The risk of osteoporotic fracture can be viewed as a function of loading conditions and the ability of the bone to withstand the load. Skeletal loads are dominated by muscle action. Recently, it has become clear that bone and muscle share genetic determinants. Involution of the musculoskeletal system manifests as bone loss (osteoporosis) and muscle wasting (sarcopenia). Therefore, the consideration of pleiotropy is an important aspect in the study of the genetics of osteoporosis and sarcopenia. This Perspective will provide the evidence for a shared genetic influence on bone and muscle. We will start with an overview of accumulating evidence that physical exercise produces effects on the adult skeleton, seeking to unravel some of the contradictory findings published thus far. We will provide indications that there are pleiotropic relationships between bone structure/mass and muscle mass/function. Finally, we will offer some insights and practical recommendations as to the value of studying shared genetic factors and will explore possible directions for future research. We consider several related questions that together comprise the general paradigm of bone responses to mechanical loading and the relationship between muscle strength and bone parameters, including the genetic factors that modulate these responses. We believe that further progress in understanding the common genetic etiology of osteoporosis and sarcopenia will provide valuable insight into important biological underpinnings for both conditions and may translate into new approaches to reduce the burdens of both conditions through improved diagnosis, prevention, and early targeted treatment.