Sarcopenia and osteoporosis are two sides of the same coin. They represent different aspects of the same age-related process of musculoskeletal atrophy and together culminate in falls, fractures, deconditioning, and increased mortality in older individuals. However, the current therapeutic approach to the prevention of minimal trauma fracture is unilateral and focuses solely on bone. In theory, an integrated approach that recognizes the interaction between muscle and bone could break the vicious cycle of their combined involution and more effectively minimize falls/fractures. In this review, signaling pathways and cross-talk mechanisms that integrate bone/muscle, and the emergence of novel therapies that exploit these pathways to target osteoporosis/sarcopenia will be discussed. In broad terms, these agents act on nuclear receptors (e.g., VDR, AR) or transmembrane receptors (e.g., activins, GH/IGF-1) expressed in muscle and bone, and seek to alter biologic responses to musculoskeletal aging, loading, and injury. Challenges in the development of these dual bone-muscle therapies, early clinical trials examining their safety/efficacy, and novel targets that hold promise in the reversal of musculoskeletal aging will be discussed.