Researcher Spotlight: Studying Bone Loss After Spinal Cord Injury

Joshua F. Yarrow, MS, PhD (Spotlight: January 2023)
Acting Associate Chief of Staff, Research
North Florida/South Georgia Veterans Health System
Division of Endocrinology, Diabetes, & Metabolism
University of Florida, College of Medicine

To highlight various applications of micro-CT technology, Micro Photonics will be featuring monthly Q & As with investigators working in both life science and materials science. We open this series with an interview with Joshua F. Yarrow, MS, PhD, who uses micro-CT and DEXA technology in his spinal cord injury research.

I know you are a health scientist working in the area of spinal cord injury (SCI). Can you expand briefly on what you are focused on in your research?

Severe bone loss occurs in the paralyzed limbs after spinal cord injury (SCI). To date, there is no known pharmacologic therapy or physical rehabilitation modality that has been consistently shown to prevent bone loss after SCI or to regenerate bone in the paralyzed limbs. My lab is focused on (1) identifying the molecular pathways that drive the uncoupled bone turnover and the bone loss that occurs subsequent to SCI, and (2) developing combinatory therapies that target these molecular pathways and the disuse that exists in this population.

What is important about this research today, and what are you hoping to achieve through your work?

Bone loss after SCI influences the extremely high fracture risk that exists in this population. The vast majority of fractures after SCI occur at non-traditional osteoporosis sites (i.e., distal femur and proximal tibia regions near the knee) and result in extended in-patient hospitalization that negatively impacts quality of life and increases healthcare costs. Moreover, the risks for various medical comorbidities (e.g., venous thromboembolic events, respiratory illness, and pressure ulcer) more than double in persons with SCI within one month of fracture, contributing to the 30% higher five-year mortality risk for those with fracture versus without fracture after SCI. The long-term goal of our research is to identify effective therapies to restore bone integrity and improve bone strength after SCI.

After spinal cord injury, I am assuming the patients cannot walk due to paralysis. Would the goal of preventing bone loss go beyond the specific medical issues you mention — fractures and other comorbidities — to maintain the bone heath so that with other future medical advances a patient might actually be able to walk again?

The ability to voluntarily contract muscles and to move the limbs (e.g., perform walking) after spinal cord injury (SCI) depends on the spinal level of injury and the injury severity. For example, some individuals retain walking function after SCI (termed functionally incomplete) and others are completely paralyzed below the level of the spinal lesion (termed functionally complete).

A major goal within the entire SCI field is to improve functional recovery, which includes the restoration of walking/locomotor function and improving function in other limbs/organs. If the goal of restoring walking function after SCI is achieved, individuals will require sufficient bone integrity/strength to both support the body weight during normal standing and to withstand the muscle forces that are applied to the skeleton during movement.

The Yarrow Lab focuses on improving bone integrity and bone strength. In addition, we are hopeful that walking function can be restored in the future and that our work will assist in preserving sufficient bone strength to reduce fracture risk while standing/walking.

How are you using micro-CT technology in your research?

My lab houses Skyscan 1172, 1176, and 1272 micro-CT systems, a Medikors InAlyzer rodent DEXA, and a Hologic Discovery A DEXA w/rodent imaging package. These devices are used extensively in my research to evaluate bone microstructural and bone mineral density (BMD) changes that develop in the tibia and femur in our SCI models and to evaluate the skeletal changes that result from various pharmacologic and physical rehabilitation modalities implemented after SCI. In addition, we use micro-CT to examine morphologic changes in other tissues in collaboration with investigators who study bone biology, oral biology, vascular biology, and osteoarthritis (Figures 1, 2, 3).

Figure 1: 3D micro-CT imaging of the primary nutrient artery in an undecalcified rat femur. Photo courtesy of Preclinical Musculoskeletal Imaging Core Lab at North Florida/South Georgia Veterans Health System using SkyScan 1172. © 2023 Joshua Yarrow. All rights reserved.
Figure 2: Micro-CT of primary nutrient artery in rat femur perfused with microfil® (vascular casting agent) for imaging. Photo courtesy of Preclinical Musculoskeletal Imaging Core Lab at North Florida/South Georgia Veterans Health System using SkyScan 1172. © 2023 Joshua Yarrow. All rights reserved.
Figure 3: Micro-CT images of the distal femur of a rat with longitudinal 3d sections. Photo courtesy of Preclinical Musculoskeletal Imaging Core Lab at North Florida/South Georgia Veterans Health System using SkyScan 1172. © 2023 Joshua Yarrow. All rights reserved.

Can you explain how you are using DEXA and micro-CT in conjunction in your research?

We use in vivo DEXA (Medikors InAlyzer) to track changes in whole-body and whole-bone BMD, along with body composition (fat mass and lean mass), in live lab animals throughout our longitudinal experiments. This approach allows us to determine the deficits that occur after SCI and the subsequent improvements that may occur in response to different pharmacologic or reloading-based (physical therapy) interventions.

In these studies, in vivo micro-CT (Skyscan 1176) is also used to track changes in cancellous and cortical bone microarchitecture at key bone regions (e.g., distal femur and proximal tibia) that are considered highly fracture-prone after SCI. These in vivo techniques reduce inter-animal variability by accounting for baseline bone structure, which improves data quality. We often supplement these in vivo techniques with high resolution micro-CT of excised bones (via Skyscan 1172, 1272), which improves image resolution and allows determination of outcomes that cannot typically be visualized with in vivo imaging techniques (e.g., bone microporosity).

What has been the most important discovery or unexpected outcome in your research?

Our lab was the first to identify the involvement of two distinct signaling pathways in SCI-induced bone loss (i.e., androgen signaling and Wnt signaling). In doing so, we demonstrated that pharmacologic targeting of these pathways completely prevented cancellous bone loss at the distal femur and proximal tibia in our SCI models, via distinct antiresorptive and bone anabolic actions. Both drugs have advanced to early-stage clinical trials in persons with SCI, so we are hopeful that an effective treatment for this currently unresolvable condition may be identified soon.

Selected publications:

Bone loss after severe spinal cord injury coincides with reduced bone formation and precedes bone blood flow deficits | Journal of Applied Physiology

Testosterone Plus Finasteride Prevents Bone Loss without Prostate Growth in a Rodent Spinal Cord Injury Model – PubMed (nih.gov)

Microcomputed Tomography (microCT)‐based Three‐Dimensional (3D) Image Registration to Assess Bone Loss in Spinal Cord Injured Rats

Longitudinal Examination of Bone Loss in Male Rats After Moderate-Severe Contusion Spinal Cord Injury – PubMed (nih.gov)

Sclerostin inhibition prevents spinal cord injury-induced cancellous bone loss – PubMed (nih.gov)

 

More Information:

To contact Joshua Yarrow, please email:  Joshua.Yarrow@medicine.ufl.edu

If you are interested in being featured in a future Researcher Spotlight, please contact ann@microphotonics.com. We love to hear how our instruments are being used in the field!

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