Increased Bone Mineral Content During Rapid Weight Gain Therapy in Anorexia Nervosa.

Patients with anorexia nervosa (AN) are at high risk of reduced bone mass. Osteocalcin (OC), a bone formation marker, has been proposed to act as a link between bone and energy metabolism. We investigated how the 3 forms of OC respond during a 12-week intensive nutrition therapy in AN patients, in whom large changes in energy metabolism are expected.Twenty-two female AN patients, mean 20.9 years of age, with a starting mean body mass index (BMI) 15.5 kg/m2 (minimum-maximum) (13.4-17.3 kg/m2) completed the study. Biochemical markers, body composition, bone mass by DXA, and pQCT were assessed. Subjects gained in median 9.9 kg (5.5-17.0 kg), and BMI increased from median 15.4 kg/m2 (13.4-17.3 kg/m2) to 19.0 kg/m2 (16.2-20.6 kg/m2), p<0.0001. Fat mass increased from median 11.4% (4.4-24.8%) to 26.7% (16.9-39.8%). Total OC, carboxylated OC (cOC), undercarboxylated OC (ucOC), and bone-specific alkaline phosphatase (BALP) increased during the study period. No change was observed for the resorption marker carboxy-terminal cross-linking telopeptide of type I collagen (CTX). Total body bone mineral content (BMC) increased, but no changes were found for whole body or lumbar spine bone mineral density. Tibial trabecular density measured by pQCT decreased. Total OC, cOC, and ucOC were not associated with BMI, insulin or body composition parameters. This prospective study demonstrates that all 3 forms of OC (total OC, cOC, ucOC) increase during rapid weight gain. BALP increased while the resorption marker CTX was unchanged, which corroborate with the increased total body BMC.

Seasonal variations in vitamin D in relation to growth in short prepubertal children before and during first year growth hormone treatment.

PURPOSE: This study investigated the relationship between seasonal variations in 25-hydroxyvitamin D (25(OH)D) levels and growth in prepubertal children during both the pretreatment year and the first year of GH treatment. METHODS: The study included 249 short prepubertal children with a broad range of GH secretion, GH(max) during a 24 h profile median 23; range 1-127 mU/L, 191 boys (mean age ± SD, 8.6 ± 2.6 years), 58 girls (7.5 ± 1.9 years) receiving GH treatment (mean 43 µg/kg/day; range 17-99 µg/kg/day). Serum 25(OH)D was measured using an automated IDS-iSYS immunoassay. RESULTS: 25(OH)D levels showed seasonal variation, and decreased significantly during GH treatment. 25(OH)D levels at start and first year reduction in 25(OH)D, correlated (-) with the first year growth response during treatment. The degree of GH secretion capacity within our study population of mainly non-GH deficient children and 25(OH)D sufficient (67 ± 29 nmol/L) had no influence on 25(OH)D levels. Growth during GH treatment were independent of seasonal variations in 25(OH)D. Multiple regression analysis showed that 25(OH)D levels at treatment start, together with auxological data and IGF-binding protein-(3)SDS, explained 61 % of the variation in first year gain in heightSDS. CONCLUSION: 25(OH)D levels were associated with first year growth response to GH and may be a useful contribution to future growth prediction models.

Whole body vibration therapy in patients with Duchenne muscular dystrophy--a prospective observational study.

OBJECTIVES: To study the tolerability of whole body vibration (WBV) exercise in patients with Duchenne muscular dystrophy (DMD) and its effects on muscle and bone. METHODS: WBV was performed two to three times a week for three months. Motor function, muscle strength, bone mass and biochemical markers of bone and mineral metabolism were analyzed before and after the WBV period at 0, 3, 6 and 12 months. RESULTS: Six ambulatory patients with DMD aged 5.7-12.5 years completed the study. No changes in creatine kinase activity were found, indicating that the WBV exercise did not further damage the skeletal muscle. No significant changes in bone mass, muscle strength or bone markers were found. However, there was a non-significant trend for the bone formation marker, bone-specific alkaline phosphate, to increase from a mean of 59 U/L to 73 U/L after three months of WBV. The bone formation marker levels returned to baseline three months after discontinuing WBV and were still at that level after nine months. CONCLUSIONS: WBV therapy appears to be safe and well tolerated among ambulatory DMD patients. The potential benefits of WBV on bone and muscle in DMD remain to be elucidated.

Relation between bone mineral density, biological markers and anthropometric measures in 4-year-old children: a pilot study within the IDEFICS study.

OBJECTIVE: To investigate the relationship between bone mineral density (BMD), anthropometric characteristics, levels of biological markers for growth, bone turnover, insulin resistance and fat mass in 4-year-old Swedish children. METHODS: Descriptive study with 41 children (28 boys) who had anthropometric measurements and blood samples taken and heel dual-energy X-ray absorptiometry and laser (DXL) performed. The study participants were divided into groups of normal-weight (n=28) and overweight or obese (n=13) children. RESULTS: There was a significant difference in bone mineral content (BMC), BMD and bone mineral apparent density (BMAD) between overweight and normal-weight children. There was a significant positive correlation between BMC, BMD, BMAD and body mass index standard deviation scores (r=0.36, 0.34 and 0.29, P<0.01, respectively), waist circumference (r=0.32, 0.30, P<0.01 and r=0.26, P<0.05, respectively) and subscapular skinfold (r=0.26, 0.25 and 0.23, P<0.05, respectively). BMC and BMD correlated significantly with the sum of skinfold measures (r=0.25 and 0.23, P<0.05, respectively). Adiponectin was significantly inversely correlated with BMC, BMD and BMAD (r=-0.41, -0.40 and -0.41, P<0.01, respectively). Adiponectin was not correlated with skinfold measures. Multiple regression analysis revealed that adiponectin was an independent determinant of BMD, BMC and BMAD. CONCLUSION: To our knowledge, this is the first study investigating BMD assessed by heel-DXL in relation to anthropometry and metabolic markers in 4-year-old children. Adiponectin was significantly inversely correlated with bone mass parameters. Adiponectin may have an independent role in bone development and metabolism in young children.

The relationship between paediatric calcaneal quantitative ultrasound measurements and dual energy X-ray absorptiometry (DXA) and DXA with laser (DXL) as well as body composition.

BACKGROUND: Quantitative ultrasound (QUS) is a quick, non-invasive and inexpensive method to measure bone strength. Moreover, the device is portable, which makes it easy to be used in the field. In contrast to other bone measuring techniques, QUS does not use any ionised radiation. However, the validity of QUS in the measurement of bone health and the relationship between QUS output and body composition have not been assessed in very young children. OBJECTIVE: To investigate the relationship between paediatric calcaneal QUS and both dual-energy X-ray absorptiometry (DXA) and calcaneal DXA with laser (DXL) and body composition parameters. SUBJECTS: A total of 37 Belgian children (10 boys and 27 girls; 4 to 8 years old) underwent a calcaneal QUS as well as a DXA scan. A total of 24 Swedish children (15 boys and 9 girls; 3 to 5 years old) underwent a calcaneal QUS as well as a heel DXL scan. The height and weight of all children were measured. RESULTS: The QUS stiffness index (SI) was significantly negatively correlated with bone mineral density (BMD) of the total body (r=-0.370, P=0.02). No significant correlations were found between the SI and DXL results. In the total sample, the SI showed a significant positive correlation with body mass index (BMI) (r=0.298, P=0.02), even after correction for age, gender and centre. In the Belgian sample, the SI was also significantly positively correlated with total body fat mass content (r=0.416, P=0.01) and body fat percentage (r=0.566, P<0.01) obtained by whole-body DXA. CONCLUSION: The SI measured by QUS does not correlate significantly with BMD values measured by DXA or DXL in 3- to 8-year-old children. However, there is a significant positive correlation between SI and BMI and body fat %.

Prospective study of growth and bone mass in Swedish children treated with the modified Atkins diet.

PURPOSE: The modified Atkins diet (MAD) is a less restrictive treatment option than the ketogenic diet (KD) for intractable epilepsy and some metabolic conditions. Prolonged KD treatment may decrease bone mineralization and affect linear growth; however, long-term studies of MAD treatment are lacking. This study was designed to assess growth, body composition, and bone mass in children on MAD treatment for 24 months. METHODS: Thirty-eight patients, mean age (SD) 6.1 years (4.8 years), 21 girls, with intractable epilepsy (n = 22), glucose transporter type 1 deficiency syndrome (n = 7), or pyruvate dehydrogenase complex deficiency (n = 9) were included. Body weight, height, body mass index (BMI), bone mass, and laboratory tests (calcium, phosphorus, magnesium, alkaline phosphatase, cholesterol, 25-hydroxyvitamin D, insulin-like growth factor-I and insulin-like growth factor binding protein 3) were assessed at baseline and after 24 months of MAD treatment. RESULTS: Approximately 50% of the patients responded with more than 50% seizure reduction. Weight and height standard deviation score (SDS) were stable over 24 months, whereas median (minimum - maximum) BMI SDS increased from 0.2 (-3.3 to 4.5) to 0.7 (-0.9 to 2.6), p < 0.005. No effects were observed for bone mass (total body, lumbar spine and hip) or fat mass. CONCLUSIONS: The MAD was efficient in reducing seizures, and no negative effect was observed on longitudinal growth or bone mass after MAD treatment for 24 months.

Pediatric reference data for bone mineral density in the calcaneus for healthy children 2, 4, and 7 years of age by dual-energy x-ray absorptiometry and laser.

Dual-energy X-ray absorptiometry and laser (DXL) Calscan measures bone mineral density (BMD) in the calcaneus. In the present study, the DXL Calscan device has been modified for use in pediatric practice. It includes a function for measuring calcaneal height, which makes it possible to calculate volumetric bone mineral apparent density (BMAD). The aims of the present study were to evaluate the method when used in children, to create pediatric reference values in healthy Swedish 2-, 4-, and 7-yr-old children for BMD, bone mineral content (BMC), and BMAD, and to study whether these parameters were related to auxological data. The method was well tolerated by all children. Intraindividual coefficients of variation for BMC and BMD decreased with increasing age. The mean BMD was 0.17+/-0.003 g/cm2 in 2-yr-old children, 0.22+/-0.003 g/cm2 in 4-yr-old children, and 0.30+/-0.005 g/cm2 in 7-yr-old children. This study provides normative data as percentile values for BMD, BMC, and BMAD in young children measured with DXL Calscan. BMD was significantly correlated with age (p<0.001), height (p=0.001), weight (p<0.001), and body mass index standard deviation score (p<0.001). Seven-year-old girls showed significantly higher BMD than boys.

Cartilage oligomeric matrix protein increases in serum after the start of growth hormone treatment in prepubertal children.

Both GH and IGF-I stimulate bone growth, but the molecular mechanisms mediating their effects on the growth plate are not fully understood. We measured gene expression by microarray analysis in primary cultured human chondrocytes treated with either GH or IGF-I. One of the genes found to be up-regulated by both GH and IGF-I was that encoding cartilage oligomeric matrix protein (COMP). This protein is predominantly found in the extracellular matrix of cartilage. Mutations in the COMP gene have been associated with syndromes of short stature. To verify that COMP is regulated by GH in vivo, we measured COMP levels in serum in short children treated with GH. The study included 113 short prepubertal children (14 girls and 99 boys) with a mean (+/- sd) age of 8.84 +/- 2.76 yr, height sd score of -2.74 +/- 0.67, and IGF-I sd score of -1.21 +/- 1.07 at the start of GH administration. Serum levels of COMP were 1.58 +/- 0.28, 1.83 +/- 0.28 (P < 0.0001), 1.91 +/- 0.28 (P < 0.0001), 1.78 +/- 0.28 (P < 0.001), and 1.70 +/- 0.24 (P < 0.05) microg/ml at baseline and after 1 wk and 1, 3, and 12 months, respectively. In conclusion, we have demonstrated that COMP expression is up-regulated by both GH and IGF-I in primary cultured human chondrocytes. Furthermore, serum levels of COMP increase after the start of GH treatment in short children.

Effects of cortisol on the expression of interleukin-6 and interleukin-1 beta in human osteoblast-like cells.

High levels of glucocorticoids are believed to alter bone remodeling by decreasing bone formation and increasing bone resorption. It has been suggested that different cytokines, like interleukin-6 (IL-6) and interleukin-1 (IL-1), are involved in bone resorption by activating immature osteoclasts, and some studies indicate that IL-6 promotes bone formation by a mitogenic effect on osteoblasts. The aim of the present investigation was to study whether cortisol regulates the expression of IL-6 and IL-1 beta in human osteoblast-like cells. A high dose of cortisol (10(-7)M) decreased, as expected, the C-terminal propeptide of type I collagen released into the culture medium. The IL-6 mRNA levels and IL-6 protein released into the culture medium were also decreased by cortisol in a dose-dependent manner. The maximum effect was seen at 1 microM cortisol (mRNA 23.1 +/- 7.9% of control culture; protein 28.2 +/- 8.3% of control culture). The decrease in IL-6 mRNA levels was apparent 4 h after the addition of cortisol and was still present 20 h later. The decrease in IL-6 protein released into the culture medium was seen 20 h later than the decrease in IL-6 mRNA levels. The production of IL-1 beta protein released into the culture medium was decreased in a dose-dependent manner after the addition of cortisol with a maximum effect at 1 microM. The effect of cortisol on IL-1 beta protein released into the culture medium was seen 16 h after the addition of cortisol. To summarize, cortisol decreases the expression of IL-6 as well as IL-1 beta in human osteoblast-like cells.

Cortisol increases growth hormone-receptor expression in human osteoblast-like cells.

It is well known that high levels of glucocorticoids cause osteoporosis and that physiologic levels of growth hormone (GH) are required for normal bone remodeling. It has been suggested that glucocorticoids regulate GH-responses via the regulation of GH-receptor expression. The aim of the present study was to investigate whether cortisol plays a role in the regulation of GH-receptor expression in cultured human osteoblasts. The effect of serum starvation and cortisol on GH-receptor expression was tested in human osteoblast (hOB)-like cells. Serum starvation for 24 h resulted in an increase in GH-receptor mRNA levels (90 +/- 1% over control culture). Cortisol increased GH-receptor mRNA levels in a dose-dependent manner with a maximal effect at 10(-6)M. The stimulating effect of cortisol on GH-receptor mRNA levels was time-dependent, reaching a peak 12 h after the addition of cortisol (126 +/- 29% over control culture) and remaining up to 12 h later. The increase in GH-receptor mRNA levels was accompanied by an increase in 125I-GH binding which reached a maximum at 24 h (196 +/- 87% over control culture). In conclusion, glucocorticoids increase GH-receptor expression in hOB-like cells. Further studies are needed to clarify whether glucocorticoid-induced regulation of the GH-receptor is important in human bone physiology.

Reductions in adipose tissue and skeletal growth in rat adult offspring after prenatal leptin exposure.

Leptin is involved in regulating food intake, energy balance and bone formation. Increasing evidence suggests that leptin is also involved in fetal growth and development. The aim of this study was to determine if increased maternal leptin is followed by changes in body composition, skeletal growth or hormonal regulation in the adult rat offspring. Pregnant rats were given injections of either human recombinant leptin (3.5 mg/kg, i.p.) or vehicle on days 8, 10 and 12 of gestation. Both genders of leptin-exposed offspring showed significantly reduced adipose tIssue weight at adult age. Skeletal growth and cortical bone dimensions were significantly reduced. Circulating testosterone levels were significantly increased in female leptin-exposed offspring, and male leptin-exposed offspring had significant testicular enlargement. No significant effects were seen on circulating leptin levels or hypothalamic protein levels of the leptin receptor. The results demonstrate that maternally administered leptin is involved in fetal growth and development, leading to lean offspring with reduced skeletal growth.