Parathyroid hormone bone formation

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). 

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 ... 

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. 

Teriparatide is a recombinant product representing the first 34 amino acids in human parathyroid hormone. Teriparatide increases bone formation, the bone remodeling rate, and osteoblast number and activity. Both bone mass and architecture are improved. 

Fox J. Developments in parathyroid hormone and related peptides as bone-formation agents. Curr Opin Pharmacol 2002 2 338 44. 

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. 

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... 

Typical changes in bone mineral density with time after the onset of menopause, with and without treatment. In the untreated condition, bone is lost during aging in both men and women. Fluoride, strontium (Sr2+), and parathyroid hormone (PTH) promote new bone formation and can increase bone mineral density in subjects who respond to it throughout the period of treatment, although PTH also activates bone resorption. In contrast, estrogen, calcitonin, and bisphosphonates block bone resorption. This leads to a transient increase in bone mineral density because bone formation is not initially decreased. However, with time, both bone formation and bone resorption are decreased with these pure antiresorptive agents, and bone mineral density reaches a new plateau. 

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. 

The controlled deposition of calcium salts is essential for the development of extracellular structures such as bones, teeth and shell. The process begins with uptake of calcium in the intestine, followed by transport, and then the laying down of structures. A complex system is necessary for the control of all these stages, and involves, for example, vitamin D, parathyroid hormone, calcium-binding proteins for transport, and a range of other proteins and polysaccharides for ordered deposition. Precipitation of calcium salts in the incorrect location can result in stone formation, osteoarthritis, cataracts and arterial disorders. 

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. 

Gowen, M, Stroup, GB, Dodds, RA, James, IE, Votta, BJ, Smith, BR, Bhatnagar, PK, Lago, AM, Callahan, JF, DelMar, EG, Miller, MA, Nemeth, EF and Fox, J, 2000, Antagonizing the parathyroid calcium receptor stimulates parathyroid hormone secretion and bone formation in osteopenic rats, J Clin Invest 105 1595-1604... 

FIG. 15 Effect of lycopene on resorption of the calcium phosphate substrate coating of osteologic multitest slides in the presence of osteoclasts (Rao et al., 2003). (Lycopene I -Effect on osteoclasts Lycopene inhibits basal and parathyroid hormone-stimulated osteoclast formation and mineral resorption mediated by reactive oxygen species in ray bone marrow cultures. Reprint from Journal of Medicinal Food. 2003 6, pp. 69-78 by permission of Mary Ann Liebert, Inc., Publishers.)... 

Parathyroid hormone (PTH) is an 84-amino acid polypeptide hormone that mediates bone remodeling and is an essential regulator of calcium homeostasis. Prolonged exposure to PTH changes the phenotype of the osteoblast from a cell involved in bone formation to one directing bone... 

Soma S, Matsumoto S,Takano-Yamamoto T. Enhancement by conditioned medium of stretched calvarial bone cells of the osteoclast-like cell formation induced by parathyroid hormone in mouse bone marrow cultures. Archs Oral Biol. 1996 42(3) 205-211. 

Teriparatide (a recombinant human parathyroid hormone) stimulates bone formation and is given daily by subcutaneous injection. There is evidence that teriparatide reduces vertebral and non-vertebral fractures. NICE recommends that it should be considered for the secondary prevention of osteoporotic fragility fractures in women aged 65 years and over who are intolerant of... 

The polypeptide parathormone is released from the parathyroid glands when the plasma Ca2+ level falls. It stimulates osteoclasts to increase bone resorption in the kidneys it promotes calcium reabsorption, while phosphate excretion is enhanced. As blood phosphate concentration diminishes, the tendency of Ca2+ to precipitate as bone mineral decreases. By stimulating the formation of vitamin D hormone, parathormone has an indirect effect on the enteral uptake of Ca2+ and phosphate. In parathormone deficiency, vitamin D can be used as a substitute that, unlike parathormone, is effective orally. Teriparatide is a recombinant shortened parathormone derivative containing the portion required for binding to the receptor. It can be used in the therapy of postmenopausal osteoporosis and promotes bone formation. While this effect seems paradoxical in comparison with hyperparathyroidism, it obviously arises from the special mode of administration the once daily s.c. injection generates a quasi-pulsatile stimulation. Additionally, adequate intake of calcium and vitamin D must be ensured. 

Q2 The hormones that are normally involved in the control of calcium balance are parathyroid hormone (PTH) from the parathyroid gland calcitonin, which is secreted by the thyroid gland and 1,25-dihydroxycholecalciferol (1,25-DHCC, or calcitriol), which is produced in the kidneys. Calcitonin reduces the level of plasma calcium by attenuating its release from bone and by increasing its excretion. The PTH and 1,25-DHCC increase the level of plasma calcium by two mechanisms (1) a combination of an increase in calcium absorption by the gut and an increase in the release of calcium from bone and (2) a reduction in both bone formation and calcium excretion. The three hormones act together to maintain the physiological level of calcium and normal bone turnover. Over 95% of body calcium is located in bone as hydroxyapatite. 

There is evidence that 24-hydroxycalcidiol has physiological functions distinct from those of calcitriol, and the regulation of the 24-hydroxylase suggests that it functions to provide a metabolically active product, as well as diverting calcidiol away from calcitriol synthesis (Henry, 2001). Studies of knockout mice lacking the 24-hydroxylase show that 24-hydroxycalcidiol has a role in both in-tramembranous bone formation during development and the suppression of parathyroid hormone secretion (St-Arnaud, 1999 van Leeuwen et al., 2001). 

Immunoreactive parathyroid hormone concentrations may be increased by anticonvulsants, while bone mineral content is reduced. Hypocalcemia and osteopenia can occur, despite normal serum concentrations of active vitamin D metabolites, suggesting that they may be independent of drug effects on vitamin D metabolism. Bone biopsies have shown increased osteoid but normal calcification front formation, accelerated rate of mineralization, and reduced mineralization lag time, suggesting increased skeletal turnover rather than osteomalacia (96). The risk of age-related fractures in drug-treated epileptic patients is not greatly increased (97). 

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