# Novel Molecular Biomarkers of Bone Microarchitecture

> **NIH NIH R01** · HEBREW REHABILITATION CENTER FOR AGED · 2024 · $672,587

## Abstract

Dual energy x-ray absorptiometry (DXA) that is used in clinical practice to detect bone loss, may not be
sufficiently sensitive to identify those individuals who are losing structural integrity of the skeleton over time. High
resolution peripheral quantitative computed tomography (HR-pQCT) scanning can detect age-related
compartmental skeletal deterioration that independently predicts incident fracture even after considering DXA-
derived bone mineral density. This project will perform follow-up high resolution imaging in the third generation
cohort of the Framingham Study (Gen3) that will be used to assess the contributions of novel molecular
biomarkers of longitudinal deterioration of bone microarchitecture, as there are almost no longitudinal studies of
contributors to the loss of bone microarchitecture and strength. The long term goal of this research is to identify
novel molecular biomarkers of age-related changes in bone microarchitecture and strength that could be used
to predict skeletal fragility by acting as a proxy for HR-pQCT, and that identify mechanistic pathways that could
be targeted for drug development. The objective of this proposal is to determine the contribution of two different
novel molecular biomarkers to age-related changes in bone microarchitecture and incident fractures in the
Framingham Osteoporosis Study. The central hypothesis is that plasma metabolites and clonal hematopoiesis
of indeterminate potential (CHIP) will be associated with declines in bone microarchitecture and strength. The
hypotheses are based on recently generated preliminary data showing associations between these two novel
risk factors and both BMD and fracture. Aim 1 will determine the association between plasma metabolites and
a) longitudinal changes in bone microarchitecture and strength, and b) incident fracture. Approximately 700
metabolite measures have already been performed in the Gen3 cohort as well as the Offspring cohort, which will
permit a replication of findings generated the Gen3 cohort by analyzing data that will be available in the Offspring.
Aim 2 will determine the association of clonal hematopoiesis of indeterminate potential (CHIP) with bone density,
microarchitecture and strength in the Gen3 cohort after performing deep targeted sequencing of the four most
common genes implicated in CHIP (DNMT3A, TET2, ASXL1, JAK2). This proposal addresses key knowledge
gaps by using state-of-the-art technologies to identify molecular determinants of longitudinal age-related declines
in bone microarchitecture and strength in a large, well-characterized cohort. Results from this project will be
impactful, as they will provide unique insights into the molecular mechanisms underlying age-related skeletal
fragility, and may ultimately identify targets for future diagnostics and/or therapeutics. This study has the potential
to transform the field in terms of defining the impact of reduced muscle mass.

## Key facts

- **NIH application ID:** 10831499
- **Project number:** 5R01AR041398-29
- **Recipient organization:** HEBREW REHABILITATION CENTER FOR AGED
- **Principal Investigator:** DOUGLAS P. KIEL
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $672,587
- **Award type:** 5
- **Project period:** 1991-09-30 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10831499

## Citation

> US National Institutes of Health, RePORTER application 10831499, Novel Molecular Biomarkers of Bone Microarchitecture (5R01AR041398-29). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10831499. Licensed CC0.

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