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.