Plasma calcium levels are regulated by the polypeptides parathyroid hormone and calcitonin. Parathyroid hormone, secreted by the parathyroid glands embedded in the thyroid, acts to increase plasma calcium levels. Parathyroid hormone also decreases plasma PO4. Calcitonin, secreted from the parafollicular cells of the thyroid, acts to decrease plasma Ca++. of the two hormones, parathyroid hormone is the more biologically powerful regulator of plasma Ca++, and calcitonin has only a minor role.

Actions of Parathyroid Hormone

Parathyroid hormone (PTH) increases free plasma Ca++. PTH-stimulated bone reabsorption acutely increases absorption of recently deposited Ca++ salts, and chronically increases osteoclast number and activity. PTH increases renal activation of vitamin D3, which increases GI absorption of dietary Ca++. PTH decreases renal Ca++ excretion by increasing Ca++ reabsorption in the renal distal tubule and collecting duct.

PTH decreases plasma PO4 and body PO4 stores. PTH significantly enhances renal excretion of PO4. The decrease in plasma PO4 occurs because the magnitude of the increased renal PO4 excretion is greater than the increase in plasma PO4 from bone reabsorption. The increased dietary absorption of PO4 from vitamin D3 activation also is insufficient to overcome the enhanced renal PO4 loss. The decrease in plasma PO4 increases the percentage of plasma Ca++ that circulates in the free, or unbound, state.

Free plasma Ca++ is the primary determinant of PTH release. Hypocalcemia increases PTH synthesis and release. Hypocalcemia can occur during pregnancy and lactation. Prolonged hypocalcemia causes excessive PTH-mediated bone reabsorption and can cause osteoporosis and rickets. Stimuli that increase the release of PTH also cause hypertrophy of the parathyroid gland. Hypercalcemia decreases PTH synthesis and release.

Actions of Calcitonin

Calcitonin decreases plasma Ca++ concentration by enhancing Ca++ crystal deposition in bone, transiently increasing osteoblast activity, and chronically stimulating the formation of new osteoblast cells. Calcitonin effects are more pronounced in children, who have a more labile bone Ca++ storage pool, and calcitonin is of limited importance in adults. Calcitonin responds more rapidly than PTH but is a less powerful regulator of Ca++ balance. No disease states are associated with calcitonin deficiency or calcitonin excess.

Integrated Calcium Balance

Plasma Ca++ is tightly regulated, around 9.4 mg/dL, with a normal range of 9 to 10 mg/dL. Forty percent of plasma Ca++ is tightly bound to plasma proteins, 10% is combined in unionized salts with citrate and PO4, and 50% is free, about 5 mg/dL.

Bone contains cells, Ca++ and PO4 hydroxyapatite crystals, and an organic matrix. Osteocytes are the primary bone cells, formed when hydroxyapatite crystals surround osteoblasts. Osteoblasts promote growth or formation of new bone. Osteoclasts promote reabsorption of bone, returning Ca++ and PO4 to the circulation. Bone is constantly remodeled in response to mechanical stress and endocrine regulation of plasma Ca++. In bone, newly deposited Ca++ salts are more easily reabsorbed than are hydroxyapatite crystals.

Dietary absorption of Ca++ requires activated vitamin D3. Vitamin D is absorbed from the diet or through ultraviolet (sunlight) action on 7-dehydrocholesterol. Vitamin D is then converted successively in liver and kidney to 1,25- dihydroxycholecalciferol. Renal vitamin D activation requires PTH. Vitamin D stimulates intestinal epithelial cell synthesis of Ca++-binding protein, which enhances apical transport of Ca++ into the cells. End-product inhibition by 1,25-vitamin D3 provides hepatic regulation of vitamin D activation.

Hypercalcemia decreases parathyroid hormone secretion. This results in a decrease in vitamin D activation, reduced dietary Ca++ absorption, increased osteoblast activity and bone growth, and enhanced urinary loss of Ca++.

Hypocalcemia increases neuronal excitability. Motor neurons exhibit spontaneous depolarizations, leading to tetanic muscular contractions. The muscles of the hand are particularly susceptible, and the tetany is called carpopedal spasm. Spontaneous depolarization of sensory neurons gives rise to paresthesias. In contrast, hypercalcemia depresses neuronal and muscle activity.

Phosphate Metabolism

Plasma PO4 exists in two forms: HPO4 and H2PO4. Plasma HPO4    (1.0 mmol/L) is about fourfold higher than plasma

H2PO4 (0.26 mmol/L).Total inorganic plasma phosphorus is the sum of these two ions, normally about 4 mg/dL. Plasma PO4 is not tightly regulated and can vary up to threefold without significant physiologic effects.

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