Differences in Bone Strength across the Skeleton Have Genetic Roots

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Children's Hospital of Philadelphia (CHOP) researchers with a longstanding focus on pediatric bone health have used a clever method to analyze discrepancies in bone density across the skeleton, teasing out genetic factors that could eventually help physicians prevent osteoporosis.

“We leveraged a different way to look at the skeleton,” said genomics researcher Jonathan A. Mitchell, PhD. Mitchell and colleagues Struan F.A. Grant, PhD, and Babette S. Zemel, PhD, have long collaborated in investigating genetic contributions to lifelong bone health. They have drawn on a trove of data from the NIH-sponsored Bone Mineral Density in Childhood Study (BMDCS), which measured bone mineral density and other data in over 2,000 healthy 6- to 18-year-olds at five centers from 2002 to 2009. Zemel, who directs CHOP’s Nutrition and Growth Laboratory, led the CHOP site for that study.

“Multiple genes play a role in bone density, and while dozens of gene variants have been discovered, many remain unknown,” said Mitchell. “But we have a unique advantage with the BMDCS data—a large pediatric cohort with bone data from sites all over the skeleton.”

Because bone accrual ends in early adulthood but has major consequences for the risk of osteoporosis in later life, a comprehensive understanding of the biology of bone accretion could inform early intervention and potentially have a large impact on public health. In osteoporosis, effects are not uniform—a patient may have normal bone density in the hip, but low density in the lower spine, an example of what the scientists call a discordant phenotype.

Bone densities that are consistent across the skeleton are called concordant. In a BMDCS longitudinal cohort of 1,293 children, the CHOP team used a novel analytical approach to sort out gene variants that were associated with discordant versus concordant skeletal measurements.

The team learned that most of the genetic variants for bone mineral density previously discovered are linked to a concordant model of the skeleton. They discovered novel variants linked to a discordant model, suggesting that many more remain to be discovered. “This study is a proof-of-principle for larger genomic efforts to further unveil genetic regulation of the pediatric skeleton,” said Mitchell. “Because a significant proportion of osteoporosis cases follow a discordant model, it’s important to better understand the underlying genetics and biology, with the aim of designing more precise treatments and preventive strategies.”

Jonathan A. Mitchell et al, “Multi-dimensional bone density phenotyping reveals new insights in genetic regulation of the pediatric skeleton,” Journal of Bone and Mineral Research, published online Dec. 14, 2017.

Contact: The Children’s Hospital of Philadelphia,

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