Browsing by Author "Surowiec, Rachel K."
Now showing 1 - 9 of 9
Results Per Page
Sort Options
Item Assessing cortical bone porosity with MRI in an animal model of chronic kidney disease(Elsevier, 2023) Newman, Christopher L.; Surowiec, Rachel K.; Swallow, Elizabeth A.; Metzger, Corinne E.; Kim, Jieun; Tomaschke, Andrew A.; Chen, Neal X.; Allen, Matthew R.; Wallace, Joseph M.; Moe, Sharon M.; Wu, Yu-Chien; Niziolek, Paul J.; Radiology and Imaging Sciences, School of MedicineChronic kidney disease (CKD) is characterized by secondary hyperparathyroidism and an increased risk of hip fractures predominantly related to cortical porosity. Unfortunately, bone mineral density measurements and high-resolution peripheral computed tomography (HR-pQCT) imaging have shortcomings that limit their utility in these patients. Ultrashort echo time magnetic resonance imaging (UTE-MRI) has the potential to overcome these limitations by providing an alternative assessment of cortical porosity. The goal of the current study was to determine if UTE-MRI could detect changes in porosity in an established rat model of CKD. Cy/+ rats (n = 11), an established animal model of CKD-MBD, and their normal littermates (n = 12) were imaged using microcomputed tomography (microCT) and UTE-MRI at 30 and 35 weeks of age (which approximates late-stage kidney disease in humans). Images were obtained at the distal tibia and the proximal femur. Cortical porosity was assessed using the percent porosity (Pore%) calculated from microCT imaging and the porosity index (PI) calculated from UTE-MRI. Correlations between Pore% and PI were also calculated. Cy/+ rats had higher Pore% than normal rats at both skeletal sites at 35 weeks (tibia = 7.13 % +/- 5.59 % vs. 0.51 % +/- 0.09 %, femur = 19.99 % +/- 7.72 % vs. 2.72 % +/- 0.32 %). They also had greater PI at the distal tibia at 30 weeks of age (0.47 +/- 0.06 vs. 0.40 +/- 0.08). However, Pore% and PI were only correlated in the proximal femur at 35 weeks of age (ρ = 0.929, Spearman). These microCT results are consistent with prior studies in this animal model utilizing microCT imaging. The UTE-MRI results were inconsistent, resulting in variable correlations with microCT imaging, which may be related to suboptimal bound and pore water discrimination at higher magnetic field strengths. Nevertheless, UTE-MRI may still provide an additional clinical tool to assess fracture risk without using ionizing radiation in CKD patients.Item Bone hydration: How we can evaluate it, what can it tell us, and is it an effective therapeutic target?(Elsevier, 2021-12-21) Surowiec, Rachel K.; Allen, Matthew R.; Wallace, Joseph M.; Anatomy, Cell Biology and Physiology, School of MedicineWater constitutes roughly a quarter of the cortical bone by volume yet can greatly influence mechanical properties and tissue quality. There is a growing appreciation for how water can dynamically change due to age, disease, and treatment. A key emerging area related to bone mechanical and tissue properties lies in differentiating the role of water in its four different compartments, including free/pore water, water loosely bound at the collagen/mineral interfaces, water tightly bound within collagen triple helices, and structural water within the mineral. This review summarizes our current knowledge of bone water across the four functional compartments and discusses how alterations in each compartment relate to mechanical changes. It provides an overview on the advent of- and improvements to- imaging and spectroscopic techniques able to probe nano-and molecular scales of bone water. These technical advances have led to an emerging understanding of how bone water changes in various conditions, of which aging, chronic kidney disease, diabetes, osteoporosis, and osteogenesis imperfecta are reviewed. Finally, it summarizes work focused on therapeutically targeting water to improve mechanical properties.Item Changes in Bone Quality after Treatment with Etelcalcetide(Wolters Kluwer, 2023) Khairallah, Pascale; Cherasard, Jenna; Sung, Joshua; Agarwal, Sanchita; Aponte, Maria Alejandra; Bucovsky, Mariana; Fusaro, Maria; Silberzweig, Jeffrey; Frumkin, Gail N.; El Hachem, Karim; Schulman, Linda; McMahon, Donald; Allen, Matthew R.; Metzger, Corinne E.; Surowiec, Rachel K.; Wallace, Joseph; Nickolas, Thomas L.; Anatomy, Cell Biology and Physiology, School of MedicineIntroduction: Secondary hyperparathyroidism is associated with osteoporosis and fractures. Etelcalcetide is an intravenous calcimimetic for the control of hyperparathyroidism in patients on hemodialysis. Effects of etelcalcetide on the skeleton are unknown. Methods: In a single-arm, open-label, 36-week prospective trial, we hypothesized that etelcalcetide improves bone quality and strength without damaging bone-tissue quality. Participants were 18 years or older, on hemodialysis ≥1 year, without calcimimetic exposure within 12 weeks of enrollment. We measured pretreatment and post-treatment areal bone mineral density by dual-energy X-ray absorptiometry, central skeleton trabecular microarchitecture by trabecular bone score, and peripheral skeleton volumetric bone density, geometry, microarchitecture, and estimated strength by high-resolution peripheral quantitative computed tomography. Bone-tissue quality was assessed using quadruple-label bone biopsy in a subset of patients. Paired t tests were used in our analysis. Results: Twenty-two participants were enrolled; 13 completed follow-up (mean±SD age 51±14 years, 53% male, and 15% White). Five underwent bone biopsy (mean±SD age 52±16 years and 80% female). Over 36 weeks, parathyroid hormone levels declined 67%±9% ( P < 0.001); areal bone mineral density at the spine, femoral neck, and total hip increased 3%±1%, 7%±2%, and 3%±1%, respectively ( P < 0.05); spine trabecular bone score increased 10%±2% ( P < 0.001); and radius stiffness and failure load trended to a 7%±4% ( P = 0.05) and 6%±4% increase ( P = 0.06), respectively. Bone biopsy demonstrated a decreased bone formation rate (mean difference -25±4 µ m 3 / µ m 2 per year; P < 0.01). Conclusions: Treatment with etelcalcetide for 36 weeks was associated with improvements in central skeleton areal bone mineral density and trabecular quality and lowered bone turnover without affecting bone material properties.Item Enhanced Bone Size, Microarchitecture, and Strength in Female Runners with a History of Playing Multidirectional Sports(Wolters Kluwer, 2022-12) Warden, Stuart J.; Sventeckis, Austin M.; Surowiec, Rachel K.; Fuchs, Robyn K.; Physical Therapy, School of Health and Human SciencesPurpose: Female runners have high rates of bone stress injuries (BSIs), including stress reactions and fractures. The current study explored multidirectional sports (MDS) played when younger as a potential means of building stronger bones to reduce BSI risk in these athletes. Methods: Female collegiate-level cross-country runners were recruited into groups: 1) RUN: history of training and/or competing in cross-country, recreational running/jogging, swimming and/or cycling only and 2) RUN+MDS: additional prior history of training and/or competing in soccer or basketball. High-resolution peripheral quantitative computed tomography was used to assess the distal tibia, common BSI sites (diaphysis of the tibia, fibula and 2nd metatarsal), and high-risk BSI sites (base of the 2nd metatarsal, navicular and proximal diaphysis of the 5th metatarsal). Scans of the radius were used as control sites. Results: At the distal tibia, RUN+MDS (n=18) had enhanced cortical area (+17.1%) and thickness (+15.8%) and greater trabecular bone volume fraction (+14.6%) and thickness (+8.3%) compared to RUN (n=14) (all p<0.005). Failure load was 19.5% higher in RUN+MDS (p<0.001). The fibula diaphysis in RUN+MDS had 11.6% greater total area and 11.1% greater failure load (all p≤0.03). At the 2nd metatarsal diaphysis, total area in RUN+MDS was 10.4% larger with greater cortical area and thickness and 18.6% greater failure load (all p<0.05). RUN+MDS had greater trabecular thickness at the base of the 2nd metatarsal and navicular and greater cortical area and thickness at the proximal diaphysis of the 5th metatarsal (all p≤0.02). No differences were observed at the tibial diaphysis or radius. Conclusion: These findings support recommendations that athletes delay specialization in running and play MDS when younger to build a more robust skeleton and potentially prevent BSIs.Item Ex vivo Exposure to Calcitonin or Raloxifene Improves Mechanical Properties of Diseased Bone through Non-cell Mediated Mechanisms(Elsevier, 2023) Surowiec, Rachel K.; Saldivar, Rosario; Rai, Ratan K.; Metzger, Corinne E.; Jacobson, Andrea M.; Allen, Matthew R.; Wallace, Joseph M.; Radiology and Imaging Sciences, School of MedicineRaloxifene (RAL) reduces clinical fracture risk despite modest effects on bone mass and density. This reduction in fracture risk may be due to improved material level-mechanical properties through a non-cell mediated increase in bone hydration. Synthetic salmon calcitonin (CAL) has also demonstrated efficacy in reducing fracture risk with only modest bone mass and density improvements. This study aimed to determine if CAL could modify healthy and diseased bone through cell-independent mechanisms that alter hydration similar to RAL. 26-week-old male C57BL/6 mice induced with chronic kidney disease (CKD) beginning at 16 weeks of age via 0.2 % adenine-laced casein-based (0.9 % P, 0.6 % C) chow, and their non-CKD control littermates (Con), were utilized. Upon sacrifice, right femora were randomly assigned to the following ex vivo experimental groups: RAL (2 μM, n = 10 CKD, n = 10 Con), CAL (100 nM, n = 10 CKD, n = 10 Con), or Vehicle (VEH; n = 9 CKD, n = 9 Con). Bones were incubated in PBS + drug solution at 37 °C for 14 days using an established ex vivo soaking methodology. Cortical geometry (μCT) was used to confirm a CKD bone phenotype, including porosity and cortical thinning, at sacrifice. Femora were assessed for mechanical properties (3-point bending) and bone hydration (via solid state nuclear magnetic resonance spectroscopy with magic angle spinning (ssNMR)). Data were analyzed by two-tailed t-tests (μCT) or 2-way ANOVA for main effects of disease, treatment, and their interaction. Tukey's post hoc analyses followed a significant main effect of treatment to determine the source of the effect. Imaging confirmed a cortical phenotype reflective of CKD, including lower cortical thickness (p < 0.0001) and increased cortical porosity (p = 0.02) compared to Con. In addition, CKD resulted in weaker, less deformable bones. In CKD bones, ex vivo exposure to RAL or CAL improved total work (+120 % and +107 %, respectively; p < 0.05), post-yield work (+143 % and +133 %), total displacement (+197 % and +229 %), total strain (+225 % and +243 %), and toughness (+158 % and +119 %) vs. CKD VEH soaked bones. Ex vivo exposure to RAL or CAL did not impact any mechanical properties in Con bone. Matrix-bound water by ssNMR showed CAL treated bones had significantly higher bound water compared to VEH treated bones in both CKD and Con cohorts (p = 0.001 and p = 0.01, respectively). RAL positively modulated bound water in CKD bone compared to VEH (p = 0.002) but not in Con bone. There were no significant differences between bones soaked with CAL vs. RAL for any outcomes measured. RAL and CAL improve important post-yield properties and toughness in a non-cell mediated manner in CKD bone but not in Con bones. While RAL treated CKD bones had higher matrix-bound water content in line with previous reports, both Con and CKD bones exposed to CAL had higher matrix-bound water. Therapeutic modulation of water, specifically the bound water fraction, represents a novel approach to improving mechanical properties and potentially reducing fracture risk.Item Impact of Diet on the KK-Ay Mouse Model of Type 2 Diabetes(2024-05) Reul, Olivia; Wallace, Joseph M.; Allen, Matthew R.; Surowiec, Rachel K.Diabetes is an international health crisis with 1 in 10 (537 million) adults worldwide living with diabetes, and type 2 diabetes (T2D) composing 90% of these cases [1]. T2D is a disease characterized by insulin resistance that leads to pancreatic β cell dysfunction and hyperglycemia. It is known to have deleterious effects on various organ systems, including the skeletal system, leading to an increased fracture risk, despite normal or elevated bone mineral density (BMD). Due to this unique facet of T2D, the cause of this elevated fracture risk has recently become an area of focus both in the clinic and in research. One of the primary concerns when researching this disease state is the use of a model capable of mimicking the complex multisystem effects of diabetes, including the skeletal outcomes. The Yellow Kuo Kondo (KK-Ay) mouse model has shown promise as a non-diet dependent obese model of T2D. In this model, mice heterozygous for a mutation in the agouti gene (Ay) are treated as an obese model of T2D (KK-Ay) while those that are homozygous (no mutation) are a non-diabetic obese control [2]. Although previous studies have revealed this model can display the multisystem effects of diabetes [3,4], data suggest that the efficacy of the model may in fact be reliant on diet. To explore this, mice were placed on separate diets, half on a standard chow (LabDiet 5001) diet and the other half on a diet recommended by Jackson Laboratory for this strain (LabDiet 5LG4). Animals were aged to 16 weeks (wks) with blood glucose (BG) and body weight (BW) monitored every other week and glucose tolerance tests (GTT) and insulin tolerance tests (ITT) performed at 15 wks. At 16 wks, animals were sacrificed via cardiac exsanguination to collect whole blood and blood serum followed by cervical dislocation. The pancreas, bilateral tibiae, and bilateral femora were collected from each animal immediately following sacrifice. Diet did in fact have a significant impact on both the skeletal and metabolic phenotype associated with T2D. Results suggest that future studies should employ the 5LG4 diet in heterozygous animals and the 5001 diet in homozygous animals to better explore the impacts of T2D against a non-diabetic control.Item In Vivo Quantitative Imaging Biomarkers of Bone Quality and Mineral Density using Multi-Band-SWIFT Magnetic Resonance Imaging(Elsevier, 2021) Surowiec, Rachel K.; Ram, Sundaresh; Idiyatullin, Djaudat; Goulet, Robert; Schlecht, Stephen H.; Galban, Craig J.; Kozloff, Kenneth M.; Radiology and Imaging Sciences, School of MedicineBone is a composite biomaterial of mineral crystals, organic matrix, and water. Each contributes to bone quality and strength and may change independently, or together, with disease progression and treatment. Even so, there is a near ubiquitous reliance on ionizing x-ray-based approaches to measure bone mineral density (BMD) which is unable to fully characterize bone strength and may not adequately predict fracture risk. Characterization of treatment efficacy in bone diseases of altered remodeling is complicated by the lack of imaging modality able to safely monitor material-level and biochemical changes in vivo. To improve upon the current state of bone imaging, we tested the efficacy of Multi Band SWeep Imaging with Fourier Transformation (MB-SWIFT) magnetic resonance imaging (MRI) as a readout of bone derangement in an estrogen deficient ovariectomized (OVX) rat model during growth. MB-SWIFT MRI-derived BMD correlated significantly with BMD measured using micro-computed tomography (μCT). In this rodent model, growth appeared to overcome estrogen deficiency as bone mass continued to increase longitudinally over the duration of the study. Nonetheless, after 10 weeks of intervention, MB-SWIFT detected significant changes consistent with estrogen deficiency in cortical water, cortical matrix organization (T1), and marrow fat. Findings point to MB-SWIFT's ability to quantify BMD in good agreement with μCT while providing additive quantitative outcomes about bone quality in a manner consistent with estrogen deficiency. These results indicate MB-SWIFT as a non-ionizing imaging strategy with value for bone imaging and may be a promising technique to progress to the clinic for monitoring and clinical management of patients with bone diseases such as osteoporosis.Item Metabolic and Skeletal Characterization of the KK/Ay Mouse Model – a Polygenic Mutation Model of Obese Type 2 Diabetes(Springer, 2024) Chowdhury, Nusaiba N.; Surowiec, Rachel K.; Kohler, Rachel K.; Reul, Olivia N.; Segvich, Dyann M.; Wallace, Joseph M.; Radiology and Imaging Sciences, School of MedicineType 2 diabetes (T2D) increases fracture incidence and fracture-related mortality rates (KK.Cg-Ay/J. The Jackson Laboratory; Available from: https://www.jax.org/strain/002468 ). While numerous mouse models for T2D exist, few effectively stimulate persistent hyperglycemia in both sexes, and even fewer are suitable for bone studies. Commonly used models like db/db and ob/ob have altered leptin pathways, confounding bone-related findings since leptin regulates bone properties (Fajardo et al. in Journal of Bone and Mineral Research 29(5): 1025-1040, 2014). The Yellow Kuo Kondo (KK/Ay) mouse, a polygenic mutation model of T2D, is able to produce a consistent diabetic state in both sexes and addresses the lack of a suitable model of T2D for bone studies. The diabetic state of KK/Ay stems from a mutation in the agouti gene, responsible for coat color in mice. This mutation induces ectopic gene expression across various tissue types, resulting in diabetic mice with yellow fur coats (Moussa and Claycombe in Obesity Research 7(5): 506-514, 1999). Male and female KK/Ay mice exhibited persistent hyperglycemia, defining them as diabetic with blood glucose (BG) levels consistently exceeding 300 mg/dL. Notably, male control mice in this study were also diabetic, presenting a significant limitation. Nevertheless, male and female KK/Ay mice showed significantly elevated BG levels, HbA1c, and serum insulin concentration when compared to the non-diabetic female control mice. Early stages of T2D are characterized by hyperglycemia and hyperinsulinemia resulting from cellular insulin resistance, whereas later stages may feature hypoinsulinemia due to β-cell apoptosis (Banday et al. Avicenna Journal of Medicine 10(04): 174-188, 2020 and Klein et al. Cell Metabolism 34(1): 11-20, 2022). The observed hyperglycemia, hyperinsulinemia, and the absence of differences in β-cell mass suggest that KK/Ay mice in this study are modeling the earlier stages of T2D. While compromised bone microarchitecture was observed in this study, older KK/Ay mice, representing more advanced stages of T2D, might exhibit more pronounced skeletal manifestations. Compared to the control group, the femora of KK/Ay mice had higher cortical area and cortical thickness, and improved trabecular properties which would typically be indicative of greater bone strength. However, KK/Ay mice displayed lower cortical tissue mineral density in both sexes and increased cortical porosity in females. Fracture instability toughness of the femora was lower in KK/Ay mice overall compared to controls. These findings indicate that decreased mechanical integrity noted in the femora of KK/Ay mice was likely due to overall bone quality being compromised.Item Tracking changes of individual cortical pores over 1 year via HR-pQCT in a small cohort of 60-year-old females(Elsevier, 2022-11-02) Surowiec, Rachel K.; Swallow, Elizabeth A.; Warden, Stuart J.; Allen, Matthew R.; Anatomy, Cell Biology and Physiology, School of MedicineIntroduction: High-resolution peripheral quantitative computed tomography (HR-pQCT) is a powerful tool that has revolutionized 3D longitudinal assessment of bone microarchitecture. However, cortical porosity, a common characteristic of cortical bone loss, is still often determined by static evaluation of overall porosity at one timepoint. Therefore, we sought to 1) describe a technique to evaluate individual cortical pore dynamics in aging females over one year using HR-pQCT imaging and 2) determine whether formation and expansion of pores would exceed contraction and infilling of pores. Methods: HR-pQCT (60.7 μm resolution) images were acquired one year apart at the distal tibia and distal radius in seven female volunteers (60-72 years of age). Baseline and one-year images were registered at each bone site and a custom software was used to quantify dynamic activity of individual cortical pores using the following categories: developed, infilled, expanded, contracted, and static. Results: Over the one-year period, cortical pores actively developed, contracted, expanded, and infilled. More pores expanded and developed vs. infilled or contracted leading to increased pore area in both tibial and radial sites (p = 0.0034 and p = 0.0474, respectively). Closed pores in the tibia, those that were not connected to the endosteal or periosteal surfaces, were the most dynamic of any pores type (open/closed) at either bone site. Conclusion: This study demonstrates an approach to longitudinally track individual cortical pore activity in tibial and radial sites. These data expand conventional parameters for assessing cortical porosity and show increased porosity in one year of aging is caused by newly developed pores and expansion of existing pores.