CYP11B1 variants influence skeletal maturation via alternative splicing.

We performed genome-wide association study meta-analysis to identify genetic determinants of skeletal age (SA) deviating in multiple growth disorders. The joint meta-analysis (N = 4557) in two multiethnic cohorts of school-aged children identified one locus, CYP11B1 (expression confined to the adrenal gland), robustly associated with SA (rs6471570-A; β = 0.14; P = 6.

Genome-wide association study implicates novel loci and reveals candidate effector genes for longitudinal pediatric bone accrual.

Background: Bone accrual impacts lifelong skeletal health, but genetic discovery has been primarily limited to cross-sectional study designs and hampered by uncertainty about target effector genes. Here, we capture this dynamic phenotype by modeling longitudinal bone accrual across 11,000 bone scans in a cohort of healthy children and adolescents, followed by genome-wide association studies (GWAS) and variant-to-gene mapping with functional follow-up.

Results: We identify 40 loci, 35 not previously reported, with various degrees of supportive evidence, half residing in topological associated domains harboring known bone genes.

Intermachine differences in DXA measurements vary by skeletal site, and impact the assessment of low bone density in children.

Background: Bone mineral content (BMC) and areal-bone mineral density (aBMD) measurements of the lumbar spine (LS) and whole body less head (WBLH) by dual energy X-ray absorptiometry (DXA) are recommended for bone health assessment in children. Intermachine differences were not considered previously in formulating these recommendations.

Methodology: DXA measurements of the LS, WBLH, total hip, femoral neck and distal 1/3 radius from the Bone Mineral Density in Childhood Study were examined.

Pediatric Reference Ranges for Ultradistal Radius Bone Density: Results from the Bone Mineral Density in Childhood Study.

Context: The ultradistal (UD) radius is rich in trabecular bone and is easily measured by dual energy X-ray absorptiometry (DXA). UD radius areal bone mineral density (aBMD) may help identify trabecular bone deficits, but reference data are needed for research and clinical interpretation of this measure.

Objective: We developed age-, sex-, and population ancestry-specific reference ranges for UD radius aBMD assessed by DXA and calculated Z-scores.

Myosteatosis in adolescents and young adults treated for acute lymphoblastic leukemia.

Myosteatosis refers to fat deposition within muscle and is linked to risk of cardiovascular disease and metabolic disorders. Though these comorbidities are common during and after therapy for acute lymphoblastic leukemia (ALL), little is known about tissue distribution, including myosteatosis, in this population. Using quantitative computed tomography, we assessed the impact of ALL therapy on bone, muscle, subcutaneous, and muscle-associated (MA) fat in 12 adolescents and young adults (AYA) treated for ALL as compared to a healthy control group without ALL ( = 116).

Postmenopausal osteoporotic fracture-associated COLIA1 variant impacts bone accretion in girls.

Over the past two decades, a low frequency variant (rs1800012) within the first intron of the type I collagen alpha 1 (COLIA1) gene has been implicated in lower areal BMD (aBMD) and increased risk of osteoporotic fracture. This association is particularly strong in postmenopausal women, in whom net bone loss arises in the context of high bone turnover. High bone turnover also accompanies childhood linear growth; however, the role of rs1800012 in this stage of net bone accretion is less well understood.

Pediatric Bone Mineral Accrual Z-Score Calculation Equations and Their Application in Childhood Disease.

Annual gains in BMC and areal bone mineral density (aBMD) in children vary with age, pubertal status, height-velocity, and lean body mass accrual (LBM velocity). Evaluating bone accrual in children with bone health-threatening conditions requires consideration of these determinants. The objective of this study was to develop prediction equations for calculating BMC/aBMD velocity SD scores (velocity-Z) and to evaluate bone accrual in youth with health conditions.

Lumbar Spine Bone Mineral Apparent Density in Children: Results From the Bone Mineral Density in Childhood Study.

Context: Dual-energy X-ray absorptiometry (DXA) is a cornerstone of pediatric bone health assessment, yet differences in height-for-age confound the interpretation of areal bone mineral density (aBMD) measures. To reduce the confounding of short stature on spine bone density, use of bone mineral apparent density (BMAD) and height-for-age Z-score (HAZ)‒adjusted aBMD (aBMDHAZ) are recommended. However, spine BMAD reference data are sparse, and the degree to which BMAD and aBMDHAZ account for height-related artifacts in bone density remains unclear.

Physical Activity and Bone Accretion: Isotemporal Modeling and Genetic Interactions.

Purpose: This study aimed to determine if replacing time spent in high- and low-impact physical activity (PA) predicts changes in pediatric bone mineral density (BMD) and content (BMC).

Methods: We analyzed data from the longitudinal Bone Mineral Density in Childhood Study (N = 2337 with up to seven visits). The participants were age 5-19 yr at baseline, 51.

Sexual Dimorphism and the Origins of Human Spinal Health.

Recent observations indicate that the cross-sectional area (CSA) of vertebral bodies is on average 10% smaller in healthy newborn girls than in newborn boys, a striking difference that increases during infancy and puberty and is greatest by the time of sexual and skeletal maturity. The smaller CSA of female vertebrae is associated with greater spinal flexibility and could represent the human adaptation to fetal load in bipedal posture. Unfortunately, it also imparts a mechanical disadvantage that increases stress within the vertebrae for all physical activities.

Transethnic Evaluation Identifies Low-Frequency Loci Associated With 25-Hydroxyvitamin D Concentrations.

Context: Vitamin D inadequacy is common in the adult population of the United States. Although the genetic determinants underlying vitamin D inadequacy have been studied in people of European ancestry, less is known about populations with Hispanic or African ancestry.

Objective: The Trans-Ethnic Evaluation of Vitamin D (TRANSCEN-D) genomewide association study (GWAS) consortium was assembled to replicate genetic associations with 25-hydroxyvitamin D [25(OH)D] concentrations from the Study of Underlying Genetic Determinants of Vitamin D and Highly Related Traits (SUNLIGHT) meta-analyses of European ancestry and to identify genetic variants related to vitamin D concentrations in African and Hispanic ancestries.

Vertebral cross-sectional growth: A predictor of vertebral wedging in the immature skeleton.

The degree of vertebral wedging, a key structural characteristic of spinal curvatures, has recently been found to be negatively related to vertebral cross-sectional area (CSA). The purpose of this longitudinal study was to examine the relation between vertebral cross-sectional growth and vertebral wedging progression within the immature lumbar spine. Using magnetic resonance imaging (MRI), we analyzed the potential association between increases in lumbar vertebral CSA and changes in L5 vertebral wedging in 27 healthy adolescent girls (ages 9-13 years) twice within a two-year period.

Multidimensional Bone Density Phenotyping Reveals New Insights Into Genetic Regulation of the Pediatric Skeleton.

Osteoporosis is a complex disease with developmental origins. It is therefore important to understand the genetic contribution to pediatric areal bone mineral density (aBMD). Individual skeletal site phenotyping has been primarily used to identify pediatric aBMD loci.

Advanced skeletal maturity in children and adolescents with myelomeningocele.

Purpose: Atypical skeletal development is common in youth with myelomeningocele (MM), though the underlying reasons have not been fully elucidated. This study assessed skeletal maturity in children and adolescents with MM and examined the effects of sex, age, sexual development, ethnicity, anthropometrics and shunt status.

Methods: Forty-three males and 35 females with MM, 6-16 years old, underwent hand radiographs for bone age determination.

Increased Lumbar Lordosis and Smaller Vertebral Cross-Sectional Area Are Associated With Spondylolysis.

Study Design: A cross-sectional comparison of vertebral morphology and lumbar lordosis (LL) in adolescents with and without spondylolysis.

Objective: To test the hypothesis that in addition to LL, vertebral cross-sectional area (CSA) is also associated with spondylolysis.

Summary Of Background Data: Recent data indicate that the CSA of the vertebral body is a determinant of LL, which has been shown to be associated with spondylolysis.

Genetically Determined Later Puberty Impacts Lowered Bone Mineral Density in Childhood and Adulthood.

Later puberty associates with lower areal bone mineral density (aBMD), and both are risk factors for osteoporosis. However, the association between puberty timing-associated genetic variants and aBMD during development, and the causal relationship between puberty timing and aBMD, remain uncharacterized. We constructed sex-specific polygenic risk scores (GRS) consisting of 333 genetic variants associated with later puberty in European-descent children in the Bone Mineral Density in Childhood Study (BMDCS), consisting of a longitudinal cohort with up to seven assessments (n = 933) and a cross-sectional cohort (n = 486).

Association Between Linear Growth and Bone Accrual in a Diverse Cohort of Children and Adolescents.

Importance: Prevention of osteoporosis in adulthood begins with optimizing bone health in early life. The longitudinal association between growth and bone accretion during childhood is not fully understood.

Objectives: To assess the acquisition of whole-body (WB) and skeletal site-specific bone mineral content (BMC) relative to linear growth in a healthy, diverse, longitudinal cohort of children, adolescents, and young adults and to test for differences related to sex and African American race.

Association Between Vertebral Cross-sectional Area and Vertebral Wedging in Children and Adolescents: A Cross-sectional Analysis.

A small vertebral cross-sectional area (CSA) imparts a mechanical disadvantage that escalates the risk for vertebral fractures in elderly populations. We examined whether a small vertebral CSA is also associated with a greater degree of vertebral wedging in children. Measurements of vertebral CSA, lumbar lordosis (LL) or thoracic scoliosis angle, and vertebral wedging were obtained in 100 healthy adolescents (50 boys and 50 girls) and 25 girls with adolescent idiopathic scoliosis (AIS) using magnetic resonance imaging.

Biomechanical Modeling of Spine Flexibility and Its Relationship to Spinal Range of Motion and Idiopathic Scoliosis.

Study Design: Cross-sectional.

Objective: To examine the relationships between spine morphology, spine flexibility, and idiopathic scoliosis.

Background: Girls have a higher incidence of clinically significant scoliosis than boys, along with smaller vertebrae and greater flexibility.

A randomized controlled trial testing an adherence-optimized Vitamin D regimen to mitigate bone change in adolescents being treated for acute lymphoblastic leukemia.

Adolescents with acute lymphoblastic leukemia (ALL) develop osteopenia early in therapy, potentially exacerbated by high rates of concurrent Vitamin D deficiency. We conducted a randomized clinical trial testing a Vitamin D-based intervention to improve Vitamin D status and reduce bone density decline. Poor adherence to home supplementation necessitated a change to directly observed therapy (DOT) with intermittent, high-dose Vitamin D3 randomized versus standard of care (SOC).

Association between vertebral cross-sectional area and lumbar lordosis angle in adolescents.

Lumbar lordosis (LL) is more prominent in women than in men, but the mechanisms responsible for this discrepancy are poorly defined. A recent study indicates that newborn girls have smaller vertebral cross-sectional area (CSA) when compared to boys-a difference that persists throughout life and is independent of body size. We determined the relations between vertebral cross-sectional area (CSA) and LL angle and whether sex differences in lumbar lordosis are related to sex differences in vertebral CSA.

A Genomewide Association Study Identifies Two Sex-Specific Loci, at SPTB and IZUMO3, Influencing Pediatric Bone Mineral Density at Multiple Skeletal Sites.

Failure to achieve optimal bone mineral accretion during childhood and adolescence results in subsequent suboptimal peak bone mass, contributing to osteoporosis risk later in life. To identify novel genetic factors that influence pediatric bone mass at discrete skeletal sites, we performed a sex-stratified genomewide association study of areal bone mineral density (BMD) measured by dual-energy X-ray absorptiometry at the 1/3 distal radius, spine, total hip, and femoral neck in a cohort of 933 healthy European American children. We took forward signals with p < 5 × 10 and minor allele frequency (MAF) >5% into an independent cohort of 486 European American children in search of replication.

Vertebral cross-sectional area: an orphan phenotype with potential implications for female spinal health.

A high priority in imaging-based research is the identification of the structural basis that confers greater risk for spinal disorders. New evidence indicates that factors related to sex influence the fetal development of the axial skeleton. Girls are born with smaller vertebral cross-sectional area compared to boys-a sexual dimorphism that is present throughout life and independent of body size.