# Reducing Post-Radiotherapy Bone Fragility Through Orchestrated Cell Survival

> **NIH NIH R01** · UPSTATE MEDICAL UNIVERSITY · 2021 · $345,708

## Abstract

PROJECT SUMMARY
Post-radiotherapy fragility fractures of the skeleton are a prevalent complication in patients following treatment
for urologic, gynecologic, and lung cancers. Commonly occurring in the pelvis and ribs, these fractures may
have potentially devastating effects, including amputation when occurring in the extremities. The unpredictable,
late onset nature and variable pathology of these fragility fractures contribute to the lack of clinical
interventions. Radiation therapy (RTx) has been shown to induce an early, transient increase in osteoclast
numbers with substantial concurrent osteoclastic bone resorption, followed by long-term loss of osteoclasts.
This results in loss of trabecular bone that does not later regenerate. Depletion of osteoclasts prevents
homeostatic remodeling, resulting in unopposed anabolic modeling and persistence of lower quality radiation-
damaged bone matrix. Functionally, this manifests as material embrittlement and increased fracture risk.
These findings suggest that modulating marrow progenitor cell responses following RTx could improve the
morphology and quality of bone by recoupling osteoblast-osteoclast signaling, thereby reducing fracture risk.
Studies in animal models of RTx have demonstrated bisphosphonate (e.g. zoledronic acid, ZA) and
parathyroid hormone (PTH) interventions show some promise in attenuating select aspects of radiation
damage to bone. Unfortunately neither drug alone has demonstrated long-term efficacy in maintaining matrix
quality, osteoclastic remodeling, and bone strength. There is direct evidence that PTH can act as a
radioprotectant for sensitive hematopoietic progenitor populations, and indirect indications that PTH may also
preserve osteoclastogenic potential of marrow cells, and thereby maintain long-term homeostatic remodeling.
Using an established mouse model of limited field, clinically relevant fractionated irradiation, this proposal will
investigate the natural time course and pharmacologic modulation of RTx-induced bone fragility in terms of
local and distant cellular, tissue, and mechanical functions. Specifically, the goals are to 1) use an in vitro
approach to identify RTx-upregulation of cytokine production by primary marrow cells that may regulate bone
damage outside the irradiated field, comparing human and murine responses; 2) characterize the progression
of marrow progenitor cell damage and recovery cycles post-RTx, including osteoblastic and osteoclastic
lineages; 3) determine the efficacy of PTH as a progenitor cell radioprotectant; and 4) evaluate a short, tailored
PTH–ZA co-treatment for radioprotection of progenitor cells, normalizing matrix remodeling, and restoring bone
strength. Our overall goal is to identify translatable strategies to preserve post-RTx local and systemic bone
quality and strength long-term, compatible with the clinical manifestation of fragility fractures years post-RTx.

## Key facts

- **NIH application ID:** 10226949
- **Project number:** 5R01AR070142-05
- **Recipient organization:** UPSTATE MEDICAL UNIVERSITY
- **Principal Investigator:** Megan Elizabeth Oest
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $345,708
- **Award type:** 5
- **Project period:** 2017-08-01 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10226949

## Citation

> US National Institutes of Health, RePORTER application 10226949, Reducing Post-Radiotherapy Bone Fragility Through Orchestrated Cell Survival (5R01AR070142-05). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10226949. Licensed CC0.

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