Muscle and bone are anatomically and functionally closely connected. The traditional concept that skeletal muscles serve to load bone and transform skeletal segments into a system of levers has been further refined into the mechanostat theory, according to which striated muscle is essential for bone development and maintenance, modelling and remodelling. Besides biomechanical function, skeletal muscle and bone are endocrine organs able to secrete factors capable of modulating biological function within their microenvironment, in nearby tissues or in distant organs. The endocrine properties of muscle and bone may serve to sense and transduce biomechanical signals such as loading, unloading or exercise, or systemic hormonal stimuli into biochemical signals. Nonetheless, given the close anatomical relationship between skeletal muscle and bone, paracrine interactions particularly at the periosteal interface can be hypothesized. These mechanisms can assume particular importance during bone and muscle healing after musculoskeletal injury. Basic studies in vitro and in rodents have helped to dissect the multiple influences of skeletal muscle on bone and/or expression of inside-organ metabolism and have served to explain clinical observations linking muscle-to-bone quality. Recent evidences pinpoint that also bone tissue is able to modulate directly or indirectly skeletal muscle metabolism, thus empowering the crosstalk hypothesis to be further tested in humans in vivo.