For humans to explore and colonize the universe, both engineering and physiological obstacles must be successfully addressed. A major physiological problem is that humans lose bone rapidly in microgravity. Understanding the underlying mechanisms for this bone loss is crucial for designing strategies to ameliorate these effects. Because bone physiology is entangled with other organ systems, and bone loss is a component of human adaptation to microgravity, strategies to reduce bone loss must also account for potential effects on other systems. Here, we consider the receptors involved in normal bone remodeling and how this regulation is altered in low-gravity environments. We examine how single cells, tissues and organs, and humans as a whole are affected by low gravity, and the role of receptors that have been implicated in responses leading to bone loss. These include receptors linking cells to the extracellular matrix and to each other, alterations in the extracellular matrix associated with changes in gravity, and changes in fluid distribution and fluid behavior due to lack of gravity that may have effects on receptor-based signaling shared by bone and other regulatory systems. Inflammatory responses associated with the environment in space, which include microgravity and radiation, can also potentially trigger bone loss.