5 179 P R Ebeling and others Vitamin D 179:5 R239–R259 Review MANAGEMENT OF ENDOCRINE DISEASE Therapeutics of vitamin D P R Ebeling1, R A Adler2, G Jones3, U A Liberman4, G Mazziotti5, S Minisola6, C F Munns7, N Napoli8,13, A G Pittas9, A Giustina10, J P Bilezikian11 and R Rizzoli12 1Department of Medicine, School of Clinical Sciences, Monash University, Clayton, Victoria, Australia, 2McGuire Veterans Affairs Medical Center and Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA, 3Department of Biomedical and Molecular Sciences in the School of Medicine, Queen’s University, Kingston, Ontario, Canada, 4Department of Physiology and Pharmacology and The Felsenstein Medical Research Center, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel, 5Endocrine Unit, ASST Carlo Poma, Mantua, Italy, 6‘Sapienza’ Rome University, Rome, Italy, 7Department of Paediatrics, Westmead Children’s Hospital, The University of Sydney, Westmead, New South Wales, Australia, 8Unit of Endocrinology and Diabetes, Department of Medicine, Università Campus Bio-Medico di Roma, Rome, Italy, 9Division of Endocrinology, Tufts Medical Center, Boston, Massachusetts, USA, 10Vita-Salute, San Raffaele University, Milan, Italy, 11Division of Correspondence Endocrinology, College of Physicians & Surgeons, Columbia University, New York, New York, USA, 12Divison of Bone should be addressed Diseases, Geneva University Hospitals and Faculty of Medicine, Geneva, Switzerland, 13IRCCS, Istituto Ortopedico to P R Ebeling Galeazzi, Milan, Italy Email [email protected] Abstract Objective: 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. Design: Narrative and systematic literature review. Methods: 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. Results: 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 European Journal European of Endocrinology 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. Conclusions: 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. European Journal of Endocrinology (2018) 179, R239–R259 Introduction The central role of vitamin D in bone health is well skeletal effects of vitamin D and the different therapeutic recognized. However, a series of controversies regarding modalities available. To identify the controversial issues, its clinical application remain. They primarily concern summarize the present state of knowledge and formulate how to define hypovitaminosis D, the skeletal and extra- some research questions to answer these controversies, https://eje.bioscientifica.com © 2018 European Society of Endocrinology Published by Bioscientifica Ltd. https://doi.org/10.1530/EJE-18-0151 Printed in Great Britain Downloaded from Bioscientifica.com at 09/30/2021 10:50:24PM via free access -18-0151 Review P R Ebeling and others Vitamin D 179:5 R240 a meeting was held in June 2017, during which the such as in Scandanavian countries, the use of cod liver various aspects of vitamin D measurement, its effects and oil and food fortification with vitamin D leads to higher therapeutic applications were reviewed and discussed by levels of 25-hydroxyvitamin D than would be expected international experts in the field. In this paper, we address (5, 6). Methods to increase vitamin D intake across a these issues. given population, including bio-fortification consisting of adding vitamin D to livestock feeds or UVB-irradiation of mushrooms and baker’s yeast are under evaluation (7, 8). Methods For the treatment of hypovitaminosis D, either sun exposure or increased intake of vitamin D-fortified This commentary reflects the discussion of a working foods may not be sufficient. In these settings, vitamin group that reviewed the current evidence linking bone D supplements should be considered, with various health and vitamin D therapy. It is based on both narrative guidelines suggesting either vitamin D2 (ergocalciferol) or and systematic literature reviews, focusing on the most vitamin D3 (cholecalciferol) (9). Vitamin D3 seems to be robust clinical evidence, which constituted the search preferred by many experts because of its greater potency criteria in PubMed. (10, 11). Interestingly, a meta-analysis of double-blind RCTs Vitamin D as a therapeutic agent and document that focused on a dose of vitamin D >480 IU/ its administration day the pooled effect of vitamin D3 on fractures was significantly lower by 23%, while the pooled effect on Questions relating to areas of agreement: fractures was not significant with vitamin 2D (12). When vitamin D and D are considered together, a Cochrane • Is vitamin D3 superior to D2? – Pharmacokinetics, 2 3 clinical data. analysis showed a significant decrease in incidence of hip • What is the role for 25-hydroxyvitamin D in fractures and non-vertebral fractures in patients treated replacement and its availability? with vitamin D plus calcium vs no treatment (13). • Is there a place for active vitamin D metabolites in Regarding vitamin D metabolites in cases of age- or treating vitamin deficiency? disease-related declines in hepatic and renal function • Is daily dosing of vitamin D preferred to larger weekly, (14), 25-hydroxyvitamin D (calcidiol) can be used, when monthly or annual doses? available. However, calcidiol is not available in the United • Does the baseline level of serum 25-hydroxyvitamin D States. In patients with advanced liver disease in whom European Journal European of Endocrinology influence the choice and frequency of dose? the hepatic hydroxylation of vitamin D is impaired, • Does BMI or race influence the dose or mode of calcidiol would be a logical form because it bypasses that administration? hydroxylation step in the liver (14). It is also a logical • What is the role of fortification in increasing vitamin form of vitamin D to use in the setting of glucocorticoid- D? induced inhibition of hepatic 25-hydroxylase. (15). • How much is too much vitamin D? Since glucocorticoids may inhibit not only the hepatic • What adverse outcomes are important? 25-hydroxylation of vitamin D, but also the subsequent 1-hydroxylation step in the kidney, to form active calcitriol, the use of calcitriol has been proposed as a way Type and source of vitamin D: metabolites, active forms of bypassing both hydroxylation steps for the treatment and analogues of glucocorticoid-induced osteoporosis (GIOP). Indeed, Skin is the major source of cholecalciferol in humans, in some clinical studies, active vitamin D analogues which is formed after exposure to the ultraviolet B were shown to be more effective than native vitamin D3 (UVB) wavelength of sunlight. A number of personal in terms of bone mineral density (BMD) improvement and environmental factors reduce the skin production and reduction of fracture risk in GIOP (16). However, in of vitamin D, such as low UVB availability, which is other studies of GIOP, the effects of native vitamin D3 dependent, in part, on latitude, season, time of day were comparable with those achieved by active vitamin and extent of air pollution (1, 2, 3). Even so, in regions D analogues (17). Moreover, calcidiol has been proposed of high UVB availability, a substantial prevalence of for the treatment of hypovitaminosis D in obese patients hypovitaminosis D has been reported (4). On the other due to its greater hydrophilic properties, in comparison hand, in countries where UVB availability is generally low, with vitamin D itself, resulting in a smaller volume of https://eje.bioscientifica.com Downloaded from Bioscientifica.com at 09/30/2021 10:50:24PM via free access Review P R Ebeling and others Vitamin D 179:5 R241 distribution and potentially more rapid and effective prevalence of vitamin D deficiency in older individuals, a normalization of serum 25-hydroxyvitamin D values daily intake of 600–800 IU is recommended (21). At both (14). Calcidiol may also be the most preferred form of ends of the life span, an adequate intake of calcium is vitamin D in cases of fat malabsorption due to a variety also necessary. of diseases or following bariatric surgery (14). This discussion of advantages of calcidiol over vitamin D itself Mode of administration and