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.

Public Health Relevance

/ HEALTH RELEVANCE Radiation therapy is an effective and invaluable tool for treating cancer, however post-radiotherapy fragility fractures of the skeleton remain a significant health concern. The goal of this work is to preserve normal, intrinsic bone repair processes by protecting the patient's bone cells from radiation damage. These studies focus on identifying when and how bone cells are damaged by radiation, and will test the ability of short-term drug treatments to prevent this damage and restore long-term skeletal health.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR070142-04
Application #
9989584
Study Section
Skeletal Biology Structure and Regeneration Study Section (SBSR)
Program Officer
Chen, Faye H
Project Start
2017-08-01
Project End
2022-07-31
Budget Start
2020-08-01
Budget End
2021-07-31
Support Year
4
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Upstate Medical University
Department
Orthopedics
Type
Schools of Medicine
DUNS #
058889106
City
Syracuse
State
NY
Country
United States
Zip Code
13210