Endocortical bone loss in osteoporosis: The role of bone surface availability

Age-related bone loss and postmenopausal osteoporosis are disorders of bone remodelling, in which less bone is reformed than resorbed. Yet, this dysregulation of bone remodelling does not occur equally in all bone regions. Loss of bone is more pronounced near and at the endocortex, leading to cortical wall thinning and medullary cavity expansion, a process sometimes referred to as "trabecularisation" or "cancellisation". Cortical wall thinning is of primary concern in osteoporosis due to the strong deterioration of bone mechanical properties that it is associated with. In this paper, we examine the possibility that the non-uniformity of microscopic bone surface availability could explain the non-uniformity of bone loss in osteoporosis. We use a computational model of bone remodelling in which microscopic bone surface availability influences bone turnover rate and simulate the evolution of the bone volume fraction profile across the midshaft of a long bone. We find that bone loss is accelerated near the endocortical wall where the specific surface is highest. Over time, this leads to a substantial reduction of cortical wall thickness from the endosteum. The associated expansion of the medullary cavity can be made to match experimentally observed cross-sectional data from the Melbourne Femur Collection. Finally, we calculate the redistribution of the mechanical stresses in this evolving bone structure and show that mechanical load becomes critically transferred to the periosteal cortical bone.Comment: 13 pages, 3 figures. V2: minor stylistic improvements in text/figures; more accurately referenced subsection "Internal mechanical stress distribution"; some improved remarks in the Discussion sectio

A convolutional neural network to characterize mouse hindlimb foot strikes during voluntary wheel running

Voluntary wheel running (VWR) is widely used to study how exercise impacts a variety of physiologies and pathologies in rodents. The primary activity readout of VWR is aggregated wheel turns over a given time interval (most often, days). Given the typical running frequency of mice (∼4 Hz) and the intermittency of voluntary running, aggregate wheel turn counts, therefore, provide minimal insight into the heterogeneity of voluntary activity. To overcome this limitation, we developed a six-layer convolutional neural network (CNN) to determine the hindlimb foot strike frequency of mice exposed to VWR. Aged female C57BL/6 mice (22 months, n = 6) were first exposed to wireless angled running wheels for 2 h/d, 5 days/wk for 3 weeks with all VWR activities recorded at 30 frames/s. To validate the CNN, we manually classified foot strikes within 4800 1-s videos (800 randomly chosen for each mouse) and converted those values to frequency. Upon iterative optimization of model architecture and training on a subset of classified videos (4400), the CNN model achieved an overall training set accuracy of 94%. Once trained, the CNN was validated on the remaining 400 videos (accuracy: 81%). We then applied transfer learning to the CNN to predict the foot strike frequency of young adult female C57BL6 mice (4 months, n = 6) whose activity and gait differed from old mice during VWR (accuracy: 68%). In summary, we have developed a novel quantitative tool that non-invasively characterizes VWR activity at a much greater resolution than was previously accessible. This enhanced resolution holds potential to overcome a primary barrier to relating intermittent and heterogeneous VWR activity to induced physiological responses

Rescuing Loading Induced Bone Formation at Senescence

The increasing incidence of osteoporosis worldwide requires anabolic treatments that are safe, effective, and, critically, inexpensive given the prevailing overburdened health care systems. While vigorous skeletal loading is anabolic and holds promise, deficits in mechanotransduction accrued with age markedly diminish the efficacy of readily complied, exercise-based strategies to combat osteoporosis in the elderly. Our approach to explore and counteract these age-related deficits was guided by cellular signaling patterns across hierarchical scales and by the insight that cell responses initiated during transient, rare events hold potential to exert high-fidelity control over temporally and spatially distant tissue adaptation. Here, we present an agent-based model of real-time Ca2+/NFAT signaling amongst bone cells that fully described periosteal bone formation induced by a wide variety of loading stimuli in young and aged animals. The model predicted age-related pathway alterations underlying the diminished bone formation at senescence, and hence identified critical deficits that were promising targets for therapy. Based upon model predictions, we implemented an in vivo intervention and show for the first time that supplementing mechanical stimuli with low-dose Cyclosporin A can completely rescue loading induced bone formation in the senescent skeleton. These pre-clinical data provide the rationale to consider this approved pharmaceutical alongside mild physical exercise as an inexpensive, yet potent therapy to augment bone mass in the elderly. Our analyses suggested that real-time cellular signaling strongly influences downstream bone adaptation to mechanical stimuli, and quantification of these otherwise inaccessible, transient events in silico yielded a novel intervention with clinical potential

Anemia in relation to body mass index and waist circumference among Chinese women

Extent: 3 p.BACKGROUND: This study aimed to investigate the relationship of anemia and body mass index among adult women in Jiangsu Province, China. Data were collected in a sub-national cross-sectional survey, and 1,537 women aged 20 years and above were included in the analyses. Subjects were classified by body mass index (BMI) categories as underweight, normal weight, overweight and obese according to the Chinese standard. Central obesity was defined as a waist circumference ≥ 80 cm. Anemia was defined as hemoglobin concentration < 12 g/dl. Prevalence ratios (PRs) of the relationship between anemia and BMI or waist circumference were calculated using Poisson regression. FINDINGS: Overall, 31.1% of the Chinese women were anemic. The prevalence of overweight, obesity and central obesity was 34.2%, 5.8% and 36.2%, respectively. The obese group had the highest concentrations of haemoglobin compared with other BMI groups. After adjustment for confounders, overweight and obese women had a lower PR for anemia (PR: 0.72, 95% CI: 0.62-0.89; PR: 0.59, 95% CI: 0.43-0.79). Central obesity was inversely associated with anemia. CONCLUSION: In this Chinese population, women with overweight/obesity or central obesity were less likely to be anemic as compared to normal weight women. No measures are required currently to target anemia specifically for overweight and obese people in China.Yu Qin, Alida Melse-Boonstra, Xiaoqun Pan, Baojun Yuan, Yue Dai, Jinkou Zhao, Michael B. Zimmermann, Frans J. Kok, Minghao Zhou and Zumin Sh

An Enclosing Analytic Element

University of Minnesota Ph.D. dissertation. February 2019. Major: Civil Engineering. Advisor: Otto Strack. 1 computer file (PDF); viii, 100 pages.The main contributions described in this thesis are two-fold: 1. A new analytic element for a closed boundary of a chosen shape that may contain internal elements. The element, referred to as the enclosing analytic element, is valid for steady three-dimensional flow. We outline the general method for constructing these new analytic elements and provide several examples: (1) an elliptic enclosing element, (2) a square enclosing element, (3) a rectangular enclosing element, and (4) a slotted enclosing element. We combine the enclosing analytic element with other established analytic elements via superposition, including uniform flow, recharge, wells, line-sinks, and elliptic lakes. 2. A new technique for expanding the original shape into a family of shapes. Each new shape within the family set results in a reduction in the sharpness of the corners. We refer to these new shapes as smooth boundary shapes

Identifying the Origins of Bone Loss Induced by Transient Muscle Paralysis Using Novel MicroCT Image Registration Techniques

Thesis (Ph.D.)--University of Washington, 2013The co-dependency of bone and muscle is exemplified by concomitant catabolic and/or anabolic tissue adaptations, as induced by respective decreases or increases in mechanical loading. Given that muscular contraction is responsible for skeletal loading during normal locomotion, this co-dependency has been attributed to an indirect consequence of muscle function. However, recent data from our group and others now indicate that direct communication between muscles, nerves and bone can significantly alter bone homeostasis independent of mechanical loading. In this dissertation, three independent studies explored the relation between impaired muscle function and bone homeostasis using our murine model in which rapid and profound bone loss is induced in the tibia following transient paralysis of the calf muscles. In the first study, we quantified endocortical expansion in the tibial diaphysis following transient muscle paralysis using a novel microCT image registration approach. This approach identified a complex, but highly repeatable, resorptive response implicating osteoclast recruitment and focal activation of osteoclastic resorption underlies the spatially consistent endocortical resorption induced by transient muscle paralysis. Importantly, this study also validated the use of serial microCT image registration to track focal bone alterations. In the second study, we characterized the spatiotemporal parameters of bone resorption in our model, which revealed that tibia metaphyseal and diaphyseal bone loss induced by transient calf paralysis are spatially and temporally discrete events. By expanding our image registration approach, we determined that the initiating event in acute bone loss (within 3 days of paralysis) occurs in the proximal tibia metaphysis as a result of enhanced activity of resident osteoclasts adjacent to the growth plate. In contrast to the focal activation of osteoclasts in the proximal metaphysis, bone loss occurs throughout the diaphysis between 6 and 13 days post-paralysis; an observation that is temporally consistent with de novo osteoclastogenesis as a mediator of the diaphyseal resorption. These findings clarified the timing and origins of discrete resorptive events and allowed for investigation of the upstream cellular mechanisms responsible for their initiation. In the final study, we sought to determine if bone loss induced by transient muscle paralysis is a result of neurogenic inflammation of the bone marrow, which leads to enhanced osteoclastogenesis. Though attempts to suppress inflammatory mechanisms were unable to block bone loss following paralysis, we were able to demonstrate that inflammatory cell infiltration, pro-osteoclastogenic inflammatory gene expression and an alterations in bone marrow osteoclastogenic permissiveness occurred in a manner temporally consistent with observed bone loss. Further, we identified giant osteoclast formation, implicating enhanced osteoclast fusion as a potential mechanism for the extensive bone resorption. Taken together, these studies defined the spatiotemporal origins and potential mechanisms (enhanced osteoclast function in the metaphysis and de novo giant cell osteoclastogenesis in the diaphysis) of bone loss following transient muscle paralysis. More broadly, by characterizing the rapid and spatially distinct bone loss precipitated by transient muscle paralysis, we have provided evidence that muscle and bone are directly coupled and that altered muscle function can activate cellular events that profoundly alter bone homeostasis