Translating Metabolic Responses to Mechanical Insult into Early Interventions to Prevent PTOA
Abstract
We propose a research program that addresses the Topic Areas and Areas of Encouragement Arthritis, Musculoskeletal Disorders, and Post-Traumatic Osteoarthritis (PTOA). Progressive loss of the smooth surface of a joint causes pain, joint stiffness, deformity, and inability to stay active, a condition called osteoarthritis (OA). The pain is frequently severe and debilitating, and the loss of mobility limits work and recreational activities. Joint injuries and, in particular, joint fractures cause a common form of OA termed PTOA. Nearly half of patients with joint fractures have poor results because of PTOA, despite best current treatments. PTOA is a severe, unsolved, and regrettably common problem. In the United States, it affects over six million civilians at a cost of nearly 15 billion dollars annually. Ankle PTOA is as disruptive to patients’ lives as end-stage kidney disease and congestive heart failure. PTOA is the number one disabling condition leading to medical discharge of Wounded Warriors from active duty and the most common cause of permanent disability in U.S. Service personnel due to combat injuries. It is largely a disease of young active people. In civilians, 76% of joint fractures occur in patients less than 45 years old; in military populations, 60% of patients who sustained war-related joint injuries were less than 30 years of age. Unfortunately, once PTOA begins, it is progressive and irreversible, and despite decades of surgical advances in joint fracture treatment, the risk of developing PTOA following joint fracture has not decreased. Therefore, there is a critical need to find new treatments that prevent PTOA after joint fracture: the goal of this research program. Unlike many diseases in which the time of onset is unknown, PTOA caused by joint fractures arises from a single, known event. This offers the opportunity to begin therapies after injury, but before the disease begins. We have discovered that after injury there is a sequence of cellular reactions leading a fractured joint to develop PTOA. We have also identified a drug, amobarbital, that when injected in a fractured injured joint, prevented PTOA (in a large animal model). This proposal will test amobarbital in a group human of patients who have a joint fracture that puts them at high risk for PTOA. We will also further optimize its use in an animal model by combining it with other treatments and assess amobarbital’s effect on a wide range of injuries that can occur in a joint. We have developed a method for predicting risk of developing PTOA based on the severity of a joint fracture and joint smoothness after treatment, which will allow us to intervene in patients most in need of help. Based on our previous work, we designed this research program to develop and begin to use clinically effective joint fracture treatments. Our goals are to improve the results of patients with joint fractures at high risk of PTOA by developing: (1) methods of identifying patients at greatest risk of PTOA, (2) customized bracing that will protect injured joints during healing, and (3) joint injection therapies that prevent or minimize PTOA and can be used safely by a wide range of medical personnel in most civilian and military environments. We propose four projects based on the hypotheses that PTOA after a joint fracture results from cellular responses to the joint injury, that a single injection of a therapeutic agent can inhibit or prevent these cellular responses in humans, and that improved joint lubrication and individualized bracing can reduce PTOA following joint fracture. Project 1 is a patient study that will assess safety and begin to evaluate effectiveness of amobarbital joint injections for preventing PTOA from developing after ankle joint fractures. In Project 2, we propose to use clinical imaging-based methods to accurately measure severity of a joint fracture and any ongoing abnormal joint loading after the fracture is tr
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810658
Entities
People
- Joseph Buckwalter
Organizations
- United States Army
- University of Iowa