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Vitamin D in the older population: a consensus statement.
Giustina, A, Bouillon, R, Dawson-Hughes, B, Ebeling, PR, Lazaretti-Castro, M, Lips, P, Marcocci, C, Bilezikian, JP
Endocrine. 2023;(1):31-44
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Abstract
BACKGROUND This paper reports results from the 5th International Conference "Controversies in Vitamin D" that was held in Stresa, Italy, 15-18 September 2021. The conference is part of this series that started in 2017 and has been conducted annually since. The objective of these conferences is to identify timely and controversial topics related to Vitamin D. Dissemination of the results of the conference through publications in peer-reviewed journals is an important means by which the most up to date information can be shared with physicians, investigators, and other health care professionals. Vitamin D and aging, the subject of this paper was featured at the conference. METHODS Participants were selected to review available literature on assigned topics related to vitamin D and aging and to present their findings with illustrative material, the intent of which was to stimulate discussion and to arrive at a consensus. The presentations were directed towards the following areas: impact of aging on vitamin D production and levels; skeletal effects of vitamin D deficiency in the older population; falls and vitamin D in the aging; potential extra skeletal effects of vitamin D; and strategies to prevent vitamin D deficiency. A final topic was related to how vitamin D might influence the efficacy of vaccines for Covid-19. RESULTS Hypovitaminosis D can lead to several skeletal and extra-skeletal outcomes. Older adults are at risk for vitamin D deficiency as both production and metabolism of vitamin D change with aging due to factors, such as reduced sun exposure and reduced production capacity of the skin. Skeletal consequences of these age-related changes can include reduced bone mineral density, osteomalacia and fractures. Potential extra-skeletal effects can include added risks for falls, reduced muscle strength, diabetes, cancer, and cardiovascular disease. Strategies to avoid these vitamin D deficiency-related negative outcomes include sun exposure, food fortification, and supplementation. While aging does not diminish sufficient reserve capacity for cutaneous vitamin D production, concerns about skin cancers and practical matters for the institutionalized elderly limit this option. Supplementation with vitamin D is the best option either pharmacologically or through food fortification. Regardless of treatment strategies, interventions to restore sufficient vitamin D status will show positive results only in those who are truly deficient. Thus, treatment goals should focus on avoiding 25(OH)D serum levels <30 nmol/l, with a goal to reach levels >50 nmol/l. CONCLUSIONS The results of this conference has led to consensus on several issues. Vitamin D supplementation should be combined with calcium to reduce fractures in the older population. The goal for adequate Vitamin D status should be to reach a serum level of 25(OH)D >50 nmol/l. It appears that daily low-dose vitamin D regimens reduce the risk of falling, especially in the elderly, compared with infrequent, large bolus doses that may increase it. The role of Vitamin D supplementation on muscle strength remains to be clarified. On the other hand, supplementation decreases the risk of progression to T2D from prediabetes among those who are Vitamin Ddeficient. Of three possible strategies to establish vitamin D sufficiency - sunshine exposure, food fortification, and supplementation - the latter seems to be the most effective and practical in the aging population.
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Clinical aspects of SARS-CoV-2 infection and vitamin D : COVID-19 and the endocrine system: special issue for reviews in endocrine and metabolic disorders (Felipe Casaneuva, Editor in Chief) A. Giustina and JP Bilezikian, Guest Editors.
Bandeira, L, Lazaretti-Castro, M, Binkley, N
Reviews in endocrine & metabolic disorders. 2022;(2):287-291
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Abstract
In December 2019, the first cases of severe acute respiratory syndrome due to a new coronavirus (SARS-Cov-2), later designated as Covid-19, were described in China. With rapid advance of the infection to several continents, in March 2020, WHO declared this to be a pandemic. In April 2020, the first papers suggesting a possible role of Vitamin D deficiency in the severity of this infection began to appear and dozens of articles evaluating a potential relationship of vitamin D with COVID have emerged subsequntly. This possibility was raised based on pre-existing evidence of the effects of Vitamin D on the immune system, and more specifically on acute respiratory viral infections. In addition, most Covid-19 victims belong to groups at risk for vitamin D deficiency such as the elderly, obese, chronically ill, and specific ethnic groups. Although with some contradictory reports exist, most observational and cohort studies find a relationship of low vitamin D status with greater Covid severity, others, including the few interventional studies available show inconsistent results. This paper aims to present the rapidly expanding literature to date regarding the clinical relevance of vitamin D in Covid-19 and, consequently, the reasonableness of avoiding its deficiency to keep the immune system able to respond in the best way to this acute viral infection. In the meantime, we wait for publication of several prospective randomized controlled studies that are underway, evaluating the effects of treatment with vitamin D or metabolites on the severity of Covid-19 outcomes.
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Vitamin D metabolism and extraskeletal outcomes: an update.
Silva, ICJ, Lazaretti-Castro, M
Archives of endocrinology and metabolism. 2022;(5):748-755
Abstract
Vitamin D deficiency is a general health problem affecting individuals at all stages of life and on different continents. The musculoskeletal effects of vitamin D are well known. Its deficiency causes rickets, osteomalacia, and secondary hyperparathyroidism and increases the risk of fractures. Clinical and experimental evidence suggests that vitamin D performs multiple extraskeletal functions. Several tissues unrelated to calcium and phosphate metabolism express vitamin D receptor (VDR) and are directly or indirectly influenced by 1,25(OH)2D (calcitriol). Some also express the enzyme 1 alpha-hydroxylase (CYP27B1) and produce 1,25(OH)2D, inducing autocrine or paracrine effects. Among the pleiotropic effects of vitamin D are the regulation of cell proliferation and differentiation, hormone secretion, and immune function. In this review, we outline vitamin D physiology and the outcomes of recent large RCTs on its potential extraskeletal effects. Those studies exhibit a need for continued clinical analysis to elucidate whether vitamin D status can influence extraskeletal health. Longer longitudinal follow-up and standardized assays are crucial to better assess potential outcomes.
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Hepatitis C-Associated Osteosclerosis: Improvement After Treatment with Sofosbuvir, Daclatasvir, and Ibandronate: Case Report and Literature Review.
de Camargo Vieira, MC, Gonçalves, WRB, Guerra, RA, Callegaro, FS, Lazaretti-Castro, M, Maeda, SS
Calcified tissue international. 2021;(1):104-109
Abstract
Hepatitis C-associated osteosclerosis (HCAO) remains a rare condition despite the growing prevalence of hepatitis C virus (HCV) infection worldwide. Since the first case reported in 1992, this is the twenty-second case described. Patients with HCAO present with severe bone pain and elevated serum levels of bone markers, especially alkaline phosphatase (ALP), with increased bone density. We report here the case of a 59-year-old man with generalized bone pain and diagnosis of HCV infection. Biochemical tests showed elevated bone turnover markers, specifically, ALP, carboxy-terminal collagen crosslinks and osteocalcin. Imaging studies revealed generalized bone sclerosis. Bone mineral density was elevated in all validated sites. His clinical symptoms and bone-related findings were attributed to HCAO. He was sequentially treated with cholecalciferol, prednisone, sofosbuvir associated with daclatasvir and ibandronate, and progressed with undetectable viral load after HCV treatment, normalization of ALP levels after introduction of ibandronate, and pain improvement 1 year after discontinuation of the bisphosphonate. Bone pain complaints must be investigated in patients with HCV. HCAO is a differential diagnosis of increased bone mass.
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Reasons to avoid vitamin D deficiency during COVID-19 pandemic.
Dos Santos, RN, Maeda, SS, Jardim, JR, Lazaretti-Castro, M
Archives of endocrinology and metabolism. 2021;(5):498-506
Abstract
The effects of vitamin D on the musculoskeletal system are well established. Its deficiency causes osteomalacia, secondary hyperparathyroidism, and an increased risk for fractures and falls. However, clinical and experimental evidence points to extra-skeletal actions of vitamin D, including on immune and respiratory systems. Thus, during this COVID-19 pandemic, a possible deleterious role of vitamin D deficiency has been questioned. This paper aims to present a brief review of the literature and discuss, based on evidence, the role of vitamin D in the lung function and in the prevention of respiratory infections. Relevant articles were searched in the databases MEDLINE/PubMed and SciELO/LILACS. The mechanisms of vitamin D action in the immune system response will be discussed. Clinical data from systematic reviews and meta-analyses show benefits in the prevention of respiratory infections and improvement of pulmonary function when vitamin D-deficient patients are supplemented. At the time of writing this paper, no published data on vitamin D supplementation for patients with COVID-19 have been found. Vitamin D supplementation is recommended during this period of social isolation to avoid any deficiency, especially in the context of bone outcomes, aiming to achieve normal values of 25(OH)D. The prevention of respiratory infections and improvement of pulmonary function are additional benefits observed when vitamin D deficiency is treated. Thus far, any protective effect of vitamin D specifically against severe COVID-19 remains unclear. We also emphasize avoiding bolus or extremely high doses of vitamin D, which can increase the risk of intoxication without evidence of benefits.
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Vitamin D: Dosing, levels, form, and route of administration: Does one approach fit all?
Bilezikian, JP, Formenti, AM, Adler, RA, Binkley, N, Bouillon, R, Lazaretti-Castro, M, Marcocci, C, Napoli, N, Rizzoli, R, Giustina, A
Reviews in endocrine & metabolic disorders. 2021;(4):1201-1218
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The 4th International Conference on Controversies in Vitamin D was held as a virtual meeting in September, 2020, gathering together leading international scientific and medical experts in vitamin D. Since vitamin D has a crucial role in skeletal and extra-skeletal systems, the aim of the Conference was to discuss improved management of vitamin D dosing, therapeutic levels and form or route of administration in the general population and in different clinical conditions. A tailored approach, based on the specific mechanisms underlying vitamin D deficiency in different diseases that were discussed, was recommended. Specifically, in comparison to healthy populations, higher levels of vitamin D and greater amounts of vitamin D were deemed necessary in osteoporosis, diabetes mellitus, obesity (particularly after bariatric surgery), and in those treated with glucocorticoids. Emerging and still open issues were related to target vitamin D levels and the role of vitamin D supplementation in COVID-19 since low vitamin D may predispose to SARS-CoV-2 infection and to worse COVID-19 outcomes. Finally, whereas oral daily cholecalciferol appears to be the preferred choice for vitamin D supplementation in the general population, and in most clinical conditions, active vitamin D analogs may be indicated in patients with hypoparathyroidism and severe kidney and liver insufficiency. Parenteral vitamin D administration could be helpful in malabsorption syndromes or in states of vitamin D resistance.Specific guidelines for desired levels of vitamin D should be tailored to the different conditions affecting vitamin D metabolism with the goal to define disease-specific normative values.
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Controversies in Vitamin D: A Statement From the Third International Conference.
Giustina, A, Bouillon, R, Binkley, N, Sempos, C, Adler, RA, Bollerslev, J, Dawson-Hughes, B, Ebeling, PR, Feldman, D, Heijboer, A, et al
JBMR plus. 2020;(12):e10417
Abstract
The Third International Conference on Controversies in Vitamin D was held in Gubbio, Italy, September 10-13, 2019. The conference was held as a follow-up to previous meetings held in 2017 and 2018 to address topics of controversy in vitamin D research. The specific topics were selected by the steering committee of the conference and based upon areas that remain controversial from the preceding conferences. Other topics were selected anew that reflect specific topics that have surfaced since the last international conference. Consensus was achieved after formal presentations and open discussions among experts. As will be detailed in this article, consensus was achieved with regard to the following: the importance and prevalence of nutritional rickets, amounts of vitamin D that are typically generated by sun exposure, worldwide prevalence of vitamin D deficiency, the importance of circulating concentrations of 25OHD as the best index of vitamin D stores, definitions and thresholds of vitamin D deficiency, and efficacy of vitamin D analogues in the treatment of psoriasis. Areas of uncertainly and controversy include the following: daily doses of vitamin D needed to maintain a normal level of 25OHD in the general population, recommendations for supplementation in patients with metabolic bone diseases, cutaneous production of vitamin D by UVB exposure, hepatic regulation of 25OHD metabolites, definition of vitamin D excess, vitamin D deficiency in acute illness, vitamin D requirements during reproduction, potential for a broad spectrum of cellular and organ activities under the influence of the vitamin D receptor, and potential links between vitamin D and major human diseases. With specific regard to the latter area, the proceedings of the conference led to recommendations for areas in need of further investigation through appropriately designed intervention trials. © 2020 The Authors. JBMR Plus published by Wiley Periodicals LLC. on behalf of American Society for Bone and Mineral Research.
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Consensus statement from 2nd International Conference on Controversies in Vitamin D.
Giustina, A, Adler, RA, Binkley, N, Bollerslev, J, Bouillon, R, Dawson-Hughes, B, Ebeling, PR, Feldman, D, Formenti, AM, Lazaretti-Castro, M, et al
Reviews in endocrine & metabolic disorders. 2020;(1):89-116
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Abstract
The 2nd International Conference on Controversies in Vitamin D was held in Monteriggioni (Siena), Italy, September 11-14, 2018. The aim of this meeting was to address ongoing controversies and timely topics in vitamin D research, to review available data related to these topics and controversies, to promote discussion to help resolve lingering issues and ultimately to suggest a research agenda to clarify areas of uncertainty. Several issues from the first conference, held in 2017, were revisited, such as assays used to determine serum 25-hydroxyvitamin D [25(OH)D] concentration, which remains a critical and controversial issue for defining vitamin D status. Definitions of vitamin D nutritional status (i.e. sufficiency, insufficiency and deficiency) were also revisited. New areas were reviewed, including vitamin D threshold values and how they should be defined in the context of specific diseases, sources of vitamin D and risk factors associated with vitamin D deficiency. Non-skeletal aspects related to vitamin D were also discussed, including the reproductive system, neurology, chronic kidney disease and falls. The therapeutic role of vitamin D and findings from recent clinical trials were also addressed. The topics were considered by 3 focus groups and divided into three main areas: 1) "Laboratory": assays and threshold values to define vitamin D status; 2) "Clinical": sources of vitamin D and risk factors and role of vitamin D in non-skeletal disease and 3) "Therapeutics": controversial issues on observational studies and recent randomized controlled trials. In this report, we present a summary of our findings.
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MECHANISMS IN ENDOCRINOLOGY: Vitamin D and COVID-19.
Bilezikian, JP, Bikle, D, Hewison, M, Lazaretti-Castro, M, Formenti, AM, Gupta, A, Madhavan, MV, Nair, N, Babalyan, V, Hutchings, N, et al
European journal of endocrinology. 2020;(5):R133-R147
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The SARS-CoV-2 virus responsible for the COVID-19 pandemic has generated an explosion of interest both in the mechanisms of infection leading to dissemination and expression of this disease, and in potential risk factors that may have a mechanistic basis for disease propagation or control. Vitamin D has emerged as a factor that may be involved in these two areas. The focus of this article is to apply our current understanding of vitamin D as a facilitator of immunocompetence both with regard to innate and adaptive immunity and to consider how this may relate to COVID-19 disease. There are also intriguing potential links to vitamin D as a factor in the cytokine storm that portends some of the most serious consequences of SARS-CoV-2 infection, such as the acute respiratory distress syndrome. Moreover, cardiac and coagulopathic features of COVID-19 disease deserve attention as they may also be related to vitamin D. Finally, we review the current clinical data associating vitamin D with SARS-CoV-2 infection, a putative clinical link that at this time must still be considered hypothetical.
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Controversies in Vitamin D: Summary Statement From an International Conference.
Giustina, A, Adler, RA, Binkley, N, Bouillon, R, Ebeling, PR, Lazaretti-Castro, M, Marcocci, C, Rizzoli, R, Sempos, CT, Bilezikian, JP
The Journal of clinical endocrinology and metabolism. 2019;(2):234-240
Abstract
CONTEXT Vitamin D is classically recognized as a regulator of calcium and phosphorus metabolism. Recent advances in the measurement of vitamin D metabolites, diagnosis of vitamin D deficiency, and clinical observations have led to an appreciation that along with its role in skeletal metabolism, vitamin D may well have an important role in nonclassical settings. Measurement of the circulating form of vitamin D that best describes total body stores, namely 25-hydroxyvitamin D, can be unreliable despite many sophisticated methodologies that have been proposed and implemented. Likewise, evidence from clinical studies showing a beneficial role of vitamin D in different disease states has been controversial and at times speculative. Moreover, the target concentrations of 25-hydroxyvitamin D to address a number of putative links between vitamin D inadequacy and nonskeletal diseases are further areas of uncertainty. SETTING To address these issues, an international conference on "Controversies in Vitamin D" was held in Pisa, Italy, in June 2017. Three main topics were addressed: (i) vitamin D assays and the definition of hypovitaminosis D; (ii) skeletal and extraskeletal effects of vitamin D; (iii) therapeutics of vitamin D. RESULTS This report provides a summary of the deliberations of the expert panels of the conference. CONCLUSIONS Despite great advances in our appreciation of vitamin D metabolism, measurements, biological actions on classical and nonclassical tissues, and therapeutics, all of which this report summarizes, much more work remains to be done so that our knowledge base can become even more secure.