Children’s Hospital of Philadelphia researchers identify genetic factors influencing bone density in pediatric patients

(Press-News.org) Philadelphia, November 19, 2025 – Researchers at Children’s Hospital of Philadelphia (CHOP) revealed important genetic components that affect bone density in children and adolescents. This information could help identify pediatric patients who may benefit from strategies to help improve their bone health at an early 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 for developing fragile bones. Chronic health conditions, dietary restrictions and steroid use all impact bone mineral metabolism. Genetics plays an additional role, and while most studies have been conducted on adults for whom a fracture could be life-threatening, the role that genetics plays in affecting bone mineral density during childhood has historically been much less understood. Two recent studies from 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 Biology, looked at genetic signals associated with bone mineral density that had been previously identified by genome-wide association studies (GWAS) across adults and children. Prior studies had not been able to identify a causal gene linked to those signals.

Understanding the causal gene was related to the dynamic between osteoblasts, which form new bone tissue, and osteoclasts, which break down old bone tissue. When children are growing, osteoblasts are far more active to help achieve proper bone growth.

The researchers used CRISPRi – which helps silence gene expression without cutting the DNA like CRISPR-based therapies – and identified four genes (ARID5B, CC2D1B, EIF4G2, and NCOA3) that are linked to osteoblasts and their ability to mature. Additionally, the researchers found that many genetic signals associated with bone mineral density also exhibit their effects on other tissues, indicating that bone density might signify other potential health issues.

“With this information, our hope is to further study these signals specifically in pediatrics and help identify which children are more likely to get a fracture to optimize their bone health for life,” said senior study author Struan F.A. Grant, PhD, Director of the Center for Spatial and Functional Genomics and the Daniel B. Burke Endowed Chair for Diabetes Research at CHOP.

The second study, published in the Journal of Bone and Mineral Research, used a polygenic risk score called genetic quantitative ultrasound speed of sound (gSOS). gSOS had been previously used to study the risk of fracture in adults, and CHOP researchers sought to determine whether it was associated with bone health in children. This study utilized two observational studies and associated genetic data, the Bone Mineral 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 across both observational studies. This is particularly important since the researchers’ investigation accounted for a wide range of factors, including sex, puberty stage, levels of calcium in the diet, height, weight and BMI, as well as accidents that could have resulted in fractures.

“Our study found that genetics represent a powerful component of bone density across the entire lifespan,” said senior study author Babette S. Zemel, PhD, Professor of Pediatrics at CHOP. “We were very surprised to see that the polygenic risk score could accurately predict which patients were more likely to experience a fracture, even accounting for the normal childhood activities we most closely associate with broken bones.”

Both methods could potentially be utilized to enhance bone health earlier in life. While a good diet and regular weight bearing physical activity, particularly sports like volleyball and basketball, are important for bone health, Zemel said, these remain particularly helpful for improving bone health even if genetic risk of fracture is high.

The first study was supported by the University of Colorado Gates Grubstake Award, the National Science Foundation grants DMS 2113072 and DMS 2310654, National Institutes of Health grants R01AI154773, R01DK122586, UL1 TR001878, R01 HD100406, R01 AG072705, and  UM1 DK126194, the Henry Ruppenthal Family Professorship for Bioengineering and Orthopaedic Surgery and the Daniel B. Burke Endowed Chair for Diabetes Research.

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

Conery et al, “GWAS‑informed data integration and non‑coding CRISPRi screen illuminate genetic etiology of bone mineral density.” Genome Biol. Online October 3, 2025. DOI: 10.1186/s13059-025-03802-4.

Mitchell et al, “The gSOS Polygenic Score is Associated with Bone Density and Fracture Risk in Childhood.” J Bone Miner Res. Online October 14, 2025. DOI: 10.1093/jbmr/zjaf149.

About Children’s Hospital of Philadelphia: 
A non-profit, charitable organization, Children’s Hospital of Philadelphia was founded in 1855 as the nation’s first pediatric hospital. Through its long-standing commitment to providing exceptional patient care, training new generations of pediatric healthcare professionals, and pioneering major research initiatives, the hospital has fostered many discoveries that have benefited children worldwide. Its pediatric research program is among the largest in the country. The institution has a well-established history of providing advanced pediatric care close to home through its CHOP Care Network, which includes more than 50 primary care practices, specialty care and surgical centers, urgent care centers, and community hospital alliances throughout Pennsylvania and New Jersey. CHOP also operates the Middleman Family Pavilion and its dedicated pediatric emergency department in King of Prussia, the Behavioral Health and Crisis Center (including a 24/7 Crisis Response Center) and the Center for Advanced Behavioral Healthcare, a mental health outpatient facility. Its unique family-centered care and public service programs have brought Children’s Hospital of Philadelphia recognition as a leading advocate for children and adolescents. For more information, visit https://www.chop.edu.

 

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