Calcium homeostasis has a pivotal role in regulating many biological processes. The interplay of calcium-regulating hormones, including parathyroid hormone (PTH), vitamin D, and calcitonin, is crucial in tightly maintaining serum calcium levels. Deregulation of calcium homeostasis has clinical implications resulting in hypercalcemia or hypocalcemia, which can lead to metabolic bone disease (MBD). MBD is a group of multifactorial bone diseases, caused by bone demineralization and characterized by an increased susceptibility to fracture risk. This chapter aims to provide an overview of associated risk factors and diagnostic, prevention, and recent treatment methods for MBD. The diagnosis of MBD is based on the assessment of clinical signs, radiological findings, quantitative ultrasonography, and biochemical evaluation of serum calcium, phosphate, PTH, alkaline phosphatase, and vitamin D. Current pharmacological treatments include antiresorptive and anabolic conventional therapies. Additionally, the efficacy of herbal extracts and nutritional supplements have been evaluated. Recent advances in the MBD management include drugs targeting calcium-sensing receptor and parathyroid hormone-related proteins, leading to the development of cathepsin K and Src tyrosine kinase inhibitors, calcilytics, and monoclonal antibodies against sclerostin or Dickkopf-1. Moreover, new nanomaterials have been used for improving the surgical treatment of vertebral fractures.