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Calcium and Vitamin D Intake of Children and Adolescents with Asthma

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PAGE 1

CALCIUM AND VITAMIN D INTAKE OF CHILDREN AND ADOLESCENTS WITH ASTHMA By MELISSA R. METZ A THESIS PRESENTED TO THE GRADUATE SCHOOL OF THE UNIVERSITY OF FLORID A IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE UNIVERSITY OF FLORIDA 2004

PAGE 2

Copyright 2004 By Melissa R. Metz

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This thesis is dedicated to children and adolescents with asthma with the hope that through research the qualit y of their lives will be improved.

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ACKNOWLEDGMENTS I would like to thank my outstanding committee members, Dr. Gail P.A. Kauwell, Ellen Bowser, and Dr. Sarah E. Chesrown. I would especially like to thank Dr. Kauwell for her excellent advice, wisdom, and friendship, Mrs. Bowser for her patience, enthusiasm, kindness, and friendship, and Dr. Chesrown for her strong support in this project. I truly could not have successfully completed this project without their help. I would like to thank the Pediatric Pulmonary Center physicians, faculty, and staff for their constant willingness to provide any help they could. I also would like to extend my thanks to Dr. Karla Shelnutt for her assistance with this project, and my classmates, Lisa Fish, Elizabeth Haire (Citro), Mandy Layman, Carolina Lima, and Jaimie Vaughn (Proctor), for their friendship. Finally, I would like to extend my gratitude to my wonderful husband for his patience, encouraging words, calm spirit, and unconditional love, and my parents for their wisdom, encouragement, and never-ending love. I truly could not have been successful in life without them. This research was supported by an unrestricted donation to Dr. Gail P. A. Kauwell from Dairy Farmers Inc. iv

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TABLE OF CONTENTS page ACKNOWLEDGMENTS.......................................................................................iv LIST OF TABLES...............................................................................................viii LIST OF FIGURES...............................................................................................x LIST OF ABBREVIATIONS..................................................................................xi ABSTRACT........................................................................................................xiv CHAPTER 1 INTRODUCTION............................................................................................1 Hypotheses....................................................................................................2 Specific Aims.................................................................................................2 2 BACKGROUND AND LITERATURE REVIEW..............................................3 Asthma...........................................................................................................3 Overview..................................................................................................3 Etiology....................................................................................................4 Pathophysiology......................................................................................4 Diagnosis.................................................................................................5 Monitoring................................................................................................7 Asthma Management.....................................................................................8 Medical Management..............................................................................8 Environmental Management..................................................................13 Dietary Management....................................................................................13 Calcium........................................................................................................14 Structure and Function..........................................................................14 Digestion and Absorption.......................................................................15 Transport...............................................................................................17 Homeostasis..........................................................................................17 Deficiency..............................................................................................18 Status Assessment................................................................................19 Dietary Reference Intakes (DRIs)..........................................................19 Adequate Intake (AI).......................................................................19 v

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Tolerable Upper Intake Level (UL)..................................................20 Sources.................................................................................................20 Calcium Intake in the U.S......................................................................21 Vitamin D.....................................................................................................22 Structure and Function..........................................................................22 Digestion, Absorption, and Transport....................................................22 Deficiency..............................................................................................23 Status Assessment................................................................................24 Dietary Reference Intakes (DRIs)..........................................................24 Adequate Intake (AI).......................................................................24 Tolerable Upper Intake Level (UL)..................................................24 Sources.................................................................................................24 Vitamin D Intake in the U.S....................................................................25 Factors Influencing Bone Health during Childhood and Adolescence..........25 Factors Influencing Bone Health during Adulthood......................................29 Factors Influencing Bone Health in Children and Adolescents with Asthma.............................................................................................31 Health Beliefs about the Impact of Milk and Dairy Products on Asthma..........................................................................................31 Calcium and vitamin D intake and bone health in cows milk-free and cows milk-limited diets.........................................33 Cows milk and pulmonary function.................................................34 Cows milk or food allergy, adverse reactions to milk, and asthma.................................................................................36 Physical Activity.....................................................................................37 Inhaled Corticosteroid Use....................................................................39 Systemic Corticosteroid Use..................................................................42 Bone Density of Children with Asthma and Risk for Osteoporosis........42 Research Significance...........................................................................43 3 MATERIALS AND METHODS.....................................................................45 Subject Description......................................................................................45 Study Design................................................................................................45 Dietary Intake Tool and Analysis..................................................................48 Overview of Three-day Food Diary Method Used to Assess Dietary Intake...........................................................................................49 Comparison of Methodologies to Assess Dietary Intake..............................50 Overview of the 1994 to 1996, 1998 CSFII..................................................52 Statistical Analysis.......................................................................................53 Comparison of Dietary Intake to AI........................................................54 Comparison of Dietary Intake to 1994 to 1996, 1998 CSFII..................54 4 RESULTS....................................................................................................55 Subjects.......................................................................................................55 Demographics.......................................................................................55 vi

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Dietary Intake of Calories, Protein, and Fat...........................................56 Dietary Intake of Calcium and Vitamin D...............................................56 Comparison of Dietary Calcium and Vitamin D Intake to the AI...................57 Comparison of Dietary Calcium Intake to 1994 to 1996, 1998 CSFII...........58 Intake of Milk and Milk Products...................................................................60 Comparison of Milk and Milk Products Intake to 1994 to 1996, 1998 CSFII...............................................................................................62 5 DISCUSSION AND CONCLUSIONS...........................................................72 APPENDIX A THREE-DAY FOOD AND SUPPLEMENT DIARY DIRECTIONS................79 B THREE-DAY FOOD AND SUPPLEMENT DIARY FORM............................83 C DAIRY PRODUCT CATEGORY DEFINITIONS...........................................87 LIST OF REFERENCES....................................................................................89 BIOGRAPHICAL SKETCH.................................................................................98 vii

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LIST OF TABLES Table page 1 Medications used to treat or prevent asthma symptoms............................10 2 Long-term control medications for infants and children with asthma 5 years of age and younger..........................................................................11 3 Long-term control medications for children with asthma over 5 years of age and adults...........................................................................................12 4 Dietary Reference Intakes for calcium for children and adolescents 1 to 18 years..............................................................................................20 5 Vitamin D status assessment according to serum 25(OH) D3 concentrations............................................................................................24 6 Number of subjects who enrolled and completed the study and percent return rate by age category and gender.....................................................55 7 Three-day dietary intake of calories, protein, and fat by study subjects.....56 8 Calcium intake of children and adolescents with asthma compared to the AI by age category...............................................................................58 9 Vitamin D intake of children and adolescents with asthma compared to the AI by age category...........................................................................59 10 Calcium intake of study subjects (asthma) compared to CSFII by age group...................................................................................................60 11 Calcium intake and percent of total calcium intake from dairy product categories..................................................................................................62 12 Total milk and milk products intake of study subjects (asthma) compared to CSFII by age group...............................................................63 13 Total milk, milk drinks, and yogurt intake of study subjects (asthma) compared to CSFII by age group...............................................................64 14 Total fluid milk intake of study subjects (asthma) compared to CSFII by age group..............................................................................................65 viii

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15 Whole milk intake of study subjects (asthma) compared to CSFII by age group..........................................................................................................66 16 Lowfat milk intake of study subjects (asthma) compared to CSFII by age group..........................................................................................................67 17 Skim milk intake of study subjects (asthma) compared to CSFII by age group..........................................................................................................68 18 Yogurt intake by study subjects (asthma) compared to CSFII by age group..........................................................................................................69 19 Milk desserts intake of study subjects (asthma) compared to CSFII by age group...................................................................................................70 20 Cheese intake of study subjects (asthma) compared to CSFII by age group..........................................................................................................71 ix

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LIST OF FIGURES Figure page 1 Calcium intake of study subjects (asthma) compared to the AI by age group..........................................................................................................58 2 Vitamin D intake of study subjects (asthma) compared to the AI by age group..........................................................................................................59 3 Calcium intake of study subjects (asthma) compared to CSFII by age group..........................................................................................................61 4 Variance from the mean calcium intake of study subjects (asthma) compared to CSFII by age group...............................................................61 5 Total milk and milk products intake by study subjects (asthma) compared to CSFII by age group...............................................................63 6 Total milk, milk drinks, and yogurt intake by study subjects (asthma) compared to CSFII by age group...............................................................64 7 Total fluid milk intake by study subjects (asthma) compared to CSFII by age group..............................................................................................65 8 Whole milk intake by study subjects (asthma) compared to CSFII by age group..............................................................................................66 9 Lowfat milk intake by study subjects (asthma) compared to CSFII by age group..............................................................................................67 10 Skim milk intake by study subjects (asthma) compared to CSFII by age group..............................................................................................68 11 Yogurt intake by study subjects (asthma) compared to CSFII by age group...................................................................................................69 12 Milk dessert intake by study subjects (asthma) compared to CSFII by age group..............................................................................................70 13 Cheese intake by study subjects (asthma) compared to CSFII by age group..........................................................................................................71 x

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LIST OF ABBREVIATIONS AI Adequate Intake BDP beclomethasone dipropionate BMC bone mineral content BMD bone mineral density BM bone mass BMI body mass index BUD budesonide CaSR calcium sensing receptor CF cystic fibrosis CSFII Continuing Survey of Food Intakes by Individuals d day DBP vitamin D-binding protein DPI dry powder inhaler DRI Dietary Reference Intake EAR Estimated Average Requirement EIA exercise-induced asthma FEF25-75% forced expiratory flow at 25-75% forced vital capacity FEV1 forced expiratory volume in 1 second FFQ food frequency questionnaire FVC forced vital capacity xi

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g grams GI gastrointestinal IOM Institute of Medicine IU International Unit kcals calories LTRA leukotriene receptor antagonist MDI metered dose inhaler mcg micrograms mg milligrams NAEPP National Asthma Education and Prevention Program NHANES National Health and Examination Survey NHLBI National Heart, Lung, and Blood Institute nmol/l nanomoles per liter PBM peak bone mass PEF peak expiratory flow PFT pulmonary function test PTH parathyroid hormone RDA Recommended Dietary Allowance SD standard deviation UF University of Florida UL Tolerable Upper Intake Level U.S. United States xi i

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USDA United States Department of Agriculture V50 airflow at 50% of vital capacity xiii

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Abstract of Thesis Presented to the Graduate School of the University of Florida in Partial Fulfillment of the Requirements for the Degree of Master of Science CALCIUM AND VITAMIN D INTAKE OF CHILDREN AND ADOLESCENTS WITH ASTHMA By Melissa R. Metz December 2004 Chair: Gail P. A. Kauwell Major Department: Food Science and Human Nutrition Asthma is a chronic inflammatory disease of the airways that currently affects 6.1 million children under the age of 18 years. Parents of children with asthma commonly avoid or eliminate foods from their childrens diets in an attempt to reduce the onset of asthmatic symptoms. Milk and dairy products are the foods most often reported to be eliminated or avoided, although studies do not support a connection between milk intake and a reduction in pulmonary function. Inadequate milk and dairy products consumption could have an adverse effect on the intake of calcium and vitamin D, nutrients associated with favorable bone growth and development. Other factors that may affect bone health and future risk for osteoporosis in this population include restricted physical activity and corticosteroid use. No studies have examined the calcium and vitamin D intake of children and adolescents with asthma, which was the purpose of this study. It was hypothesized that asthmatic children and xiv

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adolescents do not meet the adequate intake (AI) for calcium and vitamin D and that they consume less calcium than what has been reported in national survey data from children of the same age. Subjects with asthma were recruited from the Pediatric Pulmonary Center Asthma Clinic and the UF Research Asthma Lab. Three-day food records were collected and analyzed for calcium and vitamin D intake using Food Processor. Calcium and vitamin D intake was compared to the AI and to data for an age-matched reference population (i.e., Continuing Survey of Food Intakes of Individuals, CSFII). The 3-day mean dietary calcium intake for the 1 to 3 year old group was significantly less (p = 0.001) than that of the age-matched reference population. The 3-day mean dietary calcium intake for the 9 to 18 year old age group was significantly lower than the AI (p = 0.02). Vitamin D intake met the AI for all age groups, and no differences were detected between the vitamin D intake of subjects with asthma compared to the respective age group using the CSFII database. Dietitians and other healthcare providers should encourage adequate consumption of milk and dairy products in children and adolescents with asthma with the goal of ensuring adequate calcium intake and reducing future risk for osteoporosis in this vulnerable population. xv

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CHAPTER 1 INTRODUCTION Asthma is a chronic inflammatory disease of the airways (1-3) that currently affects 6.1 million children under the age of 18 years (1). It is the leading serious chronic illness among children (4), and recent increases in asthma prevalence have been steepest among the young (5). A potential concern for pediatric asthma patients is the future risk for osteoporosis. Adequate intake of calcium and vitamin D and regular physical activity are essential for normal growth, development, and maintenance of bone. Inadequate calcium and vitamin D intake, limited physical activity, and corticosteroid use are important factors that can affect bone formation and bone health in children with asthma, thus affecting bone mineral density (BMD), stature, achievement of peak bone mass (PBM), and risk for osteoporosis later in life. Several research groups (2,6-8) have reported that avoidance or elimination of dairy products (6,7), low physical activity (8,9), use of oral corticosteroids (2), and long-term use of inhaled corticosteroids (2) are seen among children and adolescents with asthma. Inadequate milk and dairy products consumption could have an adverse effect on the intake of calcium and vitamin D, nutrients associated with favorable bone growth and development. The calcium and vitamin D intake of pediatric patients with asthma has not been reported previously in the literature, and it is possible that due to avoidance or elimination of milk and dairy products from their diets, their intake of these nutrients are less 1

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2 than the AI levels set by the Institute of Medicine (IOM). Evaluating the adequacy of calcium and vitamin D intake in the pediatric asthma population will help to identify whether there is a need for targeted intervention strategies to improve the intake of these nutrients with the goal of reducing the risk for osteoporosis later in life. Hypotheses It was hypothesized that children and adolescents with asthma 1) do not meet the AI for calcium and vitamin D 2) consume less calcium than what has been reported in national survey data from children of the same age, and 3) consume a different amount of total milk and dairy products and specific types of dairy products than reported in national survey data from children of the same age. Specific Aims The specific aims of this study were to determine calcium and vitamin D intake of children and adolescents with asthma using a 3-day food and supplement diary and to compare their intake of these nutrients to the AIs for each age category (i.e., 1 to 3, 4 to 8, and 9 to 18 years) and to compare calcium intake of our pediatric asthma population to survey data from the 1994 to 1996 and 1998 CSFII. Another specific aim was to compare dairy product consumption of our pediatric asthma population to survey data from the 1994 to 1996 and 1998 CSFII.

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CHAPTER 2 BACKGROUND AND LITERATURE REVIEW Asthma Overview Asthma is a reversible, recurrent obstructive lung disease (3) that currently affects 6.1 million children under the age of 18 years (1). Approximately 9 million U.S. children under the age of 18 years have been diagnosed with asthma, and boys are more likely to be diagnosed with asthma than girls (10). In 2002, 4.2 million children under the age of 18 years suffered an asthma attack or episode (1,10). It is the leading serious chronic illness among children (4,11), and recent increases (55% from 1980 to 1996) (4) in asthma prevalence have been steepest among the young (5). Asthma is the third leading cause of hospitalization among children under the age of 15 years and causes 14.6 million lost school days annually, making it the leading cause of school absenteeism attributed to chronic conditions (1). The working definition of asthma developed by the National Heart, Lung, and Blood Institute (NHLBI) is a chronic inflammatory disorder of the airways in which many cells and cellular elements play a role, in particular, mast cells, eosinophils, T lymphocytes, neutrophils, and epithelial cells. In susceptible individuals, this inflammation causes recurrent episodes of wheezing, breathlessness, chest tightness, and cough, particularly at night and in the early morning. These episodes are usually associated with widespread but variable airflow obstruction that is often reversible either spontaneously or with treatment. The inflammation also causes an associated increase in the existing bronchial hyperresponsiveness to a variety of stimuli. (2, p.11) 3

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4 Recent observations indicate that reversibility of airflow obstruction may be incomplete in some individuals with asthma (12). Etiology Numerous factors may play an important role in the etiology of asthma, some of which may increase the risk for developing asthma and others which may provide protection against asthma. According to the NHLBI, atopy, which is an IgE-mediated allergic response to common aeroallergens, is the strongest identifiable factor associated with increased risk for developing asthma (13). There also is a strong genetic component to the development of asthma. Therefore, the propensity for developing asthma is influenced by genetic and environmental factors and interactions among these factors. Factors that may decrease the risk for developing asthma include exposure to various aeroallergens early in life, certain early childhood bacterial and viral infections (i.e., pneumonia, respiratory syncytial virus, M. tuberculosis, measles, hepatitis A, etc.), exposure to other children (e.g., presence of an older sibling and early enrollment in childcare), less frequent use of antibiotics, farming environment (i.e., contact with barn animals), breast feeding (breast milk protection), season of birth (i.e., spring), and nutrition (e.g., intake of polyunsaturated fatty acids, omega-3 fatty acids, etc.) (2,3,14,15). Pathophysiology In general, asthma occurs as a result of the interaction between genetic predisposition and certain environmental triggers that result in peribronchial inflammation (3). The major pathophysiologic features of asthma include denudation of airway epithelium, collagen deposition, edema, mast cell

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5 activation, and inflammatory cell infiltration (2, p.11). Inflammation results in bronchial hyperresponsiveness, airflow limitation, respiratory symptoms, acute bronchoconstriction, airway edema, mucus plug formation, airway wall remodeling, and disease chronicity (13). Bronchial hyperresponsiveness, an exaggerated bronchoconstrictor response to a stimulus such as an allergen or irritant, occurs as a result of thickening of the airway wall (13,14). The chronic, persistent airway inflammation that occurs in asthma is caused by activation of recruited and resident immune cells that initiate a persistent level of cell damage and an ongoing repair process (13,14). During an asthma exacerbation or episode, the airways become narrow as a result of a series of events that include swelling of the airway lining, tightening of the airway muscles, and increased secretion of mucus in the airway (1). As a result, individuals experience coughing, wheezing, and difficulty breathing (16). Although asthma symptoms are often triggered by allergens such as a pollen, mold, animal dander, feathers, dust, food, or cockroaches, it also can be triggered by respiratory infections, colds, vigorous exercise, cold air, sudden temperature changes, cigarette smoke, excitement, stress, or exercise (1). Asthma episodes or exacerbations may resolve spontaneously or following treatment with medication (14). Diagnosis Important information to gather in order to diagnose asthma in children includes onset and history of symptoms; description of a typical episode; conditions associated with onset of symptoms; type and pattern of symptoms; perception of severity; physical examination of the head, neck, upper respiratory

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6 tract, chest, and skin; hyperexpansion of the thorax; wheezing during normal breathing; prolonged phase of forced exhalation; increased nasal secretion; mucosal swelling; nasal polyps; and atopic dermatitis/eczema (3,13,14). In children 5 years of age and older, diagnostic tests such as spirometry and bronchoprovocation challenge are used in addition to the history and physical examination to diagnose asthma. In children younger than 5 years, it is difficult to objectively measure lung function using spirometry, so diagnosis is primarily based on symptoms, physical examination, and response to therapy (15). Spirometry, or pulmonary function testing (PFT), is the best method for evaluating lung function in patients who may have asthma. Spirometry can detect several physiological abnormalities that occur in asthma, such as decreased airflow and lung volumes, increased work of breathing, increased airway responsiveness to stimuli, and variability of airway flow (14). The results of PFT are used to diagnose and categorize the severity of asthma in children over 5 years of age and adults. These include forced expiratory volume in 1 second (FEV1), ratio of FEV1 to forced vital capacity (FEV1/FVC), and forced expiratory flow during the middle portion of exhalation (FEF25-75%). Forced expiratory volume in 1 second is defined as the volume that is exhaled in the first second in liters per second (3). This measurement provides pulmonologists with information about large to medium sized airways (3). Forced vital capacity is the maximum volume of air that can be exhaled after maximal inhalation (14). The ratio of FEV1 to FVC measures general airway obstruction (3). Forced expiratory flow during the middle portion of exhalation, is the average flow of air during the

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7 middle portion of the FVC and provides pulmonologists with information about the small airways (3). In children 5 years of age and older, an FEV1 below 80% of predicted is diagnostic for asthma (2). An increase in FEV1 of more than 12% following use of a short-acting bronchodilator also is diagnostic for asthma (2,3). Another method that can be used to diagnose asthma is a bronchoprovocation challenge. This method is useful for evaluating children 5 years of age an older who have a chronic cough and/or vague exercise intolerance, but do not display a change in FEV1 in response to short-acting bronchodilators (14). A bronchoprovocation challenge is performed by slowly administering a low dose of a challenging agent (i.e., an irritant, bronchoconstrictor chemical, an antigen, etc.) into the airway until a 20% decrease in FEV1 from baseline is achieved or the highest predetermined dose of challenging agent is reached (14). Asthma is classified as mild intermittent, mild persistent, moderate persistent, or severe persistent. Severity is based on the frequency and occurrence of symptoms during the day and night in infants and children 5 years of age and younger (2). In children over 5 years of age and adults, the degree of asthma severity is based on frequency and occurrence of symptoms during the day and night as well as FEV1 measurements (2). Monitoring Asthma can be monitored by PFTs, airway challenge, peak flow monitoring, asthma exacerbation history, signs and symptoms, quality of life, pharmacotherapy, patient-provider communication, and/or patient satisfaction (2). The methods used to monitor asthma are spirometry and peak flow

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8 monitoring. Unfortunately, because spirometry and peak flow monitoring are largely effort dependent, it is difficult to objectively monitor lung function in infants and children under 5 years of age (15). As a result, monitoring asthma in this age group is largely based on asthma symptoms, the need for a rescue bronchodilator and oral corticosteroid therapy, and emergency room visits or hospitalizations (15). Pulmonary Function Testing (Spirometry). Spirometry is often conducted every 3 months during a regular pulmonary visit. A change of 1 standard deviation (SD) in any of the pulmonary function measures (i.e., FEV1, FEV1/FVC ratio, and FEF25-75%) is considered significant (14). If the change in one or more of the pulmonary function measures is significant, adjustments to the type or dose of medication(s) are made. Peak Flow Monitoring. Peak flow monitoring is another way to monitor asthma and aid in its management. Peak expiratory flow (PEF) is a measure of the most rapid flow of air during a forced expiration and it provides pulmonologists with information about the function and condition of larger airways (3). Compared to spirometry, peak flow monitoring is considered to be a less technological approach; however, it is an objective, quantifiable, reproducible, and sensitive measure of airway obstruction that changes dramatically during the early stages of an asthma exacerbation (2,3,14). Asthma Management Medical Management According to the NHLBI, the goals of therapy in asthma control include minimal or no chronic symptoms during the day or night, minimal or no

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9 exacerbations, no limitations on activities, no school missed by the child or work missed by the parent as a result of asthma symptoms, minimal use of short-acting inhaled 2-agonists, and minimal or no adverse effects from medications (2). Medical management of asthma focuses on decreasing airway inflammation to minimize airflow obstruction and asthma symptoms (2,15). There are two main categories of medications used to manage asthma: reliever medications and controller medications (Table 1). Asthma is managed through a stepwise approach based on severity of the disease. The preferred and alternative treatments used to manage asthma in children 5 years and younger and older than 5 years are outlined in Tables 2 and 3, respectively. During an asthma exacerbation, the focus shifts toward controlling and relieving the smooth muscle airway spasms using reliever medications (14). Reliever medications are short-acting bronchodilators such as short-acting 2-agonists and anticholinergics and anti-inflammatory medications, including systemic corticosteroids (2,3). These are used to relieve acute bronchoconstriction (3). They are effective in treating acute asthma exacerbations, but do not prevent an exacerbation from occurring (3). The short-acting 2-agonists can be administered in an oral, nebulized, or metered dose inhaler (MDI) form. Anti-inflammatory medications, such as systemic or oral corticosteroids, also are used to relieve asthma symptoms; however, they are not intended for daily use and are reserved for acute asthmatic episodes (3). Long

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10 Table 1. Medications used to treat or prevent asthma symptoms. Medication Category Mechanism of Action Examples Reliever Medications : Use: treatment of acute asthma exacerbations Short-acting 2-agonist Dilate airways by relaxing bronchial smooth muscle Albuterol (Ventolin, Proventil),Pirbuterol (Maxair Autohaler), Bitolterol, Levalbuterol, Salmeterol (Serevent) Anticholinergic Dilate airways by relaxing bronchial smooth muscle Ipatropium (Atrovent) Systemic (oral) corticosteroid Reduce airway inflammation Prednisone, prednisolone, methylprednisolone Controller Medications : Use: long-term control of asthma Reduce frequency of acute asthma exacerbation Inhaled Corticosteroid Reduce airway inflammation Decrease transport of fluid across the capillaries Decrease mucus production Fluticasone (Flovent), Budesonide (Pulmicort), Beclomethasone (Beclovent, Qvar, Vanceril), Flunisolide (Aerobid), Triamcinolone (Azmacort) Long-acting 2-agonist Relieve airway constriction Salmeterol (Serevent discus), Formoterol (Foradil) Leukotriene modifier Decrease inflammation by reducing the production or blocking the action of leukotrienes Montelukast (Singulair), Zafirlukast (Accolate), Zileuton Sources: (1-3,17)

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11 Table 2. Long-term control medications for infants and children with asthma 5 years of age and younger. Asthma Severity Classification Long-term Control Medications Severe persistent Preferred treatments : High-dose inhaled corticosteroid and long-acting inhaled beta2-agonist If needed : Oral corticosteroid Moderate persistent Preferred treatments : Low-dose inhaled corticosteroid (medium-dose, if needed) and long-acting inhaled beta2-agonist or, Medium-dose inhaled corticosteroid Alternative Treatments : Low-dose inhaled corticosteroid (medium-dose, if needed) and leukotriene receptor antagonist or theophylline Mild persistent Preferred treatment : Low-dose inhaled corticosteroid Alternative Treatments : Cromolyn or leukotriene receptor antagonist Mild intermittent No daily medication needed Source: (2) term use of these medications should be avoided due to the side effects associated with them (3). Controller medications aid in long-term control of asthma and are used to reduce peribronchial inflammation and frequency of acute asthma exacerbations (3). They are taken on a daily basis, regardless of symptoms, and are available in a nebulized, MDI, or dry powder inhaler (DPI) form (3). The controller medications include anti-inflammatory agents such as inhaled corticosteroids, leukotriene modifiers, mast cell stabilizing drugs, and long-acting

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12 Table 3. Long-term control medications for children with asthma over 5 years of age and adults. Asthma Severity Classification Long-term Control Medications Severe persistent Preferred treatment : High-dose inhaled corticosteroid and long-acting inhaled beta2-agonist If needed : Oral corticosteroid Moderate persistent Preferred treatments : Lowto medium-dose inhaled corticosteroid and long-acting inhaled beta2-agonist Alternative Treatments : Increase inhaled corticosteroid up to medium-dose range; or low-to-medium dose inhaled corticosteroid and leukotriene modifier or theophylline Mild persistent Preferred treatment : Low-dose inhaled corticosteroid Alternative Treatments : Cromolyn, leukotriene receptor antagonist, nedocromil, or sustained release theophylline Mild intermittent No daily medication needed Severe exacerbations : Oral corticosteroid Source: (2) bronchodilators (Table 1) (18). Inhaled corticosteroids, which are intended for daily use, are the most effective controller medications available; therefore they are the most preferred medication for asthma control when pharmacotherapy is indicated (2,3,18). Long-acting 2-agonists are not the preferred treatment for asthma, but may be used concomitantly with inhaled corticosteroids in moderate and severe persistent asthma to control nighttime and exercise induced symptoms (2,17). Similar to long-acting 2-agonists, leukotriene modifiers serve as an alternative to inhaled corticosteroids and can be used in combination with

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13 inhaled corticosteroids for the treatment of mild persistent asthma (2). Although they are not as effective as inhaled corticosteroids, they are effective in controlling asthma in approximately two-thirds of the population with asthma (3). The preferred medical therapy for children 5 years of age and younger includes low-dose inhaled corticosteroids, administered using a nebulizer, DPI, or a MDI with a holding chamber, with or without a face mask (2). Alternative therapies include cromolyn or a leukotriene receptor antagonist (LTRA) (2). A low-dose inhaled corticosteroid also is the preferred medication for children over 5 years of age and adults (2). Alternative therapies include cromolyn, LTRAs, nedocromil, or sustained release theophylline (2). Environmental Management Altering the indoor and outdoor environment is another way to aid in the management of asthma. Indoor environmental management may include decreasing or eliminating allergens, mold, insects (i.e., house dust mites, cockroaches), animals (domestic and pests), or irritants (i.e., tobacco, perfumes and scents, household cleaners, wood-burning fireplaces, heating and air conditioning), or controlling humidity in the home, school, and office (3). Outdoor environmental management may include decreasing or eliminating exposure to cold or exercise (3). Dietary Management Parents of children with asthma commonly avoid or eliminate foods from their childrens diets in an attempt to reduce the onset of asthmatic symptoms (6). Milk and dairy products are the foods most often reported to be eliminated or avoided (6), although studies do not support a connection between milk intake

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14 and a reduction in pulmonary function (19-21). Restriction or avoidance of milk and dairy products consumption could have an adverse effect on the intake of calcium and vitamin D, nutrients associated with favorable bone growth, development, and maintenance. Inadequate calcium and vitamin D intake, as well as restricted physical activity and oral corticosteroid use, place children and adolescents with asthma at risk for osteoporosis. Calcium Structure and Function Calcium is the most abundant divalent cation in the human body, and 99% of calcium is found in bones and teeth, mainly in the form of hydroxyapatite (Ca10(PO4)6(OH)2) (22-25). The remaining 1% of calcium in the body is present in intracellular and extracellular fluids, muscle, and other tissues (22). In general, calcium plays a vital role in normal growth, development, and maintenance of bone and other calcified tissues (22). Other functions of calcium include blood clotting, nerve conduction and transmission, muscle contraction, enzyme regulation, hormone release, vision, mediating vascular contraction, vasodilation, and glandular secretion (22,24,25). During bone formation and mineralization, calcium enters bone fluid from blood in the free, ionized form (i.e., Ca2+) or as a calcium salt (i.e., Ca3(PO4)2) (24). It is thought that during the process of bone mineralization, osteoblasts secrete a substance onto the bone surface to enhance calcium precipitation. Calcium, in the form of a calcium salt, binds to the bone surface and is laid down on collagen to form bone.

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15 Within the intracellular compartment of the body, calcium acts as a second messenger to activate physiological responses (25). It functions in activating these physiological responses by binding to specific proteins such as calmodulin and troponin C (24). The binding of calcium to calmodulin activates enzymes that serve to function in smooth muscle contraction, glycogenolysis, and other functions. When calcium binds to troponin C, skeletal muscle contraction is stimulated (24). In the extracellular compartment, which includes blood, lymph, and body fluids, calcium is present primarily in the free, ionized form, but also can be bound to albumin or globulin, or complexed to phosphate, citrate, or other anions (24,25). Extracellular calcium serves as a source of ionized calcium for the skeleton and cells (25). Digestion and Absorption In order for calcium to be digested, it must be in the free, ionized form. Calcium derived from food and supplements is in the form of insoluble salts, and calcium must be released from these salts for proper absorption (24). Absorption of calcium occurs throughout the small intestine by one of two processes. The first process, which takes place primarily in the duodenum and the proximal jejunum, is transcellular, saturable, and requires energy (i.e., active transport) (24,25). It is under homeostatic control, involves a calcium-binding protein, and is regulated by calcitriol (1,25 (OH)2 D3), making it a vitamin D-dependent process (24,25). This route of absorption occurs at low (<400 mg) and moderate calcium intakes, during periods of growth, and during pregnancy and lactation (22,24). The second process of absorption, which takes place primarily in the

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16 jejunum and ileum, is nonsaturable, passive, paracellular, not under homeostatic control, and dependent on the amount of calcium available in the intestinal lumen (22,24,25). As a result, the more dietary calcium ingested, up to a certain threshold, the greater the amount of calcium absorbed through this route (24). Approximately 25 to 35% of dietary calcium is absorbed through both of these routes combined. In addition, it is thought that a modest amount of calcium is absorbed in the large intestine through the release of calcium from bacteria after ingestion of some fermentable fibers such as pectin. There are several dietary factors that may influence calcium absorption. Dietary components that increase the absorption of calcium include vitamin D, sugars such as lactose, sugar alcohols such as xylitol, inulin, fructooligosaccharides, and protein (23-25). The presence of food in the gastrointestinal (GI) tract also improves calcium absorption as does the calcium content of a meal (22,25). Dietary components that may decrease absorption of calcium include oxalate or oxalic acid; nonfermentable fiber such as the fiber found in wheat bran, hemicelluloses, phytate or phytic acid; divalent cations and other minerals such as magnesium or zinc; caffeine; unabsorbed dietary fatty acids; and a low dietary calcium/phosphorus intake ratio (22-26). This reduction in calcium absorption can occur through several mechanisms including decreased transit time, binding, chelation, competition for absorptive sites, and the formation of insoluble salts (24). Overall, calcium absorption ranges from 20 to 50% (24).

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17 Transport Calcium is transported through the blood bound to proteins, complexed, or in the free, ionized form. Approximately 40% of calcium in the blood is bound to proteins (i.e., albumin and prealbumin), 10% is complexed to sulfate, phosphate or citrate, and 50% is found in the free, ionized form (24). Homeostasis Calcium homeostasis is tightly controlled both intracellularly and extracellularly. Extracellular homeostasis (i.e., blood calcium) is maintained primarily through the actions of three hormones: parathyroid hormone (PTH), calcitriol, and calcitonin (24). Additionally, a calcium-sensing receptor (CaSR or CaR), which is found in the parathyroid gland, thyroid gland, distal nephron, GI tract, skin, brain, and in osteoblast cell lines, is involved in calcium homeostasis (25,27). When blood calcium concentration is low, a PTH-vitamin D-dependent process returns blood calcium concentration to normal by increasing calcium absorption, renal tubular reabsorption, and bone resorption (25). When low concentrations of ionized calcium are detected by the CaSRs of the parathyroid gland, intact PTH is released (27). The release of PTH affects the kidneys and bones (24). In the kidney, PTH stimulates the synthesis and activation of calcitriol, the active form of vitamin D, which induces reabsorption of calcium in kidneys (24,28). Calcitriol also upregulates the production of calbindin by binding to the nuclear receptors of enterocytes thereby stimulating transcription of the gene that encodes calbindin (24). Increased calbindin production is associated with increased calcium absorption from the GI tract. In the bone, PTH interacts

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18 with receptors on osteoblasts to signal osteoclasts to break down bone and release calcium into the blood by way of calcium pumps. As a result of these actions, the blood calcium concentration is returned to normal. When the blood calcium concentration is high, ionized calcium binds to the CaSR on the parathyroid gland to induce a conformational change and PTH secretion is inhibited (25). As a result, PTH cannot activate calcitriol. Instead, calcitonin is secreted, which serves to decrease calcium absorption by inhibiting vitamin D activation, increasing urinary calcium excretion in the kidney, and decreasing bone resorption by inhibiting osteoclasts from metabolizing bone (24,25,28). As a result of these actions, the blood calcium concentration is returned to normal. Intracellular calcium homeostasis is maintained through the action of ATP-dependent calcium pumps and calcium storage in the mitochondria, endoplasmic reticulum, nucleus, and vesicles (24). Calcium pumps transport Ca2+ out of the cell to maintain low intracellular concentrations within the cell or to the mitochondria for storage until it is needed by the cell. To control the calcium concentration in the cytoplasm, calcium may be transported from extracellular sites into the cell by a sodium-calcium exchange. Deficiency Calcium deficiency may occur as a result of inadequate intake, poor absorption, or excessive losses. The consequence of a calcium deficiency is a decrease in bone mass (BM), which may lead to osteopenia and eventually osteoporosis if bone loss continues (24,29-32). The loss of BM associated with

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19 the development of osteoporosis results in increased bone fragility and increased fracture risk (33). Risk for calcium deficiency is higher in vegetarians or individuals who are lactose intolerant or have high protein and fiber intakes. Other factors that contribute to calcium deficiency include fat malabsorption, immobilization, which promotes calcium loss from the bones, decreased GI transit time, or short-term use of thiazide diuretics (22,24). Status Assessment Methods used to determine calcium status include measurement of serum calcium and serum ionized calcium. Serum calcium, which includes protein-bound, complexed, and ionized calcium, is very tightly regulated and is affected by albumin status so it is not a good indicator of calcium status (24). Serum ionized calcium is reflective of abnormal calcium metabolism when albumin status is normal, but a correction factor must be applied when serum albumin is low. Dietary Reference Intakes (DRIs) Dietary Reference Intakes are nutrition-based reference values that can be used for planning and assessing diets (22). Those that pertain to calcium are the AI and Tolerable Upper Intake Level (UL). Adequate Intake (AI) The AI is defined as the observed or experimentally derived intake by a defined population or subgroup that, in the judgment of the DRI Committee, appears to sustain a defined nutritional state, such as normal circulating nutrient values, growth, or other functional indicators of health (22, p.25). An AI, rather

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20 than a Recommended Dietary Allowance (RDA), is used when sufficient data are not available to establish an Estimated Average Requirement (EAR) (22). The AI is the amount of a nutrient that is expected to meet or exceed the amount needed to maintain a defined nutritional state or criterion of adequacy in essentially all members of a specific healthy population (22, p.25). The AI for calcium for children and adolescents 1 to 18 years of age ranges from 500 to 1300 mg/d (Table 4). Tolerable Upper Intake Level (UL) The UL is defined as the highest level of daily nutrient intake that is likely to pose no risk of adverse health effects to almost all individuals in the general population (22, p.26). As intake increases above the UL, the risk for adverse effects increases. The UL is based solely on intake from supplements and fortified foods and applies to chronic daily use only. The UL for children and adolescents 1 to 18 years of age is set at 2,500 mg/d (22). Table 4. Dietary Reference Intakes for calcium for children and adolescents 1 to 18 years. Age AI (mg) UL (mg) 1-3 years 500 2,500 4-8 years 800 2,500 9-18 years 1,300 2,500 Source: (22) Sources Calcium is widely available in the U.S. food supply. Sources of calcium include milk, cheese, ice cream, yogurt, calcium-set tofu, soy milk, salmon, sardines (with bones), clams, oysters, turnip and mustard greens, broccoli, kale,

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21 rhubarb, Chinese cabbage, legumes, dried fruits, and calcium-fortified foods such as orange juice and some cereals (22,24,25). Calcium bioavailability is fairly similar in dairy products such as milk and cheddar cheese, as well as fortified juices, soy milk, and yogurt (25). Calcium is poorly absorbed from spinach, rhubarb, and legumes, which are sources of oxalic acid, and from legumes, grains, and soy isolates, which are sources of phytic acid (22). Milk, cheese, and yogurt are the most calcium-dense foods consumed by Americans, providing approximately 300 mg per serving (22). According to data for 1999, 73% of calcium in the U.S. food supply is from milk products, 9% is from fruits and vegetables, 5% is from grain products, and the remaining 13% is from all other sources (34). Calcium Intake in the U.S. Overall, calcium intake in the U.S. has declined because grains have become staples in the diets of Americans (25). The calcium content of grains and fruits are typically quite low, except in fortified cereals and grains (25). Calcium intake of Americans, especially adolescent girls, are below current recommendations (25). According to data from the 1994-1996 and 1998 CSFII, higher intake of total dairy and milk were associated with statistically significant increases in calcium intake (35). Additionally, the authors found that individuals with low dairy or milk intake did not compensate for their lower intake of these calcium-rich foods by consuming other foods that are good sources of calcium. Other factors that may affect dietary calcium intake in the U.S. are lactose intolerance, which occurs in 25% of adults, and consumption of vegetarian diets (22).

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22 Vitamin D Structure and Function Vitamin D is a fat-soluble vitamin that plays a key role in normal growth, development, and maintenance of bone and other calcified tissues through its effect on calcium (22). Vitamin D also is active in cardiac tissue, muscle, brain, skin, hematopoietic cells, and immune system tissues (24). Blood is the primary storage sight for 25-OH D3. The primary biologic function of vitamin D is to maintain adequate serum concentrations of calcium and phosphorus through its actions on the intestinal, kidney, and bone cells (22,24). In the intestine, vitamin D primarily functions by increasing the absorption of calcium and phosphorus by upregulating the production of calbindin. In the kidney, PTH activates vitamin D (calcitriol) to stimulate calcium and phosphorus reabsorption. Vitamin D also functions with PTH in the bone to mobilize calcium and phosphorus by inducing differentiation of cells to osteoclasts and/or increasing osteoclast activity (24). Vitamin D also is involved in bone formation and remodeling through its role in promoting the synthesis of osteocalcin. Digestion, Absorption, and Transport Dietary vitamin D is absorbed primarily in the distal small intestine in association with fat through passive diffusion (24). Approximately 50% of vitamin D is absorbed. Once absorbed into the enterocytes of the small intestine, dietary vitamin D, in the form of D3, is incorporated into chylomicrons that enter the lymphatic system. Vitamin D-binding protein (DBP) transports vitamin D to the liver through the blood. In the liver, vitamin D (cholecalciferol) undergoes a

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23 hydroxylation at carbon 25 to form 25(OH) D3. It is released back into the blood and transported to the kidney via DBP (24,36,37). In the kidney, 25(OH) D3 undergoes another hydroxylation to form 1,25(OH)2 D3 (calcitriol), the active form of vitamin D. Calcitriol is released from the kidney, transported to target tissues on DBP, released by DBP, and bound to receptors in the target tissues. In addition, vitamin D can be synthesized in the skin through exposure to sunlight. A sterol found in the skin, 7-dehydrocholesterol, absorbs ultraviolet (UV) light from the sun and is converted to vitamin D3 (cholecalciferol) (24,36). Cholecalciferol enters the blood to be activated by the same mechanism as dietary vitamin D. Deficiency A potential cause of abnormal calcium and bone metabolism is vitamin D deficiency (22,38), which can lead to rickets in infants and children and osteomalacia in adults. Both rickets and osteomalacia are a result of failure of the organic matrix of bone to calcify or mineralize (24,36). In children less than 6 months of age, vitamin D deficiency is associated with convulsions or tetany (36). Vitamin D deficiency in children 6 months of age and older is associated with tetany, bone pain, and bone deformity. Adults with osteomalacia are likely to experience bone pain and osteopenia, which increase the risk for skeletal fractures (24,36,39). Risk for vitamin D deficiency is associated with advancing age; fat malabsorption; disorders affecting the parathyroid gland, liver, or kidney; insufficient sun exposure; dark skin pigmentation; anticonvulsant therapy; unsupplemented breastfeeding infants; and renal disease (24,36). The

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24 prevalence of vitamin D insufficiency in adults living in the U.S. and Canada ranges anywhere from 1 to 76% depending on the latitude and the season (40). Status Assessment Serum 25(OH) D3 is the most accurate and reliable measure of vitamin D status (41,42). The ranges of serum 25(OH) D3 concentrations used to determine vitamin D status are listed in Table 5. Table 5. Vitamin D status assessment according to serum 25(OH) D3 concentrations. Vitamin D Status Serum 25(OH) D3 (nmol/L) Normal/Adequate 100-200 Hypovitaminosis 50-100 Insufficiency <40-50 At risk for deficiency 13-25 Deficient <13 Sources: (36,37) Dietary Reference Intakes (DRIs) Adequate Intake (AI) Similar to calcium, an AI rather than an RDA was established for vitamin D due to lack of sufficient data for setting an EAR. The AI for vitamin D for children and adolescents 1 to 18 years of age is 5.0 mcg/d (200 IU/d) (22). Tolerable Upper Intake Level (UL) The UL for vitamin D for children and adolescent 1 to 18 years of age is 50 mcg (2,000 IU)/d (22). Sources Vitamin D is not as widely available in the food supply as calcium. It is found primarily in saltwater fish such as herring, salmon, tuna, and sardines and

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25 fish liver oils (24,36). Small quantities of vitamin D also are found in eggs, veal, beef, butter, cheese, and vegetable oils. Fortification of foods with vitamin D is an inexpensive approach for promoting adequate vitamin D intake for all children and adults. The U.S. fortifies milk, some butter, margarine, cereals, and chocolate mixes with vitamin D3 (calciferol) (24,36). Recently some types of fruit juice, such as orange juice, and some brands of yogurt also have been fortified with vitamin D (43). Vitamin-D fortified juice provides approximately 100 IU (50% AI) of highly bioavailable vitamin D per serving for children and adults (43,44). Vitamin D Intake in the U.S. Most humans obtain their vitamin D requirement from exposure to sunlight, which accounts for 80 to 100% of the bodys requirement (42). It has been estimated that 53% to 63% of all children meet the AI for vitamin D, with adolescent and adult females being half as likely to obtain the AI as males (44). The majority of dietary intake of vitamin D in the U.S. comes from fortified dairy products (45 to 47%) (44). Factors Influencing Bone Health during Childhood and Adolescence Several studies have identified factors that may influence bone health in children and adolescents. These factors include age, Tanner stage (i.e., stage of puberty), height, weight, body mass index (BMI), and dietary intake of calcium, vitamin D, and milk and dairy products. Numerous studies, including cross-sectional, intervention, and longitudinal studies, have reported a positive correlation between bone density or BM development in children and calcium, vitamin D, and milk and dairy products

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26 intake (22,45). In a 3-month study of healthy, Caucasian children and adolescents, researchers found that dietary calcium intake, age, weight, and height were positively correlated with BMD (46). These researchers also observed that children whose average daily intake of calcium was at least 1000 mg had higher bone mineral content (BMC) than those ingesting less than this amount. Serum calcium, vitamin D, phosphorous, magnesium, or alkaline phosphatase concentrations were not correlated with bone mineral status in this study. Similarly, Ruiz and colleagues determined that body weight, physical activity, and dietary calcium intake (expressed as Z scores) were significant determinants of femoral and vertebral bone density in healthy, Caucasian, physically active children and adolescents with normal growth velocity (47). Height and Tanner stage also were significant determinants of vertebral BMD, and age influenced femoral BMD in this population. Sentipal and colleagues also found dietary calcium intake to have a positive effect on bone density (48). These researchers conducted a cross-sectional study of healthy, Caucasian female children and adolescents that examined the contribution of calcium intake on vertebral BMD and observed that current calcium intake was a significant contributor to vertebral BMD after adjusting for weight, height, age, and total energy expenditure. Sexual maturity rating, age, and calcium intake accounted for 81% of the variance in vertebral BMD. Calcium supplementation also has been shown to positively affect BMD in children and adolescents. A 3-year, double-blind, placebo controlled, co-twin trial conducted with healthy, 6 to 14 year old identical twins sought to determine

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27 whether calcium alone was effective in increasing the rate of change in BMD (49). These researchers found that calcium supplementation had a positive effect on the rate of increase in BMD at several skeletal sites. Consumption of milk and dairy products, which are good sources of calcium and vitamin D, also has been shown to positively affect BMD. A large, cross-sectional study of randomly selected Chinese adolescent girls found that milk consumption, total calcium intake from milk, and vitamin D intake were positively associated with BMD (50). Body weight and Tanner stage also were predictors of BMD. Another study conducted in Yugoslavia reported that despite almost identical lifestyles, BM by 30 years of age was greater in individuals living in a region of Yugoslavia where consumption of dairy products was twice that of another region of the country (51). These studies suggest that elimination of dairy products from a growing childs diet may have a negative impact on BMD. Achievement of PBM also has been studied. A cross-sectional study of premenopausal, Caucasian, children and adults conducted by Matkovic and colleagues sought to determine the timing of PBM, the maximum attainable BM within an individuals genetic potential, and BMD (52). Researchers did not detect a significant difference in BM or BMD for most skeletal sites except for the skull after 18 years of age, indicating early attainment of PBM for the hip and spine. Similarly, Henry and colleagues found that the majority of the bodys bone mass (i.e., BMC and BMD) was achieved by late adolescence, with peak BMC being achieved between 21 and 22 years of age in men and 23 and 28 years in women, and peak BMD being achieved between 12 and 22 years in men and 12

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28 to 29 years in women (53). This suggests that PBM is achieved sometime between the end of adolescence and early adulthood. Overall, the research studies summarized in this section support the importance of adequate intake of calcium, vitamin D, and dairy products during childhood and adolescence to promote bone health and achievement of PBM. A limited number of studies have not observed a positive correlation between bone density in children and calcium intake or physical activity level as reviewed by the IOM (22). This could be due to other factors that affect BMD, such as maturational and chronological age and genetics. A study of physically active children and adolescents did not detect a significant positive correlation between calcium intake and bone density when stage of puberty and body weight were controlled (54). Researchers concluded that in healthy, physically active children with adequate calcium intake there is no appreciable effect of calcium on bone density. Bone density may be a function of the relationships between calcium intake, body weight, and stage of puberty. Similarly, in a prospective, longitudinal, 1 year-long study of healthy Finnish children and adolescents, physical activity and daily calcium intake were not correlated with BMD (55). It is important to note that calcium intake in the majority of study subjects was relatively high (> 800 mg/d). It is important to note that these 2 studies did not compare the relationship between the type of exercise in which study subjects participated (i.e., weight-bearing or non-weight-bearing exercise) and BMD. Although a few studies suggest that calcium, vitamin D, and dairy products intake do not influence bone health, most of the studies conducted support the

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29 role of dietary intake of calcium, vitamin D, and dairy products in promoting bone health during childhood and adolescence. Factors Influencing Bone Health during Adulthood Several factors that may influence bone health during adulthood have been identified from research studies. These factors include dietary intake of calcium, vitamin D, milk and dairy products, and level of physical activity during childhood and adolescence. Numerous retrospective studies have reported an association between higher calcium intake during childhood and adolescence with achievement of maximal PBM and greater BM in adulthood (22,45,56). As discussed earlier, calcium is important for healthy skeletal growth and development throughout life and because PBM is achieved by early adulthood, early calcium intake can significantly influence the degree to which PBM is achieved (53). Insufficient PBM has been shown to contribute significantly to the risk of osteoporosis later in life (57). Halioua and Anderson assessed the independent and combined effects of lifetime calcium intake and physical activity on BMD, as well as body weight, in healthy, ambulatory, premenopausal Caucasian women (58). This cross-sectional study found that both lifetime calcium intake and physical activity were significant positive predictors of BMD and BMC. Individuals with low lifetime calcium intake and sedentary lifestyles were found to have the lowest bone BMD and BMC. A similar study was conducted by Sandler and colleagues (59). These researchers conducted a retrospective study of white, middle to upper-middle class women in which information about milk consumption and calcium intake during childhood and adolescence were collected. These researchers

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30 observed that women who reported drinking milk with every meal during childhood and adolescence had significantly higher bone density measurements than women who reported drinking milk less frequently. As a result, the researchers concluded that milk consumption during childhood and adolescence appears to be necessary for optimal PBM. Results from a large, cross-sectional survey of women also suggest the importance of milk and dietary calcium consumption during childhood and adolescence on bone density of adults. Kalkwarf et al. examined data collected on non-Hispanic, white women 20 years of age and older from the third National Health and Nutrition Examination Survey (NHANES III) conducted from 1988 to 1994 (60). Milk and dietary calcium intake was determined through household surveys on milk consumption during specific periods of life, including childhood, adolescence, and adulthood. Milk intake during childhood, adjusted for confounders, was positively associated with total hip BMC and bone area in women between 20 and 49 years of age. In addition, milk intake during adolescence was positively associated with hip BMD in women between 20 and 49 years of age. In women over the age of 50 years, milk intake during childhood and adolescence positively influenced total hip BMD, and low BMD was associated with a significantly greater incidence of lifetime fracture. Also, low calcium intake during childhood was significantly associated with an increased risk for osteoporotic fractures in women over 50 years of age, thereby supporting the importance of milk consumption and adequate calcium intake during childhood and adolescence. Collectively, these studies strongly suggest

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31 that dietary intake of calcium, vitamin D, and dairy products are important during childhood and adolescence because of the impact on bone health later in life. Factors Influencing Bone Health in Children and Adolescents with Asthma Calcium and vitamin D intake is important for promoting bone health in all children and adolescents, including those with asthma; however, health beliefs and practices among this population may interfere with achieving optimal intake of these nutrients. Furthermore, other factors may put children and adolescents with asthma at higher risk for poor bone health including altered metabolism related to the disease, the medications used to treat asthma, and the restriction of physical activity to avoid exercise-induced asthma (EIA) symptoms. Health Beliefs about the Impact of Milk and Dairy Products on Asthma One of the health beliefs adopted by some parents of children with asthma is that cows milk and cows milk products affect asthma symptoms. For this reason, some parents may eliminate or restrict the intake of milk and dairy products in their childrens diets, which could severely limit their intake of calcium and vitamin D and have a negative impact on bone health over time. Research has shown that parents of children with asthma commonly (47%) avoid or eliminate foods from their childrens diets, with milk and dairy products being the primary (79%) category of foods eliminated or avoided (6). As reported by Dawson et al., parents reported family, friends, and the media as the most common (77%) sources of advice that influenced their decision to make a change in their childs diet (6). Only 14% of parents reported receiving this advice from a medical source (i.e., family doctor, dietitian, specialist, etc.). A similar study conducted by Woods and colleagues on pediatric and adult asthma

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32 patients showed that 45% of subjects had been advised by a doctor, specialist, or a dietitian to avoid or eliminate specific foods, such as milk and dairy products, at some time in their lives to improve asthma symptoms, and approximately 61% were currently eliminating or avoiding these foods or had in the past (7). Dairy products were one of the most commonly (36%) reported food categories to induce asthma symptoms, the most commonly advised dietary restriction, and the most commonly avoided food category. Another factor that may influence milk and dairy intake by children with asthma are the attitudes and beliefs held by them and their parents or caregivers. For example, a survey was completed by 330 parents waiting in a pediatric pulmonology office (61). Parents were asked if they avoided serving milk to their child when they were ill, whether they thought their child was allergic to milk, if their child had allergies, asthma, or cystic fibrosis (CF), and other questions related to health beliefs and practices. Over half of the parents surveyed had a child with asthma. Approximately 62% of parents of children with asthma believed that drinking milk increased mucus. Family members were the most common source of this information followed by pediatricians, physicians, and others. Additionally, 8.2% of parents believed that their child was allergic to milk and of these, approximately 70% believed that milk increased mucus production. Overall, the studies summarized in this section suggest that intake of milk and dairy products may be restricted or avoided in the diets of children and adolescents with asthma due to health beliefs about the role of these foods in producing asthma symptoms and allergies.

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33 Calcium and vitamin D intake and bone health in cows milk-free and cows milk-limited diets Several studies suggest that the calcium intake of children on cows milk-free or cows milk-limited diets is inadequate. A prospective, 2-year study of male and female prepubertal children who were milk-avoiders (i.e., individuals with a history of avoiding the consumption of cows milk for more than 4 months at some stage in their lives) found that milk-avoiders not only had lower calcium intake, but also smaller bones, significantly lower bone area and BMC, and lower volumetric BMD (62). The researchers concluded that children with a history of long-term avoidance of cows milk have low dietary calcium intake and poor bone health in comparison to children who drink milk. In a two-year follow-up of this same population milk-avoiding children had a significantly higher prevalence of bone fractures compared to milk drinkers (controls). Furthermore, milk-avoiding children did not make appropriate dietary substitutions to compensate for their low calcium intake (63). In a younger population of children, calcium intake also was found to be inadequate in cows milk-free and cows milk-limited diets. Henriksen et al. conducted a prospective, cohort-based study to evaluate the nutrient intake of children (mean age = 33 months) whose parents perceived that their child had reactions to milk or egg when they were 2 years of age (64). Each subject was categorized into one of four groups (i.e., milk-free, formula, low milk, and milk consumers) based on their current diet. The milk-free group included subjects on a diet completely free of cows milk protein; the formula group included subjects who consumed various amounts of hypoallergenic formula (i.e., soy-based or hydrolyzed); the low milk group consumed some dairy products, but

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34 did not drink cows milk; and the milk consumers group included children who were milk-drinkers. Subjects in the milk-free, formula, and low-milk groups had significantly lower calcium intake than the milk-consuming group. In fact, children in the milk-free group had an average daily calcium intake of less than 300 mg and children in the low milk and formula groups each had an average daily calcium intake of less than 500 mg. These studies suggest that childrens calcium needs most likely will not be met on a cows milk-free or cows milk-limited diet. Cows milk and pulmonary function Despite the popular belief that ingestion of cows milk and other dairy products increases mucus and negatively affects pulmonary function in individuals with asthma, studies have shown that cows milk ingestion does not decrease pulmonary function, as evidenced by FEV1, FVC and/or PEF, nor does it induce bronchoconstriction (20,21). A statistically significant difference was not detected in pulmonary function (i.e., FEV1 and PEF) between a cows milk challenge and a placebo challenge (i.e., rice milk) in a randomized, double-blind, placebo-controlled, cross-over study conducted in adults with asthma (21). Additionally, a statistically significant difference was not detected in pulmonary function from baseline after cows milk challenge even in those subjects who perceived that their asthma worsened after ingestion of dairy products. No subjects reported an increase in cough or sputum production after any of the challenges. A study using water instead of rice milk as the control reported similar results (19). This 3-day pilot study designed to assess the effects of milk ingestion on pulmonary function, recruited adults with and without asthma who

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35 did not have a history of milk protein allergy or lactose intolerance, and randomly assigned them to consume 10 ounces of water, whole milk, or skim milk after which lung function was evaluated using FVC, FEV1, and V50 (i.e., airflow at 50% of vital capacity) (19). Neither group (i.e., subjects with asthma or subjects without asthma) showed a significant change in any lung function parameters from baseline over three hours following ingestion of any of the test beverages (i.e., water, skim milk, or whole milk) and there were no significant differences in lung function parameters between the subjects with asthma and the subjects without asthma for any of the test beverages. The authors concluded that because they did not detect a significant increase in airway resistance (i.e., a decrease in FVC, FEV1, or V50), there was not a significant increase in mucus production in the airways. A prospective, randomized, double-blind, placebo-controlled study of adult patients with mild asthma and no history of milk allergy reported similar results with regard to the lack of a clinically significant effect of cows milk on pulmonary function (i.e., FEV1 and FEV1/FVC) (20). No clinically significant effect of cows milk on pulmonary function was detected at any time point (i.e., 30 minutes, 1 hour, or 7 hours) compared to a placebo solution. There also was no evidence of asthma symptoms, acute or delayed, after either challenge. The authors concluded that pulmonary function does not deteriorate in response to cows milk ingestion. The studies presented in this section suggest that cows milk ingestion does not have a negative impact on pulmonary function in people with asthma.

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36 Cows milk or food allergy, adverse reactions to milk, and asthma A potential reason that parents of children with asthma may eliminate milk and dairy products from their childrens diets is related to the concern that their child may be allergic to milk. This concern may be real or perceived. A double blind placebo-controlled trial showed that incidence of cows milk allergy was low in children with asthma even in those who perceived that their asthma worsened after ingestion of dairy products (65). Similarly, a double-blind, placebo controlled, cross-over study conducted in children and adults with asthma found that of those subjects who by history, skin prick test, or radioallergosorbent test had a response suggestive of food allergy (8.3%), asthma was induced in only 30% of these subjects following a food challenge (e.g., milk, cheese, etc.), suggesting that food-induced asthma occurs in only 2% of individuals with asthma (66). A study conducted by Emery et al. also found a low prevalence of food allergy in individuals with asthma (67). This cross-sectional survey study of a well-characterized population of children and adults with asthma found that 45% of the subjects reported adverse reactions to foods, with milk being the leading cause of reactions (9.7% of the total surveyed, 21.5% of those reporting food reactions). Only 32% of those reporting adverse reactions to foods (14% of total surveyed) indicated that they had been diagnosed with a food allergy. Similarly, a study conducted with children who had bronchial asthma found that only 8.5% of the subjects had asthma due to a food allergy (68). All food allergies were confirmed by a positive intracutaneous test and hemagglutination test. Additionally, approximately 34% of those with food allergy were allergic to milk.

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37 These studies indicate that although there is a low prevalence of food allergy and food-induced asthma in children with asthma, a significant proportion of the observed cases are caused by milk. Physical Activity Observational and intervention studies have led to generalizations that regular, moderate physical activity throughout childhood and adolescence positively affects BMD, particularly at weight-bearing sites (45,69). The prevalence of EIA, bronchial hyperresponsiveness, or wheezing during exercise, as well as physical fitness and reported exercise limitations in children and adolescents with asthma may have an impact on the type and amount of physical activity in which they participate. This can potentially impact their bone health. Acute and chronic diseases of the respiratory tract and supporting structures, such as asthma, are potential barriers to participation in various forms of physical activity by children and adolescents (70). The prevalence of EIA has been estimated to be anywhere from 9 to 23% in the general population of children and adolescents (71). In contrast, the prevalence of EIA has been estimated to be 50 to 100% in children and adolescents with asthma (70,72). In a study of children and adolescents with asthma, 76% reported that wheezing increased after exercise (73). Both EIA and increased wheezing during exercise have the potential to cause individuals with asthma to limit the amount and type of physical activity in which they participate. This large range in EIA prevalence among individuals with asthma is affected by type, intensity, and duration of activity, environmental conditions, severity of disease, and variations in preventive therapy (72). Overall, these research studies indicate a relatively high

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38 prevalence of EIA, wheezing, and/or bronchial hyperresponsiveness during exercise among children and adolescents with asthma. Inadequate management or control of EIA may lead to unnecessary avoidance of physical activity and sports (74). There is general agreement that children with mild to moderate asthma are less fit than children without asthma (74). In fact, Kitsantas and Zimmerman reported that adolescent girls with asthma were less physically fit and participated less often in vigorous activities compared with non-asthmatic girls (8). Decreased aerobic capacity among asthmatic children and adolescents may be due to a sedentary lifestyle that results from a lack of full lung expansion during exercise and/or a negative attitude towards sports and other physical activities (72,74,75). Many preconceptions regarding the effect of exercise on asthma symptoms in children and adolescents have developed (76). A survey administered to Swedish children with asthma was conducted to identify the types of limitations in activities they experienced (9). Approximately 84% of these children reported three restricted activities during the previous week. The most commonly restricted activity was running, which accounted for 74% of restricted activities. Another study found that 52% of those who did not exercise limited their participation because they experienced shortness of breath or wheezing (73). Sixty-five percent of the adults and children in this study did not regularly participate in physical activity, but 64% indicated that their participation in physical activities would be greater if their asthma was under better control.

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39 In contrast, a large cross-sectional, multi-center survey of randomly selected school-aged children living in three different areas of Norway found that asthmatic children were as physically active as their non-asthmatic peers (77). In addition, no significant differences were detected between exercise frequency and hours of exercise per week for asthmatic compared to non-asthmatic children. However, the authors noted that this finding could be due to parents of children with asthma being aware of the importance of physical activity in the management of asthma, leading to overreporting the overall physical activity of their children. In a sub-group analysis, which included individuals only from one region of the country, researchers also found no difference in physical activity levels between children with or without asthma (78). Even though no significant difference in exercise frequency between those with or without asthma was detected, 12% of those with asthma exercised less than one hour per week and 38% exercised 4 to 6 hours per week (79). Although inconclusive, there is some evidence to suggest that children and adolescents with asthma are less fit, participate less frequently in physical activity, and have limitations in terms of the type of physical activity in which they can participate. This lack of physical activity has the potential to negatively impact bone health in this population. Inhaled Corticosteroid Use Another factor that may influence bone health is the use of inhaled corticosteroids. Many asthmatic children use inhaled corticosteroids daily. The role of inhaled corticosteroids on bone health (i.e., BMD and BM) in children and adolescents with asthma is controversial.

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40 The National Asthma Education and Prevention Program (NAEPP) Expert Panel of the NHLBI conducted a systematic review of available literature on the effect of inhaled corticosteroids on BMD through August 2000 (2). A total of 2 studies (i.e., 1 short-term and 1 long-term study) were identified that met the study criteria. The first study was a prospective study of Chinese patients with bronchial asthma using inhaled steroids (i.e., beclomethasone dipropionate (BDP) or budesonide (BUD)) regularly for at least 3 months. Researchers found that total body BMC was similar, but the BMD of the lumbar spine, femur, trochanter major, and Wards triangle were all significantly lower than that of matched control subjects (i.e., individuals without asthma who were not using inhaled corticosteroids) (80). In female subjects, there was a significant negative correlation between the average daily dose of inhaled steroid and BMD of the lumbar spine and trochanter of the femur. It is important to note that this study did not evaluate children and adolescents, had a small sample size (n = 30), and was short-term. The second study was conducted by the Childhood Asthma Management Program Research Group (81). This study was a 6-year, randomized, clinical trial of a large group of children with mild to moderate asthma. Subjects were randomized to BUD, nedocromil sodium, or a placebo. Prednisone administration was permitted as needed. No significant difference in the change in bone density was detected among the 3 groups. The NAEPP concluded that based on available research, inhaled corticosteroids taken in recommended doses do not have frequent, clinically significant, or irreversible effects on BMD in individuals with asthma (2, p.38).

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41 The report also noted that chronic use of inhaled corticosteroids could potentially have cumulative effects on bone health (i.e., increased relative risk for osteoporosis) when initiated during childhood and continued through adulthood, but the lack of high-quality studies assessing this outcome make it difficult to formulate a definitive conclusion. Studies conducted after this extensive review have not shown an association between inhaled corticosteroid use and a decrease in BMD and/or BM in children and adolescents with asthma. A 6-month randomized, pilot study was conducted with infants, children, and adolescents who had symptoms suggestive of asthma and who were nave to prophylactic therapy (e.g., corticosteroids) (82). Subjects were randomized to receive either a 2-agonist, an active control, or a 2-agonist combined with an inhaled steroid (i.e., BDP or BUD). Bone density was measured using two different radiation free predictors of bone density, broadband ultrasound attenuation and velocity of sound. No significant difference in bone density adjusted for age was detected between the control and each of the treatment groups. It is important to note that compliance with therapy in this study ranged from 25 to 100% (median 50%). A long-term study on children with asthma also found similar results. This 2-year randomized, open, multi-center, parallel-group, study was conducted with children with asthma who had only been treated in the past with a 2-agonist (83). Subjects were randomized by balanced block randomization to fluticasone propionate, an inhaled steroid, or nedocromil sodium, an active control. Bone mineral density measurements were performed by individuals who were blind to

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42 subject treatment. No significant difference in BMD was detected between the groups. Overall, the studies presented in this section suggest that inhaled corticosteroids do not have a long-term effect on BMD in children and adolescents with asthma. Systemic Corticosteroid Use In contrast to research on inhaled corticosteroid use, research suggests that oral or systemic corticosteroid use may have a negative impact on bone health. Oral or systemic administration of corticosteroids may indirectly affect bone health by reducing absorption of calcium in the gut and increasing renal clearance of calcium, resulting in decreased blood calcium. As a result, PTH is secreted, which inhibits the hypothalamo-pituitary-adrenal/gonadal axis and negatively impacts bone by increasing bone resorption (84). Oral corticosteroids also act directly on bone by inhibiting recruitment, differentiation and life span of osteoblasts; production of type 1 collagen; and synthesis of osteocalcin, insulin-like growth factors, and prostaglandin E. Bone Density of Children with Asthma and Risk for Osteoporosis Research strongly suggests that children and adolescents with asthma have significantly lower-than-expected BMD. For example, a cross-sectional study in which bone density, bone metabolism, and adrenal function were measured in children who were either exposed or unexposed to oral bursts (i.e., 5-day courses) of oral corticosteroids during the preceding year was conducted (85). Researchers found that even though bursts of oral corticosteroids did not have a prolonged or cumulative impact on bone metabolism, both groups had lower-than-expected bone density (i.e., negative mean Z score) for age, gender,

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43 and race. The researchers concluded that this finding may be due to inadequate protein, calcium, or vitamin D intake, or physical inactivity, factors that increase the risk for developing osteoporosis later in life. It is important to call attention to the fact that researchers did not address dietary calcium and vitamin D intake in this population. Research Significance Asthma affects 6.1 million children and adolescents in the United States (U.S.), and its prevalence is on the rise (1). The elimination of dairy products, potentially resulting in low calcium and vitamin D intake, low physical activity, 5-day courses of oral corticosteroids, and long-term use of inhaled corticosteroids seen among children and adolescents with asthma may have negative implications on bone health later in life. The only study identified following an extensive library search that examined the dietary intake of individuals with asthma, was conducted by Woods and colleagues (86). These researchers conducted a survey by mail on a large sample of adults to determine if there were differences in dietary intake between subjects with or without asthma. They found that intake of some foods, such as dairy products, were different between subjects with asthma compared to those without asthma, but intake of nutrients including calcium, were not. Specifically, asthma was negatively associated with whole milk and butter consumption and positively associated with ricotta and low-fat cheese consumption, but overall intake of dairy products was not significantly different between those with and without asthma. To date, no studies have specifically looked at the dietary intake of calcium and vitamin D in children and adolescents with asthma. Therefore, the purpose of this study was to examine

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44 calcium and vitamin D intake of children and adolescents with asthma to determine if they are meeting the recommended intake levels for these nutrients and to compare their intake of these nutrients with national intake data. Inadequate intake of these nutrients may suggest the need for supplementation as a way to promote bone health in children and adolescents, with the goal of decreasing the risk for osteoporosis in adulthood. It was hypothesized that children and adolescents with asthma would not meet the AI for calcium and vitamin D, and that they would consume less calcium than what has been reported in national survey data from children and adolescents of the same age.

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CHAPTER 3 MATERIALS AND METHODS Subject Description Subjects recruited for this study were patients with asthma between 1 and 18 years of age. Subjects were recruited from the University of Florida (UF) Pediatric Pulmonary Division during a normal clinic visit and from individuals screened by the UF Asthma Research Lab for participation in other studies. Subjects were excluded if they were less than 1 year of age or greater than 18 years of age; discontinued being followed by the Pediatric Pulmonary Division prior to completing their 3-day food and supplement diary; clinically diagnosed with CF, developmental delay, any GI disorders or diseases that affect absorption of nutrients, milk or dairy allergy, or bone disorders; were unable to speak and/or write in English; or were on tube feeding or intravenous feeding at the time of recruitment. Study Design The study design and protocol were approved by the UF Health Science Center Institutional Review Board. The primary objective of this study was to estimate calcium and vitamin D intake from foods, beverages, and supplements of children and adolescents with asthma and to compare their intake without supplement intake with the AI set by the IOM. A second objective of this study was to compare calcium and vitamin D intake without supplement intake of these subjects to those of an age-matched population using survey data from the 1994 45

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46 to 1996 and 1998 CSFII. To obtain this information, each participant or caregiver completed a 3-day food and supplement diary (Appendix B) that included intake for at least one weekend day. Subjects were recruited through advertisements, letters, as part of outpatient clinical care and/or referral by their primary caregiver, and through review of medical records and databases maintained by the UF Asthma Research Lab. Patients followed by the UF Pediatric Pulmonary Division and children that were screened for studies performed at the UF Asthma Research Lab that met study criteria were sent a letter to determine their interest in participating in this study. Subjects who met study criteria and attended the UF Pediatric Pulmonary Division clinic were contacted during their clinic visit to ascertain their interest in participating in this study. A complete explanation of the study was given and informed consent was obtained. Subjects were given verbal instructions for completing the food diary. Written instructions (Appendix A) were also provided, as well as a sample 1-day food diary (Appendix A), a portion size estimation aid with written information and pictures (Appendix A), a 3-day food diary record form (Appendix B), and a postage-paid envelope. The 3-day food and supplement diary was returned to the study investigators in the postage paid envelope. Subjects received follow-up phone calls, as necessary. Individuals interested in participating who did not reside in Gainesville or did not have an appointment scheduled in the following month were met at a location convenient for them within the UF Health Science Center or Shands Healthcare System (Gainesville, FL), or they were mailed two copies of the Informed Consent Form signed by the Principal Investigator and all of the materials as

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47 described above. A complete explanation of the study and how to complete the food diary was given by the Principal Investigator over the phone. These subjects received follow-up phone calls, as necessary. The subject signed one copy of the Informed Consent Form and returned it in the postage paid envelope with the completed 3-day food and supplement diary. The 3-day food and supplement diary needed to be postmarked by May 31, 2004 to be included in the study, and consented subjects who had not completed and returned the 3-day food and supplement diary were notified of this deadline by phone at least one month in advance of the close of the study. The completed 3-day food and supplement diary for each study participant was manually entered and analyzed using the ESHA (version 8.1) Food Processor software for Windows to determine the 3-day average intake for calcium, vitamin D, calories, protein, and fat (87). The medical records of study subjects also were reviewed to obtain information such as address, phone number, insurance, gender, ethnicity, age, prescribed medications, BMI, and growth percentiles for height, weight and weight-for-height, although these data were not available for all subjects. In cases where this information was not available in the medical record, subjects were contacted by phone to collect the information. After the 3-day food and supplement intake diaries were returned and the other information was collected, a $10 gift card to Target, Wal-mart, or another national chain discount store was mailed to each participant. The results of the 3-day calcium and vitamin D intake analysis were summarized and mailed to

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48 each subject. Average calcium and vitamin D intake was compared to the AI and the CSFII. Other nutrient analysis information may be evaluated at a later date. In order to protect patient confidentiality, all subject information was coded. The code key was kept in a locked filing cabinet to minimize risk for breech of confidentiality. The study code key will be destroyed upon completion of the final study report. Dietary Intake Tool and Analysis The dietary intake tool used to enter and analyze dietary intake in this study was ESHA Food Processor (version 8.1) for Windows (87). Food Processor 8.1 is an accurate, complete, versatile, quick, and easy-to-use diet analysis program (88). It can be used to analyze dietary intake and compare them to recommended standards. The data source is primarily derived from the latest U.S. Department of Agriculture (USDA) Standard Reference database, as well as the CSFII survey database, and data available from manufacturers, fast food companies, and published research. To determine the 3-day average intake of calcium and vitamin D, each 3-day food and supplement diary was manually entered by the Principal Investigator into Food Processor 8.1 (87). This automated program was used to calculate the 3-day average intake of calories, protein, fat, calcium, and vitamin D for each study subject. The average intake values for calcium and vitamin D without supplement intake were compared with age-appropriate calcium and vitamin D intake reported in the CSFII database and the AI.

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49 Overview of Three-day Food Diary Method Used to Assess Dietary Intake The dietary assessment method selected for use in this study was a 3-day food diary. This method requires that subjects or caregivers record detailed information about all foods and beverages consumed during a specified time period, usually 3 to 7 days (89,90). Foods and beverages ingested are ideally recorded at the time of consumption (91) and portion sizes are recorded based on actual weights or measures or visual estimation (90,91). Multiple days are usually recorded due to variation in dietary intake from day to day (91). Food diaries are appropriate to use when the research question focuses on a select group of nutrients or when nutrient intake is compared to a nutrient-specific standard, such as the AI (92). Data obtained from food diaries can be used to rank and quantify nutrient intake (91). A food diary is considered the most accurate and precise method for dietary assessment (93) and is often used as the gold standard (93-95). Ideally, this method reflects usual current intake (93,94). Several studies have used food diaries to validate other types of dietary assessments, such as food recalls and food frequency questionnaires (FFQs) (91). This method is accurate and quantitative (93,94) and can be more economical than some dietary intake methodologies because it eliminates the need for interviewing (93). Compared to retrospective methods, estimation of portion size is likely to be better since there is decreased reliance on memory. Another advantage is that this method requires little adaptation for different populations or age groups (91). In addition, incorrect statements about food habits are less likely to occur when food diaries are used compared to interview methods (96).

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50 Potential drawbacks of the food diary method are that is has the potential to be tedious and time-consuming (93), and it requires the child, adult, or caregiver to be literate and motivated (94,95), write legibly (92), recognize and describe quantities accurately (92,95), decipher food label information (92), and immediately record foods and portions consumed (91,94). Much of this can be resolved or improved with proper instruction. Disadvantages may include poor compliance (93) and alteration of diet by subject caregiver to ease recording of foods (93,96). An appropriate computerized database is needed for analysis of the data and a nutritionist or appropriately trained staff is needed for instructing subjects, checking records for accuracy, and completing the computerized nutrient analysis (91,93,95). Comparison of Methodologies to Assess Dietary Intake In addition to a food diary, there are several other commonly used methods to assess the dietary intake of individuals. These include FFQs, 24 hour recalls, and diet histories. Twenty-four hour recalls involve recollection of all food and beverages consumed during the previous 24 hours (90). A drawback of this method is that it does not represent and reflect an accurate picture of habitual or usual intake in children unless multiple recalls are obtained (91,93-95). Food frequency questionnaires require subjects to report frequency of consumption and sometimes portion sizes of foods and beverages from a long list (91). This method ranks intake and cannot be used to quantify usual intake of nutrients (91,95), and it generally overestimates intake (91). It also needs to be culture (93,97) and population (91) specific and may lack the unique details of an individuals diet (94,95).

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51 Diet histories are used to assess usual meal patterns, food intake, and other information in an extensive 1to 2-hour interview or questionnaire (91, p.493). This method, which is generally used to establish intake in the distant past, can be costly and time consuming (96). Several studies of older children, adolescents, and adults have provided evidence that no one method used for dietary assessment is consistently more accurate than the others and that underreporting often occurs (90,97,98). Serdula et al. reviewed the available literature on validity of food recalls, food diaries, FFQs, and diet histories in preschool children (91). The authors were unable to form any general conclusions because of the varied study designs, small sample sizes, and the limited number of studies examined (91). Crawford et al. conducted a validation study with 9 to 10 year old girls to compare 3 methods (i.e., 24-hour recall, 3-day food diary, and FFQ) against observed intake (99). They found that the 3-day food diary had the lowest percentage of missing food items and fewest phantom food items (i.e., foods reported, but not observed) compared to the other methods, and it was highly correlated with observed intake. Thus, the food agreement score (i.e., accuracy of reporting observed intake) was the highest for the 3-day food diary. These researchers concluded that the higher agreement score for the food diary methodology was due to the fact it did not rely as heavily on the subjects memory as the other methods. The 5-day FFQ was found to consistently overestimate intake and correlation with observed intake was low. The 24-hour recall had an intermediate correlation with observed intake. Hill and Davies

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52 reviewed self-reported energy intake obtained from using different dietary assessment methods and compared these data to the results obtained using doubly labeled water (90). They found that in studies of young children where the parent or guardian completed the food diary, there was good agreement between reported intake and measured energy expenditure. Finally, food diaries have been shown to be accurate measures of intake in lean subjects up to 9 years of age, but may not be as accurate in adolescents and younger adults where intake may be underreported by approximately 20% (100). Overview of the 1994 to 1996, 1998 CSFII Intake data from the 1994 to 1996, and 1998 CSFII was used as the age-matched reference population to which data from our subjects was compared. The CSFII is a national survey conducted by the Agricultural Research Service, USDA to gather data on the food and nutrient intake of the U.S. population, including the general population, as well as low-income individuals (101). The National Nutrition Monitoring and Related Research Program uses data from this survey and others to provide continuous monitoring of food use and consumption to determine the dietary and nutritional status of the U.S. population. The target population includes noninstitutionalized individuals residing in all U.S. states and Washington, DC. The 1994 to 1996 CSFII included collection of data from individuals of all ages and the 1998 CSFII included children from birth through 9 years of age (102). The dietary assessment method used to determine the food and nutrient intake was a multiple-pass 24-hour recall (101). Two, in-person, detailed twenty-four hour recalls collected 3 to 10 days apart were conducted by well-trained interviewers. They also gathered information on vegetarianism,

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53 supplement use, height and weight, allergies, smoking, exercise frequency, dieting, health status, and consumption of alcoholic beverages. In addition, the 2-day dietary recall included a food list in which subjects identified foods consumed during the past year. Statistical Analysis Statistical analyses were conducted using SAS version 8.02 (103) and Microsoft Excel 2002 (104). Average age and average intake of calories, protein, fat, calcium, vitamin D, and dairy products by age category and gender were calculated using Microsoft Excel 2002 (104). A power analysis was conducted to determine the sample size needed for each age category. An alpha of 0.05, beta of 0.2, power of 0.8, and the SD from the CSFII for each age category were used to calculate these sample sizes. The delta value, also used to calculate these sample sizes, was based on results from BMD studies used in establishing the AI for calcium. The delta value was defined as the difference in milligrams of calcium that is considered to be significantly different when comparing 2 populations. A range of delta values were used due to the highly variable results in the studies examined. The range for delta was determined to be 200 to 300 mg, 220 to 300 mg, and 400 to 443 mg for the 1 to 3, 4 to 8, and 9 to 18 year old age categories, respectively. It was determined that sample sizes of 22 to 48, 19 to 35, and 17 to 20 was were needed to yield adequate statistical power for the 1 to 3, 4 to 8, and 9 to 18 year old age categories, respectively.

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54 Comparison of Dietary Intake to AI A one-tailed small sample t-test was used to compare the 3-day average calcium intake without supplements and the 3-day average vitamin D intake without supplements to the recommendations set by the IOM for each age category (22). The study sample size was small and the true population SD was unknown, so the t-distribution rather than the standard normal z-distribution was used for comparisons of average intake to the AI. Comparison of Dietary Intake to 1994 to 1996, 1998 CSFII A one-tailed large sample z-test was used to compare the difference in mean intake of calcium without supplement intake of the study subjects to the age-matched CSFII population. A two-tailed large sample z-test was used to compare the difference in mean dairy intake of the study subjects to the age-matched CSFII population. The sample size in this study was extremely small compared to that of the CSFII, so the CSFII mean more likely reflected the true population mean than the mean of the study sample. The population (i.e., CSFII) SD was known, so the standard normal z-distribution was used for these comparisons.

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CHAPTER 4 RESULTS Subjects Demographics Eighty-four subjects (i.e., 56 males, 28 females) enrolled in the study and 36 subjects (i.e., 26 males, 10 females) completed and returned a food and supplement diary. The number of male and female subjects in each category and the number of males and females who completed the food and supplement diary are listed in Table 6. The average age of subjects who completed the study Table 6. Number of subjects who enrolled and completed the study and percent return rate by age category and gender. Age category (years) Gender Number enrolled Number completed % Return rate All 22 9 40.9% Males 19 9 47.4% 1 to 3 Females 3 0 0.0% All 27 14 51.9% Males 15 9 60.0% 4 to 8 Females 12 5 41.7% All 35 13 37.1% Males 22 8 36.4% 9 to 18 Females 13 5 38.5% All 84 36 42.9% Males 56 26 46.4% Total Females 28 10 35.7% by age category was 2.5 years, 6.4 years, and 13.9 years in the 1 to 3 year old, 4 to 8 year old, and 9 to 18 year old age categories, respectively. Due to new 55

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56 restrictions on health information, race was not obtained for study subjects. Reasons for not completing the study that were relayed by some of the subjects caregivers were that they were too busy, it was too difficult to arrange cooperation with the daycare to record food intake, or they didnt wish to complete the 3-day food and supplement diary. Dietary Intake of Calories, Protein, and Fat Mean dietary intake of calories, protein, and fat are presented in Table 7. Subjects in the 1 to 3 year old age group consumed a 3-day mean intake of 1,616 calories, 58 g of protein, and 57 g of fat. Subjects in the 4 to 8 year old age group consumed a 3-day mean intake of 1,994 calories, 72 g of protein, and 75 g of fat. Subjects in the 9 to 18 year old age group consumed a 3-day mean intake of 2,285 calories, 87 g of protein, and 91 g of fat. Table 7. Three-day dietary intake of calories, protein, and fat by study subjects. Age category (years) Gender Calories* (kcals) Calories (% of AI) Protein* (g) Protein (% of AI) Fat* (g) 1 to 3 Both 1,616 251 118% 58 15 360% 57 18 Males 2,214 625 112% 78 26 322% 85 35 Females 1,598 458 87% 63 12 279% 58 27 4 to 8 Both 1,994 631 N/A 72 23 N/A 75 34 Males 2,573 835 94% 92 30 167% 102 43 Females 1,824 479 78% 78 31 156% 74 26 9 to 18 Both 2,285 793 N/A 87 30 N/A 91 39 *Values represent mean SD. N/A = not applicable Dietary Intake of Calcium and Vitamin D Three subjects consumed a calcium-containing supplement during the 3-day recording period, 1 subject in the 1 to 3 year old group and 2 subjects in the 4 to 8 year old group. The mean dietary intake of calcium by gender and age

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57 categories are presented in Table 9. The mean 3-day dietary intake of calcium in the 1 to 3 year old age group was 891 mg (178% AI) not including supplement intake and 899 mg (180% AI) including supplement intake. The mean 3-day dietary intake of calcium in the 4 to 8 year old age group was 883 mg (110% AI) not including supplement intake and 888 mg (111% AI) including supplement intake. The mean 3-day dietary intake of calcium in the 9 to 18 year old group was 973 mg (75% AI). Mean dietary intake of vitamin D by age and gender categories are presented in Table 9. Mean 3-day dietary intake of vitamin D in the 1 to 3 year old age group was 209 IU (5.2 mcg; 104% AI) not including supplement intake and 239 IU (5.9 mcg; 119% AI) including supplement intake. Mean 3-day dietary intake of vitamin D in the 4 to 8 year old age group was 180 IU (4.5 mcg; 90% AI) and 227 IU (5.7 mcg; 114% AI) not including supplement intake and including supplement intake. Mean 3-day dietary intake of vitamin D in the 9 to 18 year old group was 198 IU (4.96 mcg; 99% AI). Comparison of Dietary Calcium and Vitamin D Intake to the AI The one-tailed small sample t-test was used to compare the calcium and vitamin D intake of study subjects to the AI based on age and gender. The 3-day mean dietary calcium intake without supplements for the 1 to 3 year old group was significantly greater than the AI (p = 0.001) (Figure 1). The 3-day mean dietary calcium intake for the 9 to18 year old age group was significantly lower than the AI (p = 0.02). No significant difference was detected between the 3-day mean dietary calcium intake and the AI for the 4 to 8 year old age group. No

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58 significant differences were detected between the 3-day mean dietary vitamin D intake and the AI for all age groups (Figure 2). Comparison of Dietary Calcium Intake to 1994 to 1996, 1998 CSFII The one-tailed large sample z-test was used to compare the mean calcium Table 8. Calcium intake of children and adolescents with asthma compared to the AI by age category. Calcium intake*(mg) (% of AI) AI (mg) Test of equal mean Age category (years) Mean p-value 1 to 3 (n = 9) 890 244 (178%) 500 0.001 4 to 8 (n = 14) 883 359 (110%) 800 0.200 9 to 18 (n = 13) 973 517 (75%) 1300 0.021 *Values represent mean SD. 1 to 34 to 89 to 18 0 500 1000 1500Asthma AI *p = 0.001** p = 0.021 p = 0.001bap = 0.021abAge groups (years)Calcium intake (mg) Figure 1. Calcium intake of study subjects (asthma) compared to the AI by age group.

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59 Table 9. Vitamin D intake of children and adolescents with asthma compared to the AI by age category. Vitamin D intake*(mcg) (% of AI) A I (mcg) Test of equal mean Age category (years) Mean p-value 1 to 3 (n = 9) 5.19 2.43 (104%) 5.0 0.412 4 to 8 (n = 14) 4.49 2.32 (90%) 5.0 0.213 9 to 18 (n = 13) 4.96 3.71 (99%) 5.0 0.484 *Values represent mean SD. 1 to 34 to 89 to 18 1 3 5 7 9Asthma AIAge groups (years)Vitamin D intake (mcg) Figure 2. Vitamin D intake of study subjects (asthma) compared to the AI by age group. intake of study subjects to data from the 1994 to 1996 and 1998 CSFII. The 3day mean dietary calcium intake of study subjects in the 1 to 3 year old age category was significantly (p = 0.001) less than the mean dietary calcium intake of the age-matched reference population (i.e., CSFII) (Table 10 and Figure 3),

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60 although the mean intake for both groups exceeded the AI. No significant (p > 0.05) differences in mean dietary calcium intake between the study subjects and the age-matched reference population were detected in any other age category. The two-tailed chi-square test was used to compare the variance of the mean calcium intake of study subjects to the variance of the age-matched reference population. The variance of the mean calcium intake of study subjects in the 9 to 18 year old age category was significantly different than the variance of the mean calcium intake of the age-matched reference population (Figure 4). No significant differences were detected in the variance of the mean for calcium intake of the subjects compared to the age-matched reference population in the remaining age categories. Table 10. Calcium intake of study subjects (asthma) compared to CSFII by age group. Calcium intake* (mg) Test of equal mean Test of equal variance Age category (years) CSFII Asthma p-value p-value 1 to 3 1297 397 (n = 4,027) 891 244 (n = 9) 0.001 0.934 4 to 8 721 99 (n = 3,935) 883 359 (n = 14) 1.000 0.188 9 to 18 392 110 (n = 2130) 973 517 (n = 13) 1.000 <0.001 *Values represent mean SD. Intake of Milk and Milk Products Intake of dairy products was determined based on the categories used for the CSFII (Appendix C). The percent of total calcium intake from several dairy

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61 1 to 34 to 89 to 18 0 500 1000 1500 2000CSFII Asthma *p = 0.001 abp = 0.001Age groups (years)Calcium intake (mg) Figure 3. Calcium intake of study subjects (asthma) compared to CSFII by age group. 1 to 34 to 89 to 18 0 50 100 150 200CSFII Asthma *p = 0.001 Age groups (years)abp < 0.001Variance from meancalcium intake (thousands)abp < 0.001 Figure 4. Variance from the mean calcium intake of study subjects (asthma) compared to CSFII by age group. product categories by age are expressed in Table 11. Mean dietary intake for each dairy product category by age and gender are presented in Tables 12 to 20.

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62 Table 11. Calcium intake and percent of total calcium intake from dairy product categories. Calcium intake* (mg) (% of total) Age category (years) Total calcium intake (mg) Total milk & milk products Total milk, milk drinks, and yogurt Milk desserts Cheese 1 to 3 891 572 238 64.2% 456 247 51.2% 31 47 3.4% 86 85 9.6% 4 to 8 883 543 290 61.4% 386 284 43.7% 71 75 8.0% 84 85 9.5% 9 to 18 973 535 417 55.0% 378 361 38.8% 20 39 2.0% 136 128 14.0% 1 to 18 918 547 323 59.6% 401 299 43.7% 42 60 4.6% 103 120 11.2% *Values represent mean SD. Comparison of Milk and Milk Products Intake to 1994 to 1996, 1998 CSFII The two-tailed large sample z-test was used to compare the 3-day mean dietary intake of various categories of dairy products of the study subjects to the age-matched reference population. No significant differences were detected between the intake of study subjects compared to the age-matched reference population for any of the dairy product categories for any of the age categories (Figures 5 to 13).

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63 Table 12. Total milk and milk products intake of study subjects (asthma) compared to CSFII by age group. Total milk and milk products intake* (g) Test of equal mean Age category (years) CSFII Asthma p-value 1 to 3 438 324 (n = 11,737) 423 200 (n = 9) 0.444 4 to 8 409 279 (n = 11,473) 391 245 (n = 14) 0.405 9 to 18 362 345 (n = 6,204) 386 336 (n = 13) 0.595 *Values represent mean SD. 1 to 34 to 89 to 18 0 200 400 600 800CSFII Asthma *p = 0.001 Age groups (years)Total milk andmilk products intake (g) Figure 5. Total milk and milk products intake by study subjects (asthma) compared to CSFII by age group.

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64 Table 13. Total milk, milk drinks, and yogurt intake of study subjects (asthma) compared to CSFII by age group. Total milk, milk drinks, and yogurt intake* (g) Test of equal mean Age category (years) CSFII Asthma p-value 1 to 3 411 322 (n = 11,737) 384 208 (n = 9) 0.397 4 to 8 367 271 (n = 11,473) 321 241 (n = 14) 0.261 9 to 18 313 353 (n = 6,204) 334 335 (n = 13) 0.583 *Values represent mean SD. 1 to 34 to 89 to 18 0 100 200 300 400 500 600 700 800CSFII Asthma *p = 0.001 Age groups (years)Total milk, milk drinks,and yogurt intake (g) Figure 6. Total milk, milk drinks, and yogurt intake by study subjects (asthma) compared to CSFII by age group.

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65 Table 14. Total fluid milk intake of study subjects (asthma) compared to CSFII by age group. Total fluid milk intake* (g) Test of equal mean Age category (years) CSFII Asthma p-value 1 to 3 374 317 (n= 11,737) 289 172 (n = 9) 0.212 4 to 8 315 259 (n = 11,473) 263 247 (n = 14) 0.227 9 to 18 263 308 (n = 6,204) 269 300 (n = 13) 0.528 *Values represent mean SD. 1 to 34 to 89 to 18 0 100 200 300 400 500 600 700CSFII Asthma *p = 0.001 Age groups (years)Total fluid milk intake (g) Figure 7. Total fluid milk intake by study subjects (asthma) compared to CSFII by age group.

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66 Table 15. Whole milk intake of study subjects (asthma) compared to CSFII by age group. Whole milk intake* (g) Test of equal mean Age category (years) CSFII Asthma p-value 1 to 3 221 313 (n = 11,737) 198 177 (n = 9) 0.417 4 to 8 125 211 (n = 11,473) 139 234 (n = 14) 0.603 9 to 18 89 204 (n = 6,204) 138 233 (n = 13) 0.805 *Values represent mean SD. 1 to 34 to 89 to 18 0 100 200 300 400 500 600CSFII Asthma *p = 0.001 Age groups (years)Whole milk intake (g) Figure 8. Whole milk intake by study subjects (asthma) compared to CSFII by age group.

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67 Table 16. Lowfat milk intake of study subjects (asthma) compared to CSFII by age group. Lowfat milk intake* (g) Test of equal mean Age category (years) CSFII Asthma p-value 1 to 3 132 238 (n = 11,737) 55 125 (n = 9) 0.164 4 to 8 156 232 (n = 11,473) 76 137 (n = 14) 0.099 9 to 18 136 257 (n = 6,204) 75 245 (n = 13) 0.195 *Values represent mean SD. 1 to 34 to 89 to 18 0 100 200 300 400CSFII Asthma *p = 0.001 Age groups (years)Lowfat milk intake (g) Figure 9. Lowfat milk intake by study subjects (asthma) compared to CSFII by age group.

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68 Table 17. Skim milk intake of study subjects (asthma) compared to CSFII by age group. Skim milk intake* (g) Test of equal mean Age category (years) CSFII Asthma p-value 1 to 3 15 88 (n = 11,737) 36 56 (n = 9) 0.764 4 to 8 25 75 (n = 11,473) 45 79 (n = 14) 0.839 9 to 18 35 135 (n = 6,204) 38 136 (n = 13) 0.532 *Values represent mean SD. 1 to 34 to 89 to 18 0 20 40 60 80 100 120 140 160 180CSFII Asthma *p = 0.001 Age groups (years)Skim milk intake (g) Figure 10. Skim milk intake by study subjects (asthma) compared to CSFII by age group.

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69 Table 18. Yogurt intake by study subjects (asthma) compared to CSFII by age group. Yogurt intake* (g) Test of equal mean Age category (years) CSFII Asthma p-value 1 to 3 11 41 (n = 11,737) 4 13 (n = 9) 0.312 4 to 8 7 34 (n = 11,473) 12 25 (n = 14) 0.702 9 to 18 4 30 (n = 6,204) 0 0 (n = 13) 0.305 *Values represent mean SD. 1 to 34 to 89 to 18 0 10 20 30 40 50 60CSFII Asthma *p = 0.001 Age groups (years)x x = no yogurt intakeYogurt intake (g) Figure 11. Yogurt intake by study subjects (asthma) compared to CSFII by age group.

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70 Table 19. Milk desserts intake of study subjects (asthma) compared to CSFII by age group. Milk desserts intake* (g) Test of equal mean Age category (years) CSFII Asthma p-value 1 to 3 16 41 (n = 11,737) 27 41 (n = 9) 0.794 4 to 8 27 59 (n = 11,473) 55 64 (n = 14) 0.960 9 to 18 30 81 (n = 6,204) 20 37 (n = 13) 0.316 *Values represent mean SD. 1 to 34 to 89 to 18 0 20 40 60 80 100 120CSFII Asthma *p = 0.001 Age groups (years)xMilk desserts intake (g) Figure 12. Milk dessert intake by study subjects (asthma) compared to CSFII by age group.

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71 Table 20. Cheese intake of study subjects (asthma) compared to CSFII by age group. Cheese intake* (g) Test of equal mean Age category (years) CSFII Asthma p-value 1 to 3 11 22 (n = 11,737) 13 12 (n = 9) 0.610 4 to 8 13 27 (n = 11,473) 14 23 (n = 14) 0.587 9 to 18 16 35 (n = 6,204) 24 21 (n = 13) 0.797 *Values represent mean SD. 1 to 34 to 89 to 18 0 15 30 45 60CSFII Asthma *p = 0.001 Age groups (years)xCheese intake (g) Figure 13. Cheese intake by study subjects (asthma) compared to CSFII by age group.

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CHAPTER 5 DISCUSSION AND CONCLUSIONS Adequate calcium and vitamin D intake is important during childhood and adolescence to promote adequate bone mineralization and achievement of PBM (22,45-48,56). Inadequate intake of these nutrients increases the risk for osteoporosis (22). Milk and dairy products are good dietary sources of calcium and vitamin D. Children and adolescents with asthma may be at risk for osteoporosis for several reasons, one of which may be related to inadequate calcium and vitamin D intake due to the restriction or avoidance of milk and dairy products intake. Parents of children with asthma and adults with asthma have been reported to avoid these foods due to the unfounded belief that they worsen or contribute to asthma symptoms (6,7). This could have a negative impact on bone density, especially in a population that is already at risk due the use of certain medications that may negatively influence bone density, as well as the tendency to restrict the frequency and type of physical activity in an effort to avoid wheezing and other asthma symptoms (2,8,9). The objectives of this study were to determine the adequacy of calcium and vitamin D intake of children and adolescents with asthma using a 3-day food and supplement diary and to compare their intake of these nutrients to an age-appropriate AI. Another objective was to determine if calcium and milk and dairy products intake of children and adolescents with asthma are less than those of an age-matched reference population. 72

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73 After reviewing the published research, only one study examining dietary intake of calcium and dairy products in individuals with asthma was identified. This study was conducted in adults. The researchers found that consumption of certain types of dairy products, such as whole milk, butter, ricotta cheese, and low-fat cheese, were different in adult subjects with asthma compared to those without asthma, but there was no difference in the overall intake of dairy products and nutrients, including calcium, between the groups (86). A total of 84 subjects (i.e., 56 males, 28 females) were enrolled in the study; however only 36 (i.e., 26 males, 10 females) returned the 3-day food and supplement diary for an overall return rate of 42.9%. The return rates by age categories were 40.9%, 51.9%, and 37.1% for the 1 to 3 year old, 4 to 8 year old, and 9 to 18 year old age categories, respectively. Our return rate was relatively consistent with the dietary intake survey conducted by mail with adults diagnosed with asthma, in which the overall response rate was 36% (86). It is possible that the 9 to 18 year old age group had the lowest return rate because of greater independence from parental guidance, related to a higher level of reading and writing skills. In contrast, the younger age groups required parental assistance with this task, which may have increased the return rate. Currently, there are no published data on calcium and vitamin D intake in children and adolescents with asthma. Data from our study indicated that the 3-day mean dietary calcium intake for the 1 to 3 year old group was significantly greater than the AI for this nutrient (p = 0.001), but significantly less than the mean dietary calcium intake of the age-matched reference population (i.e.,

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74 CSFII) (p = 0.001). Despite our efforts to recruit as many subjects as possible and to increase return rate, the sample size for the 1 to 3 year old age category did not have adequate statistical power. This also is true for the 4 to 8 year old and the 9 to 18 year old age categories and this is important to keep in mind for those comparisons in which a significant difference was not detected. No significant differences in the 3-day mean dietary calcium intake for the 4 to 8 year old children with asthma compared to the AI and the age-matched reference population were detected in our study. This suggests that children with asthma in this age group are meeting their needs for calcium and are consuming amounts of calcium similar to non-asthmatic children. In addition, children with asthma between the ages of 4 and 8 years consumed approximately 61% of their calcium from milk and dairy products. These results differ from reports of milk and dairy products avoidance in children with asthma (6,7). In the general population of children, adolescents, and adults, as estimated from data from the 1994 to 1996 and 1998 CSFII and the NHANES III, milk and dairy products are major sources of dietary calcium, accounting for 48% of calcium intake (44). In children and adolescents between the ages of 1 and 18 years, as estimated from the 1994 to 1996 and 1998 CSFII, dairy foods and ingredients contribute to approximately 62% of calcium intake (35). This suggests that children with asthma between the ages of 4 to 8 years are generally consuming a similar amount of calcium from milk dairy products as children without asthma and thus are not avoiding or eliminating milk and dairy products due to their asthma.

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75 In the 9 to 18 year old age group, the 3-day mean dietary calcium intake for our study population was significantly lower than the AI (p = 0.02), but not significantly different from the age-matched reference population. This finding suggests that all children and adolescents between the ages of 9 and 18 years, regardless of whether they have asthma, are not consuming adequate amounts of dietary calcium to promote optimal bone health. In addition, children and adolescents with asthma between the ages of 9 and 18 years consumed approximately 55% of their calcium from milk and dairy products. These results differ from reports of milk and dairy products avoidance in children and adolescents with asthma (6,7). It has been estimated that children, adolescents, and adults, consume approximately 48% of their calcium from milk and dairy products and specifically children and adolescents consume 62% of their calcium from dairy foods (35,44). This suggests that children with asthma between the ages of 9 to 18 years are generally consuming a similar amount of calcium from milk dairy products as children without asthma and thus are not avoiding or eliminating milk and dairy products due to their asthma. The inadequate dietary calcium intake observed in 9 to 18 year old children and adolescents in this study is consistent with reports of milk intake patterns in this age group. Mean intake of milk decreases 38% from 1 to 18 years of age and is due to the dramatic increase in soft drink consumption that begins around 8 years of age (105). Intake of soft drinks exceeds that of milk by 13 years of age. This is important because dietary calcium intake during childhood and adolescence is positively associated with bone density throughout adulthood

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76 (22,45-48). As a result of the inadequate dietary calcium intake observed in this study, children with asthma between the ages of 9 and 18 years may be at risk for low bone density and poor bone health in adulthood. In addition to calcium, vitamin D intake also was analyzed for each of the 3 age groups. No significant differences were detected between the 3-day mean dietary vitamin D intake and the AI for any of the age categories. The database (Food Processor 8.1 for Windows) (87) used to analyze the 3-day food and supplement diaries does not have complete data for the vitamin D content of foods, so it is possible that the actual vitamin D intake of our study population was higher than reflected by our data. The findings of our study suggest that children and adolescents with asthma between the ages of 1 and 18 years are consuming adequate amounts of vitamin D to promote bone health. Another aim of our study was to examine dairy intake in our population. Currently, there are no published studies that have reported dairy products intake in children and adolescents with asthma, but there is one study that reported the intake of dairy products in adults with asthma. Woods et al. found that overall intake of dairy products was not significantly different between adults with and without asthma, although the types of dairy products consumed by these 2 groups were significantly different (86). Specifically, asthma was negatively associated with whole milk and butter consumption and positively associated with ricotta and low-fat cheese in adults with asthma. Similarly, no significant difference in total milk and milk products intake of children and adolescents with asthma and the age-matched reference population was detected in our study, but

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77 a significant difference was not detected in the types of dairy products consumed by children and adolescents with asthma compared to the age-matched reference population for each of the age categories. There are several potential clinical applications extending from our research. Health care professionals, such as dietitians, pediatricians, pulmonologists, and nurses, as well as dietitians in community settings who provide services to children and adolescents with asthma should promote adequate consumption of calciumand vitamin D-containing foods such as milk and dairy products in this population, especially in children between the ages of 9 and 18 years. If milk or dairy products need to be avoided due to the lack of tolerance, a disease that necessitates restriction of milk or dairy, or for other reasons (e.g., lack of acceptance, religious beliefs, health beliefs, etc.), health professionals should recommend suitable calcium-containing foods and/or a supplement. Although this study provides preliminary data on the dietary intake of calcium, vitamin D, and dairy products in children with asthma, a larger study is needed to confirm our findings. A large, multi-center study may be needed to accomplish this goal. Researchers also could examine the relationship between dietary calcium, vitamin D, and dairy products intake in relation to BMD in children and adolescents with asthma, while controlling for other factors that may influence BM such as physical activity and medications. In summary, this study compared dietary calcium and vitamin D intake of children and adolescents with asthma to the age-appropriate AIs and to survey

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78 data from an age-matched reference population. The results of this study, which indicated that 1 to 3 and 4 to 8 year old children with asthma met or exceeded the AI for calcium and vitamin D and 9 to 18 year old children and adolescents with asthma consumed less than the AI for calcium have potential clinical applications. Although 9 to 18 year old children and adolescents with asthma consumed less than the AI for calcium, their intake paralleled that of intake data from a national survey. The level of calcium intake from milk and dairy products that was consumed by children and adolescents in our study was similar to the level of intake estimated for the general population. This suggests that in our small study population, individuals with asthma do not avoid or restrict their intake of dairy products; however there is still a need to focus on encouraging adequate intake of calciumand vitamin D-containing foods such as milk and dairy products, especially in 9 to 18 year old children and adolescents. The results from this study are novel because this is the first study to examine the dietary intake of calcium and vitamin D in children and adolescents with asthma and will pave the way for future studies.

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APPENDIX A THREE-DAY FOOD AND SUPPLEMENT DIARY DIRECTIONS *Please record everything your child consumes for 3 days, including foods, beverages, and supplements. 1. Please select three days, including one weekend day (Friday, Saturday, or Sunday). 2. Please record the foods, beverages, and supplements you consume and the amounts of each that you consume as soon after eating as possible. This prevents you from forgetting foods, or overor underestimating what you have consumed. 3. In the column labeled Foods, Beverages, and Supplements Consumed record what you ate. Please be as specific as possible. For example if you consumed milk: indicate skim, 1%, 2%, or whole. If you consumed cereal, indicate what kind of cereal. If you consumed bread, indicate what kind of bread (white, wheat, rye, oat bran, etc.). Dont forget to include condiments, such as catsup, mustard, jelly, salad dressing, sauces, etc. For example: Foods, Beverages, Supplements Consumed Description Amount Consumed Milk 1% low fat 1 cup Cornflakes Kelloggs 1 cups Bread Publix honey wheat 1 slice Jelly (on bread) Smuckers strawberry jam 1 teaspoon Sugar (on cereal) White granulated 2 teaspoons 4. In the column labeled Description please list the brand name and give a product description or include the product label or recipe whenever possible. Tell how the food was cooked (fried, baked, etc). If you ate away from home, list the name of the restaurant or food shop. Be sure to include information about things that you add to your food before you eat it, like margarine, salt, sugar, milk, etc. Please refer to the example above. 79

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80 5. In the column labeled Amount Consumed please list the amount of each food, beverage or supplement you consume. Tell how many cups, ounces (oz), teaspoons (tsp), tablespoons (tbsp) you eat or the weight or number of portions or pieces you eat. 6. A sample food diary is included on the next page to help you. 7. When you have completed the diary, please return in the postage-paid stamped envelope that has been provided.

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81 Sample: Foods, Beverages, Supplements Consumed List each food, beverage or supplement you consume. List only one item per line. Description List the brand name and product description or include the product label or recipe for everything you eat. Tell how the food was cooked (fried, baked, etc). If you ate away from home, list the name of the restaurant or food shop. Be sure to include information about things that you add to your food before you eat it, like margarine, salt, sugar, milk, etc Amount Consumed List the amount of each food, beverage or supplement you consume. Tell how many cups, ounces (oz), teaspoons (tsp), tablespoons (tbsp) you eat or the weight or number of portions or pieces you eat. Corn Flakes Kelloggs brand 1 cup Milk 2% 1/2 cup Banana Small 1 Turkey Baked 2 oz. Bread whole wheat, toasted 2 slices Mayonnaise Hellmanns brand-Light 1 tsp. Tomato 2 slices Apple With skin Pepsi, can 12 oz. Ice cream Albertsons brand 1 cup Chicken Breast Grilled, no skin 3 oz. Green beans Canned, prepared with 1 tbsp. butter and 1 tsp. salt cup Rice White, Boiled 1 cup Apple pie Store bought, bakery 1/5 pie Childrens multivitamin Flintstones Brand 1 1 cup = 8 fluid ounces (8 fl. oz.) = 237 ml 3 teaspoons = 1 tablespoon 4 tablespoons = cup 1 oz. = 28 g (grams)

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82 Estimating Portion Sizes 3 ounces of meat, poultry, or fish is about the size and thickness of a deck of playing cards = A medium-size piece of fruit (e.g., apple or peach) is about the size of a tennis ball = 1 ounce of cheese is about the size of 4 dice = cup of ice cream, frozen yogurt, yogurt, or cottage cheese is about the size of a tennis ball = 1 cup of mashed potatoes or broccoli is about the size of your fist Or = 1 teaspoon of butter, margarine, or peanut butter is about the size of the tip of your thumb = 1 ounce of nuts or small candies is about one handful = Adapted from: Southern Illinois University Carbondale Wellness Center Nutrition Program. 3-day recall. Available at: http://www.siu.edu/~shp/Acrobat2002/Recall.pdf Accessed February 2002.

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APPENDIX B THREE-DAY FOOD AND SUPPLEMENT DIARY FORM

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Name:________________________ 3-day Food and Supplement Diary Day 1 Foods, Beverages and Supplements Consumed List each food, beverage or supplement you consume. List only one item per line. Description List the brand name and product description or include the product label or recipe for everything you eat. Tell how the food was cooked (fried, baked, etc). If you ate away from home, list the name of the restaurant or food shop. Be sure to include information about things that you add to your food before you eat it, like margarine, salt, sugar, milk, etc. Amount Consumed List the amount of each food, beverage or supplement you consume. Tell how many cups, ounces (oz), teaspoons (tsp), tablespoons (tbsp) you eat or the weight or number of portions or pieces you eat. 84

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Name:________________________ 3-day Food and Supplement Diary Day 2 Foods, Beverages and Supplements Consumed List each food, beverage or supplement you consume. List only one item per line. Description List the brand name and product description or include the product label or recipe for everything you eat. Tell how the food was cooked (fried, baked, etc). If you ate away from home, list the name of the restaurant or food shop. Be sure to include information about things that you add to your food before you eat it, like margarine, salt, sugar, milk, etc. Amount Consumed List the amount of each food, beverage or supplement you consume. Tell how many cups, ounces (oz), teaspoons (tsp), tablespoons (tbsp) you eat or the weight or number of portions or pieces you eat. 85

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86 Name:________________________ 3-day Food and Supplement Diary Foods, Beverages and Supplements Consumed List each food, beverage or supplement you consume. List only one item per line. Description List the brand name and product description or include the product label or recipe for everything you eat. Tell how the food was cooked (fried, baked, etc). If you ate away from home, list the name of the restaurant or food shop. Be sure to include information about things that you add to your food before you eat it, like margarine, salt, sugar, milk, etc. Amount Consumed List the amount of each food, beverage or supplement you consume. Tell how many cups, ounces (oz), teaspoons (tsp), tablespoons (tbsp) you eat or the weight or number of portions or pieces you eat. Day 3

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APPENDIX C DAIRY PRODUCT CATEGORY DEFINITIONS MILK AND MILK PRODUCTS Total milk and milk products: Includes milk and milk drinks, yogurt, milk desserts, and cheese. Fluid and whipped cream, half-and-half, sour cream, and milk sauces and gravies are included in this total but not in any of the following subgroups. Excludes butter and nondairy sweet cream and sour cream substitutes, which are tabulated under Fats and Oils. Excludes milk and milk products that were ingredients in food mixtures coded as a single item and tabulated under another food group. For example, cheese on pizza is tabulated under Grain Products. Total milk, milk drinks, yogurt: Includes fluid milk and yogurt. Flavored milk and milk drinks, meal replacements with milk, milk-based infant formulas, and unreconstituted dry milk and powdered mixtures are included in this total but not in any of the following subgroups. Total fluid milk: Includes fluid whole, lowfat, skim, and acidophilus milk; buttermilk; reconstituted dry milk; evaporated milk; and sweetened condensed milk. Whole milk: Includes whole fluid milk, low-sodium whole milk, and reconstituted whole dry milk. Lowfat milk: Includes lowfat (1 and 2 percent) milk, buttermilk (lowfat and nonfat), acidophilus milk, lowfat lactose-reduced fluid milk, and reconstituted lowfat dry milk. Skim milk: Includes skim or nonfat fluid milk, lactose-reduced fluid nonfat milk, and reconstituted nonfat dry milk. Yogurt: Includes plain, flavored, and fruit-variety yogurt. Excludes frozen yogurt, which is tabulated under "milk desserts." Milk desserts: Includes ice cream, imitation ice cream, ice milk, sherbet, frozen yogurt, and other desserts made with milk, such as pudding, custard, and baby-food pudding. Cheese: Includes natural hard and soft cheeses, cottage cheese, cream cheese, processed cheese and spreads, imitation cheeses, and mixtures having cheese 87

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88 as a main ingredient, such as cheese dips and cheese sandwiches coded as a single item. Source: United States Department of Agriculture (USDA), Agricultural Research Service. Food and Nutrient Intakes by Children 1994-1996, 1998. Table Set 17. 1999. On Continuing Survey of Food Intakes by Individuals, 1994-1996, 1998. CD-ROM.

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LIST OF REFERENCES 1. American Lung Association (ALA). Asthma and children fact sheet. Available at: http://www.lungusa.org/site/pp.asp?c=dvLUK9O0E&b=44352 Accessed September, 2004. 2. National Heart, Lung, and Blood Institute (NHLBI), National Asthma Education and Prevention Program (NAEPP). Expert Panel Report: Guidelines for the Diagnosis and Management of Asthma. Update on Selected Topics 2002. Publication No. 02-507. Bethesda, MD: U.S. Department of Health and Human Services; 2003. 3. Wolf RL. Essential Pediatric Allergy, Asthma, & Immunology. New York, NY: McGraw-Hill Medical Publishing Company; 2004. 4. American Lung Association (ALA). FOCUS: Asthma minority lung disease data. Available at: http://www.lungusa.org/pub/minority/asthma_00.html Accessed November, 2002. 5. American Lung Association (ALA). Childhood asthma: an overview. Available at: http:// www.lungusa.org/asthma/ ascchildhoo.html Accessed November, 2002. 6. Dawson KP, Ford RPK, Mogridge N. Childhood asthma: what do parents add or avoid in their childrens diets? NZ Med J. 1990;103:239-240. 7. Woods RK, Weiner J, Abramson M, Thien F, Walters EH. Patients perceptions of food-induced asthma. Aust NZ J Med. 1996;26(4):504-512. 8. Kitsantas A, Zimmerman BJ. Self-efficacy, activity participation, and physical fitness of asthmatic and nonasthmatic adolescent girls. J Asthma. 2000;37(2):163-174. 9. Reichenberg K, Broberg AG. Quality of life in childhood asthma: use of the Paediatric Asthma Quality of Life Questionnaire in a Swedish sample of children 7 to 9 years old. Acta Paediatr. 2000;89:989-995. 10. Dey AN, Schiller JS, Tai DA. Summary Health Statistics for U.S. Children: National Health Interview Survey, 2002. National Center for Healthcare Statistics: Hyattsville, MD; 2004. 89

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90 11. American Lung Association (ALA). Asthma in children fact sheet. Available at: http://www.lungusa.org/asthma/aspedfac99.html Accessed November, 2002. 12. Bousquet J, Jeffrey PK, Busse WW, Johnson M, Vignola AM. Asthma. From bronchoconstriction to airways inflammation and remodeling. Am J Respir Crit Care Med 2000;161(5):1720-1745. 13. National Heart, Lung, and Blood Institute (NHLBI), National Asthma Education and Prevention Program (NAEPP). Guidelines for the Diagnosis and Management of Asthma. Expert Panel Report 2, Publication No. 97-4051. Bethesda, MD: U.S. Department of Health and Human Services; 1997. 14. Murphy S, Kelly HW. Lung Biology in Health and Disease, Vol. 126: Pediatric Asthma. New York, NY: Marcel Dekker, Inc.; 1999. 15. Dunitz M. Textbook of Pediatric Asthma: An International Perspective. London, England: Dunitz Ltd; 2001. 16. National Institute of Allergy and Infectious Diseases. Asthma basics. Available at: http://www2.niaid.nih.gov/newsroom/focuson/asthma01/basics.htm. Accessed September, 2004. 17. Mayo Clinic, Mayo Foundation for Medical Education and Research. Medications and immunotherapy for asthma. Available at: http://www.mayoclinic.com/invoke.cfm?id=AP00008 Accessed September, 2004. 18. American Medical Association (AMA). Medical library: asthma glossary. Available at: http://www.medem.com/MedLB/article_detaillb.cfm?article _ID=ZZZSLQTU18C&sub_cat=80. Accessed September, 2004. 19. Haas F, Bishop MC, Salazar-Schicchi J, Axen KV, Lieberman D, Axen K. Effect of milk ingestion on pulmonary function in healthy asthmatic subjects. J Asthma. 1991;28(5):349-355. 20. Nguyen MT. Effect of cow milk on pulmonary function in atopic asthmatic patients. Ann Allergy Asthma Immunol. 1997;79(1):62-64. 21. Woods RK, Weiner JM, Abramson M, Thien F, Walters EH. Do dairy products induce bronchoconstriction in adults with asthma? J Allergy Clin Immunol. 1998;101:45-50. 22. Institute of Medicine (IOM), Food and Nutrition Board (FNB). Dietary Reference Intakes for Calcium, Phosphorus, Magnesium, Vitamin D, and Fluoride. Washington, DC: National Academies Press; 1997.

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91 23. Power ML, Heaney RP, Kalkwarf HJ, Pitkin RM, Repke JT, Tsang RC, Schulkin J. The role of calcium in health and disease. Am J Obstet Gynecol. 1999;181:1560-1569. 24. Groff JL, Gropper SS. Advanced Nutrition and Human Metabolism. 3rd ed. Belmont, CA: Wadsworth, Thomson Learning; 2000. 25. Weaver CM. Calcium. In Bowman BA, Russell RM. Present Knowledge in Nutrition. 8th ed. Washington, DC: ILSI Press; 2001. 26. Heaney RP. Bone mass, nutrition, and other lifestyle factors. Nutr Rev. 1996;54(4):S3-S10. 27. Langman CB. New developments in calcium and vitamin D metabolism. Curr Opin Pediatr. 2000;12:135-139. 28. Whitney EN, Rolfes SR. Understanding Nutrition. 8th ed. Belmont, CA: Wadsworth Publishing Co.; 1999. 29. National Research Council (NRC). Diet and Health: Implications for Reducing Chronic Disease Risk. Report of the Committee on Diet and Health, Food and Nutrition Board, Commission on Life Sciences. Washington, DC: National Academy Press; 1989. 30. Department of Health and Human Services (DHHS). Healthy People 2000: National Health Promotion and Disease Prevention Objectives. DHHS Publ. No. (PHS) 91-50212. Washington, DC: US Government Printing Office; 1990. 31. Osteoporosis Society of Canada. Consensus on calcium nutrition. Official position of the Osteoporosis Society of Canada. Nutr Quart. 1993;18:62-69. 32. National Institutes of Health (NIH). Optimal Calcium Intake. NIH consensus Statement 12:4. Bethesda, MD: NIH; 1994. 33. World Health Organization (WHO). Assessment of Fracture Risk and its Application to Screening for Postmenopausal Osteoporosis. Technical Report Series 843. Geneva: World Health Organization; 1994. 34. Gerrior S, Bente L. Nutrient Content of the U.S. Food Supply, 1909-99: A Summary Report. U.S. Department of Agriculture, Center for Nutrition Policy and Promotion. Home Economics Research Report No. 55. Available at: www.usda.gov/cnpp/Pubs/Food%20Supply/foodsupply09_99.pdf Accessed September, 2004. 35. Weinberg LG, Berner LA, Groves JE. Nutrient contributions of dairy foods in the United States, Continuing Survey of Food Intakes by Individuals, 1994-1996, 1998. J Am Diet Assoc. 2001;104:895-902.

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BIOGRAPHICAL SKETCH Melissa Metz (Myers) was born in Cincinnati, Ohio, and raised in Mobile, Alabama, and Clearwater, Florida. She attended Countryside High School and graduated with honors in 1998. She attended the University of Florida for her undergraduate studies and graduated with honors in 2002 with a Bachelor of Science in food science and human nutrition, specializing in dietetics. During her undergraduate studies she was actively involved in the Food Science and Human Nutrition Club and held several offices, including President in 2002. She also received several scholarships, including the Dorothy MacRae Hyman Memorial Scholarship, SHARE Scholarship, and the Earl Wilmott Hartt Scholarship. During her graduate program, she completed a Pediatric Pulmonary Traineeship at the UF College of Medicine Pediatric Pulmonary Center and received the Beechnut Dietetic Internship/Pre-professional Practice Program scholarship from the American Dietetic Association Pediatric Nutrition Practice Group. She is a member of the American Dietetic Association, Florida Dietetic Association, Gainesville District Dietetic Association, and the ADA Pediatric Nutrition Practice Group. She plans to pursue a career in pediatric nutrition. Her long-term goals are to establish a private practice to counsel overweight and obese children and adolescents and actively promote nutrition and oral health. 98


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CALCIUM AND VITAMIN D
INTAKE OF CHILDREN AND ADOLESCENTS WITH ASTHMA













By

MELISSA R. METZ


A THESIS PRESENTED TO THE GRADUATE SCHOOL
OF THE UNIVERSITY OF FLORIDA IN PARTIAL FULFILLMENT
OF THE REQUIREMENTS FOR THE DEGREE OF
MASTER OF SCIENCE

UNIVERSITY OF FLORIDA


2004
































Copyright 2004

By

Melissa R. Metz
































This thesis is dedicated to children and adolescents with asthma with the hope
that through research the quality of their lives will be improved.















ACKNOWLEDGMENTS

I would like to thank my outstanding committee members, Dr. Gail P.A.

Kauwell, Ellen Bowser, and Dr. Sarah E. Chesrown. I would especially like to

thank Dr. Kauwell for her excellent advice, wisdom, and friendship, Mrs. Bowser

for her patience, enthusiasm, kindness, and friendship, and Dr. Chesrown for her

strong support in this project. I truly could not have successfully completed this

project without their help. I would like to thank the Pediatric Pulmonary Center

physicians, faculty, and staff for their constant willingness to provide any help

they could. I also would like to extend my thanks to Dr. Karla Shelnutt for her

assistance with this project, and my classmates, Lisa Fish, Elizabeth Haire

(Citro), Mandy Layman, Carolina Lima, and Jaimie Vaughn (Proctor), for their

friendship.

Finally, I would like to extend my gratitude to my wonderful husband for his

patience, encouraging words, calm spirit, and unconditional love, and my parents

for their wisdom, encouragement, and never-ending love. I truly could not have

been successful in life without them. This research was supported by an

unrestricted donation to Dr. Gail P. A. Kauwell from Dairy Farmers Inc.















TABLE OF CONTENTS

page

ACKNOWLEDGMENTS ............... .................. ...............iv

LIST OF TABLES .......................... ......... ......... viii

LIST OF FIGURES ......................... ................... x

LIST O F A B B R EV IA T IO N S ............................................. ........... ................ xi

ABSTRACT .................. ......... .... ............... xiv

CHAPTER

1 INTRODUCTION........................ .......... ................ ......... 1

H ypotheses ....................................................................... 2
S p e c ific A im s ........................................................................ 2

2 BACKGROUND AND LITERATURE REVIEW ...................................... 3

A sthm a .................................................................................. 3
Overview ........................................... ............... 3
E tio logy ... ......................... ..... ................ ............ 4
Pathophysiology ................................. .......... ....... ........ .............. 4
D ia g n o s is .................................................. 5
M monitoring .............................................. .. .............................. 7
Asthma Management ...... ..................................... ............ 8
Medical Management .................................... 8
Environmental Management........... ..................... 13
Dietary Management................................. .................... 13
C alcium .............. ..................................................................................... 14
Structure and Function ..................................... 14
Digestion and Absorption........................................... .................... 15
Transport ................................................... 17
Homeostasis ..................... ......... .... ...................... 17
Deficiency ......... ......... .. ............. ........ ............... 18
Status Assessment .................. .......... .......... 19
Dietary Reference Intakes (DRIs) ............... ....... .. ................. 19
Adequate Intake (Al) ................. .. .. ......... .................. 19









Tolerable Upper Intake Level (UL) ...... ..... .................................. 20
Sources .............. .. ..... ...... ................. 20
C alcium Intake in the U .S. ............. .......... .. ........... .. ......... 21
Vitamin D ....................... ....................... 22
Structure and Function ................. ....... ... .. ......... .............. 22
Digestion, Absorption, and Transport ............ ................................... 22
Deficiency ............ ......... ...... ............ .. ....................... 23
Status Assessment ....................... .. .................. ............. 24
Dietary Reference Intakes (DRIs).................... .......... ................... 24
Adequate Intake (Al) ................................. ... ........ .. .......... 24
Tolerable Upper Intake Level (UL) ...... ..... .................................. 24
Sources ........................ ........... ..................... 24
Vitamin D Intake in the U.S ............................. ....................... 25
Factors Influencing Bone Health during Childhood and Adolescence.......... 25
Factors Influencing Bone Health during Adulthood .................................... 29
Factors Influencing Bone Health in Children and Adolescents
w ith Asthm a ......... ...................................... .. .... ....... .......... 31
Health Beliefs about the Impact of Milk and Dairy Products
on Asthma ............................ .......... .. .. ..... ... ... .......... 31
Calcium and vitamin D intake and bone health in cow's
milk-free and cow's milk-limited diets ...................................... 33
Cow's milk and pulmonary function........................................... 34
Cow's milk or food allergy, adverse reactions to milk,
a n d a sth m a .................................. ................. ............. 3 6
Physical Activity ...................... ......... .... ............... 37
Inhaled Corticosteroid Use ...................... ........... ....... ............. 39
Systemic Corticosteroid Use............................................................. 42
Bone Density of Children with Asthma and Risk for Osteoporosis ........ 42
Research Significance ........... ...... .... .................. .............. 43

3 MATERIALS AND METHODS .......... ............ .................... .............. 45

S subject D description ...................... ....... ......... .. ............................ 45
Study Design................................................. ............... 45
Dietary Intake Tool and Analysis....................................... 48
Overview of Three-day Food Diary Method Used to Assess
D ieta ry Inta ke .............................. ......... ........ .... .......... ... 4 9
Comparison of Methodologies to Assess Dietary Intake........................... 50
Overview of the 1994 to 1996, 1998 CSFII .............. .............. .............. 52
Statistical A analysis .............. ......... ......................... ... ............ 53
Com prison of Dietary Intake to Al ........ ............ ............... ............ ... 54
Comparison of Dietary Intake to 1994 to 1996, 1998 CSFII .................. 54

4 RESULTS ................ ......... ............... ................. 55

S u bje cts ............. ............................................................ ..... ............ 5 5
Demographics ............................................... 55


vi









Dietary Intake of Calories, Protein, and Fat ................ ............ ....... 56
Dietary Intake of Calcium and Vitam in D .......... .................. ...... ......... 56
Comparison of Dietary Calcium and Vitamin D Intake to the Al................... 57
Comparison of Dietary Calcium Intake to 1994 to 1996, 1998 CSFII........... 58
Intake of M ilk and M ilk Products..................................... .................... 60
Comparison of Milk and Milk Products Intake to 1994 to 1996,
1998 C S F I I... ...... ........................... ................. .... ........ 62

5 DISCUSSION AND CONCLUSIONS................ ................ 72

APPENDIX

A THREE-DAY FOOD AND SUPPLEMENT DIARY DIRECTIONS ................ 79

B THREE-DAY FOOD AND SUPPLEMENT DIARY FORM.......................... 83

C DAIRY PRODUCT CATEGORY DEFINITIONS........................ ............... 87

LIST OF REFERENCES ............. ............. .................... 89

BIOGRAPHICAL SKETCH .......... ..................... ...... ..... 98















LIST OF TABLES


Table page

1 Medications used to treat or prevent asthma symptoms.............. ........... 10

2 Long-term control medications for infants and children with asthma 5
years of age and younger. ................................................. 11

3 Long-term control medications for children with asthma over 5 years of
age and adults. ........... ................. ............... .......... ............... 12

4 Dietary Reference Intakes for calcium for children and adolescents
1 to 18 years ...... ........ ......... ................ ...... ......... 20

5 Vitamin D status assessment according to serum 25(OH) D3
co n ce ntra tio n s ....................................................................... ... ..... 2 4

6 Number of subjects who enrolled and completed the study and percent
return rate by age category and gender ........................ ....... ............... 55

7 Three-day dietary intake of calories, protein, and fat by study subjects..... 56

8 Calcium intake of children and adolescents with asthma compared to
the Al by age category. ............ .... ..... ... ......... .... ... ........ 58

9 Vitamin D intake of children and adolescents with asthma compared
to the A l by age category. .................. ......................... ................. 59

10 Calcium intake of study subjects (asthma) compared to CSFII by
age g group ......... .................................................................. . .......... 6 0

11 Calcium intake and percent of total calcium intake from dairy product
categories. ............... ................. ............................. 62

12 Total milk and milk products intake of study subjects (asthma)
compared to CSFII by age group............... ...................... .............. 63

13 Total milk, milk drinks, and yogurt intake of study subjects (asthma)
compared to CSFII by age group............... ...................... .............. 64

14 Total fluid milk intake of study subjects (asthma) compared to CSFII
by age group............... ..... .......... .............. ... .. ....... ........ 65
viii









15 Whole milk intake of study subjects (asthma) compared to CSFII by age
group............... .. ......................... .. .. ................... 66

16 Lowfat milk intake of study subjects (asthma) compared to CSFII by age
group............... .. ......................... .. .. ................... 67

17 Skim milk intake of study subjects (asthma) compared to CSFII by age
group............... .. ......................... .. .. ................... 68

18 Yogurt intake by study subjects (asthma) compared to CSFII by age
group............... .. ......................... .. .. ................... 69

19 Milk desserts intake of study subjects (asthma) compared to CSFII by
a g e g ro u p ......... ......... .......... ......... ..... ................................ 7 0

20 Cheese intake of study subjects (asthma) compared to CSFII by age
group............... .. ......................... .. .. ............ ... ...... 71















LIST OF FIGURES


Figure page

1 Calcium intake of study subjects (asthma) compared to the Al by age
g ro u p ......... .. .. ........................................ .................... .. .... 5 8

2 Vitamin D intake of study subjects (asthma) compared to the Al by age
g ro u p ......... .. .. ........................................ .................... .. .... 5 9

3 Calcium intake of study subjects (asthma) compared to CSFII by age
g ro u p ......... .. .. ........................................ .................... .. .... 6 1

4 Variance from the mean calcium intake of study subjects (asthma)
compared to CSFII by age group. .......... ........... .... ....... ........... 61

5 Total milk and milk products intake by study subjects (asthma)
compared to CSFII by age group. .......... ........... .... .................. 63

6 Total milk, milk drinks, and yogurt intake by study subjects (asthma)
compared to CSFII by age group. .......... ........... .... .................. 64

7 Total fluid milk intake by study subjects (asthma) compared to CSFII
by age group.................. ................................ ............... 65

8 Whole milk intake by study subjects (asthma) compared to CSFII
by age group.................. ................................ ............... 66

9 Lowfat milk intake by study subjects (asthma) compared to CSFII
b y a g e g ro u p ............... ....................................................... 6 7

10 Skim milk intake by study subjects (asthma) compared to CSFII
b y a g e g ro u p ............... ....................................................... 6 8

11 Yogurt intake by study subjects (asthma) compared to CSFII by
a g e g ro u p ................ ......................................................... 6 9

12 Milk dessert intake by study subjects (asthma) compared to CSFII
b y a g e g ro u p ............... ....................................................... 7 0

13 Cheese intake by study subjects (asthma) compared to CSFII by age
g ro u p ................ ................................................................... ........ . 7 1















LIST OF ABBREVIATIONS


Al Adequate Intake

BDP beclomethasone dipropionate

BMC bone mineral content

BMD bone mineral density

BM bone mass

BMI body mass index

BUD budesonide

CaSR calcium sensing receptor

CF cystic fibrosis

CSFII Continuing Survey of Food Intakes by Individuals

d day

DBP vitamin D-binding protein

DPI dry powder inhaler

DRI Dietary Reference Intake

EAR Estimated Average Requirement

EIA exercise-induced asthma

FEF25-75% forced expiratory flow at 25-75% forced vital capacity

FEV1 forced expiratory volume in 1 second

FFQ food frequency questionnaire

FVC forced vital capacity









g grams

GI gastrointestinal

IOM Institute of Medicine

IU International Unit

kcals calories

LTRA leukotriene receptor antagonist

MDI metered dose inhaler

mcg micrograms

mg milligrams

NAEPP National Asthma Education and Prevention Program

NHANES National Health and Examination Survey

NHLBI National Heart, Lung, and Blood Institute

nmol/1 nanomoles per liter

PBM peak bone mass

PEF peak expiratory flow

PFT pulmonary function test

PTH parathyroid hormone

RDA Recommended Dietary Allowance

SD standard deviation

UF University of Florida

UL Tolerable Upper Intake Level

U.S. United States









USDA United States Department of Agriculture

Vso airflow at 50% of vital capacity















Abstract of Thesis Presented to the Graduate School
of the University of Florida in Partial Fulfillment of the
Requirements for the Degree of Master of Science

CALCIUM AND VITAMIN D INTAKE OF CHILDREN AND ADOLESCENTS
WITH ASTHMA

By

Melissa R. Metz

December 2004

Chair: Gail P. A. Kauwell
Major Department: Food Science and Human Nutrition

Asthma is a chronic inflammatory disease of the airways that currently

affects 6.1 million children under the age of 18 years. Parents of children with

asthma commonly avoid or eliminate foods from their children's diets in an

attempt to reduce the onset of asthmatic symptoms. Milk and dairy products are

the foods most often reported to be eliminated or avoided, although studies do

not support a connection between milk intake and a reduction in pulmonary

function. Inadequate milk and dairy products consumption could have an

adverse effect on the intake of calcium and vitamin D, nutrients associated with

favorable bone growth and development. Other factors that may affect bone

health and future risk for osteoporosis in this population include restricted

physical activity and corticosteroid use. No studies have examined the calcium

and vitamin D intake of children and adolescents with asthma, which was the

purpose of this study. It was hypothesized that asthmatic children and









adolescents do not meet the adequate intake (Al) for calcium and vitamin D and

that they consume less calcium than what has been reported in national survey

data from children of the same age. Subjects with asthma were recruited from

the Pediatric Pulmonary Center Asthma Clinic and the UF Research Asthma Lab.

Three-day food records were collected and analyzed for calcium and vitamin D

intake using Food Processor. Calcium and vitamin D intake was compared to

the Al and to data for an age-matched reference population (i.e., Continuing

Survey of Food Intakes of Individuals, CSFII). The 3-day mean dietary calcium

intake for the 1 to 3 year old group was significantly less (p = 0.001) than that of

the age-matched reference population. The 3-day mean dietary calcium intake

for the 9 to 18 year old age group was significantly lower than the Al (p = 0.02).

Vitamin D intake met the Al for all age groups, and no differences were detected

between the vitamin D intake of subjects with asthma compared to the respective

age group using the CSFII database. Dietitians and other healthcare providers

should encourage adequate consumption of milk and dairy products in children

and adolescents with asthma with the goal of ensuring adequate calcium intake

and reducing future risk for osteoporosis in this vulnerable population.














CHAPTER 1
INTRODUCTION

Asthma is a chronic inflammatory disease of the airways (1-3) that currently

affects 6.1 million children under the age of 18 years (1). It is the leading serious

chronic illness among children (4), and recent increases in asthma prevalence

have been steepest among the young (5).

A potential concern for pediatric asthma patients is the future risk for

osteoporosis. Adequate intake of calcium and vitamin D and regular physical

activity are essential for normal growth, development, and maintenance of bone.

Inadequate calcium and vitamin D intake, limited physical activity, and

corticosteroid use are important factors that can affect bone formation and bone

health in children with asthma, thus affecting bone mineral density (BMD),

stature, achievement of peak bone mass (PBM), and risk for osteoporosis later in

life. Several research groups (2,6-8) have reported that avoidance or elimination

of dairy products (6,7), low physical activity (8,9), use of oral corticosteroids (2),

and long-term use of inhaled corticosteroids (2) are seen among children and

adolescents with asthma. Inadequate milk and dairy products consumption could

have an adverse effect on the intake of calcium and vitamin D, nutrients

associated with favorable bone growth and development. The calcium and

vitamin D intake of pediatric patients with asthma has not been reported

previously in the literature, and it is possible that due to avoidance or elimination

of milk and dairy products from their diets, their intake of these nutrients are less









than the Al levels set by the Institute of Medicine (IOM). Evaluating the

adequacy of calcium and vitamin D intake in the pediatric asthma population will

help to identify whether there is a need for targeted intervention strategies to

improve the intake of these nutrients with the goal of reducing the risk for

osteoporosis later in life.

Hypotheses

It was hypothesized that children and adolescents with asthma 1) do not

meet the Al for calcium and vitamin D 2) consume less calcium than what has

been reported in national survey data from children of the same age, and 3)

consume a different amount of total milk and dairy products and specific types of

dairy products than reported in national survey data from children of the same

age.

Specific Aims

The specific aims of this study were to determine calcium and vitamin D

intake of children and adolescents with asthma using a 3-day food and

supplement diary and to compare their intake of these nutrients to the Als for

each age category (i.e., 1 to 3, 4 to 8, and 9 to 18 years) and to compare calcium

intake of our pediatric asthma population to survey data from the 1994 to 1996

and 1998 CSFII. Another specific aim was to compare dairy product

consumption of our pediatric asthma population to survey data from the 1994 to

1996 and 1998 CSFII.














CHAPTER 2
BACKGROUND AND LITERATURE REVIEW

Asthma

Overview

Asthma is a reversible, recurrent obstructive lung disease (3) that currently

affects 6.1 million children under the age of 18 years (1). Approximately 9 million

U.S. children under the age of 18 years have been diagnosed with asthma, and

boys are more likely to be diagnosed with asthma than girls (10). In 2002, 4.2

million children under the age of 18 years suffered an asthma attack or episode

(1,10). It is the leading serious chronic illness among children (4,11), and recent

increases (55% from 1980 to 1996) (4) in asthma prevalence have been steepest

among the young (5). Asthma is the third leading cause of hospitalization among

children under the age of 15 years and causes 14.6 million lost school days

annually, making it the leading cause of school absenteeism attributed to chronic

conditions (1).

The working definition of asthma developed by the National Heart, Lung,

and Blood Institute (NHLBI) is a

chronic inflammatory disorder of the airways in which many cells and
cellular elements play a role, in particular, mast cells, eosinophils, T
lymphocytes, neutrophils, and epithelial cells. In susceptible individuals,
this inflammation causes recurrent episodes of wheezing, breathlessness,
chest tightness, and cough, particularly at night and in the early morning.
These episodes are usually associated with widespread but variable airflow
obstruction that is often reversible either spontaneously or with treatment.
The inflammation also causes an associated increase in the existing
bronchial hyperresponsiveness to a variety of stimuli. (2, p. 11)









Recent observations indicate that reversibility of airflow obstruction may be

incomplete in some individuals with asthma (12).

Etiology

Numerous factors may play an important role in the etiology of asthma,

some of which may increase the risk for developing asthma and others which

may provide protection against asthma. According to the NHLBI, atopy, which is

an IgE-mediated allergic response to common aeroallergens, is the strongest

identifiable factor associated with increased risk for developing asthma (13).

There also is a strong genetic component to the development of asthma.

Therefore, the propensity for developing asthma is influenced by genetic and

environmental factors and interactions among these factors.

Factors that may decrease the risk for developing asthma include exposure

to various aeroallergens early in life, certain early childhood bacterial and viral

infections (i.e., pneumonia, respiratory syncytial virus, M. tuberculosis, measles,

hepatitis A, etc.), exposure to other children (e.g., presence of an older sibling

and early enrollment in childcare), less frequent use of antibiotics, farming

environment (i.e., contact with barn animals), breast feeding (breast milk

protection), season of birth (i.e., spring), and nutrition (e.g., intake of

polyunsaturated fatty acids, omega-3 fatty acids, etc.) (2,3,14,15).

Pathophysiology

In general, asthma occurs as a result of the interaction between genetic

predisposition and certain environmental triggers that result in peribronchial

inflammation (3). The major pathophysiologic features of asthma include

denudationn of airway epithelium, collagen deposition, edema, mast cell









activation, and inflammatory cell infiltration" (2, p.11). Inflammation results in

bronchial hyperresponsiveness, airflow limitation, respiratory symptoms, acute

bronchoconstriction, airway edema, mucus plug formation, airway wall

remodeling, and disease chronicity (13). Bronchial hyperresponsiveness, an

exaggerated bronchoconstrictor response to a stimulus such as an allergen or

irritant, occurs as a result of thickening of the airway wall (13,14). The chronic,

persistent airway inflammation that occurs in asthma is caused by activation of

recruited and resident immune cells that initiate a persistent level of cell damage

and an ongoing repair process (13,14).

During an asthma exacerbation or episode, the airways become narrow as

a result of a series of events that include swelling of the airway lining, tightening

of the airway muscles, and increased secretion of mucus in the airway (1). As a

result, individuals experience coughing, wheezing, and difficulty breathing (16).

Although asthma symptoms are often triggered by allergens such as a pollen,

mold, animal dander, feathers, dust, food, or cockroaches, it also can be

triggered by respiratory infections, colds, vigorous exercise, cold air, sudden

temperature changes, cigarette smoke, excitement, stress, or exercise (1).

Asthma episodes or exacerbations may resolve spontaneously or following

treatment with medication (14).

Diagnosis

Important information to gather in order to diagnose asthma in children

includes onset and history of symptoms; description of a typical episode;

conditions associated with onset of symptoms; type and pattern of symptoms;

perception of severity; physical examination of the head, neck, upper respiratory









tract, chest, and skin; hyperexpansion of the thorax; wheezing during normal

breathing; prolonged phase of forced exhalation; increased nasal secretion;

mucosal swelling; nasal polyps; and atopic dermatitis/eczema (3,13,14). In

children 5 years of age and older, diagnostic tests such as spirometry and

bronchoprovocation challenge are used in addition to the history and physical

examination to diagnose asthma. In children younger than 5 years, it is difficult

to objectively measure lung function using spirometry, so diagnosis is primarily

based on symptoms, physical examination, and response to therapy (15).

Spirometry, or pulmonary function testing (PFT), is the best method for

evaluating lung function in patients who may have asthma. Spirometry can

detect several physiological abnormalities that occur in asthma, such as

decreased airflow and lung volumes, increased work of breathing, increased

airway responsiveness to stimuli, and variability of airway flow (14). The results

of PFT are used to diagnose and categorize the severity of asthma in children

over 5 years of age and adults. These include forced expiratory volume in 1

second (FEVi), ratio of FEV1 to forced vital capacity (FEV1/FVC), and forced

expiratory flow during the middle portion of exhalation (FEF25-75%). Forced

expiratory volume in 1 second is defined as the volume that is exhaled in the first

second in liters per second (3). This measurement provides pulmonologists with

information about large to medium sized airways (3). Forced vital capacity is the

maximum volume of air that can be exhaled after maximal inhalation (14). The

ratio of FEV1 to FVC measures general airway obstruction (3). Forced expiratory

flow during the middle portion of exhalation, is the average flow of air during the









middle portion of the FVC and provides pulmonologists with information about

the small airways (3). In children 5 years of age and older, an FEV1 below 80%

of predicted is diagnostic for asthma (2). An increase in FEV1 of more than 12%

following use of a short-acting bronchodilator also is diagnostic for asthma (2,3).

Another method that can be used to diagnose asthma is a

bronchoprovocation challenge. This method is useful for evaluating children 5

years of age an older who have a chronic cough and/or vague exercise

intolerance, but do not display a change in FEV1 in response to short-acting

bronchodilators (14). A bronchoprovocation challenge is performed by slowly

administering a low dose of a challenging agent (i.e., an irritant,

bronchoconstrictor chemical, an antigen, etc.) into the airway until a 20%

decrease in FEV1 from baseline is achieved or the highest predetermined dose of

challenging agent is reached (14).

Asthma is classified as mild intermittent, mild persistent, moderate

persistent, or severe persistent. Severity is based on the frequency and

occurrence of symptoms during the day and night in infants and children 5 years

of age and younger (2). In children over 5 years of age and adults, the degree of

asthma severity is based on frequency and occurrence of symptoms during the

day and night as well as FEV1 measurements (2).

Monitoring

Asthma can be monitored by PFTs, airway challenge, peak flow monitoring,

asthma exacerbation history, signs and symptoms, quality of life,

pharmacotherapy, patient-provider communication, and/or patient satisfaction

(2). The methods used to monitor asthma are spirometry and peak flow









monitoring. Unfortunately, because spirometry and peak flow monitoring are

largely effort dependent, it is difficult to objectively monitor lung function in infants

and children under 5 years of age (15). As a result, monitoring asthma in this

age group is largely based on asthma symptoms, the need for a rescue

bronchodilator and oral corticosteroid therapy, and emergency room visits or

hospitalizations (15).

Pulmonary Function Testing (Spirometry). Spirometry is often

conducted every 3 months during a regular pulmonary visit. A change of 1

standard deviation (SD) in any of the pulmonary function measures (i.e., FEV1,

FEV1/FVC ratio, and FEF25-75%) is considered significant (14). If the change in

one or more of the pulmonary function measures is significant, adjustments to

the type or dose of medications) are made.

Peak Flow Monitoring. Peak flow monitoring is another way to monitor

asthma and aid in its management. Peak expiratory flow (PEF) is a measure of

the most rapid flow of air during a forced expiration and it provides

pulmonologists with information about the function and condition of larger

airways (3). Compared to spirometry, peak flow monitoring is considered to be a

less technological approach; however, it is an objective, quantifiable,

reproducible, and sensitive measure of airway obstruction that changes

dramatically during the early stages of an asthma exacerbation (2,3,14).

Asthma Management

Medical Management

According to the NHLBI, the goals of therapy in asthma control include

minimal or no chronic symptoms during the day or night, minimal or no









exacerbations, no limitations on activities, no school missed by the child or work

missed by the parent as a result of asthma symptoms, minimal use of short-

acting inhaled P2-agonists, and minimal or no adverse effects from medications

(2). Medical management of asthma focuses on decreasing airway inflammation

to minimize airflow obstruction and asthma symptoms (2,15). There are two

main categories of medications used to manage asthma: reliever medications

and controller medications (Table 1).

Asthma is managed through a stepwise approach based on severity of the

disease. The preferred and alternative treatments used to manage asthma in

children 5 years and younger and older than 5 years are outlined in Tables 2 and

3, respectively. During an asthma exacerbation, the focus shifts toward

controlling and relieving the smooth muscle airway spasms using reliever

medications (14).

Reliever medications are short-acting bronchodilators such as short-acting

P2-agonists and anticholinergics and anti-inflammatory medications, including

systemic corticosteroids (2,3). These are used to relieve acute

bronchoconstriction (3). They are effective in treating acute asthma

exacerbations, but do not prevent an exacerbation from occurring (3). The short-

acting P2-agonists can be administered in an oral, nebulized, or metered dose

inhaler (MDI) form. Anti-inflammatory medications, such as systemic or oral

corticosteroids, also are used to relieve asthma symptoms; however, they are not

intended for daily use and are reserved for acute asthmatic episodes (3). Long-









Table 1. Medications used to treat or prevent asthma symptoms.

Medication Category Mechanism of Action Examples

Reliever Medications: Use: treatment of acute
asthma exacerbations

Short-acting P2-agonist Dilate airways by Albuterol (Ventolin,
relaxing bronchial Proventil), Pirbuterol
smooth muscle (MaxairTM AutohalerTM),
Bitolterol, Levalbuterol,
Salmeterol (Serevent)

Anticholinergic Dilate airways by Ipatropium (Atrovent)
relaxing bronchial
smooth muscle

Systemic (oral) Reduce airway Prednisone, prednisolone,
corticosteroid inflammation methylprednisolone


Controller Medications:


Inhaled Corticosteroid







Long-acting P2-agonist



Leukotriene modifier


Sources: (1-3,17)


Use: long-term control of
asthma

Reduce frequency of
acute asthma
exacerbation

Reduce airway
inflammation
Decrease transport of
fluid across the
capillaries
Decrease mucus
production

Relieve airway
constriction


Decrease inflammation
by reducing the
production or blocking
the action of
leukotrienes


Fluticasone (Flovent),
Budesonide (Pulmicort),
Beclomethasone
(Beclovent, Qvar,
Vanceril), Flunisolide
(Aerobid), Triamcinolone
(Azmacort)

Salmeterol (Serevent
discuss), Formoterol
(Foradil)

Montelukast (Singulair),
Zafirlukast (Accolate),
Zileuton









Table 2. Long-term control medications for infants and children with asthma 5
years of age and younger.
Asthma Severity
Classification Long-term Control Medications
Severe persistent Preferred treatments: If needed:
High-dose inhaled Oral corticosteroid
corticosteroid and
long-acting inhaled
beta2-agonist

Moderate persistent Preferred treatments: Alternative Treatments:
Low-dose inhaled Low-dose inhaled
corticosteroid corticosteroid (medium-
(medium-dose, if dose, if needed) and
needed) and long- leukotriene receptor
acting inhaled beta2- antagonist or
agonist or, theophylline

Medium-dose inhaled
corticosteroid

Mild persistent Preferred treatment: Alternative Treatments:
Low-dose inhaled Cromolyn or leukotriene
corticosteroid receptor antagonist
Mild intermittent No daily medication
needed
Source: (2)

term use of these medications should be avoided due to the side effects

associated with them (3).

Controller medications aid in long-term control of asthma and are used to

reduce peribronchial inflammation and frequency of acute asthma exacerbations

(3). They are taken on a daily basis, regardless of symptoms, and are available

in a nebulized, MDI, or dry powder inhaler (DPI) form (3). The controller

medications include anti-inflammatory agents such as inhaled corticosteroids,

leukotriene modifiers, mast cell stabilizing drugs, and long-acting









Table 3. Long-term control medications for children with asthma over 5 years of
age and adults.
Asthma Severity
Classification Long-term Control Medications
Severe persistent Preferred treatment: If needed:
High-dose inhaled Oral corticosteroid
corticosteroid and
long-acting inhaled
beta2-agonist

Moderate persistent Preferred treatments: Alternative Treatments:
Low- to medium-dose Increase inhaled
inhaled corticosteroid corticosteroid up to
and long-acting medium-dose range; or
inhaled beta2-agonist low-to-medium dose
inhaled corticosteroid
and leukotriene
modifier or theophylline

Mild persistent Preferred treatment: Alternative Treatments:
Low-dose inhaled Cromolyn, leukotriene
corticosteroid receptor antagonist,
nedocromil, or
sustained release
theophylline

Mild intermittent No daily medication Severe exacerbations:
needed Oral corticosteroid
Source: (2)

bronchodilators (Table 1) (18). Inhaled corticosteroids, which are intended for

daily use, are the most effective controller medications available; therefore they

are the most preferred medication for asthma control when pharmacotherapy is

indicated (2,3,18). Long-acting P2-agonists are not the preferred treatment for

asthma, but may be used concomitantly with inhaled corticosteroids in moderate

and severe persistent asthma to control nighttime and exercise induced

symptoms (2,17). Similar to long-acting P2-agonists, leukotriene modifiers serve

as an alternative to inhaled corticosteroids and can be used in combination with









inhaled corticosteroids for the treatment of mild persistent asthma (2). Although

they are not as effective as inhaled corticosteroids, they are effective in

controlling asthma in approximately two-thirds of the population with asthma (3).

The preferred medical therapy for children 5 years of age and younger

includes low-dose inhaled corticosteroids, administered using a nebulizer, DPI, or

a MDI with a holding chamber, with or without a face mask (2). Alternative

therapies include cromolyn or a leukotriene receptor antagonist (LTRA) (2). A

low-dose inhaled corticosteroid also is the preferred medication for children over

5 years of age and adults (2). Alternative therapies include cromolyn, LTRAs,

nedocromil, or sustained release theophylline (2).

Environmental Management

Altering the indoor and outdoor environment is another way to aid in the

management of asthma. Indoor environmental management may include

decreasing or eliminating allergens, mold, insects (i.e., house dust mites,

cockroaches), animals (domestic and pests), or irritants (i.e., tobacco, perfumes

and scents, household cleaners, wood-burning fireplaces, heating and air

conditioning), or controlling humidity in the home, school, and office (3). Outdoor

environmental management may include decreasing or eliminating exposure to

cold or exercise (3).

Dietary Management

Parents of children with asthma commonly avoid or eliminate foods from

their children's diets in an attempt to reduce the onset of asthmatic symptoms

(6). Milk and dairy products are the foods most often reported to be eliminated or

avoided (6), although studies do not support a connection between milk intake









and a reduction in pulmonary function (19-21). Restriction or avoidance of milk

and dairy products consumption could have an adverse effect on the intake of

calcium and vitamin D, nutrients associated with favorable bone growth,

development, and maintenance. Inadequate calcium and vitamin D intake, as

well as restricted physical activity and oral corticosteroid use, place children and

adolescents with asthma at risk for osteoporosis.

Calcium

Structure and Function

Calcium is the most abundant divalent cation in the human body, and 99%

of calcium is found in bones and teeth, mainly in the form of hydroxyapatite

(Calo(PO4)6(OH)2) (22-25). The remaining 1% of calcium in the body is present

in intracellular and extracellular fluids, muscle, and other tissues (22). In general,

calcium plays a vital role in normal growth, development, and maintenance of

bone and other calcified tissues (22). Other functions of calcium include blood

clotting, nerve conduction and transmission, muscle contraction, enzyme

regulation, hormone release, vision, mediating vascular contraction, vasodilation,

and glandular secretion (22,24,25).

During bone formation and mineralization, calcium enters bone fluid from

blood in the free, ionized form (i.e., Ca2+) or as a calcium salt (i.e., Ca3(PO4)2)

(24). It is thought that during the process of bone mineralization, osteoblasts

secrete a substance onto the bone surface to enhance calcium precipitation.

Calcium, in the form of a calcium salt, binds to the bone surface and is laid down

on collagen to form bone.









Within the intracellular compartment of the body, calcium acts as a second

messenger to activate physiological responses (25). It functions in activating

these physiological responses by binding to specific proteins such as calmodulin

and troponin C (24). The binding of calcium to calmodulin activates enzymes

that serve to function in smooth muscle contraction, glycogenolysis, and other

functions. When calcium binds to troponin C, skeletal muscle contraction is

stimulated (24).

In the extracellular compartment, which includes blood, lymph, and body

fluids, calcium is present primarily in the free, ionized form, but also can be

bound to albumin or globulin, or completed to phosphate, citrate, or other anions

(24,25). Extracellular calcium serves as a source of ionized calcium for the

skeleton and cells (25).

Digestion and Absorption

In order for calcium to be digested, it must be in the free, ionized form.

Calcium derived from food and supplements is in the form of insoluble salts, and

calcium must be released from these salts for proper absorption (24). Absorption

of calcium occurs throughout the small intestine by one of two processes. The

first process, which takes place primarily in the duodenum and the proximal

jejunum, is transcellular, saturable, and requires energy (i.e., active transport)

(24,25). It is under homeostatic control, involves a calcium-binding protein, and

is regulated by calcitriol (1,25 (OH)2 D3), making it a vitamin D-dependent

process (24,25). This route of absorption occurs at low (<400 mg) and moderate

calcium intakes, during periods of growth, and during pregnancy and lactation

(22,24). The second process of absorption, which takes place primarily in the









jejunum and ileum, is nonsaturable, passive, paracellular, not under homeostatic

control, and dependent on the amount of calcium available in the intestinal lumen

(22,24,25). As a result, the more dietary calcium ingested, up to a certain

threshold, the greater the amount of calcium absorbed through this route (24).

Approximately 25 to 35% of dietary calcium is absorbed through both of these

routes combined. In addition, it is thought that a modest amount of calcium is

absorbed in the large intestine through the release of calcium from bacteria after

ingestion of some fermentable fibers such as pectin.

There are several dietary factors that may influence calcium absorption.

Dietary components that increase the absorption of calcium include vitamin D,

sugars such as lactose, sugar alcohols such as xylitol, inulin,

fructooligosaccharides, and protein (23-25). The presence of food in the

gastrointestinal (GI) tract also improves calcium absorption as does the calcium

content of a meal (22,25). Dietary components that may decrease absorption of

calcium include oxalate or oxalic acid; nonfermentable fiber such as the fiber

found in wheat bran, hemicelluloses, phytate or phytic acid; divalent cations and

other minerals such as magnesium or zinc; caffeine; unabsorbed dietary fatty

acids; and a low dietary calcium/phosphorus intake ratio (22-26). This reduction

in calcium absorption can occur through several mechanisms including

decreased transit time, binding, chelation, competition for absorptive sites, and

the formation of insoluble salts (24). Overall, calcium absorption ranges from 20

to 50% (24).









Transport

Calcium is transported through the blood bound to proteins, completed, or

in the free, ionized form. Approximately 40% of calcium in the blood is bound to

proteins (i.e., albumin and prealbumin), 10% is completed to sulfate, phosphate

or citrate, and 50% is found in the free, ionized form (24).

Homeostasis

Calcium homeostasis is tightly controlled both intracellularly and

extracellularly. Extracellular homeostasis (i.e., blood calcium) is maintained

primarily through the actions of three hormones: parathyroid hormone (PTH),

calcitriol, and calcitonin (24). Additionally, a calcium-sensing receptor (CaSR or

CaR), which is found in the parathyroid gland, thyroid gland, distal nephron, GI

tract, skin, brain, and in osteoblast cell lines, is involved in calcium homeostasis

(25,27).

When blood calcium concentration is low, a PTH-vitamin D-dependent

process returns blood calcium concentration to normal by increasing calcium

absorption, renal tubular reabsorption, and bone resorption (25). When low

concentrations of ionized calcium are detected by the CaSRs of the parathyroid

gland, intact PTH is released (27). The release of PTH affects the kidneys and

bones (24). In the kidney, PTH stimulates the synthesis and activation of

calcitriol, the active form of vitamin D, which induces reabsorption of calcium in

kidneys (24,28). Calcitriol also upregulates the production of calbindin by binding

to the nuclear receptors of enterocytes thereby stimulating transcription of the

gene that encodes calbindin (24). Increased calbindin production is associated

with increased calcium absorption from the GI tract. In the bone, PTH interacts









with receptors on osteoblasts to signal osteoclasts to break down bone and

release calcium into the blood by way of calcium pumps. As a result of these

actions, the blood calcium concentration is returned to normal.

When the blood calcium concentration is high, ionized calcium binds to the

CaSR on the parathyroid gland to induce a conformational change and PTH

secretion is inhibited (25). As a result, PTH cannot activate calcitriol. Instead,

calcitonin is secreted, which serves to decrease calcium absorption by inhibiting

vitamin D activation, increasing urinary calcium excretion in the kidney, and

decreasing bone resorption by inhibiting osteoclasts from metabolizing bone

(24,25,28). As a result of these actions, the blood calcium concentration is

returned to normal.

Intracellular calcium homeostasis is maintained through the action of ATP-

dependent calcium pumps and calcium storage in the mitochondria, endoplasmic

reticulum, nucleus, and vesicles (24). Calcium pumps transport Ca2+ out of the

cell to maintain low intracellular concentrations within the cell or to the

mitochondria for storage until it is needed by the cell. To control the calcium

concentration in the cytoplasm, calcium may be transported from extracellular

sites into the cell by a sodium-calcium exchange.

Deficiency

Calcium deficiency may occur as a result of inadequate intake, poor

absorption, or excessive losses. The consequence of a calcium deficiency is a

decrease in bone mass (BM), which may lead to osteopenia and eventually

osteoporosis if bone loss continues (24,29-32). The loss of BM associated with









the development of osteoporosis results in increased bone fragility and increased

fracture risk (33).

Risk for calcium deficiency is higher in vegetarians or individuals who are

lactose intolerant or have high protein and fiber intakes. Other factors that

contribute to calcium deficiency include fat malabsorption, immobilization, which

promotes calcium loss from the bones, decreased GI transit time, or short-term

use of thiazide diuretics (22,24).

Status Assessment

Methods used to determine calcium status include measurement of serum

calcium and serum ionized calcium. Serum calcium, which includes protein-

bound, completed, and ionized calcium, is very tightly regulated and is affected

by albumin status so it is not a good indicator of calcium status (24). Serum

ionized calcium is reflective of abnormal calcium metabolism when albumin

status is normal, but a correction factor must be applied when serum albumin is

low.

Dietary Reference Intakes (DRIs)

Dietary Reference Intakes are nutrition-based reference values that can be

used for planning and assessing diets (22). Those that pertain to calcium are the

Al and Tolerable Upper Intake Level (UL).

Adequate Intake (Al)

The Al is defined as the "observed or experimentally derived intake by a

defined population or subgroup that, in the judgment of the DRI Committee,

appears to sustain a defined nutritional state, such as normal circulating nutrient

values, growth, or other functional indicators of health" (22, p.25). An Al, rather









than a Recommended Dietary Allowance (RDA), is used when sufficient data are

not available to establish an Estimated Average Requirement (EAR) (22). The Al

is the amount of a nutrient that is "expected to meet or exceed the amount

needed to maintain a defined nutritional state or criterion of adequacy in

essentially all members of a specific healthy population" (22, p.25). The Al for

calcium for children and adolescents 1 to 18 years of age ranges from 500 to

1300 mg/d (Table 4).

Tolerable Upper Intake Level (UL)

The UL is defined as "the highest level of daily nutrient intake that is likely to

pose no risk of adverse health effects" to almost all individuals in the general

population (22, p.26). As intake increases above the UL, the risk for adverse

effects increases. The UL is based solely on intake from supplements and

fortified foods and applies to chronic daily use only. The UL for children and

adolescents 1 to 18 years of age is set at 2,500 mg/d (22).

Table 4. Dietary Reference Intakes for calcium for children and adolescents 1 to
18 years.

Al UL
Age (mg) (mg)
1-3 years 500 2,500
4-8 years 800 2,500
9-18 years 1,300 2,500
Source: (22)

Sources

Calcium is widely available in the U.S. food supply. Sources of calcium

include milk, cheese, ice cream, yogurt, calcium-set tofu, soy milk, salmon,

sardines (with bones), clams, oysters, turnip and mustard greens, broccoli, kale,









rhubarb, Chinese cabbage, legumes, dried fruits, and calcium-fortified foods such

as orange juice and some cereals (22,24,25). Calcium bioavailability is fairly

similar in dairy products such as milk and cheddar cheese, as well as fortified

juices, soy milk, and yogurt (25). Calcium is poorly absorbed from spinach,

rhubarb, and legumes, which are sources of oxalic acid, and from legumes,

grains, and soy isolates, which are sources of phytic acid (22).

Milk, cheese, and yogurt are the most calcium-dense foods consumed by

Americans, providing approximately 300 mg per serving (22). According to data

for 1999, 73% of calcium in the U.S. food supply is from milk products, 9% is

from fruits and vegetables, 5% is from grain products, and the remaining 13% is

from all other sources (34).

Calcium Intake in the U.S.

Overall, calcium intake in the U.S. has declined because grains have

become staples in the diets of Americans (25). The calcium content of grains

and fruits are typically quite low, except in fortified cereals and grains (25).

Calcium intake of Americans, especially adolescent girls, are below current

recommendations (25). According to data from the 1994-1996 and 1998 CSFII,

higher intake of total dairy and milk were associated with statistically significant

increases in calcium intake (35). Additionally, the authors found that individuals

with low dairy or milk intake did not compensate for their lower intake of these

calcium-rich foods by consuming other foods that are good sources of calcium.

Other factors that may affect dietary calcium intake in the U.S. are lactose

intolerance, which occurs in 25% of adults, and consumption of vegetarian diets

(22).









Vitamin D

Structure and Function

Vitamin D is a fat-soluble vitamin that plays a key role in normal growth,

development, and maintenance of bone and other calcified tissues through its

effect on calcium (22). Vitamin D also is active in cardiac tissue, muscle, brain,

skin, hematopoietic cells, and immune system tissues (24). Blood is the primary

storage sight for 25-OH D3.

The primary biologic function of vitamin D is to maintain adequate serum

concentrations of calcium and phosphorus through its actions on the intestinal,

kidney, and bone cells (22,24). In the intestine, vitamin D primarily functions by

increasing the absorption of calcium and phosphorus by upregulating the

production of calbindin. In the kidney, PTH activates vitamin D (calcitriol) to

stimulate calcium and phosphorus reabsorption. Vitamin D also functions with

PTH in the bone to mobilize calcium and phosphorus by inducing differentiation

of cells to osteoclasts and/or increasing osteoclast activity (24). Vitamin D also is

involved in bone formation and remodeling through its role in promoting the

synthesis of osteocalcin.

Digestion, Absorption, and Transport

Dietary vitamin D is absorbed primarily in the distal small intestine in

association with fat through passive diffusion (24). Approximately 50% of vitamin

D is absorbed. Once absorbed into the enterocytes of the small intestine, dietary

vitamin D, in the form of D3, is incorporated into chylomicrons that enter the

lymphatic system. Vitamin D-binding protein (DBP) transports vitamin D to the

liver through the blood. In the liver, vitamin D cholecalciferoll) undergoes a









hydroxylation at carbon 25 to form 25(OH) D3. It is released back into the blood

and transported to the kidney via DBP (24,36,37). In the kidney, 25(OH) D3

undergoes another hydroxylation to form 1,25(OH)2 D3 (calcitriol), the active form

of vitamin D. Calcitriol is released from the kidney, transported to target tissues

on DBP, released by DBP, and bound to receptors in the target tissues.

In addition, vitamin D can be synthesized in the skin through exposure to

sunlight. A sterol found in the skin, 7-dehydrocholesterol, absorbs ultraviolet

(UV) light from the sun and is converted to vitamin D3 cholecalciferoll) (24,36).

Cholecalciferol enters the blood to be activated by the same mechanism as

dietary vitamin D.

Deficiency

A potential cause of abnormal calcium and bone metabolism is vitamin D

deficiency (22,38), which can lead to rickets in infants and children and

osteomalacia in adults. Both rickets and osteomalacia are a result of failure of

the organic matrix of bone to calcify or mineralize (24,36). In children less than 6

months of age, vitamin D deficiency is associated with convulsions or tetany (36).

Vitamin D deficiency in children 6 months of age and older is associated with

tetany, bone pain, and bone deformity. Adults with osteomalacia are likely to

experience bone pain and osteopenia, which increase the risk for skeletal

fractures (24,36,39).

Risk for vitamin D deficiency is associated with advancing age; fat

malabsorption; disorders affecting the parathyroid gland, liver, or kidney;

insufficient sun exposure; dark skin pigmentation; anticonvulsant therapy;

unsupplemented breastfeeding infants; and renal disease (24,36). The









prevalence of vitamin D insufficiency in adults living in the U.S. and Canada

ranges anywhere from 1 to 76% depending on the latitude and the season (40).

Status Assessment

Serum 25(OH) D3 is the most accurate and reliable measure of vitamin D

status (41,42). The ranges of serum 25(OH) D3 concentrations used to

determine vitamin D status are listed in Table 5.

Table 5. Vitamin D status assessment according to serum 25(OH) D3
concentrations.
Serum 25(OH) D3
Vitamin D Status
(nmol/L)
Normal/Adequate 100-200
Hypovitaminosis 50-100
Insufficiency <40-50
At risk for deficiency 13-25
Deficient <13
Sources: (36,37)

Dietary Reference Intakes (DRIs)

Adequate Intake (Al)

Similar to calcium, an Al rather than an RDA was established for vitamin D

due to lack of sufficient data for setting an EAR. The Al for vitamin D for children

and adolescents 1 to 18 years of age is 5.0 mcg/d (200 IU/d) (22).

Tolerable Upper Intake Level (UL)

The UL for vitamin D for children and adolescent 1 to 18 years of age is 50

mcg (2,000 IU)/d (22).

Sources

Vitamin D is not as widely available in the food supply as calcium. It is

found primarily in saltwater fish such as herring, salmon, tuna, and sardines and









fish liver oils (24,36). Small quantities of vitamin D also are found in eggs, veal,

beef, butter, cheese, and vegetable oils. Fortification of foods with vitamin D is

an inexpensive approach for promoting adequate vitamin D intake for all children

and adults.

The U.S. fortifies milk, some butter, margarine, cereals, and chocolate

mixes with vitamin D3 calciferoll) (24,36). Recently some types of fruit juice, such

as orange juice, and some brands of yogurt also have been fortified with vitamin

D (43). Vitamin-D fortified juice provides approximately 100 IU (50% Al) of highly

bioavailable vitamin D per serving for children and adults (43,44).

Vitamin D Intake in the U.S.

Most humans obtain their vitamin D requirement from exposure to sunlight,

which accounts for 80 to 100% of the body's requirement (42). It has been

estimated that 53% to 63% of all children meet the Al for vitamin D, with

adolescent and adult females being half as likely to obtain the Al as males (44).

The majority of dietary intake of vitamin D in the U.S. comes from fortified dairy

products (45 to 47%) (44).

Factors Influencing Bone Health during Childhood and Adolescence

Several studies have identified factors that may influence bone health in

children and adolescents. These factors include age, Tanner stage (i.e., stage of

puberty), height, weight, body mass index (BMI), and dietary intake of calcium,

vitamin D, and milk and dairy products.

Numerous studies, including cross-sectional, intervention, and longitudinal

studies, have reported a positive correlation between bone density or BM

development in children and calcium, vitamin D, and milk and dairy products









intake (22,45). In a 3-month study of healthy, Caucasian children and

adolescents, researchers found that dietary calcium intake, age, weight, and

height were positively correlated with BMD (46). These researchers also

observed that children whose average daily intake of calcium was at least 1000

mg had higher bone mineral content (BMC) than those ingesting less than this

amount. Serum calcium, vitamin D, phosphorous, magnesium, or alkaline

phosphatase concentrations were not correlated with bone mineral status in this

study. Similarly, Ruiz and colleagues determined that body weight, physical

activity, and dietary calcium intake (expressed as Z scores) were significant

determinants of femoral and vertebral bone density in healthy, Caucasian,

physically active children and adolescents with normal growth velocity (47).

Height and Tanner stage also were significant determinants of vertebral BMD,

and age influenced femoral BMD in this population. Sentipal and colleagues also

found dietary calcium intake to have a positive effect on bone density (48).

These researchers conducted a cross-sectional study of healthy, Caucasian

female children and adolescents that examined the contribution of calcium intake

on vertebral BMD and observed that current calcium intake was a significant

contributor to vertebral BMD after adjusting for weight, height, age, and total

energy expenditure. Sexual maturity rating, age, and calcium intake accounted

for 81% of the variance in vertebral BMD.

Calcium supplementation also has been shown to positively affect BMD in

children and adolescents. A 3-year, double-blind, placebo controlled, co-twin trial

conducted with healthy, 6 to 14 year old identical twins sought to determine









whether calcium alone was effective in increasing the rate of change in BMD

(49). These researchers found that calcium supplementation had a positive

effect on the rate of increase in BMD at several skeletal sites.

Consumption of milk and dairy products, which are good sources of calcium

and vitamin D, also has been shown to positively affect BMD. A large, cross-

sectional study of randomly selected Chinese adolescent girls found that milk

consumption, total calcium intake from milk, and vitamin D intake were positively

associated with BMD (50). Body weight and Tanner stage also were predictors

of BMD. Another study conducted in Yugoslavia reported that despite almost

identical lifestyles, BM by 30 years of age was greater in individuals living in a

region of Yugoslavia where consumption of dairy products was twice that of

another region of the country (51). These studies suggest that elimination of

dairy products from a growing child's diet may have a negative impact on BMD.

Achievement of PBM also has been studied. A cross-sectional study of

premenopausal, Caucasian, children and adults conducted by Matkovic and

colleagues sought to determine the timing of PBM, the maximum attainable BM

within an individual's genetic potential, and BMD (52). Researchers did not

detect a significant difference in BM or BMD for most skeletal sites except for the

skull after 18 years of age, indicating early attainment of PBM for the hip and

spine. Similarly, Henry and colleagues found that the majority of the body's bone

mass (i.e., BMC and BMD) was achieved by late adolescence, with peak BMC

being achieved between 21 and 22 years of age in men and 23 and 28 years in

women, and peak BMD being achieved between 12 and 22 years in men and 12









to 29 years in women (53). This suggests that PBM is achieved sometime

between the end of adolescence and early adulthood. Overall, the research

studies summarized in this section support the importance of adequate intake of

calcium, vitamin D, and dairy products during childhood and adolescence to

promote bone health and achievement of PBM.

A limited number of studies have not observed a positive correlation

between bone density in children and calcium intake or physical activity level as

reviewed by the IOM (22). This could be due to other factors that affect BMD,

such as maturational and chronological age and genetics. A study of physically

active children and adolescents did not detect a significant positive correlation

between calcium intake and bone density when stage of puberty and body weight

were controlled (54). Researchers concluded that in healthy, physically active

children with adequate calcium intake there is no appreciable effect of calcium on

bone density. Bone density may be a function of the relationships between

calcium intake, body weight, and stage of puberty. Similarly, in a prospective,

longitudinal, 1 year-long study of healthy Finnish children and adolescents,

physical activity and daily calcium intake were not correlated with BMD (55). It is

important to note that calcium intake in the majority of study subjects was

relatively high (>800 mg/d). It is important to note that these 2 studies did not

compare the relationship between the type of exercise in which study subjects

participated (i.e., weight-bearing or non-weight-bearing exercise) and BMD.

Although a few studies suggest that calcium, vitamin D, and dairy products

intake do not influence bone health, most of the studies conducted support the









role of dietary intake of calcium, vitamin D, and dairy products in promoting bone

health during childhood and adolescence.

Factors Influencing Bone Health during Adulthood

Several factors that may influence bone health during adulthood have been

identified from research studies. These factors include dietary intake of calcium,

vitamin D, milk and dairy products, and level of physical activity during childhood

and adolescence. Numerous retrospective studies have reported an association

between higher calcium intake during childhood and adolescence with

achievement of maximal PBM and greater BM in adulthood (22,45,56). As

discussed earlier, calcium is important for healthy skeletal growth and

development throughout life and because PBM is achieved by early adulthood,

early calcium intake can significantly influence the degree to which PBM is

achieved (53). Insufficient PBM has been shown to contribute significantly to the

risk of osteoporosis later in life (57).

Halioua and Anderson assessed the independent and combined effects of

lifetime calcium intake and physical activity on BMD, as well as body weight, in

healthy, ambulatory, premenopausal Caucasian women (58). This cross-

sectional study found that both lifetime calcium intake and physical activity were

significant positive predictors of BMD and BMC. Individuals with low lifetime

calcium intake and sedentary lifestyles were found to have the lowest bone BMD

and BMC. A similar study was conducted by Sandier and colleagues (59).

These researchers conducted a retrospective study of white, middle to upper-

middle class women in which information about milk consumption and calcium

intake during childhood and adolescence were collected. These researchers









observed that women who reported drinking milk with every meal during

childhood and adolescence had significantly higher bone density measurements

than women who reported drinking milk less frequently. As a result, the

researchers concluded that milk consumption during childhood and adolescence

appears to be necessary for optimal PBM. Results from a large, cross-sectional

survey of women also suggest the importance of milk and dietary calcium

consumption during childhood and adolescence on bone density of adults.

Kalkwarf et al. examined data collected on non-Hispanic, white women 20 years

of age and older from the third National Health and Nutrition Examination Survey

(NHANES III) conducted from 1988 to 1994 (60). Milk and dietary calcium intake

was determined through household surveys on milk consumption during specific

periods of life, including childhood, adolescence, and adulthood. Milk intake

during childhood, adjusted for confounders, was positively associated with total

hip BMC and bone area in women between 20 and 49 years of age. In addition,

milk intake during adolescence was positively associated with hip BMD in women

between 20 and 49 years of age. In women over the age of 50 years, milk intake

during childhood and adolescence positively influenced total hip BMD, and low

BMD was associated with a significantly greater incidence of lifetime fracture.

Also, low calcium intake during childhood was significantly associated with an

increased risk for osteoporotic fractures in women over 50 years of age, thereby

supporting the importance of milk consumption and adequate calcium intake

during childhood and adolescence. Collectively, these studies strongly suggest









that dietary intake of calcium, vitamin D, and dairy products are important during

childhood and adolescence because of the impact on bone health later in life.

Factors Influencing Bone Health in Children and Adolescents with Asthma

Calcium and vitamin D intake is important for promoting bone health in all

children and adolescents, including those with asthma; however, health beliefs

and practices among this population may interfere with achieving optimal intake

of these nutrients. Furthermore, other factors may put children and adolescents

with asthma at higher risk for poor bone health including altered metabolism

related to the disease, the medications used to treat asthma, and the restriction

of physical activity to avoid exercise-induced asthma (EIA) symptoms.

Health Beliefs about the Impact of Milk and Dairy Products on Asthma

One of the health beliefs adopted by some parents of children with asthma

is that cow's milk and cow's milk products affect asthma symptoms. For this

reason, some parents may eliminate or restrict the intake of milk and dairy

products in their children's diets, which could severely limit their intake of calcium

and vitamin D and have a negative impact on bone health over time. Research

has shown that parents of children with asthma commonly (47%) avoid or

eliminate foods from their children's diets, with milk and dairy products being the

primary (79%) category of foods eliminated or avoided (6). As reported by

Dawson et al., parents reported family, friends, and the media as the most

common (77%) sources of advice that influenced their decision to make a

change in their child's diet (6). Only 14% of parents reported receiving this

advice from a medical source (i.e., family doctor, dietitian, specialist, etc.). A

similar study conducted by Woods and colleagues on pediatric and adult asthma









patients showed that 45% of subjects had been advised by a doctor, specialist,

or a dietitian to avoid or eliminate specific foods, such as milk and dairy products,

at some time in their lives to improve asthma symptoms, and approximately 61%

were currently eliminating or avoiding these foods or had in the past (7). Dairy

products were one of the most commonly (36%) reported food categories to

induce asthma symptoms, the most commonly advised dietary restriction, and

the most commonly avoided food category.

Another factor that may influence milk and dairy intake by children with

asthma are the attitudes and beliefs held by them and their parents or caregivers.

For example, a survey was completed by 330 parents waiting in a pediatric

pulmonology office (61). Parents were asked if they avoided serving milk to their

child when they were ill, whether they thought their child was allergic to milk, if

their child had allergies, asthma, or cystic fibrosis (CF), and other questions

related to health beliefs and practices. Over half of the parents surveyed had a

child with asthma. Approximately 62% of parents of children with asthma

believed that drinking milk increased mucus. Family members were the most

common source of this information followed by pediatricians, physicians, and

others. Additionally, 8.2% of parents believed that their child was allergic to milk

and of these, approximately 70% believed that milk increased mucus production.

Overall, the studies summarized in this section suggest that intake of milk and

dairy products may be restricted or avoided in the diets of children and

adolescents with asthma due to health beliefs about the role of these foods in

producing asthma symptoms and allergies.









Calcium and vitamin D intake and bone health in cow's milk-free and cow's
milk-limited diets

Several studies suggest that the calcium intake of children on cow's milk-

free or cow's milk-limited diets is inadequate. A prospective, 2-year study of

male and female prepubertal children who were milk-avoiders (i.e., individuals

with a history of avoiding the consumption of cow's milk for more than 4 months

at some stage in their lives) found that milk-avoiders not only had lower calcium

intake, but also smaller bones, significantly lower bone area and BMC, and lower

volumetric BMD (62). The researchers concluded that children with a history of

long-term avoidance of cow's milk have low dietary calcium intake and poor bone

health in comparison to children who drink milk. In a two-year follow-up of this

same population milk-avoiding children had a significantly higher prevalence of

bone fractures compared to milk drinkers (controls). Furthermore, milk-avoiding

children did not make appropriate dietary substitutions to compensate for their

low calcium intake (63). In a younger population of children, calcium intake also

was found to be inadequate in cow's milk-free and cow's milk-limited diets.

Henriksen et al. conducted a prospective, cohort-based study to evaluate the

nutrient intake of children (mean age = 33 months) whose parents perceived that

their child had reactions to milk or egg when they were 2 years of age (64). Each

subject was categorized into one of four groups (i.e., milk-free, formula, low milk,

and milk consumers) based on their current diet. The milk-free group included

subjects on a diet completely free of cow's milk protein; the formula group

included subjects who consumed various amounts of hypoallergenic formula (i.e.,

soy-based or hydrolyzed); the low milk group consumed some dairy products, but









did not drink cow's milk; and the milk consumers group included children who

were milk-drinkers. Subjects in the milk-free, formula, and low-milk groups had

significantly lower calcium intake than the milk-consuming group. In fact,

children in the milk-free group had an average daily calcium intake of less than

300 mg and children in the low milk and formula groups each had an average

daily calcium intake of less than 500 mg. These studies suggest that children's

calcium needs most likely will not be met on a cow's milk-free or cow's milk-

limited diet.

Cow's milk and pulmonary function

Despite the popular belief that ingestion of cow's milk and other dairy

products increases mucus and negatively affects pulmonary function in

individuals with asthma, studies have shown that cow's milk ingestion does not

decrease pulmonary function, as evidenced by FEV1, FVC and/or PEF, nor does

it induce bronchoconstriction (20,21). A statistically significant difference was not

detected in pulmonary function (i.e., FEV1 and PEF) between a cow's milk

challenge and a placebo challenge (i.e., rice milk) in a randomized, double-blind,

placebo-controlled, cross-over study conducted in adults with asthma (21).

Additionally, a statistically significant difference was not detected in pulmonary

function from baseline after cow's milk challenge even in those subjects who

perceived that their asthma worsened after ingestion of dairy products. No

subjects reported an increase in cough or sputum production after any of the

challenges. A study using water instead of rice milk as the control reported

similar results (19). This 3-day pilot study designed to assess the effects of milk

ingestion on pulmonary function, recruited adults with and without asthma who









did not have a history of milk protein allergy or lactose intolerance, and randomly

assigned them to consume 10 ounces of water, whole milk, or skim milk after

which lung function was evaluated using FVC, FEV1, and V50 (i.e., airflow at 50%

of vital capacity) (19). Neither group (i.e., subjects with asthma or subjects

without asthma) showed a significant change in any lung function parameters

from baseline over three hours following ingestion of any of the test beverages

(i.e., water, skim milk, or whole milk) and there were no significant differences in

lung function parameters between the subjects with asthma and the subjects

without asthma for any of the test beverages. The authors concluded that

because they did not detect a significant increase in airway resistance (i.e., a

decrease in FVC, FEV1, or V50), there was not a significant increase in mucus

production in the airways. A prospective, randomized, double-blind, placebo-

controlled study of adult patients with mild asthma and no history of milk allergy

reported similar results with regard to the lack of a clinically significant effect of

cow's milk on pulmonary function (i.e., FEV1 and FEV1/FVC) (20). No clinically

significant effect of cow's milk on pulmonary function was detected at any time

point (i.e., 30 minutes, 1 hour, or 7 hours) compared to a placebo solution. There

also was no evidence of asthma symptoms, acute or delayed, after either

challenge. The authors concluded that pulmonary function does not deteriorate

in response to cow's milk ingestion. The studies presented in this section

suggest that cow's milk ingestion does not have a negative impact on pulmonary

function in people with asthma.









Cow's milk or food allergy, adverse reactions to milk, and asthma

A potential reason that parents of children with asthma may eliminate milk

and dairy products from their children's diets is related to the concern that their

child may be allergic to milk. This concern may be real or perceived. A double

blind placebo-controlled trial showed that incidence of cow's milk allergy was low

in children with asthma even in those who perceived that their asthma worsened

after ingestion of dairy products (65). Similarly, a double-blind, placebo

controlled, cross-over study conducted in children and adults with asthma found

that of those subjects who by history, skin prick test, or radioallergosorbent test

had a response suggestive of food allergy (8.3%), asthma was induced in only

30% of these subjects following a food challenge (e.g., milk, cheese, etc.),

suggesting that food-induced asthma occurs in only 2% of individuals with

asthma (66).

A study conducted by Emery et al. also found a low prevalence of food

allergy in individuals with asthma (67). This cross-sectional survey study of a

well-characterized population of children and adults with asthma found that 45%

of the subjects reported adverse reactions to foods, with milk being the leading

cause of reactions (9.7% of the total surveyed, 21.5% of those reporting food

reactions). Only 32% of those reporting adverse reactions to foods (14% of total

surveyed) indicated that they had been diagnosed with a food allergy. Similarly,

a study conducted with children who had bronchial asthma found that only 8.5%

of the subjects had asthma due to a food allergy (68). All food allergies were

confirmed by a positive intracutaneous test and hemagglutination test.

Additionally, approximately 34% of those with food allergy were allergic to milk.









These studies indicate that although there is a low prevalence of food allergy and

food-induced asthma in children with asthma, a significant proportion of the

observed cases are caused by milk.

Physical Activity

Observational and intervention studies have led to generalizations that

regular, moderate physical activity throughout childhood and adolescence

positively affects BMD, particularly at weight-bearing sites (45,69). The

prevalence of EIA, bronchial hyperresponsiveness, or wheezing during exercise,

as well as physical fitness and reported exercise limitations in children and

adolescents with asthma may have an impact on the type and amount of physical

activity in which they participate. This can potentially impact their bone health.

Acute and chronic diseases of the respiratory tract and supporting

structures, such as asthma, are potential barriers to participation in various forms

of physical activity by children and adolescents (70). The prevalence of EIA has

been estimated to be anywhere from 9 to 23% in the general population of

children and adolescents (71). In contrast, the prevalence of EIA has been

estimated to be 50 to 100% in children and adolescents with asthma (70,72). In

a study of children and adolescents with asthma, 76% reported that wheezing

increased after exercise (73). Both EIA and increased wheezing during exercise

have the potential to cause individuals with asthma to limit the amount and type

of physical activity in which they participate. This large range in EIA prevalence

among individuals with asthma is affected by type, intensity, and duration of

activity, environmental conditions, severity of disease, and variations in

preventive therapy (72). Overall, these research studies indicate a relatively high









prevalence of EIA, wheezing, and/or bronchial hyperresponsiveness during

exercise among children and adolescents with asthma.

Inadequate management or control of EIA may lead to unnecessary

avoidance of physical activity and sports (74). There is general agreement that

children with mild to moderate asthma are less fit than children without asthma

(74). In fact, Kitsantas and Zimmerman reported that adolescent girls with

asthma were less physically fit and participated less often in vigorous activities

compared with non-asthmatic girls (8). Decreased aerobic capacity among

asthmatic children and adolescents may be due to a sedentary lifestyle that

results from a lack of full lung expansion during exercise and/or a negative

attitude towards sports and other physical activities (72,74,75).

Many preconceptions regarding the effect of exercise on asthma symptoms

in children and adolescents have developed (76). A survey administered to

Swedish children with asthma was conducted to identify the types of limitations in

activities they experienced (9). Approximately 84% of these children reported

three restricted activities during the previous week. The most commonly

restricted activity was running, which accounted for 74% of restricted activities.

Another study found that 52% of those who did not exercise limited their

participation because they experienced shortness of breath or wheezing (73).

Sixty-five percent of the adults and children in this study did not regularly

participate in physical activity, but 64% indicated that their participation in

physical activities would be greater if their asthma was under better control.









In contrast, a large cross-sectional, multi-center survey of randomly

selected school-aged children living in three different areas of Norway found that

asthmatic children were as physically active as their non-asthmatic peers (77). In

addition, no significant differences were detected between exercise frequency

and hours of exercise per week for asthmatic compared to non-asthmatic

children. However, the authors noted that this finding could be due to parents of

children with asthma being aware of the importance of physical activity in the

management of asthma, leading to overreporting the overall physical activity of

their children. In a sub-group analysis, which included individuals only from one

region of the country, researchers also found no difference in physical activity

levels between children with or without asthma (78). Even though no significant

difference in exercise frequency between those with or without asthma was

detected, 12% of those with asthma exercised less than one hour per week and

38% exercised 4 to 6 hours per week (79).

Although inconclusive, there is some evidence to suggest that children and

adolescents with asthma are less fit, participate less frequently in physical

activity, and have limitations in terms of the type of physical activity in which they

can participate. This lack of physical activity has the potential to negatively

impact bone health in this population.

Inhaled Corticosteroid Use

Another factor that may influence bone health is the use of inhaled

corticosteroids. Many asthmatic children use inhaled corticosteroids daily. The

role of inhaled corticosteroids on bone health (i.e., BMD and BM) in children and

adolescents with asthma is controversial.









The National Asthma Education and Prevention Program (NAEPP) Expert

Panel of the NHLBI conducted a systematic review of available literature on the

effect of inhaled corticosteroids on BMD through August 2000 (2). A total of 2

studies (i.e., 1 short-term and 1 long-term study) were identified that met the

study criteria. The first study was a prospective study of Chinese patients with

bronchial asthma using inhaled steroids (i.e., beclomethasone dipropionate

(BDP) or budesonide (BUD)) regularly for at least 3 months. Researchers found

that total body BMC was similar, but the BMD of the lumbar spine, femur,

trochanter major, and Ward's triangle were all significantly lower than that of

matched control subjects (i.e., individuals without asthma who were not using

inhaled corticosteroids) (80). In female subjects, there was a significant negative

correlation between the average daily dose of inhaled steroid and BMD of the

lumbar spine and trochanter of the femur. It is important to note that this study

did not evaluate children and adolescents, had a small sample size (n = 30), and

was short-term. The second study was conducted by the Childhood Asthma

Management Program Research Group (81). This study was a 6-year,

randomized, clinical trial of a large group of children with mild to moderate

asthma. Subjects were randomized to BUD, nedocromil sodium, or a placebo.

Prednisone administration was permitted as needed. No significant difference in

the change in bone density was detected among the 3 groups.

The NAEPP concluded that based on available research, inhaled

corticosteroids taken in recommended doses do not have "frequent, clinically

significant, or irreversible effects" on BMD in individuals with asthma (2, p.38).









The report also noted that chronic use of inhaled corticosteroids could potentially

have cumulative effects on bone health (i.e., increased relative risk for

osteoporosis) when initiated during childhood and continued through adulthood,

but the lack of high-quality studies assessing this outcome make it difficult to

formulate a definitive conclusion.

Studies conducted after this extensive review have not shown an

association between inhaled corticosteroid use and a decrease in BMD and/or

BM in children and adolescents with asthma. A 6-month randomized, pilot study

was conducted with infants, children, and adolescents who had symptoms

suggestive of asthma and who were naive to prophylactic therapy (e.g.,

corticosteroids) (82). Subjects were randomized to receive either a P2-agonist,

an active control, or a p2-agonist combined with an inhaled steroid (i.e., BDP or

BUD). Bone density was measured using two different radiation free predictors

of bone density, broadband ultrasound attenuation and velocity of sound. No

significant difference in bone density adjusted for age was detected between the

control and each of the treatment groups. It is important to note that compliance

with therapy in this study ranged from 25 to 100% (median 50%). A long-term

study on children with asthma also found similar results. This 2-year

randomized, open, multi-center, parallel-group, study was conducted with

children with asthma who had only been treated in the past with a P2-agonist

(83). Subjects were randomized by balanced block randomization to fluticasone

propionate, an inhaled steroid, or nedocromil sodium, an active control. Bone

mineral density measurements were performed by individuals who were blind to









subject treatment. No significant difference in BMD was detected between the

groups. Overall, the studies presented in this section suggest that inhaled

corticosteroids do not have a long-term effect on BMD in children and

adolescents with asthma.

Systemic Corticosteroid Use

In contrast to research on inhaled corticosteroid use, research suggests

that oral or systemic corticosteroid use may have a negative impact on bone

health. Oral or systemic administration of corticosteroids may indirectly affect

bone health by reducing absorption of calcium in the gut and increasing renal

clearance of calcium, resulting in decreased blood calcium. As a result, PTH is

secreted, which inhibits the hypothalamo-pituitary-adrenal/gonadal axis and

negatively impacts bone by increasing bone resorption (84). Oral corticosteroids

also act directly on bone by inhibiting recruitment, differentiation and life span of

osteoblasts; production of type 1 collagen; and synthesis of osteocalcin, insulin-

like growth factors, and prostaglandin E.

Bone Density of Children with Asthma and Risk for Osteoporosis

Research strongly suggests that children and adolescents with asthma

have significantly lower-than-expected BMD. For example, a cross-sectional

study in which bone density, bone metabolism, and adrenal function were

measured in children who were either exposed or unexposed to oral bursts (i.e.,

5-day courses) of oral corticosteroids during the preceding year was conducted

(85). Researchers found that even though bursts of oral corticosteroids did not

have a prolonged or cumulative impact on bone metabolism, both groups had

lower-than-expected bone density (i.e., negative mean Z score) for age, gender,









and race. The researchers concluded that this finding may be due to inadequate

protein, calcium, or vitamin D intake, or physical inactivity, factors that increase

the risk for developing osteoporosis later in life. It is important to call attention to

the fact that researchers did not address dietary calcium and vitamin D intake in

this population.

Research Significance

Asthma affects 6.1 million children and adolescents in the United States

(U.S.), and its prevalence is on the rise (1). The elimination of dairy products,

potentially resulting in low calcium and vitamin D intake, low physical activity, 5-

day courses of oral corticosteroids, and long-term use of inhaled corticosteroids

seen among children and adolescents with asthma may have negative

implications on bone health later in life. The only study identified following an

extensive library search that examined the dietary intake of individuals with

asthma, was conducted by Woods and colleagues (86). These researchers

conducted a survey by mail on a large sample of adults to determine if there

were differences in dietary intake between subjects with or without asthma. They

found that intake of some foods, such as dairy products, were different between

subjects with asthma compared to those without asthma, but intake of nutrients

including calcium, were not. Specifically, asthma was negatively associated with

whole milk and butter consumption and positively associated with ricotta and low-

fat cheese consumption, but overall intake of dairy products was not significantly

different between those with and without asthma. To date, no studies have

specifically looked at the dietary intake of calcium and vitamin D in children and

adolescents with asthma. Therefore, the purpose of this study was to examine









calcium and vitamin D intake of children and adolescents with asthma to

determine if they are meeting the recommended intake levels for these nutrients

and to compare their intake of these nutrients with national intake data.

Inadequate intake of these nutrients may suggest the need for supplementation

as a way to promote bone health in children and adolescents, with the goal of

decreasing the risk for osteoporosis in adulthood. It was hypothesized that

children and adolescents with asthma would not meet the Al for calcium and

vitamin D, and that they would consume less calcium than what has been

reported in national survey data from children and adolescents of the same age.














CHAPTER 3
MATERIALS AND METHODS

Subject Description

Subjects recruited for this study were patients with asthma between 1 and

18 years of age. Subjects were recruited from the University of Florida (UF)

Pediatric Pulmonary Division during a normal clinic visit and from individuals

screened by the UF Asthma Research Lab for participation in other studies.

Subjects were excluded if they were less than 1 year of age or greater than 18

years of age; discontinued being followed by the Pediatric Pulmonary Division

prior to completing their 3-day food and supplement diary; clinically diagnosed

with CF, developmental delay, any GI disorders or diseases that affect

absorption of nutrients, milk or dairy allergy, or bone disorders; were unable to

speak and/or write in English; or were on tube feeding or intravenous feeding at

the time of recruitment.

Study Design

The study design and protocol were approved by the UF Health Science

Center Institutional Review Board. The primary objective of this study was to

estimate calcium and vitamin D intake from foods, beverages, and supplements

of children and adolescents with asthma and to compare their intake without

supplement intake with the Al set by the IOM. A second objective of this study

was to compare calcium and vitamin D intake without supplement intake of these

subjects to those of an age-matched population using survey data from the 1994









to 1996 and 1998 CSFII. To obtain this information, each participant or caregiver

completed a 3-day food and supplement diary (Appendix B) that included intake

for at least one weekend day. Subjects were recruited through advertisements,

letters, as part of outpatient clinical care and/or referral by their primary

caregiver, and through review of medical records and databases maintained by

the UF Asthma Research Lab. Patients followed by the UF Pediatric Pulmonary

Division and children that were screened for studies performed at the UF Asthma

Research Lab that met study criteria were sent a letter to determine their interest

in participating in this study. Subjects who met study criteria and attended the

UF Pediatric Pulmonary Division clinic were contacted during their clinic visit to

ascertain their interest in participating in this study. A complete explanation of

the study was given and informed consent was obtained. Subjects were given

verbal instructions for completing the food diary. Written instructions (Appendix

A) were also provided, as well as a sample 1-day food diary (Appendix A), a

portion size estimation aid with written information and pictures (Appendix A), a

3-day food diary record form (Appendix B), and a postage-paid envelope. The 3-

day food and supplement diary was returned to the study investigators in the

postage paid envelope. Subjects received follow-up phone calls, as necessary.

Individuals interested in participating who did not reside in Gainesville or did

not have an appointment scheduled in the following month were met at a location

convenient for them within the UF Health Science Center or Shands Healthcare

System (Gainesville, FL), or they were mailed two copies of the Informed

Consent Form signed by the Principal Investigator and all of the materials as









described above. A complete explanation of the study and how to complete the

food diary was given by the Principal Investigator over the phone. These

subjects received follow-up phone calls, as necessary. The subject signed one

copy of the Informed Consent Form and returned it in the postage paid envelope

with the completed 3-day food and supplement diary.

The 3-day food and supplement diary needed to be postmarked by May 31,

2004 to be included in the study, and consented subjects who had not completed

and returned the 3-day food and supplement diary were notified of this deadline

by phone at least one month in advance of the close of the study. The

completed 3-day food and supplement diary for each study participant was

manually entered and analyzed using the ESHA (version 8.1) Food Processor

software for Windows to determine the 3-day average intake for calcium, vitamin

D, calories, protein, and fat (87). The medical records of study subjects also

were reviewed to obtain information such as address, phone number, insurance,

gender, ethnicity, age, prescribed medications, BMI, and growth percentiles for

height, weight and weight-for-height, although these data were not available for

all subjects. In cases where this information was not available in the medical

record, subjects were contacted by phone to collect the information.

After the 3-day food and supplement intake diaries were returned and the

other information was collected, a $10 gift card to Target, Wal-mart, or another

national chain discount store was mailed to each participant. The results of the

3-day calcium and vitamin D intake analysis were summarized and mailed to









each subject. Average calcium and vitamin D intake was compared to the Al and

the CSFII. Other nutrient analysis information may be evaluated at a later date.

In order to protect patient confidentiality, all subject information was coded.

The code key was kept in a locked filing cabinet to minimize risk for breech of

confidentiality. The study code key will be destroyed upon completion of the final

study report.

Dietary Intake Tool and Analysis

The dietary intake tool used to enter and analyze dietary intake in this study

was ESHA Food Processor (version 8.1) for Windows (87). Food Processor 8.1

is an accurate, complete, versatile, quick, and easy-to-use diet analysis program

(88). It can be used to analyze dietary intake and compare them to

recommended standards. The data source is primarily derived from the latest

U.S. Department of Agriculture (USDA) Standard Reference database, as well as

the CSFII survey database, and data available from manufacturers, fast food

companies, and published research.

To determine the 3-day average intake of calcium and vitamin D, each 3-

day food and supplement diary was manually entered by the Principal

Investigator into Food Processor 8.1 (87). This automated program was used to

calculate the 3-day average intake of calories, protein, fat, calcium, and vitamin D

for each study subject. The average intake values for calcium and vitamin D

without supplement intake were compared with age-appropriate calcium and

vitamin D intake reported in the CSFII database and the Al.









Overview of Three-day Food Diary Method Used to Assess Dietary Intake

The dietary assessment method selected for use in this study was a 3-day

food diary. This method requires that subjects or caregivers record detailed

information about all foods and beverages consumed during a specified time

period, usually 3 to 7 days (89,90). Foods and beverages ingested are ideally

recorded at the time of consumption (91) and portion sizes are recorded based

on actual weights or measures or visual estimation (90,91). Multiple days are

usually recorded due to variation in dietary intake from day to day (91). Food

diaries are appropriate to use when the research question focuses on a select

group of nutrients or when nutrient intake is compared to a nutrient-specific

standard, such as the Al (92). Data obtained from food diaries can be used to

rank and quantify nutrient intake (91). A food diary is considered the most

accurate and precise method for dietary assessment (93) and is often used as

the "gold standard" (93-95). Ideally, this method reflects usual current intake

(93,94). Several studies have used food diaries to validate other types of dietary

assessments, such as food recalls and food frequency questionnaires (FFQs)

(91). This method is accurate and quantitative (93,94) and can be more

economical than some dietary intake methodologies because it eliminates the

need for interviewing (93). Compared to retrospective methods, estimation of

portion size is likely to be better since there is decreased reliance on memory.

Another advantage is that this method requires little adaptation for different

populations or age groups (91). In addition, incorrect statements about food

habits are less likely to occur when food diaries are used compared to interview

methods (96).









Potential drawbacks of the food diary method are that is has the potential to

be tedious and time-consuming (93), and it requires the child, adult, or caregiver

to be literate and motivated (94,95), write legibly (92), recognize and describe

quantities accurately (92,95), decipher food label information (92), and

immediately record foods and portions consumed (91,94). Much of this can be

resolved or improved with proper instruction. Disadvantages may include poor

compliance (93) and alteration of diet by subject caregiver to ease recording of

foods (93,96). An appropriate computerized database is needed for analysis of

the data and a nutritionist or appropriately trained staff is needed for instructing

subjects, checking records for accuracy, and completing the computerized

nutrient analysis (91,93,95).

Comparison of Methodologies to Assess Dietary Intake

In addition to a food diary, there are several other commonly used methods

to assess the dietary intake of individuals. These include FFQs, 24 hour recalls,

and diet histories. Twenty-four hour recalls involve recollection of all food and

beverages consumed during the previous 24 hours (90). A drawback of this

method is that it does not represent and reflect an accurate picture of habitual or

usual intake in children unless multiple recalls are obtained (91,93-95).

Food frequency questionnaires require subjects to report frequency of

consumption and sometimes portion sizes of foods and beverages from a long

list (91). This method ranks intake and cannot be used to quantify usual intake of

nutrients (91,95), and it generally overestimates intake (91). It also needs to be

culture (93,97) and population (91) specific and may lack the unique details of an

individual's diet (94,95).









Diet histories are used to "assess usual meal patterns, food intake, and

other information in an extensive 1- to 2-hour interview or questionnaire" (91,

p.493). This method, which is generally used to establish intake in the distant

past, can be costly and time consuming (96).

Several studies of older children, adolescents, and adults have provided

evidence that no one method used for dietary assessment is consistently more

accurate than the others and that underreporting often occurs (90,97,98).

Serdula et al. reviewed the available literature on validity of food recalls, food

diaries, FFQs, and diet histories in preschool children (91). The authors were

unable to form any general conclusions because of the varied study designs,

small sample sizes, and the limited number of studies examined (91).

Crawford et al. conducted a validation study with 9 to 10 year old girls to

compare 3 methods (i.e., 24-hour recall, 3-day food diary, and FFQ) against

observed intake (99). They found that the 3-day food diary had the lowest

percentage of missing food items and fewest phantom food items (i.e., foods

reported, but not observed) compared to the other methods, and it was highly

correlated with observed intake. Thus, the food agreement score (i.e., accuracy

of reporting observed intake) was the highest for the 3-day food diary. These

researchers concluded that the higher agreement score for the food diary

methodology was due to the fact it did not rely as heavily on the subjects'

memory as the other methods. The 5-day FFQ was found to consistently

overestimate intake and correlation with observed intake was low. The 24-hour

recall had an intermediate correlation with observed intake. Hill and Davies









reviewed self-reported energy intake obtained from using different dietary

assessment methods and compared these data to the results obtained using

doubly labeled water (90). They found that in studies of young children where

the parent or guardian completed the food diary, there was good agreement

between reported intake and measured energy expenditure. Finally, food diaries

have been shown to be accurate measures of intake in lean subjects up to 9

years of age, but may not be as accurate in adolescents and younger adults

where intake may be underreported by approximately 20% (100).

Overview of the 1994 to 1996, 1998 CSFII

Intake data from the 1994 to 1996, and 1998 CSFII was used as the age-

matched reference population to which data from our subjects was compared.

The CSFII is a national survey conducted by the Agricultural Research Service,

USDA to gather data on the food and nutrient intake of the U.S. population,

including the general population, as well as low-income individuals (101). The

National Nutrition Monitoring and Related Research Program uses data from this

survey and others to provide continuous monitoring of food use and consumption

to determine the dietary and nutritional status of the U.S. population. The target

population includes noninstitutionalized individuals residing in all U.S. states and

Washington, DC. The 1994 to 1996 CSFII included collection of data from

individuals of all ages and the 1998 CSFII included children from birth through 9

years of age (102). The dietary assessment method used to determine the food

and nutrient intake was a multiple-pass 24-hour recall (101). Two, in-person,

detailed twenty-four hour recalls collected 3 to 10 days apart were conducted by

well-trained interviewers. They also gathered information on vegetarianism,









supplement use, height and weight, allergies, smoking, exercise frequency,

dieting, health status, and consumption of alcoholic beverages. In addition, the

2-day dietary recall included a food list in which subjects identified foods

consumed during the past year.

Statistical Analysis

Statistical analyses were conducted using SAS version 8.02 (103) and

Microsoft Excel 2002 (104). Average age and average intake of calories, protein,

fat, calcium, vitamin D, and dairy products by age category and gender were

calculated using Microsoft Excel 2002 (104).

A power analysis was conducted to determine the sample size needed for

each age category. An alpha of 0.05, beta of 0.2, power of 0.8, and the SD from

the CSFII for each age category were used to calculate these sample sizes. The

delta value, also used to calculate these sample sizes, was based on results

from BMD studies used in establishing the Al for calcium. The delta value was

defined as the difference in milligrams of calcium that is considered to be

significantly different when comparing 2 populations. A range of delta values

were used due to the highly variable results in the studies examined. The range

for delta was determined to be 200 to 300 mg, 220 to 300 mg, and 400 to 443 mg

for the 1 to 3, 4 to 8, and 9 to 18 year old age categories, respectively. It was

determined that sample sizes of 22 to 48, 19 to 35, and 17 to 20 was were

needed to yield adequate statistical power for the 1 to 3, 4 to 8, and 9 to 18 year

old age categories, respectively.









Comparison of Dietary Intake to Al

A one-tailed small sample t-test was used to compare the 3-day average

calcium intake without supplements and the 3-day average vitamin D intake

without supplements to the recommendations set by the IOM for each age

category (22). The study sample size was small and the true population SD was

unknown, so the t-distribution rather than the standard normal z-distribution was

used for comparisons of average intake to the Al.

Comparison of Dietary Intake to 1994 to 1996, 1998 CSFII

A one-tailed large sample z-test was used to compare the difference in

mean intake of calcium without supplement intake of the study subjects to the

age-matched CSFII population. A two-tailed large sample z-test was used to

compare the difference in mean dairy intake of the study subjects to the age-

matched CSFII population. The sample size in this study was extremely small

compared to that of the CSFII, so the CSFII mean more likely reflected the true

population mean than the mean of the study sample. The population (i.e., CSFII)

SD was known, so the standard normal z-distribution was used for these


comparisons.














CHAPTER 4
RESULTS

Subjects


Demographics

Eighty-four subjects (i.e., 56 males, 28 females) enrolled in the study and

36 subjects (i.e., 26 males, 10 females) completed and returned a food and

supplement diary. The number of male and female subjects in each category

and the number of males and females who completed the food and supplement

diary are listed in Table 6. The average age of subjects who completed the study

Table 6. Number of subjects who enrolled and completed the study and percent
return rate by age category and gender.
Age
category Number
(years) Gender enrolled Number completed % Return rate
1 to 3 All 22 9 40.9%
Males 19 9 47.4%
Females 3 0 0.0%
4 to 8 All 27 14 51.9%
Males 15 9 60.0%
Females 12 5 41.7%
9 to 18 All 35 13 37.1%
Males 22 8 36.4%
Females 13 5 38.5%
Total All 84 36 42.9%
Males 56 26 46.4%
Females 28 10 35.7%

by age category was 2.5 years, 6.4 years, and 13.9 years in the 1 to 3 year old, 4

to 8 year old, and 9 to 18 year old age categories, respectively. Due to new









restrictions on health information, race was not obtained for study subjects.

Reasons for not completing the study that were relayed by some of the subjects'

caregivers were that they were too busy, it was too difficult to arrange

cooperation with the daycare to record food intake, or they didn't wish to

complete the 3-day food and supplement diary.

Dietary Intake of Calories, Protein, and Fat

Mean dietary intake of calories, protein, and fat are presented in Table 7.

Subjects in the 1 to 3 year old age group consumed a 3-day mean intake of

1,616 calories, 58 g of protein, and 57 g of fat. Subjects in the 4 to 8 year old

age group consumed a 3-day mean intake of 1,994 calories, 72 g of protein, and

75 g of fat. Subjects in the 9 to 18 year old age group consumed a 3-day mean

intake of 2,285 calories, 87 g of protein, and 91 g of fat.

Table 7. Three-day dietary intake of calories, protein, and fat by study subjects.

Age
category Calories* Calories Protein* Protein Fat*
(years) Gender (kcals) (% of AI) (g) (% of AI) (g)
1 to3 Both 1,616 251 118% 58 15 360% 57 18
Males 2,214 625 112% 78 26 322% 85 35
4 to 8 Females 1,598 458 87% 63 12 279% 58 27
Both 1,994 631 N/A 72 23 N/A 75 34
Males 2,573 835 94% 92 30 167% 102 43
9 to 18 Females 1,824 + 479 78% 78 31 156% 74 26
Both 2,285 793 N/A 87 30 N/A 91 39
*Values represent mean SD.
N/A = not applicable

Dietary Intake of Calcium and Vitamin D

Three subjects consumed a calcium-containing supplement during the 3-

day recording period, 1 subject in the 1 to 3 year old group and 2 subjects in the

4 to 8 year old group. The mean dietary intake of calcium by gender and age









categories are presented in Table 9. The mean 3-day dietary intake of calcium in

the 1 to 3 year old age group was 891 mg (178% Al) not including supplement

intake and 899 mg (180% Al) including supplement intake. The mean 3-day

dietary intake of calcium in the 4 to 8 year old age group was 883 mg (110% Al)

not including supplement intake and 888 mg (111% Al) including supplement

intake. The mean 3-day dietary intake of calcium in the 9 to 18 year old group

was 973 mg (75% Al).

Mean dietary intake of vitamin D by age and gender categories are

presented in Table 9. Mean 3-day dietary intake of vitamin D in the 1 to 3 year

old age group was 209 IU (5.2 mcg; 104% Al) not including supplement intake

and 239 IU (5.9 mcg; 119% Al) including supplement intake. Mean 3-day dietary

intake of vitamin D in the 4 to 8 year old age group was 180 IU (4.5 mcg; 90% Al)

and 227 IU (5.7 mcg; 114% Al) not including supplement intake and including

supplement intake. Mean 3-day dietary intake of vitamin D in the 9 to 18 year old

group was 198 IU (4.96 mcg; 99% Al).

Comparison of Dietary Calcium and Vitamin D Intake to the Al

The one-tailed small sample t-test was used to compare the calcium and

vitamin D intake of study subjects to the Al based on age and gender. The 3-day

mean dietary calcium intake without supplements for the 1 to 3 year old group

was significantly greater than the Al (p = 0.001) (Figure 1). The 3-day mean

dietary calcium intake for the 9 to18 year old age group was significantly lower

than the Al (p = 0.02). No significant difference was detected between the 3-day

mean dietary calcium intake and the Al for the 4 to 8 year old age group. No








significant differences were detected between the 3-day mean dietary vitamin D

intake and the Al for all age groups (Figure 2).

Comparison of Dietary Calcium Intake to 1994 to 1996, 1998 CSFII

The one-tailed large sample z-test was used to compare the mean calcium

Table 8. Calcium intake of children and adolescents with asthma compared to
the Al by age category.
Calcium intake*
(mg) Al Test of
(% of AI) (mg) equal mean
Age Mean p-value
category
(years)
1 to 3 890 244
500 0.001
(n = 9) (178%)
4 to 8 883 359
800 0.200
(n = 14) (110%)
9 to 18 973 517
1300 0.021
(n = 13) (75%)
*Values represent mean SD.


p = 0.021


1500

E

S1000


S500
=lOO


AI
m Asthma


1 to 3 4 to 8 9 to 18
Age groups (years)

Figure 1. Calcium intake of study subjects (asthma) compared to the Al by age
group.








Table 9. Vitamin D intake of children and adolescents with asthma compared to
the Al by age category.
Vitamin D intake*
(mcg) Al Test of
(% of AI) (mcg) equal mean
Age Mean p-value
category
(years)
1 to 3 5.19 2.43
5.0 0.412
(n = 9) (104%)
4 to 8 4.49 2.32
5.0 0.213
(n = 14) (90%)
9 to 18 4.96 3.71
5.0 0.484
(n = 13) (99%)
*Values represent mean SD.


-5 9
o)

07


. 5

r 3
E
S1


- Asth ma


1to3 4to8 9to18
Age groups (years)

Figure 2. Vitamin D intake of study subjects (asthma) compared to the Al by age
group.

intake of study subjects to data from the 1994 to 1996 and 1998 CSFII. The 3-

day mean dietary calcium intake of study subjects in the 1 to 3 year old age

category was significantly (p = 0.001) less than the mean dietary calcium intake

of the age-matched reference population (i.e., CSFII) (Table 10 and Figure 3),









although the mean intake for both groups exceeded the Al. No significant (p >

0.05) differences in mean dietary calcium intake between the study subjects and

the age-matched reference population were detected in any other age category.

The two-tailed chi-square test was used to compare the variance of the

mean calcium intake of study subjects to the variance of the age-matched

reference population. The variance of the mean calcium intake of study subjects

in the 9 to 18 year old age category was significantly different than the variance

of the mean calcium intake of the age-matched reference population (Figure 4).

No significant differences were detected in the variance of the mean for calcium

intake of the subjects compared to the age-matched reference population in the

remaining age categories.

Table 10. Calcium intake of study subjects (asthma) compared to CSFII by age
group .
Calcium intake* Test of Test of
(mg) equal mean equal variance
Age CSFII Asthma p-value p-value
category
(years)
1297 + 397 891 + 244
1 to 3 397 891 0.001 0.934
(n = 4,027) (n=9)
721 + 99 883 + 359
4 to 8 883359 1.000 0.188
(n = 3,935) (n = 14)
392 + 110 973 + 517
9 to 18 92110 9 17 1.000 <0.001
(n = 2130) (n = 13)
*Values represent mean SD.

Intake of Milk and Milk Products

Intake of dairy products was determined based on the categories used for

the CSFII (Appendix C). The percent of total calcium intake from several dairy










2000 p = 0.001
a


1500

1000

500


- CSFII
m Asthma


1to3 4 to 8 9 to 18
Age groups (years)

Figure 3. Calcium intake of study subjects (asthma) compared to CSFII by age
group.


u,



O
o
o

(I-


m


p < 0.001


-- CSFII
- Asthma


S1 to3 4to8 9to18
Age groups (years)

Figure 4. Variance from the mean calcium intake of study subjects (asthma)
compared to CSFII by age group.
product categories by age are expressed in Table 11. Mean dietary intake for

each dairy product category by age and gender are presented in Tables 12 to 20.


I









Table 11. Calcium intake and percent of total calcium intake from dairy product
categories.
Calcium intake*
(mg)
(% of total)

Age Total Total milk & Total milk, Milk Cheese
category calcium milk products milk drinks, desserts
(years) intake and yogurt
(mg)
1 to 3 572 238 456 247 31 47 86 85
891 64.2% 51.2% 3.4% 9.6%
4 o 8 543 290 386 284 71 75 84 85
883 61.4% 43.7% 8.0% 9.5%
136
9 to 18 535 417 378 361 20 39 128
973 55.0% 38.8% 2.0% 14.0%
103
1 to 18 547 323 401 299 42 60 120
918 59.6% 43.7% 4.6% 11.2%
*Values represent mean SD.

Comparison of Milk and Milk Products Intake to 1994 to 1996, 1998 CSFII

The two-tailed large sample z-test was used to compare the 3-day mean

dietary intake of various categories of dairy products of the study subjects to the

age-matched reference population. No significant differences were detected

between the intake of study subjects compared to the age-matched reference

population for any of the dairy product categories for any of the age categories

(Figures 5 to 13).






63

Table 12. Total milk and milk products intake of study subjects (asthma)
compared to CSFII by age group.
Total milk and milk
products intake* Test of
(g) equal mean
Age CSFII Asthma p-value
category
(years)
438 324 423 200
1 to 3 0.444
(n= 11,737) (n =9)

4 o 409 279 391 245
4 to 8 0.405
(n = 11,473) (n =14)
9to362 345 386 336
9 to 18 0.595
S(n = 6,204) (n =13)
*Values represent mean SD.


1 to 3 4 to 8 9 to 18
Age groups (years)

Figure 5. Total milk and milk products intake by study subjects (asthma)
compared to CSFII by age group.


S CSFII
m Asthma


4 )

*0 0
C1

I- Q.
m
E









Table 13. Total milk,
compared


800


milk drinks, and yogurt intake of study subjects (asthma)
to CSFII bv ane around


- CSFII
m Asthma


1to3 4 to 8 9 to 18
Age groups (years)


Figure 6. Total milk, milk drinks, and yogurt intake by study subjects (asthma)
compared to CSFII by age group.


v


- .. I -j -*_i- _r,--*i-*----------------
Total milk, milk drinks, and
yogurt intake* Test of
(g) equal mean
Age CSFII Asthma p-value
category
(years)
411 322 384 208
1 to 3 0.397
(n= 11,737) (n =9)

4t8 367 271 321 241 2
4 to 8 0.261
(n = 11,473) (n = 14)
313 353 334 335
9 to 18 0.583
(n = 6,204) (n =13)
*Values represent mean SD.









intake of study subjects (asthma) compared to CSFII by


a


E CSFII
m Asth ma


1to3 4 to 8 9 to 18
Age groups (years)

Figure 7. Total fluid milk intake by study subjects (asthma) compared to CSFII by
age group.


ge group.

Total fluid milk intake* Test of
(g) equal mean
Age CSFII Asthma p-value
category
(years)
374 317 289 172
1 to 3 0.212
(n= 11,737) (n=9)
4t8 315 259 263 247 .
4 to 8 0.227
(n = 11,473) (n = 14)
263 308 269 300
9 to 18 0.528
S(n = 6,204) (n =13)
*Values represent mean SD.


Table 14. Total fluid milk








Table 15. Whole milk intake of study subjects (asthma) compared to CSFII by
age group.

Whole milk intake* Test of
(g) equal mean
Age CSFII Asthma p-value
category
(years)
221 313 198 177
1 to 3 0.417
(n = 11,737) (n=9)
4 8 125 211 139 234 0
4 to 8 0.603
(n = 11,473) (n =14)
89 204 138 233
9 to 18 0.805
S(n = 6,204) (n =13)
*Values represent mean SD.


600

500
400

300
200

100

0


-- CSFII
SAsthma


1to3 4 to 8 9 to 18
Age groups (years)

Figure 8. Whole milk intake by study subjects (asthma) compared to CSFII by
age group.









Table 16. Lowfat milk intake of study subjects (asthma)
aae ground


compared to CSFII by


N CSFII
SAsthma


1 to 3 4 to 8 9 to 18
Age groups (years)

Figure 9. Lowfat milk intake by study subjects (asthma) compared to CSFII by
age group.


Lowfat milk intake* Test of
(g) equal mean
Age CSFII Asthma p-value
category
(years)
132 238 55 125
1 to 3 0.164
(n = 11,737) (n =9)

4t8 156 232 76 137 0.
4 to 8 0.099
(n = 11,473) (n = 14)
136 + 257 75 + 245
9 to 18 257 750.195
(n = 6,204) (n 13)
*Values represent mean SD.








Table 17. Skim milk intake of study subjects (asthma) compared to CSFII by age
group.

Skim milk intake* Test of
(g) equal mean
Age CSFII Asthma p-value
category
(years)
15 + 88 36 + 56
1 to 3 88 3656 0.764
(n = 11,737) (n =9)
25 + 75 45 + 79
4 to 8 25750.839
(n = 11,473) (n = 14)
35 + 135 38 + 136
9 to 18 35135 38136 0.532
(n = 6,204) (n 13)
*Values represent mean SD.


180
160- CSFII
160
S140- M Asthma
S120-
.S 100
80o
E 60-
.E 40
Cn 20
0-
1to3 4 to8 9 to 18
Age groups (years)

Figure 10. Skim milk intake by study subjects (asthma) compared to CSFII by
age group.






69

Table 18. Yogurt intake by study subjects (asthma)
groun


5

4S

.S 3

2

> 1


compared to CSFII by age


- CSFII
Asthma

x = no yogurt intake


1 to 3 4 to 8 9 to 18
Age groups (years)

Figure 11. Yogurt intake by study subjects (asthma) compared to CSFII by age
group.


Yogurt intake* Test of
(g) equal mean
Age CSFII Asthma p-value
category
(years)
11 +41 4+13
1 to 3 0.312
(n= 11,737) (n=9)
7 + 34 12 + 25
4 to 8 34 10.702
(n = 11,473) (n = 14)
4+30 0+0
9 to 18 0.305
S(n = 6,204) (n =13)
*Values represent mean SD.


^









Table 19. Milk desserts intake of study subjects (asthma) compared to CSFII by
age group.
Milk desserts intake* Test of
(g) equal mean
Age CSFII Asthma p-value
category
(years)
16 + 41 27 + 41
1 to 3 1641 2741 0.794
S(n = 11,737) (n =9)
27 + 59 55 + 64
4 to 8 0.960
(n = 11,473) (n = 14)
30 + 81 20 37
9 to 18 0.316
(n = 6,204) (n = 13)
*Values represent mean SD.


"- -- CSFII
S100- m Asthma

80-
60-

Cl 40-

S20-

1 to 3 4 to 8 9 to 18
Age groups (years)

Figure 12. Milk dessert intake by study subjects (asthma) compared to CSFII by
age group.









Table 20. Cheese intake of study subjects (asthma) compared to CSFII by age
group.
Cheese intake* Test of
(g) equal mean
Age CSFII Asthma p-value
category
(years)
11 + 22 13 + 12
1 to 3 1122 1312 0.610
(n = 11,737) (n =9)
13 + 27 14 + 23
4 to 8 1327 140.587
(n = 11,473) (n = 14)
16 + 35 24 + 21
9 to 18 1635 240.797
(n = 6,204) (n = 13)
*Values represent mean SD.


--CSFII
5 Asthma
45-


30





1to3 4 to 8 9 to 18
Age groups (years)

Figure 13. Cheese intake by study subjects (asthma) compared to CSFII by age
group.














CHAPTER 5
DISCUSSION AND CONCLUSIONS

Adequate calcium and vitamin D intake is important during childhood and

adolescence to promote adequate bone mineralization and achievement of PBM

(22,45-48,56). Inadequate intake of these nutrients increases the risk for

osteoporosis (22). Milk and dairy products are good dietary sources of calcium

and vitamin D. Children and adolescents with asthma may be at risk for

osteoporosis for several reasons, one of which may be related to inadequate

calcium and vitamin D intake due to the restriction or avoidance of milk and dairy

products intake. Parents of children with asthma and adults with asthma have

been reported to avoid these foods due to the unfounded belief that they worsen

or contribute to asthma symptoms (6,7). This could have a negative impact on

bone density, especially in a population that is already at risk due the use of

certain medications that may negatively influence bone density, as well as the

tendency to restrict the frequency and type of physical activity in an effort to

avoid wheezing and other asthma symptoms (2,8,9).

The objectives of this study were to determine the adequacy of calcium and

vitamin D intake of children and adolescents with asthma using a 3-day food and

supplement diary and to compare their intake of these nutrients to an age-

appropriate Al. Another objective was to determine if calcium and milk and dairy

products intake of children and adolescents with asthma are less than those of

an age-matched reference population.









After reviewing the published research, only one study examining dietary

intake of calcium and dairy products in individuals with asthma was identified.

This study was conducted in adults. The researchers found that consumption of

certain types of dairy products, such as whole milk, butter, ricotta cheese, and

low-fat cheese, were different in adult subjects with asthma compared to those

without asthma, but there was no difference in the overall intake of dairy products

and nutrients, including calcium, between the groups (86).

A total of 84 subjects (i.e., 56 males, 28 females) were enrolled in the study;

however only 36 (i.e., 26 males, 10 females) returned the 3-day food and

supplement diary for an overall return rate of 42.9%. The return rates by age

categories were 40.9%, 51.9%, and 37.1% for the 1 to 3 year old, 4 to 8 year old,

and 9 to 18 year old age categories, respectively. Our return rate was relatively

consistent with the dietary intake survey conducted by mail with adults diagnosed

with asthma, in which the overall response rate was 36% (86). It is possible that

the 9 to 18 year old age group had the lowest return rate because of greater

independence from parental guidance, related to a higher level of reading and

writing skills. In contrast, the younger age groups required parental assistance

with this task, which may have increased the return rate.

Currently, there are no published data on calcium and vitamin D intake in

children and adolescents with asthma. Data from our study indicated that the 3-

day mean dietary calcium intake for the 1 to 3 year old group was significantly

greater than the Al for this nutrient (p = 0.001), but significantly less than the

mean dietary calcium intake of the age-matched reference population (i.e.,









CSFII) (p = 0.001). Despite our efforts to recruit as many subjects as possible

and to increase return rate, the sample size for the 1 to 3 year old age category

did not have adequate statistical power. This also is true for the 4 to 8 year old

and the 9 to 18 year old age categories and this is important to keep in mind for

those comparisons in which a significant difference was not detected.

No significant differences in the 3-day mean dietary calcium intake for the 4

to 8 year old children with asthma compared to the Al and the age-matched

reference population were detected in our study. This suggests that children with

asthma in this age group are meeting their needs for calcium and are consuming

amounts of calcium similar to non-asthmatic children. In addition, children with

asthma between the ages of 4 and 8 years consumed approximately 61% of their

calcium from milk and dairy products. These results differ from reports of milk

and dairy products avoidance in children with asthma (6,7). In the general

population of children, adolescents, and adults, as estimated from data from the

1994 to 1996 and 1998 CSFII and the NHANES III, milk and dairy products are

major sources of dietary calcium, accounting for 48% of calcium intake (44). In

children and adolescents between the ages of 1 and 18 years, as estimated from

the 1994 to 1996 and 1998 CSFII, dairy foods and ingredients contribute to

approximately 62% of calcium intake (35). This suggests that children with

asthma between the ages of 4 to 8 years are generally consuming a similar

amount of calcium from milk dairy products as children without asthma and thus

are not avoiding or eliminating milk and dairy products due to their asthma.









In the 9 to 18 year old age group, the 3-day mean dietary calcium intake for

our study population was significantly lower than the Al (p = 0.02), but not

significantly different from the age-matched reference population. This finding

suggests that all children and adolescents between the ages of 9 and 18 years,

regardless of whether they have asthma, are not consuming adequate amounts

of dietary calcium to promote optimal bone health. In addition, children and

adolescents with asthma between the ages of 9 and 18 years consumed

approximately 55% of their calcium from milk and dairy products. These results

differ from reports of milk and dairy products avoidance in children and

adolescents with asthma (6,7). It has been estimated that children, adolescents,

and adults, consume approximately 48% of their calcium from milk and dairy

products and specifically children and adolescents consume 62% of their calcium

from dairy foods (35,44). This suggests that children with asthma between the

ages of 9 to 18 years are generally consuming a similar amount of calcium from

milk dairy products as children without asthma and thus are not avoiding or

eliminating milk and dairy products due to their asthma.

The inadequate dietary calcium intake observed in 9 to 18 year old children

and adolescents in this study is consistent with reports of milk intake patterns in

this age group. Mean intake of milk decreases 38% from 1 to 18 years of age

and is due to the dramatic increase in soft drink consumption that begins around

8 years of age (105). Intake of soft drinks exceeds that of milk by 13 years of

age. This is important because dietary calcium intake during childhood and

adolescence is positively associated with bone density throughout adulthood









(22,45-48). As a result of the inadequate dietary calcium intake observed in this

study, children with asthma between the ages of 9 and 18 years may be at risk

for low bone density and poor bone health in adulthood.

In addition to calcium, vitamin D intake also was analyzed for each of the 3

age groups. No significant differences were detected between the 3-day mean

dietary vitamin D intake and the Al for any of the age categories. The database

(Food Processor 8.1 for Windows) (87) used to analyze the 3-day food and

supplement diaries does not have complete data for the vitamin D content of

foods, so it is possible that the actual vitamin D intake of our study population

was higher than reflected by our data. The findings of our study suggest that

children and adolescents with asthma between the ages of 1 and 18 years are

consuming adequate amounts of vitamin D to promote bone health.

Another aim of our study was to examine dairy intake in our population.

Currently, there are no published studies that have reported dairy products intake

in children and adolescents with asthma, but there is one study that reported the

intake of dairy products in adults with asthma. Woods et al. found that overall

intake of dairy products was not significantly different between adults with and

without asthma, although the types of dairy products consumed by these 2

groups were significantly different (86). Specifically, asthma was negatively

associated with whole milk and butter consumption and positively associated with

ricotta and low-fat cheese in adults with asthma. Similarly, no significant

difference in total milk and milk products intake of children and adolescents with

asthma and the age-matched reference population was detected in our study, but









a significant difference was not detected in the types of dairy products consumed

by children and adolescents with asthma compared to the age-matched

reference population for each of the age categories.

There are several potential clinical applications extending from our

research. Health care professionals, such as dietitians, pediatricians,

pulmonologists, and nurses, as well as dietitians in community settings who

provide services to children and adolescents with asthma should promote

adequate consumption of calcium- and vitamin D-containing foods such as milk

and dairy products in this population, especially in children between the ages of 9

and 18 years. If milk or dairy products need to be avoided due to the lack of

tolerance, a disease that necessitates restriction of milk or dairy, or for other

reasons (e.g., lack of acceptance, religious beliefs, health beliefs, etc.), health

professionals should recommend suitable calcium-containing foods and/or a

supplement.

Although this study provides preliminary data on the dietary intake of

calcium, vitamin D, and dairy products in children with asthma, a larger study is

needed to confirm our findings. A large, multi-center study may be needed to

accomplish this goal. Researchers also could examine the relationship between

dietary calcium, vitamin D, and dairy products intake in relation to BMD in

children and adolescents with asthma, while controlling for other factors that may

influence BM such as physical activity and medications.

In summary, this study compared dietary calcium and vitamin D intake of

children and adolescents with asthma to the age-appropriate Als and to survey









data from an age-matched reference population. The results of this study, which

indicated that 1 to 3 and 4 to 8 year old children with asthma met or exceeded

the Al for calcium and vitamin D and 9 to 18 year old children and adolescents

with asthma consumed less than the Al for calcium have potential clinical

applications. Although 9 to 18 year old children and adolescents with asthma

consumed less than the Al for calcium, their intake paralleled that of intake data

from a national survey. The level of calcium intake from milk and dairy products

that was consumed by children and adolescents in our study was similar to the

level of intake estimated for the general population. This suggests that in our

small study population, individuals with asthma do not avoid or restrict their

intake of dairy products; however there is still a need to focus on encouraging

adequate intake of calcium- and vitamin D-containing foods such as milk and

dairy products, especially in 9 to 18 year old children and adolescents. The

results from this study are novel because this is the first study to examine the

dietary intake of calcium and vitamin D in children and adolescents with asthma

and will pave the way for future studies.














APPENDIX A
THREE-DAY FOOD AND SUPPLEMENT DIARY DIRECTIONS

*Please record everything your child consumes for 3
days, including foods, beverages, and supplements.

1. Please select three days, including one weekend day (Friday, Saturday, or
Sunday).

2. Please record the foods, beverages, and supplements you consume and
the amounts of each that you consume as soon after eating as possible.
This prevents you from forgetting foods, or over- or under- estimating what
you have consumed.

3. In the column labeled "Foods, Beverages, and Supplements
Consumed" record what you ate. Please be as specific as possible. For
example, if you consumed milk: indicate skim, 1%, 2%, or whole. If you
consumed cereal, indicate what kind of cereal. If you consumed bread,
indicate what kind of bread (white, wheat, rye, oat bran, etc.). Don't forget
to include condiments, such as catsup, mustard, jelly, salad dressing,
sauces, etc.

For example:
Foods, Beverages, Description Amount Consumed
Supplements
Consumed
Milk 1% low fat 1 cup
Cornflakes Kellogg's 1 12 cups
Bread Publix honey wheat 1 slice
Jelly (on bread) Smucker's strawberry 1 teaspoon
jam
Sugar (on cereal) White granulated 2 teaspoons

4. In the column labeled "Description" please list the brand name and give
a product description or include the product label or recipe whenever
possible. Tell how the food was cooked (fried, baked, etc). If you ate
away from home, list the name of the restaurant or food shop. Be sure to
include information about things that you add to your food before you eat
it, like margarine, salt, sugar, milk, etc. Please refer to the example above.






80


5. In the column labeled "Amount Consumed" please list the amount of
each food, beverage or supplement you consume. Tell how many cups,
ounces (oz), teaspoons (tsp), tablespoons (tbsp) you eat or the weight or
number of portions or pieces you eat.

6. A sample food diary is included on the next page to help you.

7. When you have completed the diary, please return in the postage-paid
stamped envelope that has been provided.









Sample:


Foods, Beverages,
Supplements
Consumed
List each food,
beverage or
supplement you
consume. List only
one item per line.


Description

List the brand name and
product description or
include the product label or
recipe for everything you
eat. Tell how the food was
cooked (fried, baked, etc). If
you ate away from home,
list the name of the
restaurant or food shop. Be
sure to include information
about things that you add to
your food before you eat it,
like margarine, salt, sugar,
milk, etc


Amount Consumed

List the amount of each
food, beverage or
supplement you consume.
Tell how many cups,
ounces (oz), teaspoons
(tsp), tablespoons (tbsp)
you eat or the weight or
number of portions or
pieces you eat.


Corn Flakes Kellogg's brand 1 cup
Milk 2% 1/2 cup
Banana Small 1
Turkey Baked 2 oz.
Bread whole wheat, toasted 2 slices
Mayonnaise Hellmann's brand-Light 1 tsp.
Tomato 2 slices
Apple With skin
Pepsi, can 12 oz.
Ice cream Albertson's brand 1 cup
Chicken Breast Grilled, no skin 3 oz.
Green beans Canned, prepared with 1 1/ cup
tbsp. butter and 1 tsp. salt
Rice White, Boiled 1 cup
Apple pie Store bought, bakery 1/5 pie
Children's multivitamin Flintstone's Brand 1


1 cup = 8 fluid ounces (8 fl. oz.) = 237 ml
3 teaspoons = 1 tablespoon
4 tablespoons = 1/4 cup
1 oz. = 28 g (grams)


I I









Estimating Portion Sizes


3 ounces of meat, poultry, or
fish is about the size and
thickness of a deck of playing
cards


A medium-size piece of fruit
(e.g., apple or peach) is about
the size of a tennis ball


1 ounce of cheese is about the
size of 4 dice


2 cup ot ice cream, trozen
yogurt, yogurt, or cottage
cheese is about the size of a
tennis ball


1 cup of mashed potatoes or
broccoli is about the size of
your fist


1 teaspoon of butter,
margarine, or peanut butter is
about the size of the tip of your
thumb


- 0 aD,
01 0100


Adapted from: Southern Illinois University Carbondale Wellness Center Nutrition
Program. 3-day recall. Available at:
http://www.siu.edu/-shp/Acrobat2002/Recall.pdf. Accessed February 2002.














APPENDIX B
THREE-DAY FOOD AND SUPPLEMENT DIARY FORM











Name:


3-day Food and Supplement Diary


Day 1


Foods, Beverages and Supplements
Consumed
List each food, beverage or supplement
you consume. List only one item per line.


Description
List the brand name and product
description or include the product label or
recipe for everything you eat. Tell how the
food was cooked (fried, baked, etc). If you
ate away from home, list the name of the
restaurant or food shop. Be sure to include
information about things that you add to
your food before you eat it, like margarine,
salt, sugar, milk, etc.


Amount Consumed
List the amount of each food,
beverage or supplement you
consume. Tell how many
cups, ounces (oz), teaspoons
(tsp), tablespoons (tbsp) you
eat or the weight or number of
portions or pieces you eat.











Name:


3-day Food and Supplement Diary


Day 2


Foods, Beverages and Supplements
Consumed
List each food, beverage or supplement
you consume. List only one item per line.


Description
List the brand name and product
description or include the product label or
recipe for everything you eat. Tell how the
food was cooked (fried, baked, etc). If you
ate away from home, list the name of the
restaurant or food shop. Be sure to include
information about things that you add to
your food before you eat it, like margarine,
salt, sugar, milk, etc.


Amount Consumed
List the amount of each food,
beverage or supplement you
consume. Tell how many
cups, ounces (oz), teaspoons
(tsp), tablespoons (tbsp) you
eat or the weight or number of
portions or pieces you eat.