Scientists discover genetic components linked to bone density in young people

Researchers at the Children’s Hospital of Philadelphia (CHOP) have uncovered important genetic components that influence bone density in children and adolescents. This information could help identify pediatric patients who may benefit from strategies to improve their bone health at a young age, helping them maintain healthy bones and prevent fractures in adulthood.

Many children experience fractures due to accidents and recover quickly, but there are many reasons why children may have weak bones or be at risk of developing brittle bones. Chronic health conditions, dietary restrictions, and steroid use affect bone mineral metabolism. Genetics play an additional role, and while most studies have been conducted in adults for whom a fracture could be life-threatening, the role that genetics play in influencing childhood bone density has historically been much less understood. Two recent studies by researchers at CHOP explored the importance of genetic and genomic information when it comes to understanding pediatric bone development.

The first study, published in the journal Genome Biologyexamined genetic signals associated with bone mineral density previously identified by genome-wide association studies (GWAS) in adults and children. Previous studies have been unable to identify a causative gene linked to these signals.

Understanding the causative gene was related to the dynamic between osteoblasts, which form new bone tissue, and osteoclasts, which break down old bone tissue. As children grow, osteoblasts are much more active to help achieve proper bone growth.

The researchers used CRISPRi – which helps silence gene expression without cutting DNA like CRISPR-based therapies – and identified four genes (ARID5B, CC2D1B, EIF4G2and NCOA3) associated with osteoblasts and their ability to mature. In addition, the researchers found that many genetic signals associated with bone density also show their effects in other tissues, indicating that bone density may signal other potential health problems.

“With this information, we hope to further study these pediatric-specific signals and help identify which children are more likely to sustain a fracture to optimize their bone health for life,” said senior study author Struan FA Grant, PhD, Director of the Center for Spatial and Functional Genomics and the Daniel B. Burke Research Chair at DiCHa OPbetes.

The second study, published in Journal of Bone and Mineral Researchused a polygenic risk score called genetic quantitative speed of sound ultrasound (gSOS). gSOS had previously been used to study fracture risk in adults, and CHOP researchers sought to determine whether it was associated with bone health in children. This study used two observational studies and related genetic data, the Bone Density in Childhood Study (BMDCS) as well as data from CHOP’s Center for Applied Genomics spanning more than two decades.

The study found that a higher gSOS score was associated with higher bone mineral density at multiple skeletal sites and reduced odds of fracture in both observational studies. This is especially important since the researchers’ study took into account a wide range of factors, including gender, stage of puberty, dietary calcium levels, height, weight and BMI, as well as accidents that could have led to fractures.

Our study found that genetics represent a strong component of bone density across the lifespan. We were very surprised to see that the polygenic risk score could accurately predict which patients were more likely to fracture, even taking into account the normal childhood activities that we most associate with broken bones.”

Babette S. Zemel, PhD, Senior Study Author, Professor of Pediatrics at CHOP

Both methods could potentially be used to boost bone health earlier in life. While good nutrition and regular weight-bearing physical activity, especially sports like volleyball and basketball, are important for bone health, Zemel said, they remain especially useful for improving bone health even if the genetic risk of fracture is high.

The first study was supported by a University of Colorado Gates Grubstake Award, National Science Foundation grants DMS 2113072 and DMS 2310654, National Institutes of Health grants R01AI154773, R01DK122586, UL1 TR001878, R0501, R0507, R0507, R0507, R001, HD07 UM1 DK126194, The Henry Ruppenthal Family Professor of Industrial and Orthopedic Surgery and the Daniel B. Burke Endowed Chair in Diabetes Research.

The second study was supported by National Institutes of Health grants R01HD100406, R01HD58886, and UL1TR000077, and the endowed Daniel B. Burke Chair for Diabetes Research. The Bone Mineral Density in Childhood Study (BMDCS) was also supported by contracts N01-HD-1-3228, -3329, -3330, -3331, -3332, -3333, Eunice Kennedy Shriver National Institute of Child Health and Human Development.