Parathyroid hormone phosphates

Although it is being found that vitamin D metaboUtes play a role ia many different biological functions, metaboHsm primarily occurs to maintain the calcium homeostasis of the body. When calcium semm levels fall below the normal range, 1 a,25-dihydroxy-vitainin is made when calcium levels are at or above this level, 24,25-dihydroxycholecalciferol is made, and 1 a-hydroxylase activity is discontiaued. The calcium homeostasis mechanism iavolves a hypocalcemic stimulus, which iaduces the secretion of parathyroid hormone. This causes phosphate diuresis ia the kidney, which stimulates the 1 a-hydroxylase activity and causes the hydroxylation of 25-hydroxy-vitamin D to 1 a,25-dihydroxycholecalciferol. Parathyroid hormone and 1,25-dihydroxycholecalciferol act at the bone site cooperatively to stimulate calcium mobilization from the bone (see Hormones). Calcium blood levels are also iafluenced by the effects of the metaboUte on intestinal absorption and renal resorption. 

Most GPCRs interact with and activate more than one G-protein subfamily, e.g., with Gs plus Gq/n (histamine H2, parathyroid hormone and calcitonin recqrtors), Gs plus G (luteinising hormone receptor, 32-adrenoceptor) or Gq/11 plus G12/13 (thromboxane A2, angiotensin ATb endothelin ETA receptors). Some receptors show even broader G-protein coupling, e.g., to Gi, Gq/n plus Gi n ( protease-activated receptors, lysophosphatidate and sphingosine-1-phosphate receptors) or even to all four G-protein subfamilies (thyrotropin receptor). This multiple coupling results in multiple signaling via different pathways and in a concerted reaction of the cell to the stimulus. 

Check parathyroid hormone (PTH), vitamin D and precursors, magnesium, and phosphate levels ° Pharmacological causes of decreased ionized calcium may include excess infusions of citrate, EDTA, lactate, fluoride poisoning, foscarnet, cinacalcet, bisphosphates, or unrelated increase in serum phosphate or decrease in serum magnesium levels... 

More than 99% of total body calcium is found in bone the remaining less than 1% is in the ECF and ICE Calcium plays a critical role in the transmission of nerve impulses, skeletal muscle contraction, myocardial contractions, maintenance of normal cellular permeability, and the formation of bones and teeth. There is a reciprocal relationship between the serum calcium concentration (normally 8.6 to 10.2 mg/dL [2.15 to 2.55 mmol/L]) and the serum phosphate concentration that is regulated by a complex interaction between parathyroid hormone, vitamin D, and calcitonin. About one-half of the serum calcium is bound to plasma proteins the other half is free ionized calcium. Given that the serum calcium has significant protein binding, the serum calcium concentration must be corrected in patients who have low albumin concentrations (the major serum protein). The most commonly used formula adds 0.8 mg/dL (0.2 mmol/L) of calcium for each gram of albumin deficiency as follows ... 

Phosphate, which is also freely filtered with plasma through the nephrons of the kidney, is reabsorbed into the blood from the proximal tubule. Parathyroid hormone acts on this segment to decrease phosphate reabsorption and increase the amount excreted in the urine. 

Parathyroid hormone stimulates bone resorption by increasing the number and activity of osteoclasts. This demineralization process in the bone releases calcium and phosphate into the blood. Although the action of PTH on the bone appears to increase blood phosphate, its action on the kidney, which increases phosphate excretion in the urine, more than compensates for this increase and the net effect is a decrease in serum phosphate. 

Marcus, R., Agents affecting calcification and bone turnover calcium, phosphate, parathyroid hormone, vitamin D, calcitonin, and other compounds, in Goodman and Gilman s The Pharmacological Basis of Therapeutics, 9th ed., Hardman, J.G. and Limbird, L.E., Eds., McGraw-Hill, New York, 1996, chap. 61. 

The a ns wer is a. (Hardman, pp 1525-1528.) Pa r a thyroid ho r m o ne is synthesized by and released from the parathyroid gland increased synthesis of PTI1 is a response to low serum Ca concentrations. Resorption and mobilization of Ca and phosphate from bone are increased in response to elevated PTI1 concentrations. Replacement of body stores of Ca is enhanced by the capacity of PTH to promote increased absorption of Ca by the small intestine in concert with vitamin D, which is the primary factor that enhances intestinal Ca absorption. Parathyroid hormone also causes an increased renal tubular reabsorption of Ca and excretion of phosphate. As a consequence of these effects, the extracellular Ca concentration becomes elevated. 

Human parathyroid hormone (hPTH) is an 84 amino acid polypeptide that functions as a primary regulator of calcium and phosphate metabolism in bones. It stimulates bone formation by osteoblasts, which display high-affinity cell surface receptors for the hormone. PTH also increases intestinal absorption of calcium. 

FIGURE 76-7. Pathogenesis of secondary hyperparathyroidism and renal osteodystrophy in patients with chronic kidney disease. These adaptations are lost as renal failure progresses. (Ca, calcium, P04 phosphate PTH, parathyroid hormone.)... 

High phosphate diets cause decreased Ca absorption, secondary hyperparathyroidism, accelerated bone resorption and soft tissue calcification in some animals, but not in normal humans. Although phosphates may decrease Ca absorption in man at very high (> 2000 mg/day) Ca intakes, they do not do so at more moderate Ca levels and enhance Ca absorption at very low levels (< 500 mg/day). Phosphates increase renal tubular reabsorption and net retention of Ca. At low Ca intakes, phosphates stimulate parathyroid hormone (PTH) secretion without causing net bone resorption. 

Many of the adverse effects of lithium can be ascribed to the action of lithium on adenylate cyclase, the key enz)nne that links many hormones and neurotransmitters with their intracellular actions. Thus antidiuretic hormone and thyroid-stimulating-hormone-sensitive adenylate cyclases are inhibited by therapeutic concentrations of the drug, which frequently leads to enhanced diuresis, h)rpoth)n oidism and even goitre. Aldosterone synthesis is increased following chronic lithium treatment and is probably a secondary consequence of the enhanced diuresis caused by the inhibition of antidiuretic-hormone-sensitive adenylate cyclase in the kidney. There is also evidence that chronic lithium treatment causes an increase in serum parathyroid hormone levels and, with this, a rise in calcium and magnesium concentrations. A decrease in plasma phosphate and in bone mineralization can also be attributed to the effects of the drug on parathyroid activity. Whether these changes are of any clinical consequence is unclear. 

Enzyme induction properties Rifampin has enzyme induction properties that can enhance the metabolism of endogenous substrates including adrenal hormones, thyroid hormones, and vitamin D. Rifampin and isoniazid have been reported to alter vitamin D metabolism. In some cases, reduced levels of circulating 25-hydroxy vitamin D and 1,25-dihydroxy vitamin D have been accompanied by reduced serum calcium and phosphate, and elevated parathyroid hormone. 

Calcitonin is a polypeptide hormone which (along with parathyroid hormone and the vitamin D derivative, 1,25-dihydroxycholecalciferol) plays a central role in regulating serum ionized calcium (Ca +) and inorganic phosphate (P,) levels. The adult human body contains up to 2 kg of calcium, of which 98% is present in the skeleton (i.e. bone). Up to 85% of the 1kg of phosphorus present in the body is also found in the skeleton (the so-called mineral fraction of bone is largely composed of Ca3 (P04)2 which acts as a body reservoir for both calcium and phosphorus). Calcium concentrations in human serum approximate to O.lmg/ml and are regulated very tightly (serum phosphate levels are more variable). 

Parathyroid hormone is a single-chain polypeptide of 84 amino acids which is produced in the parathyroid glands. It increases serum calcium and decreases serum phosphate. In bone it promotes resorption of calcium. It indirectly increases osteoclastic activity by promoting the action of osteoblasts. It has been shown that in low doses PTH may even increase bone formation without stimulating bone resorption. In the kidney PTH increases resorption of calcium and it increases excretion of phosphate. An other important activity in the kidney is the enhanced synthesis of 1,25-dihydroxyvitamin D. An increased serum calcium level inhibits PTH secretion and increased serum phosphate decreases free serum calcium and thus stimulates PTH secretion. 

Osteomalacia is the condition in which bone becomes demineralised due to deficiency of vitamin D. In this condition parathyroid hormone (PTH) acts on the bone to maintain serum calcium, resulting in demineralisation. Serum calcium is usually normal or slightly low alkaline phosphatase levels are high, reflecting excessive osteoblast activity, and serum phosphate falls as an effect of PTH on the kidney. The same condition in children results in defects in long bone formation, and is termed rickets. 

Mechanism of Action An antibiotic that forms complexes with DNA, inhibiting DNA-directed RNA synthesis. May inhibit parathyroid hormone effect on osteoclasts and inhibit bone resorption. TherapeuticEffect Lowers serum calcium and phosphate levels. Blocks hypercalcemic action of vitamin Dand action of parathyroid hormone. Decreases serum calcium. 

Three hormones serve as the principal regulators of calcium and phosphate homeostasis parathyroid hormone (PTH), fibroblast growth factor 23 (FGF23), and the steroid vitamin D (Figure 42-2). Vitamin D is a prohormone rather than a true hormone, because it must be further metabolized to gain biologic activity. PTH stimulates the production of the active metabolite of vitamin D, l,25(OH)2D. l,25(OH)2D, on the other hand, suppresses the production of PTH. l,25(OH)2D stimulates the intestinal absorption of calcium and phosphate. l,25(OH)2D and PTH promote both bone formation and resorption in part by stimulating the proliferation and differentiation of osteoblasts and osteoclasts. Both... 

Cholecalciferol Regulate gene transcription via the vitamin D receptor Stimulate intestinal calcium absorption, bone resorption, renal calcium and phosphate reabsorption decrease parathyroid hormone (PTH) promote innate immunity inhibit adaptive immunity Osteoporosis, osteomalacia, renal failure, malabsorption Hypercalcemia, hypercalciuria the vitamin D preparations have much longer half-life than the metabolites and analogs... 

The changes in calvarial phosphatase activities observed in animals treated with 25-(OH)D3 are totally different from those obtained with either 1.25-(OH)2D3 or 24.25—(OH)2D3. This fact indicates that physiological doses of 25-(OH)D3 may have an effect on cellular activity, independent of the conversion of this metabolite into these dihydroxyderivatives. The various effects of these vitamin D3 metabolites cannot be correlated with changes in serum calcium and/or phosphate concentrations. Among those factors other than serum calcium and phosphate concentrations that may be involved in the mechanism of action of vitamin D3 metabolites on bone phosphatase activities, the parathyroid hormone is of importance. This hormone is known to be a potent activator of bone phosphatases223,224,228. Parathormone increases the content of alkaline, neutral and acid phosphatases in mouse calvaria in vitro. Calcitonin does not prevent the increase of those enzymes while dichloromethylene diphosphonate causes a decrease in acid phosphatase and pyrophosphatase226. ... 

Morgan, D. B., Monod, A., Russell, R. G. G., Fleisch, H. Influence of dichlormethylene diphosphonate (C12MDP) and calcitonin on bone resorption, lactate production and phosphate and pyrophosphatase content of mouse calvaria treated with parathyroid hormone in vitro. Calc. Tiss. Res. 13, 287 (1973)... 

Regulation of 25-hydroxycholecalciferol 1-hydroxylase 1,25-diOH D3 is the most potent vitamin D metabolite. Its formation is tightly i regulated by the level of plasma phosphate and calcium ions (Figure 28.24). 25-Hydroxycholecalciferol1 -hydroxylase activity is I increased directly by low plasma phosphate or indirectly by bw I plasma calcium, which triggers the release of parathyroid hormone I... 

Other target organs for the action of 1,25-dihydroxyvitamin D include the kidneys, bone, muscle,vwand skin. The hormone promotes reabsorption of both Ca2+ and inorganic phosphate by kidney tubules. In bone it binds to a specific receptor where it promotes the mobilization of calcium ions. This effect may result in part from stimulation of calcium-activated ATPase of the outer membrane of bone cells. Dissolution of bone also requires the presence of parathyroid hormone (PTH), the 83-residue hormone secreted by the parathyroid gland. In women past the age of menopause and in elderly men the production of 1,25-dihydroxyvitamin D decreases.w This may be a cause of the serious bone loss (osteoporosis) frequently observed. Treatment with 1,25-dihydroxyvitamin D3 or a synthetic analog seems to be helpful to such individuals. /Xy See also Chapter 30, Section A,5. 

The more classical Itinehoii of parathyroid hormone is concerned with its control of the maintenance of constant circulating calcium levels. Its action is on 11) Ihe kidney, where it increases the phosphate in the urine. (2) the skeletal system, where it causes calcium resorplion from bone, and t3l the digestive system, where it accelerates (stimulates) calcium absorption into the hitskI The hormone and gland exhibit characteristics of feedback control when the concentration of calcium tons in the blood falls, the secretion of the hormone increases, and when their concentration rises, the secretion of hormone decreases... 

Plasma phosphate appears to be homeostahcally controlled. The primary organ concerned appears to be the kidney, although the skeleton also may play a role. Parathyroid hormone, by way of its direct action on the kidney and bone, is a significant hormonal factor. 

Certain human populations depend on dietary sources of vitamin D because of insufficient biosynthesis of the vitamin due to inadequate skin exposure to sunlight. The classic symptoms of vitamin D deficiency are rickets in children and osteomalacia in adults. 25-Hydroxyvitamin D3 is the major circulating metabolite in the blood, but the hormonally active form of the vitamin is 1,25-dihydroxyvitamin D3. The latter metabolite stimulates the intestine to absorb calcium and phosphate by two independent mechanisms and acts with parathyroid hormone to mobilize calcium, accompanied by phosphate, from the bone fluid compartment into the bloodstream. 1,25-dihydroxyvitamin D 3 is also involved in the formation of osteoclasts—giant cells that are solely responsible for the resorption of bone matrix (33). Resorption is an essential process for the development, growth, maintenance, and repair of bone. 

Uptake of Ca2+ from the intestine is stimulated by vitamin D.447 Vitamin D3 is converted to the 25-hydroxy derivative in the liver (equation 11) by a two component mixed-function hydroxylase.448 The metabolically active 1,25-dihydroxy form is synthesized by further hydroxylation in the kidney. This latter stage involves the renal 25-hydroxyvitamin D3- 1-hydroxylase in a reaction which is controlled by Ca2+, parathyroid hormone and phosphate. This renal hydroxylase contains a flavoprotein, an iron-sulfur protein (with an Fe2S2 cluster) and cytochrome P-450.447... 

Mild asymptomatic hypercalcemia is common during treatment with parathyroid hormone (15). The hypercalcemia is persistent, and requires dosage reduction in 3% of patients using 20 micrograms/day and in 11% using 40 micrograms/day (16). Transient mild hypercalciuria and increased serum phosphate are common but do not usually limit therapy. 

The major location of calcium in the body is in the skeleton, which contains more than 90% of the body calcium as phosphate and carbonate. Bone resorption and formation keeps this calcium in dynamic equilibrium with ionized and complexed calcium in blood, cellular fluids and membranes. Homeostasis is mainly regulated by the parathyroid hormone and vitamin D which lead to increased blood calcium levels, and by a thyroid hormone, calcitonin, which controls the plasma calcium concentration J5 Increasing the concentration of calcitonin decreases the blood calcium level, hence injections of calcitonin are used to treat severe hyperalcaemia arising from hyperparathyroidism, vitamin D intoxication or the injection of too high a level of parathyroid extract. High levels of calcitonin also decrease resorption of calcium from bone. Hypocalcaemia stimulates parathyroid activity, leading to increased release of calcium from bone, reduction in urinary excretion of calcium and increased absorption of calcium from the intestine. Urinary excretion of phosphate is enhanced. 

---