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Context Osteoporotic fractures are an important cause of morbidity in children with glucocorticoid-treated rheumatic disorders. Objective This work aims to evaluate the incidence and predictors of osteoporotic fractures and potential for recovery over six years following glucocorticoid (GC) initiation in children with rheumatic disorders. Methods Children with GC-treated rheumatic disorders were evaluated through a prospective inception cohort study led by the Canadian STeroid-induced Osteoporosis in the Pediatric Population (STOPP) Consortium. Clinical outcomes included lumbar spine bone mineral density (LS BMD), vertebral fractures (VF), non-VF, and vertebral body reshaping. Results A total of 136 children with GC-treated rheumatic disorders were enrolled (mean age 9.9 years, SD 4.4). The 6-year cumulative fracture incidence was 16.3% for VF, and 10.1% for non-VF. GC exposure was highest in the first 6 months, and 24 of 38 VF (63%) occurred in the first 2 years. Following VF, 16 of 19 children (84%) had complete vertebral body reshaping. Increases in disease activity and body mass index z scores in the first year and declines in LS BMD z scores in the first 6 months predicted incident VF over the 6 years, while higher average daily GC doses predicted both incident VF and non-VF. LS BMD z scores were lowest at 6 months (mean –0.9, SD 1.2) and remained low by 6 years even when adjusted for height z scores (–0.6, SD 0.9). Conclusion VF occurred early and were more common than non-VF in children with GC-treated rheumatic disorders. Eighty-four percent of children with VF underwent complete vertebral body reshaping, whereas vertebral deformity persisted in the remainder of children. On average, LS BMD z scores remained low at 6 years, consistent with incomplete recovery.

Background: Sparse data exists on the utility of individual serum non-esterified fatty acids (NEFAs) as clinical and dietary biomarkers and how reporting methods could affect these associations. We investigated the associations of 19 serum NEFAs expressed as µM or mol%, with self-reported dietary intake data, and cardiometabolic health indicators in pregnant women. Methods: In this cross-sectional study, 273 pregnant women in their second trimester each completed a semi-quantitative food-frequency questionnaire and provided fasting serum samples. Comprehensive serum NEFA analysis was performed by multisegment injection-nonaqueous capillary electrophoresis-mass spectrometry. We evaluated the associations of NEFAs using two different reporting methods, with diet quality, specific foods intake, and measures of adiposity and glucose homeostasis. Results: Consistently stronger dietary correlations were observed when expressed as mol%. Serum ω-3 NEFAs were associated with diet quality and fish/fish oil daily servings (DHA mol%, r=0.37; p=4.8e-10), and odd-chain NEFAs were associated with full-fat dairy intake (15:0 mol%, r=0.23; p=9.0e-5). Glucose intolerance was positively associated with odd chain NEFAs as expressed in µM (r=0.21; p=0.001) but inversely associated when expressed as mol% (r=-0.31; p=2.2e-7). In contrast, monounsaturated NEFAs (µM and mol%) had robust positive associations with pre-pregnancy BMI, second trimester skin-fold thickness, glycated hemoglobin, fasting glucose, and glucose intolerance. Conclusions: This study demonstrates the utility of specific NEFAs and their sub-classes as viable dietary and clinical biomarkers when reported as their relative proportions. More research is needed to investigate inconsistencies between absolute concentrations and relative proportions when reporting fatty acids.

Objective The effects of maternal prepregnancy body mass index (BMI) and gestational weight gain (GWG) on maternal and offspring obesity traits, as well as the maternal and offspring genetic contribution to GWG and postpartum weight retention, were examined. Methods Blood samples from mothers (n = 608) and offspring (n = 541) were genotyped for 83 BMI-associated SNPs and 47 waist-to-hip ratio (WHR)-associated SNPs. Linear regression and mixed-effects regression models were performed to examine clinical epidemiological and genetic associations with unweighted and weighted BMI and WHR genetic risk scores (GRS). Results Prepregnancy BMI was positively associated with offspring weight and BMI Z-score from birth to 5 years. GWG was positively associated with maternal postpartum weight retention at 1 and 5 years and with offspring weight Z-score from birth to 5 years old. The maternal unweighted BMI GRS was associated with prepregnancy BMI, postpartum weight retention at 5 years, and offspring weight Z-score from birth to 5 years old, but not associated with GWG. Both maternal and offspring unweighted WHR GRSs were negatively associated with GWG. Conclusions Maternal BMI-associated SNPs may contribute to the genetic link between prepregnancy BMI variation, long-term postpartum weight retention, and offspring birth weight and longitudinal weight. Maternal and offspring WHR-associated SNPs may contribute to GWG variation.

In 2016, the Multiple Sclerosis (MS) Society of Canada convened a panel of expert scientists, clinicians and patient advocate to review the evidence for an association between vitamin D status and MS prevention and/or disease modification. The goal was to develop clear and accurate recommendations on optimal vitamin D intake and status for people affected by MS for use in clinical practice and public health policy. The final consensus report was based on a review and grading of existing published papers combined with expert opinions of panel members. The report led to recommendations published in November of 2018 on the website of the MS Society of Canada, one in a format for use by health professionals and another in a question and answer format that was targeted to persons affected by MS and the general public. For people at risk of developing MS, the vitamin D recommendations are similar to those for the general public following the Dietary Reference Intakes (DRI) for Canada and the United States. Adults should achieve and maintain a normal vitamin D status with monitoring by physicians (serum 25-hydroxyvitamin D (25(OH)D) = 50−125 nmol/L, requiring 600–4000 IU vitamin D/d intake). For pregnant women, newborn infants, and all youth at risk of MS, vitamin D intakes should also follow DRI recommendations but additionally their serum 25-(OH)D should be monitored. For persons living with MS, existing evidence did not allow prediction of a vitamin D intake that might modify MS disease course. For this group the recommendations included: (1) serum 25-(OH)D should be maintained in the range of 50–125 nmol/L (600–4000 IU/d intake).; and (2) vitamin D should not be used as a standalone treatment for MS. For children and adolescents, serum 25OHD status was recommended to be measured upon diagnosis of a first clinical demyelinating event, and monitored every 6 months to achieve a target of 75 nmol/L Since people living with MS are at increased risk of osteoporosis, falls, and bone fractures, it was recommended to achieve a minimum serum 25OHD concentration that is protective for bone health in the general population. The revision of the MS Society recommendations on vitamin D awaits future clinical trial evidence.

OBJECTIVE: To assess the effect of vertebral fractures (VF) and glucocorticoid (GC) exposure on height deficits in children during treatment of acute lymphoblastic leukemia (ALL). METHODS: Children with ALL treated without cranial radiation therapy (n = 160; median age, 5.1 years; 58.1% male) were followed prospectively for 6 years. Spinal deformity index (SDI) was used to quantify VF status. RESULTS: Baseline height z score ± SD was 0.3 ± 1.2. It fell by 0.5 ± 0.4 in the first 6 months for boys and by 0.4 ± 0.4 in the first 12 months for girls (P < 0.01 for both) and then subsequently recovered. The prevalence of VF peaked at 1 year (17.6%). Among those with VF, median SDI rose from 2 [interquartile range (IQR): 1, 7] at baseline to 8 (IQR: 1, 8) at 1 year. A mixed model for repeated measures showed that height z score declined by 0.13 (95% CI: 0.02 to 0.24; P = 0.02) for each 5-unit increase in SDI during the previous 12 months. Every 10 mg/m(2) increase in average daily GC dose (prednisone equivalent) in the previous 12 months was associated with a height z score decrement of 0.26 (95% CI: 0.20 to 0.32; P < 0.01). CONCLUSIONS: GC likely plays a major role in the observed height decline during therapy for ALL. Because only a minority of children had VF, fractures could not have contributed significantly to the height deficit in the entire cohort but may have been important among the subset with VF.

Background Dietary inadequacy and adiposity, both prevalent in the chronic spinal cord injury (SCI) population, are known to influence bone turnover and may be potential modifiable risk factors for the development of sublesional osteoporosis following SCI. This pilot study in an SCI cohort aimed to assess measures of nutrition and obesity, to determine if these measures were associated with bone mineral density (BMD), and to compare these measures to a non-SCI control cohort. Methods In a cross-sectional observational study, volunteers with chronic SCI (> 1 year post-injury, lesions from C1 to T12 and severity category A–D by the American Spinal Injury Association Impairment Scale) were assessed, and 8 non-SCI individuals were recruited as a comparison group. BMD at the femoral neck (FN) and lumbar spine (LS), and an estimate of visceral adipose tissue (VAT) from lumbar vertebrae 1 through 4 were measured using dual energy X-ray absorptiometry (DXA); nutrient intake of calcium, vitamins D & K, and protein were estimated using a food frequency questionnaire; plasma 25-hydroxyvitamin D (25(OH)D) was analyzed using ultra-high performance liquid chromatography/tandem mass spectroscopy; and serum leptin, adiponectin and insulin were analyzed using a multiplex assay. Results A total of 34 individuals with SCI (n = 22 tetraplegic; n = 12 paraplegic; 94% male) who averaged 12.7 (9.0) years post-injury, age 40.0 (10.9) years and % body fat of 28.4 (7.3) were assessed. Multiple linear regression analyses in the SCI cohort showed significant associations between BMD at the FN and LS with leptin (FN: r = 0.529, p = 0.005; LS: r = 0.392, p = 0.05), insulin (FN: r = 0.544, p = 0.003; LS: r = 0.388, p = 0.05), and VAT percent (FN: r = 0.444, p = 0.02; LS: r = 0.381, p = 0.05). Adiponectin was only correlated with LS BMD (r = 0.429, p = 0.03). No significant relationships were found between BMD and serum 25(OH)D, or intakes of calcium, vitamins D & K, and protein. Intake of vitamin D was adequate in 69% of participants with SCI, where 91% of those persons consumed either vitamin D and/or multivitamin supplements. Vitamin D status was similar between SCI and non-SCI groups as was sub-optimal status (25(OH)D, Highlights • In SCI subjects, BMD was positively associated with adiposity. • Adipokine regulation may be more important for bone status in chronic SCI. • Compromised BMD in SCI was not attributed to suboptimal vitamin D or bone nutrients. • Widespread variability in SCI stage/severity may have influenced lack of association. • Suboptimal 25(OH)D status was seen in 60% of an SCI cohort, despite vitamin D supplement use in 63%.

OBJECTIVES: Maternal bone health can be compromised in pregnancy if diet and exercise are inadequate. Our objective was to determine the changes of calciotropic hormones and bone biomarkers in response to a maternal high-dairy diet plus exercise intervention compared to usual care from early to late pregnancy. METHODS: As part of the Be Healthy in Pregnancy RCT (Southern Ontario, Canada) (NCT01689961), healthy pregnant women (≤ 17 wk gestation) were randomized to the control or treatment group (Nutrition: 25% protein energy with ∼50% from dairy and Exercise plan: 10,000 daily steps) for the duration of pregnancy. Calcium and vitamin D intakes were analyzed from 3-day diet and supplement records (Nutritionist Pro). Fasted serum was analyzed for 25(OH)D(2) and D(3) and 1,25(OH)(2)D by LC-MS/MS (Waters Corp.); procollagen type I N-terminal propeptide (PINP, Cloud Clone Corp., TX, USA) and insulin growth factor-1 (IGF-1, R&D Systems, MN, USA) by ELISA) at 12–17 and 36–38 wk gestation. T-tests were used to compare groups at baseline. Two-way ANOVA were performed to assess time and treatment effect. RESULTS: In 118 women (86% of European descent, mean (range) pre-pregnancy BMI 24.9 kg/m2 (17.9 – 39.6 kg/m2)), baseline median (Q1, Q3) vitamin D and calcium intakes (585 IU/d (453, 823) and 1192 mg/d (979, 1512)) and bone biomarkers were similar between control and treatment groups. Baseline 25(OH)D was 79.6 nmol/L (66.1, 97.7), 1,25(OH)(2)D was 71.5 pmol/L (62.3, 89.8), PINP was 57.0 ng/mL (37.4, 74.2) and IGF-1 was 178.0 ng/mL (132.0, 212.0). At the end of pregnancy, concentrations of 25(OH)D, 1,25(OH)(2)D and IGF-1 increased significantly (P

BACKGROUND:Metabolic abnormalities that lead to type 2 diabetes mellitus begin in early childhood. OBJECTIVES:We investigate whether common genetic variants identified in adults have an effect on glucose in early life. METHODS:610 newborns, 463 mothers, and 366 fathers were included in the present study. Plasma glucose and anthropometric characteristics were collected at birth, 3, and 5 years. After quality assessment, 37 SNPs, which have demonstrated an association with fasting plasma glucose at the genome-wide threshold in adults, were studied. Quantitative trait disequilibrium tests and mixed-effects regressions were conducted to estimate an effect of the SNPs on glucose. RESULTS:Risk alleles for 6 loci increased glucose levels from birth to 5 years of age (ADCY5, ADRA2A, CDKAL1, CDKN2A/B, GRB10, and TCF7L2, 4.85x10-3 ≤ P ≤ 4.60x10-2). Together, these 6 SNPs increase glucose by 0.05 mmol/L for each risk allele in a genotype score (P = 6.33x10-5). None of the associations described in the present study have been reported previously in early childhood. CONCLUSION:Our data support the notion that a subset of loci contributing to plasma glucose variation in adults has an effect at birth and in early life.

Background.Osteoporosis is a chronic disease that can significantly impact numerous aspects of health and wellness. The individual consequences of osteoporosis can be devastating, often resulting in substantial loss of independence and sometimes death. One of the few illnesses with greater disease burden than low bone mineral density (BMD) is major depressive disorder (MDD). Both depression and antidepressant use have been identified as secondary causes of osteoporosis. The objective of this paper is to review and summarize the current findings on the relationship between antidepressant use and BMD.Methods.Relevant sources were identified from the Pubmed and MEDLINE databases, citing articles from the first relevant publication to September 1st, 2010.Results.2001 articles initially met the search criteria, and 35 studies were thoroughly reviewed for evidence of an association between SSRI use and BMD, and 8 clinical studies were detailed and summarized in this paper.Conclusions.Current findings suggest a link between mental illness and osteoporosis that is of clinical relevance. Additional longitudinal studies and further research on possible mechanisms surrounding the association between SSRI use on bone metabolism need to be conducted. Treatment algorithms need to recognize this association to ensure that vulnerable populations are screened.

Consolidation and maintenance of peak bone mass in young adulthood may be compromised by inactivity, low dietary calcium, and diet-induced weight loss.We aimed to determine whether higher intakes of dairy foods, dietary calcium, and protein during diet- and exercise-induced weight loss affected markers of bone health.Participants included premenopausal overweight and obese women.Ninety participants were randomized into three groups (n = 30 per group): high protein and high dairy (HPHD), adequate protein and medium dairy (APMD), and adequate protein and low dairy (APLD), differing in dietary protein (30, 15, or 15% of energy, respectively), dairy foods (15, 7.5, or2% of energy from protein, respectively), and dietary calcium (∼1600, ∼1000, or500 mg/d, respectively).Serum and urine bone turnover biomarkers, serum osteoprotegerin (OPG), receptor activator of nuclear factor-κB ligand (RANKL), PTH, 25-hydroxyvitamin D, leptin, and adiponectin measured at 0 and 16 wk.All groups lost equivalent body weight (P0.05). N-telopeptide, C-telopeptide (CTX), urinary deoxypyridinoline, and osteocalcin increased in APLD (P0.01), whereas in HPHD, osteocalcin and procollagen 1 amino-terminal propeptide (P1NP) increased (P0.05), and all resorption markers remained unchanged. P1NP to CTX and OPG to RANKL ratios increased in HPHD (P0.005), and P1NP to CTX ratio decreased in APLD (P0.05). PTH decreased in HPHD and APMD vs. APLD (P0.005), and 25-hydroxyvitamin D increased in HPHD (P0.05), remained unchanged in APMD, and decreased in APLD (P0.05). Leptin decreased and adiponectin increased in APMD and HPHD only (P0.001).Hypoenergetic diets higher in dairy foods, dietary calcium, and protein with daily exercise, favorably affected important bone health biomarkers vs. diets with less of these bone-supporting nutrients.

Objective Adults with type 2 diabetes mellitus (DM) have an elevated fracture risk despite normal areal bone mineral density (aBMD). The study objective was to compare trabecular bone microarchitecture of postmenopausal women with type 2 DM and women without type 2 DM. Methods An extremity 1T magnetic resonance imaging system was used to acquire axial images (195 × 195 × 1,000 μm3 voxel size) of the distal radius of women recruited from outpatient clinics or by community advertisement. Image segmentation yielded geometric, topologic, and stereologic outcomes, i.e., number and size of trabecular bone network holes (marrow spaces), endosteal area, trabecular bone volume fraction, nodal and branch density, and apparent trabecular thickness, separation, and number. Lumbar spine (LS) and proximal femur BMD were measured with dual x-ray absorptiometry. Microarchitectural differences were assessed using linear regression and adjusted for percent body fat, ethnicity, timed up-and-go test, Charlson Index, and calcium and vitamin D intake; aBMD differences were adjusted for body mass index (BMI). Results Women with type 2 DM (n = 30, mean ± SD age 71.0 ± 4.8 years) had larger holes (+13.3%; P = 0.001) within the trabecular bone network than women without type 2 DM (n = 30, mean ± SD age 70.7 ± 4.9 years). LS aBMD was greater in women with type 2 DM; however, after adjustment for BMI, LS aBMD did not differ between groups. Conclusion In women with type 2 DM, the average hole size within the trabecular bone network at the distal radius is greater compared to controls. This may explain the elevated fracture risk in this population.

Weight loss can have substantial health benefits for overweight or obese persons; however, the ratio of fat:lean tissue loss may be more important. We aimed to determine how daily exercise (resistance and/or aerobic) and a hypoenergetic diet varying in protein and calcium content from dairy foods would affect the composition of weight lost in otherwise healthy, premenopausal, overweight, and obese women. Ninety participants were randomized to 3 groups (n = 30/group): high protein, high dairy (HPHD), adequate protein, medium dairy (APMD), and adequate protein, low dairy (APLD) differing in the quantity of total dietary protein and dairy food-source protein consumed: 30 and 15%, 15 and 7.5%, or 15 and

Introduction The current dietary reference intakes (DRI) for calcium for North America were set by the Food and Nutrition Board a decade ago. As pediatric calcium researchers, we considered the need for revising the recommended intakes for calcium in children in light of issues and evidence that have emerged since the mid-1990s. We approached the question of whether or not calcium requirements are unnecessarily high in the form of a debate. In this commentary, our goal is not to systematically review the evidence base for considering revision of calcium intakes, but rather to discuss the pros and cons of changing calcium requirements for building peak bone mass in light of recent evidence. A particular emphasis is given to statistical issues that arise in long-term intervention studies and how these issues influence the impact of the findings. Current calcium intake recommendations for North America were published by the Institute of Medicine in 1997 (1). The panel considered calcium recommendations from several points of view, including published randomized, controlled trials (RCT), applying the factorial approach that accounted for daily calcium losses plus growth needs, adjusted for fractional calcium absorption, and the intake to achieve maximal calcium retention. The latter approach was prioritized because reports of calcium retention over a range of calcium intakes were available in adolescents, whereas dose-response RCT with bone outcome measures were not. The intake for maximal calcium retention was determined to be 1300 mg/d, using a nonlinear regression model (2), which became the adequate intake (AI) for ages 9–18 y for North America (1). Calcium retention largely reflects bone mass, because 99% of the body’s calcium is in the skeleton and exists as a constant percentage of bone mineral. Bone mass is an important component of bone strength (3). Thus, the panel reasoned that achieving maximal calcium retention would remove dietary calcium as a limiting factor for maximizing peak bone mass within one’s genetic potential to offer the greatest protection against fracture later in life. Because the DRI for calcium for adolescents was set as an AI and not an estimated average requirement (EAR) with a derived recommended dietary allowance (RDA), this value should be flagged for reconsideration. The criteria for triggers to stimulate a revision of DRI values were outlined as follows at an Institute of Medicine workshop (4): presence of an AI value, that the nutrient for the age group was identified as a research priority, that substantive new research has emerged, or that the nutrient for the age group would affect important public health policy. For the DRI value for calcium for adolescents, all of these criteria apply. The key considerations for setting recommended intakes for any nutrient are the choice of indicator of nutritional adequacy and the strength of the evidence for that chosen indicator. For calcium recommendations for adolescents, the quality of the evidence should be assessed on the following criteria: availability of dose response data, that a period of adaptation to different intakes of calcium has been included in the study design, that response has been measured for both dietary sources of calcium and calcium supplements, and that data from more than 1 laboratory are available, with adequate representation of males and females and ethnic groups. The debate outlined in this article addresses whether or not sufficient new evidence exists to revise the calcium recommendations for adolescents for North America. The debate is broadly relevant beyond North America because average calcium intakes for females are frequently low, but they range from 800 to 1500 mg/d (5). The percentage of adolescents in 20 countries meeting or exceeding country-specific calcium recommendations was 65% for males and 50% for females (6).

The derivation of reference values in 11 current dietary reference standards is often based on methods of extrapolation or interpolation, but these are not consistent across reports. Such methods are frequently employed to derive nutrient intake values (NIVs) for infants and children owing to the paucity of relevant research data available. The most common method is to extrapolate values for children down from those of adults, employing a weight or metabolic factor and adjusting for growth. In some instances, values for young children are extrapolated up from infants, values for adults are extrapolated up from children, or values for older adults are extrapolated up from young adults. Extrapolation is employed to estimate not only nutrient requirement or adequate intake but also the upper tolerable levels of intake. Extrapolation methods may also form the basis of estimates of tissue deposition of nutrients during growth in children and for the maternal/fetal dyad in pregnancy with adjustments for metabolic efficiency. Likewise, recommended intakes during lactation are extrapolated from known secretion of the nutrient in milk with adjustments for bioavailability. For future dietary standards, a first priority is to obtain relevant scientific data using current methodology, such as stable isotope tracers, body composition analysis, and appropriate biomarkers, from which NIVs for each age group can be derived. Extrapolation to derive an NIV is only acceptable in the sheer absence of sound scientific data and must be modeled with a consistent approach. For the purpose of harmonization of dietary standards, we recommend the following approaches that should be clearly described in reports: standardization of age groups on a biological basis (growth and pubertal stages) with consideration of relevant developmental milestones throughout childhood; application of internationally accepted standards for growth, body size, body composition, fetal and maternal nutrient accretion in pregnancy, and milk composition; and inclusion of appropriate adjustments (metabolic efficiency, weight change, or physical activity).

Early detection of abnormalities in bone turnover may be facilitated by assessing biomarkers of bone metabolism including vitamin D status. In many children with cancer, biomarkers of bone formation (osteocalcin, bone specific alkaline phosphatase and carboxy-(or N terminal) propeptide of type 1 procollagen) were observed to be suppressed, while bone resorption was elevated as measured by serum cross-linked (or C-terminal) telopeptide of type 1 collagen. Insulin-like growth factor 1, which stimulates bone formation, may be suppressed indirectly indicating a growth hormone insufficiency. Leptin may also play a role in bone remodeling as hyperleptinemia has been observed in association with acute lymphoblastic leukemia. Evaluation of bone status using such biomarkers is complicated by the lack of universally accepted reference values and the variation by age, gender, or pubertal status. Etiologic factors contributing to the observed skeletal morbidities include disease process, chemotherapy (drugs such as glucocorticoids and methotrexate) and radiotherapy. Other factors common to children with cancer, such as chronic inflammation, dietary changes and physical inactivity, must also be taken into account. The current evidence for abnormalities in biomarkers of vitamin D status and bone turnover will be the focus of this review of published studies.

There is some evidence that a combination of factors can reduce inflammation and associated metabolic risk factors. We studied the early cardiometabolic and inflammatory adaptations to a short-term exercise intervention with and without milk in obese adolescents. Fifty-four adolescents were randomized to consume milk post exercise (MILK) or a carbohydrate beverage (CONT) during one-week of daily exercise. Insulin levels were not different between the groups post training. Glucose was reduced over time in both groups (-9 ± 13 mg/dl MILK and -6 ± 14 mg/dl CONT, p < .05) but not different between groups. There was a greater decrease in mean arterial pressure (MAP) in the MILK group (-3 ± 6 mmHg MILK vs. 2 ± 7 mmHg CONT, p < .04). Milk provided postexercise did not affect C-reactive protein (CRP), tumor necrosis factor-α (TNF-α) or interleukin-6 (IL-6). The exercise intervention led to an increase in TNF-α in both groups (0.27 ± 0.7 pg/ml MILK and 0.48 ± 0.6 pg/ml CONT, p < .001). The early adaptations to a short-term exercise intervention in obese adolescents include a reduction in MAP and an increase in some inflammatory markers.

The trajectory for bone mineral deposition through the periods of fetal and infant development is becoming better defined as more data emerge on wholebody and regional analysis of bone mineral content (BMC) using dual-energy X-ray absorptiometry (DXA). Previously, knowledge of fetal accretion of nutrients was based on analysis of the chemical composition of fetal and neonatal bodies (1), and more recently for minerals by neutron activation analysis (2). Accretion of nutrients after birth was derived primarily from metabolic balance studies that yielded retention of mineral. Beginning in the early 1980s, BMC of the radius or humerus using single-photon absorptiometry (SPA) was possible to quantitate in small premature infants, but it was not until the early 1990s that the measurement of whole-body BMC by DXA was sufficiently sophisticated to be validated as a tool (3,4) for estimating bone, lean and fat mass in small infants. All three sources of information—fetal tissue analysis, metabolic balance studies, and estimation of BMC by DXA—have contributed to the determination of recommended intakes of minerals and vitamin D to support healthy bone growth. In addition to nutrients, early skeletal development is dependent on genetics, an appropriate endocrine environment including parathyroid hormone (PTH), 1,25dihydroxycholecalciferol, growth hormone (GH), insulin and insulin-like growth factors (IGFs), as well as physical activity.

Intestinal magnesium (Mg) absorption was measured in six healthy children (control) and in four children treated for acute lymphoblastic leukemia with the single-isotope fecal recovery technique (SIFRT). The objective of this study was to determine Mg absorption in young children with acute lymphoblastic leukemia using stable isotope tracers. Fractional and absolute absorption levels determined by SIFRT were not significantly different between children with acute lymphoblastic leukemia (fractional absorption: 58.3 +/- 10.6% [mean +/- SEM], absolute absorption: 3.66 +/- 0.71 mg x kg(-1) x d(-1), [0.15 +/- 0.03 mmol x kg(-1) x d(-1)]) and control children (fractional absorption: 61.4 +/- 7.5%, absolute absorption: 5.69 +/- 0.85 mg x kg(-1) x d(-1), [0.23 +/- 0.03 mmol x kg(-1) x d(-1)]). Average Mg absorption in young children (aged 3--8 y) was 60.2 +/- 5.8%. This study describes the first application of the SIFRT to assess Mg absorption in young children and illustrates the feasibility of the SIFRT in this age group to obtain more accurate information on Mg absorption.

The objectives of this study were 1) to determine whether a zenith in bone formation (indicated by circulating osteocalcin) existed at night in early life, and 2) to compare the effects of three different dexamethasone (DEX) treatment regimens on bone turnover, bone mineral content, and growth. Three DEX treatment regimens were tested in 8-d-old piglets (n = 8/group):1) low evening dose of DEX (0.5 mg/kg/d) as 70% in the morning and 30% in the evening for 10 d;2) tapering course of DEX (0.5, 0.3, and 0.2 mg/kg/d) as 50% in the morning and 50% in the evening for 14 d; and 3) constant dose of DEX (0.5 mg/kg/d) as 50% in the morning and 50% in the evening for 10 d. Oral water placebo groups were tested with the same time courses. At pretreatment, plasma osteocalcin was significantly higher (p < 0.05) at 0100 than at 0900 and 1700. At necropsy, measures for DEX groups were calculated as Z-scores using values from the placebo groups. The low evening DEX dose led to a significantly lower reduction in plasma osteocalcin compared with the tapered and constant dosing regimens (p < 0.05). The significant weight reduction in the DEX group occurred at d 9 in the low evening dose regimen but at d 7 in the constant dosing regimen, compared with the placebo group. Bone mineral content Z-score was reduced similarly in all DEX-treated groups across the three dosing regimens. We conclude that a plasma osteocalcin zenith at night exists in early life. A high DEX dose in the morning and low DEX dose in the evening may partially attenuate corticosteroid-induced suppression of bone formation and growth restriction.

(1) To determine whether nutrient malabsorption or inadequate nutrient intake were involved in the cause of growth delay in patients with bronchopulmonary dysplasia, and (2) to determine whether a nutrient-enriched formula given to infants with bronchopulmonary dysplasia to 3 months corrected age improves the rate of growth with greater lean and bone mass accretion when compared with infants fed an isoenergetic standard infant formula.A blinded, nutrition intervention trial of 60 preterm infants with bronchopulmonary dysplasia (birth weight, 866 +/- 169 g, gestational age, 26 +/- 1.5 weeks) randomized to either nutrient-enriched formula or standard formula. Growth, body composition, and nutrient retention were compared between groups by Student's t tests and analysis of covariance.Infants fed the enriched formula had significantly greater nitrogen and mineral retention at 38 weeks' postmenstrual age, and only the infants fed enriched formula had zinc retention similar to the intrauterine accretion. At 3 months corrected age infants fed enriched formula attained greater length (P.05), greater radial bone mineral content (P.01), and greater lean mass (P.01). The male infants in the enriched formula group had greater whole body bone mineral content than did male infants in the standard formula group (P = .02).Greater linear growth and lean and bone mass in the enriched formula group suggests that infants with bronchopulmonary dysplasia attain faster "catch-up" growth when fed higher intakes of protein, calcium, phosphorus, and zinc than provided in standard proprietary formulas.

Dexamethasone (DEX) therapy improves pulmonary compliance in premature infants with chronic lung disease; however, normal growth and bone development are impaired. Because DEX may mediate its effects by altering the GH-IGF-I axis, we investigated whether adjunctive therapy with GH or GH + IGF-I during DEX therapy could attenuate these DEX-induced effects. Piglets were randomized to placebo, oral tapered DEX (0.5, 0.3, and 0.2 mg kg(-1) d(-1) over 14 d), DEX + GH (0.1 mg kg(-1) d(-1)) or DEX + GH + IGF-I (0.1 mg kg(-1) d(-1)). Final whole body weight and length were improved with GH or GH + IGF-I compared with the DEX alone group. Plasma GH and IGF-I were not influenced by DEX, but infusion of IGF-I resulted in higher (p0.05) plasma IGF-I compared with all other groups at d 15. DEX reduced (p0.05) circulating IGFBP-2 and IGFBP-3 and liver IGFBP-2 and IGFBP-4 mRNA expression compared with controls. Treatment with DEX alone resulted in lower (p0.05) plasma osteocalcin, urinary N-telopeptide, and whole body and femur bone mineral density compared with controls, whereas results with piglets receiving adjunctive GH or GH + IGF-I were similar to those of controls. Given adjunctively, GH alone appears to partially counter the abnormalities in growth and bone metabolism associated with DEX therapy; however, this improvement cannot be attributed to higher circulating IGF-I, because combined therapy did not further improve growth or bone homeostasis compared with DEX + GH treatment. Growth hormone therapy has the potential to stimulate growth in infants exposed to steroid treatment.

Tamoxifen (Tam) has been shown to inhibit dexamethasone (Dex)-mediated effects on bone formation in vitro. Our objective was to determine whether Tam would block Dex-induced osteopenia and growth inhibition in growing piglets. Four-day-old male Yorkshire piglets were adapted to a liquid formula diet (400 ml/kg x day) and randomized to one of four groups (n = 5/group): Dex (0.5 mg/kg x day), Tam (1 mg/kg x day), Dex plus Tam, or placebo control (vehicle only). Both drugs were administered by orogastric gavage twice daily for 12 days. At baseline and at the end of treatment, whole body bone mineral density (BMD) was determined by dual energy x-ray absorptiometry (Hologic QDR1000W). Plasma osteocalcin and PTH were measured on days 0 and 12, and urinary N-telopeptide was measured on day 12. Changes in axial length and daily weight were also measured. Delta whole body BMD was 29% lower (P0.05) in Dex alone treated piglets than in controls (0.033 vs. 0.047 g/cm2, respectively), whereas the maximum change in BMD in Dex plus Tam group (0.046 g/cm2) was similar to that in controls. Concurrent Tam administration reduced the Dex-induced deficit in weight gain by 56% (P0.05) and the deficit in axial length gain by 72% (P0.01). In Dex alone treated piglets, PTH was significantly elevated (7-fold), whereas osteocalcin and N-telopeptide were significantly reduced compared with control values. These effects were prevented by Tam. These data suggest that the suppression of growth and other changes in parameters of bone metabolism induced by glucocorticoids in vivo can be attenuated by Tam.

In children with acute lymphoblastic leukemia (ALL), abnormalities in mineral homeostasis and bone mass were first reported by our group in the late 1980s. Prospective longitudinal cohort studies in 40 consecutive patients receiving treatment according to the Dana-Farber Cancer Institute (DFCI) protocol 87-001 and 16 children receiving DFCI protocol 91-001 afforded us the opportunity to explore various etiologies of the observed abnormalities in mineral and bone metabolism, specifically the leukemic disease process and chemotherapeutic drugs such as steroids and aminoglycoside antibiotics. At diagnosis of ALL, >70% of children had abnormally low plasma 1,25-dihydroxyvitamin D, 73% had low osteocalcin and 64% had hypercalciuria, indicating an effect of the leukemic process on vitamin D metabolism and bone turnover. During remission induction, treatment with high-dose steroid (prednisone or dexamethasone) resulted in further reduction in plasma osteocalcin and elevated parathyroid hormone levels. During 24 months of chemotherapy-maintained remission, reduction in bone mineral content (BMC), as measured by Z-scores, occurred in 64% of children, most severely affecting those >11 years of age. A reduction in BMC during the first 6 months had a positive predictive value of 64% for subsequent fracture. By the end of 2 years of therapy, fractures occurred in 39% of children and radiographic evidence of osteopenia was found in 83% of the entire study group. Investigations of the biochemical basis of the bone abnormalities revealed that by 6 months hypomagnesemia developed in 84% of children (of whom 52% were hypermagnesuric) and plasma 1,25-dihydroxyvitamin D remained abnormally low in 70%. Altered magnesium status was attributed to renal wastage of magnesium following cyclical prednisone therapy and treatment with aminoglycoside antibiotics such as amikacin for fever accompanying neutropenia. Dietary intake and absorption of magnesium were normal. In 10 children treated for hypomagnesemia with supplemental magnesium for up to 16–20 weeks, plasma magnesium normalized in only 50% of subjects. Int. J. Cancer Supplement 11:35–39, 1998. © 1998 Wiley-Liss, Inc.

Background: We have previously shown that the majority of survivors treated for acute lymphoblastic leukemia (ALL) in childhood recovered their bone mineral density (BMD) despite disease effects and prolonged therapy with steroids and methotrexate. However, for a subset of patients who received higher total doses of methotrexate or prednisone, bone mass remained sub-optimal. This study’s objective was to determine whether altered bone turnover was reflected in profiles of bone biomarkers as a cause of their persistently reduced bone mass. Methods: Markers of bone metabolism were measured in 31 survivors of ALL with low BMD. The results were compared to 29 ALL survivors with normal BMD that were matched for gender, age and years since diagnosis. Blood samples obtained at the time of the scan by dual energy x-ray absorptiometry for BMD measure were assayed for 25-hydroxyvitamin D, parathyroid hormone (PTH), and serum CrossLaps. Results: No difference was found between survivors with low BMD and those with normal BMD for serum 25-OH Vitamin D, PTH or serum C-terminal telopeptide of type-1 collagen (CrossLaps). Vitamin D status was lower than accepted for normal bone health in 37% of subjects and 27% of controls. Conclusion: Survivors of childhood ALL as a whole recover normal BMD. Those that have low BMD after treatments do not have evidence of any permanent alterations in markers of bone turnover. Thus, survivors of childhood ALL who have low BMD likely do so for the same reasons as the general population, such as inadequate Vitamin D status.

The purpose of this study was to determine whether trabecular bone mineralization differed in adults with type 2 diabetes compared to adults without type 2 diabetes.Proximal femur specimens were obtained following a total hip replacement procedure from men and women ≥65 years of age with and without type 2 diabetes. A scanning electron microscope was used for quantitative backscattered electron imaging (qBEI) analysis of trabecular bone samples from the femoral neck. Gray scale images (pixel size=5.6 μm(2)) were uploaded to ImageJ software and gray level (GL) values were converted to calcium concentrations (weight [wt] % calcium [Ca]) using data obtained with energy dispersive X-ray spectrometry. The following bone mineralization density distribution (BMDD) outcomes were collected: the weighted mean bone calcium concentration (CaMEAN), the most frequently occurring bone calcium concentration (CaPEAK) and mineralization heterogeneity (CaWIDTH). Differences between groups were assessed using the Student's t-test for normally distributed data and Mann-Whitney U-test for non-normally distributed data. An alpha value of0.05 was considered significant.Thirty-five Caucasian participants were recruited (mean [standard deviation, SD] age, 75.5 [6.5]years): 14 adults with type 2 diabetes (years since type 2 diabetes diagnosis, 13.5 [7.4]years) and 21 adults without type 2 diabetes. In the adults with type 2 diabetes, bone CaMEAN was 4.9% greater (20.36 [0.98]wt.% Ca versus 19.40 [1.07]wt.% Ca, p=0.015) and CaWIDTH was 9.4% lower (median [interquartile range] 3.55 [2.99-4.12]wt.% Ca versus 3.95 [0.71]wt.% Ca, p0.001) compared to controls. There was no between-group difference in CaPEAK (21.12 [0.97]wt.% Ca for type 2 diabetes versus 20.44 [1.30]wt.% Ca for controls, p=0.121).The combination of elevated mean calcium concentration in bone and lower mineralization heterogeneity in adults with type 2 diabetes may have deleterious effects on the biomechanical properties of bone. These microscopic alterations in bone mineralization, which may be mediated by suppressed bone remodeling, further elucidate higher fracture risk in adults with type 2 diabetes.

We studied the effects of different CHO supplements on exercise metabolism (1 hr at 75% ) and performance (fatigue time at 85% ) in 8 male endurance athletes Four treatments were administered in a randomized, double-blind fashion: Trial A = 3-day pretest, postexercise supplementation (177 kcal [81% carbohydrate, 19% protein] consumed < 10 min after exercise) + 600 ml 8% glucose polymers/ fructose 1 hr pretesting + 600 ml 8% glucose polymers/glucose during testing; Trial B = placebo during 3-day pretest + remainder same as Trial A; Trial C = placebo at all time points; and Trial D = same as Trial B with 8% glucose 1 hr before the test as well as during the test. Time to fatigue at 85% (Í24%) and total CHO oxidation were greater for A versus C (p < .05). Plasma glucose concentration was higher for A and B versus C, while increases in plasma potassium concentration were attenuated for A versus C (both p < .05). None of the supplements had differential effects upon hematocrit, plasma sodium [Na+] and lactate, , or rating of perceived exertion during exercise. Three-day preexercise protein + carbohydrate supplements followed by 1-hr pre- and during-exercise mixed carbohydrate supplements increased time to fatigue and carbohydrate oxidation and attenuated rises in plasma [K+] com pared to placebo.

Calcium and vitamin D metabolism, bone mineralization, and growth were studied in piglets randomly assigned to 15 d of dexamethasone (0.5 mg.kg-1.d-1, orally) or placebo. Growth velocity was significantly reduced by dexamethasone treatment (P < 0.001). Pigs in the dexamethasone group demonstrated lower 45Ca absorption by in situ intestinal perfusion (P < 0.01). Plasma 25-hydroxycholecalciferol (calcidiol) and 1,25-dihydroxycholecalciferol (calcitriol) were lower (P < 0.05) and the urinary ratio of calcium to creatinine was higher (P < 0.05) after 15 d of dexamethasone compared with placebo. Differences between pre- and postosteocalcin (P < 0.01) and pyridinoline (P < 0.01) were higher and wholebody, lumbar, and femur bone mineral density were lower (P < 0.05) in dexamethasone-treated piglets. Dexamethasone-induced reductions in bone mineral mass likely result from reduced vitamin D status, reduced intestinal calcium absorption, elevated urinary calcium loss and direct effects of the steroid on bone. When dexamethasone is used in premature infants to improve lung function, negative effects on growth and bone metabolism could occur.

BACKGROUND: The influence of multiple maternal and pregnancy characteristics on offspring cardiometabolic traits at birth is not well understood and was evaluated in this study. METHODS AND FINDINGS: The Family Atherosclerosis Monitoring In earLY life (FAMILY) Study prospectively evaluated 11 cardiometabolic traits in 901 babies born to 857 mothers. The influence of maternal age, health (pre-pregnancy weight, blood pressure, glycemic status, lipids), health behaviors (diet, activity, smoking) and pregnancy characteristics (gestational age at birth, gestational weight gain and placental-fetal ratio) were examined. Greater gestational age influenced multiple newborn cardiometabolic traits including cord blood lipids, glucose and insulin, body fat and blood pressure. In a subset of 442 singleton mother/infant pairs, principal component analysis grouped 11 newborn cardiometabolic traits into 5 components (anthropometry/insulin, 2 lipid components, blood pressure and glycemia), accounting for 74% of the variance of the 11 outcome variables. Determinants of these components, corrected for sex and gestational age, were examined. Baby anthropometry/insulin was independently predicted by higher maternal pre-pregnancy weight (standardized estimate 0.30) and gestational weight gain (0.30; both p

Premature infants receive high dietary zinc and often glucocorticoids as a treatment for chronic lung disease. A piglet model was developed to investigate intestinal zinc transport and distribution of tissue zinc in response to treatment with short-term (5 d) glucocorticoid therapy or a high zinc diet. Piglets (13–15 d old; n = 21) were randomly allocated to: 1) dexamethasone (DEX) therapy (1.5 mg/kg intramuscularly twice a day), 2) high zinc diet (15.3 mmol/kg), or 3) control group (0.3 mmol dietary zinc/kg and saline intramuscularly twice a day). Pig weight, formula intake, urine volume, and blood glucose were monitored. At necropsy, tissue samples were obtained to measure zinc in plasma and zinc and metallothionein in liver and small intestinal mucosa. Velocity of zinc uptake by intestinal brush border membrane vesicles was measured using 65Zn tracer. Maximum uptake rate and Km for zinc uptake by brush border membrane vesicles were significantly greater (p < 0.05) in DEX compared with control and high zinc groups. DEX-treated piglets had a significantly lower (p < 0.05) zinc efflux rate across brush border membrane vesicles compared with that of the control. The high zinc group had a higher liver (p < 0.05) and mucosal (p < 0.05) zinc content and higher liver metallothionein concentration (p < 0.001) compared with the control and DEX groups. Weight gain over 5 d was not different among groups. Daily blood glucose was higher (p < 0.05) in DEX versus control and high zinc groups. Short-term DEX treatment induced changes in mucosal uptake of zinc that are consistent with up-regulation of specific mucosal proteins, but this was not the case with metallothionein. These alterations in zinc metabolism may have consequences for zinc status in premature infants who receive glucocorticoids such as DEX and/or high zinc diets.

The study objective was to validate a food frequency questionnaire (FFQ) to assess calcium, vitamin D and vitamin K intakes in overweight and obese postmenopausal community-dwelling women. The FFQ was validated against intakes derived from a 5-day diet record (5DDR) that also included assessment of supplement intake. Strong correlations between methods were observed for all nutrients (r = 0.63, 0.89, 0.54 for calcium, vitamin D and vitamin K, respectively) and cross-classification analyses demonstrated no major misclassification of participants into intake quartiles. Bland-Altman analysis showed that the FFQ overestimated intakes for calcium, by 576 mg/day (95% CI, −668 to 1,821 mg/day), for vitamin D by 75 IU/day (95% CI, −359 to 510 IU/day), and for vitamin K by 167 mcg/day (95% CI, −233 to 568 mcg/day). This pilot study showed promising validation evidence for the use of this FFQ, which focuses on calcium, vitamin D and vitamin K intakes in postmenopausal women, as a screening tool in clinical and research settings.

OBJECTIVE. In this cross-sectional observational study, we assessed both vitamins D and K status and bone health in pancreatic insufficient pediatric patients with cystic fibrosis from 3 Canadian cystic fibrosis centers. METHODS. Eighty-one patients who had cystic fibrosis and were clinically stable for at least 3 months were enrolled. At the time of the clinic visit, anthropometric variables, lung function, pubertal status, intake of calcium and vitamins D and K, and physical activity were assessed. Blood was taken for analysis of biochemical biomarkers of bone turnover and status of vitamins D and K, and a urine sample was obtained for calcium, creatinine, sodium, and deoxypyridoline analyses. Whole-body bone mineral content and lumbar spine (L1–L4) bone mineral density were measured. RESULTS. The children were relatively well nourished and had moderate to mild lung disease. Low bone mineral mass defined as a z score between −1.0 and −2.0, for gender and age was detected in 38% of the children for whole body and in 28% for lumbar spine. z score less than −2.0 was observed in 7 children for both bone measures. Suboptimal vitamin D status occurred in 95% of patients; suboptimal vitamin K status occurred in 82% of patients. Measures of plasma osteocalcin and carboxy-terminal propeptide type 1 procollagen and urinary deoxypyridoline compared with reference values for age, gender, and pubertal status reflected a state of suppressed bone formation and elevated bone resorption in a large proportion of the patients. CONCLUSIONS. Bone mass of the whole body and spine was lower than expected for chronological age in approximately one third of pediatric patients with cystic fibrosis irrespective of gender or age. This may be explained by the observation of low bone turnover for developmental stage as indicated by bone biomarkers. Suboptimal status of vitamins D and K may be key causative factors of the low bone status for age.

Perfluoroalkyl compounds (PFCs) are end-stage metabolic products from industrial flourochemicals used in the manufacture of plastics, textiles, and electronics that are widely distributed in the environment. The objective of the present study was to quantify exposure to perfluorooctane sulfonate (PFOS), perfluorooctanoate (PFOA), perfluorodecanoic acid (PFDeA), perfluorohexane sulfonate (PFHxS), perfluoroheptanoic acid (PFHpA), and perfluorononanoic acid (PFNA) in serum samples collected from pregnant women and the umbilical cord at delivery. Pregnant women (n=101) presenting for second trimester ultrasound were recruited and PFC residue levels were quantified in maternal serum at 24-28 weeks of pregnancy, at delivery, and in umbilical cord blood (UCB; n=105) by liquid chromatography-mass spectrometry. Paired t-test and multiple regression analysis were performed to determine the relationship between the concentrations of each analyte at different sample collection time points. PFOA and PFOS were detectable in all serum samples analyzed including the UCB. PFOS serum levels (mean+/-S.D.) were significantly higher (p

Body weight, height and lumbar spine bone mineral density (BMD) were measured in 40 children (27 male, 13 female, aged 0.3-17.0 years) with acute lymphoblastic leukemia (ALL) at diagnosis and 6 months after initiation of chemotherapy, and in 40 age- and sex-matched local healthy children. Serum and urinary biochemical indices of mineral metabolism were measured in the children with ALL at both time points. From diagnosis to 6 months, a reduction in the fractional excretion of magnesium was found. Serum osteocalcin was low at diagnosis and increased during chemotherapy, whereas 24-h urinary type I collagen cross-linked N-telopeptide was unchanged. The Z-scores for lumbar spine BMD increased and were correlated with the serum osteocalcin at 6 months. The change in serum magnesium was correlated negatively with the change in lumbar spine BMD, and with the lumbar spine BMD Z-score at 6 months. After initiation of treatment for ALL, rapid recovery in bone formation, which results in the movement of extracellular magnesium into the skeleton through bone formation, may be an important contributor to hypomagnesemia.

Diminished bone mass (osteopenia) is recognized increasingly as a consequence of therapy in survivors of cancer in childhood. It has been reported in two small series of survivors of Wilms tumor. The objectives of this study were to explore, in a larger sample of such subjects, the prevalence of osteopenia and a possible relationship between osteopenia of the lumbar spine and abdominal irradiation. All survivors of Wilms tumor (n=49) in a single institution were considered eligible for study. Thirty-one agreed to participate; the non-participants were not notably different in their demographic characteristics and diseases/treatment experience. Information was obtained about prior treatment, and usual diet, sun exposure and physical activity. Bone mineral content was measured by dual energy X-ray absorptiometry, and biochemical markers of bone turnover, calciotropic hormones and minerals were assessed in a single blood sample. By Z-scores of whole body bone mineral content, 8 subjects were osteopenic. This was unrelated to milk intake or sun exposure and was not more common in the lumbar spine of those who had been irradiated (15/31 subjects). Physical activity correlated positively with bone mineral density Z-scores (p

Seven-day-old male Yorkshire piglets were randomized to receive either dexamethasone (DEX) 0.5 mg/kg/day or placebo (water) for 15 days (n = 8/group). Body weight and length, plasma intact parathyroid hormone (PTH), N-Mid osteocalcin and C-terminal telopeptide of type I collagen (CTx) were measured at baseline and end of the study. The indices of bone metabolism did not differ between DEX and placebo groups at baseline. At the end of the study, plasma intact PTH was increased (p < 0.01) and N-Mid osteocalcin (p < 0.01) and CTx (p < 0.01) were decreased from baseline value in the DEX group but not in the placebo group. The reduction (Z-score) in N-Mid osteocalcin was greater than that in CTx (p < 0.05). We conclude that exogenous DEX in young piglets stimulates a rise in circulating intact PTH. Both circulating CTx and osteocalcin are reduced with the decline in osteocalcin greater than that in CTx.

Summary: Purpose: To determine whether long-term treatment with valproate (VPA) and/or lamotrigine (LTG) in children with epilepsy is associated with altered growth and/or bone metabolism. Methods: Twenty-seven boys and 26 girls, aged 3 to 17 years (9.2 ± 3.9, mean ± SD), with epilepsy treated with VPA and/or LTG for ≥2 years were evaluated for growth, nutrient intakes, physical activity, bone mineral density (BMD), and blood biochemical indices of mineral and bone metabolism. Results: Twenty-three (43.4%) of the children had a body height below the 10th percentile. Z-scores for BMD below –1.5 occurred in 24.4% of the children. When patients were divided into two groups according to daily activity score, a significantly lower Z-score for total body BMD (p = 0.007), percentile for body height (p = 0.05), and plasma parathyroid hormone (PTH; p = 0.04), osteocalcin (p = 0.04) and 25-hydroxyvitamin D (25OHD) (p = 0.01) were found in the inactive compared with the active group. Z-score for total body BMD was correlated with daily activity score (r = 0.43, p = 0.008). Plasma intact osteocalcin and intact PTH values correlated significantly (r = 0.36, p = 0.02). Plasma 1,25-dihydroxyvitamin D was within normal range for all subjects. When patients were divided into LTG-alone, VPA-alone, and LTG-plus-VPA treatment groups, significantly lower (p < 0.05) plasma osteocalcin and percentile for body height were found in the VPA-plus-LTG treatment group. Conclusions: Long-term VPA and LTG therapy, particularly when combined, is associated with short stature, low BMD, and reduced bone formation. These alterations may be mediated primarily through reduced physical activity rather than through a direct link to the VPA and/or LTG therapy.

There is increasing evidence that feeding of mother's milk to very low-birth weight and extremely low-birth weight infants has both immediate and long-term benefits to growth and development of this vulnerable infant population. Although clinically mother's milk is increasingly the feeding of choice for tiny premature infants for the healthcare provider, this practice presents challenges such as: careful collection and storage of the milk in order to preserve the native milk nutrients and immune factors; identification of the need for fortification of mother's milk with single or multiple nutrients to ensure optimal growth and normal biochemical status (such as plasma sodium, phosphorus, and protein); and achievement of successful transition for gavage feeding of expressed milk to suckling by the tiny premature infant. Although initial growth and bone mass accretion may be slower in infants fed mother's milk compared with those infants fed formula, current evidence suggests that catch-up growth occurs. The potential for benefits of human milk feeding in early life for neurodevelopment and protection against infections must be weighed against any possible detrimental effects of slower growth in early life.

Aim: To characterize the ontogeny of circulating IGF-I, the IGF binding proteins (IGFBPs) and biochemical markers of bone turnover in dexamethasone (DEX)-treated preterm infants with chronic lung disease. Methods: Plasma and urine samples from 17 infants were obtained prior to DEX, after 9–12 days of DEX and 10 days after the completion of DEX to assess plasma IGF-I, IGFBPs, osteocalcin and urinary N-telopeptide. Nutrient intakes and growth were monitored from birth until term corrected age at which time body composition was evaluated by dual energy X-ray absorptiometry. Results: Although nutrient intakes did not differ during or after DEX, weight gain (115 vs. 174 g/week) and length gain (0.7 vs. 1.0 cm/week) were higher after DEX treatment. Plasma IGF-I, IGFBP-3 and osteocalcin increased over time. N-telopeptide was the only biochemical parameter which appeared to be suppressed during DEX (1342 nM bone collagen equivalents/mM creatinine vs. 2486 (pre-DEX) and 2292 (post-DEX)). At term corrected age, bone mineral content was lower in dexamethasone-treated infants compared to preterm and term reference infants. Conclusion: Changes in circulating IGFBP-2 and IGFBP-3 paralleled the changes reported in non-steroid-treated infants; however, it remains uncertain whether the natural rise in IGF-I was suppressed by DEX treatment. Assessment of these circulating components provided limited insight into the mechanisms by which DEX alters growth and bone turnover.

Background: Dexamethasone treatment facilitates the weaning of premature infants from mechanical ventilation but impairs protein homeostasis, lean tissue deposition, and growth. The current study was conducted to investigate whether dexamethasone mediates these effects by reducing protein synthesis or elevating protein breakdown, and whether adjuvant growth hormone ± insulin-like growth factor-I therapy can attenuate such effects. Methods: Piglets (n = 24) were randomized to placebo, a tapered course of dexamethasone (0.5, 0.3. 0.2 mg/kg per day for 5. 5 and 4 days each, respectively), dexamethasone + growth hormone 0.1 mg/kg per day, or dexamethasone + growth hormone + insulin-like growth factor-I 0.1 mg/kg per day for 14 days. On day 13, 15 N-glycine was administered as a single oral dose, and urine was collected at timed intervals during the subsequent 48 hours. Results: Total urinary N and cumulative 15 N excretion were higher in all dexamethasone groups than in control subjects. Protein synthesis was suppressed, whereas protein breakdown was unaltered by dexamethasone. Adjunctive growth hormone ± insulin-like growth factor-I therapy enhanced protein synthesis, but only combined therapy improved net protein gain compared with dexamethasone alone. Higher circulating insulin-like growth factor-I may have mediated the greater net protein gain. Blood urea nitrogen was elevated in all dexamethasone-treated groups at days 6 and I 1 but was normalized by day 15 with adjunctive growth hormone ± insulin-like growth factor-I. From a functional perspective, both adjunctive growth hormone and growth hormone ± insulin-like growth factor-I partially attenuated the dexamethasone-induced reduction in weight and length gain but not in whole body lean and fat mass. Conclusion: Adjunctive growth hormone ± insulin-like growth factor-I therapy partially reverses the dexamethasone-induced reduction in protein synthesis, resulting in improved growth when given concurrently with a low tapering dose of dexamethasone.

The purpose of this study was to investigate whether a dietary calcium:iron ratio similar to that often consumed by premature human infants inhibits iron absorption in infant piglets adapted to a high calcium diet. Male Yorkshire piglets were randomized at 3 to 4 d of age to a high calcium diet (4.67 g/L = HC) or a normal calcium diet (2.0 g/L = NC) and fed for 2 to 2.5 wk. An iron dextran injection was administered in amounts to achieve a marginal state of iron repletion to simulate iron status of premature infants. In vivo iron absorption from the diet was determined using the radiotracers 55 Fe and 59 Fe and whole body counting. Calcium:iron interactions at absorption sites in piglets fed HC and NC were investigated by measurements of time-dependent 59 Fe uptake in response to different calcium:iron ratios in vitro in brush border membrane vesicles (BBMV). In vivo iron absorption from the diet did not differ between NC and HC diet groups [57 ± 8% versus 55 ± 17% (mean ± SD), respectively]. Iron status and iron contencentrations in spleen, liver, intestine, kidney and heart did not differ between diet groups. Iron uptake in BBMV was significantly reduced by calcium in both HC and NC (P < 0.001); but there were no significant differences in iron uptake in response to different calcium:iron ratios between HC and NC. With feeding a HC diet for 2 wk there may be an adaptive response to counteract the inhibitory effects of calcium on iron absorption, thus resulting in similar in vivo iron absorption and iron status irrespective of the 1.3-fold difference in dietary calcium:iron ratio between piglet groups. However, future studies are needed to determine the specific sites of calcium:iron interactions and adaptation mechanisms. Since the calcium:iron ratios used in this study reflect the usual calcium:iron ratios in diets for premature infants, it is unlikely that interactive effects of calcium with iron will compromise iron status in this infant population when diets are supplemented with calcium.

Our objectives were 1) to determine whether moderate nutrient supplementation of mother's milk (MM) for preterm infants, in the form of a new multinutrient fortifier (MNF), would improve short-term growth and bone mineral content (BMC) when compared with supplementation with calcium and phosphorus alone; and 2) to investigate whether moderate calcium and phosphorus intakes, in the form of calcium glycerophosphate (CaGP), resulted in a BMC similar to that of term corrected infants. Twenty-five preterm infants fed MM were randomly assigned to receive either MM+MNF or MM+CaGP. A third group of infants fed preterm formula (PTF) served as a comparison group. Whole-body BMC and lean and fat mass were determined by dual-energy X-ray absorptiometry (DXA) at full-term age. Nitrogen retention and calcium, phosphorus, and zinc intakes were determined by using mass balance techniques. Nitrogen retention was significantly lower in the MM+CaGP group than in the PTF group as were both weight and length gain (weight gain: 16.6 +/- 1.6, 14.2 +/- 2.0, and 16.1 +/- 2.9 g x kg(-1) x d(-1); length gain: 1.1 +/- 0.2, 0.9 +/- 0.2, and 1.1 +/- 0.3 cm/wk for the MM+MNF, MM+CaGP, and PTF groups, respectively). Biochemical indexes of mineral status and bone turnover were normal. Conservative amounts of calcium and phosphorus, as CaGP, resulted in adequate BMC. Moderate amounts of protein, calcium, and phosphorus plus trace elements added to MM in the form of an MNF resulted in improved linear growth but did not provide any advantages to BMC when compared with supplementation with calcium and phosphorus alone.

The objective of this study in premature infants was to assess the relationship between dexamethasone, growth and bone mineral accretion. Nine appropriate size for gestational age premature infants treated for chronic lung disease with tapering doses of dexamethasone (0.5-0.1 mg/kg/day over 37 +/- 7 days) were individually matched to a comparison infant by sex, gestational age, birth-weight, and type of feed. Infant growth and bone mineral accretion were measured at equivalent gestational ages from recruitment until 6 months corrected age. During hospitalization, mean rate of weight, length and head circumference growth and bone mineral accretion in the distal radius were significantly lower in the dexamethasone-treated infants in spite of similar nutrient intakes. Dexamethasone infants had significantly lower plasma phosphorus, and urinary calcium, pyridinoline and N-telopeptide excretion. Dexamethasone affected absolute length, but not weight, throughout the study. No significant differences were observed in body composition or absolute radial and whole body bone mineral content. The results indicate that dexamethasone therapy compromises growth and bone mineral accretion in small premature infants. 'Catch-up' linear growth was not evident at 6 months of age and reflects the importance of early nutrition interventions.

The objective of this study was to assess the effect of dexamethasone on growth, body composition and protein metabolism using the piglet as a model for rapidly growing premature infants. Seven-day-old male pigs (n = 18) were randomized to 0.5 mg/kg/day oral dexamethasone or placebo for 15 consecutive days. Weight and length gains and weight gained per energy or protein consumed were significantly lower in the dexamethasone group. Serum urea nitrogen was significantly higher in the dexamethasone group by day 15 of the study. No differences were observed between groups for urinary creatinine. The whole body percent lean mass was significantly lower and percent fat mass was significantly higher in the dexamethasone piglets, as measured by dual energy X-ray absorptiometry. In young piglets, dexamethasone, at doses similar to those in premature infants, induces protein catabolism, impairs growth and alters its composition.

Purpose : The purpose of this study is to assess the effects of amikacin on renal proximal tubular function, and on magnesium (Mg) and calcium (Ca) status in children treated for acute lymphoblastic leukemia (ALL). Patients and Methods : Eighteen children (11 male/7 female, ages 2-18 years) receiving antileukemic therapy (Dana Farber Cancer Institute protocols 87-001 or 91-001) and admitted for febrile neutropenia to The Children's Hospital at Chedoke-Mc-Master, Hamilton, Ontario were recruited into this descriptive prospective study. Each child was treated with amikacin (7.5 mg/kg/12 hx10-14 days) for one or more courses. Results : No patient demonstrated elevations in amikacin trough levels. β 2 -Microglobulinuria, glucosuria, proteinuria, and hyperphosphaturia were absent. Children (50%) presenting with hypomagnesemia (

During endurance exercise at approximately 65% maximal O2 consumption, women oxidize more lipids, and therefore decrease carbohydrate and protein oxidation, compared with men (L.J. Tarnopolsky, M.A. Tarnopolsky, S.A. Atkinson, and J.D. MacDougall. J. Appl. Physiol. 68: 302–308, 1990; S.M. Phillips, S.A. Atkinson, M.A. Tarnopolsky, and J.D. MacDougall. J. Appl. Physiol. 75: 2134–2141, 1993). The main purpose of this study was to examine the ability of similarly trained male (n = 7) and female (n = 8) endurance athletes to increase muscle glycogen concentrations in response to an increase in dietary carbohydrate from 55–60 to 75% of energy intake for a period of 4 days (carbohydrate loading). In addition, we sought to examine whether gender differences existed in metabolism during submaximal endurance cycling at 75% peak O2 consumption (VO2 peak) for 60 min. The men increased muscle glycogen concentration by 41% in response to the dietary manipulation and had a corresponding increase in performance time during an 85% VO2 peak trial (45%), whereas the women did not increase glycogen concentration (0%) or performance time (5%). The women oxidized significantly more lipid and less carbohydrate and protein compared with the men during exercise at 75% VO2-peak. We conclude that women did not increase muscle glycogen in response to the 4-day regimen of carbohydrate loading described. In addition, these data support previous observations of greater lipid and lower carbohydrate and protein oxidation by women vs. men during submaximal endurance exercise.

Objective: To determine whether the osteopenia and unusual fractures observed in children with acute lymphoblastic leukemia (ALL) were related to the disease rather than to its treatment. Design: Prospective analysis of the bone and mineral status in 40 consecutive children with ALL seen in a pediatric tertiary-care referral center. Methods: Biochemical indicators of mineral, endocrine, and vitamin D status were measured before initiation of therapy. Bone mass was determined radiographically and by dual-photon absorptiometry of the lumbar region of the spine (L2-L4). Correlations between clinical observations, leukemia variables, bone mass, and biochemical assessment were determined. Results: At the time of diagnosis musculoskeletal pain was present in 36% of patients and was more common in children with CD10-positive leukemia and leukocyte counts less than 20 × 109 cells/L. Radiographic evidence of osteopenia and fractures was observed in 13% and 10% of children, respectively. The mean bone mineral content was normal. Bone mass measurement z scores correlated with plasma 1,25-dihydroxyvitamin D3 concentrations (r = 0.43, p