Dissertations / Theses on the topic 'Bone marrow lesions'

Bone marrow lesions (BML) are well described in osteoarthritis (OA) using magnetic resonance imaging (MRI) and are associated with pain, however little is known about their pathological characteristics and gene expression. This study evaluated BMLs using tissue analysis tools to gain a deeper understanding of how they mediate pain. A total of 117 participants were recruited, 74 with advanced OA requiring total knee replacement (TKR), 23 with mild OA, 7 healthy controls and 13 non-OA tissue comparator controls. A multidimensional approach was taken to investigate how clinical, radiological and molecular changes in OA knee joints correlate with pain perception. Pain scoring (Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), Pain DETECT) and quantitative sensory testing (QST) were used to characterise the pain experienced by participant. To assess structural changes MR images were scored using MRI Osteoarthritis Knee Score (MOAKS) by two independent scorers. The MRI scans were used to localise BMLs for whole transcriptomic analysis, qPCR for array validation, histological evaluation, scanning electron microscopy and quantitative protein expression. Serum samples obtained at baseline visits were used for biomarker investigation. The result demonstrates that BMLs are regions of increased cellular and metabolic activity and correlated with increased pain and sensitisation. The findings contribute to the understanding of OA pathogenesis and could help lead to the development of new diagnostic tools and future therapies for the improved management of this increasingly prevalent condition.

This thesis presents the findings from three studies that examined the clinical and biological effects of Focused-Extracorporeal Shockwave Therapy (ESWT) on knee osteoarthritis (OA) related bone marrow lesions (BML). Previous research has indicated that ESWT can influence the underlying pathophysiological process of musculoskeletal disorders. This research showed that focused-ESWT is safe and has a dose-dependent effect on clinical outcomes in knee OA-related BMLs. However, the effects on underlying pathophysiological mechanisms were not conclusive.

Background L’edema osseo è una condizione riscontrata con la Risonanza Magnetica Nucleare in associazione a patologie di origine meccanica, infiammatoria e reumatologica. Caratterizzato da un’alterazione del segnale dovuta ad un aumentato contenuto d’acqua nella midollare ossea, l’edema osseo è spesso associato a dolore, impotenza funzionale e accelerazione dei processi degenerativi articolari. Considerata la rilevanza clinica e la probabile correlazione tra BME ed Osteonecrosi, emerge la necessità di identificare opzioni di trattamento efficaci al fine di ridurre la sintomatologia ed evitare l’evoluzione di tale lesione. Obiettivo L’obiettivo di questa Scoping Review è quello di identificare gli interventi fisioterapici di maggior efficacia nel trattamento di BML e BMES ponendo come misure di outcome il miglioramento della funzione, la riduzione del dolore e della dimensione dell’edema osseo in RMN. Metodi Nel periodo aprile-agosto 2021 sono state esplorate le seguenti banche dati: PubMed, Cochrane Library e PEDro. Sono stati selezionati 5 studi che indagavano interventi conservativi del BME coerenti con outcome clinici e radiologici presenti nel quesito di ricerca. Risultati Gli studi mostrano miglioramenti statisticamente significativi negli outcome indagati grazie all’utilizzo di Magnetoterapia, onde d’urto e camera iperbarica nel trattamento di soggetti con BME. Gli studi che indagano l’efficacia degli ultrasuoni e della limitazione del carico sull’arto affetto non mostrano differenze statisticamente significative tra i gruppi di trattamento e controllo. Conclusioni In soggetti con BME, l’intervento mediante Magnetoterapia, Onde d’urto o Camera iperbarica, sembra migliorare l’evoluzione della lesione nei tre outcomes indagati. Gli ultrasuoni e l’utilizzo di un bastone sembrano invece non favorire la guarigione del BME. Sono necessari studi di maggior qualità che valutino l’efficacia dei trattamenti analizzati proponendo anche protocolli terapeutici specifici.

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Introdução: o dano endotelial microvascular é um processo bem reconhecido como complicação do transplante de células tronco hematopoiéticas, os mecanismos dessa desordem ainda são pouco conhecidos. Diante desse cenário objetiva-se avaliar a relação entre marcadores inflamatórios e outros fatores que influenciam no consumo de plaquetas e o rendimento transfusional plaquetário, bem como a presença de eventos trombo embólicos e/ou vasculares em pacientes submetidos a condicionamento com quimioterapia em altas doses para transplante de células tronco hematopoiéticas. Método: análise prospectiva de pacientes, onde foram incluídos 25 pacientes que foram submetidos ao transplante de células tronco hematopoiéticas autólogo e alogênico. Os pacientes foram avaliados em relação a radioterapia previa, contagem de células CD 34 +, período de neutropenia, índice de massas corpórea, ferritina, Proteína C reativa relacionando esses fatores ao número de transfusões de plaquetas, refratariedade plaquetária e eventos vasculares como síndrome da obstrução sinusoidal e síndrome da enxertia. Resultado: das variáveis estudadas, apenas o IMC > 25 Kg/m2, apresentou um valor estatisticamente significativo (p = 0,003) em relação a menor necessidade transfusional de concentrado de plaquetas. Para a refratariedade plaquetária e/ou eventos vasculares nenhuma das variáveis foi estatisticamente significativa. Conclusão: pacientes com índice de massa corporal elevado apresentam menor necessidade transfusional de plaquetas. As condições encontradas nos três casos de refratariedade plaquetária e nos dois casos de eventos vasculares apresentam características semelhantes as descritas na literatura. Estudos relacionados à ativação endotelial e seus efeitos sobre o organismo devem ser estimulados.
Introduction: the objective of this Study is to evaluate the relationship between inflammatory markers and other factors that influence platelet consumption and platelet transfusion increment, as well as the presence of thromboembolic events in patients submitted to high-dose chemotherapy regimens for Bone Marrow Transplantation. Method: prospective analysis of patients, including 25 patients who underwent autologous and allogenic Bone Marrow Transplantation. The patients were evaluated in relation to previous radiotherapy, CD34+ cell count, period of neutropenia, body mass index, ferritin, C-reactive protein, relating these factors to the number of platelet transfusions, platelet refractoriness and vascular events such as sinusoidal obstruction syndrome and Engraftment Syndrome. Results: only body mass index > 25 Kg/m2 of the studied variables presented a statistically significant value (p = 0.003) in relation to the lower rates of platelet transfusion. For platelet refractoriness and/or vascular events none of the variables was statistically significant. Conclusion: the conditions found in the three cases of platelet refractoriness and in the two cases of vascular events have characteristics similar to those described in the literature. We agree with preexisting data reported in the literature, where patients with high BMI have lower need of platelets transfusion.

Diversos estudos sugerem que as células-tronco da medula óssea podem ser úteis no tratamento de lesões do tecido nervoso. O presente estudo investigou se a terapia com células medulares seria capaz de modificar os efeitos comportamentais de lesões no hipocampo. Células mononucleares da medula óssea marcadas com a proteína fluorescente verde (EGFP) foram transplantadas em camundongos C57BL/6 que tiveram o hipocampo dorsal danificado por lesão eletrolítica bilateral. Os resultados da avaliação comportamental no labirinto em cruz elevado mostraram que a lesão hipocampal produziu ansiólise, quadro que foi atenuado nos animais transplantados. Na análise imuno-histoquímica do tecido cerebral, foi observada presença limitada de células EGFP+ no cérebro dos animais lesionados. Dada a não recuperação da citoarquitetura tissular, acredita-se que os benefícios observados sobre o comportamento tenham resultado de um efeito parácrino das células mononucleares, que auxiliaram na ação de mecanismos endógenos para restituição parcial das funções do hipocampo.
Several studies suggest that stem cells from bone marrow may be useful in treating lesions of the nervous tissue. This study investigated if bone marrow cell therapy would be able to modify the behavioral effects of lesions in the hippocampus. Bone marrow mononuclear cells labeled with the enhanced green fluorescent protein (EGFP) were transplanted into C57BL/6 mice which had the dorsal hippocampus damaged by bilateral electrolytic lesion. The results of the behavioral assessment in the elevated plus-maze showed that the hippocampal lesion produced anxiolysis, an effect that was attenuated in transplanted animals. Immunohistochemical analysis of brain tissue revealed, however, a limited presence of EGFP+ cells into the brains of injured animals. Given the non-recovery of the tissue cytoarchitecture, it is believed that the observed benefits on the behavior resulted from a paracrine effect of the mononuclear cells, which possibly helped in the action of endogenous mechanisms for partial reimbursement of the hippocampal functions.

Bone marrow lesions (BMLs) are magnetic resonance imaging (MRI)-identified pathological changes in subchondral bone, closely associated with joint pain and osteo-chondral structural degeneration in knee osteoarthritis (KOA). Despite the usefulness of BMLs as diagnostic and prognostic markers in KOA, what they represent at the tissue level remains unclear. Thus, the thesis aim was to perform a comprehensive investigation of BMLs at the tissue level and their relationship with the structural changes in KOA. We hypothesised that BML imaged using MRI reflect changes in subchondral tissue of proximal tibia that related to OA disease severity and/or progression. The first study provided comprehensive tissue characterization of BMLs detected using two [proton density fat saturated (PDFS) and T1)] specific MRI sequences. Multi-modal tissue level analyses of the whole depth of the tibial osteochondral unit were performed. The results from tissue level analyses showed that BMLs detected by specific MRI sequences associate strongly with the degree of structural change in the osteochondral unit in KOA. Specifically, BMLs detected by the combination of PDFS and T1 weighted MR-sequences represent an advanced structural stage of OA disease, while BMLs detected only by PDFS weighted sequence represent less severe OA, and potentially have the ability to resolve. In the second study, potential causal factors (mechanical loading and vascular pathology) of BML formation were investigated by assessing the accumulation of microdamage, and the qualitative and quantitative aspects of blood vessels in BML and non-BML tissue. Increased microdamage density and increased arteriolar density, with altered characteristics of vascular walls, were found in the zones of BML tissue, supporting the notion that both excessive and biomechanically unfavourable loading and vascular pathology contribute to the occurrence of BMLs in tibial subchondral bone tissue. In the third study, a potential role for components of the metabolic syndrome in BML development and its potential influences on the progression of KOA was investigated. Results from this study suggested that a combination of specific metabolic factors such as central obesity with BMI 30 or greater, dyslipidaemia, high blood pressure and high fasting glucose levels might promote the occurrence of BMLs in tibial subchondral bone tissue and that metabolic factors might contribute to the progressive osteochondral degeneration in KOA. The fourth study described microarchitectural changes in whole tibial plateaus (TP), based on the presence/absence of a BML. Tissue from healthy/control knees was also used to compare with that from OA with no BML and OA with BML, to better understand the course of OA disease and BML involvement in disease progression. In comparison with non-OA (control) subjects, the bone microstructure of the subchondral plate and trabeculae varies significantly between subregions of the TP in KOA. Secondly, in KOA subjects, two types of structural changes were identified, which were dependent on the presence or absence of a BML in the TP, and which related to the extent of cartilage degradation. Thirdly, the presence of a BML had implications for the microstructure of regions of the TP beyond the zone of the BML. In conclusion, this series of related studies demonstrates that BMLs as a feature of subchondral bone strongly associate with the progressive state of OA disease and therefore play a significant role in KOA pathogenesis. This demonstrated that BMLs are valuable imaging biomarkers of KOA and that BMLs might provide attractive targets for therapeutic intervention in OA.
Thesis (Ph.D.) -- University of Adelaide, Adelaide Medical School, 2018

Bone marrow lesions (BMLs) are common in osteoarthritis (OA) of the hip and knee and present as cysts in computed tomography scans. BMLs in knee OA are associated with pain, cartilage loss, and attrition of subchondral bone, suggesting that they play a key role in progression of OA. However, the etiology of BMLs remains unclear. The goal of this study was to better understand the changes that occur in bone in OA, through the characterization of BMLs, bone microarchitecture, and bone stiffness. Femoral heads obtained from patients undergoing total hip arthroplasty because of end-stage OA were imaged using micro-computed tomography (µCT) to identify the cysts. The bone volume fraction (BV/TV), bone mineral density (BMD), and tissue mineral density (TMD) were evaluated for two volumes of interest: an area immediately surrounding the cysts and a cylindrical core from the primary load-bearing region of the femoral head. Further, the cylindrical core was modeled using finite element analysis in order to evaluate the stiffness of this mechanically critical region. After imaging, the heads were sectioned and stained for histological analysis. Overall, the specimens exhibited wide variation in the number of cysts and cyst volume normalized by total volume of the femoral head (CV/TV). The cysts were found primarily in the subchondral bone underlying regions of damaged cartilage. The µCT images and histological sections revealed the presence of sclerotic bone around the cysts. vi The lesions themselves contained fibrous, fatty, osseous, and cartilaginous tissues. Lesions were absent from the cylindrical cores, and no correlations were found between core stiffness and any cyst properties. The cores were also found to have a higher bone volume fraction compared to values from published studies on cadaveric samples obtained from a pool of donors not specifically limited to those with end-stage OA. The cores also exhibited a modestly different dependence of apparent modulus on volume fraction, as compared to those published data. A pilot study was next carried out on the femoral necks from four of the patients. This study consisted of using nanoindentation to measure the modulus of cortical, trabecular, and periosteal bone. These preliminary results suggested that the moduli varied substantially among patients, and that the modulus of cortical tissue was in some locations for some patients, lower than that of trabecular tissue, despite published reports to the contrary in non-OA bone. The results of this project demonstrate that cysts associated with severe OA involve extensive perturbations in local bone morphology and cellular activity, and yet comparatively minimal disruption to the primary load-bearing region of the femoral head. These findings suggest that despite the association of cysts with symptoms of OA in the knee, cysts in hip OA are not strongly associated with a global loss of function of the primary bony structure of the joint. Further study of these cysts is necessary to identify their mechanistic relationship with the progression of hip OA.

Osteoarthritis (OA) is a complex disease characterised by involvement of multiple tissues in the synovial joint. It is a leading cause of pain and disability in older adults. It has long been hypothesised that subchondral bone plays an important role in the development and progression of the disease. This thesis aims to investigate how subchondral bone measures of the knee such as subchondral bone mineral density (sBMD), bone size, and bone marrow lesions (BMLs) are associated with important disease outcomes in OA. A population-based sample of older adults aged 50–80 years (51% female; mean age 62 years) participated at baseline and approximately 3.0 years later. sBMD was assessed using dual-energy x-ray absorptiometry (DXA). Cartilage volume, cartilage defects, bone area, and BMLs were determined using magnetic resonance imaging (MRI). X-ray was used to assess radiographic osteoarthritis [joint space narrowing (JSN) and osteophytes]. Blood samples were collected to assess vitamin D and high-density lipoprotein (HDL) cholesterol. Multiple questionnaires were used to assess pain, function, dietary intake, physical activity, sun exposure, and total knee replacement surgery. The first study examined the cross-sectional correlates of sBMD and found that many factors were associated with sBMD including age, sex, body mass index (BMI), vitamin D, sun exposure, physical activity, and knee structural measures. The most novel structural measure was cartilage defects and a longitudinal study was required to address causality. In the second study, bone area at baseline predicted cartilage defect development and cartilage volume loss. Baseline sBMD predicted cartilage defect development, which confirmed the cross-sectional findings above. These associations were independent of each other, indicating there are multiple mechanisms by which subchondral bone may lead to cartilage damage. In the third and fourth study, 43% of participants presented with a BML at baseline with 25% improving in size and 24% worsening in size over time. Baseline BMLs predicted cartilage defect development and cartilage volume loss, suggesting BMLs may have a local effect on cartilage homeostasis. Baseline cartilage defects predicted BML progression, which may represent increased bone loading adjacent to defects. These results suggest BMLs and cartilage defects are interconnected and play key roles in knee cartilage volume loss; thus, both should be considered targets for intervention. BMLs also predicted total knee replacement surgery. A change in BML size was associated with a change in pain, only in those participants without radiographic osteoarthritis. Importantly a decrease in BML size was associated with a decrease in pain. In the final study, baseline energy, carbohydrate and sugar intake (but not fat) were positively associated with a change in BML size. Baseline HDL cholesterol was negatively associated with BML change. In conclusion, this series of related studies indicate that subchondral bone plays a significant role in OA pathogenesis. Features of the subchondral bone contribute to knee pain and predict important disease outcomes such as cartilage loss and joint replacement surgery. This suggests that subchondral bone is an attractive target for therapeutic intervention in OA. Future work should consider subchondral bone treatments when developing disease-modifying OA drugs (DMOADs).

Osteoarthritis (OA) is the most common type of arthritis, with prevalence estimates expected to increase dramatically worldwide due to ageing and increasingly obese populations. The knee is the most commonly affected joint, leading to pain, loss of function and disability. Magnetic resonance imaging (MRI)-detected bone marrow lesions (BMLs) and osteophytes (OPs) are types of subchondral bone abnormalities whose aetiology and predictive value are uncertain. The aims of this thesis are to investigate associations between local cartilage morphology, systemic inflammatory cytokines and knee BMLs, and the predictive value of MRI-detected OPs on knee OA structural and symptomatic changes. Two data sources were used in this thesis. The first was a population-based study of older adults aged 50-80 years (mean age: 62 years; 51% female). Participants were randomly selected from the electoral roll in Southern Tasmania (population 229, 000) using sex-stratified random sampling. Follow-up measurements were performed at about 2.6 years later and again for questionnaire data at about 5.0 years later. MRI scans of the right knees were conducted at baseline and first follow-up. Knee cartilage defects, cartilage volume, tibial bone area, BMLs, effusion synovitis, infrapatellar fat pad and OPs were measured or scored based on MRI images. A standing anteroposterior semi-flexed view right knee with 15° of fixed knee flexion was performed at baseline with joint space narrowing (JSN) and radiographic OPs scored according to the Osteoarthritis Research Society International (OARSI) atlas. Knee pain was assessed using the Western Ontario McMaster Osteoarthritis Index (WOMAC) at all phases. The second was a randomized, multi-centre, placebo-controlled and double-blinded clinical trial that was designed to evaluate the effect of vitamin D supplementation on knee OA. Eligible participants were aged 50 to 79 years who had symptomatic knee OA (according to American College of Rheumatology criteria) for at least 6 months, and had pain of 20 to 80 mm on a 100-mm visual analog scale (VAS). Additionally, participants’ serum 25OHD levels were >12.5 nmol/L and < 60 nmol/L. Knee cartilage defects, cartilage volume, BMLs and OPs were measured or scored based on MRI images at baseline and after 24 months. WOMAC knee pain, serum levels of inflammatory cytokines were assessed at baseline and after 24 months using enzyme-linked immunosorbent assay. This thesis encompasses five studies. In the first study, the natural history of patellofemoral joint (PFJ) BMLs over 2.6 years was described and associations between PFJ BMLs, knee pain and knee cartilage morphology were evaluated in a population-based sample of older adults. 109 (27%) of 406 participants who completed follow-up had PFJ BMLs at baseline. Of these participants, 49 (45%) of these participants’ PFJ BMLs persisted in the same grade, 26 (24%) increased in grade, and 34 (31%) decreased in grade. Change in PFJ BMLs over 2.6 years was deleteriously associated with change of knee pain when going up/down stairs over 5 years. Baseline PFJ cartilage morphology predicted increases in PFJ BMLs over 2.6 years. In the second study, cross-sectional and longitudinal associations between serum high sensitivity C reactive protein (hs-CRP), knee BMLs and knee pain were investigated in a sample of knee OA patients. In these patients, serum hs-CRP is associated with knee BML scores and pain both cross-sectionally and longitudinally, suggesting inflammation is linked with BMLs and their associated pain. The third study described cross-sectional and longitudinal associations between serum levels of IL-17A, IL-17F, IL-23, IL-6 and knee BMLs in patients with knee OA. Baseline IL-6 were significantly associated with total knee BMLs as well as increased knee BML scores in both females and males. Baseline IL-17F and IL-23 predicted increased BML scores in females only. In the fourth study, MRI-detected OPs were measured and the cross-sectional and longitudinal association with knee structural abnormalities and knee pain were examined in older adults. Baseline MRI-detected OPs were significantly, independently and site-specifically associated with increases in cartilage defects, BMLs and loss of cartilage volume over 2.6 years. Medial tibiofemoral and total OP scores were dose-dependently associated with total knee pain change over 2.6 and 5 years but these became non-significant after further adjustment for cartilage defects and BMLs. In the fifth study, the prevalence of MRI-OPs detected only by MRI but not by standard x-ray was described, and the longitudinal associations with knee pain and structural changes were investigated in a population-based older adult sample. The prevalence of MRI-OPs was about 75%. Compared with participants without any OPs, participants with MRI-OPs had greater cartilage volume loss and increased cartilage defects and BMLs. MRI-OPs and established-OPs both predicted progression of knee structural abnormalities, but the associations for MRI-OPs were not as prominent as those for established-OPs. This suggests MRI-OPs may have a role to play in knee early-stage osteoarthritic progression. In conclusion, this series of studies indicate that BMLs are not static and changes in BMLs are clinically relevant. Systemic inflammation is important in the aetiology of BMLs in OA. MRI-detected OPs can predict knee OA structural and symptomatic progressions. MRI-OP detected only by MRI but not by standard x-ray can also lead to OA progression, suggesting MRI-OP, which largely represent early OP formation, can also serve as a biomarker to predict knee structural progression over time.

Introduction Osteoarthritis (OA) is a multifactorial musculoskeletal disorder and its aetiology is under investigation. Current research and therapeutic interventions for hip OA are limited. In early or advanced stages of hip OA, imaging techniques can be used to scrutinize overall structural and muscular changes in the joint such as bone marrow lesions (BMLs), hip cartilage defects, hip effusion-synovitis, bone shape and muscle health. Investigating these factors can provide information on interactive pathways vital for understanding the aetiology of OA. This thesis reports the results of six such investigations. Materials and Methods The Tasmanian Older Adult Cohort (TASOAC) is a large population based cohort study initiated in 2002. Older adults aged 50-80 years (51% female, mean age 62yrs) were enrolled into the study at baseline (Phase 1) with a first follow-up approximately 3 years later (Phase 2), a second follow up (Phase 3) approximately 5 years from baseline and a third follow up (Phase 4) approximately 10 years from baseline. Hip and knee pain was assessed using the WOMAC (Western Ontario and McMaster Universities Osteoarthritis). Pedometers and a dynamometer were used to measure physical activity and muscle strength respectively. Hip structural abnormalities and hip muscle cross-sectional area (CSA) were assessed from MRI scans. Bone mineral density (BMD) was estimated by dual-energy x-ray absorptiometry (DXA). Morphological shape of the hip was assessed by Active Shape Modelling (ASM) imaging software and radiographic hip OA (ROA) was determined from X-rays. Results The first two studies focus on hip BMLs and their cross-sectional and longitudinal associations with hip and knee pain, high cartilage signal and BMD. Overall, the proportion of hip BMLs at the femoral and/or acetabular site was 28%. About 8% of the population had a large hip BML. In the first study, those with large hip BMLs had greater hip pain. Incidence of larger hip BMLs (femoral and acetabular) was associated with an increase in hip pain. On the other hand, resolution of femoral BMLs was associated with a decrease in knee pain. Additionally, 1 S.D increase in hip BML size was associated with worsening hip pain. High cartilage signal intensity was strongly associated with hip BMLs but not with hip pain. This study identified that hip BMLs associate not only with hip and knee pain but also with early changes in the hip cartilage. In the second study, irrespective of size, hip BMLs were found to be associated with local (total hip and femoral neck) BMD but not with distant (spine) BMD. Femoral BMLs were associated with higher femoral neck BMD while acetabular BMLs were associated with lower hip and femoral neck BMD. This novel study suggests that hip BMLs located in two different compartments might represent bone areas undergoing different pathological changes. In the third study, correlates of hip cartilage defects were examined. About 76% of the subjects had a hip cartilage defect. Any and grade 2 hip cartilage defects were associated with higher prevalence of hip pain. Any hip cartilage defects associated with lower muscle strength, particularly among men. The associations of grade 1 defect with high cartilage signal were stronger for men than for women. However, associations between grade 1 defects and BMLs were equivalent in both sexes. Grade 2 defects were linked with several outcomes such as hip BML, larger hip effusion-synovitis and hip ROA (in men), and lower steps per day. This study indicates that cartilage defects/damage, especially grade 2 hip cartilage defects are associated with major clinical and structural risk factors relevant to hip OA even in the general population. The fourth study describes the cross-sectional and longitudinal correlates of hip effusion-synovitis. Cross-sectionally, presence of hip effusion-synovitis at multiple sites was associated with presence of hip pain, and hip cartilage defects were associated with greater hip effusion-synovitis CSA. No other associations were found. Longitudinally, independently of each other, persistent hip BMLs and incident hip cartilage defects predicted larger hip effusion-synovitis size. However, change in hip pain from baseline to follow up and baseline hip ROA were not associated with hip effusion-synovitis. Additionally, baseline hip cartilage defects were associated with worsening hip BMLs at follow up. Similarly, baseline hip BMLs were associated with hip cartilage defects at follow-up. Overall, these results suggest that hip cartilage defects, hip BMLs and hip effusion-synovitis share possible causal pathways and the extent of hip effusion-synovitis might influence hip pain. The fifth study explored the link between hip musculature (hip muscle CSA), muscle strength and bone mass (BMD). Among older adults, hip flexor CSA had the strongest association with BMD of the hip. The associations for pectineus and sartorius hip muscles CSA with BMD were stronger for women in comparison to men. Most of hip muscles CSA were associated with muscle strength and muscle strength was weakly associated with BMD. These findings suggest that for older adults, muscle bulk contributes to hip bone mass more so than muscle strength and maintaining muscle mass would aid in preservation of bone health. The sixth and the final study focused on hip morphology (shape) and its associations with various outcomes. Using Active shape modelling (ASM) imaging software and SHAPE software, hip shape was assessed and the first six principal components (modes) describing the variations in measurements of hip shape were extracted. These modes explained 68% of total hip shape variations in the sample population. At baseline, modes 1, 2, 4 and 6 were associated with hip ROA, modes 1, 3, 4 and 6 correlated with hip cartilage volume and all except mode 2 with muscle strength. Higher mode 1, and lower mode 3 and 6 scores at baseline predicted greater hip pain at follow-up and higher mode 1 and mode 2 scores were associated with hip effusion-synovitis. Greater scores for modes 2 (decreasing acetabular coverage) and 4 (non-spherical femoral head) at baseline predicted 10-year total hip replacement (THR); while mode 4 alone correlated with bone marrow lesions (BMLs), effusion-synovitis, and increased cartilage signal. Conclusions Overall, structural changes are slow and relatively uncommon in the preclinical stages of hip OA. Nevertheless, hip BMLs, hip cartilage defects, high cartilage signal and hip effusion-synovitis are inter-related and contribute to changes in the subchondral bone; with a probable role in the pathogenesis of hip OA. Additionally, muscle bulk and strength could aid in preservation of bone density and assessing bone shape using ASM could benefit in improving assessment and monitoring of disease progression and identifying those at higher risk of OA.

This thesis evaluates the effect of bone-targeted therapies on new indications in two areas of major clinical and public health significance, namely osteoarthritis and vascular calcification. The first of these indications is osteoarthritis (OA). OA is the most common joint disease characterised by articular cartilage loss, joint pain and disability. There are currently no approved disease-modifying OA drugs (DMOADs), and conservative treatments only have small to moderate effects on joint symptoms. Subchondral bone abnormalities predict both structural and symptomatic progression of OA and have increasingly been recognised as a potential treatment target. Bone-targeted therapies (e.g. bisphosphonates and denosumab) are anti-resorptive agents that have been widely used for the prevention and treatment of osteoporosis. Previous evidence has indicated that these bone-targeted therapies may be promising DMOADs especially in patients with a marker of high bone turnover (e.g. subchondral bone marrow lesions [BMLs], Modic type vertebral endplate changes). The second indication, vascular calcification, is important as it is an independent predictor of cardiovascular disease. Animal studies and small trials suggest that bisphosphonates may be protective against the progression of vascular calcification, but data from large trials are lacking. A further issue in the clinical use of bone-targeted therapies is that intravenous (IV) bisphosphonates frequently lead to a high incidence of acute phase responses (APRs). This thesis aims to investigate whether zoledronic acid (an IV bisphosphonate) and/or denosumab are effective for the treatment of knee and spine OA and abdominal aortic calcification (AAC), and whether co-administration of methylprednisolone reduces the high incidence of APRs caused by zoledronic acid. Data from four multi- or single-centre, double-blinded, randomised, placebo-controlled trials were analysed. Cartilage volume, BMLs, Modic changes and disc degeneration were evaluated using magnetic resonance imaging (MRI). Radiographic joint space narrowing (JSN) and AAC were measured on knee and spine x-rays, respectively. Bone mineral density (BMD) was assessed using dual energy x-ray absorptiometry (DXA). Multiple questionnaires were used to assess pain and functional disability of the knee and the low back. APRs and other adverse events were recorded throughout the trials. Chapter 4 evaluates the effect of zoledronic acid on tibiofemoral cartilage volume loss and change in BML size and knee pain over 2 years in 223 patients with symptomatic knee OA and BMLs. Annual infusion of 5 mg zoledronic acid did not significantly slow the progression of cartilage volume loss, reduce the size of BMLs, or alleviate knee pain compared to placebo, but may be beneficial for knee pain in patients without radiographic JSN. Adverse events, particularly APRs, were more frequent with zoledronic acid than placebo as expected. Chapter 5 assesses the effect of zoledronic acid plus methylprednisolone versus zoledronic acid alone and placebo on the incidence of APRs and changes in knee pain, disability and BML size over 6 months in 117 patients with symptomatic knee OA and BMLs. Adding 10 mg methylprednisolone to zoledronic acid showed no effect on APRs compared to zoledronic acid alone but may have symptomatic benefits compared to placebo. Chapter 6 evaluates the effect of zoledronic acid and denosumab on low back pain (LBP) and Modic changes over 6 months in 103 patients with chronic LBP and type I, II or mixed Modic change. Both zoledronic acid and denosumab improved LBP and the effect was stronger in patients with type I Modic change, non-neuropathic pain or mild disc degeneration. While neither treatment reduced the size of Modic change overall, denosumab decreased the size of type I Modic change. Chapter 7 investigates the effect of annual infusion of zoledronic acid on the progression of AAC over 3 years in 502 postmenopausal women with osteoporosis, and the correlation between change in BMD and AAC progression. Zoledronic acid showed no beneficial effect on AAC progression, and there were no correlations between change in femoral neck or total hip BMD and change in AAC scores. In conclusion, these randomised controlled trials (RCTs) indicate that bone-targeted therapies have at best a small to moderate effect on clinical symptoms in early OA with BML/Modic change, and that zoledronic acid does not affect structural progression of knee OA or the progression of vascular calcification. APRs caused by zoledronic acid cannot be reduced by co-administration of 10 mg methylprednisolone. These findings imply a limited role of bonetargeted therapies in the treatment of OA and vascular calcification. Future work should confirm the symptomatic benefit of bone-targeted therapies in early OA and evaluate the effect of bone-targeted therapies on Modic change over a longer time interval (e.g. 1 year).

Osteoarthritis (OA) is a chronic disease that affects the joints, most commonly hands, hips, knees, feet, and spine (Litwic et al. 2013). The disease becomes more common with advanced age and is one of the most prevalent causes of disability in older populations. Currently there is no cure besides total joint replacement surgery, and there will be approximately 4 million Americans living with a hip replacement by the end of the next decade (Maradit Kremers et al. 2015). Osteoarthritis was classically characterized as a disease of progressive articular cartilage degradation, but the degeneration involves all tissues of the synovial joint including the periarticular muscles, joint capsule, synovium, ligaments, and subchondral and metaphyseal bone. The cause of pain in OA is not well understood, but it is known that bone marrow lesions (BMLs) identified in subchondral bone by MRI are an important determinant of pain (Felson et al. 2001; Kumar et al. 2013). Abnormal blood vessel growth may be responsible MRI signature of BMLs, and the commonality between pathways for angiogenesis and neurogenesis suggests this pathologic process may be the source of pain in OA. The objective of this study was to characterize the histologic nature of subchondral cysts identified by micro computed tomography (μCT) which had been registered with MRI images in which marrow lesions were identified. Femoral heads were collected from 10 patients (6 females and 4 females; age 29-80) who underwent total hip arthroplasty. All patients had MRIs performed within 6 months prior to surgery. The heads were fixed and scanned with μCT to identify cysts in the subchondral bone. A block of the femoral head containing the cyst of interest was resected and processed for histologic analysis. The sections were stained with either Safranin-O and Fast Green or hematoxylin and eosin to view the nature and composition of the tissue. A two-dimensional image from the μCT that corresponded to the histologic slice was matched with a coronal view from the MRI. The primary compressive group was reliably identified on μCT images and served as good indicator for orienting the CT to match with the MRI. The subchondral cysts that were matched to MRI all consisted of predominantly fibrous bone marrow and frequently had a large number of blood vessels within the tissue. Three of the eight cysts had cartilage intrusions that were located mostly within peripheral trabecular bone, though one cyst contained a nodule of cartilage surrounded by organized fibers with the texture of granulation tissue. The process of image registration was mostly performed manually, but the development of this process will contribute to a more refined, semi-automated process in the future. The ability to correlate the histopathology of CT-identified lesions with a signature patter on MRI will be an important tool for better characterizing the nature of BMLs and understanding the pathogenesis of OA.