INTRODUCTION — Parathyroid hormone (PTH) is one of three key hormones modulating calcium and phosphate homeostasis; the other two are calcitriol (1,25-dihydroxyvitamin D) and fibroblast growth factor 23 (FGF23) . The minute-to-minute control of serum ionized calcium concentration is exclusively mediated by PTH, maintaining the concentration of this divalent cation within a narrow range through stimulation of renal tubular calcium reabsorption and bone resorption [2,3].
On a more chronic basis, PTH also stimulates the conversion of calcidiol (25-hydroxyvitamin D) to calcitriol in renal tubular cells, thereby stimulating intestinal calcium absorption as well as bone turnover. Calcitriol feeds back to inhibit PTH secretion indirectly through its calcemic action, as well as by exerting a direct inhibitory action on PTH biosynthesis and parathyroid cell proliferation .
This topic will review PTH secretion and action. Clinical disorders related to PTH excess or insufficiency, as well as the use of PTH for the treatment of osteoporosis, are reviewed separately.
PTH SECRETION AND ITS REGULATION
PTH synthesis and degradation — PTH is synthesized as a 115-amino acid polypeptide called pre-pro-PTH, which is cleaved within parathyroid cells at the amino-terminal portion first to pro-PTH (90 amino acids) and then to PTH (84 amino acids). The latter is the major storage, secreted, and biologically active form of the hormone [1,5]. The biosynthetic process is estimated to take less than one hour. PTH 1-84 is secreted by exocytosis within seconds after induction of hypocalcemia .
Once secreted, PTH is rapidly cleared from plasma through uptake principally by the liver and kidney, where PTH 1-84 is cleaved into active amino- and inactive carboxyl-terminal fragments that are then cleared by the kidney. Intact PTH has a plasma half-life of two to four minutes. In comparison, the carboxyl-terminal fragments have half-lives that are 5 to 10 times greater. Circulating immunoreactive PTH in normal subjects comprises:
●Intact PTH – 5 to 30 percent
●Carboxyl-terminal fragments – 70 to 95 percent
●Amino-terminal fragments – A small percentage
Calcium regulates not only the release but also the synthesis and intraglandular degradation of PTH, in all its molecular forms . During hypocalcemia, intracellular degradation of PTH within the parathyroid cells decreases, and a greater proportion of PTH 1-84 is secreted relative to other molecular species of the hormone. In comparison, during hypercalcemia, intracellular degradation of intact PTH increases and reduces the availability of biologically active PTH 1-84 for secretion; consequently, mostly biologically inactive carboxyl-terminal fragments of PTH are secreted during hypercalcemia (figure 1) [1,3,6]. Under normocalcemic conditions, PTH 1-84 constitutes 20 percent of total circulating PTH molecules. This proportion increases to 33 percent under hypocalcemic conditions and decreases to 4 percent in the presence of hypercalcemia .
The currently available PTH assays are discussed in detail elsewhere. (See "Parathyroid hormone assays and their clinical use", section on 'PTH assays'.)
Regulation — PTH secretion is primarily regulated by extracellular calcium, along with extracellular phosphate, calcitriol, and fibroblast growth factor 23 (FGF23).
●Extracellular calcium – The relationship between the serum calcium concentration and PTH secretion is described by an inverse, sigmoidal curve, based on studies of calcium-regulated PTH secretion both in vivo and in vitro (figure 2) [2,7]. The midpoint or set-point of the calcium-PTH curve is a key determinant of the level at which serum ionized calcium concentration is "set" in vivo, and the steepness of the curve ensures that this concentration varies little. In normal individuals, a decrease in serum ionized calcium concentration of as little as 0.1 mg/dL (0.025 mmol/L) produces a large increase in serum PTH concentration within seconds to minutes; conversely, an equally small increase in serum ionized calcium rapidly lowers the serum PTH concentration.
The change in calcium concentration is sensed by an exquisitely sensitive calcium-sensing receptor (CaSR) on the surface of parathyroid cells . The receptor has a long amino terminus, seven transmembrane segments, and a shorter intracellular carboxyl terminus (figure 3).
When activated by a small increase in serum ionized calcium, the calcium-CaSR complex acts via one or more guanine nucleotide-binding (G) proteins through second messengers, such as increases in the intracellular calcium concentration and inositol phosphates or inhibition of cyclic adenosine monophosphate (cAMP) accumulation, to inhibit PTH secretion and decrease renal tubular reabsorption of calcium by the CaSR's actions on parathyroid and kidney, respectively. Conversely, the effect of deactivation of the receptor by a small decrease in serum ionized calcium concentration is to stimulate PTH secretion and enhance renal tubular reabsorption of calcium.
The PTH response to hypocalcemia has the following temporal profile; all of these actions are mediated by the CaSR [1,3]:
•Seconds to minutes – Exocytosis of PTH from secretory vesicles into the extracellular fluid
•Minutes to one hour – Reduction in the intracellular degradation of PTH
•Hours to days – Increase in PTH gene expression as a result of stabilization of PTH mRNA  (also stimulated by low serum calcitriol concentration, which increases transcription of the PTH gene owing to the normal inhibitory action of calcitriol on PTH gene transcription)
•Days to weeks – Proliferation of parathyroid cells (also stimulated by low serum calcitriol concentrations)
●Extracellular phosphate – Phosphate, like calcium, acts as an extracellular ionic messenger. Hyperphosphatemia modulates several of the same parameters of parathyroid function that are regulated by extracellular calcium, calcitriol, and FGF23, namely, stimulating PTH secretion, likely in large part by increasing PTH mRNA stability and promoting parathyroid cell growth [10-12]. These responses may be mediated, in part, by the induction of hypocalcemia owing to the increase in serum phosphate concentration.
However, small elevations in serum phosphate concentrations may not be sufficient to lower serum calcium concentration to a level that stimulates PTH secretion . In addition, there is increasing evidence that hyperphosphatemia (independent of the serum concentrations of calcium and calcitriol) directly stimulates PTH synthesis as well as parathyroid cellular proliferation in patients with advanced renal failure, the most common cause of hyperphosphatemia [10-12] (see "Overview of the causes and treatment of hyperphosphatemia", section on 'Acute or chronic kidney disease'). The nature of the putative phosphate-sensing mechanism is unknown. A direct role of phosphate in inhibiting the CaSR activity via noncompetitive antagonism has been suggested .
●Calcitriol – Parathyroid cells contain vitamin D receptors, and the PTH gene contains a vitamin D-response element. Calcitriol, by binding to the vitamin D receptor, inhibits PTH gene expression and, therefore, PTH synthesis . Calcitriol also inhibits parathyroid cell proliferation. Some of the actions of calcitriol on parathyroid function may result from its capacity to increase the expression of the CaSR .
●FGF23 – In addition to its phosphaturic action, FGF23 exerts direct actions on the parathyroid gland, inhibiting PTH synthesis and secretion [16,17]. In fact, PTH, calcitriol, and FGF23 all participate in maintaining both calcium and phosphate homeostasis, and there are extensive interactions between these two homeostatic systems.
Effect of altered calcium-sensing on calcium-regulated PTH secretion
Mutations in the calcium-sensing receptor — Activating or inactivating mutations in the CaSR produce altered extracellular calcium-sensing and, therefore, inappropriate PTH release with respect to the prevailing serum calcium concentration [18-22].
●In familial hypocalciuric hypercalcemia (FHH), serum PTH concentrations are inappropriately normal or high in the presence of mild hypercalcemia
●In autosomal dominant hypocalcemia, serum PTH concentrations are inappropriately normal or low despite the presence of mild or, in occasional cases, more severe hypocalcemia
These disorders are caused, respectively, by loss-of-function and gain-of-function mutations of the CaSR. An inactivating mutation produces a shift in the calcium-PTH curve to the right and thereby causing hypercalcemia since higher concentrations of calcium are required to suppress PTH release [18-20], while an activating mutation shifts the curve to the left and causes hypocalcemia (figure 2) . (See "Disorders of the calcium-sensing receptor: Familial hypocalciuric hypercalcemia and autosomal dominant hypocalcemia".)
Primary hyperparathyroidism — In patients with hyperparathyroidism caused by a parathyroid adenoma or hyperplasia, PTH secretion is inappropriately high in relation to the serum calcium concentration (the serum calcium-PTH curve is shifted to the right) . The cellular basis for the shift is probably a combination of decreased sensitivity of the parathyroid cells to calcium, possibly due to a decrease in the number of functional CaSRs and/or its downstream signaling pathways, an increase in parathyroid cell mass, or both. The molecular basis of primary hyperparathyroidism is known in a minority of cases, although there has been substantial progress in this area in the past decade, particularly in familial forms of hyperparathyroidism. Some examples are genetic defects in menin (in multiple endocrine neoplasia 1 [MEN1] and adenomas), parafibromin (in sporadic and familial parathyroid cancer), cyclin D1 (in adenomas), and the CaSR (in atypical FHH presenting as primary hyperparathyroidism) . (See "Pathogenesis and etiology of primary hyperparathyroidism".)
Secondary hyperparathyroidism — In patients with kidney failure who have uncontrolled hyperparathyroidism, increased secretion of PTH is related not only to gland hyperplasia and enlargement but also to reduced expression of CaSRs and, perhaps, its downstream signaling elements [24,25]. This results in reduced responsiveness to serum calcium levels, with continued secretion of PTH despite normal or high serum calcium levels and ultimately, in some cases, in true parathyroid autonomy (secretion of PTH independent of the prevailing level of serum calcium). In patients with secondary hyperparathyroidism from severe vitamin D deficiency, four-gland parathyroid hyperplasia constitutes the primary pathophysiology, and such hyperplasia may take months to over a year to reverse to normal . (See "Management of secondary hyperparathyroidism in adult dialysis patients".)
Lithium and PTH secretion — Lithium is a mood stabilizer that is used in the management of bipolar disorder. It has been associated with several metabolic complications, including nephrogenic diabetes insipidus, hypothyroidism, and hyperparathyroidism.
Lithium affects calcium-sensing in vitro and in vivo [27,28]. In a study of calcium-PTH dynamics in seven young, normocalcemic women who had taken lithium for a mean of 5.2 years, the serum calcium-PTH curve was shifted to the right, as compared with normal subjects, reflecting reduced sensitivity of PTH secretion to inhibition by calcium (figure 4) .
Lithium also affects renal calcium-sensing by decreasing renal calcium excretion , an effect that seems to be independent of PTH levels. This dual effect of lithium at the level of the parathyroid gland and kidney is reminiscent of the pathophysiology of FHH and is highly suggestive of altered calcium-sensing at the level of the CaSR. This would also be consistent with the observation that although serum calcium concentrations increase with lithium, they remain within the normal range in most lithium-treated patients.
However, from 10 to 25 percent of patients receiving chronic lithium therapy develop mild hypercalcemia and slightly high serum PTH concentrations [29,30]. Some of these patients probably have coincidental mild primary hyperparathyroidism that becomes more apparent during lithium therapy because the hypercalcemia persists after lithium is discontinued. (See "Pathogenesis and etiology of primary hyperparathyroidism", section on 'Lithium therapy' and "Primary hyperparathyroidism: Diagnosis, differential diagnosis, and evaluation", section on 'Drugs'.)
Calcimimetic drugs — Since the cloning and sequencing of the CaSR, efforts have focused on synthesizing agonists of the CaSR (calcimimetics) that would inhibit PTH secretion and synthesis and also parathyroid cell proliferation. Such a drug might be useful for the treatment of patients with primary or secondary hyperparathyroidism, provided that it did not mimic the effects of calcium in other tissues. A calcimimetic drug, cinacalcet, is approved in the United States for the treatment of secondary hyperparathyroidism in stage 5 chronic kidney disease (CKD) and for hypercalcemia in patients with severe primary hyperparathyroidism who are not suitable candidates for surgery, as well as in parathyroid cancer. A second drug, etelcalcetide, which is administered intravenously, is also available for use in severe hyperparathyroidism in renal dialysis patients . (See "Management of secondary hyperparathyroidism in adult dialysis patients", section on 'Calcimimetics' and "Primary hyperparathyroidism: Management", section on 'Calcimimetics' and "Parathyroid carcinoma", section on 'Calcimimetics'.)
Nonhypercalcemic vitamin D analogs — Some of the actions of calcitriol on parathyroid function may result from its capacity to increase the expression of the CaSR . Several calcitriol analogs (oxacalcitriol, paricalcitol, and 1-alpha-hydroxyvitamin D2) have been developed that inhibit PTH synthesis and secretion to a greater extent than they stimulate intestinal calcium absorption or bone resorption [32,33]. Such analogs are available for use in patients with chronic renal failure and secondary hyperparathyroidism. (See "Management of secondary hyperparathyroidism in adult dialysis patients" and "Management of secondary hyperparathyroidism in adult nondialysis patients with chronic kidney disease".)
PTH RECEPTOR ACTIVATION — PTH, in its various molecular forms, acts by binding to and activating one of several types of PTH receptors recognized to date [1,34]:
●PTH1R – The classical PTH/PTH-related protein (PTHrP) receptor, otherwise known as PTH1R, binds intact PTH and biologically active amino-terminal fragments of PTH, such as PTH 1-34 . It recognizes both PTH and PTHrP due to the substantial degree of homology in the amino-terminal parts of these two peptides. This receptor is heavily expressed in bone and kidney and is also present in additional tissues such as breast, skin, heart, blood vessels, pancreas, and others that are not regarded as classical PTH target tissues .
●PTH2R – The PTH2 receptor (PTH2R) selectively binds PTH but not PTHrP . It is heavily expressed in the central nervous system, cardiovascular, and gastrointestinal systems, as well as in lung and testes, and may be involved in the perception of pain . It binds PTH only weakly in rodents; the physiologically relevant ligand for this wrongly named receptor is TIP39, a distant member of the PTH family. The physiologic TIP39 and its receptor appear to have nothing to do with calcium metabolism [36,37].
●Novel receptors – Increasing evidence points to the presence of novel PTH receptors with specificity for the carboxyl-terminal region of PTH (C-PTHRs), a region of the hormone that was previously thought to be biologically inert but has now been shown to possess hypocalcemic activity. The C-PTHRs are present in various tissues but are most heavily expressed in bone (figure 1) [34,38].
Activation of the PTH1R activates multiple guanine nucleotide-binding (G) protein-dependent and -independent cellular signaling pathways, including cyclic adenosine monophosphate (cAMP), the phospholipase C (PLC) pathway, protein kinase C (PKC), and release of intracellular calcium stores, and others [34,39-41]. A key role of salt-inducible kinases in the downstream actions of the PTH1R in bone cells has been elucidated . The details of how these intracellular signal transduction pathways ultimately stimulate bone resorption, renal tubular calcium reabsorption, hydroxylation of calcidiol, and other biological actions of PTH 1-84 are still under active investigation.
The biologic activity of PTH (at least its hypercalcemic effect) resides in its amino-terminus, as demonstrated by the observation that the activities of PTH 1-34 and PTH 1-84 are similar on a molar basis. However, not all amino-terminal fragments are equally biopotent in assays of receptor binding and cAMP activation . Conversely, an increasing body of evidence supports a hypocalcemic effect of carboxyl-terminal fragment of PTH, PTH 7-84, which is reversed by PTH 1-34 and PTH 1-84 . The amino terminus of PTHrP is structurally similar to that of PTH; it causes hypercalcemia in patients with PTHrP-secreting tumors by activating the same receptor. (See "Hypercalcemia of malignancy: Mechanisms".)
BIOLOGICAL ACTIONS OF PTH — PTH is secreted almost instantaneously in response to very small reductions in serum ionized calcium, which are sensed by the calcium-sensing receptor (CaSR). The increase in PTH release raises the serum calcium concentration toward normal via three actions:
●Increased bone resorption, which occurs within minutes after PTH secretion increases
●Increased intestinal calcium absorption mediated by increased production of calcitriol, the most active form of vitamin D, which occurs a day or more after PTH secretion increases
●Decreased urinary calcium excretion due to stimulation of calcium reabsorption in the distal tubule, which occurs within minutes after PTH secretion increases
Skeletal actions of PTH — PTH acts on bone, the main reservoir of calcium, to release calcium in two phases :
●The immediate effect of PTH is to mobilize calcium from skeletal stores that are readily available and in equilibrium with the extracellular fluid
●Later, PTH stimulates release of calcium (and also phosphate) by activation of bone resorption
The prevailing view has been that osteoblasts, but not osteoclasts, express PTH receptors [1,37]. PTH targets osteoblasts and osteocytes to enhance bone remodeling. With PTH stimulation, preosteoblasts mature into bone-forming osteoblasts that lay down collagen and subsequently mineralize matrix . Since the remodeling unit is always coupled (ie, bone formation equals bone resorption), once preosteoblasts are stimulated, they release cytokines that can activate osteoclasts resulting in bone resorption. Thus, osteoclast formation requires an interaction with cells of the osteoblastic lineage, which may depend upon cell-cell contact and regulators of osteoclast formation such as RANK (the receptor activator of nuclear factor kappa-B), osteoprotegerin, and RANK ligand (RANKL) . PTH increases osteoclast activity and number indirectly through effects on RANKL and osteoprotegerin  (see "Normal skeletal development and regulation of bone formation and resorption"). However, some evidence suggests a biologically relevant binding of intact PTH, but not PTH 1-34, to osteoclasts, possibly through the novel but incompletely characterized PTH receptors with specificity for the carboxyl-terminal region of PTH (C-PTHRs) . (See 'PTH receptor activation' above.)
The net effect of PTH on bone varies according to the severity and chronicity of the PTH excess. Chronic exposure to high serum PTH concentrations (as seen with primary or secondary hyperparathyroidism) results in bone resorption, whereas intermittent administration of recombinant human PTH (both full-length 1-84 or fragment 1-34) has been shown to stimulate bone formation more than resorption. (See "Primary hyperparathyroidism: Clinical manifestations", section on 'Skeletal' and "Parathyroid hormone/parathyroid hormone-related protein analog for osteoporosis", section on 'Choice of therapy'.)
Specific elements of the PTH molecule seem essential for bone anabolism. PTH 1-31 and 1-34 retain all of the biologic activity of the intact peptide (1-84) . On the other hand, amino-terminal truncation of the first two amino acids of PTH eliminates most of the cyclic adenosine monophosphate (cAMP) signaling, a pathway that seems important for, but not predictive of, the anabolic effect of PTH on bone [43,50].
Renal actions of PTH — The kidney plays a major role in mineral ion homeostasis that is largely mediated by the actions of PTH and extracellular calcium ions on their respective receptors.
Reabsorption of calcium — Filtered calcium is reabsorbed along much of the nephron. The mechanisms by which it is reabsorbed and their regulation, however, vary as a function of location along the nephron. Most filtered calcium is reabsorbed passively in the proximal tubule down the favorable electrochemical gradients created by sodium and water reabsorption. In contrast, calcium transport is actively regulated in the distal nephron according to the needs of the organism. This takes place in the cortical thick ascending limb of the loop of Henle (cTAL), as well as in the distal convoluted tubule (DCT) and adjacent connecting segment (a small segment between the distal tubule and cortical collecting tubule) [51,52].
PTH acts at both cTAL and DCT in the distal tubule to stimulate calcium reabsorption . Thus, if PTH secretion falls appropriately after an increase in serum ionized calcium, the ensuing fall in tubular calcium reabsorption and increase in calcium excretion will contribute to restoring normocalcemia. The high serum calcium itself also contributes to the calciuresis, acting via the CaSR, particularly in cTAL [54,55].
Reabsorption of phosphate — PTH, along with fibroblast growth factor 23 (FGF23), is a key hormonal determinant of serum phosphate concentration. It inhibits mostly proximal tubular reabsorption of phosphorus. This effect is primarily mediated by decreased activity, internalization, and degradation of the Npt2A and Npt2C sodium-phosphate cotransporters in the luminal membrane of the proximal tubules that mediate tubular reabsorption of phosphate [56,57].
Synthesis of calcitriol — PTH stimulates the synthesis of 1-alpha hydroxylase in the proximal tubules and, thus, conversion of calcidiol to calcitriol (see "Overview of vitamin D", section on 'Metabolism'). Approximately 50 percent of patients with primary hyperparathyroidism have high serum calcitriol concentrations as a result of this action of PTH .
PTH also decreases the activity of a 24-hydroxylase that inactivates calcitriol. This is a particularly important action of PTH in maintaining calcium homeostasis in states of vitamin D deficiency.
Other actions of PTH — The possibility that PTH acts on other tissues has been raised in attempts to explain certain clinical manifestations of hyperparathyroidism, and some experimental studies have found effects of PTH on the intestine, liver, adipose tissue, cardiovascular function, and neuromuscular function. As an example, impaired glucose tolerance and alterations in lipid metabolism reminiscent of the metabolic syndrome have been described in hyperparathyroidism. Similarly, patients with primary hyperparathyroidism have an increased incidence of hypertension, left ventricular hypertrophy, and neuromuscular abnormalities. (See "Primary hyperparathyroidism: Clinical manifestations".)
In addition, chronic excess of PTH, along with the associated elevations in the level of FGF23, has been implicated in the pathogenesis of vascular calcification and hypertension in patients with chronic kidney disease (CKD) [59,60] (see "Vascular calcification in chronic kidney disease"). These nonclassical effects of PTH may be mediated by differing PTH moieties and/or differing PTH receptors . Moreover, the extent to which these abnormalities improve after parathyroidectomy varies considerably, and whether they are actually directly caused by PTH excess is uncertain.
THERAPEUTIC IMPLICATIONS OF PTH1R ACTIVATION — The classical PTH/PTHrP receptor, PTH1R, binds intact PTH and biologically active amino-terminal fragments of PTH, such as PTH 1-34. It recognizes both PTH and PTHrP due to the substantial degree of homology in the amino-terminal parts of these two peptides. Agents (available or in development) that activate PTH1R have therapeutic implications:
●PTH – Although chronic hyperparathyroidism results in bone resorption, intermittent administration of PTH stimulates bone formation more than bone resorption. Thus, administration of PTH subcutaneously once daily results in substantial increments in bone mineral density and a decrease in the risk of both vertebral and nonvertebral fractures in patients with osteoporosis [49,61-64]. The positive effect of intermittent PTH on bone appears to be mediated through the PTH1R, in view of the equivalence of PTH 1-84 and PTH 1-34 in bone anabolism. The exact mechanisms for this anabolism have not been fully elucidated. It involves the induction of multiple target genes promoting enhanced osteoblastic activity, including insulin-like growth factor-1 (IGF-1), transforming growth factor (TGF)-beta, Runx2, receptor activator of nuclear factor kappa-B ligand (RANKL), 1-alpha hydroxylase, and macrophage colony-stimulating factor (M-CSF); while sclerostin, an inhibitor of the wnt signaling pathway, is suppressed. (See "Parathyroid hormone/parathyroid hormone-related protein analog for osteoporosis".)
In addition, administration of PTH subcutaneously once daily has been shown to maintain serum calcium levels while reducing the need for large doses of calcium and vitamin D in patients with hypoparathyroidism. In view of the fact that hypoparathyroidism is a hormonal deficiency, replacement of the missing hormone (eg, PTH 1-84), is a potentially attractive intervention. (See "Hypoparathyroidism", section on 'Second-line therapy'.)
●PTHrP 1-34 – PTHrP 1-34 (abaloparatide) is a synthetic analog of PTHrP (76 percent homology) that binds more selectively than PTH 1-34 (teriparatide) to the RG conformation of the PTH1R . It also exerts anabolic actions on bone and may have less calcemic action that PTH 1-34 [66,67], perhaps because it binds preferentially to a guanine nucleotide-binding (G) protein-bound form of PTH1R, which produces in a more transient action on the receptor than PTH 1-34. (See "Parathyroid hormone/parathyroid hormone-related protein analog for osteoporosis".)
●PTH analogs in development – There are PTH analogs currently in development with :
•Differential modulation of downstream signaling pathways activated by PTH1R, and, in turn, selective regulation of relevant aspects of cellular function in PTH target tissues (so-called biased agonists, for example, exert an anabolic effect on bone without the usual accompanying hypercalcemic action of the native hormone)
•Prolonged biological actions making them more suitable, for example, for treating hypoparathyroidism than PTH 1-84
Small molecule agonist for the PTH1R can be administered orally. PCO371 is such a molecule; in preclinical models, it has shown promise as a candidate for the treatment of hypoparathyroidism . Long-acting forms of PTH (LA-PTH) have been developed that produce prolonged receptor binding and signaling. One such LA-PTH exerts a long-lasting calcemic action in experimental animals and could potentially be useful in the future for treating hypoparathyroidism .
Finally, studies in mice with ablation of the calcium-sensing receptor (CaSR) in osteoblasts have shown that the receptor has important actions in promoting the normal growth and development of bone through its action on osteoblasts, raising the possibility of an enhanced anabolic action of combined therapy in the future with a calcimimetic and PTH 1-34 or PTH 1-84 .
●Parathyroid hormone (PTH) is synthesized as a 115-amino acid polypeptide called pre-pro-PTH, which is cleaved within parathyroid cells at the amino-terminal portion first to pro-PTH (90 amino acids) and then to PTH (84 amino acids). (See 'PTH synthesis and degradation' above.)
●PTH 1-84 has a plasma half-life of two to four minutes. Once secreted, PTH is rapidly cleared from plasma through uptake principally by the liver and kidney, where PTH 1-84 is cleaved into amino- and carboxyl-terminal fragments, which are then cleared by the kidney. (See 'PTH synthesis and degradation' above.)
●PTH secretion is primarily regulated by extracellular calcium, along with extracellular phosphate, calcitriol, and fibroblast growth factor 23 (FGF23). The change in calcium concentration is sensed by an exquisitely sensitive calcium-sensing receptor (CaSR) on the surface of parathyroid cells. In normal individuals, a decrease in serum ionized calcium concentration of as little as 0.1 mg/dL (0.025 mmol/L) produces a large increase in serum PTH concentration within minutes; conversely, an equally small increase in serum ionized calcium rapidly lowers the serum PTH concentration (figure 2). (See 'Regulation' above.)
●Activating or inactivating mutations in the CaSR produce altered extracellular calcium-sensing and therefore inappropriate PTH release with respect to the prevailing serum calcium concentration. (See 'Effect of altered calcium-sensing on calcium-regulated PTH secretion' above.)
●PTH acts by binding to and activating one of several types of PTH receptors. The classical PTH receptor is PTH1R, which is heavily expressed in bone and kidney, and is also present in other tissues such as growth plate chondrocytes, breast, skin, heart, blood vessels, and pancreas. The PTH1R binds PTH 1-84 and biologically active amino-terminal hormone fragments of PTH, such as PTH 1-34. It recognizes both PTH and PTH-related protein (PTHrP) due to the substantial degree of homology in the amino-terminal parts of these two proteins. (See 'PTH receptor activation' above.)
●Activation of the PTH1R by PTH triggers multiple cellular signaling pathways, which ultimately stimulate bone resorption; renal tubular calcium reabsorption and phosphate excretion; and/or hydroxylation of calcidiol to calcitriol, which enhances gastrointestinal absorption of calcium. (See 'Biological actions of PTH' above.)
●Administration of PTH 1-34, PTH 1-84, or a PTHrP(1-34) analog by daily subcutaneous injection can exert anabolic actions in humans. The use of certain PTH analogs, including those with long-lasting actions, are candidates for the treatment of hypoparathyroidism. (See 'Therapeutic implications of PTH1R activation' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Edward M Brown, MD, and Ghada El-Hajj Fuleihan, MD, MPH, who contributed to earlier versions of this topic review.