PTH is secreted in response to low blood serumcalcium (Ca2+) levels and is a key regulator ofbone remodeling, the continuous process of bone resorption and formation. PTH indirectly stimulatesosteoclast activity, promoting the release of calcium from thebone matrix to restore serum calcium levels. Thebones serve as a reservoir of calcium, releasing it as needed to maintain homeostasis in the face of fluctuatingmetabolism,stress, andnutritional status.
Produced primarily by thechief cells of the parathyroid glands, PTH is apolypeptide prohormone consisting of 84amino acids and has a molecular mass of approximately 9500Da. Its gene is located onchromosome 11.[6]
hPTH-(1-84) crystallizes as a slightly bent, long, helical dimer. The extendedhelical conformation of hPTH-(1-84) is the likely bioactive conformation.[9] TheN-terminal fragment 1-34 of parathyroid hormone (PTH) has been crystallized and the structure has been refined to 0.9Å resolution.
A diagrammatic representation of the movements of calcium ions into and out of the blood plasma (the central square labeled PLASMA Ca2+) in an adult in calcium balance: The widths of the red arrows indicating movement into and out of the plasma are roughly in proportion to the daily amounts of calcium moved in the indicated directions. The size of the central square is not in proportion to the size of the diagrammatic bone, which represents the calcium present in the skeleton, and contains about 25,000 mmol (or 1 kg) of calcium compared to the 9 mmol (360 mg) dissolved in the blood plasma. The differently colored narrow arrows indicate where the specified hormones act, and their effects (“+” means stimulates; “-“ means inhibits) when their plasma levels are high. PTH is parathyroid hormone, 1,25 OH VIT D3 iscalcitriol or 1,25 dihydroxyvitamin D3, andcalcitonin is a hormone secreted by thethyroid gland when the plasma ionized calcium level is high or rising. The diagram does not show the extremely small amounts of calcium that move into and out of the cells of the body, nor does it indicate the calcium that is bound to the extracellular proteins (in particular the plasma proteins) or to plasma phosphate.[11][12][13][14][15]
Parathyroid hormone regulatesserum calcium through its effects on bone, kidney, and the intestine:[16]
In bone, PTH enhances the release of calcium from the large reservoir contained in the bones.[17]Bone resorption is the normal destruction of bone byosteoclasts, which are indirectly stimulated by PTH. Stimulation is indirect since osteoclasts do not have a receptor for PTH; rather, PTH binds toosteoblasts, the cells responsible for creating bone. Binding stimulates osteoblasts to increase their expression of RANKL and inhibits their secretion ofosteoprotegerin (OPG). Free OPG competitively binds toRANKL as adecoy receptor, preventing RANKL from interacting withRANK, a receptor for RANKL. The binding of RANKL to RANK (facilitated by the decreased amount of OPG available for binding the excess RANKL) stimulates osteoclast precursors, which are of amonocyte lineage, to fuse. The resulting multinucleated cells are osteoclasts, which ultimately mediatebone resorption. Estrogen also regulates this pathway through its effects on PTH. Estrogen suppresses T cell TNF production by regulating T cell differentiation and activity in the bone marrow, thymus, and peripheral lymphoid organs. In the bone marrow, estrogen downregulates the proliferation of hematopoietic stem cells through an IL-7 dependent mechanism.[18]
In the kidney, around 250 mmol of calcium ions are filtered into theglomerular filtrate per day. Most of this (245 mmol/d) is reabsorbed from the tubular fluid, leaving about 5 mmol/d to be excreted in the urine. This reabsorption occurs throughout the tubule (most, 60–70%, of it in theproximal tubule), except in the thin segment of theloop of Henle.[11] Circulating parathyroid hormone only influences the reabsorption that occurs in thedistal tubules and therenal collecting ducts[11] (but see Footnote[nb 1]). A more important effect of PTH on the kidney is, however, its inhibition of the reabsorption ofphosphate (HPO42−) from the tubular fluid, resulting in a decrease in the plasma phosphate concentration. Phosphate ions form water-insoluble salts with calcium. Thus, a decrease in the phosphate concentration of the blood plasma (for a given total calcium concentration) increases the amount of calcium that is ionized.[21][22] A third important effect of PTH on the kidney is its stimulation of the conversion of25-hydroxy vitamin D into1,25-dihydroxy vitamin D (calcitriol), which is released into the circulation. This latter form of vitamin D is the active hormone which stimulates calcium uptake from the intestine.[23]
Via the kidney, PTH enhances the absorption of calcium in theintestine by increasing the production of activatedvitamin D. Vitamin D activation occurs in the kidney. PTH up-regulates25-hydroxyvitamin D3 1-alpha-hydroxylase, the enzyme responsible for 1-alphahydroxylation of25-hydroxy vitamin D, converting vitamin D to its active form (1,25-dihydroxy vitamin D). This activated form of vitamin D increases the absorption of calcium (as Ca2+ ions) by the intestine viacalbindin.
PTH was one of the first hormones to be shown to use the G-proteinadenylyl cyclase second messenger system.
PTH reduces the reabsorption ofphosphate from theproximal tubule of the kidney,[24] which means more phosphate is excreted through the urine.
However, PTH enhances the uptake of phosphate from the intestine and bones into the blood. In the bone, slightly more calcium than phosphate is released from the breakdown of bone. In the intestines, absorption of both calcium and phosphate is mediated by an increase in activated vitamin D. The absorption of phosphate is not as dependent on vitamin D as is that of calcium. The result of PTH release is a small net drop in the serum concentration of phosphate.
PTH upregulates the activity of1-α-hydroxylase enzyme, which converts 25-hydroxycholecalciferol, the major circulating form of inactive vitamin D, into 1,25-dihydroxycholecalciferol, the active form of vitamin D, in the kidney.
Secretion of parathyroid hormone is determined chiefly byserumionized calcium concentration throughnegative feedback. Parathyroid cells expresscalcium-sensing receptors on the cell surface. PTH is secreted when [Ca2+] is decreased (calcitonin is secreted when serum calcium levels are elevated). The G-protein-coupled calcium receptors bind extracellular calcium and may be found on the surface on a wide variety of cells distributed in thebrain,heart,skin,stomach, C cells, and other tissues. In the parathyroid gland, high concentrations of extracellular calcium result in activation of the Gq G-protein coupled cascade through the action ofphospholipase C. This hydrolyzesphosphatidylinositol 4,5-bisphosphate (PIP2) to liberate intracellular messengersIP3 anddiacylglycerol (DAG). Ultimately, these two messengers result in a release of calcium from intracellular stores into the cytoplasmic space. Hence a high extracellular calcium concentration leads to an increase in the cytoplasmic calcium concentration. In contrast to the mechanism that most secretory cells use, this high cytoplasmic calcium concentration inhibits the fusion of vesicles containing granules of preformed PTH with the membrane of the parathyroid cell, and thus inhibits release of PTH.
In the parathyroids, magnesium serves this role in stimulus-secretion coupling. A mild decrease in serum magnesium levels stimulates the reabsorptive activity PTH has on the kidneys. Severehypomagnesemia inhibits PTH secretion and also causes resistance to PTH, leading to a form of hypoparathyroidism that is reversible.[25]
An increase in serum phosphate (increased phosphate causes it to complex with serum calcium, forming calcium phosphate, which reduces stimulation of Ca-sensitive receptors (CaSr) that do not sense calcium phosphate, triggering an increase in PTH).
Increase in serum phosphate. Fibroblast growth factor-23 (FGF23) is produced in osteoblasts (from bone) in response to increases in serum phosphate (Pi). It binds to the fibroblast growth factor receptor of the parathyroid and suppresses PTH release. This may seem contradictory because PTH actually helps rid the blood of phosphates but it is also causes release of phosphate into the blood from bone resorption. FGF23 inhibits PTH and then takes its place helping inhibit re-absorption of phosphate in the kidney without the phosphate releasing effect on bones.[27][28]
Hyperparathyroidism, the presence of excessive amounts of parathyroid hormone in the blood, occurs in two very distinct sets of circumstances. Primary hyperparathyroidism is due to autonomous, abnormal hypersecretion of PTH from the parathyroid gland, whilesecondary hyperparathyroidism is an appropriately high PTH level seen as a physiological response tohypocalcemia. A low level of PTH in the blood is known ashypoparathyroidism and is most commonly due to damage to or removal of parathyroid glands during thyroid surgery.
There are a number of rare but well-described genetic conditions affecting parathyroid hormone metabolism, includingpseudohypoparathyroidism,familial hypocalciuric hypercalcemia, and autosomal dominant hypercalciuric hypocalcemia. Of note, PTH is unchanged inpseudopseudohypoparathyroidism. Inosteoporotic women, administration of an exogenous parathyroid hormone analogue (teriparatide, by daily injection) superimposed on estrogen therapy produced increases in bone mass and reduced vertebral and nonvertebral fractures by 45–65%.[29]
PTH can be measured in the blood in several different forms: intact PTH; N-terminal PTH; mid-molecule PTH, and C-terminal PTH, and different tests are used in different clinical situations. The level may be stated in pg/dL or pmol/L (sometimes abbreviated mmol/L); multiply by 0.1060 to convert from pg/dL to pmol/L.[30]
A US source states the average PTH level to be 8–51 pg/mL.[31] In the UK thebiological reference range is considered to be 1.6–6.9 pmol/L.[32] Normal total plasma calcium level ranges from 8.5 to 10.2 mg/dL (2.12 mmol/L to 2.55 mmol/L).[33]
The PTH assay may be liable to interference in rare cases.[34]
^abcLow Normal or Normal only for Quest Lab, not LabCorp
^Both primary and tertiary hyperparathyroidism may have high PTH and high calcium. Tertiary is differentiated from primary hyperparathyroidism by a history ofchronic kidney failure and secondary hyperparathyroidism.
Recombinant human parathyroid hormone (Preotact) received market authorization in the European Union in April 2006 to treat osteoporosis in postmenopausal women at high risk of fractures. Preotact marketing authorisation was later voluntarily withdrawn in 2014 by the holderNPS Pharma.[40] FDA approval (as Preos) was not granted in the US for the same indication due tohypercalcemia and injection device issues.[41]
Recombinant human parathyroid hormone (Natpara) was approved for medical use in the United States in January 2015, and received (as Natpar) conditional market authorization in the European Union in February 2017 as orphan drug.[42][43] On 2019 Natpara was recalled in the US due to rubber particle issues emerging from daily use of the cartridge.[44]Takeda announced in 2022 its decision to stop manufacturing Natpara/Natpar globally at the end of 2024.[45]
Teriparatide, sold under the brand name Forteo, is a form of parathyroid hormone (PTH) consisting of the first (N-terminus) 34amino acids, which is the portion of the hormone activating theParathyroid hormone 1 receptor.[46] It is an effectiveanabolic (promoting bone formation) agent[47] used in the treatment of some forms ofosteoporosis.[46][48] Teriparatide is a recombinant human parathyroid hormone analog (PTH 1-34).[46] It has an identical sequence to the 34 N-terminal amino acids of the 84-amino acid human parathyroid hormone.[46]
^This reduction in the rate of calcium excretion via the urine is a minor effect of high parathyroid hormone levels in the blood. The main determinant of the amount of calcium excreted into the urine per day is the plasma ionized calcium concentration itself. The plasma parathyroid hormone (PTH) concentration only increases or decreases the amount of calcium excreted at anyspecified plasma ionized calcium concentration. Thus, in primaryhyperparathyroidism, the quantity of calcium excreted in the urine per day isincreased despite the high levels of PTH in the blood, because hyperparathyroidism results inhypercalcemia, which increases the urinary calcium concentration (hypercalcuria) despite the moderately increased rate of calcium reabsorption from the renal tubular fluid caused by PTH's direct effect on those tubules.Renal stones are, therefore, often a first indication of hyperparathyroidism, especially since the hypercalcuria is accompanied by an increase in urinary phosphate excretion (a direct result of the high plasma PTH levels). Together the calcium and phosphate tend to precipitate out as water-insoluble salts, which readily form solid "stones".[11][19][20]
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