The skeletal extracellular matrix (ECM) is more than a passive mineralized framework; it is a dynamic, instructive milieu that governs cellular behavior through a complex interplay of biochemical signaling and mechanical cues. This chapter explores the foundational theories of bone biology, emphasizing how the unique composition of the bone ECM—comprising hydroxyapatite, type I collagen, and specialized noncollagenous proteins—maintains skeletal integrity. We explored the pathophysiology of bone disorders, examining how metabolic imbalances (such as osteoporosis) and genetic mutations (such as osteogenesis imperfecta) fundamentally alter the matrix architecture, leading to increased fragility and systemic dysfunction. A central focus is placed on the “mechanopathology” of the bone niche, specifically the role of matrix stiffness in driving tumorigenesis. We discussed the feedback loops where increased stiffness facilitates the malignant transformation of bone cells and promotes a pro-metastatic microenvironment. To explore these phenomena, we evaluate advanced characterization techniques for ECM monitoring. Finally, we highlighted the emerging clinical applications, including the development of biomimetic scaffolds and ECM-targeted therapies, which aim to restore the “mechanical homeostasis” of the bone. This chapter serves as a roadmap for understanding how the invisible architecture of the bone dictates the visible outcomes of health and disease.