Summary
This review describes the vitamin D status in different regions of the world with the objective of understanding the scope of hypovitaminosis D and the factors related to its prevalence that may contribute to the pathogenesis of osteoporosis and fragility fractures.

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Global vitamin D status and determinants of hypovitaminosis D.

Is vitamin D deficiency a major global public health problem

Objectives To review and synthesize the literature in the following areas: the association of specific circulating 25(OH)D concentrations with bone health outcomes in children, women of reproductive age, postmenopausal women and elderly men; the effect of dietary intakes (foods fortified with vitamin D and/or vitamin D supplementation) and sun exposure on serum 25(OH)D; the effect of vitamin D on bone mineral density (BMD) and fracture or fall risk; and the identification of potential harms of vitamin D above current reference intakes. Data sources MEDLINE(R) (1966-June Week 3 2006); Embase (2002-2006 Week 25); CINAHL (1982-June Week 4, 2006); AMED (1985 to June 2006); Biological Abstracts (1990-February 2005); and the Cochrane Central Register of Controlled Trials (2nd Quarter 2006). Review methods Two independent reviewers completed a multi-level process of screening the literature to identify eligible studies (title and abstract, followed by full text review, and categorization of study design per key question). To minimize bias, study design was limited to randomized controlled trials (RCTs) wherever possible. Study criteria for question one were broadened to include observational studies due to a paucity of available RCTs, and question four was restricted to systematic reviews to limit scope. Data were abstracted in duplicate and study quality assessed. Differences in opinion were resolved through consensus or adjudication. If clinically relevant and statistically feasible, meta-analyses of RCTs on vitamin D supplementation and bone health outcomes were conducted, with exploration of heterogeneity. When meta-analysis was not feasible, a qualitative systematic review of eligible studies was conducted. Results 167 studies met our eligibility criteria (112 RCTs, 19 prospective cohorts, 30 case-controls and six before-after studies). The largest body of evidence on vitamin D status and bone health was in older adults with a lack of studies in premenopausal women and infants, children and adolescents. The quality of RCTs was highest in the vitamin D efficacy trials for prevention of falls and/or fractures in older adults. There was fair evidence of an association between low circulating 25(OH)D concentrations and established rickets. However, the specific 25(OH)D concentrations associated with rickets is uncertain, given the lack of studies in populations with dietary calcium intakes similar to North American diets and the different methods used to determine 25(OH)D concentrations. There was inconsistent evidence of an association of circulating 25(OH)D with bone mineral content in infants, and fair evidence that serum 25(OH)D is inversely associated with serum PTH. In adolescents, there was fair evidence for an association between 25(OH)D levels and changes in BMD. There were very few studies in pregnant and lactating women, and insufficient evidence for an association between serum 25(OH)D and changes in BMD during lactation, and fair evidence of an inverse correlation with PTH. In older adults, there was fair evidence that serum 25(OH)D is inversely associated with falls, fair evidence for a positive association with BMD, and inconsistent evidence for an association with fractures. The imprecision of 25(OH)D assays may have contributed to the variable thresholds of 25(OH)D below which the risk of fractures, falls or bone loss was increased. There was good evidence that intakes from vitamin D-fortified foods (11 RCTs) consistently increased serum 25(OH)D in both young and older adults. Eight randomized trials of ultraviolet (UV)-B radiation (artificial and solar exposure) were small and heterogeneous with respect to determination of the exact UV-B dose and 25(OH)D assay but there was a positive effect on serum 25(OH)D concentrations. It was not possible to determine how 25(OH)D levels varied by ethnicity, sunscreen use or latitude. Seventy-four trials examined the effect of vitamin D(3) or D(2) on 25(OH)D concentrations. Most trials used vitamin D(3), and the majority enrolled older adults. In three trials, there was a greater response of serum 25(OH)D concentrations to vitamin D(3) compared to vitamin D(2), which may have been due to more rapid clearance of vitamin D(2) in addition to other mechanisms. Meta-analysis of 16 trials of vitamin D(3) was consistent with a dose-response effect on serum 25(OH)D when comparing daily doses of /= 400 IU. An exploratory analysis of the heterogeneity demonstrated a significant positive association comparable to an increase of 1 - 2 nmol/L in serum 25(OH)D for every 100 additional units of vitamin D although heterogeneity remained after adjusting for dose. Vitamin D(3) in combination with calcium results in small increases in BMD compared to placebo in older adults although quantitative synthesis was limited due to variable treatment durations and BMD sites. The evidence for fracture reduction with vitamin D supplementation was inconsistent across 15 trials. The combined results of trials using vitamin D(3) (700 - 800 IU daily) with calcium (500 - 1,200 mg) was consistent with a benefit on fractures although in a subgroup analysis by setting, benefit was primarily in elderly institutionalized women (fair evidence from two trials). There was inconsistent evidence across 14 RCTs of a benefit on fall risk. However, a subgroup analysis showed a benefit of vitamin D in postmenopausal women, and in trials that used vitamin D(3) plus calcium. In addition, there was a reduction in fall risk with vitamin D when six trials that adequately ascertained falls were combined. Limitations of the fall and fracture trials included poor compliance with vitamin D supplementation, incomplete assessment of vitamin D status and large losses to follow-up. We did not find any systematic reviews that addressed the question on the level of sunlight exposure that is sufficient to maintain serum 25(OH)D concentrations but minimizes risk of melanoma and non-melanoma skin cancer. There is little evidence from existing trials that vitamin D above current reference intakes is harmful. In most trials, reports of hypercalcemia and hypercalciuria were not associated with clinically relevant events. The Women's Health Initiative study did report a small increase in kidney stones in postmenopausal women aged 50 to 79 years whose daily vitamin D(3) intake was 400 IU (the reference intake for 50 to 70 years, and below the reference intake for > 70 years) combined with 1000 mg calcium. The increase in renal stones corresponded to 5.7 events per 10,000 person-years of exposure. The women in this trial had higher calcium intakes than is seen in most post-menopausal women. Conclusions The results highlight the need for additional high quality studies in infants, children, premenopausal women, and diverse racial or ethnic groups. There was fair evidence from studies of an association between circulating 25(OH)D concentrations with some bone health outcomes (established rickets, PTH, falls, BMD). However, the evidence for an association was inconsistent for other outcomes (e.g., BMC in infants and fractures in adults). It was difficult to define specific thresholds of circulating 25(OH)D for optimal bone health due to the imprecision of different 25(OH)D assays. Standard reference preparations are needed so that serum 25(OH)D can be accurately and reliably measured, and validated. In most trials, the effects of vitamin D and calcium could not be separated. Vitamin D(3) (>700 IU/day) with calcium supplementation compared to placebo has a small beneficial effect on BMD, and reduces the risk of fractures and falls although benefit may be confined to specific subgroups. Vitamin D intake above current dietary reference intakes was not reported to be associated with an increased risk of adverse events. However, most trials of higher doses of vitamin D were not adequately designed to assess long-term harms.

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Effectiveness and safety of vitamin D in relation to bone health.

Background:
Vitamin D and calcium deficiencies are common worldwide, causing nutritional rickets and osteomalacia, which have a major impact on health, growth, and development of infants, children, and adolescents; the consequences can be lethal or can last into adulthood. The goals of this evidence-based consensus document are to provide health care professionals with guidance for prevention, diagnosis, and management of nutritional rickets and to provide policy makers with a framework to work toward its eradication.

Consensus Statement: Global Consensus Recommendations on Prevention and Management of Nutritional Rickets

This book on vitamin A deficiency not only addresses ocular manifestations but also the broader context of child health and survival. The introduction examines the historical and modern perspectives of vitamin deficiency what vitamin A is and the relationship of xerophthalmia (severe vitamin A deficiency) to vitamin A status. The second section of the book discusses consequences of vitamin A deficiency. Chapter 2 looks at mortality associated with moderate to severe deficiency and the fact that vitamin A supplementation reduces preschool-age mortality and measles mortality. Chapter 3 covers infectious morbidity particularly diarrhea measles respiratory disease urinary tract infection otitis and other infections (e.g. HIV). Chapter 4 examines ocular manifestations (xerophthalmia keratomalacia night blindness and conjunctiva). The effect of vitamin A on anemia and iron metabolism and the extent of vitamin A deficiency-associated anemia are discussed in chapter 5. Chapter 6 examines vitamin As role in growth in animals and children. The third section of the book is dedicated to mechanisms of vitamin A. Chapter 7 looks at contributory and precipitating events (i.e. systemic infections and protein energy malnutrition). Chapter 8 addresses the biochemistry of vitamin A and carotenoids. Chapter 9 examines the relationship between immunocompetence and vitamin A status particularly lymphoid organs and hematopoiesis cell-mediated immunity humoral immunity effect of vitamin A administration on immune response and identification of and requirements for immunoregulatory retinoids. The fourth section chapter 10 is dedicated to treatment of vitamin A deficiency and xerophthalmia. The last section covers assessment and prevention. Chapters 11 and 12 discuss assessment of vitamin A status and epidemiology of deficiency respectively. The last three chapters examine prevention interventions: dietary interventions supplementation and fortification of dietary items with vitamin A.

Vitamin A Deficiency: Health, Survival, and Vision

During the 9th month (Ramadan) of the Islamic calendar (Hijra) many millions of adult Muslims all over the world fast during the daylight hours. Since Hijra is a lunar calendar, Ramadan occurs at different times in the seasonal year over a 33-year cycle. Fasting during Ramadan is partial because the abstention from food, fluid, tobacco and caffeine is from sunrise to sunset. Several categories of people are exempt or can postpone the Ramadan fast. The effect on health and well being of the month-long intermittent fast and fluid restriction has been studied in various potentially vulnerable groups in addition to normal healthy individuals in many countries. The majority of the studies have found significant metabolic changes, but few health problems arising from the fast. A reduction in drug compliance was an inherent negative aspect of the fast. Common findings of the studies reviewed were increased irritability and incidences of headaches with sleep deprivation and lassitude prevalent. A small body mass loss is a frequent, but not universal, outcome of Ramadan. During the daylight hours of Ramadan fasting, practising Muslims are undoubtedly dehydrating, but it is not clear whether they are chronically hypohydrated during the month of Ramadan. No detrimental effects on health have as yet been directly attributed to negative water balance at the levels that may be produced during Ramadan.

Effects on health of fluid restriction during fasting in Ramadan

Background: There has been a resurgence of nutritional rickets in children in many developing countries and some of the developed countries. Children between 6 and 18 months old are commonly affected. In order to find out the association between vitamin D and rickets we studied the vitamin D status of the neonates and their mothers in Kuwait.



Methods: Two hundred and fourteen full-term pregnant mothers and their neonates were selected from two hospitals in Kuwait. All mothers had normal vaginal delivery. On the day of delivery 2.5 mL of maternal blood and 2.5 mL of cord blood samples were withdrawn. Serum 25-hydroxyvitamin D (25OHD) was determined in duplicate by radioimmunoassay using an Incstar kit. Quality control analyses were done using several between and within run experiments.



Results: A total of 128 mother–neonate pairs were selected from the Al-Adan hospital and 86 from the Maternity Hospital. The mean age and parity of the mothers were similar in both hospitals. The mean (± SD) 25OHD levels of the mothers and the neonates in the Adan hospital were 13.3 (6.5) ng/mL and 8.2 (6.5) ng/mL, respectively. The corresponding values in the Maternity Hospital were 17.6 (12.4) and 8.1 (7.3) ng/mL for the mothers and the neonate, respectively. Serum 25OHD of the mothers and their newborn infants were highly correlated (r = 0.790, P < 0.001).



Conclusions: Results demonstrate that 40% of the mothers and 60% of the neonates are vitamin D deficient on the day of delivery. The vitamin D of the mothers and neonates are highly correlated (r = 0.790, P < 0.001).

Vitamin D status of mothers and their neonates in Kuwait.

Objectives: To evaluate the effect of vitamin A supplementation 24 h after delivery on breastmilk retinol concentration. Methods: Fifty low income women were randomly assigned to a single oral dose of 209 μmol of Vitamin A or none at delivery. Maternal serum and breastmilk retinol levels and infant morbidity and anthropometry were serially assessed. Results: Mean (95% CI) serum retinol levels increased in the supplemented mothers at 2.77 (2.3, 3.2) compared to 1.15 (0.9, 1.4) μmol/l in controls (P<0.05) and remained at a significantly higher level of 1.59 (1.4, 1.8) μmul/l compared to 1.33 (1.8, 1.5) μmol/l in the control group (P<0.001) up to a period of three months. Breastmilk retinol concentration was also greater at 24 h after supplementation, mean (CI) 11.34 (9.0, 13.7) μmol/l, compared to 2.95 (2.3, 3.6) μmol/l in the control group (P<0.0001), and remained higher for the next six months at 1.06 (0.9, ,1.3) μmol/l compared to 0.73 (0.6, 0.8) μmol/l in the control group (P<0.02). Infants of the supplemented mothers had reduced mean duration of respiratory tract infection of 3.1 (2.7, 3.5) days compared to 3.7 (3.3, 4.2) days (P<0.03) and mean incidence of febrile illness 0.1 (0.1, 0.1) compared to control infants 0.3 (0.3, 0.3) days, (P<0.002). Conclusion: Vitamin A supplementation of malnourished mothers maintains higher breastmilk retinol concentration for at least six months and reduces the duration of respiratory tract infection and febrile illness in their breastfed infants. Sponsorship: The study was supported by the International Centre for Diarrhoeal Disease Research and the United States Agency for International Development.

Impact of a single megadose of vitamin A at delivery on breastmilk of mothers and morbidity of their infants

Aim: To assess the risk factors for nutritional rickets among children in Kuwait.



Methods: One hundred and three children with rickets and 102 control children matched for age and socioethnic characteristics were recruited over a 2 year period (January 1995 to January 1997) in Al-Adan Hospital in Kuwait. Diagnosis was made on clinical, radiologic and biochemical parameters. A specially designed questionnaire was administered by one of the investigators to both mothers of patients and mothers of control subjects to assess the role of social, nutritional and other related factors in the pathogenesis of nutritional rickets. Biochemical investigations included estimation of hemoglobin, serum calcium, serum phosphorus, serum alkaline phosphatase and serum 25-hydroxy vitamin D.



Results: The mean birthweights of rickets patients and control subjects were 3.20~0.46 and 3.19~0.45 kg, respectively. At the time of diagnosis, bodyweights of the patients and controls were 9.36~1.50 and 10.15~2.10 kg, respectively. Heights at the time of diagnosis were 73.58 and 77.24 cm for the patients and the controls, respectively. Mean hemoglobin, serum calcium and serum phosphate were significantly lower in the patients compared with the controls. Alkaline phosphatase was higher among the patients (P<0.0001). The mean serum 25-hydroxy vitamin D level of the patients was 26.5 nmol/L, compared with 83.5 nmol/L in the controls. The mean age of starting semisolid feeds for the patients was 8.12 months, compared with 5.7 months in the controls. The nutritional quality of semisolid feeds was adequate among 71.6% of the controls as opposed to 13.6% of the patients.



Conclusion: Nutritional rickets is a multifactorial condition. However, several factors seem to make important contributions. Among these, lack of exposure to sunlight, prolonged breast feeding without supplementation and inadequate weaning practices are important. Maternal education is important as it can influence all of the above factors.

Risk factors for nutritional rickets among children in Kuwait.

A preliminary baseline survey was conducted to estimate the prevalence of anemia in a group of 391 children aged 6-60 months randomly selected from 3 urban slums of Karachi. Hemoglobin and red cell indices including hematocrit MCV MCH MCHC RBC and red cell distribution width (RDW) were estimated for each of the selected children. Ferritin estimation was done on 354 (91%) children to assess the iron storage status. According to WHO criteria the accepted cutoff point for anemia screening in children is set at 11 gm/dl 70 fl and 20 pg for hemoglobin MCV and MCH respectively. Following these criteria 118 (30%) children were classified as normals (Hg = or > 11 gm/dl) and 273 (70%) as anemic (Hg = or < 11 gm/dl). Of the 354 ferritin estimations 225 (64%) children had ferritin levels lower than normal (< 11 ng/ml) and 128 (36%) had ferritin levels within normal limit (11-120 ng/ml). From this group a total of 61% (214/354) children were classified as microcytic hypochromic (MIH) and 11% (39/354) of which had normal ferritin levels suggesting the presence of thalassemia minor trait. The overall results obtained indicate that iron deficiency anemia is highly prevalent among these children. (authors)

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Abdul Majid Molla

Papers

Effects on health of fluid restriction during fasting in Ramadan

Vitamin D status of mothers and their neonates in Kuwait.

Impact of a single megadose of vitamin A at delivery on breastmilk of mothers and morbidity of their infants

Risk factors for nutritional rickets among children in Kuwait.

Prevalence of iron deficiency anaemia in children of the urban slums of Karachi.