Vicente Gilsanz

Human BAT Possesses Molecular Signatures That Resemble Beige/Brite Cells

Brown adipose tissue (BAT) dissipates chemical energy and generates heat to protect animals from cold and obesity. Rodents possess two types of UCP-1 positive brown adipocytes arising from distinct developmental lineages: “classical” brown adipocytes develop during the prenatal stage whereas “beige” or “brite” cells that reside in white adipose tissue (WAT) develop during the postnatal stage in response to chronic cold or PPARγ agonists. Beige cells’ inducible characteristics make them a promising therapeutic target for obesity treatment, however, the relevance of this cell type in humans remains unknown. In the present study, we determined the gene signatures that were unique to classical brown adipocytes and to beige cells induced by a specific PPARγ agonist rosiglitazone in mice. Subsequently we applied the transcriptional data to humans and examined the molecular signatures of human BAT isolated from multiple adipose depots. To our surprise, nearly all the human BAT abundantly expressed beige cell-selective genes, but the expression of classical brown fat-selective genes were nearly undetectable. Interestingly, expression of known brown fat-selective genes such as PRDM16 was strongly correlated with that of the newly identified beige cell-selective genes, but not with that of classical brown fat-selective genes. Furthermore, histological analyses showed that a new beige cell marker, CITED1, was selectively expressed in the UCP1-positive beige cells as well as in human BAT. These data indicate that human BAT may be primary composed of beige/brite cells.

Changes in Vertebral Bone Density in Black Girls and White Girls during Childhood and Puberty

BACKGROUND The prevalence of osteoporosis and the incidence of vertebral fractures are lower in black women than in white women, findings generally attributed to racial differences in adult bone mass. Little is known, however, about the factors that contribute to racial variations in bone mass or the time of life when such differences become manifest. This study was done to characterize the changes in vertebral bone density at various stages of sexual development in black and white females. METHODS We measured cancellous vertebral bone density by quantitative computed tomography in 75 black female subjects between 2 and 20 years old and 75 whites matched for age and stage of sexual development. RESULTS The vertebral bone density did not differ between black girls and white girls before puberty. Bone density increased during puberty in each racial group, but the magnitude of the increase from prepubertal values was substantially greater in black than in white subjects (34 percent vs. 11 percent). CONCLUSIONS The marked difference between black and white females in cancellous vertebral bone density occurs during a relatively brief period late in puberty. Metabolic and hormonal events related to the achievement of sexual maturity during adolescence may be important determinants of racial differences in bone mass in women.

Low‐Level, High‐Frequency Mechanical Signals Enhance Musculoskeletal Development of Young Women With Low BMD

The potential for brief periods of low‐magnitude, high‐frequency mechanical signals to enhance the musculoskeletal system was evaluated in young women with low BMD. Twelve months of this noninvasive signal, induced as whole body vibration for at least 2 minutes each day, increased bone and muscle mass in the axial skeleton and lower extremities compared with controls.

VITAMIN D-RECEPTOR GENE POLYMORPHISMS AND BONE DENSITY IN PREPUBERTAL AMERICAN GIRLS OF MEXICAN DESCENT

BACKGROUND Bone mass is under strong genetic control, and recent studies in adults have suggested that allelic differences in the gene for the vitamin D receptor may account for inherited variability in bone mass. We studied the relations of the vitamin D-receptor genotype to skeletal development and variation in the size, volume, and density of bone in children. METHODS We identified three allelic variants of the vitamin D-receptor gene using the polymerase chain reaction and three restriction enzymes (ApaI, BsmI, and TaqI) in 100 normal prepubertal American girls of Mexican descent. We then determined the relations of the different vitamin D-receptor genotypes (AA, Aa, aa, BB, Bb, bb, TT, Tt, and tt) to the cross-sectional area, cortical area, and cortical bone density of the femoral shaft and the cross-sectional area and density of the lumbar vertebrae. RESULTS The vitamin D-receptor genotype was associated with femoral and vertebral bone density. Girls with aa and bb genotypes had 2 to 3 percent higher femoral bone density (P=0.008 and P=0.04, respectively) and 8 to 10 percent higher vertebral bone density (P=0.01 and P=0.03, respectively) than girls with AA and BB genotypes. There was no association between the cross-sectional area of the vertebrae or the cross-sectional or cortical area of the femur and the vitamin D-receptor genotype. The chronologic age, bone age, height, weight, body-surface area, and body-mass index did not differ significantly among girls with different vitamin D-receptor genotypes. CONCLUSIONS Vitamin D-receptor gene alleles predict the density of femoral and vertebral bone in prepubertal American girls of Mexican descent.

Reciprocal Relations of Subcutaneous and Visceral Fat to Bone Structure and Strength

CONTEXT Increased body fat is a risk factor for cardiovascular and metabolic disease, yet it is uncertain whether obesity protects against osteoporosis or adiposity is harmful to bone. OBJECTIVE The aim of the study was to assess whether the pattern of adipose tissue deposition influences bone structure and strength. DESIGN The relations between sc and visceral adiposity and the cross-sectional dimensions and polar and principal moments of the femur in 100 healthy women ages 15 to 25 years were obtained using computed tomography. RESULTS Multiple linear regression analyses indicated that, after adjusting for leg length and thigh musculature, both sc and visceral fat had strong and independent associations with femoral cross-sectional area, cortical bone area, principal moment maximum, principal moment minimum, and polar moment (all P values < 0.03). However, whereas sc fat had a positive predictive value with all femoral bone phenotypes, a similar but negative effect was observed between visceral fat and these measures (all P values < 0.01). CONCLUSIONS We found that visceral and sc fat have opposite effects on the appendicular skeleton; whereas sc fat is beneficial to bone structure and strength, visceral fat serves as an unique pathogenic fat depot.

Peak trabecular vertebral density: a comparison of adolescent and adult females

SummaryTo determine when spinal bone density reaches its peak, the trabecular vertebral density was assessed, via quantitative computed tomography, among females from two age groups: (1) adolescents (aged 14–19 years; n=24); and (2) young adults (aged 25–35 years; n=24). The adolescent girls had a higher mean trabecular vertebral density (P<0.01), suggesting that spinal density reaches its peak around the time of cessation of longitudinal growth and epiphyseal closure.

Increased Body Weight and Decreased Radial Cross‐Sectional Dimensions in Girls with Forearm Fractures

A large number of children sustain fractures after relatively minor trauma and several investigators have associated these fractures to a deficient accumulation of bone during growth. This study was conducted to better characterize the skeletal phenotype associated with low‐energy impact fractures of the forearm in girls. The densities of cancellous, cortical, and integral bone and the cross‐sectional area were measured in the radius of 100 healthy white girls (aged 4‐15 years) using computed tomography (CT); 50 girls had never fractured and 50 girls had sustained a forearm fracture within the previous month. Fractured and nonfractured groups were matched for age, height, weight, and Tanner stage of sexual development. Compared with controls, girls with fractures had, on average, 8% smaller cross‐sectional area at the distal radius (1.82 ± 0.50 cm2 vs. 1.97 ± 0.42 cm2; p < 0.0001) but similar cancellous, integral, and cortical bone densities. Neither radial length nor the amount of fat or muscle at the midshaft of the radius differed between girls with and without fractures. Both study subjects and matched controls were overweight. Although mean height was at the 50th percentile, mean weight was at the 90th percentile for age‐adjusted normal values. Girls who sustain forearm fractures after minor trauma have small cross‐sectional dimensions of the radius and tend to be overweight. The smaller cross‐sectional area confers a biomechanical disadvantage that, coupled with the greater body weight, increases the vulnerability to fracture after a fall.

Height Adjustment in Assessing Dual Energy X- Ray Absorptiometry Measurements of Bone Mass and Density in Children

CONTEXT In children, bone mineral content (BMC) and bone mineral density (BMD) measurements by dual-energy x-ray absorptiometry (DXA) are affected by height status. No consensus exists on how to adjust BMC or BMD (BMC/BMD) measurements for short or tall stature. OBJECTIVE The aim of this study was to compare various methods to adjust BMC/BMD for height in healthy children. DESIGN Data from the Bone Mineral Density in Childhood Study (BMDCS) were used to develop adjustment methods that were validated using an independent cross-sectional sample of healthy children from the Reference Data Project (RDP). SETTING We conducted the study in five clinical centers in the United States. PARTICIPANTS We included 1546 BMDCS and 650 RDP participants (7 to 17 yr of age, 50% female). INTERVENTION No interventions were used. MAIN OUTCOME MEASURES We measured spine and whole body (WB) BMC and BMD Z-scores for age (BMC/BMD(age)), height age (BMC/BMD(height age)), height (BMC(height)), bone mineral apparent density (BMAD(age)), and height-for-age Z-score (HAZ) (BMC/BMD(haz)). RESULTS Spine and WB BMC/BMD(age)Z and BMAD(age)Z were positively (P < 0.005; r = 0.11 to 0.64) associated with HAZ. Spine BMD(haz) and BMC(haz)Z were not associated with HAZ; WB BMC(haz)Z was modestly associated with HAZ (r = 0.14; P = 0.0003). All other adjustment methods were negatively associated with HAZ (P < 0.005; r = -0.20 to -0.34). The deviation between adjusted and BMC/BMD(age) Z-scores was associated with age for most measures (P < 0.005) except for BMC/BMD(haz). CONCLUSIONS Most methods to adjust BMC/BMD Z-scores for height were biased by age and/or HAZ. Adjustments using HAZ were least biased relative to HAZ and age and can be used to evaluate the effect of short or tall stature on BMC/BMD Z-scores.

Revised Reference Curves for Bone Mineral Content and Areal Bone Mineral Density According to Age and Sex for Black and Non-Black Children: Results of the Bone Mineral Density in Childhood Study

CONTEXT Deficits in bone acquisition during growth may increase fracture risk. Assessment of bone health during childhood requires appropriate reference values relative to age, sex, and population ancestry to identify bone deficits. OBJECTIVE The objective of this study was to provide revised and extended reference curves for bone mineral content (BMC) and areal bone mineral density (aBMD) in children. DESIGN The Bone Mineral Density in Childhood Study was a multicenter longitudinal study with annual assessments for up to 7 yr. SETTING The study was conducted at five clinical centers in the United States. PARTICIPANTS Two thousand fourteen healthy children (992 males, 22% African-Americans) aged 5-23 yr participated in the study. INTERVENTION There were no interventions. MAIN OUTCOME MEASURES Reference percentiles for BMC and aBMD of the total body, lumbar spine, hip, and forearm were obtained using dual-energy x-ray absorptiometry for Black and non-Black children. Adjustment factors for height status were also calculated. RESULTS Extended reference curves for BMC and aBMD of the total body, total body less head, lumbar spine, total hip, femoral neck, and forearm for ages 5-20 yr were constructed relative to sex and age for Black and non-Black children. Curves are similar to those previously published for 7-17 year olds. BMC and aBMD values were greater for Black vs. non-Black children at all measurement sites. CONCLUSIONS We provide here dual-energy x-ray absorptiometry reference data on a well-characterized cohort of 2012 children and adolescents. These reference curves provide the most robust reference values for the assessment and monitoring of bone health in children and adolescents in the literature to date.

Bone density in children: a review of the available techniques and indications.

The recent development of methods for measuring bone mineral content in children has markedly improved our ability to determine changes in bone mass during growth. Currently, the three most generally accepted techniques for measuring the bones of children are dual-energy X-ray absorbtiometry (DXA), quantitative computed tomography (QCT) and quantitative ultrasound (QUS). These techniques vary considerably in their acquisition of data and comparisons between them are difficult and, more often than not, judgment regarding their value has been, at least partially, subjective. DXA is, by far, the most widely used technique for bone measurements. It is low in cost, accessible, easy to use, and provides an accurate and precise quantitation of bone mass in adults. Unfortunately, DXA is unable to account for the large changes in body and skeletal size that occur during growth, limiting its use in longitudinal studies in children. QCT can asses both the volume and the density of bone in the axial and appendicular skeletons, without influence from body or skeletal size, giving it a major advantage over other modalities for bone measurements in children. The cost and inaccessibility of CT scanners, however, has significantly limited its use for bone measurements. Measuring the bones of children by QUS is appealing because ultrasound is low in cost, portable, easy to use and does not emit radiation. In adults, this technique is able to predict fracture risk independent of bone mass determinations in patients with osteoporosis and, therefore, its measurements must be related to certain aspects of bone strength. However, ultrasound values are dependent on so many structural properties not yet fully understood, that it is difficult to use the information meaningfully in children.