocalcemia, secondary hyperparathyroidism, together with biochemical features indicating a consistent bone loss. Serum C-terminal cross-linking telopeptide, a specific marker of bone resorption was elevated in 92% of these subjects. Moreover, it has been found that several femoral fractures had occurred after 90 years of age. These data offer a rational for the possible prevention of elevated bone turnover, bone loss and consequently the reduction of osteoporotic fractures and fractures-induced disability, in the oldest olds, through the simple supplementation with calcium and vitamin D.

Low vitamin D status, high bone turnover, and bone fractures in centenarians.

The oldest olds, including centenarians, are increasing worldwide and, in the near future, will represent a consistent part of the population. We have studied bone status and metabolism in 104 subjects over 98 yr of age to evaluate possible interventions able to avoid fragility fractures and disability. Ninety females and 14 males not affected by any acute disease were considered. After a complete clinical assessment, blood was drawn for evaluating bone turnover markers, and performance tests together with skeletal ultrasonography (either at the phalanges or at the heel) were performed. We found that 38 subjects had sustained a total of 55 fractures throughout their lives, and 75% of these were fragility fractures. Twenty-eight fractures occurred at the proximal femur, with 14 after the age of 94 yr. Serum 25-hydroxyvitamin D was undetectable in 99 of 104 centenarians. PTH and serum C-terminal fragment of collagen type I were elevated in 64 and 90% of centenarians, respectively, with a trend toward hypocalcemia. Bone alkaline phosphatase levels were close to the upper limit. Serum IL-6 was elevated in 81% of centenarians and was positively correlated with PTH and negatively correlated with serum calcium. Serum creatinine was not correlated with PTH. Bone ultrasonography showed that most centenarians had low values, and ultrasonographic parameters were correlated with resorption markers. We conclude that the extreme decades of life are characterized by a pathophysiological sequence of events linking vitamin D deficiency, low serum calcium, and secondary hyperparathyroidism with an increase in bone resorption and severe osteopenia. These data offer a rationale for the possible prevention of elevated bone turnover, bone loss, and consequently the reduction of osteoporotic fractures and fracture-induced disability in the oldest olds through the supplementation with calcium and vitamin D.