vitD concensus

Maturitas 71 (2012) 83– 88 Contents lists available at SciVerse ScienceDirect Maturitas j ourna l h o me page: www.elsev ier .com/ EMAS p me Faustino lore Irene Lam sta Serge Ro a Department of Obstetrics and Gynecology, Universidad de Zaragoza, Facultad de Medicina, Hospital Clínico, Domingo Miral s/n, Zaragoza 50009, Spain b Department of Obstetrics and Gynaecology, Mater Dei Hospital, B’Kara NXR2130, Malta c Department of Obstetrics and Gynecology, Istanbul University, Cerrahpasa School of Medicine, Valikonagi Cad. No. 93/4, Nisantasi 34365, Istanbul, Turkey d Menopause and Metabolic Bone Disease Unit, Hôpital Paule de Viguier, F-31059 Toulouse Cedex 09, France e University of Pisa, Department of Obstetrics and Gynecology, Via Roma 67, 56100 Pisa, Italy f 2nd Department of Obstetrics and Gynecology, University of Athens, Aretaieio Hospital, GR-11528 Athens, Greece g Department o h Department o i Department o j Institute of En k Department o l Women’s Cen a r t i c l Article history: Received 1 No Accepted 1 No Keywords: Postmenopaus Vitamin D3 Cholecalcifero Vitamin D2 Ergocalciferol 25-Hydroxyvi Calcidiol Calcitriol Sunlight Mortality Osteoporosis 1. Introdu Vitamin ulates calci gastrointes otal role in ∗ Correspon E-mail add (F.R. Pérez-Lóp 0378-5122/$ – doi:10.1016/j. f Laboratory Medicine, Children’s and Women’s Health, Faculty of Medicine, Norwegian university of Science and Technology, NO-7491 Trondheim, Norway f Obstetrics and Gynecology, St Olavs Hospital, Trondheim University Hospital, NO-7006 Trondheim, Norway f Medicine, Cardiology Unit and Head Centre for Gender Medicine, Karolinska Institutet and Karolinska University Hospital, Thorax N3:06, SE 17176 Stockholm, Sweden docrinology, Clinical Center of Serbia, Belgrade School of Medicine, Dr Subotica 13, 11000 Beograd, Serbia f Obstetrics and Gynecology, CHU Saint Pierre, Université Libre de Bruxelles, 1000 Brussels, Belgium tre, John Radcliffe Hospital, Oxford OX3 9DU, UK e i n f o vember 2011 vember 2011 al women l tamin D a b s t r a c t Introduction: There is emerging evidence on the widespread tissue effects of vitamin D. Aims: To formulate a position statement on the role of vitamin D in postmenopausal women. Materials and methods: Literature review and consensus of expert opinion. Results and conclusions: Epidemiological and prospective studies have related vitamin D deficiency with not only osteoporosis but also cardiovascular disease, diabetes, cancer, infections and neurodegenerative disease. However the evidence is robust for skeletal but not nonskeletal outcomes where data from large prospective studies are lacking. The major natural source of vitamin D is cutaneous synthesis through exposure to sunlight with a small amount from the diet in animal-based foods such as fatty fish, eggs and milk. Vitamin D status is determined by measuring serum 25-hydroxyvitamin D [25(OH)D] levels. Optimal serum 25(OH)D levels are in the region of 30–90 ng/mL (75–225 nmol/L) though there is no international consensus. Levels vary according to time of the year (lower in the winter), latitude, altitude, air pollution, skin pigmentation, use of sunscreens and clothing coverage. Risk factors for low serum 25(OH)D levels include: obesity, malabsorption syndromes, medication use (e.g. anticonvulsants, antiretrovirals), skin aging, low sun exposure and those in residential care. Fortified foods do not necessarily provide sufficient amounts of vitamin D. Regular sunlight exposure (without sunscreens) for 15 min, 3–4 times a week, in the middle of the day in summer generate healthy levels. The recommended daily allowance is 600 IU/day increasing to 800 IU/day in those aged 71 years and older. Supplementation can be undertaken with either vitamin D2 (ergocalciferol) or vitamin D3 (cholecalciferol) with monitoring depending on the dose used and the presence of concomitant medical conditions such as renal disease. © 2011 Elsevier Ireland Ltd. All rights reserved. ction D comprises a group of lipophilic hormones that reg- um homeostasis through its actions on the kidney, tinal tract, skeleton and parathyroid. It plays a piv- maintaining skeletal health. The two major forms ding author. Tel.: +34 976 761 734; fax: +34 976 761 735. resses: faustino.perez@unizar.es, gineblog@hotmail.com ez). are vitamin D2 (ergocalciferol) and vitamin D3 (cholecalciferol). Vitamin D2 is produced from ergosterol by several organisms: phy- toplankton, invertebrates and fungi in response to ultraviolet (UV) irradiation. The major natural source of vitamin D3 is cutaneous synthesis from 7-dehydrocholesterol through exposure to sunlight with a small amount from the diet in animal-based foods such as fatty fish, eggs and milk. There are wide individual variations in both cutaneous synthesis and gastrointestinal absorption of vita- min D. Two hydroxylations are needed to obtain the bioactive hormone 1,25-dihydroxyvitamin D or calcitriol. In the liver, the first metabolizes vitamin D into 25-hydroxyvitamin D [25(OH)D] see front matter © 2011 Elsevier Ireland Ltd. All rights reserved. maturitas.2011.11.002 osition statement: Vitamin D and post R. Pérez-Lópeza,∗, Marc Brincatb, C. Tamer Erel c, F brinoudaki f, Mette H. Moeng,h, Karin Schenck-Gu zenbergk, Margaret Rees l locate /matur i tas nopausal health nce Tremollieresd, Marco Gambaccianie, fssoni, Svetlana Vujovic j, 84 F.R. Pérez-López et al. / Maturitas 71 (2012) 83– 88 or calcidiol; and the second produces calcitriol in the kidneys and other tissues [1–5]. Both vitamin D3 and vitamin D2 are synthe- sized commercially and found in dietary supplements or fortified foods. Calcitrio participates genes. In h of non-calc duction, m antimicrobi ptosis [2,4,6 2. Assessm There ar compounds needed to s [11]. Curren circulating roid functio potent than target cells eases more seem to be at which pa tion from b stabilized th Hypovit off values: and 29.99 n below 10 n absolute le 70% of the had insuffic [13–17]. Severe v tion, leadin vitamin D menopausa diseases wh cancer, diab 3. Risk fac General induced ski obesity, ma sant, antire more comm Since vi atinocytes, poor sunlig or resident year (winte amount of e extensive c interferenc natural dar with fair (w sunscreens skin aging [2,4,16] wh tosynthesis 25(OH)D tor for vitam coeliac disease, Crohn’s disease, gastrointestinal bypass surgery, cystic fibrosis with pancreatic insufficiency) may have difficulties in absorbing vitamin D [24] whereas those with renal insufficiency may have an increased urinary loss of 25(OH)D and limited capac- calci conv ation ntire itriol ditio tami ystem ld hi )D le plem card leme men effe rand (med n D reas s did ted reatm syst trial nific ion a tami eopo ong con usc quar acto <47. ith plem es b k of f ing d s with 000 )D le l red or se [34] effe , at ausa sugg non tmen ed by clude ed th his e l stimulates calcium and phosphate absorption and in regulating the transcription of a large number of umans, locally synthesized calcitriol has a wide range iotropic functions including among others: insulin pro- yocardial contraction, immunomodulation, monocyte al action, innate immunity, cell proliferation and apo- –10]. ent of vitamin D status e many forms of the vitamin D in blood. To identify these liquid chromatography and mass spectrometry are eparate active forms from inactive related compounds tly the best available indicator of vitamin D status is serum 25(OH)D which is most closely linked to parathy- n and calcium homeostasis, although biologically less calcitriol. In addition, serum 25(OH)D is taken up by and would determine the risk of age-related chronic dis- directly than calcitriol. Adequate plasma 25(OH)D levels between 30 ng/mL and 90 ng/mL (1 ng/mL = 2.5 nmol/L) rathyroid hormone (PTH) secretion and calcium resorp- one are minimized, and intestinal calcium absorption is ough there is no international consensus [2,12]. aminosis D includes three categories according to cut- insufficiency if serum 25(OH)D levels are between 20 g/mL, deficiency below 20 ng/mL, and severe deficiency g/mL [2,4,12,13] but again there is controversy about vels. Even taking into account sunny regions nearly European population displays suboptimal levels (35% ient, 25% deficient and 10% severely deficient levels) itamin deficiency affects bone health and muscle func- g to rickets, osteomalacia and myopathy [18,19]. Low levels are also prevalent among osteoporotic post- l women [20] and have been associated to other ich include among others cardiovascular disease (CVD), etes, infections and neurological diseases [2,4,9,10]. tors for hypovitaminosis D risk factors for hypovitaminosis D include low UV- n synthesis, dark skin, skin aging, poor dietary intake, labsorption, and certain medications (e.g. anticonvul- trovirals). Furthermore low plasma vitamin D levels are on in women than in men [4,9,13]. tamin D synthesis depends on UV action on the ker- its deficiency is common especially in individuals with ht exposure such as those living at higher latitudes ial care homes. Thus, latitude, altitude, time of the r), time of the day (early morning and late afternoon), xposed skin, skin pigmentation, sun protection (shade, lothing cover, sunscreen use), and air pollution may e with vitamin D skin synthesis [1,2,21]. People with k skin produce half to a fifth of vitamin D than those hite) for a similar level of sun exposure [22]. The use of may drastically reduce cutaneous synthesis. In addition, is associated with lower 7-dehydrocholesterol levels ich is the vitamin D precursor required for skin pho- . is stored in adipose tissue, and obesity is a risk fac- in D deficiency [23]. Patients with malabsorption (e.g., ity for as anti inactiv [26]. A to calc 4. Con 4.1. Vi A s five-fo 25(OH of sup quent D supp supple The in 50 ment Vitami D3 dec pound be trea cium t recent trolled not sig infarct 4.2. Vi Ost lem am D may neurom across other f tions ( those w Sup produc the ris includ vidual (700–1 25(OH 23% fal 700 IU of falls The calcium menop results porotic D trea obtain that in report falls. T triol synthesis [2,25]. Chronic use of certain drugs, such ulsants, may reduce 25(OH)D levels due to accelerated of calcitriol caused by increased expression of CYP24 troviral agents may increase the conversion of 25(OH)D and accelerate its catabolism [27]. ns associated to low vitamin D status n D and mortality atic review of prospective studies reported a two- to gher mortality risk among subjects with lower serum vels [28]. A systematic review reported the effect entation with vitamin D, calcium, or both on subse- iovascular events. This review concluded that vitamin ntation may reduce cardiovascular risk while calcium tation has minimal cardiovascular effects [29]. ct of vitamin D supplementation has been studied omised trials which have compared vitamin D treat- ian of two years) versus placebo or no intervention. treatment decreased mortality, although only vitamin ed mortality significantly whereas other related com- not. It has been estimated that 161 individuals should to prevent one death. Vitamin D3 associated with cal- ent, increases the risk of nephrolithiasis [30]. A more ematic review and meta-analysis of randomised con- s related with bone health, reported that vitamin D was antly associated to outcomes such as death, myocardial nd stroke [31]. n D, bone metabolism and fractures rotic fractures are common and a serious health prob- postmenopausal women. Adequate levels of vitamin tribute not only to skeletal conservation but also to ular function [20]. Fracture risk significantly increases tiles of serum 25(OH)D levels, and is independent of rs. Thus, women with the lowest 25(OH)D concentra- 6 nmol/L, 19 ng/mL) had higher fracture risk than do the highest levels (>70.6 nmol/L, 28.2 ng/mL) [32]. entation with vitamin D3 (>700 IU/day) and calcium enefits on bone mineral density (BMD) and reduces ractures as compared to placebo [33]. A meta-analysis ouble blind randomised controlled trials studying indi- a mean age of 65 years or older who received vitamin D IU/day) had a 19% reduction in the risk of falls. If serum vels reached 60 nmol/L (24 ng/mL) or more there was a uction rate. However, daily vitamin D doses of less than rum 25(OH)D levels < 60 nmol/L did not reduce the risk . ctiveness of 800 IU day of vitamin D3, with or without increasing BMD and preventing fractures in post- l women has been assessed in a meta-analysis. The est that vitamin D reduces fracture incidence of osteo- -vertebral, hip, and other locations. In addition, vitamin t benefits related to fractures are greater than those calcium alone [35]. A more recent systematic review d more than 45,000 subjects, mostly elderly and female, at vitamin D treatment significantly reduces the risk of ffect is more important in individuals with low vitamin F.R. Pérez-López et al. / Maturitas 71 (2012) 83– 88 85 D status and in studies in which vitamin D was complemented with calcium [36]. Vitamin D insufficiency may also be an important factor in the diminished response to bisphosphonates seen in clinical practice. Thus, postm 33 ng/mL (l times more with lower ficient seru non-respon It seems prevent BM falls. When be added to 4.3. Vitamin Muscle m min D statu strength in ated with lo predominan the lower li ing [12]. In h have been different in handgrip st D levels we [41]. The effe without cal systematic trials. Poole plementatio 25(OH)D le involved in 4.4. Cardiov Hypovit factors, suc sity, periph infarction, h In youn (<80 nmol/L risk of syst serum 25(O risk. In a do (40 nmol/L) with reduce In adults ultrasound thickness. C measures o The use has been a the Women In this stud (400 IU/day myocardial plementatio health. The women wh 4.5. Diabetes mellitus and vitamin D Vitamin D is involved in the regulation of insulin secretion, as suggested by the presence of vitamin D receptors in pancreatic In ad erse ely a tein coho 25(O jects serum dise d by ) lev ted t ted t tami min etast tic a L (2 ted ore, i nship eta-a n se tive )D le luded mbi fican canc )D le com highe st ca ser orre sed w l/L ( with met dwin a me ne s ive 1 n D/d en o gro eatm tly in is of the n, se ted t ong c els a t ser -rela leve nific recta 0% l enopausal women with 25(OH)D blood levels above ower levels were considered as insufficient) were 7 likely to respond to osteoporosis therapy than those levels. In this study, 16.8% of responders had insuf- m 25(OH)D levels as compared to 54.9% among those ders to bisphosphonate treatment [37]. that adequate amounts of calcium and vitamin D may D loss, and increase muscle strength and reduce risk of osteoporosis is present, vitamin D supplements should antiresorptives or other appropriate treatments. D, physical fitness and frailty ass and strength declines in aged individuals and vita- s may contribute to this involution [13]. Reduced muscle creases the risk of falls in older women and is associ- w serum 25(OH)D levels [38,39]. Vitamin D deficiency tly affects the weight-bearing antigravity muscles of mbs which are pivotal for postural balance and walk- ealthy postmenopausal women, serum 25(OH)D levels related to physical fitness, and is a common factor in dices such as android fat mass, lean mass, balance and rength [40]. In individuals aged 65 and older, vitamin re inversely associated with poor physical performance ct of vitamin D supplementation in adults, with or cium, on muscle strength has also been studied in a review and meta-analysis of 17 randomised controlled d data showed a considerable effect of vitamin D sup- n over hip muscle strength only in subjects with serum vels <25 nmol/L (10 ng/mL) [42]. Thus vitamin D may be maintaining muscle strength. ascular disease risk factors and vitamin D aminosis D has been associated with a series of risk h as hypertension, glucose and lipid metabolism, obe- eral artery disease, coronary artery disease, myocardial eart failure and stroke [43,44]. g adult women baseline 25(OH)D insufficiency , 32 ng/mL) was significantly associated to a higher olic hypertension [45]. A meta-analysis reported that H)D levels were inversely associated to hypertension se–response meta-analysis an increment of 16 ng/mL in serum 25(OH)D levels was significantly associated d blood pressure levels [46]. , serum 25(OH)D levels are inversely associated with measured intima–media and maximal carotid plaque alcium, PTH and calcitriol were not associated with f carotid health [47]. of calcium supplements, with and without vitamin D, ssociated to cardiovascular events in a reanalysis of ’s Health Initiative cohort and a meta-analysis [48,49]. y calcium supplements, with or without vitamin D ), increased the risk of cardiovascular events, especially infarction, suggesting that the excess of calcium sup- n may have negative consequences on cardiovascular refore, there is now concern about giving calcium in ose diet is replete as well as vitamin D. islets. are inv positiv lipopro center lower Sub lower of the reduce 25(OH associa associa 4.6. Vi Vita and m apopto 10 ng/m associa Theref relatio A m betwee of rela 25(OH for inc both co a signi breast 25(OH risk as in the of brea Low were c diagno 10 nmo ciated distant by Goo up for In o to rece vitami in wom placeb that tr nifican analys versus additio associa Am sis lev highes cancer lowest and sig of colo had a 4 ults without diabetes mellitus, serum 25(OH)D levels ly associated to fasting glucose and insulin levels, and ssociated to insulin sensitivity index and high density cholesterol levels [50]. In a US cross-sectional multi- rt study, only diabetes was significantly associated with H)D and calcitriol levels [51]. who developed type 2 diabetes in a 5-year period, had 25(OH)D as compared to those who remained free ase. It was estimated that the diabetes risk would be 24% for each 25 nmol/L (10 ng/mL) increment in serum els. In addition, serum 25(OH)D levels were positively o insulin sensitivity. High calcium diet content was not o diabetes risk [52]. n D, breast cancer and colon cancer D induces cell differentiation and inhibits proliferation atic potential and hence may be considered as an anti- gent [53,54]. A meta-regression analysis found that a 5 nmol/L) increase in serum 25(OH) D was significantly to a lower risk for colorectal and breast cancer [55]. t seems that 25(OH)D levels display a consistent inverse with these two types of cancer. nalysis of observational studies reported an association rum 25(OH)D levels and breast cancer. The summary risks for a 20 ng/mL (50 nmol/L) increase of serum vels and decreased breast cancer risk were significant case–control studies, nested case–control studies and ned study designs [56]. Another meta-analysis reported t inverse relationship between vitamin D intake and er risk. In addition, the highest quartile of serum vels was associated to a 45% decrease in breast cancer pared to the lowest quartile. On the other hand, women st quartile of calcium intake displayed a 19% reduction ncer risk as compared to the lowest quartile [57]. um 25(OH)D levels measured before chemotherapy lated to more deaths among postmenopausal women ith breast cancer and followed up for 5.8 years. Hence, a 4 ng/mL) decrement in serum 25(OH)D levels was asso- an 8% increase in death risk and a 14% increase in risk of astasis [58]. These results are similar to those reported et al. [59] in women with early breast cancer followed an of 11.6 years. tudy postmenop