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Determining the pharmacologic window of bisphosphonates that mitigates severe injury-induced osteoporosis and muscle calcification, while preserving fracture repair

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Abstract

Summary

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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Availability of data and material

All pertinent data can be found within the following manuscript. Raw data will be provided by the senior author upon request.

Code availability

Not applicable

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Acknowledgements

The authors would like to thank the members of the Schoenecker lab, in particular Mr. Zachary Backstrom, Mr. J. Court Reese, Dr. Joey Barnett, Dr. Rivka Ihejirika, Dr. Alex Hysong, and Dr. Deke Blum, for their experimental assistance, and help in critically reviewing this manuscript. We would also like to acknowledge our family, friends, and academic colleagues for supporting this work. Finally, we would like to acknowledge the Vanderbilt Small Animal-Imaging Core and the Vanderbilt Animal Care staff for supplying and maintaining the imaging equipment and our animal facility, respectively.

Funding

Funding for this work was provided by the National Institutes of Health ([1R01GM126062-01A1, NIGMS, JGS], [T32GM007628, NIGMS, SNML], [T32AR059039, NIAMS, BGHY], [1F31HL149340, NHLBI, BGHY]), the Vanderbilt University Medical Center Department of Orthopaedics and Rehabilitation (JGS), the Jeffrey W. Mast Chair in Orthopaedics Trauma and Hip Surgery (JGS), the Department of Veterans Affairs (JSN, BX005062), and the Caitlin Lovejoy Fund (JGS). Use of the Translational Pathology Shared Resource was supported by NCI/NIH Cancer Center Support Grant (2P30 CA068485-14) and the Vanderbilt Mouse Metabolic Phenotyping Center Grant (5U24DK059637-13). μCT imaging and analysis were supported in part by the Center for Small Animal Imaging at the Vanderbilt University Institute of Imaging Sciences (S10RR027631) from the NIH. Grant 1S10OD021804-01A1 supported the Replacement and Upgrade of an Optical Imaging System for Small Animals, housed in the Vanderbilt Center for Small Animal Imaging, and used in this proposal. Funding sources for this project had no involvement in study design, collection, and analysis of data, writing of the report, or decision in submitting this article for publication.

Author information

Author notes

  1. M. Saito and S.N. Moore-Lotridge contributed equally to this work.

Authors and Affiliations

  1. Department of Orthopaedics and Rehabilitation, Vanderbilt University Medical Center, Nashville, TN, USA

    M. Saito, S. N. Moore-Lotridge, S. Uppuganti, S. Egawa, B. H. Y. Gibson, G. D. Hawley, J. S. Nyman & J. G. Schoenecker

  2. Department of Orthopaedic Surgery, Tokyo Medical and Dental University, Tokyo, Japan

    M. Saito, S. Egawa & T. Yoshii

  3. Center for Bone Biology, Vanderbilt University Medical Center, Nashville, TN, USA

    S. N. Moore-Lotridge, S. A. Guelcher, J. S. Nyman & J. G. Schoenecker

  4. School of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA

    J. P. Robinette & S. L. Posey

  5. Department of Pharmacology, Vanderbilt University Medical Center, 2215-B Garland Ave, 1155 Medical Research Building 4, Nashville, TN, 37232, USA

    B. H. Y. Gibson & J. G. Schoenecker

  6. Department of Nuclear Medicine, Vanderbilt University Medical Center, Nashville, TN, USA

    H. A. Cole

  7. Department of Biomedical Engineering, Vanderbilt University Medical Center, Nashville, TN, USA

    S. A. Guelcher & J. S. Nyman

  8. Department of Chemical and Biomolecular Engineering, Vanderbilt University Medical Center, Nashville, TN, USA

    S. A. Guelcher

  9. Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA

    S. B. Tanner & J. G. Schoenecker

  10. Department of Allergy, Pulmonary, and Critical Care, Vanderbilt University Medical Center, Nashville, TN, USA

    S. B. Tanner

  11. Department of Biomedical Research and Translational Medicine, Masonic Medical Research Institute, 2150 Bleecker St, Utica, NY, 13501, USA

    J. R. McCarthy

  12. Department of Veterans Affairs, Tennessee Valley Health Care System, 1215 21st Ave S, Suite 4200, Nashville, TN, 37232, USA

    J. S. Nyman

  13. Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA

    J. G. Schoenecker

  14. Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, USA

    J. G. Schoenecker

Authors
  1. M. Saito
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  2. S. N. Moore-Lotridge
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Contributions

MS*: data curation; formal analysis; methodology; validation; visualization; writing—reviews and editing

SNML*: data curation; formal analysis; methodology; validation; visualization; writing of original draft; writing—reviews and editing

SU: data curation; formal analysis; methodology; visualization; writing—reviews and editing

JPR: data curation; visualization; writing of original draft; writing—reviews and editing

SLP: data curation; visualization; writing of original draft; writing—reviews and editing

BHYG: validation; visualization; writing—reviews and editing

HAC: formal analysis; visualization; writing—reviews and editing

SE: data curation; formal analysis; methodology; writing—reviews and editing

TY: project administration; resources; supervision; writing—reviews and editing

SAG: formal analysis; methodology; writing—reviews and editing

JRM: formal analysis; resources; validation; visualization; writing—reviews and editing

SBT: formal analysis; methodology; writing—reviews and editing

JSN: formal analysis; methodology; validation; visualization; writing—reviews and editing

JGS: formal analysis; funding acquisition; project administration; supervision; writing of original draft; writing—reviews and editing

*Authors share authorship position. Order was agreed upon by authors in relation to present work, seniority, and future publications in which authorship order will be reversed.

Corresponding authors

Correspondence to J. S. Nyman or J. G. Schoenecker.

Ethics declarations

Ethics approval

Two murine models were examined as part of this study. All animal procedures were approved by the Vanderbilt Institutional Animal Care and Use Committee (M1600231 and M1600225). No human studies were conducted as part of this study.

Conflict of interest

JGS receives research funding and research support from IONIS Pharmaceuticals, PXE International, OrthoPediatrics, the United States Department of Defense, and the National Institutes of health. SNML receives research funding unrelated to this study from the American Society of Bone and Mineral Research (ASBMR). SLP is a member of the US Air Force. All other authors declare no competing interests.

Disclaimer

The views expressed in this article are those of the author and do not reflect the official policy or position of the US Air Force, Department of Defense, or the US Government.

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Supplementary information

Supplemental Figure 1

BALB/cJ mice Develop Soft Tissue Calcification Following Injury. Aligning with the previously reported genetic predisposition for soft tissue calcification [20,21,22], when skeletal muscle is injured, BALB/cJ mice develop marked dystrophic calcification that progressivly regresses over 28DPI. A) Logitudinal xray and end-point μCT analysis (Scale bar: 1mm) allow for the sensitive detection of calcification within skeletal muscle. Yellow outlines; soft tissue calcification within the injured lower limb. Comparatively, wild type C57BL/6J mice that possess no known genetic prediposition to soft tissue calcification do not develop detectable soft tissue calcification following muscle injury alone [7, 10]. B) Soft tissue calcification detected in BALB/cJ mice by xray can be quantified via the soft tissue calcification scoring system (STiCSS) [28]. Different colored lines denote individual, 6-week-old animals (N=5). C) Example histologic images (20x magnification) at 7 and 28 DPI illustratating marked soft tissue calcification in areas of damaged skeletal muscle in BALB/cJ mice that regress over 28 days. Hematoxylin and eosin (H&E) staining is utilized to denote skeletal muscle morphology. Von kossa staining denotes calcium deposits (black). Scale bar denotes 100 microns. (PNG 3871 kb)

High resolution image (TIF 11249 kb)

Supplemental Figure 2

Modified Soft Tissue Calcification Scoring System for use in Quadriceps. Images represent an ordinal scale from 0-4, with “4” representing robust calcification of greater or equal to 75% of the visible quadriceps area becoming mineralized, “3” representing 50-74% calcification of the visible quadriceps, “2” represent 25-49% calcification of the visible quadriceps, “1” representing less than 25% calcification of the quadriceps, and 0 representing no visible calcification within the quadriceps. (PNG 3482 kb)

High resolution image (TIF 6725 kb)

Supplemental Figure 3

μCT-FEA of Fracture Callus on femur mid-shaft. Boundary conditions prescribed a unit torque around the vertical axis. Displacement of nodes at the distal face (z=zmin) were fixed in all directions. At the proximal face (z=zmax), force vectors in the transverse plane (i.e. x- and y-directions) were distributed to impart a unit torque that twists the bone about center. (PNG 1868 kb)

High resolution image (TIF 3084 kb)

Supplemental Figure 4

Histological analysis of injured quadriceps at 42 DPI. Marked nodules of dystrophic calcification are still observed at 42 DPI within the damaged skeletal muscle of mice administered zoledronate beginning 7 DPI and continuing weekly through 42 DPI. N=3 animals assessed per treatment cohort. Pre-dosing: administration of zoledronate 7 days before injury and at the time of injury (pre-dosing). Continual dosing: administration of zoledronate weekly beginning 7 DPI and continuing through 42 DPI. (PNG 11574 kb)

High resolution image (TIF 38378 kb)

Supplemental Figure 5

Two Dimensional Images of Fracture Femur at 42 DPI. Axial, coronal and sagittal Images obtained following μCT imaging of two-dimensional planes of section. White arrows indicate the detection of calcified skeletal muscle, as previously visualized in 3D reconstructions (Fig. 3C); yellow arrows indicate enlarged fracture callus as quantified in Fig. 4A&B. Images are representative of the cohort. Scale bare = 1.0mm. BP: bisphosphonate. Pre-dosing: administration of zoledronate 7 days before injury and at the time of injury (pre-dosing). Continual dosing: administration of zoledronate weekly beginning 7 DPI and continuing through 42 DPI. (PNG 12617 kb)

High resolution image (TIF 17041 kb)

Supplementary Table 1

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Saito, M., Moore-Lotridge, S.N., Uppuganti, S. et al. Determining the pharmacologic window of bisphosphonates that mitigates severe injury-induced osteoporosis and muscle calcification, while preserving fracture repair. Osteoporos Int 33, 807–820 (2022). https://doi.org/10.1007/s00198-021-06208-7

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