The four parathyroid glands are located posterior to the thyroid gland. They produce parathyroid hormone (PTH), which is the primary regulator of calcium physiology. PTH acts directly on bone, where it induces calcium resorption, and on the kidney, where it enhances calcium reabsorption and synthesis of 1,25-dihydroxyvitamin D [1,25(OH)2D], a hormone that increases gastrointestinal calcium absorption. Serum PTH levels are tightly regulated by a negative feedback loop. Calcium, acting through the calcium-sensing receptor, and vitamin D, acting through its nuclear receptor, reduce PTH release and synthesis. Additional evidence indicates that fibroblast growth factor 23 (FGF23), a phosphaturic hormone, can suppress PTH secretion. Understanding the hormonal pathways that regulate calcium levels and bone metabolism is essential for effective diagnosis and management of a wide array of hyper- and hypocalcemic disorders.
Hyperparathyroidism (HPT), characterized by excess production of PTH, is a common cause of hypercalcemia and is usually the result of autonomously functioning adenomas or hyperplasia. Surgery for this disorder is highly effective and has been shown to reverse some of the deleterious effects of long-standing PTH excess on bone density. Humoral hypercalcemia of malignancy is also common and is usually due to the overproduction of parathyroid hormone–related peptide (PTHrP) by cancer cells. The similarities in the biochemical characteristics of hyperparathyroidism and humoral hypercalcemia of malignancy, first noted by Albright in 1941, are now known to reflect the actions of PTH and PTHrP through the same G protein–coupled PTH/PTHrP receptor.
The genetic basis of multiple endocrine neoplasia (MEN) types 1 and 2, familial hypocalciuric hypercalcemia (FHH), different forms of pseudohypoparathyroidism (PHP), Jansen's syndrome, disorders of vitamin D synthesis and action, and the molecular events associated with parathyroid gland neoplasia have provided new insights into the regulation of calcium homeostasis. PTH and possibly some of its analogues are promising therapeutic agents for the treatment of postmenopausal or senile osteoporosis, and calcimimetic agents, which activate the calcium-sensing receptor, have provided new approaches for PTH suppression.
The primary function of PTH is to maintain the extracellular fluid (ECF) calcium concentration within a narrow normal range. The hormone acts directly on bone and kidney and indirectly on the intestine through its effects on synthesis of 1,25(OH)2D to increase serum calcium concentrations; in turn, PTH production is closely regulated by the concentration of serum ionized calcium. This feedback system is the critical homeostatic mechanism for maintenance of ECF calcium. Any tendency toward hypocalcemia, as might be induced by calcium-deficient diets, is counteracted by an increased secretion of PTH. This in turn (1) increases the rate of dissolution of bone mineral, thereby increasing the flow of calcium from bone into blood; (2) reduces the renal clearance of calcium, returning more of the calcium filtered at the glomerulus into ECF; and (3) increases the efficiency of calcium absorption in the intestine by stimulating the production of 1,25(OH)2D. Immediate control of blood calcium is due to PTH effects on bone and, to a lesser extent, on renal calcium clearance. Maintenance of steady-state calcium balance, on the other hand, probably results from the effects of 1,25(OH)2D on calcium absorption (Chap. 352). The renal actions of the hormone are exerted at multiple sites and include inhibition of phosphate transport (proximal tubule), augmentation of calcium reabsorption (distal tubule), and stimulation of the renal 25(OH)D-1α-hydroxylase. As much as 12 mmol (500 mg) calcium is transferred between the ECF and bone each day (a large amount in relation to the total ECF calcium pool), and PTH has a major effect on this transfer. The homeostatic role of the hormone can preserve calcium concentration in blood at the cost of bone demineralization.
PTH has multiple actions on bone, some direct and some indirect. PTH-mediated changes in bone calcium release can be seen within minutes. The chronic effects of PTH are to increase the number of bone cells, both osteoblasts and osteoclasts, and to increase the remodeling of bone; these effects are apparent within hours after the hormone is given and persist for hours after PTH is withdrawn. Continuous exposure to elevated PTH (as in hyperparathyroidism or long-term infusions in animals) leads to increased osteoclast- mediated bone resorption. However, the intermittent administration of PTH, elevating hormone levels for 1–2 hours each day, leads to a net stimulation of bone formation rather than bone breakdown. Striking increases, especially in trabecular bone in the spine and hip, have been reported with the use of PTH in combination with estrogen. PTH(1-34) as monotherapy caused a highly significant reduction in fracture incidence in a worldwide placebo-controlled trial.
Osteoblasts (or stromal cell precursors), which have PTH/PTHrP receptors, are crucial to this bone-forming effect of PTH; osteoclasts, which mediate bone breakdown, lack such receptors. PTH-mediated stimulation of osteoclasts is indirect, acting in part, through cytokines released from osteoblasts to activate osteoclasts; in experimental studies of bone resorption in vitro, osteoblasts must be present for PTH to activate osteoclasts to resorb bone (Chap. 352).
PTH is an 84-amino-acid single-chain peptide. The amino-terminal portion, PTH(1–34), is highly conserved and is critical for the biologic actions of the molecule. Modified synthetic fragments of the amino-terminal sequence as small as PTH(1–11) are sufficient to activate the PTH/PTHrP receptor (see below). The carboxyl-terminal regions of the full-length PTH(1–84) molecule also can bind to a separate binding protein/receptor (cPTH-R), but this receptor has been incompletely characterized. Fragments shortened at the amino terminus possibly by binding to cPTH can inhibit some of the biologic actions of full-length PTH(1–84) and of PTH(1–34).
Biosynthesis, Secretion, and Metabolism
Parathyroid cells have multiple methods of adapting to increased needs for PTH production. Most rapid (within minutes) is secretion of preformed hormone in response to hypocalcemia. Second, within hours, PTH mRNA expression is induced by sustained hypocalcemia. Finally, protracted challenge ...