One of the unfortunate sequelae of increased life expectancy is a growing number of age-related degenerative diseases, a prime example being osteoporosis. This form of metabolic bone disease and related co-morbidities consume tremendous resources and costs from a nation's health care system. Osteoporosis results from genetic, age-related, and hormone-dependent causes as well as a compendium of secondary pathophysiological states. The presence of osteoporosis as a comorbidity confers a significant negative prognostic element following orthopedic procedures. In vitro and in vivo studies of osteoporotic bone implicate microarchitectural bone rarefaction, microenvironmental and functional disturbance of osteoblast-osteoclast coupling, and abnormal tissue and signalling molecule repertoires, each having detrimental effects on the regenerative and osteointegration processes. This review explores the pathophysiology of bone remodeling from a macro- and micro- systems biology standpoint with a focus on cytokine interactions. Furthermore, therapeutic interventions exploiting vulnerable nodes in these physiological networks will be posited. One exciting development in this area is the use of novel biomaterials.