Biochemical and cellular processes are the targets for most pharmaceutical and dietary interventions for bone diseases (Section 4). Considerable evidence from in vivo and in vitro studies have shown that prebiotics alter more than one aspect of the gut-bone axis (see and references therein). Multifactorial aspects of the pathology of bone loss in aging and menopause compounded with impacts of dietary factors on interactions between the immune, gastrointestinal, endocrine, and skeletal systems compel us to advocate for systems biology approaches to understand better this complex network of processes that connect dietary prebiotic and probiotic treatments to immune modulation and bone outcomes. Additionally, connecting the gut to bone through biological mechanisms is relevant more generally for orally administered bone therapeutics. Ultimately, bone loss is a systemic problem with multi-organ involvement. Improved mechanistic understanding of these complex relationships is needed to enhance interventions for bone loss. Multi-organ-system mathematical models of physiological and pathophysiological bone remodeling can help unravel these mechanisms while reducing the experimental costs associated with animal testing. There are few multi-compartment models of bone remodeling , and this approach warrants exploration in future models.