Quantitative assessment and mechanical consequences of bone density and microstructure in hip osteoarthritis

Osteoarthritis (OA) is a chronic, painful, and currently incurable disease characterized by structural deterioration and loss of function of synovial joints. OA is known to involve profound changes in bone density and microstructure near to, and even distal to, the joint. The prevailing view is that these changes in density and microstructure serve to stiffen the subchondral region thereby altering the mechanical environment (stresses and strains) within the epiphyseal and metaphyseal bone, and that these alterations trigger the aberrant cellular signaling and tissue damage characteristic of the progression of OA. Critically, however, these alterations in mechanical environment have never been well documented in a quantitative fashion in hip OA. Separately, although OA is generally thought to be inversely associated with fragility fracture, recent data challenge this idea and suggest that OA may actually modulate which regions of the proximal femur are at risk of fracture. Therefore, the goal of this work was to provide a spatial assessment of bone density and microstructure in hip OA and then examine the mechanical consequences of these OA-related abnormalities throughout the proximal femur. First, micro-computed tomography and data-driven computational anatomy were used to examine 3-D maps of the distribution of bone density and microstructure in human femoral neck samples with increasing severity of radiographic OA, providing evidence of the heterogeneous and multi-faceted changes in hip OA and discussion of the implications for OA progression and fracture risk. Second, the feasibility of proton density-weighted MRI in image-based finite element (FE) modeling, to examine stress, strain, and risk of failure in the proximal femur under sideways fall, was assessed by comparison to the current standard of CT-based FE modeling. Third, phantom-less calibration for CT-based FE modeling was used with clinically available pre-operative patient scans to assess bone strength and failure risk of the proximal femur in hip OA. Overall, the results of this work provide a rich, quantitative definition of the ways in which the bone mechanical environment under traumatic loading differ in association with hip OA, and then highlight the potential for clinical image-based FE methods to be used opportunistically to assess bone strength and failure risk at the hip. This work is significant because it directly tests the long-standing premise that OA is associated with changes in the mechanical environment of the bone tissue in ways that are impactful for OA progression; further, this work examines how these changes may influence risk of hip fracture. The results can be used to identify mechanistic predictors of OA progression, to inform development of bone-targeting treatments for OA, and to more broadly understand bone damage and fracture in this population

DEVELOPMENT AND APPLICATION OF A MORPHOLOGICAL MODEL FOR TRABECULAR BONE

Ph.DDOCTOR OF PHILOSOPH

Exercise and Proximal Femur Bone Strength to Reduce Fall-Induced Hip Fracture

Bone mass and structure, constituting its strength, adapt to prevalent mechanical environment. Physical activity and exercise provide natural ways to apply the mechanical loading to bone. Finding effective osteogenic exercise types to improve proximal femur bone strength is of great importance to reduce hip fracture incidence and consequent substantial socioeconomic burden. Importantly, almost all hip fractures are caused by falls. Therefore, the primary objective of the present doctoral research was to find such effective exercise types by exploring the effect of long-term specific exercise loading on proximal femur bone strength in the fall situation using a finite element (FE) method. The secondary objective was to analyze 3D morphological adaptation of proximal femur cortical bone to the specific exercise loading. The results from this secondary objective were anticipated to help understanding the findings pertinent to the primary objective. To achieve these objectives, proximal femur MRI data were obtained from 91 young adult female athletes (aged 24.7 ± 6.1 years, > 8 years competing career) and 20 nonathletic but physically active controls (aged 23.7 ± 3.8 years). The athletes were classified into five distinct exercise loading groups based on the typical loading patterns of their sports: high-impact (H-I: triple- and high-jumpers), odd-impact (O-I: soccer/football and squash players), high-magnitude (H-M: powerlifters), repetitive-impact (R-I: endurance runners), and repetitive non-impact (R-NI: swimmers). Based on their MRI data, proximal femur FE models were first created in a single fall configuration (direction) to compare 1) cortical stresses in eight anatomical octants of femoral neck cross-sections in the proximal, middle, and distal femoral neck regions and 2) fracture behavior (load, location, and mode) between each exercise loading and control groups. The athletic bones are adapted to the long- term specific exercise loading characterized by not only the loading magnitude, rate, and frequency but also direction. Given this, the study was extended to simulate the FE models in multiple fall directions to examine whether potentially identified higher proximal femur bone strength to reduce fall-induced hip fracture risk, attributed to the long-term specific exercise loading, depends on the direction of the fall onto the greater trochanter or hip. For the secondary objective, a new computational anatomy method called Ricci-flow conformal mapping (RCM) was implemented to obtain 3D distribution of the cortical thickness within the proximal femur and to perform its spatial between-group statistical comparisons. Key results from the present research demonstrated that young adult females with the exercise loading history of high ground impacts (H-I), ground impacts from unusual/odd directions (O-I), or a great number of repetitive ground impacts (R-I) had 10-22%, 12-16%, and 14-23% lower fall-induced cortical stress at the fracture-prone superolateral femoral neck and 11-17%, 10-11%, and 22-28% higher fracture loads (higher proximal femur bone strength) in the fall situations compared to the controls, respectively. These results indicate that the long-term H-I, O-I, and R-I exercise loadings may reduce the fall-induced hip fracture risk. Furthermore, the present results showed that the higher proximal femur bone strength to reduce hip fracture risk in athletes engaged in the high-impact or repetitive-impact sports are robust and independent of the direction of fall. In contrast, the higher strength attributed to the odd-impact exercise loading appears more modest and specific to the fall direction. The analysis of the minimum fall strength spanning the multiple fall directions also supported the higher proximal femur bone strength in the athletes engaged in these impact exercises. In concordance with the literature, the present results also confirmed in these young adult females that 1) the fall-induced hip fracture most likely initiates from the superolateral femoral neck’s cortical bone, particularly at its posterior aspect (superoposterior cortex) in the distal femoral neck region, and 2) the most dangerous fracture-causing fall direction is the one where the impact is imposed to the posterolateral aspect of the greater trochanter. It would be ideal if impact exercise loading could induce beneficial cortical bone adaptation in the fracture-prone posterior aspect of superolateral femoral neck cortex. However, such apparently beneficial cortical adaptation was not observed in any of the impact or nonimpact exercise loading types examined in the present research based on the supplementary RCM-based 3D morphological analyses of proximal femur cortical bone. This analysis importantly showed that the higher proximal femur bone strengths to reduce fall-induced hip fracture risk in athletes engaged in the high- or odd-impact exercise types are likely due to thicker cortical layers in other femoral neck regions including the inferior, posterior, and/or superior-to-superoanterior regions. Interestingly, the higher proximal femur strength in the athletes with the repetitive-impact exercise loading was not supported by such cortical adaptation. This suggests that other structural/geometrical adaptation contributes to their higher strength. This calls for further studies to elucidate the source of the higher proximal femur bone strength in this type of athletes. In contrast to the impact exercise loading histories, the exercise loading history of the high-magnitude (e.g., powerlifting) or repetitive, non-impact (e.g., swimming) was not associated with higher proximal femur bone strength to reduce fall-induced hip fracture risk. This most likely reflects the lack of any beneficial structural adaptations of cortical bone around the femoral neck in the athletes with these exercise loading histories. Considering the loading characteristics of the exercise types examined in the present doctoral research, the moderate-to-high loading magnitude alone appears insufficient but needs to be generated at the high loading rate and/or frequency to induce the beneficial adaptation in the proximal femur cortical bone. Therefore, in addition to aforementioned three impact exercise loading types, other exercise or sport types satisfying this condition may also be effective to increase or maintain the proximal femur bone strength to reduce fall- induced hip fracture risk. As a clinical prospect, the present findings highlight the importance of impact exercise in combating fall-induced hip fracture. Compared to the high-impact loading exercises (e.g., triple/long and high jumping exercise), the odd-impact [ball or invasion games (e.g., football/soccer, tennis)] and/or repetitive-impact loading exercises (e.g., endurance running, jogging, and perhaps vigorous walking) likely provide a safer and more feasible choice for the populations covering the sedentary adults to old people. This is due to the relatively more moderate ground impact involved in the odd- and repetitive-impact loading exercises than in the high-impact exercises. For young, physically active, and/or fit people, the above-mentioned or similar jumping exercises and any other exercise types consisting of the high ground impact (e.g., volleyball, basketball, gymnastics) can also be incorporated into their habitual exercise routines. Lastly, the present results were observed in the young adult females who had engaged in sport-specific training from their childhood/adolescence to early adulthood. Therefore, this calls for the prospective and/or retrospective observational studies to investigate whether the higher proximal femur bone strength to reduce fall-induced hip fracture risk obtained from the long-term specific impact exercise loading during these early phases of life can sustain into the later stages, especially after age of 65 years when the hip fracture is generally more common

Multiscale Geometric Methods for Isolating Exercise Induced Morphological Adaptations in the Proximal Femur

The importance of skeletal bone in the functioning of the human body is well-established and acknowledged. Less pervasive among the populace, is the understanding of bone as an adaptive tissue which modulates itself to achieve the most construction sufficient for the role it is habituated to. These mechanisms are more pronounced in the long load bearing bones such as the femur. The proximal femur especially, functions under significant loads and does so with high degree of articulation, making it critical to mobility. Thus, exercising to buttress health and reinforce tissue quality is just as applicable to bone as it is to muscles. However, the efficiency of the adaptive (modelling/remodelling) processes is subdued after maturity, which makes the understanding of its potential even more important. Classically, studies have translated the evaluation of strength in terms of its material and morphology. While the morphology of the femur is constrained within a particular phenotype, minor variations can have a significant bearing on its capability to withstand loads. Morphology has been studied at different scales and dimensions wherein parameters quantified as lengths, areas, volumes and curvatures in two and three dimensions contribute towards characterising strength. The challenge has been to isolate the regions that show response to habitual loads. This thesis seeks to build on the principles of computational anatomy and develop procedures to study the distribution of mechanically relevant parameters. Methods are presented that increase the spatial resolution of traditional cross-sectional studies and develop a conformal mapping procedure for proximal femur shape matching. In addition, prevalent methods in cross-sectional analyses and finite element simulations are employed to analyse the morphology of the unique dataset. The results present the spatial heterogeneity and a multi-scale understanding of the adaptive response in the proximal femur morphology to habitual exercise loading

Наноструктурне и микроархитектонске карактеристике врата бутне кости: утицај на повећану коштану фрагилност са старењем код жена

Background: Hip fractures are among the most important health problems in elderly population worldwide, particularly in elderly women. However, despite extensive research on age-related bone fragility, the factors leading to decreased bone strength in advanced age are not yet clear enough. Indeed, in clinical settings bone mineral density (BMD) assessed by dual energy X-ray absorptiometry has been used as an indicator of hip fracture risk. However, as it has been already pointed out that age-related decrease in BMD fails to fully explain the high increase in hip fracture risk with aging, other bone features also account for age-related deterioration in bone strength. Since bone is a hierarchically organized structure, it can be hypothesized that its strength depends on various features from nano-scale to macro-scale. Although numerous studies addressed macro- and microstructural basis of bone fragility, so far the direct data at microarchitectural level have been scarce. Moreover, nanostructure of the bone mineralized matrix has received insufficient attention with regard to effects of aging and its relation to bone fragility. Hypotheses: Our hypotheses were that region-dependant worsening of bone microarchitecture in elderly women leads to increased femoral neck fragility, and that - besides the microarchitectural deterioration - the age-related nanostructural changes at the bone matrix level contribute to increased bone fragility in elderly women. Material and methods: To test these hypotheses, we analyzed bone specimens from the femoral neck region obtained at autopsy in young and elderly women without hip fracture as well as in a group of postmenopausal women who sustained a hip fracture. Following sectioning process, micro-computed tomography was performed to assess bone microarchitectural properties. Bone nanostructure was analyzed via Topography and Phase modes of Atomic Force Microscopy (AFM), while chemical evaluation of bone material composition encompassed energy dispersive X-ray spectroscopy, quantitative backscatter electron imaging, inductively coupled plasma optical emission spectroscopy and direct current argon arc plasma optical emission spectrometry...Увод: Преломи кука су један од најзначајнијих здравствених проблема код старих особа широм света, а посебно код старијих жена. Међутим, упркос многобројним истраживањима узрока фрагилности скелета код старијих особа, још увек се врло мало зна о чиниоцима који доводе до смањене чврстоће кости у старости. Минерална густина кости (bone mineral density, BMD) утврђена применом дензитометријске методе (dual energy X-ray absorptiometry, DXA) је дуго сматрана главним показатељем коштане чврстоће и до данас коришћена у клиничкој процени коштане фрагилности и ризика за прелом кука. Међутим, будући да је више аутора указало на податак да старосни пад BMD не може потпуно објаснити значајни пораст ризика oд преломa кука код старијих особа, неопходно је испитати и допринос других коштаних карактеристика смањењу коштане чврстоће са старењем. Како је кост хијерархијски организована структура, може се претпоставити да њена чврстоћа зависи од различитих елемената коштане грађе од нанометарске до макро-скале. Премда су се многобројне студије усредсредиле на испитивање макроструктурне и микроструктурне основе коштане фрагилности, још увек недостају директни подаци о микроархитектури костију код особа са преломом кука. Поред тога, старосним променама наноструктурних параметара самог материјала од кога је кост изграђена није посвећена одговарајућа пажња, као ни њиховом значају за коштану фрагилност. Хипотеза: Нашe хипотезе су биле да регион-зависно погоршање коштане микроархитектуре код старијих жена повећава њихов ризик за прелом кука, као и да се, осим микроструктурних промена, са старењем јављају и наноструктурне промене на нивоу коштаног матрикса које такође доприносе повећаној коштаној фрагилности код старијих жена..

Skeleton geometry, physical activity and proximal femur bone mass distribution in 8-12 year old children

Doutoramento em Motricidade Humana, especialidade em Actividade Física e SaúdeIn the context of bone health promotion, the aim of this Ph.D dissertation was to analyze potential explanatory factors of the effects of physical activity and of bone geometry on bone mass distribution at the proximal femur in 8-12 year old children. Four studies were undertaken to compare the bone mineral density (BMD) between: (a) the sub-regions of the proximal femur – the neck and its superolateral and inferomedial aspects, the trochanter and the intertrochanter; (b) sexes, concerning the associations/effects of non-targeted physical activity and bone geometry. Sex and regional specific effects of non-targeted physical activity on bone mass distribution at the proximal femur in children were observed. The geometry of the pelvis and the proximal femur, namely the pelvis width and the abductor lever arm, emerged as predictors of bone mass distribution at the proximal femur, therefore as explanatory factors of both the regional and the sex specific patterns. These geometric features might mediate the physical activity effects on bone mineralization at the proximal femur, as long as, when they are considered, the power of physical activity to explain the distribution of bone mass at this skeletal site seems limited.Resumo : No contexto da promoção da saúde óssea, o objetivo desta dissertação de doutoramento foi analisar potenciais fatores explicativos dos efeitos da atividade física habitual e da geometria óssea na distribuição da massa óssea do fémur proximal, em crianças de 8-12 anos de idade. Para o efeito foram realizados quatro estudos comparando a densidade mineral óssea (DMO) entre: (a) as diversas sub-regiões do fémur proximal - o colo do fémur e os seus aspetos supero-lateral e infero-medial, o grande trocanter e a sub-região intertrocantérica; (b) os sexos, relativamente às associações/efeitos da atividade física habitual e da geometria óssea. Foram observadas associações/efeitos da atividade física habitual na massa óssea do fémur proximal diferenciados quanto ao sexo e sub-região. A geometria da pélvis e do femur proximal, nomeadamente a largura da pélvis e o braço de momento de força dos abdutores, surgiram como preditores da distribuição de massa óssea no fémur proximal e consequentemente como fatores explicativos de diferenciação da distribuição de massa óssea de acordo com o sexo e sub-região. Estas caraterísticas geométricas poderão mediar os efeitos da atividade física na mineralização do femur proximal uma vez que quando consideradas parecem limitar a capacidade explicativa da atividade física na distribuição de massa óssea no fémur proximal.FCT - Fundação para a Ciência e a Tecnologi

ITAP: Clinical outcomes and implant design optimisation using numerical modelling

Redistribution of the flow of forces through the body, such as that after amputation and/or implantation of a skeletally anchored amputation prostheses, leads to bone remodelling. Periprosthetic bone resorption can destabilise skeletally anchored amputation prostheses. Therefore, implants that minimise bone resorption will achieve a more successful long term bone fixation. Bone remodelling outcome measures rely on implant design using mechanoregulatory bone remodelling theory. Mechanoregulation is implemented by functions that link a local mechanical stimulus to a local change in the structure or properties of bone material. This thesis uses the strain adaptive remodelling theory at the time of implantation with periprosthetic strain energy density as the outcome parameter. Clinical trial data was collected from a patient with a skeletally anchored amputation prostheses; The Intraosseous Transcutaneous Amputation Prosthesis (ITAP). The clinical trial ran from 2008 – 2019, the data was investigated for patterns between implant design and fixation success. This thesis reports trends in fixation success and bone change using a developed fixation success score. There was an ideal implant length to bone length ratio range and a straight, tapered stem with a flared bone collar growth shape were beneficial to fixation success. Conversely, one or more parameters associated with pressfit fixation were detrimental to fixation success. Results between the clinical and numerical data compared favourably; clinically, regions of periprosthetic bone growth were also observed by regions of high strain energy density in the finite element analysis and vice versa at the implant tip and osteotomy face. This thesis provides skeletally anchored amputation prostheses design guidelines that will minimise bone resorption when measured with strain energy density. Moreover, that future skeletally anchored amputation prostheses parameterised design can and should be used as a tool to assess bone fixation outcome in pre-clinical assessments