PRISM :: Browsing by Author "Manske, Sarah Lynn"

Browsing by Author "Manske, Sarah Lynn"

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Open Access
The assessment of fragility fracture risk using HR-pQCT as a novel tool for diagnosis of osteoporosis
(2021-08) Whittier, Danielle Elizabeth Wein; Boyd, Steven Kyle; Schneider, Prism Steorra; Manske, Sarah Lynn; Edwards, William Brent; Forkert, Nils Daniel; Hallgrimsson, Benedikt; Jepsen, Karl
Osteoporosis is a systemic skeletal disease, characterized by reduced bone density and deterioration of bone microarchitecture, leading to increased fracture risk. However, current diagnosis using dual-energy X-ray absorptiometry (DXA) only accounts for density and consequently fails to capture most individuals who fracture. High-resolution peripheral quantitative computed tomography (HR-pQCT) is a medical imaging modality capable of characterizing three-dimensional bone microarchitecture at peripheral skeletal sites, and has demonstrated that bone microarchitecture can improve prediction of fracture risk. However, to date the improvement is modest, as interpretation of the interaction between fracture and the numerous parameters provided by HR-pQCT is complex. The objective of this dissertation was to elucidate the key microarchitectural characteristics that underpin bone fragility, and use these insights to improve assessment of fracture risk with HR-pQCT. First, reference data in the form of centile curves was established for HR-pQCT parameters using a population-based cohort (n=1,236, age 18–90 years), and a new intuitive parameter called void space was developed to capture localized regions of bone loss in HR-pQCT images. In a separate prospective multi-center cohort (n=5,873, age 40–90 years), unsupervised machine learning was implemented to identify common groupings (i.e., phenotypes) of bone microarchitecture in older adults. Three phenotypes were identified and characterized as low density, structurally impaired, and healthy bone, where the low density phenotype had the strongest association with incident osteoporotic fractures (hazard ratio = 3.28). Using the same cohort, a fracture risk assessment tool, called µFRAC, was developed using supervised machine learning methods to provide a 5-year risk of major osteoporotic fracture based on HR-pQCT parameters, and was demonstrated to significantly outperform DXA in predicting fracture risk. Finally, a new retrospective cohort of patients with fragility fractures at the hip (n=108, age 56–96 years) was used to characterize bone fragility. Hip fracture patients were significantly associated with the low density phenotype and had bone void spaces that were 2–3 times larger than controls. Together, these findings provide insight into the characteristics of bone that lead to osteoporotic fractures and introduces tools that enable insightful interpretation of HR-pQCT data for clinical use.
Open Access
Bone as an Orientable, Smooth Surface: Distance Transforms, Morphometry, and Adaptation
(2021-08) Besler, Bryce Albert Alphonsus; Boyd, Steven Kyle; Fear, Elise Carolyn; Forkert, Nils Daniel; Manske, Sarah Lynn; Cooper, David Michael Lane; Nielsen, Jorgen S
Age-related changes in bone fundamentally occur at the surface. Understanding and modeling these changes is the primary means of understanding and preventing age-related fractures. However, this is a challenging task, as the bone microarchitecture changes topology during adaption when rods disconnect and plates form holes. The primary objective is to handle topological changes mathematically and develop computational methods for the simulation of bone adaptation. This thesis develops a model of age-related bone loss based on the axioms that the bone surface is orientable and smooth. First, a novel artifact is discovered and described for the distance transform of sampled signals that limits their applicability in simulation and morphometry. Second, a new transform is defined termed the ``high-order signed distance transform'' that is better than the so-called exact signed distance transform in the sense that it has an order of accuracy greater than one. However, this transform does not permit a unique solution on sampled binary images, and another method is needed. Third, an algorithm is presented for computing the unique, high-order signed distance transform of biphasic materials from computed tomography data. Fourth, a method of performing morphometry on closed surfaces is described that relates existing global bone morphometric techniques to local curvature values. This method works on binary images without the need for signed distance transforms when small changes in the bone volume are permitted. Finally, the morphometry and high-order signed distance transform are integrated into a model of age-related bone loss. Principally, this work establishes bone adaptation as a geometric flow, simulated using level set methods that are efficient and naturally handle topological changes. The contribution of this thesis is the establishment of a strong mathematical foundation for modeling bone adaptation. High accuracy computational methods are defined to integrate the theory into practice. The theory and methods form a rigorous basis for biological theories of bone adaptation and provide techniques for measuring and falsifying theories.
Open Access
Effects of pregnancy and lactation on maternal bone status in mice artificially selected for larger skeletons
(2023-06) Tran, Vicki; Rolian, Campbell Paul; Cobb, John Andrew; Manske, Sarah Lynn; Rosa, Brielle Vastola; Gabel, Leigh Elizabeth Christine
Pregnancy and lactation are intensive physiological processes that require increased calcium demand from the maternal systems. This is mediated by changes to the maternal endocrine axes and may result in excessive bone resorption on the maternal skeleton. Pregnancy- and lactation-related changes in bone have yet to be investigated in a model with poorer bone quality and quantity. The Longshanks mouse (LS) is a mouse line selectively bred for increased tibia length. Although longer, the LS tibia is also weaker due to its altered microarchitecture of thinner and more widely spaced trabeculae. In this study, we sought to investigate the impacts of pregnancy and lactation on maternal bone microarchitecture using the LS as a model of a compromised skeletal phenotype with lower bone quality/quantity. Our study found that LS mice had increased bone quantity at postpartum and substantial decreases at mid-lactation when compared to Controls. The physiological response of increased bone postpartum thus depends on prepregnancy population characteristics and is possibly a mechanism to help protect maternal calcium reserves from excessive depletion. The differences in bone are induced by altered endocrine signaling in LS vs. CTL. The larger improvements in microarchitecture postpartum in the LS may be a result of increased OPG signalling, whereas bone resorption is likely increased in the LS during lactation by PTH and SOST action. This would allow increased mobilization of calcium stores and result in reduced maternal bone quantity/quality as seen in the LS mouse. Overall, this study demonstrated a possible protective response induced by pregnancy, resulting in increased bone volume postpartum, however lactational bone loss should be especially considered in populations with poor bone quality/quantity.
Open Access
Endogenous Articular Cartilage Regeneration After Injury
(2019-01-21) Jablonski, Christina Lynn; Krawetz, Roman J.; Cobb, John A.; McCafferty, Donna Marie; Salo, Paul T.; Manske, Sarah Lynn
Once injured, articular cartilage cannot regenerate, and a consequence of this inadequacy is osteoarthritis (OA), a chronic, degenerative joint disorder. Mesenchymal stem cells (MSCs) have shown promise in the treatment of cartilage injuries as they possess immunomodulatory properties and can differentiate into chondrocytes (e.g. cartilage cells). However, the outcomes of MSC-based therapies to date have been highly-variable, illustrating our incomplete understanding of how MSCs function in the joint. Superior cartilage healing post-injury has been observed in the MRL ‘super-healer’ mouse and has been linked to a deficiency in the cell cycle regulator, p21. Therefore, the purpose of this thesis was to determine the cell type(s) and/or mechanism(s) involved in endogenous cartilage regeneration in p21-/- mice. To accomplish this, we lineage traced Prx1+ (transcription factor specific to mesenchymal cells) MSC/progenitors in vivo after cartilage injury in p21-/- and C57 wild-type mice. We further examined the inflammatory cytokine profile of mice in the presence/absence of p21 and functionally tested the role of the CCL2/CCR2 signalling axis, which was found to be altered in p21-/- mice in response to cartilage injury. While deletion of p21 resulted in endogenous articular cartilage regeneration, Prx1+ MSC/progenitors did not differentiate into the new cartilage and/or subchondral bone observed in p21-/- mice. Furthermore, few differences in cell number (e.g. MSCs/stem cells, macrophages, proliferating cells) were observed between p21-/- mice and C57 wild-type mice suggesting that secreted factors or additional cell types may be responsible for the cartilage regeneration observed. To support this hypothesis, we further demonstrated that the cartilage regeneration ability of p21-/- mice could be recapitulated through deletion of the chemokine receptor CCR2, yet if its ligand CCL2 was deleted, cartilage regeneration ability was lost. Future studies using additional lineage reporter mice in the context of p21 deletion will be necessary to determine the cell(s)/factor(s) responsible for cartilage regeneration in these mice and to determine if targeting the cell cycle has potential as a safe and effective therapeutic strategy for treating cartilage injuries and/or OA.
Open Access
Enhanced Longitudinal Analysis of Bone Strength Estimated by 3D Bone Imaging and the Finite Element Method
(2020-10-06) Plett, Ryan Michael; Boyd, Steven Kyle; Duncan, Neil A.; Manske, Sarah Lynn; Kim, Keekyoung; Edwards, William Brent
Three-dimensional (3D) imaging with high-resolution peripheral quantitative computed tomography (HR-pQCT) and micro-finite element (FE) analysis provides important insight into bone health. Longitudinal analyses of bone morphology maximize precision by using 2D slice-matching registration (SM) or 3D rigid-body registration (3DR) to account for repositioning error between scans, however, the compatibility of these techniques with FE for longitudinal bone strength estimates is limited. This work developed and validated a FE approach for longitudinal HR-pQCT studies using 3DR to maximize reproducibility by fully accounting for misalignment between images. Using a standard imaging protocol, ex vivo (N=10) and in vivo (N=40) distal radius HR-pQCT images were acquired to estimate the efficacy of 3DR to reduce longitudinal variability due to repositioning error and assess the sensitivity of this method to detect true changes in bone strength. In our proposed approach, the full common bone volume defined by 3DR for serial scans was used for FE. Standard FE parameters were estimated by no registration (NR), SM, and 3DR. Ex vivo reproducibility was estimated by the least significant change (LSC) in each parameter with a ground truth of zero change in longitudinal estimates. In vivo reproducibility was estimated by the standard deviation of the rate of change (σ) with an ideal value that was minimized to define true changes in longitudinal estimates. Group-wise comparisons of ex vivo and in vivo reproducibility found that FE reproducibility was improved by both SM (CVRMS<0.80%) and 3DR (CVRMS<0.62%) compared to NR (CVRMS~2%), and 3DR was advantageous as repositioning error increased. Although 3D registration did not negate motion artifacts, it played an important role in detecting and reducing variability in FE estimates for longitudinal study designs. Therefore, 3D registration is ideally suited for estimating in vivo effects of interventions in longitudinal studies of bone strength.
Open Access
The Influence of Intracortical Microarchitecture on the Mechanical Fatigue of Bone
(2020-07-07) Loundagin, Lindsay Lessel; Edwards, William Brent; Boyd, Steven Kyle; Schmidt, Roel Kuijer Tannin; Duncan, Neil A.; Cooper, David Michael Lane; Taylor, David; Manske, Sarah Lynn
Mechanical fatigue is the predominant etiology of stress fracture, a known contributor to atypical femoral fracture, and may also play a critical role in fragility fracture. While these fatigue-related fractures are well-documented in humans, they are poorly understood. Extensive research has attempted to characterize the fatigue behavior of cortical bone; however, owing to the inherent variability in bone tissue, samples that appear identical in macrostructure can exhibit a large degree of scatter in fatigue life. The overarching hypothesis of this thesis is that the variance in fatigue-life data can be attributed to intracortical microarchitecture, including the size, spacing, and density of vascular canals and osteocyte lacunae. A series of studies were conducted that utilized ex vivo mechanical testing, high-resolution imaging, and finite element modeling to establish the relationship between intracortical microarchitecture and the fatigue life of bone in compression. Both porosity and canal diameter demonstrated a strong negative relationship with fatigue life, whereas lacunar density was positively correlated. The reduced fatigue life associated with higher porosity was a result of larger, rather than more abundant canals, indicating that canals act as stress concentrators that may impair the fatigue resistance of bone beyond increasing overall porosity. The stress concentrations caused by vascular canals were quantified as stressed volume (i.e., the volume of material above yield) which was positively correlated to porosity and canal diameter. Furthermore, stressed volume proved to be a strong predictor of fatigue-life variance across multiple loading magnitudes. The findings from this thesis suggest that a majority of the fatigue-life variance of cortical bone in compression is driven by intracortical microarchitecture, and fatigue failure may be predicted by quantifying the stress concentrations associated with vascular canals.
Open Access
Influence of Microarchitecture on the Mechanical Fatigue Behaviour of Equine Subchondral Bone
(2023-09-12) Koshyk, Andrew; Edwards, William Brent; Manske, Sarah Lynn; Scott, W. Michael; Sparks, Holly Danielle; Lievers, William Brent
Fractures of the equine metacarpophalangeal (MCP) joint are among the most common and fatal injuries experienced by racehorses. These bone injuries are a direct result of repetitive, high intensity loading of the skeleton during racing and training and there is consensus that they represent a mechanical fatigue phenomenon. Existing work has found the fatigue life of bone to be strongly determined by bone microarchitecture and the resulting stressed volume (i.e., the volume of bone stressed above yield). The purpose of this study was to quantify the influence of bone microarchitecture on the mechanical fatigue behaviour of equine subchondral bone from the MCP joint. Forty-eight subchondral bone samples were prepared from the third metacarpal (MC3) and proximal phalanx (P1) and subsequently imaged using high resolution micro-computed tomography (μCT) to quantify microarchitectural features of interest, including bone volume fraction, tissue mineral density, pore size, pore spacing, and pore number. Samples were cyclically loaded in compression to a stress of 70 MPa, and fatigue life was defined as the number of cycles until failure. Finite element models were created from the μCT images and used to quantify the stressed volume. Based on the expected log point-wise predictive density (ELPD), stressed volume was a strong predictor of fatigue life in both the MC3 and P1. Normalized stress (i.e., initial nominal strain) was also a strong predictor of fatigue life in samples from the MC3, but not for samples from the P1. This disparity can be attributed to differences in microstructure homogeneity. A regional analysis indicated fatigue life was more strongly associated with bone volume fraction in the superficial (r2 = 0.32, p < 0.001) and middle (r2 = 0.70, p < 0.001) regions of the subchondral bone, indicating that the cortical plate plays a more prominent role in the fatigue resistance of subchondral bone. By improving our understanding of the variance in fatigue life measurements, this research helps begin to clarify the underlying mechanisms of the mechanical fatigue process and provide a basic understanding of subchondral bone injuries in the equine fetlock joint.
Open Access
Investigating Bone Remodelling in Knee Osteoarthritis using HR-pQCT Imaging
(2023-05-12) Kaketsis, Daphne Angelique; Manske, Sarah Lynn; Bertram, John Edward Arthur; Boyd, Steven Kyle; Edwards, William Brent; Zimmermann, Elizabeth Ann
Osteoarthritis (OA) is the most common type of arthritis and a significant cause of disability worldwide. With an aging population in Canada, the prevalence and burden of OA is expected to increase. Knee OA is the most common form of OA, comprising upwards of 30% of cases. Early-stage OA can be difficult to diagnose, as often times pain and radiographical evidence do not align; however, abnormal subchondral bone remodelling has been considered to have an important role in OA pathogenesis, and some propose that it could offer a target for OA treatment. Clinically, measures of bone remodelling have been performed on iliac crest bone biopsies that are invasive and do not capture local changes. Recently, high resolution peripheral quantitative computed tomography (HR-pQCT) has been utilized in several different ways to analyse bone dynamics, or how the bone changes over time. These measurements are sensitive to several factors such as noise and motion but have yet to be validated in humans. The purpose of this study was to determine whether HR-pQCT can be used to measure longitudinal bone remodelling at the knee in humans with knee OA. Longitudinal bone remodelling results were compared to same-day rescan images to conduct a repeatability analysis. There were no significant differences between longitudinal and rescan results for bone formation (p = 0.47), bone resorption (p = 0.12), or net bone remodelling (p = 0.748). Additionally, the least detectable changes measured were 10.88% for bone formation, 10.53% for bone resorption, and 4.05% for net bone remodelling. These results indicate that with the current imaging procedures, there is too much error in the scans and processing pipeline to measure bone remodelling longitudinally in-vivo in the knee.
Open Access
Investigating musculoskeletal changes in critically ill patients with computed tomography (CT) imaging
(2024-05-23) Smith, Ainsley Catherine Joan; Manske, Sarah Lynn; Herzog, Walter; Doig, Christopher; Wong, Andy Kin On; MacInnis, Martin
Critical care patients are susceptible to musculoskeletal changes during their stay in the intensive care unit (ICU). Intensive care unit acquired weakness (ICU-AW) is a common complication of critical illness that is characterized by a significant loss of muscle strength. ICU-AW can lead to long-term weakness, fractures, physical impairment, and reduced quality of life. Evaluating musculoskeletal health in the ICU can be challenging as patients are often non-responsive and unstable. However, critical care patients typically undergo computed tomography (CT) imaging for their clinical care, which can be repurposed for musculoskeletal assessment. The purpose of this thesis was to use clinically acquired CT images and electronic medical record data to investigate the effects of critical illness on the musculoskeletal system. CT imaging provides measures of muscle cross-sectional area, indicating muscle atrophy; muscle density, indicating muscle quality; and bone mineral density (BMD), indicating fracture risk. First, I adapted and validated a CT internal calibration method for reliable muscle density analysis. I then applied this internal calibration method to clinically acquired CT images of critical care patients, and I found that critical care patients undergo a significant reduction in psoas and thigh muscle density over the course of critical illness. Further, I applied CT internal calibration to evaluate BMD changes in critical care patients, and no changes were observed. In a larger cohort, I used clinically acquired CT images to determine that critical care patients experience significant psoas muscle atrophy during their ICU stay. Using electronic medical record data, I found that this muscle atrophy was associated with length of time in the ICU and quantity of muscle at ICU admission. Further, rate of muscle atrophy was associated with ICU mortality. The findings from this thesis provide insight into the effects of critical illness on the musculoskeletal system, the risk factors and mechanisms associated with muscle loss in the ICU, and the utility of clinically acquired CT imaging for retrospective musculoskeletal assessment.
Open Access
Longitudinal assessment of mechanical strength of trabecular bone underlying bone marrow lesions following acute anterior cruciate ligament injuries.
(2019-06-17) Shtil, Mariya; Boyd, Steven Kyle; Edwards, William Brent; Manske, Sarah Lynn
Anterior cruciate ligament tears are common injuries that are often accompanied by traumatic bone marrow lesions (BML) that occur in the knee. These lesions may be linked to osteoarthritis and by understanding the indication of a bone marrow lesion, we can move towards better understanding the causes of osteoarthritis. This study explores the strength of bone within BMLs using micro-finite element modeling based on MRI and HR-pQCT images throughout an 8- month period following an ACL tear. In the BML region in the injured knee, the bone strength decreased by 20.1% (P<0.001) at ~175 days post injury relative to the corresponding region on the contralateral knee followed by a semi-recovery period. Bone strength in the reference region surrounding the BML decreased by 15.3% (P=0.002) at ~142 days post injury relative to the contralateral reference region, and 15.3% (P=0.003) at ~146 days post injury in the full injured femoral condyle relative to the contralateral condyle, followed by a gradual recovery. However, the bone in the BML region experienced accelerated loss in bone strength relative to the surrounding bone and the contralateral knee and did not fully recover. This may be indicative of long-term or potentially permanent changes in bone strength that when weakened, provides less support for articular cartilage and can lead to damage or degeneration, and further progression to osteoarthritis.
Open Access
A multimethod analysis to assess locomotor capabilities in stem tetrapods from Blue Beach (Tournaisian; Early Carboniferous), Nova Scotia
(2020-01) Lennie, Kendra Ilana; Anderson, Jason S.; Theodor, Jessica M.; Jamniczky, Heather A.; Manske, Sarah Lynn
In vertebrate evolution the fin-to-limb transition was an important precursor to the diversification and radiation of terrestrial animals into novel environments. This transition began in the Devonian and continued through the Carboniferous and involved physiological and biomechanical changes. I used a multi-method approach to assess external and internal limb bone features to evaluate Early Carboniferous (Tournaisian) limb bones from Blue Beach and associated them with aquatic to terrestrial lifestyles. Tournaisian tetrapod material was collected at Blue Beach located near Hantsport, Nova Scotia, but much of it has not been formally described because the disarticulated and isolated tetrapod elements made identification to the species level difficult. In this thesis I described new morphotypes attributable to the family level which are used in the following chapters. Once the external morphology of the Blue Beach bones was described I compared them with the femora of extant aquatic, amphibious, and terrestrial tetrapods to evaluate which locomotor behaviour the fossil femora most resembled. I additionally examined cross-sectional bone profiles of Blue Beach tetrapod femora to infer lifestyle. Midshaft analyses relied on a single two-dimensional image to represent a dynamically structured bone so I also used a novel method for assessing three-dimensional trabecular data to qualitatively and quantitatively infer lifestyle from the Blue Beach femora. From the various analyses of internal and external bone morphology it was clear that external bone features of modern and early fossil tetrapod femora are dissimilar, which lead to difficulties in drawing conclusions based off external qualitative data. Internal data, from two-dimensional midshaft and three-dimensional trabecular structures, produced quantitative results that lead to the same conclusion, that the Blue Beach femora are consistent with those of aquatic animals. This implies that the initial diversification of the tetrapod body plans present in the Early Carboniferous was not the result of terrestrialization but appears to have preceded it.
Open Access
Muscle disuse and vibration effects on bone morphology
(2010) Manske, Sarah Lynn; Boyd, Steven; Zernicke, Ronald F.
Open Access
The Natural History of Bone Marrow Lesions and Cysts in the Dunkin-Hartley Guinea Pig Knee Osteoarthritis Model
(2020-10-14) Francis, Destiny; Manske, Sarah Lynn; Matyas, John Robert; Dunn, Jeff F.
Idiopathic knee osteoarthritis (OA) is a disease with unknown etiology, where age is described as a major risk factor. There is a need to document OA's natural history to gain insight into its etiology. Therefore, an animal model like the Dunkin-Hartley (DH) guinea pig that spontaneously develops a knee OA phenotype similar to idiopathic OA observed in humans can be used to study the disease-related bony degeneration. This phenotype includes osteophyte formation, sclerosis, bone marrow lesions (BMLs), and cysts within a relatively short period. This thesis employs advanced magnetic resonance imaging (MRI), micro-computed tomography (μCT), and histological techniques to assess knee joint degeneration in DH guinea pigs at ages 2, 4, 6, 12, and 24 months. The results from this project show evidence of cartilage degradation and bone cyst formation in the 6-month age group, which becomes more apparent in the 12 and 24-month age groups. When present, cysts were primarily located in the central compartment of the bone and often accompanied by osteophytes and sclerosis. Joint degeneration was most severe in the 24-month age group with the largest cysts as well as the greatest osteophyte size and number. Bone microarchitecture was also significantly affected in this age group. Overall femoral and tibial trabecular number (Tb.N) was lowest in the 24-month age group, and it had the highest medial femoral subchondral bone plate thickness (Sbp.Th), femoral and tibial subchondral bone plate porosity (Sbp.Po), femoral trabecular separation (Tb.Sp), and medial tibial trabecular thickness (Tb.Th). The medial compartment also revealed greater joint degeneration, as demonstrated by greater femoral and tibial Sbp.Th and femoral Sbp.Po in the 12 and 24-month age groups compared with the lateral compartment. This project demonstrates that age-related joint degeneration occurs in the DH guinea pig spontaneous knee OA model with evidence of osteophytes, cysts, and bone microarchitecture alterations in older age groups. Although histology revealed abnormalities in the bone that have been associated with MRI-defined BMLs, I am unable to conclude whether or not BMLs occur in this model as a further investigation with MRI is still required.
Open Access
The progression of bone microarchitecture changes following an acute knee injury in young adults
(2019-03-18) Kroker, Andres Mauricio; Boyd, Steven Kyle; Walker, Richard E. A.; Matyas, John Robert; Manske, Sarah Lynn; Van-Rietbergen, Bert; Doyle-Baker, Patricia K.
Anterior cruciate ligament (ACL) tears are activity-related knee injuries associated with an elevated risk of developing post-traumatic osteoarthritis 10-20 years post-injury. Immediately after the injury bone mass is lost. This is followed by a recovery period, though full recovery is not achieved even years later. Due to a lack of appropriate imaging modalities, no information is available on how the underlying bone microarchitecture is affected. In addition, the effects of concurrent soft-tissue injuries, such as meniscus tears or traumatic bone marrow lesions, on the underlying bone microarchitecture in human knees are not known. In this thesis, a new method for in vivo assessment of bone microarchitecture of the human knee is introduced. Next, in two cross-sectional studies this technique is applied to populations that experienced unilateral ACL tears six to nine years earlier. Both studies revealed that bone is primarily affected in the femur of the injured knee. Trabecular bone mass is lower in the medial femur (-4.8% to -10.4%) while the subchondral bone plate is thicker in the lateral femur (9% to 29.6%) as compared to the contralateral knee. Further, the thicker subchondral bone plate is associated with surgical meniscus treatment (meniscectomy or repair) at the time of ligament reconstruction. In a year-long longitudinal study, the new imaging technique is applied to a cohort with acute unilateral ACL tears to investigate how early injury-induced bone changes affect microstructure. Immediately following the injury, trabecular bone is lost throughout the injured knee (-4.9% to -15.8%), driven by a loss of trabecular elements and increased trabecular separation. Concurrently, the subchondral bone plate of the lateral femur thins (-9%). The trabecular bone changes are further accelerated in traumatic bone marrow lesions (-18.2% to -20.6%). These findings show that while initial bone mass loss following the injury may recover six to nine years later (primarily in the tibia), the femur is affected long-term. The underlying structural changes are believed to be permanent, and while it is not known which individuals will develop osteoarthritis, limiting early injury-induced bone changes may reduce long-term risk of joint degradation.
Open Access
A quantitative computed tomography approach towards opportunistic osteoporosis screening
(2020-03-20) Michalski, Andrew Steven; Boyd, Steven Kyle; Edwards, William Brent; Powell, James N.; Johnston, James B.; Salo, Paul T.; Manske, Sarah Lynn
Opportunistic computed tomography (oCT) complements dual X-ray absorptiometry (DXA) by screening for osteoporosis and determining subject-specific fracture risk. Quantitative CT-based bone mineral density (BMD) and finite element (FE) estimated bone strength outcomes are known to improve fracture prediction, as compared to DXA areal BMD. However, there are shortcomings of oCT, which limit its ability to be clinically integrated as a skeletal health assessment tool for the purpose of identifying individuals at high risk of fracture that have not yet had any additional osteoporosis screening, such as a DXA scan. In this dissertation, the oCT limitation of understanding how CT scan acquisition parameters influence the skeletal health assessment is first investigated by identifying differences between CT reconstruction kernels. By using a bone-type kernel, the estimated FE failure load was increased by 18.2%, as compared to a standard-type kernel, suggesting that a standardized reconstruction kernel should be used when performing any oCT analyses. An internal density calibration method was then developed and validated to overcome the limitation of requiring a density calibration phantom within the scan field-of-view to perform oCT skeletal assessment. The developed internal calibration approach uses five reference regions and relates the known Hounsfield Units to equivalent mass attenuation values and then to equivalent bone density values. This approach was validated both in cadavers and an in vivo cohort, and it was shown to have a precision of 7.2% for skeletal health assessment outcomes. Finally, an oCT screening cohort was established using clinically acquired abdominal CT scans and was used to predict low energy fracture at known major osteoporotic fracture sites. Using this cohort, oCT screening resulted in a maximum predictive value of 0.710 for the area under the receiver operator characteristic curve to predict women with low energy fractures. These findings overcome some of the shortcomings currently preventing oCT screening from being clinically integrated. By using the millions of CT scans performed each year, oCT screening can repurpose these scans to assess skeletal health and reduce the costs and burden of fracture to both the healthcare system and society.
Embargo
Spectrum of Microarchitectural Bone Disease in Inborn Errors of Metabolism
(2020-08-27) Sidhu, Karamjot Kaur; Boyd, Steven Kyle; Khan, Aneal; Kline, Gregory Alan; Manske, Sarah Lynn; Aspinall, Alexander I.
Inborn errors of metabolism (IBEMs) are a heterogeneous group of inherited disorders caused by a defect in the synthesis, metabolism, transport, and/or storage of metabolites. Diagnosed patients can often present with compromised bone health and an increased risk for fragility fractures. The current standard for measuring bone health in the general population is bone density assessed by dual-energy X-ray absorptiometry (DXA). However, its utilization in understanding bone status in IBEMs is limited. The primary limiting factor is DXA’s inability to assess cortical and trabecular bone independently, which is important in understanding bone loss that is a result of complex disease processes. In this thesis, macro- and microarchitectural properties of bone were monitored in a wide range of IBEM disorders using new three-dimensional technology, high-resolution peripheral quantitative computed tomography (HR- pQCT). Moreover, bone strength was estimated by employing finite element techniques on HR- pQCT image data. A further examination of these measurements in relationship to genetic mutations, clinical history, and treatment status was investigated in Gaucher disease and hypophosphatasia as a case report and cohort study, respectively. In IBEM patients, both bone density and microarchitecture were impaired when compared to a reference database. The degree of impairment varied between IBEM subtypes, and was significantly greater in IBEMs associated with decreased bone mass mineralization, including hypophosphatasia. Cortical bone density and microarchitecture were also significantly lower in IBEM patients with previous fractures when compared to IBEM patients with no fracture history. Estimated bone strength was also significantly lower in certain IBEM disorders when compared to a reference database, including IBEM disorders of metabolism requiring diet restrictions and disorder of the nervous or muscular system resulting in impaired mobility. Investigations in Gaucher disease and hypophosphatasia suggested disease-targeting therapy may aid in preventing or delaying accelerated bone mass loss that is thought to occur from the IBEM diagnosis. In conclusion, bone density and microarchitecture are largely affected in IBEMs. Future work in understanding how therapeutic interventions, such as bone-altering therapies, impact bone density and microarchitecture in IBEMs may be highly valuable.
Open Access
The Influence of Ovariohysterectomy and Bisphosphonate Treatment on the Fatigue Behaviour of Whole-Bone and Bone Tissue
(2024-04-07) Angulo Castro, Ana Gloria; Edwards, William Brent; Manske, Sarah Lynn; Krawetz, Roman; Whittier, Danielle Elizabeth Wein
Bisphosphonates are the current front-line therapy for osteoporosis due to their effectiveness at increasing bone density and strength; nonetheless, their long-term use has been associated with rare cases of atypical femoral fracture (AFF). The mechanistic link between bisphosphonates and AFFs is unclear, but it has been hypothesized that the potent antiresorptive mechanism of bisphosphonates impairs fatigue resistance through alterations to bone material properties. The purpose of this thesis was to quantify the influence of high-dose bisphosphonate therapy on the mechanical fatigue properties of bone at different length scales using an ovariohysterectomized (OVH) and a gonad-intact (GDI) rabbit model. A total of 12 OVH and 12 GDI New Zealand White rabbits were treated for six months via subcutaneous injection with 1 ml/kg vehicle saline (VEH) or 0.15 mg/kg alendronate (ALN). Bone mineral density (BMD) and bone mineral content (BMC) were assessed longitudinally via dual-energy x-ray absorptiometry (DXA). After treatment, mechanical testing was used to determine the fatigue life of cortical bone tissue and whole-bone from lower limbs as well as the ultimate strength in lumbar vertebrae. High-resolution imaging and density measurements were performed to evaluate bone composition and microarchitecture, while finite element models were generated to predict whole-bone strain. No differences between treatment groups were observed in microarchitecture, density measurements, strain distributions or fatigue life of bone tissue and whole-bone. Differences between VEH and ALN in the vertebrae of GDI rabbits were not significant but the ALN group in OVH rabbits demonstrated significantly higher vertebrae BMD (p < 0.001), BMC (p = 0.005), and ultimate strength (p = 0.012) in addition to greater total BMD in both the femur (p = 0.002) and the tibia (p = 0.003). To summarize, this study found no detrimental effects of bisphosphonate treatment that could explain the relationship between AFFs and bisphosphonates, but extended treatment durations may be warranted.
Open Access
The Influence of Physical Activity on Bone Strength in Children and Adolescents
(2023-12-21) Alexander, Christina Jewel; Gabel, Leigh Elizabeth Christine; Edwards, William Brent; Manske, Sarah Lynn; Obeid, Joyce
Bone adapts to its loading environment throughout the lifespan, with peak bone mass accrual occurring during childhood and adolescence. Therefore, understanding how physical activity (PA) impacts bone during childhood and adolescence is especially important. Accelerometers are commonly used to measure PA and examine its associations with bone outcomes. In this thesis, I investigated whether using new accelerometry metrics to synthesize count-based accelerometry PA data would help uncover associations between specific parameters of PA and bone strength. First, I compared PA measured by older (count-based) and newer accelerometers (raw accelerations), to determine whether they were comparable. I discovered that count-based data is not directly comparable between the two accelerometers; however, minutes per day in different intensities of activity (e.g., sedentary, light, moderate, and vigorous) are comparable (mean bias <5 min/d at all intensities). I then compared count-based (older format) and raw accelerations (newer format) and found that although a conversion from count-based to raw accelerations is not possible, a metric initially designed for use with raw accelerations (the intensity gradient (IG)) can be reproduced with count data (mean bias = -0.15; 95% LOA [-0.65, 0.34]). Second, using four years of longitudinal data from over 300 children and adolescents, I examined whether IG and a daily impact score (DIS) were more strongly associated with bone strength than a metric traditionally used to examine these associations, minutes per day spent in vigorous physical activity (VPA). These metrics differ in that both the IG and DIS use the full spectrum of accelerometry data, whereas VPA does not. Furthermore, the DIS weights the intensity of the accelerations more heavily than the number. Using linear mixed effects models, I determined that the DIS was positively associated with bone strength independent of VPA (β_DIS = 25.2 (7.0, 43.6), p <0.05; β_VPA = 3.2 (-6.1, 1.4), p = 0.67), indicating that short, high-intensity physical activity is best for bone strength accrual in children and adolescents. These findings should be used to inform physical activity guidelines with the aim of improving bone strength in children and adolescents.
Open Access
Using Advanced Medical Imaging to Study Bone and Joint Changes in Rheumatoid Arthritis
(2019-06-18) Brunet, Scott Cameron; Manske, Sarah Lynn; Barnabé, Cheryl Carmelle Marie; Salat, Peter
Inflammatory processes in rheumatoid arthritis (RA) lead to the damage of joints which results in functional decline. Medical imaging plays an important role in evaluating the onset and progression of RA. High resolution peripheral quantitative computed tomography (HR-pQCT) permits 3-dimensional visualization of the bony microarchitecture allowing for improved erosion detection, joint space width, and bone microstructure measurements. The purpose of this research was to use HR-pQCT and other advanced imaging techniques to visualize and quantify bone changes in the metacarpophalangeal (MCP) joints in RA patients. First, the reproducibility of a semi-automated erosion segmentation program was assessed using intra-rater and scan-rescan measurements on a cohort of early RA participants. HR-pQCT was used to assess possible erosion healing in participants’ initiating a new biologic therapy. We observed that the majority of participants maintained stable joints space, bone mineral density, and erosion volume over a 9-month follow-up period, but 17% of the joints showed a significant decrease in total erosion volume suggesting potential erosion healing. Finally, the impact of subclinical inflammation on bone damage progression for patients in clinical remission was assessed using a combination of HR-pQCT and Magnetic Resonance Imaging (MRI). All 9 of the participants assessed in this study had evidence of subclinical inflammation on MRI, but there was no progression of joint damage seen on HR-pQCT. One participant had a significant decrease in erosion volume. An image registration algorithm, applied for the first time for MCP joints, was used to successfully localize areas of inflammation as seen on MRI with bone damage seen on HR-pQCT. It is demonstrated that even with a sensitive measure of bone damage, healing and progression can be difficult to visualize and quantify due to the heterogeneity of the disease. However, applying other imaging modalities that can provide information on inflammation, as displayed in this thesis, could allow us to gain further insight on the individual characteristics that lead to bone change. The imaging findings and techniques described in this thesis will provide a novel insight into the progression of bone damage in RA to help evaluate current treatment targets and improve patient outcomes in future research.
Open Access
Using HR-pQCT and finite element analysis to inform clinical assessment of distal radius fractures
(2020-08-05) Spanswick, Phillip; Schneider, Prism Steorra; Boyd, Steven Kyle; Manske, Sarah Lynn; Korley, Robert E. C.
Distal radius fractures (DRFs) are commonly treated non-operatively with cast immobilization; however, there are no standardized clinical practice guidelines to direct optimal duration of immobilization following a DRF. Finite element (FE) modelling coupled with high-resolution peripheral quantitative computed tomography (HR-pQCT) allows for non-invasive in vivo assessment of bone density and stiffness throughout the fracture healing process, which may inform fracture healing progression and cast removal. Many fracture assessment instruments have been developed for clinical use, but a lack of validation and standardization has led to considerable variability in the assessment of fracture healing. We hypothesized that changes in bone stiffness and bone mineral density measured using HR-pQCT can better inform the duration of casting following a DRF. We aimed to identify clinical assessment instruments that were good predictors of fracture stiffness and could inform cast removal. Participants (n=30) with a stable DRF were followed for two week intervals from the time of fracture until two months post-fracture, then at three months and six months post-fracture. At each follow-up, participants underwent clinical, radiographic, and functional assessments, as well as had their fractured wrist scanned using HR-pQCT. Recovery of bone stiffness during fracture healing was determined from micro-FE (µFE) models generated from HR-pQCT image data. During fracture healing, significant longitudinal changes were found in µFE-estimated stiffness, patient-reported outcomes, grip strength, range of motion (ROM), tenderness, number of cortices healed based on radiographs, and fracture line visibility (p<0.05); however, no significant change was detected in HR-pQCT based total bone mineral density. Grip strength, ROM, and patient-reported outcomes such as the Patient-Rated Wrist Evaluation (PRWE) and the Quick Disability of the Arm, Shoulder and Hand (QuickDASH) questionnaire correlated strongly with µFE-estimated stiffness (0.61≥ rm ≥0.71). Based on µFE-estimated stiffness, PRWE and QuickDASH are the best predictors of stiffness recovery (p<0.05) and may be used to guide duration of cast immobilization in the clinical setting.