Kathleen M. Hill

Serum Leptin, Parathyroid Hormone, 1,25-Dihydroxyvitamin D, Fibroblast Growth Factor 23, Bone Alkaline Phosphatase, and Sclerostin Relationships in Obesity

BACKGROUND Obesity is associated with hyperparathyroidism and increased bone mass and turnover, but their pathogeneses are unclear. AIMS Our aim was to determine in obesity interrelationships among serum levels of leptin, the mineral-regulating hormones, bone turnover markers, and sclerostin. METHODS This case-control study was performed in 20 women having bariatric surgery and 20 control women matched for race and age. Anthropometrics and fasting serum biochemistries were measured in controls and in bariatric patients the morning of surgery. RESULTS Body mass index (48.9 vs. 25.4 kg/m(2)), weight (128.6 vs. 71.9 kg), serum leptin (74.6 vs. 25.2 ng/ml), PTH (44.5 vs. 28.8 pg/ml), fibroblast growth factor 23 (FGF23) (42.4 vs. 25.9 pg/ml), and bone alkaline phosphatase (BAP) (25.8 vs. 17.5 U/liter) were higher, but height (162.3 vs. 167.7 cm) and 1,25-dihydroxyvitamin D (1,25D) (39.2 vs. 48.7 pg/ml) were lower in bariatric surgery patients than controls. There was no difference in serum sclerostin, amino-terminal collagen cross-links, 25-hydroxyvitamin D (25D), calcium, phosphate, and creatinine between groups. In the combined sample, leptin was positively related to PTH, FGF23, and BAP but not to 1,25D or sclerostin. Multiple regression analysis demonstrated that PTH was predicted by leptin and Ca (R(2) = 0.39); 1,25D by 25D, FGF23, and phosphate (R(2) = 0.43); FGF23 by leptin and 1,25D (R(2) = 0.27); BAP by leptin, PTH, and Ca (R(2) = 0.39); and sclerostin by leptin and PTH (R(2) = 0.20). CONCLUSIONS Women having bariatric surgery had higher leptin, PTH, FGF23, and BAP and lower 1,25D than controls. Leptin predicted the serum levels of PTH, 1,25D, and FGF23, the mineral-regulating hormones, and BAP, a bone formation marker, in women with body mass index ranging from 13.9-65.8 kg/m(2). The results suggest that leptin has an endocrine or paracrine effect on PTH and FGF23 production and that PTH may be one of the signals in obesity that leads to increased bone mass.

An Inflection Point of Serum 25-Hydroxyvitamin D for Maximal Suppression of Parathyroid Hormone Is Not Evident from Multi-Site Pooled Data in Children and Adolescents

In adults, maximal suppression of serum parathyroid hormone (PTH) has commonly been used to determine the sufficiency of serum 25-hydroxyvitamin D [25(OH)D]. In children and adolescents, the relationship between serum 25(OH)D and PTH is less clear and most studies reporting a relationship are derived from relatively small samples and homogeneous cohorts. Our objective was to determine the relationship between serum 25(OH)D and PTH in children and adolescents from a large and diverse U.S. cohort and to identify a point of inflection of serum 25(OH)D for maximal suppression of serum PTH. Data from 735 participants, ages 7-18 y, were pooled from 3 study sites located in Indiana, Texas, and Massachusetts. A two-phase linear spline was used to model the relationship between serum 25(OH)D and PTH. The value of serum 25(OH)D for maximal suppression of serum PTH was identified as the inflection point of the spline. Before adjustment for site, the inflection point of serum 25(OH)D for maximal suppression of serum PTH was 92.4 nmol/L (95% CI: 62.2, 130.7). After adjusting for site, the point of inflection was poorly defined and the relationship between serum 25(OH)D and PTH appeared to be linear. The lack of an inflection point of serum 25(OH)D for maximal suppression of PTH brings into question the value of using maximal suppression of serum PTH as a basis for determining optimal serum 25(OH)D for healthy children and adolescents.

Predictors of calcium retention in adolescent boys

CONTEXT The relationship between calcium (Ca) intake and Ca retention in adolescent boys was recently reported. OBJECTIVE This study evaluated the influence of Ca intake, serum hormone levels, biomarkers of bone metabolism, habitual physical activity, habitual Ca intake, and physical fitness on Ca retention in the same sample. DESIGN This study was a randomized, cross-over design that consisted of two 3-wk metabolic balance periods. SETTING The study took place on a university campus as a summer camp. PATIENTS OR OTHER PARTICIPANTS A total of 31 American white boys (13-15 yr) participated in the study. INTERVENTIONS Each subject consumed a controlled diet with one of five high-low Ca intake pairs that ranged from 670-2003 mg/d, which was manipulated utilizing a fortified beverage. MAIN OUTCOME MEASURES Ca retention was determined by Ca intake minus urinary and fecal Ca excretion during each balance period. RESULTS Ca intake explained 21.7% of the variability in Ca retention, and serum IGF-I concentration explained an additional 11.5%. Other serum hormone levels did not significantly add to the model. Biomarkers of bone metabolism, habitual physical activity, habitual Ca intake, and physical fitness were not significant predictors of Ca retention in adolescent boys. CONCLUSIONS IGF-I, a regulator of growth during puberty, is an important predictor of Ca retention in adolescent boys. However, dietary Ca intake is an even greater predictor of Ca retention during this period of growth.

Daily Supplementation with 25 μg Cholecalciferol Does Not Increase Calcium Absorption or Skeletal Retention in Adolescent Girls with Low Serum 25-Hydroxyvitamin D

In healthy adolescents, cross-sectional studies show either no or negative relationships between serum 25-hydroxyvitamin D [25(OH)D] and calcium (Ca) absorption. Using a 2-period metabolic balance study, the effect of vitamin D supplementation on Ca absorption and retention in adolescent girls was investigated. Eleven girls aged 12-14 y with a mean entry serum 25(OH)D of 35.1 nmol/L consumed a controlled intake (providing 5 μg vitamin D and 1117 mg Ca/d) for two 3-wk metabolic balance periods separated by a 1-wk washout period. Sunlight exposure was minimized by sunscreen with a sun protection factor ≥ 15. After the first metabolic balance period, participants received 25 μg/d cholecalciferol supplementation for 4 wk. Fractional Ca absorption was measured in each metabolic balance period using a stable Ca isotope method. All urine and fecal samples were collected and analyzed to measure net Ca absorption and Ca retention. Paired t tests and correlations were used to analyze the data. Daily supplementation with 25 μg vitamin D resulted in a mean increase in serum 25(OH)D of 13.3 nmol/L (P < 0.01) but a decrease in fractional Ca absorption of 8.3% (P < 0.05) and no significant change in fasting serum 1,25-dihydroxyvitamin D, parathyroid hormone, net Ca absorption, or Ca skeletal retention. In pubertal girls with vitamin D status considered insufficient in adults, vitamin D supplementation of 25 μg/d for 4 wk did not improve fractional Ca absorption, net Ca absorption, or Ca retention.

Top Food Sources Contributing to Vitamin D Intake and the Association of Ready‐to‐Eat Cereal and Breakfast Consumption Habits to Vitamin D Intake in Canadians and United States Americans

UNLABELLED This study aimed to determine dietary vitamin D intake of U.S. Americans and Canadians and contributions of food sources to total vitamin D intake. Total of 7- or 14-d food intake data were analyzed for vitamin D by a proprietary nutrient assessment methodology that utilized food intake data from the Natl. Eating Trends(®) service, portion size data from NHANES 1999-2004, and nutrient values using the Univ. of Minnesotas Nutrition Data System for Research software. Study participants were 7837 U.S. Americans and 4025 Canadians, ≥2-y-old males and females. The main outcome measures were total dietary vitamin D intake, percent contribution of foods to total vitamin D intake, and vitamin D intake by cereal and breakfast consumption habits. ANOVA was used to determine differences in means or proportions by age and gender and according to breakfast consumption habits. Mean vitamin D intake ranged from 152 to 220 IU/d. Less than 2% of participants in all age groups from the United States and Canada met the 2011 Recommended Daily Allowance (RDA) for vitamin D from foods. Milk, meat, and fish were the top food sources for vitamin D for both Americans and Canadians. Ready-to-eat (RTE) cereal was a top 10 source of vitamin D for Americans but not Canadians. Vitamin D intake was higher with more frequent RTE cereal and breakfast consumption in both countries, largely attributable to greater milk intake. PRACTICAL APPLICATION Most U.S. Americans and Canadians do not meet the 2011 Inst. of Medicine recommended daily allowance (RDA) for vitamin D for their age groups from foods. Increasing breakfast and cereal consumption may be a useful strategy to increase dietary vitamin D intake to help individuals meet the RDA for vitamin D, particularly by increasing milk intake. However, it is likely that additional food fortification or vitamin D supplementation is required to achieve the RDA.

Obesity Augments Calcium-Induced Increases in Skeletal Calcium Retention in Adolescents

CONTEXT Overweight adolescents have low bone mineral content for weight and are at increased risk for fractures. OBJECTIVE The aim was to determine whether overweight and obesity influence the positive relationship between dietary calcium intake and skeletal calcium retention in adolescents. DESIGN Analysis of pooled data from calcium balance studies in adolescents. SETTING Participants each underwent a 3-wk calcium balance study in a controlled environment. PARTICIPANTS Participants included 280 White, Black, and Asian boys (n = 73) and girls (n = 207) ages 10-16 yr. MAIN OUTCOME MEASURE The relationship among body mass index (BMI), calcium intake, and calcium retention was modeled using linear regression. RESULTS Calcium intake, BMI, sex, race, and age explained 27.9% of the variation in calcium retention. At low calcium intakes, there was no effect of BMI on skeletal calcium retention, but at higher calcium intakes, BMI increased skeletal calcium retention. CONCLUSIONS Greater gains in calcium retention occur with increases in calcium intake in adolescents with higher BMI compared with those with lower BMI. Additional studies are needed to investigate whether increasing calcium intake reduces the increased risk of fracture associated with overweight and obesity in adolescents.

Bone turnover is not influenced by serum 25-hydroxyvitamin D in pubertal healthy black and white children ☆

Low serum 25-hydroxyvitamin D [25 (OH) D] is common in healthy children particularly in blacks. However, serum 25 (OH) D concentrations for optimal bone turnover in children is unknown and few data exist that describe effects of increasing serum 25 (OH) D on bone turnover markers during puberty. The purpose of this study was to determine the relationships between serum 25 (OH) D and changes in serum 25 (OH) D and bone turnover in white and black pubertal adolescents. Bone turnover markers were measured in 318 healthy boys and girls from Georgia (34°N) and Indiana (40°N) who participated in a study of oral vitamin D(3) supplementation (0 to 4000 IU/d). Serum 25 (OH) D, osteocalcin, bone alkaline phosphatase, and urine N-telopeptide cross-links were measured at baseline and 12 weeks. Relationships among baseline 25 (OH) D and bone biomarkers, and between changes over 12 weeks were determined and tested for effects of race, sex, latitude, and baseline 25 (OH) D. Median 25 (OH) D was 27.6 ng/mL (n=318, range 10.1-46.0 ng/mL) at baseline and 34.5 ng/mL (n=302, range 9.7-95.1 ng/mL) at 12 weeks. Neither baseline nor change in 25 (OH) D over 12 weeks was associated with bone turnover. The lack of association was not affected by race, sex, latitude, or baseline serum 25 (OH) D. Serum 25 (OH) D in the range of 10-46 ng/mL appears to be sufficient for normal bone turnover in healthy black and white pubertal adolescents.

Effect of Calcium Carbonate Particle Size on Calcium Absorption and Retention in Adolescent Girls

Objective: Increasing calcium bioavailability by decreasing calcium salt particle size in the supplement may be one way to increase calcium absorption. The aim of the study was to compare (1) large versus small particle size CaCO3 supplements and (2) small particle size CaCO3 supplement versus placebo on calcium absorption and retention in adolescent girls. Methods: Thirty-one adolescent girls, aged 11 to 14 years, participated in two 3-week calcium balance periods separated by a 1-week washout period. During both balance periods, the subjects consumed a controlled diet containing 804 mg/d calcium. Using a crossover design, one group (n = 19) received an additional ∼600 mg/d calcium of two ∼300-mg calcium doses as either large particle (18 μm; i.e., standard commercial form) or small particle (13.5 μm) CaCO3. A second group (n = 12) received ∼600 mg/d calcium from small-particle CaCO3 or placebo. Results: The parathyroid hormone suppression curve, following a challenge, from the first arm of the study indicated that calcium absorption from the small particle size CaCO3 was less than that from the large particle size CaCO3. The parathyroid hormone suppression curve from the small particle versus placebo arm indicated that calcium absorption from small particle size CaCO3 was greater than placebo. Calcium balance (Ca intake – [urine Ca + fecal Ca]) demonstrated that the small particle size CaCO3 supplement increased Ca retention nearly 2-fold compared with placebo (p < 0.05; 496 ± 213 and 256 ± 94 mg/d, respectively). However, there was no significant difference in Ca retention due to small versus large particle size of CaCO3 (p > 0.05; 349.1 ± 131.6 and 322.0 ± 194.2 mg/d, respectively). Conclusions: Dietary supplementation with CaCO3 is effective in increasing calcium absorption and retention compared with placebo. But there is no advantage of small compared with large particle size CaCO3 on calcium absorption and retention.

Estimating Calcium Requirements

Nutrient requirements are used by many groups to determine food choices and meal plans for feeding people across the lifespan. They are used to evaluate sources of nutrients and for food labels to educate the consumer. Requirements also provide a guideline to determine whether supplements are needed. If calcium requirements are underestimated, inadequate intakes are more likely, which may compromise bone health and increase risk of chronic disease. The evidence supporting calcium requirements is stronger than for most nutrients. Yet, we lack consensus on the appropriate approach for determining calcium requirements. The various approaches for determining calcium requirements are reviewed in this chapter. We conclude that efficacy studies including well-controlled feeding studies are best for determining calcium intake requirements, and effective research including randomized controlled trials is best for evaluating how well various interventions work in translating the results of efficacy studies to the individual or community.