Metabolic Interventions to Mitigate Acute and Chronic Bone Disease
Abstract
Fiscal Year 2022 Peer Reviewed Medical Research Program (FY22 PRMRP) Investigator-Initiated Research Award Focus Area to be addressed: This project aligns with the PRMRP Focus Area to: (1) understand the mechanisms underlying the pathobiology of associated musculoskeletal disorders, (2) develop strategies for improved care at point of injury to prevent musculoskeletal disorder onset, (3) develop and test strategies to increase quality of life or halt/slow disease progression, including regenerative medicine approaches and biologics for associated musculoskeletal disorders, and (4) understand correlations between nutrition and disease susceptibility. Specifically, we propose to validate an early dietary modification protocol/standard practice guideline and therapeutic intervention to prevent the most common complication of extremity trauma that limit return to duty: heterotopic ossification (HO). HO is the pathologic formation of extra-skeletal bone within soft tissues which occurs in patients with severe trauma and significantly limits return to duty given its cause of chronic pain and limitation of prosthetic use. This proposal has been developed to specifically address HO prevention after extremity trauma and treatment. The goal of this proposal is to validate a new standard practice guideline for a dietary protocol and a metabolite intervention to prevent posttraumatic HO in patients with severe trauma such as is seen with orthopedic and blast-related injuries. With dramatic improvements in survival from combat-related blast injuries due to tourniquet use, we have witnessed a concomitant increase in patients with debilitating injuries which drastically diminish quality of life. Of the nearly 15,000 battle injuries suffered in Operations Iraqi Freedom/New Dawn and Enduring Freedom, over 50% of those injuries were extremity injuries. Of these wounded Soldiers with extremity injuries, over 60% of them will go on to develop HO. HO also causes significant disability in hundreds of thousands of civilians and Veterans with joint arthroplasties, amputations, and orthopedic injuries. For example, over 80% of patients with fractures and revision joint replacements will develop HO. As a result of forming bone outside of the skeleton, HO causes severe chronic pain, open wounds, and limited range of motion. Current treatment strategies address HO after its development with surgical excision. However, surgery is unable to restore range-of-motion, which has often been chronically limited due to HO, cannot address chronic pain, and causes prolonged wounds with poor healing. After excision, patients often develop recurrence within the original tissue bed, which necessitates re-excision, or continues to cause the original signs and symptoms. Though several prophylactic medications have been previously trialed, all have negative side effects, and all fail to target the causative signaling mediators that lead to HO. We offer a paradigm shift in the prevention and management of HO through an easily implemented dietary protocol and a metabolite-based therapeutic with minimal adverse effects to improve our precision treatment of combat casualties with extremity trauma in a prolonged field care (PFC) scenario. Potential clinical applications, benefits, and risks: This proposal is designed to be translatable and simulates real-world PFC trauma and management that patients may expect to receive. First, we use clinically relevant models of trauma-induced HO that are broadly applicable to combat-wounded military personnel and to civilians with significant trauma. Secondly, we utilize an approved metabolite (itaconate) and diet strategy; this method is highly translatable, cost-effective and easily implemented. Thirdly, this proposal addresses duration of treatment by selecting a short time period of treatment to minimize cost, improve adherence, and avoid adverse consequences. The combination of these techniques makes thi
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310535
Entities
People
- Benjamin Lévi
Organizations
- United States Army
- University of Texas Southwestern Medical Center