The calcium-sensing receptor (CaSR) represents the molecular mechanism by which parathyroid cells detect changes in blood ionized calcium concentration and modulate parathyroid hormone (PTH) secretion to maintain serum calcium levels within a narrow physiological range. Much has been learned in recent years about  the diversity of signal transduction through the CaSR and the various factors that affect receptor expression. Beyond its classic role as a determinant of calcium-regulated PTH secretion, signaling through the CaSR also influences both  gene transcription and cell proliferation in parathyroid cells. The CaSR thus serves a broad physiological role by integrating several distinct aspects of parathyroid gland function. The current review summarizes recent developments that enhance our understanding of the CaSR and its fundamental importance in parathyroid gland physiology.

Hypercalcemia is a disorder commonly encountered by primary care physicians. The  diagnosis often is made incidentally in asymptomatic patients. Clinical manifestations affect the neuromuscular, gastrointestinal, renal, skeletal, and cardiovascular systems. The most common causes of hypercalcemia are primary hyperparathyroidism and malignancy. Some other important causes of hypercalcemia  are medications and familial hypocalciuric hypercalcemia. An initial diagnostic work-up should include measurement of intact parathyroid hormone, and any medications that are likely to be causative should be discontinued. Parathyroid hormone is suppressed in malignancy-associated hypercalcemia and elevated in primary hyperparathyroidism. It is essential to exclude other causes before considering parathyroid surgery, and patients should be referred for parathyroidectomy only if they meet certain criteria. Many patients with primary  hyperparathyroidism have a benign course and do not need surgery. Hypercalcemic crisis is a life-threatening emergency. Aggressive intravenous rehydration is the mainstay of management in severe hypercalcemia, and antiresorptive agents, such as calcitonin and bisphosphonates, frequently can alleviate the clinical manifestations of hypercalcemic disorders.