PTH action

In the kidney, PTH stimulates the conversion of 25-(0H)D3 into 1,25-(0H)2D3. Intrarenal l,25-(OH)2D3 causes an amplification of the PTH-induced calcium reabsorption and phosphate diuresis. l,25-(OH)2D3 enhances PTH action in bone also. Once again, PTH does not directly affect intestinal calcium absorption, but it does so indirectly through induction of l,25-(OH)2D3 synthesis and enhanced enterocyte absorption. 

The normal physiological action of PTH on bone is blunted in patients with renal failure, because their renal cells are not synthesizing the 1,25 dfliydroxy vitamin D required for normal PTH action. It is typical for patients in renal failure to have high serum PTH values this represents secondary hyperparathyroidism, the normal physiological response to vitamin D deficit. Deposition of vM at the bone mineralization front and binding to parathyroid calcium receptors interferes with this physiologic process. The usual parathyroid response to these conditions decreases secretion of PTH. The result is lower-than-expected serum PTH concentration for the degree of renal disease present. 

Vitamin D traditionally was viewed as a permissive factor in calcium metabolism, facilitating efficient absorption of dietary calcium and allowing full expression of PTH action. Vitamin D is a hormone, rather than a vitamin, and plays an active role in calcium homeostasis. 

Combined deprivation of Ca and vitamin D, as observed in malabsorption states, readily promotes hypocalcemia. Serum phosphate also will be low. Hypoparathyroidism is most often a consequence of thyroid or neck surgery, but also may be due to genetic or autoimmune disorders. Pseudohypoparathyroidism, a rare group of genetic disorders associated with decreased PTH action, results from mutations in the gene encoding the a subunit of which mediates PTH action in the renal tubules. These patients can also exhibit impaired action of multiple other hormones that couple to but the impaired response to PTH is most severe. 

As blood calcium levels fall, PTH is released from the parathyroid gland and acts directly upon the kidney and bone as well as indirectly on the intestines. The renal actions of PTH, mostly mediated by cAHP, are summarized in Table I. These direct renal PTH actions, therefore, elevate blood calcium levels by enhancing calcium reabsorption and by lowering blood phosphate concentrations and pH. The latter two actions of PTH allow calcium levels to rise to a greater extent without precipitating calcium phosphate. 

Factors controlling calcium homeostasis are calcitonin, parathyroid hormone(PTH), and a vitamin D metabolite. Calcitonin, a polypeptide of 32 amino acid residues, mol wt - SGOO, is synthesized by the thyroid gland. Release is stimulated by small increases in blood Ca " concentration. The sites of action of calcitonin are the bones and kidneys. Calcitonin increases bone calcification, thereby inhibiting resorption. In the kidney, it inhibits Ca " reabsorption and increases Ca " excretion in urine. Calcitonin operates via a cyclic adenosine monophosphate (cAMP) mechanism. 

Parathyroid hormone, a polypeptide of 83 amino acid residues, mol wt 9500, is produced by the parathyroid glands. Release of PTH is activated by a decrease of blood Ca " to below normal levels. PTH increases blood Ca " concentration by increasing resorption of bone, renal reabsorption of calcium, and absorption of calcium from the intestine. A cAMP mechanism is also involved in the action of PTH. Parathyroid hormone induces formation of 1-hydroxylase in the kidney, requited in formation of the active metabolite of vitamin D (see Vitamins, vitamin d). 

Metabolites of vitamin D, eg, cholecalciferol (CC), are essential in maintaining the appropriate blood level of Ca ". The active metabolite, 1,25-dihydroxycholecalciferol (1,25-DHCC), is synthesized in two steps. In the fiver, CC is hydroxylated to 25-hydroxycholecalciferol (25-HCC) which, in combination with a globulin carrier, is transported to the kidney where it is converted to 1,25-DHCC. This step, which requites 1-hydroxylase formation, induced by PTH, may be the controlling step in regulating Ca " concentration. The sites of action of 1,25-DHCC are the bones and the intestine. Formation of 1,25-DHCC is limited by an inactivation process, ie, conversion of 25-HCC to 24,25-DHCC, catalyzed by 24-hydroxylase. 

Three hormones regulate turnover of calcium in the body (22). 1,25-Dihydroxycholecalciferol is a steroid derivative made by the combined action of the skin, Hver, and kidneys, or furnished by dietary factors with vitamin D activity. The apparent action of this compound is to promote the transcription of genes for proteins that faciUtate transport of calcium and phosphate ions through the plasma membrane. Parathormone (PTH) is a polypeptide hormone secreted by the parathyroid gland, in response to a fall in extracellular Ca(Il). It acts on bones and kidneys in concert with 1,25-dihydroxycholecalciferol to stimulate resorption of bone and reabsorption of calcium from the glomerular filtrate. Calcitonin, the third hormone, is a polypeptide secreted by the thyroid gland in response to a rise in blood Ca(Il) concentration. Its production leads to an increase in bone deposition, increased loss of calcium and phosphate in the urine, and inhibition of the synthesis of 1,25-dihydroxycholecalciferol. 

Primary hyperparathyroidism occurs as a result of hyperplasia or the occurrence of adenoma. Secondary hyperparathyroidism may result from renal failure because of the associated phosphate retention, resistance to the metabolic actions of PTH, or impaired vitamin D metabolism. The last-mentioned factor is primarily responsible for the development of osteomalacia. Muscle symptoms are much more common in patients with osteomalacia than in primary hyperparathyroidism. Muscle biopsy has revealed disseminated atrophy, sometimes confined to type 2 fibers, but in other cases involving both fiber types. Clinical features of osteomalacic myopathy are proximal limb weakness and associated bone pain the condition responds well to treatment with vitamin D. 

Increases in parathyroid hormone (PTH) occur early as renal function begins to decline. The actions of PTH on bone... 

As renal function declines in patients with CKD, decreased phosphorus excretion disrupts the balance of calcium and phosphorus homeostasis. 0 The parathyroid glands release PTH in response to decreased serum calcium and increased serum phosphorus levels. The actions of PTH include ... 

All of these actions are directed at increasing serum calcium levels and decreasing serum phosphorus levels, although the activity of calcitriol also increases phosphorus absorption in the GI tract and mobilization from the bone, which can worsen hyperphosphatemia. Calcitriol also decreases PTH levels through a negative feedback loop. These measures are sufficient to correct serum calcium levels in the earlier stages of CKD. 

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. 

The final mechanism of action of PTH involves the activation of vitamin D3 through the stimulation of la-hydroxylase in the kidney. In the gastrointestinal tract, vitamin D3 is essential for the absorption of calcium. Enhanced absorption of calcium from dietary sources serves to further increase the concentration of calcium in the blood. Many foods, in particular, dairy products, which are rich in calcium, are fortified with vitamin D. The release of PTH from the parathyroid glands is regulated by plasma calcium levels through negative feedback. A decrease in the level of calcium in the blood stimulates the secretion of PTH and an increase in the calcium level in the blood inhibits it. 

Structure and physiology of the kidney glomerular filtration tubular activity selective reabsorption and secretion, often using specific carrier mechanisms carbonic anhydrase and acid-base balance. The kidney also produces, and is sensitive to, hormones actions of the hormones ADH, aldosterone and PTH the kidney as a secretory organ erythropoietin, the renin-angiotensin system vitamin D3. 

In addition to 1-a-hydroxylase, the kidney also possesses a 24-hydroxylase which uses calcidiol as substrate the product of the reaction, 24,25 dihydroxy D3, is biologically inactive. This represents an important control point in the pathway. The activity of the 1-a-hydroxylase is promoted by calcium ions and the action of PTH acting via a G-protein/cAMP cascade. However, calcitriol itself simultaneously induces the 24-hydroxylase and suppresses 1-a-hydroxylase creating an effective feedback loop (Figure 8.12). 

Calcium is the major mineral component of bone and normal repair and remodelling of bone is reliant on an adequate supply of this mineral. Calcium uptake in the gut, loss through the kidneys and turnover within the body are controlled by hormones, notably PTH and 1,25 dihydroxy cholecalciferol (1,25 DHCC or 1,25 dihydroxy vitamin D3 or calcitriol). Refer to Figure 8.12 for a summary of the involvement of PTH and vitamin D3 in controlling plasma calcium concentration. These two major hormones have complementary actions to raise plasma calcium concentration by promoting uptake in the gut, reabsorption in the nephron and bone resorption. Other hormones such as thyroxine, sex steroids and glucocorticoids (e.g. cortisol) influence the distribution of calcium. 

DHCC also facilitates calcium reabsorption in the kidney and mobilizes calcium from bone when PTH is also present. All these actions help bring blood calcium levels back within the normal range. 

Calcitriol (Rocaltrol, Calcnex) [Antihypocalcemic/Vitamin D Analog] Uses Reduction of i PTH levels, -iTca on dialysis Action 1,25-Dihydroxycholecalcifool (vit D analog) Dose Adul. Renal failure 0.25 mcg/d PO, t 0.25 mcg/d q4-6wk PRN 0.5 meg 3 x/wk IV, t PRN Hypoparathyroidism ... 

Teriparatide (Forteo) [Antiosteoporotic/Parathyroid Hormono] WARNING T Osteosarcoma risk in animals, therefore only use in pts for whom the potential benefits outweigh risks Uses Severe/refractory osteoporosis Action PTH (recombinant) Dose 20 meg SQ daily in thigh or abd Caution [C, /-] Contra w/ Paget Dz, prior radiation, bone metastases, T Ca caution in urolithiasis Disp Inj SE Orthostatic X BP on administration, N/D, T... 

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. 

The bisphosphonates are all analogues of pyrophosphate. They inhibit osteoclast resorption of bone and they are able to inhibit the formation and dissolution of hydroxyapatite crystals, however their exact mechanism is not well understood. Other effects which have relevance for bone homeostasis include inhibition of the activities of PTH, prostaglandins and 1,25-dihydroxy vitamin D. Bisphosphonates bind to bone with high affinity. They have therefore a duration of action that continues long after their use has been stopped. 

Mechanism of Action A calcium receptor agonist that increases the sensitivity of the calcium-sensing receptor on the parathyroid gland to extracellular calcium, thus low-eringthe parathyroid hormone (PTH) levels. TiierapeHtic Effect Decreases serum calcium and PTH levels. 

The mechanism of action of the vitamin D metabolites remains under active investigation. However, calcitriol is well established as the most potent agent with respect to stimulation of intestinal calcium and phosphate transport and bone resorption. Calcitriol appears to act on the intestine both by induction of new protein synthesis (eg, calcium-binding protein and TRPV6, an intestinal calcium channel) and by modulation of calcium flux across the brush border and basolateral membranes by a means that does not require new protein synthesis. The molecular action of calcitriol on bone has received less attention. However, like PTH, calcitriol can induce RANK ligand in osteoblasts and proteins such as osteocalcin, which may regulate the mineralization process. The metabolites 25(OH)D and 24,25(OH)2D are far less... 

Table 42-2 Actions of Parathyroid Hormone (PTH), Vitamin D, and FGF23 on Gut, Bone, and Kidney. ...

A number of hormones modulate the actions of PTH, FGF23, and vitamin D in regulating bone mineral homeostasis. Compared with that of PTH, FGF23, and vitamin D, the physiologic impact of such secondary regulation on bone mineral homeostasis is minor. However, in pharmacologic amounts, a number of these hormones have actions on the bone mineral homeostatic mechanisms that can be exploited therapeutically. 

The prevailing hypothesis advanced to explain these observations is that estrogens reduce the bone-resorbing action of PTH. Estrogen administration leads to an increased l,25(OH)2D level in blood, but estrogens have no direct effect on... 

Vaes, G. On the mechanism of bone resorption the action of PTH on the excretion and synthesis of lysosomal enzymes and the extracellular release of acid bone cells. J. Cell. Biol. 39. 676 (1968)... 

Cinacalcet (Sensipar) [Hyperparathyroidism Agent/ Calcimimetic] Uses Secondary hyperparathyroidism in CRF T Ca2+ in parathyroid carcinoma Action 4- PTH by T Ca-sensing receptor sensitivity Dose ... 

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