Impact of a Prenatal Vitamin D Supplementation Program on Vitamin D Deficiency, Rickets and Early Childhood Caries in an Alaska Native Population.

Background: Early childhood rickets increased in Alaska Native children after decreases in vitamin D-rich subsistence diet in childbearing-aged women. We evaluated the impact of routine prenatal vitamin D supplementation initiated in Alaska's Yukon Kuskokwim Delta in Fall 2016. Methods: We queried electronic health records of prenatal women with 25(OH) vitamin D testing during the period 2015−2019. We evaluated 25(OH)D concentrations, vitamin D3 supplement refills, and decayed, missing, and filled teeth (dmft) scores and rickets in offspring. Results: Mean 25(OH)D concentrations increased 36.5% from pre- to post-supplementation; the percentage with deficient 25(OH)D decreased by 66.4%. Women with ≥ 60 vitamin D3 refill days had higher late pregnancy 25(OH)D concentrations than those with no refill days (p < 0.0001). Women with late pregnancy insufficient 25(OH)D concentrations had offspring with higher dmft scores than those with sufficient 25(OH)D (RR 1.3, p < 0.0001). Three children were diagnosed with nutritional rickets during the period 2001−2021, and none after 2017. Conclusions: These findings suggest that prenatal vitamin D supplementation can improve childhood outcomes in high-risk populations with high rates of rickets.

Efficacy and Safety of Vamorolone vs Placebo and Prednisone Among Boys With Duchenne Muscular Dystrophy: A Randomized Clinical Trial.

Importance: Corticosteroidal anti-inflammatory drugs are widely prescribed but long-term use shows adverse effects that detract from patient quality of life. Objective: To determine if vamorolone, a structurally unique dissociative steroidal anti-inflammatory drug, is able to retain efficacy while reducing safety concerns with use in Duchenne muscular dystrophy (DMD). Design, Setting, and Participants: Randomized, double-blind, placebo- and prednisone-controlled 24-week clinical trial, conducted from June 29, 2018, to February 24, 2021, with 24 weeks of follow-up. This was a multicenter study (33 referral centers in 11 countries) and included boys 4 to younger than 7 years of age with genetically confirmed DMD not previously treated with corticosteroids. Interventions: The study included 4 groups: placebo; prednisone, 0.75 mg/kg per day; vamorolone, 2 mg/kg per day; and vamorolone, 6 mg/kg per day. Main Outcomes and Measures: Study outcomes monitored (1) efficacy, which included motor outcomes (primary: time to stand from supine velocity in the vamorolone, 6 mg/kg per day, group vs placebo; secondary: time to stand from supine velocity [vamorolone, 2 mg/kg per day], 6-minute walk distance, time to run/walk 10 m [vamorolone, 2 and 6 mg/kg per day]; exploratory: NorthStar Ambulatory Assessment, time to climb 4 stairs) and (2) safety, which included growth, bone biomarkers, and a corticotropin (ACTH)-challenge test. Results: Among the 133 boys with DMD enrolled in the study (mean [SD] age, 5.4 [0.9] years), 121 were randomly assigned to treatment groups, and 114 completed the 24-week treatment period. The trial met the primary end point for change from baseline to week 24 time to stand velocity for vamorolone, 6 mg/kg per day (least-squares mean [SE] velocity, 0.05 [0.01] m/s vs placebo -0.01 [0.01] m/s; 95% CI, 0.02-0.10; P = .002) and the first 4 sequential secondary end points: time to stand velocity, vamorolone, 2 mg/kg per day, vs placebo; 6-minute walk test, vamorolone, 6 mg/kg per day, vs placebo; 6-minute walk test, vamorolone, 2 mg/kg per day, vs placebo; and time to run/walk 10 m velocity, vamorolone, 6 mg/kg per day, vs placebo. Height percentile declined in prednisone-treated (not vamorolone-treated) participants (change from baseline [SD]: prednisone, -1.88 [8.81] percentile vs vamorolone, 6 mg/kg per day, +3.86 [6.16] percentile; P = .02). Bone turnover markers declined with prednisone but not with vamorolone. Boys with DMD at baseline showed low ACTH-stimulated cortisol and high incidence of adrenal insufficiency. All 3 treatment groups led to increased adrenal insufficiency. Conclusions and Relevance: In this pivotal randomized clinical trial, vamorolone was shown to be effective and safe in the treatment of boys with DMD over a 24-week treatment period. Vamorolone may be a safer alternative than prednisone in this disease, in which long-term corticosteroid use is the standard of care. Trial Registration: ClinicalTrials.gov Identifier: NCT03439670.

Preventing symptomatic vitamin D deficiency and rickets among Indigenous infants and children in Canada.

Vitamin D deficiency (VitDD) rickets and other manifestations of severe VitDD, such as cardiomyopathy and hypocalcemic seizures, continue to be diagnosed in Canada. Breastfed Indigenous infants, particularly those living in northern communities, are disproportionately impacted, although formula-fed infants are not exempt in cases where the mother's vitamin D status is critically low. This statement deals with the prevention of rickets and hypocalcemia due to VitDD for Indigenous children, and revises an earlier document from the Canadian Paediatric Society. An assessment of the risk for VitDD is recommended for each maternal-infant dyad because of the link between maternal and infant VitDD. Along with supports for enhanced adherence, additional VitD supplementation is recommended for prenatal women and infants deemed at high risk and, in certain situations, intermittent higher dose supplementation may be required. Food insecurity can also contribute to rickets, so advocacy is required to prevent VitDD rickets in Indigenous children.

Vitamin D supplementation for children with cancer: A systematic review and consensus recommendations.

BACKGROUND: Prevalent vitamin D deficiency (VDD) and low bone mineral density (BMD) have led to vitamin D supplementation for children with cancer, regardless vitamin D status. However, it remains unsettled whether this enhances bone strength. We sought to address this issue by carrying out a systematic review of the literature. METHODS: We conducted a literature search using PubMed, Embase, and Cochrane databases. Studies including children up to 5 years after cancer therapy were assessed for the association between 25-hydroxyvitamin D (25OHD) levels and BMD Z-scores or fractures, and the effect of vitamin D supplementation on BMD or fractures. Evidence quality was assessed using the GRADE methodology. RESULTS: Nineteen studies (16 observational and 3 interventional, mainly involving children with hematologic malignancies) were included. One study which analyzed 25OHD as a threshold variable (≤10 ng/ml) found a significant association between 25OHD levels and BMD Z-scores, while 25OHD as a continuous variable was not significantly associated with BMD Z-scores in 14 observational studies. We found neither a significant association between lower 25OHD levels and fractures (2 studies), nor between vitamin D (and calcium) supplementation and BMD or fracture frequency (3 studies) (very low quality evidence). CONCLUSION: There is a lack of evidence for an effect of vitamin D (and calcium) supplementation on BMD or fractures in children with cancer. Further research is needed; until then, we recommend dietary vitamin D/calcium intake in keeping with standard national guidelines, and periodic 25OHD monitoring to detect levels <20 ng/ml. Vitamin D/calcium supplementation is recommended in children with low levels, to maintain levels ≥20 ng/ml year-long.

Long-Term Follow-up of Hypophosphatemic Bone Disease Associated With Elemental Formula Use: Sustained Correction of Bone Disease After Formula Change or Phosphate Supplementation.

In this article, we describe the long-term outcomes of children who were previously reported to have developed hypophosphatemic bone disease in association with elemental formula use. An extended chart review allowed for an updated report of 34 children with regard to severity/duration of bone disease, extent of recovery, and time to correction using radiology reports and biochemical data. After implementation of formula change and/or phosphate supplementation, we found that serum phosphorus concentration increased and serum alkaline phosphatase activity decreased in all patients, normalizing by 6.6 ± 4.0 (mean ± SD) months following diagnosis. The decrease in serum alkaline phosphatase from diagnosis to the time of correction was moderately correlated with the concurrent increase in serum phosphorus (R = 0.48, P < .05). Age at diagnosis significantly correlated with time to resolution (R = 0.51, P = .01). This study supports the earlier report that bone disease associated with hypophosphatemia during elemental formula use responds to formula change and/or phosphate supplementation.

Diagnosis and management of Duchenne muscular dystrophy, part 1: diagnosis, and neuromuscular, rehabilitation, endocrine, and gastrointestinal and nutritional management.

Since the publication of the Duchenne muscular dystrophy (DMD) care considerations in 2010, multidisciplinary care of this severe, progressive neuromuscular disease has evolved. In conjunction with improved patient survival, a shift to more anticipatory diagnostic and therapeutic strategies has occurred, with a renewed focus on patient quality of life. In 2014, a steering committee of experts from a wide range of disciplines was established to update the 2010 DMD care considerations, with the goal of improving patient care. The new care considerations aim to address the needs of patients with prolonged survival, to provide guidance on advances in assessments and interventions, and to consider the implications of emerging genetic and molecular therapies for DMD. The committee identified 11 topics to be included in the update, eight of which were addressed in the original care considerations. The three new topics are primary care and emergency management, endocrine management, and transitions of care across the lifespan. In part 1 of this three-part update, we present care considerations for diagnosis of DMD and neuromuscular, rehabilitation, endocrine (growth, puberty, and adrenal insufficiency), and gastrointestinal (including nutrition and dysphagia) management.

Rickets.

Rickets is a bone disease associated with abnormal serum calcium and phosphate levels. The clinical presentation is heterogeneous and depends on the age of onset and pathogenesis but includes bowing deformities of the legs, short stature and widening of joints. The disorder can be caused by nutritional deficiencies or genetic defects. Mutations in genes encoding proteins involved in vitamin D metabolism or action, fibroblast growth factor 23 (FGF23) production or degradation, renal phosphate handling or bone mineralization have been identified. The prevalence of nutritional rickets has substantially declined compared with the prevalence 200 years ago, but the condition has been re-emerging even in some well-resourced countries; prematurely born infants or breastfed infants who have dark skin types are particularly at risk. Diagnosis is usually established by medical history, physical examination, biochemical tests and radiography. Prevention is possible only for nutritional rickets and includes supplementation or food fortification with calcium and vitamin D either alone or in combination with sunlight exposure. Treatment of typical nutritional rickets includes calcium and/or vitamin D supplementation, although instances infrequently occur in which phosphate repletion may be necessary. Management of heritable types of rickets associated with defects in vitamin D metabolism or activation involves the administration of vitamin D metabolites. Oral phosphate supplementation is usually indicated for FGF23-independent phosphopenic rickets, whereas the conventional treatment of FGF23-dependent types of rickets includes a combination of phosphate and activated vitamin D; an anti-FGF23 antibody has shown promising results and is under further study.

Unexpected widespread hypophosphatemia and bone disease associated with elemental formula use in infants and children.

OBJECTIVE: Hypophosphatemia occurs with inadequate dietary intake, malabsorption, increased renal excretion, or shifts between intracellular and extracellular compartments. We noticed the common finding of amino-acid based elemental formula [EF] use in an unexpected number of cases of idiopathic hypophosphatemia occurring in infants and children evaluated for skeletal disease. We aimed to fully characterize the clinical profiles in these cases. METHODS: A retrospective chart review of children with unexplained hypophosphatemia was performed as cases accumulated from various centres in North America and Ireland. Data were analyzed to explore any relationships between feeding and biochemical or clinical features, effects of treatment, and to identify a potential mechanism. RESULTS: Fifty-one children were identified at 17 institutions with EF-associated hypophosphatemia. Most children had complex illnesses and had been solely fed Neocate® formula products for variable periods of time prior to presentation. Feeding methods varied. Hypophosphatemia was detected during evaluation of fractures or rickets. Increased alkaline phosphatase activity and appropriate renal conservation of phosphate were documented in nearly all cases. Skeletal radiographs demonstrated fractures, undermineralization, or rickets in 94% of the cases. Although the skeletal disease had often been attributed to underlying disease, most all improved with addition of supplemental phosphate or change to a different formula product. CONCLUSION: The observed biochemical profiles indicated a deficient dietary supply or severe malabsorption of phosphate, despite adequate formula composition. When transition to an alternate formula was possible, biochemical status improved shortly after introduction to the alternate formula, with eventual improvement of skeletal abnormalities. These observations strongly implicate that bioavailability of formula phosphorus may be impaired in certain clinical settings. The widespread nature of the findings lead us to strongly recommend careful monitoring of mineral metabolism in children fed EF. Transition to alternative formula use or implementation of phosphate supplementation should be performed cautiously with as severe hypocalcemia may develop.

Clinical Guidelines for Management of Bone Health in Rett Syndrome Based on Expert Consensus and Available Evidence.

OBJECTIVES: We developed clinical guidelines for the management of bone health in Rett syndrome through evidence review and the consensus of an expert panel of clinicians. METHODS: An initial guidelines draft was created which included statements based upon literature review and 11 open-ended questions where literature was lacking. The international expert panel reviewed the draft online using a 2-stage Delphi process to reach consensus agreement. Items describe the clinical assessment of bone health, bone mineral density assessment and technique, and pharmacological and non-pharmacological interventions. RESULTS: Agreement was reached on 39 statements which were formulated from 41 statements and 11 questions. When assessing bone health in Rett syndrome a comprehensive assessment of fracture history, mutation type, prescribed medication, pubertal development, mobility level, dietary intake and biochemical bone markers is recommended. A baseline densitometry assessment should be performed with accommodations made for size, with the frequency of surveillance determined according to individual risk. Lateral spine x-rays are also suggested. Increasing physical activity and initiating calcium and vitamin D supplementation when low are the first approaches to optimizing bone health in Rett syndrome. If individuals with Rett syndrome meet the ISCD criterion for osteoporosis in children, the use of bisphosphonates is recommended. CONCLUSION: A clinically significant history of fracture in combination with low bone densitometry findings is necessary for a diagnosis of osteoporosis. These evidence and consensus-based guidelines have the potential to improve bone health in those with Rett syndrome, reduce the frequency of fractures, and stimulate further research that aims to ameliorate the impacts of this serious comorbidity.

Global Consensus Recommendations on Prevention and Management of Nutritional Rickets.

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. EVIDENCE: A systematic literature search examining the definition, diagnosis, treatment, and prevention of nutritional rickets in children was conducted. Evidence-based recommendations were developed using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system that describe the strength of the recommendation and the quality of supporting evidence. PROCESS: Thirty-three nominated experts in pediatric endocrinology, pediatrics, nutrition, epidemiology, public health, and health economics evaluated the evidence on specific questions within five working groups. The consensus group, representing 11 international scientific organizations, participated in a multiday conference in May 2014 to reach a global evidence-based consensus. RESULTS: This consensus document defines nutritional rickets and its diagnostic criteria and describes the clinical management of rickets and osteomalacia. Risk factors, particularly in mothers and infants, are ranked, and specific prevention recommendations including food fortification and supplementation are offered for both the clinical and public health contexts. CONCLUSION: Rickets, osteomalacia, and vitamin D and calcium deficiencies are preventable global public health problems in infants, children, and adolescents. Implementation of international rickets prevention programs, including supplementation and food fortification, is urgently required.

Global Consensus Recommendations on Prevention and Management of Nutritional Rickets.

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. EVIDENCE: A systematic literature search examining the definition, diagnosis, treatment, and prevention of nutritional rickets in children was conducted. Evidence-based recommendations were developed using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system that describes the strength of the recommendation and the quality of supporting evidence. PROCESS: Thirty-three nominated experts in pediatric endocrinology, pediatrics, nutrition, epidemiology, public health, and health economics evaluated the evidence on specific questions within five working groups. The consensus group, representing 11 international scientific organizations, participated in a multiday conference in May 2014 to reach a global evidence-based consensus. RESULTS: This consensus document defines nutritional rickets and its diagnostic criteria and describes the clinical management of rickets and osteomalacia. Risk factors, particularly in mothers and infants, are ranked, and specific prevention recommendations including food fortification and supplementation are offered for both the clinical and public health contexts. CONCLUSION: Rickets, osteomalacia, and vitamin D and calcium deficiencies are preventable global public health problems in infants, children, and adolescents. Implementation of international rickets prevention programs, including supplementation and food fortification, is urgently required.

Incidence and characteristics of vitamin D deficiency rickets in New Zealand children: a New Zealand Paediatric Surveillance Unit study.

OBJECTIVE: To investigate the incidence and characteristics of vitamin D deficiency rickets in New Zealand (NZ). METHODS: Prospective surveillance among paediatricians of Vitamin D Deficiency Rickets was conducted by the New Zealand Paediatric Surveillance Unit (NZPSU) for 36 months, from July 2010 to June 2013, inclusive. Inclusion criteria were: children and adolescents <15 years of age with vitamin D deficiency rickets (defined by low serum 25-hydroxyvitamin D and elevated alkaline phosphatase levels, and/or radiological rickets). RESULTS: Fifty-eight children with confirmed vitamin D deficiency rickets were identified. Median age was 1.4 (range 0.3-11) years, 47% were male, and 95% of the children were born in NZ; however, the majority of the mothers (68%) were born outside NZ. Overall annual incidence of rickets in children aged <15 years was 2.2/100,000 (95%CI 1.4-3.5); with incidence in those <3 years being 10.5/100,000 (95%CI 6.7-16.6). Skeletal abnormalities, poor growth and motor delay were the most common presenting features, with hypocalcaemic convulsion in 16% of children. Key risk factors identified were: darker skin pigment, Indian and African ethnicity, age <3 years, exclusive breast feeding, and southern latitude, particularly when combined with season (winter/spring). Of the patients reported, none had received appropriate vitamin D supplementation. CONCLUSIONS: Vitamin D deficiency rickets remains a problem for NZ children. Key risk factors remain similar to those identified in the international literature. Preventative targeted vitamin D supplementation, as per existing national guidelines, was lacking in all cases reported. IMPLICATIONS: Vitamin D deficiency rickets is the most significant manifestation of vitamin D deficiency in growing children. To reduce the incidence of this disease among those at high risk, increasing awareness and implementation of current public health policies for targeted maternal, infant and child supplementation are required.

Efficacy of food fortification on serum 25-hydroxyvitamin D concentrations: systematic review.

BACKGROUND: Many residents of the United States and Canada depend on dietary sources of vitamin D to help maintain vitamin D status. Because few natural food sources contain vitamin D, fortified foods may be required. OBJECTIVE: We aimed to determine the effects of vitamin D-fortified foods on serum 25-hydroxyvitamin D [25(OH)D] concentrations. DESIGN: We searched MEDLINE (1966 to June Week 3 2006), Embase, CINAHL, AMED, Biological Abstracts, and the Cochrane Central Register of Controlled Trials for randomized controlled trials (RCTs) comparing vitamin D-fortified foods with a control and reporting serum 25(OH)D concentrations. Two reviewers independently determined study eligibility, assessed trial quality, and extracted relevant data. Disagreements were resolved by consensus. Meta-analyses of absolute mean change in 25(OH)D were conducted by using a random-effects model, with evaluation of heterogeneity. RESULTS: Nine RCTs (n = 889 subjects) were included, of which 8 consistently showed a significant beneficial effect of food fortification on 25(OH)D concentrations. Although 7 RCTs (n = 585 subjects) potentially were meta-analyzable, we were unable to combine the overall results because of significant heterogeneity. The individual treatment effects ranged from 14.5 (95% CIs: 10.6, 18.4) nmol/L to 34.5 (17.64, 51.36) nmol/L (3.4-25 microg vitamin D/d). Subgroup analyses showed a reduction in heterogeneity and significant treatment effect when 4 trials that used milk as the fortified food source were combined. CONCLUSION: Most trials were small in size and inadequately reported allocation concealment, but results showed that vitamin D-fortified foods improved vitamin D status in adults.

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

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 to doses >/= 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.

Effect of calcium and vitamin D supplementation on bone mineral density in children with inflammatory bowel disease.

OBJECTIVES: The purpose of this study was to evaluate the effect of calcium and vitamin D2 supplementation on bone mineral density (BMD) in children with inflammatory bowel disease (IBD). PATIENTS AND METHODS: This was an open-label, prospective study conducted over a 12-month period. Seventy-two patients were divided into 2 groups based on lumbar spine areal BMD (L2-4 aBMD). Patients with an L2-4 aBMD z score of -1 or higher were assigned to the control group (n = 33; mean age, 11.0 +/- 3.5 years; 20 boys). Patients with an L2-4 aBMD of less than -1 (n = 39; mean age 11.8 +/- 2.5 years; 25 boys) were allocated to the intervention group and received 1000 mg of supplemental elemental calcium daily for 12 months (n = 19) or supplemental calcium for 12 months and 50,000 IU of vitamin D2 monthly for 6 months (n = 20). RESULTS: The 2 groups differed in L2-4 aBMD z scores (intervention, -1.9 +/- 0.6; control, -0.2 +/- 0.6; P < 0.001) and volumetric L2-4 BMD (vBMD; intervention, 0.29 +/- 0.04; control, 0.33 +/- 0.06; P < 0.001). After 1 year of therapy, the control and intervention groups had similar changes in height z scores, L2-4 aBMD, L2-4 vBMD (z score change, L2-4 aBMD: control 0.2 +/- 0.6 [n = 21], intervention 0.4 +/- 0.6; P = 0.4 [n = 26]; z score change, L2-4 vBMD: control 0.1 +/- 0.4, intervention 0.2 +/- 0.6; P = 0.74). The changes in these parameters were similar between patients who had received calcium only or calcium plus vitamin D. CONCLUSIONS: These results suggest that, in children with IBD, supplementation of calcium and vitamin D does not accelerate accrual in L2-4 BMD.

Vitamin D-deficiency rickets among children in Canada.

BACKGROUND: Based on regional and anecdotal reports, there is concern that vitamin D-deficiency rickets is persistent in Canada despite guidelines for its prevention. We sought to determine the incidence and clinical characteristics of vitamin D-deficiency rickets among children living in Canada. METHODS: A total of 2325 Canadian pediatricians were surveyed monthly from July 1, 2002, to June 30, 2004, through the Canadian Paediatric Surveillance Program to determine the incidence, geographic distribution and clinical profiles of confirmed cases of vitamin D-deficiency rickets. We calculated incidence rates based on the number of confirmed cases over the product of the length of the study period (2 years) and the estimates of the population by age group. RESULTS: There were 104 confirmed cases of vitamin D- deficiency rickets during the study period. The overall annual incidence rate was 2.9 cases per 100,000. The incidence rates were highest among children residing in the the north (Yukon Territory, Northwest Territories and Nunavut). The mean age at diagnosis was 1.4 years (standard deviation [SD] 0.9, min-max 2 weeks-6.3 years). Sixty-eight children (65%) had lived in urban areas most of their lives, and 57 (55%) of the cases were identified in Ontario. Ninety-two (89%) of the children had intermediate or darker skin. Ninety-eight (94%) had been breast-fed, and 3 children (2.9%) had been fed standard infant formula. None of the breast-fed infants had received vitamin D supplementation according to current guidelines (400 IU/d). Maternal risk factors included limited sun exposure and a lack of vitamin D from diet or supplements during pregnancy and lactation. The majority of children showed clinically important morbidity at diagnosis, including hypocalcemic seizures (20 cases, 19%). INTERPRETATION: Vitamin D-deficiency rickets is persistent in Canada, particularly among children who reside in the north and among infants with darker skin who are breast-fed without appropriate vitamin D supplementation. Since there were no reported cases of breast-fed children having received regular vitamin D (400 IU/d) from birth who developed rickets, the current guidelines for rickets prevention can be effective but are not being consistently implemented. The exception appears to be infants, including those fed standard infant formula, born to mothers with a profound vitamin D deficiency, in which case the current guidelines may not be adequate to rescue infants from the vitamin D-deficient state.