Historical overview traces evolution of hypoparathyroidism treatment toward hormone replacement

Hypoparathyroidism is a rare endocrine disorder characterized by deficient secretion of parathyroid hormone (PTH), resulting in hypocalcemia, hyperphosphatemia, and impaired mineral homeostasis. Although most cases are postsurgical, the disease encompasses a heterogeneous group of etiologies, including genetic, autoimmune, and infiltrative causes. For much of its history, hypoparathyroidism was considered unique among endocrine deficiencies in that it was not treated with hormone replacement, owing to limited understanding of parathyroid physiology and the absence of safe and effective PTH-based therapies. This review provides a historical perspective on the evolution of hypoparathyroidism, from the anatomical discovery of the parathyroid glands in the nineteenth century to recent advances in molecular biology, laboratory diagnostics, and targeted treatments. Key milestones include the elucidation of calcium and phosphate regulation, the isolation and characterization of PTH, the identification of the calcium-sensing receptor, and the discovery of regulatory pathways involving fibroblast growth factor 23 and klotho. Parallel advances in clinical chemistry enabled increasingly accurate measurement of serum calcium and PTH, facilitating improved diagnosis and disease monitoring. Therapeutic strategies have evolved from conventional treatment with calcium and active vitamin D toward physiological hormone replacement. Clinical development of recombinant PTH formulations, long-acting prodrugs, and novel receptor agonists has transformed the therapeutic landscape and renewed interest in disease-modifying approaches. Emerging therapies, including oral agents, long-acting formulations, and cell-based strategies, suggest that the management of hypoparathyroidism is entering a new era focused on restoring physiological mineral metabolism and improving long-term outcomes.