79 Parathyroid Hormone, Calcitonin, Calcium And Phosphate Metabolism, Vitamin D, Bone, And Teeth-2

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Calcium in the Plasma and Interstitial Fluid









The calcium in the plasma is present in three forms, as shown in Figure 79-1: (1) About 41 percent (1 mmol/L) of the calcium is combined with the plasma proteins and in this form is nondiffusible through the capillary membrane; (2) about 9 percent of the calcium (0.2 mmol/L) is diffusible through the capillary membrane but is combined with anionic substances of the plasma and interstitial fluids (citrate and phosphate, for instance) in such a manner that it is not ionized; and (3) the remaining 50 percent of the calcium in the plasma is both diffusible through the capillary membrane and ionized.









Thus, the plasma and interstitial fluids have a normal calcium ion concentration of about 1.2 mmol/L (or 2.4 mEq/L, because it is a divalent ion), a level only one-half the total plasma calcium concentration. This ionic calcium is the form that is important for most functions of calcium in the body, including the effect of calcium on the heart, the nervous system, and bone formation.

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Inorganic Phosphate in the Extracellular Fluids

Inorganic phosphate in the plasma is mainly in two forms:
and
. The concentration of
is about 1.05 mmol/L, and the concentration of
is about 0.26 mmol/L. When the total quantity of phosphate in the extracellular fluid rises, so does the quantity of each of these two types of phosphate ions. Furthermore, when the pH of the extracellular fluid becomes more acidic, there is a relative increase in
and a decrease in
, whereas the opposite occurs when the extracellular fluid becomes alkaline
Because it is difficult to determine chemically the exact quantities of
and
in the blood, ordinarily the total quantity of phosphate is expressed in terms of milligrams of phosphorus per deciliter (100 ml) of blood. The average total quantity of inorganic phosphorus represented by both phosphate ions is about 4 mg/dl, varying between normal limits of 3 to 4 mg/dl in adults and 4 to 5 mg/dl in children.

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Hypocalcemia Causes Nervous System Excitement and Tetany









When the extracellular fluid concentration of calcium ions falls below normal, the nervous system becomes progressively more excitable because this causes increased neuronal membrane permeability to sodium ions, allowing easy initiation of action potentials. At plasma calcium ion concentrations about 50 percent below normal, the peripheral nerve fibers become so excitable that they begin to discharge spontaneously, initiating trains of nerve impulses that pass to the peripheral skeletal muscles to elicit tetanic muscle contraction. Consequently, hypocalcemia causes tetany. It also occasionally causes seizures because of its action of increasing excitability in the brain.
Tetany ordinarily occurs when the blood concentration of calcium falls from its normal level of 9.4 mg/dl to about 6 mg/dl, which is only 35 percent below the normal calcium concentration, and it is usually lethal at about 4 mg/dl.

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Hypercalcemia Depresses Nervous System and Muscle Activity









When the level of calcium in the body fluids rises above normal, the nervous system becomes depressed and reflex activities of the central nervous system are sluggish. Also, increased calcium ion concentration decreases the QT interval of the heart and causes lack of appetite and constipation, probably because of depressed contractility of the muscle walls of the gastrointestinal tract.









These depressive effects begin to appear when the blood level of calcium rises above about 12 mg/dl, and they can become marked as the calcium level rises above 15 mg/dl. When the level of calcium rises above about 17 mg/dl in the blood, calcium phosphate crystals are likely to precipitate throughout the body; this condition is discussed later in connection with parathyroid poisoning.

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Intestinal Absorption and Fecal Excretion of Calcium and Phosphate









The usual rates of intake are about 1000 mg/day each for calcium and phosphorus, about the amounts in 1 liter of milk. Normally, divalent cations such as calcium ions are poorly absorbed from the intestines. However, as discussed later, vitamin D promotes calcium absorption by the intestines, and about 35 percent (350 mg/day) of the ingested calcium is usually absorbed; the calcium remaining in the intestine is excreted in the feces. An additional 250 mg/day of calcium enters the intestines via secreted gastrointestinal juices and sloughed mucosal cells. Thus, about 90 percent (900 mg/day) of the daily intake of calcium is excreted in the feces
Intestinal absorption of phosphate occurs easily. Except for the portion of phosphate that is excreted in the feces in combination with nonabsorbed calcium, almost all the dietary phosphate is absorbed into the blood from the gut and later excreted in the urine.

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Renal Excretion of Calcium and Phosphate









Approximately 10 percent (100 mg/day) of the ingested calcium is excreted in the urine. About 41 percent of the plasma calcium is bound to plasma proteins and is therefore not filtered by the glomerular capillaries. The rest is combined with anions such as phosphate (9 percent) or ionized (50 percent) and is filtered through the glomeruli into the renal tubules.









Normally, the renal tubules reabsorb 99 percent of the filtered calcium and about 100 mg/day are excreted in the urine. Approximately 90 percent of the calcium in the glomerular filtrate is reabsorbed in the proximal tubules, loops of Henle, and early distal tubules.









Then in the late distal tubules and early collecting ducts, reabsorption of the remaining 10 percent is selective, depending on the calcium ion concentration in the blood.









When calcium concentration is low, this reabsorption is great, so almost no calcium is lost in the urine. Conversely, even a minute increase in blood calcium ion concentration above normal increases calcium excretion markedly. We shall see later in the chapter that the most important factor controlling this reabsorption of calcium in the distal portions of the nephron, and therefore controlling the rate of calcium excretion, is PTH.

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Renal phosphate excretion is controlled by an overflow mechanism, as explained in Chapter 29. That is, when phosphate concentration in the plasma is below the critical value of about 1 mmol/L, all the phosphate in the glomerular filtrate is reabsorbed and no phosphate is lost in the urine. But above this critical concentration, the rate of phosphate loss is directly proportional to the additional increase. Thus, the kidneys regulate the phosphate concentration in the extracellular fluid by altering the rate of phosphate excretion in accordance with the plasma phosphate concentration and the rate of phosphate filtration by the kidneys.

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Bone and Its Relation to Extracellular Calcium and Phosphate



Organic Matrix of Bone









The organic matrix of bone is 90 to 95 percent collagen fibers, and the remainder is a homogeneous gelatinous medium called ground substance. The collagen fibers extend primarily along the lines of tensional force and give bone its powerful tensile strength.









The ground substance is composed of extracellular fluid plus proteoglycans, especially chondroitin sulfate and hyaluronic acid. The precise function of each of these is not known, although they do help to control the deposition of calcium salts.

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Bone Salts



The crystalline salts deposited in the organic matrix of bone are composed principally of calcium and phosphate. The formula for the major crystalline salt, known as hydroxyapatite, is the following:









Each crystal-about 400 angstroms long, 10 to 30 angstroms thick, and 100 angstroms wide-is shaped like a long, flat plate. The relative ratio of calcium to phosphorus can vary markedly under different nutritional conditions, the Ca/P ratio on a weight basis varying between 1.3 and 2.0.
Magnesium, sodium, potassium, and carbonate ions are also present among the bone salts, although x-ray diffraction studies fail to show definite crystals formed by them. Therefore, they are believed to be conjugated to the hydroxyapatite crystals rather than organized into distinct crystals of their own. This ability of many types of ions to conjugate to bone crystals extends to many ions normally foreign to bone, such as strontium, uranium, plutonium, the other transuranic elements, lead, gold, other heavy metals, and at least 9 of 14 of the major radioactive products released by explosion of the hydrogen bomb. Deposition of radioactive substances in the bone can cause prolonged irradiation of the bone tissues, and if a sufficient amount is deposited, an osteogenic sarcoma (bone cancer) eventually develops in most cases

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Tensile and Compressional Strength of Bone









Each collagen fiber of compact bone is composed of repeating periodic segments every 640 angstroms along its length; hydroxyapatite crystals lie adjacent to each segment of the fiber, bound tightly to it. This intimate bonding prevents "shear" in the bone; that is, it prevents the crystals and collagen fibers from slipping out of place, which is essential in providing strength to the bone. In addition, the segments of adjacent collagen fibers overlap one another, also causing hydroxyapatite crystals to be overlapped like bricks keyed to one another in a brick wall.









The collagen fibers of bone, like those of tendons, have great tensile strength, whereas the calcium salts have great compressional strength. These combined properties plus the degree of bondage between the collagen fibers and the crystals provide a bony structure that has both extreme tensile strength and compressional strength.

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Mechanism of Bone Calcification









The initial stage in bone production is the secretion of collagen molecules (called collagen monomers) and ground substance (mainly proteoglycans) by osteoblasts. The collagen monomers polymerize rapidly to form collagen fibers; the resultant tissue becomes osteoid, a cartilage-like material differing from cartilage in that calcium salts readily precipitate in it. As the osteoid is formed, some of the osteoblasts become entrapped in the osteoid and become quiescent. At this stage they are called osteocytes.









Within a few days after the osteoid is formed, calcium salts begin to precipitate on the surfaces of the collagen fibers. The precipitates first appear at intervals along each collagen fiber, forming minute nidi that rapidly multiply and grow over a period of days and weeks into the finished product, hydroxyapatite crystals.









The initial calcium salts to be deposited are not hydroxyapatite crystals but amorphous compounds (noncrystalline), a mixture of salts such as CaHPO4 · 2H2O, Ca3(PO4)2 · 3H2O, and others. Then by a process of substitution and addition of atoms, or reabsorption and reprecipitation, these salts are converted into the hydroxyapatite crystals over a period of weeks or months. A few percent may remain permanently in the amorphous form. This is important because these amorphous salts can be absorbed rapidly when there is need for extra calcium in the extracellular fluid.









The mechanism that causes calcium salts to be deposited in osteoid is not fully understood. One theory holds that at the time of formation, the collagen fibers are specially constituted in advance for causing precipitation of calcium salts. The osteoblasts supposedly also secrete a substance into the osteoid to neutralize an inhibitor (believed to be pyrophosphate) that normally prevents hydroxyapatite crystallization. Once the pyrophosphate has been neutralized, the natural affinity of the collagen fibers for calcium salts causes the precipitation.

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Precipitation of Calcium in Nonosseous Tissues Under Abnormal Conditions









Although calcium salts almost never precipitate in normal tissues besides bone, under abnormal conditions, they do precipitate. For instance, they precipitate in arterial walls in arteriosclerosis and cause the arteries to become bonelike tubes. Likewise, calcium salts frequently deposit in degenerating tissues or in old blood clots. Presumably, in these instances, the inhibitor factors that normally prevent deposition of calcium salts disappear from the tissues, thereby allowing precipitation.

Front 7

Deposition of Bone by the Osteoblasts









Bone is continually being deposited by osteoblasts, and it is continually being absorbed where osteoclasts are active (Figure 79-4). Osteoblasts are found on the outer surfaces of the bones and in the bone cavities. A small amount of osteoblastic activity occurs continually in all living bones (on about 4 percent of all surfaces at any given time in an adult), so at least some new bone is being formed constantly.

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Absorption of Bone-Function of the Osteoclasts









Bone is also being continually absorbed in the presence of osteoclasts, which are large, phagocytic, multinucleated cells (as many as 50 nuclei), derivatives of monocytes or monocyte-like cells formed in the bone marrow. The osteoclasts are normally active on less than 1 percent of the bone surfaces of an adult. Later in the chapter we see that PTH controls the bone absorptive activity of osteoclasts.









Histologically, bone absorption occurs immediately adjacent to the osteoclasts. The mechanism of this absorption is believed to be the following: The osteoclasts send out villus-like projections toward the bone, forming a ruffled border adjacent to the bone (Figure 79-5). The villi secrete two types of substances: (1) proteolytic enzymes, released from the lysosomes of the osteoclasts, and (2) several acids, including citric acid and lactic acid, released from the mitochondria and secretory vesicles. The enzymes digest or dissolve the organic matrix of the bone, and the acids cause dissolution of the bone salts. The osteoclastic cells also imbibe by phagocytosis minute particles of bone matrix and crystals, eventually also dissoluting these and releasing the products into the blood

Front 8

parathyroid hormone (PTH) stimulates osteoclast activity and bone resorption, but this occurs through an indirect mechanism. PTH binds to receptors on the adjacent osteoblasts, causing them to release cytokines, including osteoprotegerin ligand (OPGL), which is also called RANK ligand. OPGL activates receptors on preosteoclast cells, causing them to differentiate into mature multinucleated osteoclasts. The mature osteoclasts then develop a ruffled border and release enzymes and acids that promote bone resorption.

Back 8

Osteoblasts also produce osteoprotegerin (OPG), sometimes called osteoclastogenesis inhibitory factor (OCIF), a cytokine which inhibits bone resorption. OPG acts as a "decoy" receptor, binding to OPGL and preventing OPGL from interacting with its receptor, thereby inhibiting differentiation of preosteoclasts into mature osteoclasts that resorb bone. OPG opposes the bone resorptive activity of PTH and mice with genetic deficiency of OPG have severe decreases in bone mass compared with mice with normal OPG formation. Although the factors that regulate OPG are not well understood, vitamin D and PTH appear to stimulate production of mature osteoclasts through the dual action of inhibiting OPG production and stimulating OPGL formation. On the other hand, the hormone estrogen stimulates OPG production.









The therapeutic importance of the OPG-OPGL pathway is currently being exploited. Novel drugs that mimic the action of OPG by blocking the interaction of OPGL with its receptor appear to be useful for treating bone loss in postmenopausal women and in some patients with bone cancer

Front 9

Value of Continual Bone Remodeling









The continual deposition and absorption of bone have several physiologically important functions. First, bone ordinarily adjusts its strength in proportion to the degree of bone stress. Consequently, bones thicken when subjected to heavy loads. Second, even the shape of the bone can be rearranged for proper support of mechanical forces by deposition and absorption of bone in accordance with stress patterns. Third, because old bone becomes relatively brittle and weak, new organic matrix is needed as the old organic matrix degenerates. In this manner, the normal toughness of bone is maintained. Indeed, the bones of children, in whom the rates of deposition and absorption are rapid, show little brittleness in comparison with the bones of the elderly, in whom the rates of deposition and absorption are slow.

Back 9

Control of the Rate of Bone Deposition by Bone "Stress."









Bone is deposited in proportion to the compressional load that the bone must carry. For instance, the bones of athletes become considerably heavier than those of nonathletes. Also, if a person has one leg in a cast but continues to walk on the opposite leg, the bone of the leg in the cast becomes thin and as much as 30 percent decalcified within a few weeks, whereas the opposite bone remains thick and normally calcified. Therefore, continual physical stress stimulates osteoblastic deposition and calcification of bone.









Bone stress also determines the shape of bones under certain circumstances. For instance, if a long bone of the leg breaks in its center and then heals at an angle, the compression stress on the inside of the angle causes increased deposition of bone. Increased absorption occurs on the outer side of the angle where the bone is not compressed. After many years of increased deposition on the inner side of the angulated bone and absorption on the outer side, the bone can become almost straight, especially in children because of the rapid remodeling of bone at younger ages

Front 10

Repair of a Fracture Activates Osteoblasts









Fracture of a bone in some way maximally activates all the periosteal and intraosseous osteoblasts involved in the break. Also, immense numbers of new osteoblasts are formed almost immediately from osteoprogenitor cells, which are bone stem cells in the surface tissue lining bone, called the "bone membrane." Therefore, within a short time, a large bulge of osteoblastic tissue and new organic bone matrix, followed shortly by the deposition of calcium salts, develops between the two broken ends of the bone. This is called a callus.









Many orthopedic surgeons use the phenomenon of bone stress to accelerate the rate of fracture healing. This is done by use of special mechanical fixation apparatuses for holding the ends of the broken bone together so that the patient can continue to use the bone immediately. This causes stress on the opposed ends of the broken bones, which accelerates osteoblastic activity at the break and often shortens convalescence

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Cholecalciferol (Vitamin D3) Is Formed in the Skin









Several compounds derived from sterols belong to the vitamin D family, and they all perform more or less the same functions. Vitamin D3 (also called cholecalciferol) is the most important of these and is formed in the skin as a result of irradiation of 7-dehydrocholesterol, a substance normally in the skin, by ultraviolet rays from the sun. Consequently, appropriate exposure to the sun prevents vitamin D deficiency. The additional vitamin D compounds that we ingest in food are identical to the cholecalciferol formed in the skin, except for the substitution of one or more atoms that do not affect their function.

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Cholecalciferol Is Converted to 25-Hydroxycholecalciferol in the Liver



The first step in the activation of cholecalciferol is to convert it to 25-hydroxycholecalciferol; this occurs in the liver. The process is limited because the 25-hydroxycholecalciferol has a feedback inhibitory effect on the conversion reactions. This feedback effect is extremely important for two reasons.









First, the feedback mechanism precisely regulates the concentration of 25-hydroxycholecalciferol in the plasma, an effect that is shown in Figure 79-8. Note that the intake of vitamin D3 can increase many times and yet the concentration of 25-hydroxycholecalciferol remains nearly normal. This high degree of feedback control prevents excessive action of vitamin D when intake of vitamin D3 is altered over a wide range.
Second, this controlled conversion of vitamin D3 to 25-hydroxycholecalciferol conserves the vitamin D stored in the liver for future use. Once it is converted, it persists in the body for only a few weeks, whereas in the vitamin D form, it can be stored in the liver for many months.

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Formation of 1,25-Dihydroxycholecalciferol in the Kidneys and Its Control by Parathyroid Hormone









Figure 79-7 also shows the conversion in the proximal tubules of the kidneys of 25-hydroxycholecalciferol to 1,25-dihydroxycholecalciferol. This latter substance is by far the most active form of vitamin D because the previous products in the scheme of Figure 79-7 have less than 1/1000 of the vitamin D effect. Therefore, in the absence of the kidneys, vitamin D loses almost all its effectiveness.









Note also in Figure 79-7 that the conversion of 25-hydroxycholecalciferol to 1,25-dihydroxycholecalciferol requires PTH. In the absence of PTH, almost none of the 1,25-dihydroxycholecalciferol is formed. Therefore, PTH exerts a potent influence in determining the functional effects of vitamin D in the body.

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Calcium Ion Concentration Controls the Formation of 1,25-Dihydroxycholecalciferol


plasma concentration of 1,25-dihydroxycholecalciferol is inversely affected by the concentration of calcium in the plasma. There are two reasons for this. First, the calcium ion itself has a slight effect in preventing the conversion of 25-hydroxycholecalciferol to 1,25-dihydroxycholecalciferol. Second, and even more important, as we shall see later in the chapter, the rate of secretion of PTH is greatly suppressed when the plasma calcium ion concentration rises above 9 to 10 mg/100 ml. Therefore, at calcium concentrations below this level, PTH promotes the conversion of 25-hydroxycholecalciferol to 1,25-dihydroxycholecalciferol in the kidneys. At higher calcium concentrations, when PTH is suppressed, the 25-hydroxycholecalciferol is converted to a different compound-24,25-dihydroxycholecalciferol-that has almost no vitamin D effect.









When the plasma calcium concentration is already too high, the formation of 1,25-dihydroxycholecalciferol is greatly depressed. Lack of this in turn decreases the absorption of calcium from the intestines, the bones, and the renal tubules, thus causing the calcium ion concentration to fall back toward its normal level.

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Hormonal" Effect of Vitamin D to Promote Intestinal Calcium Absorption









1,25-Dihydroxycholecal-ciferol itself functions as a type of "hormone" to promote intestinal absorption of calcium. It does this principally by increasing, over a period of about 2 days, formation of calbindin, a calcium-binding protein, in the intestinal epithelial cells. This protein functions in the brush border of these cells to transport calcium into the cell cytoplasm. Then the calcium moves through the basolateral membrane of the cell by facilitated diffusion. The rate of calcium absorption is directly proportional to the quantity of this calcium-binding protein. Furthermore, this protein remains in the cells for several weeks after the 1,25-dihydroxycholecalciferol has been removed from the body, thus causing a prolonged effect on calcium absorption.









Other effects of 1,25-dihydroxycholecalciferol that might play a role in promoting calcium absorption are the formation of (1) a calcium-stimulated ATPase in the brush border of the epithelial cells and (2) an alkaline phosphatase in the epithelial cells. The precise details of all these effects are unclear.

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Vitamin D Promotes Phosphate Absorption by the Intestines









Although phosphate is usually absorbed easily, phosphate flux through the gastrointestinal epithelium is enhanced by vitamin D. It is believed that this results from a direct effect of 1,25-dihydroxycholecalciferol, but it is possible that it results secondarily from this hormone's action on calcium absorption, the calcium in turn acting as a transport mediator for the phosphate.

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Vitamin D Decreases Renal Calcium and Phosphate Excretion









Vitamin D also increases calcium and phosphate reabsorption by the epithelial cells of the renal tubules, thereby tending to decrease excretion of these substances in the urine. However, this is a weak effect and probably not of major importance in regulating the extracellular fluid concentration of these substances

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Effect of Vitamin D on Bone and Its Relation to Parathyroid Hormone Activity









Vitamin D plays important roles in both bone absorption and bone deposition. The administration of extreme quantities of vitamin D causes absorption of bone. In the absence of vitamin D, the effect of PTH in causing bone absorption (discussed in the next section) is greatly reduced or even prevented. The mechanism of this action of vitamin D is not known, but it is believed to result from the effect of 1,25-dihydroxycholecalciferol to increase calcium transport through cellular membranes.

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Vitamin D in smaller quantities promotes bone calcification. One of the ways in which it does this is to increase calcium and phosphate absorption from the intestines. However, even in the absence of such increase, it enhances the mineralization of bone. Here again, the mechanism of the effect is unknown, but it probably also results from the ability of 1,25-dihydroxycholecalciferol to cause transport of calcium ions through cell membranes-but in this instance, perhaps in the opposite direction through the osteoblastic or osteocytic cell membranes.

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Chemistry of Parathyroid Hormone
PTH has been isolated in a pure form. It is first synthesized on the ribosomes in the form of a preprohormone, a polypeptide chain of 110 amino acids. This is cleaved first to a prohormone with 90 amino acids, then to the hormone itself with 84 amino acids by the endoplasmic reticulum and Golgi apparatus, and finally packaged in secretory granules in the cytoplasm of the cells. The final hormone has a molecular weight of about 9500. Smaller compounds with as few as 34 amino acids adjacent to the N terminus of the molecule have also been isolated from the parathyroid glands that exhibit full PTH activity. In fact, because the kidneys rapidly remove the whole 84-amino acid hormone within minutes but fail to remove many of the fragments for hours, a large share of the hormonal activity is caused by the fragments.

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Effect of Parathyroid Hormone on Calcium and Phosphate Concentrations in the Extracellular Fluid

approximate effects on the blood calcium and phosphate concentrations caused by suddenly infusing PTH into an animal and continuing this for several hours. Note that at the onset of infusion the calcium ion concentration begins to rise and reaches a plateau in about 4 hours. The phosphate concentration, however, falls more rapidly than the calcium rises and reaches a depressed level within 1 or 2 hours. The rise in calcium concentration is caused principally by two effects: (1) an effect of PTH to increase calcium and phosphate absorption from the bone and (2) a rapid effect of PTH to decrease the excretion of calcium by the kidneys. The decline in phosphate concentration is caused by a strong effect of PTH to increase renal phosphate excretion, an effect that is usually great enough to override increased phosphate absorption from the bone

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Parathyroid Hormone Increases Calcium and Phosphate Absorption from the Bone
Rapid Phase of Calcium and Phosphate Absorption from Bone-Osteolysis

When large quantities of PTH are injected, the calcium ion concentration in the blood begins to rise within minutes, long before any new bone cells can be developed. Histological and physiological studies have shown that PTH causes removal of bone salts from two areas in the bone: (1) from the bone matrix in the vicinity of the osteocytes lying within the bone itself and (2) in the vicinity of the osteoblasts along the bone surface.

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One does not usually think of either osteoblasts or osteocytes functioning to cause bone salt absorption, because both these types of cells are osteoblastic in nature and normally associated with bone deposition and its calcification. However, studies have shown that the osteoblasts and osteocytes form a system of interconnected cells that spreads all through the bone and over all the bone surfaces except the small surface areas adjacent to the osteoclasts (see Figure 79-5). In fact, long, filmy processes extend from osteocyte to osteocyte throughout the bone structure, and these processes also connect with the surface osteocytes and osteoblasts. This extensive system is called the osteocytic membrane system, and it is believed to provide a membrane that separates the bone itself from the extracellular fluid.









Between the osteocytic membrane and the bone is a small amount of bone fluid. Experiments suggest that the osteocytic membrane pumps calcium ions from the bone fluid into the extracellular fluid, creating a calcium ion concentration in the bone fluid only one-third that in the extracellular fluid. When the osteocytic pump becomes excessively activated, the bone fluid calcium concentration falls even lower, and calcium phosphate salts are then absorbed from the bone. This effect is called osteolysis, and it occurs without absorption of the bone's fibrous and gel matrix. When the pump is inactivated, the bone fluid calcium concentration rises to a higher level and calcium phosphate salts are redeposited in the matrix.









But where does PTH fit into this picture? First, the cell membranes of both the osteoblasts and the osteocytes have receptor proteins for binding PTH. PTH can activate the calcium pump strongly, thereby causing rapid removal of calcium phosphate salts from those amorphous bone crystals that lie near the cells. PTH is believed to stimulate this pump by increasing the calcium permeability of the bone fluid side of the osteocytic membrane, thus allowing calcium ions to diffuse into the membrane cells from the bone fluid. Then the calcium pump on the other side of the cell membrane transfers the calcium ions the rest of the way into the extracellular fluid.