M Saito1,2, S N Moore-Lotridge1,3, S Uppuganti1, S Egawa1,2, T Yoshii2, J P Robinette4, S L Posey4, B H Y Gibson1,5, H A Cole6, G D Hawley1, S A Guelcher3,7,8, S B Tanner9,10, J R McCarthy11, J S Nyman12,13,14,15, J G Schoenecker16,17,18,19,20,21. 1. Department of Orthopaedics and Rehabilitation, Vanderbilt University Medical Center, Nashville, TN, USA. 2. Department of Orthopaedic Surgery, Tokyo Medical and Dental University, Tokyo, Japan. 3. Center for Bone Biology, Vanderbilt University Medical Center, Nashville, TN, USA. 4. School of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA. 5. Department of Pharmacology, Vanderbilt University Medical Center, 2215-B Garland Ave, 1155 Medical Research Building 4, Nashville, TN, 37232, USA. 6. Department of Nuclear Medicine, Vanderbilt University Medical Center, Nashville, TN, USA. 7. Department of Biomedical Engineering, Vanderbilt University Medical Center, Nashville, TN, USA. 8. Department of Chemical and Biomolecular Engineering, Vanderbilt University Medical Center, Nashville, TN, USA. 9. Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA. 10. Department of Allergy, Pulmonary, and Critical Care, Vanderbilt University Medical Center, Nashville, TN, USA. 11. Department of Biomedical Research and Translational Medicine, Masonic Medical Research Institute, 2150 Bleecker St, Utica, NY, 13501, USA. 12. Department of Orthopaedics and Rehabilitation, Vanderbilt University Medical Center, Nashville, TN, USA. Jeffry.s.nyman@vanderbilt.edu. 13. Center for Bone Biology, Vanderbilt University Medical Center, Nashville, TN, USA. Jeffry.s.nyman@vanderbilt.edu. 14. Department of Biomedical Engineering, Vanderbilt University Medical Center, Nashville, TN, USA. Jeffry.s.nyman@vanderbilt.edu. 15. Department of Veterans Affairs, Tennessee Valley Health Care System, 1215 21st Ave S, Suite 4200, Nashville, TN, 37232, USA. Jeffry.s.nyman@vanderbilt.edu. 16. Department of Orthopaedics and Rehabilitation, Vanderbilt University Medical Center, Nashville, TN, USA. Jon.schoenecker@vumc.org. 17. Center for Bone Biology, Vanderbilt University Medical Center, Nashville, TN, USA. Jon.schoenecker@vumc.org. 18. Department of Pharmacology, Vanderbilt University Medical Center, 2215-B Garland Ave, 1155 Medical Research Building 4, Nashville, TN, 37232, USA. Jon.schoenecker@vumc.org. 19. Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA. Jon.schoenecker@vumc.org. 20. Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA. Jon.schoenecker@vumc.org. 21. Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, USA. Jon.schoenecker@vumc.org.
Abstract
Following severe injury, biomineralization is disrupted and limited therapeutic options exist to correct these pathologic changes. This study utilized a clinically relevant murine model of polytrauma including a severe injury with concomitant musculoskeletal injuries to identify when bisphosphonate administration can prevent the paradoxical decrease of biomineralization in bone and increased biomineralization in soft tissues, yet not interfere with musculoskeletal repair. INTRODUCTION: Systemic and intrinsic mechanisms in bone and soft tissues help promote biomineralization to the skeleton, while preventing it in soft tissues. However, severe injury can disrupt this homeostatic biomineralization tropism, leading to adverse patient outcomes due to a paradoxical decrease of biomineralization in bone and increased biomineralization in soft tissues. There remains a need for therapeutics that restore the natural tropism of biomineralization in severely injured patients. Bisphosphonates can elicit potent effects on biomineralization, though with variable impact on musculoskeletal repair. Thus, a critical clinical question remains as to the optimal time to initiate bisphosphonate therapy in patients following a polytrauma, in which bone and muscle are injured in combination with a severe injury, such as a burn. METHODS: To test the hypothesis that the dichotomous effects of bisphosphonates are dependent upon the time of administration relative to the ongoing biomineralization in reparative bone and soft tissues, this study utilized murine models of isolated injury or polytrauma with a severe injury, in conjunction with sensitive, longitudinal measure of musculoskeletal repair. RESULTS: This study demonstrated that if administered at the time of injury, bisphosphonates prevented severe injury-induced bone loss and soft tissue calcification, but did not interfere with bone repair or remodeling. However, if administered between 7 and 21 days post-injury, bisphosphonates temporally and spatially localized to sites of active biomineralization, leading to impaired fracture callus remodeling and permanence of soft tissue calcification. CONCLUSION: There is a specific pharmacologic window following polytrauma that bisphosphonates can prevent the consequences of dysregulated biomineralization, yet not impair musculoskeletal regeneration.
Following severe injury, biomineralization is disrupted and limited therapeutic options exist to correct these pathologic changes. This study utilized a clinically relevant murine model of polytrauma including a severe injury with concomitant musculoskeletal injuries to identify when bisphosphonate administration can prevent the paradoxical decrease of biomineralization in bone and increased biomineralization in soft tissues, yet not interfere with musculoskeletal repair. INTRODUCTION: Systemic and intrinsic mechanisms in bone and soft tissues help promote biomineralization to the skeleton, while preventing it in soft tissues. However, severe injury can disrupt this homeostatic biomineralization tropism, leading to adverse patient outcomes due to a paradoxical decrease of biomineralization in bone and increased biomineralization in soft tissues. There remains a need for therapeutics that restore the natural tropism of biomineralization in severely injured patients. Bisphosphonates can elicit potent effects on biomineralization, though with variable impact on musculoskeletal repair. Thus, a critical clinical question remains as to the optimal time to initiate bisphosphonate therapy in patients following a polytrauma, in which bone and muscle are injured in combination with a severe injury, such as a burn. METHODS: To test the hypothesis that the dichotomous effects of bisphosphonates are dependent upon the time of administration relative to the ongoing biomineralization in reparative bone and soft tissues, this study utilized murine models of isolated injury or polytrauma with a severe injury, in conjunction with sensitive, longitudinal measure of musculoskeletal repair. RESULTS: This study demonstrated that if administered at the time of injury, bisphosphonates prevented severe injury-induced bone loss and soft tissue calcification, but did not interfere with bone repair or remodeling. However, if administered between 7 and 21 days post-injury, bisphosphonates temporally and spatially localized to sites of active biomineralization, leading to impaired fracture callus remodeling and permanence of soft tissue calcification. CONCLUSION: There is a specific pharmacologic window following polytrauma that bisphosphonates can prevent the consequences of dysregulated biomineralization, yet not impair musculoskeletal regeneration.
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Authors: Courtney E Baker; Stephanie N Moore-Lotridge; Alexander A Hysong; Samuel L Posey; J Patton Robinette; Deke M Blum; Michael A Benvenuti; Heather A Cole; Satoru Egawa; Atsushi Okawa; Masanori Saito; Jason R McCarthy; Jeffry S Nyman; Masato Yuasa; Jonathan G Schoenecker Journal: Clin Rev Bone Miner Metab Date: 2018-12-29
Authors: Stephanie N Moore-Lotridge; Qiaoli Li; Breanne H Y Gibson; Joseph T Martin; Gregory D Hawley; Thomas H Arnold; Masanori Saito; Sami Tannouri; Herbert S Schwartz; Richard J Gumina; Justin M M Cates; Jouni Uitto; Jonathan G Schoenecker Journal: Calcif Tissue Int Date: 2018-12-04 Impact factor: 4.333
Authors: Stephanie N Moore-Lotridge; Rivka Ihejirika; Breanne H Y Gibson; Samuel L Posey; Nicholas A Mignemi; Heather A Cole; Gregory D Hawley; Sasidhar Uppuganti; Jeffry S Nyman; Jonathan G Schoenecker Journal: Bone Rep Date: 2020-12-26