Extracellular fluid


Deposition (500 mg/day)

Absorption (500 mg/day)

Reabsorption . . (9880 mg/day)



Deposition (500 mg/day)

of the heart, changes in cellular enzyme activities, increased membrane permeability in some cells (in addition to nerve cells), and impaired blood clotting.

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.

Absorption and Excretion of Calcium and Phosphate

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 per cent (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 per cent (900 mg/day) of the daily intake of calcium is excreted in the feces (Figure 79-3).

Intestinal absorption of phosphate occurs very 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.

Renal Excretion of Calcium and Phosphate. Approximately 10 per cent (100 mg/day) of the ingested calcium is excreted in the urine. About 41 per cent 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 per cent) or ionized (50 per cent) and is filtered through the glomeruli into the renal tubules.

Normally, the renal tubules reabsorb 99 per cent of the filtered calcium, and about 100 mg/day is excreted in the urine. Approximately 90 per cent 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 per cent is very

Figure 79-3

Overview of calcium exchange between different tissue compartments in a person ingesting 1000 mg of calcium per day. Note that most of the ingested calcium is normally eliminated in the feces, although the kidneys have the capacity to excrete large amounts by reducing tubular reabsorption of calcium.

selective, depending on the calcium ion concentration in the blood.

When calcium concentration is low, this reabsorption is great, so that 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.

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.

However, as discussed later in the chapter, PTH can greatly increase phosphate excretion by the kidneys, thereby playing an important role in the control of plasma phosphate concentration as well as calcium concentration.

Bone and Its Relation to Extracellular Calcium and Phosphate

Bone is composed of a tough organic matrix that is greatly strengthened by deposits of calcium salts.

Average compact bone contains by weight about 30 per cent matrix and 70 per cent salts. Newly formed bone may have a considerably higher percentage of matrix in relation to salts.

Organic Matrix of Bone. The organic matrix of bone is 90 to 95 per cent 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.

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.

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 extreme compressional strength.

Precipitation and Absorption of Calcium and Phosphate in Bone—Equilibrium with the Extracellular Fluids

Hydroxyapatite Does Not Precipitate in Extracellular Fluid Despite Supersaturation of Calcium and Phosphate Ions. The concentrations of calcium and phosphate ions in extracellular fluid are considerably greater than those required to cause precipitation of hydroxyapatite. However, inhibitors are present in almost all tissues of the body as well as in plasma to prevent such precipitation; one such inhibitor is pyrophosphate. Therefore, hydroxyapatite crystals fail to precipitate in normal tissues except in bone despite the state of supersaturation of the ions.

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 per cent 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


Fibrous periosteum




Fibrous periosteum




Figure 79-4


Figure 79-4

Osteoblastic and osteoclastic activity in the same bone.

natural affinity of the collagen fibers for calcium salts causes the precipitation.

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 the condition called 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.

Calcium Exchange Between Bone and Extracellular Fluid

If soluble calcium salts are injected intravenously, the calcium ion concentration may increase immediately to high levels. However, within 30 minutes to 1 hour or more, the calcium ion concentration returns to normal. Likewise, if large quantities of calcium ions are removed from the circulating body fluids, the calcium ion concentration again returns to normal within 30 minutes to about 1 hour. These effects result in great part from the fact that the bone contains a type of exchangeable calcium that is always in equilibrium with the calcium ions in the extracellular fluids.

A small portion of this exchangeable calcium is also the calcium found in all tissue cells, especially in highly permeable types of cells such as those of the liver and the gastrointestinal tract. However, most of the exchangeable calcium is in the bone. It normally amounts to about 0.4 to 1 per cent of the total bone calcium. This calcium is deposited in the bones in a form of readily mobilizable salt such as CaHPO4 and other amorphous calcium salts.

The importance of exchangeable calcium is that it provides a rapid buffering mechanism to keep the calcium ion concentration in the extracellular fluids from rising to excessive levels or falling to very low levels under transient conditions of excess or decreased availability of calcium.

Deposition and Absorption of Bone—Remodeling of Bone

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 per cent of all surfaces at any given time in an adult), so that at least some new bone is being formed constantly.

Absorption of Bone—Function of the Osteoclasts. Bone is also being continually absorbed in the presence of osteo-clasts, 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 per cent 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 osteo-clasts send out villus-like projections toward the bone, forming a so-called ruffled border adjacent to the bone. 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 solution of the bone salts. The osteoclastic cells also imbibe by phagocytosis minute particles of bone matrix and crystals, eventually also dis-soluting these and releasing the products into the blood.

Bone Deposition and Absorption Are Normally in Equilibrium.

Normally, except in growing bones, the rates of bone deposition and absorption are equal to each other, so that the total mass of bone remains constant. Osteo-clasts usually exist in small but concentrated masses, and once a mass of osteoclasts begins to develop, it usually eats away at the bone for about 3 weeks, creating a tunnel that ranges in diameter from 0.2 to 1 millimeter and is several millimeters long. At the end of this time, the osteoclasts disappear and the tunnel is invaded by osteoblasts instead; then new bone begins to develop. Bone deposition then continues for several months, the new bone being laid down in successive layers of concentric circles (lamellae) on the inner surfaces of the cavity until the tunnel is filled. Deposition of new bone ceases when the bone begins to encroach on the blood vessels supplying the area. The canal through which these vessels run, called the haversian canal, is all that remains of the original cavity. Each new area of bone deposited in this way is called an osteon, as shown in Figure 79-5.

straight, especially in children because of the rapid remodeling of bone at younger ages.

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 bone 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.

Epiphyseal line

Magnified section

Magnified section

Epiphyseal line

Figure 79-5

Structure of bone.

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.

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 per cent 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, and 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

Vitamin D

Vitamin D has a potent effect to increase calcium absorption from the intestinal tract; it also has important effects on both bone deposition and bone absorption, as discussed later. However, vitamin D itself is not the active substance that actually causes these effects. Instead, vitamin D must first be converted through a succession of reactions in the liver and the kidneys to the final active product, 125-dihydroxycholecakifeml, also called 1,25(OH)2D3. Figure 79-6 shows the succession of steps that lead to the formation of this substance from vitamin D. Let us discuss these steps.

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.

Cholecalciferol Is Converted to 25-Hydroxycholecalciferol in the Liver. The first step in the activation of cholecal-ciferol is to convert it to 25-hydroxycholecalciferol; this occurs in the liver. The process is a limited one, 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 79-7. Note that the intake of vitamin D3 can increase many times,


Cholecalciferol (vitamin D3) Liver

I Inhibition




Parathyroid hormone


Intestinal epithelium

Calcium-binding protein

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