Myocardial infarction (MI) and osteoporotic fracture are the two leading causes of morbidity and mortality worldwide. These events are etiologically linked but current theories are limited to correlation of advanced stages of their underlying disease, atherosclerosis and osteoporosis (OP). To effectively inform treatments post-MI, it is crucial to investigate the possibility of a causative relationship between MI and OP. It has been established that MI causes a strong inflammatory response, and that bone is sensitive to inflammation. This suggests that an acute, systemic inflammatory response could link adaptive responses of the cardiovascular and skeletal systems, but further investigation is necessary. Two post-injury responses have shown promise as potential mediators of MI and bone loss; the sympathetic nervous system (SNS) and the complement system. Both are primary mediators of inflammation after MI, and both can affect bone by the upregulation of osteoclastogenesis. However, no studies have established these systems as mediator if MI-induced bone loss. To address these issues, we investigated the effect of MI trauma on the skeletal response in the absence of any underlying conditions. Furthermore, we determined the role of the SNS and complement system in this response. The aim of the works was to establish a causative relationship between MI and bone loss, characterize the magnitude and time course of MI-induced bone loss, and determine if SNS or complement inhibition could attenuate bone loss.

In this study, we surgically induced MI in mice and analyzed systemic and localized bone changes across multiple time points. Analysis included quantifying whole body bone mineral density using dual x-ray absorptiometry (DXA), assessing whole bone and mineral properties through 3-point bending, and measuring trabecular and cortical changes in the axial (L5 vertebra) and appendicular (femur) using micro-computed tomography (µCT). We also analyzed voluntary activity after operation to rule out any changes due to differences in mechanical loading. To determine the significance of the SNS, we used a 3-adrenoreceptor antagonist to inhibit SNS activity. To determine the role of the complement system we used transgenic mice that did not express the complement protein 5a receptor 1 (C5aR1-/-) as well as an additional group of B10.D2 C5a deficient mice. We found that in the absence of underlying chronic conditions, MI directly causes systemic bone loss and that the bone loss peaks at 7 days post-MI and recovers to baseline at later time points. We further found changes in activity were not significantly different between MI and unoperated groups. Mechanistically, we determined that inhibiting the b3-adrenoreceptor attenuated bone loss. When comparing C5aR1-/-, B10.D2, and WT mice, we found baseline differences in trabecular and cortical bone morphology and that C5aR1-/- mice had less bone loss after MI compared to WT, but the B10.D2 C5a deficient mice did not. These results are the first of their kind to investigate the possibility of bone loss as a significant comorbidity of MI. Uncovering the etiology of this phenomenon will allow us to inform treatments aimed at preserving lifelong health following traumatic injury in more vulnerable patients.

Between 45-65 million Americans run, making running the most popular physical activity in the US (other than walking). Although running is associated with many health benefits, it also causes as many as 33 running-related injuries (RRIs) per 1000 hours of running. These RRIs cause pain and reduce performance, cause a reduction or cessation of physical activity, necessitate medical visits and expenditures, and cause absenteeism from work creating a large health and financial burden. Thus, reducing RRI has been a target of much biomechanics research. Unfortunately, this research has not reduced RRI incidence, likely because it has been constrained to lab environments that may misrepresent the number and magnitude of the loads (ground reaction forces) thought to cause RRI. This dissertation overcomes this limitation by using small wearable devices to measure running in real-world settings. First, it presents a first-of-its-kind proof-of-concept study demonstrating that—when measured in the real world—the number and magnitude of loads relates to RRI development. Next, this dissertation presents a series of studies comparing methods to estimate the number and magnitude of loads using small wearable devices then validates these methods across a range of real-world conditions. Finally, applying these validated methods, this dissertation replicates the initial proof-of-concept study in a large heterogenous sample across a longer period of time. Collectively, these studies demonstrate a novel approach to studying running and RRI, provide the tools to execute that approach, and show support for the hypothesis that the magnitude and number of loads experienced by runners relates to RRI development.

Adaptation of the bones of older subjects to disuse is largely unknown and bone recovery following disuse in older subjects has not been studied. Up to half of all people over the age of 50 suffer from osteoporosis or low bone mass and older patients are more vulnerable to extended hospitalizations. With advancing age, bone experiences an age-related decline through trabecular bone loss, cortical thinning, and decreased osteocyte density. Decreased osteocyte density could contribute to the impaired adaptation of older bones to increased loading. This could affect an older subject’s ability to recover from disuse-induced bone loss. In this research we sought to quantify bone adaptation of young and old rats and mice in response to mechanical unloading via tail suspension and subsequent reloading. In addition, we aimed to compare the bone adaptation of old mice to a transgenic mouse model of low osteocyte density to determine the effect of osteocyte density on bone adaptation in response to mechanical unloading and reloading. We found that young rats lost trabecular bone quickly during unloading but recovered after only a short period of reloading. Meanwhile, old rats did not lose bone during unloading but did lose trabecular bone during early reloading that did not recover with continued reloading. In mice, we found that young, old, and transgenic mice all lost trabecular bone during unloading but young mice recovered more bone during reloading than old or transgenic mice. Old mice also lost cortical bone during unloading and reloading while transgenic mice lost no cortical bone. These results illustrate a difference in bone adaptation between different ages of mice and rats and further research into this difference may provide valuable insights for protecting the skeletal health of the elderly.