Hypoparathyroidism (HPT) is a rare disorder characterized by low parathyroid hormone (PTH) and calcium levels. Patients suffer consequences of hypocalcemia, including paresthesias, arrhythmias, and seizures. Conventional treatment to prevent these life-threatening events is calcium and active vitamin D. However, complications of HPT, including kidney and cardiovascular disease, cataracts, basal ganglia calcifications and neuropsychiatric disorders, occur despite, and possibly due to, conventional treatment. Although we found increased bone calcification may be beneficial to the skeleton, calcification of end-organs may be fully or partially responsible for these complications. Registry, retrospective, and claims studies have reported vascular calcifications in HPT patients; we noted brain calcifications, and observational data document coronary artery calcifications. Other HPT-associated metabolic derangements may also be contributory. Unfortunately, the pathogenesis, epidemiology, natural history, and links between HPT, end-organ diseases, vascular calcifications, and other derangements are unclear. This represents a significant scientific gap and impedes the: (1) diagnosis, monitoring, mitigation, and prevention of HPT associated complications; (2) development, study, and implementation of new strategies to prevent HPT-associated end-organ damage; and (3) ability to conduct studies leading to advances in the HPT treatment paradigm. These gaps are particularly relevant in light of PTH treatment, a developing off-label therapeutic for HPT. PTH treatment had pro-calcific side effects reported in FDA registry trials for osteoporosis and its possible role in calcification and end-organ diseases in HPT are not clear. Indeed, although studies reported that HPT managed with conventional treatment was associated with kidney function decline, we found that kidney function did not decline in patients managed with PTH instead of conventional therapy. Also, our data suggest a link between altered bone gene expression and dysregulation of calcium. We identified circulating microRNAs highly associated with low bone turnover, a major risk factor for extra-skeletal calcification. Data suggest these same miRs may be involved in vascular calcification development. This application will provide a rigorous standardized approach to longitudinal data collection in HPT on end-organ damage and calcification propensity. Our central hypothesis is that a natural history cohort of HPT enables the study of end-organ complications. We also hypothesize that end-organ disease is related to calcification propensity and severity. The Aims are to: 1) Build a prospective cohort of longitudinally followed HPT patients to study the epidemiology and clinical impact of end-organ damage; 2). Determine the organ- specific physiologic consequences of HPT; 3). Elucidate determinants of HPT-associated end-organ damage from biochemical testing and calcification imaging. For the first time, ...