Bone adapts to altered mechanical stimuli, dietary changes, or injury. Dietary calcium and vitamins play significant roles in maintaining skeletal health, but high-fat diets may contribute to osteopenia. Exercise, generally, helps to maintain bone mass and counter osteoporosis, but highly strenuous exercise can also have detrimental effects on bone-particularly for immature bone. Negative exercise effects may also be linked to diet, as insufficient dietary protein can impair bone development and remodeling during periods of intense exercise. Bone remodeling can contribute to tissue repair, but chronically altered loading after a joint injury can stimulate remodeling processes that negatively influence the joint. Anterior cruciate ligament injury at the knee, for example, commonly leads to osteoarthritis, and early changes in the periarticular cancellous bone may contribute to the development of knee osteoarthritis. Each of these factors can influence skeletal health, but the mechanisms remain unclear by which bone interprets its environment and responds to physical stimuli or injury. To understand why different levels of exercise are beneficial or detrimental and why altered joint loading leads to changes in periarticular bone structure, underlying mechanisms must be understood by which bone interprets its mechanical environment. Mechanical stimuli, diet, and injury have potent influences on skeletal health and function, but the underlying mechanisms for these adaptations are incompletely understood. Here, we review our research that provides important insights into bone adaptation processes.