Parathyroid hormone (PTH) is secreted as an 84-amino acid peptide with a half-life of less than 4 minutes. PTH secretion is stimulated physiologically by changes in calcium levels. A 2% change in ionized calcium levels produces a significant release of PTH. Changes in ionized calcium levels are detected by a calcium-sensing receptor located on the membranes of parathyroid gland cells. This receptor is a member of the G protein–coupled receptor superfamily consisting of seven membrane-spanning domains.

Circulating immunoreactive PTH includes less than 30% of the intact hormone due to proteolytic modifications. Inactive fragments constitute the remaining amounts. The first 34-amino acid residues contain high-affinity binding domains to PTH/PTH-related protein (PTHrP) receptors located on bone and kidney cells. C-terminal portions of PTH have a longer half-life than does the intact PTH and constitute the major fragments in the circulation. The C-terminal fragments are biologically inactive and may complicate laboratory measurements of PTH. Exogenous manipulation of the calcium levels in experimental animals alters the ratio of intact to fragmented PTH hormone components, suggesting an active intragland conversion system. Kupffer cells and hepatocytes degrade PTH in the liver, and the kidney tubular cells excrete PTH fragments in the urine. PTH exerts its major actions by binding to receptors located on osteoblastic and renal tubular cells. These target cells are activated through the adenylate cyclase or the phospholipase C and D signaling cascades. PTH indirectly activates the osteoclasts in bone to increase resorption of mineralized bone, resulting in mobilization of calcium and phosphorus. However, small amounts of PTH delivered intermittently may stimulate bone growth in specific clinical situations, probably through the production of local growth factors. PTH activates the proximal and distal tubular cells in the kidney to promote resorption of calcium and to inhibit resorption of phosphorus. In addition, PTH stimulates the production of 1-alpha,25-dihydroxyvitamin D in the kidney.

PTH closely regulates the concentration of calcium in the extracellular fluids. The concentration of ionized calcium throughout the day is relatively stable, but variations exist in the total calcium concentration secondary to changes in the concentrations of serum proteins. The usual daily variation of total calcium concentrations is less than 2%. The extracellular concentration of calcium is 10^-3 mol, contained in three major components. The unbound component, or free calcium, accounts for approximately 50% of the total amount of calcium and is the most important regulator of physiologic processes. The bound components account for the other 50%, with protein binding accounting for approximately 40% and anion binding for approximately 10%. Albumin is the most abundant protein-binding calcium, with each albumin molecule capable of binding as many as 12 calcium molecules, depending on the extracellular pH. Acidosis decreases the binding capacity and increases the free extracellular concentration of calcium, whereas alkalosis increases the binding capacity and decreases the free extracellular concentrations of calcium. These alterations in binding capacity explain the variations in clinical signs that occur with disturbances in acid-base regulation. Bicarbonate, citrate, and phosphate complexes compose the anion-binding system. The intracellular concentration of calcium is approximately 10^-6 mol and is maintained by cellular transport systems. Numerous critical metabolic processes require a rigid control of calcium concentration. These processes include the permeability of plasma membranes in neural tissue, the mineralization of developing bone, the promotion of coagulation, and cardiac contractility, as well as calcium’s intracellular role as a modulator for multiple processes.

Low levels of serum calcium stimulate the immediate release of preformed PTH, followed by increased production of prepro-PTH mRNA. The calcium-selective transmembrane channels and calcium sensors play a significant role in this process. High levels of serum calcium inhibit the previously mentioned process. The increased levels of PTH stimulate other important compensatory mechanisms, as previously mentioned.

An understanding of calcium homeostasis must include an explanation of vitamin D. Vitamin D has two entry points into the body. The first is from the skin, and the second is from dietary supplementation. The skin contains the pre-vitamin D compound 7-dehydrocholesterol. Ultraviolet B waves from the sun or other sources convert this substance to a pre-vitamin D compound, which is converted by heat-sensitive reactions to vitamin D₃. A serum-binding protein transfers vitamin D₃ to the liver. The second entry point for vitamin D is from dietary supplementation, either by irradiated ergosterol, vitamin D₂, or vitamin D₃. Vitamins D₂ and D₃ differ slightly in their structure, but they have similar functions physiologically. Vitamins D₂
and D₃ are hydroxylated in the liver at the 25 position by a cytochrome P-450-vitamin D-25-hydroxylase enzyme. Diseases of the liver, as well as pharmacologic agents such as phenytoin and phenobarbital, interfere with this important hydroxylation step. Interference in this step may result in functional vitamin D deficiency. 25-hydroxyvitamin D is transported to the kidney, where the cytochrome P-450-monooxygenase 25-hydroxy1-alpha-hydroxylase converts 25-hydroxyvitamin D to 1-alpha,25-dihydroxyvitamin D and 24,25-dihydroxyvitamin D. 1-alpha,25-dihydroxyvitamin D is the most active metabolite and is responsible for many actions of vitamin D. PTH, estrogen, growth hormone, prolactin, and insulin stimulate 1-alpha-hydroxylation. 1-alpha,25-dihydroxyvitamin D exerts its effects by binding to intracellular receptors that contain a DNA-binding region. Mutations within the vitamin D receptor gene are responsible for end-organ resistance to 1-alpha,25-dihydroxyvitamin D. The vitamin D nuclear receptor complex joins the retinoic acid X receptor to form a heterodimer. This heterodimer binds to the vitamin D-responsive element of target genes promoting or inhibiting transcription of other genes. For example, gene expression of calbindin, a calcium-binding protein, which facilitates the transport of calcium from the intraluminal space of the intestines to the extracellular compartment, is stimulated positively. However, the heterodimer-receptor complex affects PTH gene expression negatively.

Another role of vitamin D is the stimulation of osteoclasts from progenitor cells. Osteoclasts enhance the release of calcium from bone, thereby providing the body with a method to compensate for acute hypocalcemia. 1-alpha,25-dihydroxyvitamin D also has cell proliferative and differentiation effects in some biologic systems.

PTHrP produces effects similar to those of PTH. The role of PTHrP in calcium homeostasis remains poorly understood, but the hypercalcemia and hypophosphatemia of malignancy are related to its production. Islet cell tumors and pheochromocytomas are two examples of malignancies producing PTHrP. PTHrP exists in three isoforms, with initial sequences in all three similar to those of PTH. PTHrP binds to common receptors with an affinity similar to that of PTH. Fetal tissues such as placenta and parathyroid glands, as well as breast milk, contain large amounts of PTHrP. PTHrP also regulates cell and organ growth, differentiation, and migration. Loss of the PTHrP gene in experimental animals is lethal in the embryonic stage.

Calcitonin, a 32-amino acid protein secreted by the C cells of the thyroid gland, binds a G-protein coupled cell surface receptor. Calcitonin’s physiologic role remains obscure. An acute increase in serum calcium levels increases secretion of calcitonin, but a chronic increase in serum calcium levels does not always increase secretion of calcitonin. Normal gastrointestinal proteins such as gastrin and cholecystokinin are calcitonin secretagogues. Biologic effects include inhibition of osteoclastic resorption, producing hypocalcemia and hypophosphatemia. Calcitonin receptors are present also in the central nervous system, testes, lymphocytes, placenta, and skeletal muscle. Elevated levels of calcitonin are observed in medullary thyroid carcinomas (multiple endocrine neoplasia type 2), but hypocalcemia does not occur. Treatment of hypercalcemic pediatric patients with calcitonin is beneficial in some cases, such as the hypercalcemia of immobilization and neonatal hypophosphatasia.

The intracellular concentration of phosphorus is approximately 10^-4 mol, whereas that of the extracellular fraction is approximately 2 × 10^-4 mol. The serum concentration of phosphorus is less regulated than is calcium. Eighty-five percent of the phosphorus is contained in the skeleton and, with calcium, provides structural support for the body. The phosphate esters and other phosphorylated compounds provide the generation and transfer of cellular energy.

Hypoparathyroidism may occur alone or as part of the autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) syndrome. APECED is an autosomal recessive disease caused by a mutation in the autoimmune regulating (AIRE) gene. AIRE is a transcription factor with an unknown target(s). A consistent component of APECED is immunologic destruction of the hormone-producing cells. Approximately 30% to 40% of patients have antibodies against the parathyroid gland, but the role of antibodies as a causative factor is uncertain. Lymphocytic infiltration of the parathyroid glands is a common pathologic finding. Mucocutaneous candidiasis may precede the development of hypoparathyroidism. Other endocrinopathies include hypoadrenalism, hypogonadism, hypothyroidism, and diabetes mellitus. Frequent clinical, physical, and laboratory assessments are required to detect the subtle onset of these disorders.