Overview of Calcium and Phosphate Regulation in the Extracellular Fluid and Plasma
Extracellular fluid calcium concentration normally is regulated very precisely, seldom rising or falling more than a few percent from the normal value of about 9.4 mg/dl, which is equivalent to 2.4 mmol calcium per liter. This precise control is essential, because calcium plays a key role in many physiologic processes, including contraction of skeletal, cardiac, and smooth muscles; blood clotting; and transmission of nerve impulses, to name just a few. Excitable cells, such as neurons, are very sensitive to changes in calcium ion concentrations, and increases in calcium ion concentration above normal (hypercalcemia) cause progressive depression of the nervous system; conversely, decreases in calcium concentration (hypocalcemia) cause the nervous system to become more excited. An important feature of extracellular calcium regulation is that only about 0.1 per cent of the total body calcium is in the extracellular fluid, about 1 per cent is in the cells, and the rest is stored in bones. Therefore, the bones can serve as large reservoirs, releasing calcium when extracellular fluid concentration decreases and storing excess calcium.
Approximately 85 per cent of the body’s phosphate is stored in bones, 14 to 15 per cent is in the cells, and less than 1 per cent is in the extracellular fluid. Although extracellular fluid phosphate concentration is not nearly as well regulated as calcium concentration, phosphate serves several important functions and is controlled by many of the same factors that regulate calcium.

Calcium in the plasma and interstitial fluid

The calcium in the plasma is present in three forms;

(1) About 41 per cent (1 mmol/L) of the calcium is combined with the plasma proteins and in this form is non-diffusible through the capillary membrane. (2) About 9 per cent 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. (3) The remaining 50 per cent 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.

Inorganic phosphate in the extracellular fluids

Inorganic phosphate (PO4) in the plasma is mainly in two forms: HPO4- and H2PO4-. The conc. of HPO4- is about 1.05 mmol/L, and the concentration of H2PO4- is about 0.26 mmol/L. When the total quantity of PO4 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 HPO4- and a decrease in H2PO4-, whereas the opposite occurs when the extracellular fluid becomes alkaline. Because it is difficult to determine chemically the exact quantities of HPO4- and H2PO4- in the blood, ordinarily the total quantity of PO4 is expressed in terms of mg 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.

Non-bone physiologic effects of altered ca and po4 concentrations in the body fluids

Changing the level of phosphate in the extracellular fluid from far below normal to two to three times normal does not cause major immediate effects on the body. In contrast, even slight increases or decreases of calcium ion in the extracellular fluid can cause extreme immediate physiologic effects. In addition, chronic hypocalcemia or hypophosphatemia greatly decreases bone mineralization.

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. 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, 1,25-dihydroxycholecalciferol.

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 (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 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 cholecalciferol is to convert it to 25-hydroxycholecalciferol; this occurs in the liver. 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.

Formation of 1,25-dihydroxycholecalciferol in kidneys and its control by Parathyroid. Conversion of 25-hydroxycholecalciferol to 1,25- dihydroxycholecalciferol takes place in proximal tubules of the kidneys. This latter substance is by far the most active form of vitamin D. Therefore, in the absence of kidneys, vitamin D loses almost all its effectiveness.
Conversion of 25- hydroxycholecalciferol to 1,25-dihydroxycholecalciferol requires Parathyroid hormone (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.

Calcium ion concentration controls the formation of 1,25- dihydroxycholecalciferol. Calcium ion itself has a slight effect in preventing the conversion of 25-hydroxycholecalciferol to 1,25-dihydroxycholecalciferol. Even more important, 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.

Actions of Vitamin D: The active form of vitamin D, 1,25-dihydroxycholecalciferol, has several effects on the intestines, kidneys, and bones that increase absorption of calcium and phosphate into the extracellular fluid and contribute to feedback regulation of these substances.

“Hormonal” effect of Vitamin D to promote intestinal calcium absorption. 1,25-dihydroxycholecalciferol 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 a calcium-binding protein in the intestinal epithelial cells. 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.

Vitamin D promotes phosphate absorption by the intestine. 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.

Vitamin D decreases renal calcium and phosphate excretion. Vitamin D also increases calcium and phosphate absorption 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.

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. 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 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.

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.
 

Parathyroid Hormone

PTH provides a powerful mechanism for controlling extracellular calcium and phosphate concentrations by regulating intestinal reabsorption, renal excretion, and exchange of these ions between the extracellular fluid and the bone. Excess activity of the parathyroid gland causes rapid absorption of calcium salts from the bones, with resultant hypercalcemia in the extracellular fluid; conversely, hypofunction of the parathyroid glands causes hypocalcemia, often with resultant tetany.

Physiologic anatomy of the parathyroid glands. Normally there are four parathyroid glands in humans, located immediately behind the thyroid gland. Each parathyroid gland is about 6 mm long, 3 mm wide, and 2 mm thick and has a macroscopic appearance of dark brown fat. Removal of half the parathyroid glands usually causes no major physiologic abnormalities. However, removal of three of the four normal glands causes transient hypoparathyroidism. But even a small quantity of remaining parathyroid tissue is usually capable of hypertrophying satisfactorily to perform the function of all the glands.

The parathyroid gland of the adult human being, contains mainly chief cells and a small to moderate number of oxyphil cells, but oxyphil cells are absent in many animals and in young humans. The chief cells are believed to secrete most, if not all, of the PTH. Function of oxyphil cells is not certain, but believed as modified or depleted chief cells that could’t secrete hormone.

Chemistry of PTH: 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 is 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.

Effect of PTH on Ca and PO4 concentrations in extracellular fluid

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.

PTH increases calcium and phosphate absorption from the bone

PTH has two effects on bone in causing absorption of calcium and phosphate. One is a rapid phase that begins in minutes and increases progressively for several hours. This phase results from activation of the already existing bone cells (mainly the osteocytes) to promote calcium and phosphate absorption. The second phase is a much slower one, requiring several days or even weeks to become fully developed; it results from proliferation of the osteoclasts, followed by greatly increased osteoclastic reabsorption of the bone itself, not merely absorption of the calcium phosphate salts from the bone.

PTH decreases Ca excretion and increases phosphate excretion by the kidneys

Administration of PTH causes rapid loss of PO4 in the urine owing to the effect of the hormone to diminish proximal tubular reabsorption of phosphate ions. PTH also increases renal tubular reabsorption of Ca at the same time that it diminishes PO4 reabsorption. Moreover, it increases the rate of reabsorption of magnesium ions and hydrogen ions while it decreases the reabsorption of sodium, potassium, and amino acid ions in much the same way that it affects phosphate. The increased calcium absorption occurs mainly in the late distal tubules, the collecting tubules, the early collecting ducts, and possibly the ascending loop of Henle to a lesser extent. Were it not for the effect of PTH on the kidneys to increase calcium reabsorption, continual loss of calcium into the urine would eventually deplete both the extracellular fluid and the bones of this mineral.

PTH increases intestinal absorption of calcium and phosphate: As discussed earlier, the PTH greatly enhances both calcium and phosphate absorption from the intestine by increasing the formation of 1,25-dihydroxycholecalciferol from vitamin D in the kidneys.

cAMP mediates the effects of PTH: A large share of the effect of PTH on its target organs is mediated by the cyclic adenosine monophosphate (cAMP) second messenger mechanism. Within a few minutes after PTH administration, the concentration of cAMP increases in the osteocytes, osteoclasts, and other target cells. This cAMP in turn is probably responsible for such functions as osteoclastic secretion of enzymes and acids to cause bone reabsorption and formation of 1,25 dihydroxycholecalciferol in the kidneys. There are probably other direct effects of PTH that function independently of the second messenger mechanism.

Control of parathyroid secretion by calcium ion concentration

Even the slightest decrease in calcium ion concentration in the extracellular fluid causes the parathyroid glands to increase their rate of secretion within minutes; if the decreased calcium concentration persists, the glands will hypertrophy, sometimes 5-fold or more. For instance, the parathyroid glands become greatly enlarged in rickets, in which the level of Ca is usually depressed only a small amount; also, they become greatly enlarged in pregnancy, even though the decrease in calcium ion concentration in the mother’s extracellular fluid is hardly measurable; and are greatly enlarged during lactation because Ca is used for milk formation.

Conversely, conditions that increase the calcium ion concentration above normal cause decreased activity and reduced size of the parathyroid glands. Such conditions include (1) excess quantities of Ca in the diet, (2) increased vitamin D in the diet, and (3) bone absorption caused by factors other than PTH (for example, bone absorption caused by disuse of the bones). Even small decreases in calcium concentration from the normal value can double or triple the plasma PTH. The approximate chronic effect that one finds when the calcium ion concentration changes over a period of many weeks, thus allowing time for the glands to hypertrophy greatly, is shown by the dashed red line; this demonstrates that a decrease of only a fraction of a milligram per deciliter in plasma calcium concentration can double PTH secretion. This is the basis of the body’s extremely potent feedback system for longterm control of plasma calcium ion concentration.

                                                Calcitonin
A peptide hormone secreted by the thyroid gland, tends to decrease plasma-Ca concentration and, in general, has effects opposite to those of PTH. However, the quantitative role of calcitonin is far less than that of PTH in regulating calcium ion concentration. Calcitonin is a 32-amino acid peptide with a molecular weight of about 3400.

Increased plasma calcium concentration stimulates calcitonin secretion: The primary stimulus for calcitonin secretion is increased plasma calcium ion concentration. This contrasts with PTH secretion, which is stimulated by decreased Ca concentration. In young animals, but much less so in older animals and in humans, an increase in plasma-Ca concentration of about 10% causes an immediate 2-fold or more increase in the rate of secretion of calcitonin. This provides a second hormonal feedback mechanism for controlling the plasma calcium ion concentration, but it is relatively weak and works in a way opposite that of the PTH system.

Calcitonin decreases plasma calcium concentration: In some young animals, calcitonin decreases blood calcium ion concentration rapidly, beginning within minutes after injection of the calcitonin, in at least two ways.

1. The immediate effect is to decrease the absorptive activities of the osteoclasts and possibly the
osteolytic effect of the osteocytic membrane throughout the bone, thus shifting the balance in favor of deposition of calcium in the exchangeable bone calcium salts.

2. The second and more prolonged effect of calcitonin is to decrease the formation of new osteoclasts. Calcitonin also has minor effects on calcium handling in the kidney tubules and the intestines, again the effect that is opposite those of PTH.

Calcitonin has a weak effect on plasma calcium concentration in the adult human: The reason for the weak effect of calcitonin on plasma Ca is 2-fold. First, any initial reduction of the calcium ion concentration caused by calcitonin leads within hours to a powerful stimulation of PTH secretion, which almost overrides the calcitonin effect. When the thyroid gland is removed and calcitonin is no longer secreted, the long-term blood calcium ion concentration is not measurably altered, which again demonstrates the overriding effect of the PTH system of control. Second, in the adult, the daily rates of absorption and deposition of Ca are small, and even after the rate of absorption is slowed by calcitonin, this still has only a small effect on plasma calcium ion concentration. The effect of calcitonin in children is much greater because bone remodeling occurs rapidly in children, with absorption and deposition of Ca as great as 5 grams or more per day—equal to 5 to 10 times the total Ca in all the extracellular fluid. Also, in certain bone diseases, such as Paget’s disease, in which osteoclastic activity is greatly accelerated, calcitonin has a much more potent effect of reducing the Ca absorption.

Hormonal control of calcium ion concentration—the second line of defense: At the same time that the exchangeable Ca mechanism in the bones is “buffering” the Ca in the extracellular fluid, both the parathyroid and the calcitonin hormonal systems are beginning to act. Within 3 to 5 minutes after an acute increase in the calcium ion concentration, the rate of PTH secretion decreases. In prolonged Ca excess or prolonged Ca deficiency, only the PTH mechanism seems to be really important in maintaining a normal plasma calcium ion concentration. When a person has a continuing deficiency of Ca in the diet, PTH often can stimulate enough Ca absorption from the bones to maintain a normal plasma calcium ion concentration for 1 year or more, but eventually, even the bones will run out of Ca. Thus, in effect, the bones are a large buffer reservoir of Ca that can be manipulated by PTH. Yet, when the bone reservoir either runs out of Ca or, oppositely, becomes saturated with Ca, the long-term control of extracellular calcium ion concentration resides almost entirely in the roles of PTH and vitamin D in controlling Ca absorption from the gut and Ca excretion in the urine.

Pathophysiology of PTH, Vitamin D, and bone disease

Hypoparathyroidism: When the parathyroid glands do not secrete sufficient PTH, the osteocytic reabsorption of exchangeable Ca decreases and the osteoclasts become almost totally inactive. As a result, Ca reabsorption from the bones is so depressed that the level of Ca in the body fluids decreases. Yet, because Ca and phosphates are not being absorbed from the bone, the bone usually remains strong. When the parathyroid glands are suddenly removed, the Ca level in the blood falls from the normal of 9.4 mg/dl to 6 to 7 mg/dl within 2 to 3 days, and the blood-PO4 concentration may double. When this low Ca level is reached, the usual signs of tetany develop. Among the muscles of the body especially sensitive to tetanic spasm are the laryngeal muscles. Spasm of these muscles obstructs respiration, which is the usual cause of death in tetany unless appropriate treatment is applied.

Treatment of Hypoparathyroidism with PTH and Vitamin D. PTH is occasionally used for treating hypoparathyroidism. However, because of the expense of this hormone, because its effect lasts for a few hours at most, and because the tendency of the body to develop antibodies against it makes it progressively less and less effective, hypoparathyroidism is usually not treated with PTH administration. In most patients with hypoparathyroidism, the administration of extremely large quantities of vitamin D, to as high as 100,000 units per day, along with intake of 1 to 2 grams of Ca, keeps the calcium ion concentration in a normal range. At times, it might be necessary to administer 1,25-dihydroxycholecalciferol instead of non-activated form of vitamin D because of its much more potent and rapid action. This can also cause unwanted effects, because it is sometimes difficult to prevent over-activity by this activated form of vitamin D.

Primary Hyperparathyroidism: In this condition, an abnormality of the parathyroid glands causes inappropriate, excess PTH secretion. The cause of primary hyperparathyroidism ordinarily is a tumor of one of the parathyroid glands; such tumors occur much more frequently in women than in men or children, mainly because pregnancy and lactation stimulate the parathyroid glands and therefore predispose to the development of such a tumor.

Hyperparathyroidism causes extreme osteoclastic activity in the bones. This elevates the calcium ion concentration in the extracellular fluid while usually depressing the concentration of phosphate ions because of increased renal excretion of PO4.

Bone Disease in Hyperparathyroidism: Although in mild hyperparathyroidism new bone can be deposited rapidly enough to compensate for the increased osteoclastic reabsorption of bone, in severe hyperparathyroidism the osteoclastic absorption soon far outstrips osteoblastic deposition, and the bone may be eaten away almost entirely. Indeed, the reason a hyperparathyroid person seeks medical attention is often a broken bone. Radiographs of the bone show extensive decalcification and, occasionally, large punched-out cystic areas of the bone that are filled with osteoclasts in the form of so-called giant cell osteoclast “tumors.” Multiple fractures of the weakened bones can result from only slight trauma, especially where cysts develop. Osteoblastic activity in the bones also increases greatly in a vain attempt to form enough new bone to make up for the old bone absorbed by the osteoclastic activity. When the osteoblasts become active, they secrete large quantities of alkaline phosphatase. Therefore, one of the important diagnostic findings in hyperparathyroidism is a high level of plasma alkaline phosphatase.

Effects of Hypercalcemia in Hyperparathyroidism: Hyperparathyroidism can at times cause the plasma-Ca level to rise to 12 to 15 mg/dl and, rarely, even higher. The effects of such elevated Ca levels are depression of the central and peripheral nervous systems, muscle weakness, constipation, abdominal pain, peptic ulcer, lack of appetite, and depressed relaxation of the heart during diastole.

Parathyroid poisoning and metastatic calcification: When, on rare occasions, extreme quantities of PTH are secreted, the level of Ca in the body fluids rises rapidly to high values. Even the extracellular fluid phosphate concentration often rises markedly instead of falling, probably because the kidneys cannot excrete rapidly enough all the PO4 being absorbed from the bone. Therefore, the Ca and PO4 in the body fluids become greatly supersaturated, so that calcium phosphate (CaHPO4) crystals begin to deposit in the alveoli of the lungs, tubules of the kidneys, the thyroid gland, acid-producing area of the stomach mucosa, and the walls of the arteries throughout the body. This extensive metastatic deposition of calcium phosphate can develop within a few days. Ordinarily, the level of Ca in the blood must rise above 17 mg/dl before there is danger of parathyroid poisoning, but once such elevation develops along with concurrent elevation of PO4, death can occur in only a few days.

Formation of Kidney Stones in Hyperparathyroidism: Most patients with mild hyperparathyroidism show few signs of bone disease and few general abnormalities as a result of elevated Ca, but they do have an extreme tendency to form kidney stones. The reason is that the excess Ca and PO4 absorbed from the intestines or mobilized from the bones in hyperparathyroidism must eventually be excreted by the kidneys, causing a proportionate increase in the concentrations of these substances in the urine. As a result, crystals of calcium phosphate tend to precipitate in the kidney, forming calcium phosphate stones. Also, calcium oxalate stones develop because even normal levels of oxalate cause Ca precipitation at high Ca levels. Because the solubility of most renal stones is slight in alkaline media, the tendency for formation of renal calculi is considerably greater in alkaline urine than in acid urine. For this reason, acidotic diets and acidic drugs are frequently used for treating renal calculi.

Secondary Hyperparathyroidism: In secondary hyperparathyroidism, high levels of PTH occur as a compensation for hypocalcemia rather than as a primary abnormality of the parathyroid glands. This contrasts with primary hyperparathyroidism, which is associated with hypercalcemia. Secondary hyperparathyroidism can be caused by vitamin D deficiency or chronic renal disease in which the damaged kidneys are unable to produce sufficient amounts of the active form of vitamin D, 1,25- dihydroxycholecalciferol.

Rickets—Vitamin D deficiency: Occurs mainly in children due to Ca or PO4 deficiency in the extracellular fluid, usually caused by lack of vitamin D. If the child is adequately exposed to sunlight, the 7-dehydrocholesterol in the skin becomes activated by the ultraviolet rays and forms vitamin D3, which prevents rickets by promoting Ca and PO4 absorption from the intestines. Children who remain indoors through the winter in general do not receive adequate quantities of vitamin D without some supplementation in the diet. Rickets tends to occur especially in the spring months because vitamin D formed during the preceding summer is stored in the liver and available for use during the early winter months. Also, Ca and PO4 absorption from the bones can prevent clinical signs of rickets for the first few months of vitamin D deficiency.

Rickets weakens the bones: During prolonged rickets, the marked compensatory increase in PTH secretion causes extreme osteoclastic absorption of the bone; this in turn causes the bone to become progressively weaker and imposes marked physical stress on the bone, resulting in rapid osteoblastic activity as well. Consequently, the newly formed, uncalcified, and weak osteoid gradually takes the place of the older bone that is being reabsorbed.

Treatment of Rickets: The treatment of rickets depends on supplying adequate Ca and PO4 in the diet and, equally important, on administering large amounts of vitamin D.

Osteomalacia—“Adult Rickets”: Adults seldom have a serious dietary deficiency of vitamin D or Ca because large quantities of Ca are not needed for bone growth as in children. However, serious deficiencies of both vitamin D and Ca occasionally occur as a result of steatorrhea (failure to absorb fat) because vitamin D is fat-soluble and Ca tends to form insoluble soaps with fat; consequently, in steatorrhea, both vitamin D and Ca tend to pass into the feces. Under these conditions, an adult occasionally has such poor Ca and PO4 absorption that adult rickets can occur causing of severe bone disability.