ERS5719. Bone Integrity, Epigenetic Modification, and the Risk of Aging
Authors * Denotes Presenting Author
  1. Katherine Van Schaik *; Vanderbilt University Medical Center
  2. Natassja Brien; McMaster University
  3. Sasidhar Uppuganti; Vanderbilt University Medical Center
  4. Hendrik Poinar; McMaster University
  5. Jeffry Nyman; Vanderbilt University Medical Center
  6. Yi-Hsiang Hsu; Harvard Medical School; Marcus Center for Aging Research
  7. Jim Wu; Beth Israel Deaconess Medical Center; Harvard Medical School
Osteoporosis (OP) and osteopenia affect more than 60 million Americans - a number rapidly growing as the population ages - and are associated with great morbidity and mortality from insufficiency fractures. Screening and treatment for OP and osteopenia are limited, facilitating intervention only in more advanced stages. Imaging, when coupled with assessment of epigenetic modification of genes implicated in OP, may provide new opportunities for disease monitoring and intervention, especially in early stages. The growing field of epigenetics has facilitated assessment of aging and its comorbidities at a molecular and genetic level, including the aging of bone. For example, although bone mineral density (BMD)-associated loci discovered by genome-wide association studies explain up to 6% of BMD variation, methylation levels at five CpGs that differ significantly between healthy and osteoporotic women explain 14% of BMD variation. Despite these promising findings, there is a lack of understanding of the connection between epigenetic modification of genes and imaged bone findings. This is a crucial gap in existing knowledge that this project seeks to fill. Specifically, our research correlates CT findings with epigenetic modification of genes implicated in OP, as well as genes implicated in the “epigenetic clock” that some interpret as a marker of premature aging. Besides clinical applications, our study also has implications for forensic and archaeological applications, as methylation and bone integrity metrics, as determined by imaging, can assist in the assessment of age and health status of otherwise unidentified individuals.

Materials and Methods:
This project uses imaging and epigenetic data from three different cohorts: a modern clinical cohort (male and female), a modern postmortem cohort (male and female), and a historical (19th century) postmortem cohort (male only). Bone samples were assessed for methylation at 63 loci shown to demonstrate differing degrees of methylation between healthy and osteoporotic women. Findings were then compared to metrics of femoral bone integrity, including cortical thickness (CTh), cortical bone mineral density (CBMD), cortical mass surface density (CMSD), and endocortical trabecular density (ECTD).

Initial results indicate that epigenetic modification of genes implicated in osteoporosis are correlated with metrics of reduced bone integrity, and that these findings are observed in both men and women.

Ultimately, our results will facilitate identification of early evidence of bony changes in younger patients, predating a disease state, which will allow for earlier intervention and identify targets for pharmacological intervention based on epigenetic patterns. Notably, a 13-year study recently demonstrated that reversal of epigenetic modification at set loci can reverse cellular evidence of aging. It is hoped that a deeper understanding of the epigenetic mechanisms associated with imaged findings of reduced bone strength will also provide potential molecular targets for therapeutic intervention.