Bone is a dynamic living tissue that plays a crucial role in providing mechanical support to the body and maintaining systemic homeostasis. The bone remodeling cycle continuously renews bone tissue, ensuring its structural integrity and metabolic functionality. Bone remodeling is the delicately balanced process of coordinated activity of bone cells that remove and deposit new bone tissue. Multiple biochemical, physical, and mechanical factors within the bone microenvironment and throughout the body regulate bone cell activity. When these factors operate within a homeostatic range, bone removal and formation activities of bone cells are balanced, and the bone remodeling cycle ends without a net change in bone volume or mass. Perturbations outside this range can cause an imbalance between bone removal and formation. Pathological bone loss increases the risk of bone fracture. The need to understand bone pathologies and to design effective therapeutics drives researchers to study the local and systemic mechanisms that regulate bone remodeling. Mechanisms of bone remodeling are complex to capture in traditional in vivo and in vitro experiments due to the dynamic nature of the cell populations involved and the complexity of their local and systemic interactions. For preclinical in vivo studies, the measurements that can be performed at the tissue or mechanistic level are limited by the number of timepoints that are feasible from animal models. With in vitro studies, it is challenging to create an environment that allows the cells to respond to systemic changes that influence the in vivo bone microenvironment. Mathematical modeling is used to capture the dynamics of relevant cell populations by simulating multiple time points and complex interactions over time and can combine effects from multiple scales locally and systemically. Mathematical models are widely used for tasks such as understanding the biology of bone remodeling and the complexity of the dynamics of hormones that regulate this cycle. Mathematical models have the potential to integrate systemic connections for better understanding and to identify new treatment opportunities. Here, we advocate for enhancing existing mathematical models of bone remodeling from a systems biology perspective. A gap exists in tying molecular chemical signaling and cellular effects mechanistically to clinically measurable properties that correspond to tissue and patient phenotypes. Systems biology researchers aim to bridge this gap by considering the human body as an integrated whole with multiple time and length scales of interacting systems. The systems biology perspective requires acquiring and integrating many diverse data sets across scales and interacting physiological systems to understand, design, and control responses to therapeutics.