The 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 µCT 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 µCT 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.