Extraskeletal Effects Of Vitamin Research Articles

Vitamin D: Analytical Advances, Clinical Impact, and Ongoing Debates on Health Perspectives.

Vitamin D, acknowledged since the 1930s for its role in preventing rickets, gained additional prominence in relation to fragility fracture prevention in the late 1980s. From the early 2000s, connections between vitamin D deficiency and extra-skeletal pathologies emerged, alongside increased awareness of widespread deficits. This prompted crucial debates on optimal serum concentrations, expected to conclude when the outcomes of high-dose supplementation randomized controlled trials were available. Skepticism arose with inconclusive results from these trials. This review begins with an exploration of vitamin D metabolism, followed by a detailed description of the measurement of vitamin D metabolites and the crucial role of standardization. Subsequent sections focus on the association of vitamin D with bone health and explore the extra-skeletal effects. The review concludes with a comprehensive discussion on the definition of vitamin D status and its implications for supplementation. Despite standardization efforts, assay variations and challenges still exist, especially in specific patient groups. Vitamin D supplementation has a significant impact on bone metabolism and optimal vitamin D status improves the efficacy of antiresorptive drugs such as bisphosphonates. The extra-skeletal effects of vitamin D remain debated, but may include potential benefits in conditions such as respiratory infections and cancer mortality, particularly in deficient individuals. The definition of vitamin D sufficiency is nuanced, especially when variations in population groups and analytical methods are taken into account. Despite ongoing debates and recent mega-trials tempering enthusiasm, vitamin D remains a complex and essential element in human health. Further research is needed to clarify its role in various health outcomes and guide supplementation strategies.

Vitamin D and Dyslipidemia: Is There Really a Link? A Narrative Review.

Nowadays, the interest in the extraskeletal effects of vitamin D is growing. In the literature, its several possible actions have been confirmed. Vitamin D seems to have a regulatory role in many different fields-inflammation, immunity, and the endocrine system-and many studies would demonstrate a possible correlation between vitamin D and cardiovascular disease. In this paper, we deepened the relationship between vitamin D and dyslipidemia by reviewing the available literature. The results are not entirely clear-cut: on the one hand, numerous observational studies suggest a link between higher serum vitamin D levels and a beneficial lipid profile, while on the other hand, interventional studies do not demonstrate a significant effect. Understanding the possible relationship between vitamin D and dyslipidemia may represent a turning point: another link between vitamin D and the cardiovascular system.

Skeletal and Extra-Ekeletal Effects of Vitamin D Deficiency in Children

Vitamin D is essential for the maintenance of calcium and phosphorus homeostasis. It has skeletal growth and extra-skeletal effects in our body. Objective of this article is to update the information on skeletal and extra-skeletal effects of vitamin D deficiency in paediatric clinical disorders. In the paediatric population, vitamin D deficiency is associated with different clinical diseases such as rickets, insulin resistance, metabolic syndrome, respiratory tract infections, asthma, and autoimmune diseases. It is associated with prematurity, obesity, malabsorption, anticonvulsant agents, extreme latitudes, low consumption, and little sun exposure. The recommendation is to prevent vitamin D deficiency and to maintain 25(OH) D serum levels >30ng/mL (>75 nmol/L).
 Bangladesh Med J. 2021 Sept; 50(3): 36-43

Vitamin D in the older population: a consensus statement.

BackgroundThis 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.MethodsParticipants 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.ResultsHypovitaminosis 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.ConclusionsThe 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.

Vitamin D and musculoskeletal health: outstanding aspects to be considered in the light of current evidence.

Vitamin D enhances calcium absorption and bone mineralisation, promotes maintenance of muscle function, and is crucial for musculoskeletal health. Low vitamin D status triggers secondary hyperparathyroidism, increases bone loss, and leads to muscle weakness. The primary physiologic function of vitamin D and its metabolites is maintaining calcium homeostasis for metabolic functioning, signal transduction, and neuromuscular activity. A considerable amount of human evidence supports the well-recognised contribution of adequate serum 25-hydroxyvitamin D concentrations for bone homeostasis maintenance and prevention and treatment strategies for osteoporosis when combined with adequate calcium intake. This paper aimed to review the literature published, mainly in the last 20 years, on the effect of vitamin D and its supplementation for musculoskeletal health in order to identify the aspects that remain unclear or controversial and therefore require further investigation and debate. There is a clear need for consistent data to establish realistic and meaningful recommendations of vitamin D status that consider different population groups and locations. Moreover, there is still a lack of consensus on thresholds for vitamin D deficiency and optimal status as well as toxicity, optimal intake of vitamin D, vitamin D supplement alone as a strategy to prevent fractures and falls, recommended sun exposure at different latitudes and for different skin pigmentations, and the extra skeletal effects of vitamin D.

Vitamin D and Visceral Obesity in Humans: What Should Clinicians Know?

The extraskeletal effect of vitamin D on adipose tissue biology and modulation in human obesity is of great interest and has been extensively investigated. Current evidence from preclinical and clinical studies in human adipose tissue suggests that the anti-inflammatory effects of vitamin D are evident and consistent, whereas the effects of vitamin D on adipocyte differentiation, adipogenesis, and energy metabolism and the effects of vitamin D supplementation on adipokine levels are inconclusive. Interventional studies related to medical and surgical weight loss in humans have shown small or no improvement in vitamin D status. Additionally, the benefit of vitamin D supplementation for the reduction in visceral adipose tissue has only been demonstrated in a few studies. Overall, the findings on the relationship between vitamin D and visceral adipose tissue in humans are still inconclusive. Further studies are required to confirm the beneficial effects of vitamin D on ameliorating adipose tissue dysfunction.

Экстраскелетные эффекты витамина D: роль в патогенезе сердечно-сосудистых заболеваний

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Фактори ризику дефіциту вітаміну D серед українських жінок у Карпатському регіоні

Актуальність. Дефіцит вітаміну D присутній більше ніж у половини населення в усьому світі. Відомо, що дефіцит вітаміну D призводить до розвитку остеопенії та остеопорозу. Оскільки рецептори вітаміну D є у всіх клітинах організму, у дослідженнях останніх років основну увагу було придiлено позаскелетним ефектам вітаміну D та впливу на загальний стан здоров’я. Метою дослідження було оцінити деякі фактори ризику дефіциту вітаміну D серед українських жінок у Карпатському регіоні. Матеріали та методи. У дослідженні з 2014 по 2016 р. взяли участь 495 жінок віком 18–82 роки. Рівні сироваткового 25-гiдроксивітаміну D були виміряні у всіх учасників після вивчення їх демографічних і антропометричних даних та медичного анамнезу. Результати. Поширеність дефіциту та недостатності вітаміну D у жіночій популяції Карпатського регіону становила 91,1 %. Аналіз логістичної регресії показав, що вік (відношення шансів (ВШ): 0,98, довірчий інтервал (ДІ): 0,95–0,98) та менопауза (ВШ: 0,49; ДІ: 0,25–0,98) були незалежними предикторами дефіциту вітаміну D. Висновки. У дослідженнi показано високу поширеність дефіциту вітаміну D серед українських жінок, особливо в репродуктивному віці.

Role of Vitamin D in the Clinical Course of Nasal Polyposis.

Vitamin D is a lipo-soluble hormone well known for its effects on calcium homeostasis and bone metabolism. Recently, there has been growing interest in the extraskeletal effects of vitamin D. In particular, recent studies have highlighted how vitamin D plays a fundamental role in immunomodulation processes in the context of both innate and adaptive immunity, with consequent anti-inflammatory and anti-oxidant effect in different immune-mediated pathologies, such as systemic sclerosis, psoriasis, atopic dermatitis and rheumatoid arthritis; as well as in various pro-inflammatory processes affecting the airways, including chronic rhinosinusitis with (CRSwNP) or without (CRSsNP) nasal polyposis. We analyze the role of vitamin D in the genesis and progression of CRSwNP/sNP and its supplementation as a safe and valid therapeutic strategy capable of improving the clinical outcome of standard therapies.

Is Vitamin D Deficiency Associated with Chronic Lymphocytic Thyroiditis?

Objectives:Vitamin D deficiency is a very common global health problem. Evidence from recent studies focuses on the extraskeletal effects of vitamin D (Vit D) deficiency. Chronic lymphocytic thyroiditis (or Hashimoto’s thyroiditis) is an autoimmune disease of the thyroid. Although there are many studies reporting that autoimmune thyroid diseases may be associated with Vitamin D deficiency, this is still a controversial issue that has not yet been proven. In this study, we aimed to appraise whether there is a relationship between lymphocytic thyroiditis diagnosed by histopathological evaluation and Vitamin D deficiency.Methods:Data of 256 patients whom were operated by a single surgeon in a single center between 2012 and 2017 and whose preoperative vitamin D tests and thyroid pathologies have been collected, were retrospectively evaluated. Due to the pathological examination, two groups were formed considering the presence of lymphocytic thyroiditis (Group 1), and the absence of lymphocytic thyroiditis (Group 2). Vitamin D deficiency was defined as the level <20 ng/mL (50 nmol/L) and Vitamin D insufficiency was defined as the level 21–29 ng/mL (525–725 nmol/L).Results:There were 108 (92F/16M) patients in Group 1, and 148 (116F/32M) patients in Group 2, and the mean age was lower in Group 1 (p=0.053). The mean vitamin D levels (16.6±15.2 vs. 14±10, p=0.409) and vitamin D deficiency rates (67.6% vs. 72.3%, p=0.416) were found similar between the Groups 1 and 2. No positive significant correlation was found between lymphocytic thyroiditis and vitamin D level or vitamin D deficiency rates. There was a positive correlation between lymphocytic thyroiditis and age, preoperative thyroid-stimulating hormone level, preoperative anti-thyroglobulin ,and anti-thyroid peroxidase levels, but no significant relationship was found with Vitamin D level.Conclusion:According to our results, lymphocytic thyroiditis was not associated with either Vitamin D deficiency or Vitamin D level.

Витамин D при болезни Крона: участие в патогенезе и перспективы применения

As many research works show, vitamin D has pleiotropic effects, including the immune regulation and pathogenesis of Crohn’s disease. Therefore, concentrations of the active vitamin D metabolite might be associated with the development, progression and severity of the disease. The skeletal and extraskeletal effects of vitamin D are realised through its active metabolite – 1.25(OH)2D, which is a steroid hormone. The objective of the work: to analyse the accumulated evidence demonstrative of a multiple contribution of vitamin D in the pathogenesis of Crohn’s disease, and to determine the possible perspectives of using the vitamin as part of comprehensive therapy of this disease. Despite the fact, that data of in vitro and animal studies are demonstrative of multiple effects of vitamin D in the pathogenesis of Crohn’s disease, the currently available evidence based on the underlying clinical trials are insufficient yet for including vitamin D in clinical guidelines on management of Crohn’s disease. Further research work is necessary. Key words: Crohn’s disease, vitamin D, calciferol, vitamin D axis, extraskeletal effects

Is There Proof of Extraskeletal Benefits From Vitamin D Supplementation From Recent Mega Trials of Vitamin D?

ABSTRACTScientific interest in possible extraskeletal effects of vitamin D first appeared in the 1930s soon after the structure of vitamin D was characterized, and increased in the 1980s with the development of assays of 25‐hydroxyvitamin D status as a marker of vitamin D status, which in observational epidemiological studies was shown to be inversely associated with many nonskeletal diseases. This resulted in the start of seven large randomized controlled trials (n > 2000 participants in each) of vitamin D supplementation giving higher doses than previously used. The intervention periods in these trials collectively started in 2009 and continued to 2020. They have recruited participants, mostly of both sexes and over the age of 50 years, from many countries and have given either daily or monthly doses of vitamin D. Collectively, the trials have a wide range of outcomes with the main focus on the prevention of cancer, cardiovascular disease, and fractures, besides many other outcomes. The findings of four trials have been published, and they have shown that vitamin D supplementation does not prevent hard‐disease endpoints, such as cardiovascular disease, cancer, fractures, or falls, aside from a possible beneficial effect against cancer mortality. In contrast, beneficial effects were seen for intermediate outcomes such as BMD of spine and hips, arterial function, and lung function, especially in people with vitamin D deficiency. The finding of a benefit primarily in people with vitamin D deficiency, if confirmed by the other trials, would support a population approach to preventing vitamin D deficiency using fortification rather than the high‐risk approach of screening for deficiency combined with supplementation. The findings on other outcomes from the three published trials, along with the findings from the four unpublished trials, are expected within the next 2 to 3 years to clarify the role of vitamin D supplementation in preventing nonskeletal disease. © 2020 The Authors. JBMR Plus published by Wiley Periodicals LLC. on behalf of American Society for Bone and Mineral Research.

Skeletal health, redox balance and gastrointestinal functionality in dairy cows: connecting bugs and bones.

This research reflection examines the physiological links between redox balance, skeletal health and gastrointestinal functionality in dairy cows. With the increase in demand of animal products caused by the growth in human population, the dairy industry needs to develop and implement innovative strategies which are profitable, sustainable and cow friendly. Redox balance, skeletal heath and gastrointestinal functionality are three key physiological systems that are often seen as independent entities. In this research reflection we intend to stress that the antioxidant system, bone health and the microbiome are intimately intertwined. Antioxidants are crucial for the maintenance of redox homeostasis and optimal immune function. Optimal gastrointestinal functionality is important to maintain animal performance, health and welfare. In particular, the intestinal microbiome is increasingly seen as a driver of health and disease. Vitamin D metabolism is pivotal not only for optimal skeletal health, but in light of all the extra-skeletal effect of vitamin D, it is the foundation for optimal productive life. It makes sense to ask the question 'how are redox balance and the microbiome involved in the modulation of bone health and immune function?' In other words, are bugs and bones connected in dairy cows! The existing data available in the literature suggests that this might be the case. The characterization of the interactions between redox balance, skeletal health and the microbiome, will allow the development of a multisystem biological approach to refine nutritional interventions to improve dairy cattle health, welfare and productive longevity.

The Many Facets of Vitamin D in the Pediatric Population.

Vitamin D is important for skeletal growth, bone mineralization and dental health. Vitamin D deficiency is reported in many countries, may have several causes and can cause rickets in children. A guideline with recommendations of vitamin D supplementation to prevent nutritional rickets was published recently. The vitamin D receptor is present in many cells of the body including cells of the immune system. Many studies have been published on associations between vitamin D deficiency and extra skeletal effects, mainly without proof of causality in intervention studies. This review aims to summarize available evidence of the skeletal and extra-skeletal effects of vitamin D. For the extra-skeletal effects there is proof that vitamin D supplementation can prevent acute respiratory infections in children with vitamin D deficiency and can reduce the rate of asthma exacerbations requiring corticosteroids in children with vitamin D deficiency. The evidence of benefit of vitamin D supplementation is too limited for pediatric patients with other infectious, inflammatory, and autoimmune diseases.

Vitamin D deficiency and co-morbidities in COVID-19 patients – A fatal relationship?

Infections of the respiratory tract are more frequent in the winter months and especially in the northern latitudes than they are in summer [1]. This obviously also applies to the COVID-19 infectious disease that briefly spread all over the world in the winter months and became a pandemic [2,3]. A common feature of the winter months and the inhabitants of all countries north of the 42nd parallel is a hypovitaminosis D that frequently occurs during this period [4]. In addition during cold temperature the virus will be more easily transmitted. This raises the question of whether an inadequate vitamin D supply has an influence on the progression and severity of COVID-19 disease. A low vitamin D status, measured as the plasma level of the transport form of vitamin D, 25(OH)D,is widespread worldwide and is mainly found in regions of northern latitudes, but also in southern countries [5]. In Europe, vitamin D deficiency is widely prevalent during the winter months and affects mainly elderly people and migrants. In Scandinavia only 5% of the population is affected by a low vitamin D status, in Germany, France and Italy more than 25%, particularly older people e.g. in Austria up to 90% of senior citizens [6,7]. In Scandinavian countries, the low incidence of vitamin D deficiency may be due to the traditional consumption of cod liver oil rich in vitamin D and A or to genetic factors resulting in higher synthesis of vitamin D in the epidermal layer [8]. Taken together, low vitamin D status is common in Europe with the exception of the Scandinavian countries. The calculated COVID-19 mortality rate from 12 European countries shows a significant (P = .046) inverse correlation with the mean 25(OH)D plasma concentration [9]. This raises the question whether insufficient vitamin D supply has an influence on the course of COVID-19 disease? An analysis of the distribution of Covid-19 infections showed a correlation between geographical location (30–50° N+), mean temperature between 5–11 °C and low humidity [10]. In a retrospective cohort study (1382 hospitalized patients) 326 died, Among them 70.6% were black patients. However, black race was not independently associated with higher mortality [11]. An excess mortality (2 to sixfold have been described in African-Americans with average latitudes of their state of residence in higher latitudes (> 40) [12]. The mortality of COVID-19 (cases/ million population) shows a clear dependence on latitude. Below latitude 35, mortality decreases markedly [13]. Indeed, there are exceptions e.g. Brazil (tenfold higher than all other latin American countries – except mexico), however, the management of the pandemic may increase infection risk. 1.1. Vitamin D effects The skeletal and extra skeletal effects of vitamin D have recently been described in an extensive review [14]. Vitamin D exerts a genomic and non-genomic effect on gene expression. The genomic effect is mediated by the nuclear vitamin D receptor (VDR), which acts as a ligand activated transcription factor. The active form 1,25(OH)2D binds to the VDR and in most cases heterodimerizes with the retinoid X receptor (RXR), whose ligand is one of the active metabolites of vitamin A, 9-cis retinoic acid. The interaction of this complex with the vitamin D responsive element can regulate the expression of target genes either positively or negatively [15]. The non-genomic effects involve the activation of a variety of signaling molecules that interact with Vitamin D responsive element (VDRE) in the promoter regions of vitamin D dependent genes [16]. Vitamins A and D are also of particlular importance for the barrier function of mucous membranes in the respiratory tract [17,18].

Randomized clinical trials of oral vitamin D supplementation in need of a paradigm change: The vitamin D autacoid paradigm

Epidemiological studies highlight the negative correlation between vitamin D levels and the incidence of many non-skeletal diseases including inflammatory diseases, cancer, and metabolic and neurological disorders. However, most randomized controlled trials (RCTs) with oral vitamin D supplementation give mixed results or are inconclusive. It has been said that “discovery commences with the awareness of anomaly”. The “anomaly” between our preclinical and clinical data provides the opportunity to propose an alternative paradigm to the vitamin D endocrine system: the vitamin D autacoid paradigm. In the vitamin D autacoid paradigm, the extra-skeletal effects of vitamin D depend on the tissue reserves of vitamin D metabolites. These vitamin D autacoid systems are inducible oscillatory ecosystems in which 1,25D is produced, acts and is inactivated locally. In the vitamin D autacoid paradigm, attaining adequacy of vitamin D in the systemic circulation is necessary but not sufficient; we must also ensure the repletion of the tissue stores. The co-existence of two different vitamin D systems, endocrine and autacoid, with different functions and regulations leads to “significant shifts in the criteria determining the legitimacy both of problems and of proposed solutions”. With respect to our clinical trials of vitamin D supplementation for unconventional effects, the proposed solution is administering and quantifying vitamin D metabolites directly to the target tissue.

Does serum Vitamin D status influence high-sensitivity c-reactive protein and gensini score in established coronary artery disease individuals

Introduction: Over the years, the extraskeletal effects of Vitamin D (vit D) are gaining prominence. The role of vit D deficiency (VDD) in coronary artery disease (CAD) is conflicting. Hence, the present study was aimed to correlate serum vit D levels with high-sensitivity C-reactive protein (hs-CRP) and Gensini score in CAD individuals. Materials and Methods: This cross-sectional study was conducted on 70 angiographically proven CAD individuals aged between 35 and 55 years of both sexes who presented with a history of myocardial injury or ischemia for the first time. The angiographic findings were graded using Gensini score. Serum vit D and hs-CRP were estimated using enzyme-linked immunosorbent assay. Results: The average serum vit D level was 15 ng/mL, and the ratio of diabetes and nondiabetes individuals was 52:18. Among the 70 patients, 66% (n = 46) were deficient, 20% (n = 14) were insufficient, and 14% (n = 10) had normal vit D status. Although insignificant, vit D levels had negative correlation with Gensini score (r = −0.17, P = 0.14) and hs-CRP levels (r = −0.03, P = 0.77) which was not sustained after multivariate logistic regression. A significant negative correlation (r = −0.35, P = 0.01) was found between serum vit D status and duration of diabetes. Conclusion: VDD observed in diabetes individuals is inversely related to the duration of diabetes which incidentally is associated with CAD. Thus, screening for vit D status may be vital for the management of CAD particularly in diabetes individuals.

Updates in vitamin D therapy in cystic fibrosis.

To summarize recent developments the role of vitamin D and treatment of vitamin D deficiency in cystic fibrosis. Although treatment of low vitamin D levels continues to be important for optimizing bone health in cystic fibrosis, increasing data on the extraskeletal effects of vitamin D are becoming available. Exploratory studies of vitamin D in modulation of respiratory and intestinal microbiomes, and the influence of vitamin D on the metabolomic signature of cystic fibrosis, suggest expanded roles for vitamin D in cystic fibrosis disease and treatment. Emerging developments in cystic fibrosis regarding therapeutics and effects of vitamin D on bone health, inflammation, microbiome, and the metabolome are summarized.

Controversies in Vitamin D: Summary Statement From an International Conference.

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. 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. This report provides a summary of the deliberations of the expert panels of the conference. 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.

MANAGEMENT OF ENDOCRINE DISEASE: Therapeutics of Vitamin D.

The central role of vitamin D in bone health is well recognized. However, controversies regarding its clinical application remain. We therefore aimed to review the definition of hypovitaminosis D, the skeletal and extra-skeletal effects of vitamin D and the available therapeutic modalities. Narrative and systematic literature review. An international working group that reviewed the current evidence linking bone and extra-skeletal health and vitamin D therapy to identify knowledge gaps for future research. Findings from observational studies and randomized controlled trials (RCTs) in vitamin D deficiency are discordant, with findings of RCTs being largely negative. This may be due to reverse causality with the illness itself contributing to low vitamin D levels. The results of many RCTs have also been inconsistent. However, overall evidence from RCTs shows vitamin D reduces fractures (when administered with calcium) in the institutionalized elderly. Although controversial, vitamin D reduces acute respiratory tract infections (if not given as bolus monthly or annual doses) and may reduce falls in those with the lowest serum 25-hydroxyvitamin D (25OHD) levels. However, despite large ongoing RCTs with 21 000–26 000 participants not recruiting based on baseline 25OHD levels, they will contain a large subset of participants with vitamin D deficiency and are adequately powered to meet their primary end-points. The effects of long-term vitamin D supplementation on non-skeletal outcomes, such as type 2 diabetes mellitus (T2DM), cancer and cardiovascular disease (CVD) and the optimal dose and serum 25OHD level that balances extra-skeletal benefits (T2DM) vs risks (e.g. CVD), may soon be determined by data from large RCTs.