Every year, millions of Americans are affected by illnesses and injuries that force them into periods of limited mechanical loading, such as bed rest, wheelchair usage, limb casting, or spaceflight. Disuse can occur at any point throughout life for many reasons, even in otherwise healthy individuals. During disuse, bones and muscles atrophy from a lack of mechanical loading. This tissue loss can have implications for those already at risk of low bone and muscle mass, including older individuals, those undergoing weight loss, or individuals with preexisting conditions. It is also an area ripe for innovation, as new pharmaceuticals and supplements for bone and muscle mass gain have well-established medical and wellness niches. Unfortunately, bone and muscle growth research often focuses on a single age group, despite differences in musculoskeletal remodeling throughout the lifespan. Additionally, the understanding of the effect that commonly prescribed pharmaceuticals have during unloading has not been fully explored. This dissertation overcomes this limitation by including different ages and sexes in bone and muscle health investigations during unloading with pharmaceutical interventions. First, it investigates the effect of mechanical unloading across the lifespan by utilizing young, middle-aged, and old mice. Next, it explores how bone mass maintenance might support muscle mass maintenance with alendronate treatment and identifies the effect of bone-muscle crosstalk proteins. Finally, it identifies the side effects of the blockbuster pharmaceutical Semaglutide, also known as Ozempic, during periods of unloading and reloading, which could impact bone and muscle atrophy and growth. Together, these studies offer novel insight into the impact of different medications during mechanical unloading. This research also supports the hypothesis that changes in response to mechanical unloading occur across the lifespan.