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FIGURE 9-1 Schematic model of calcium and phosphorus metabolism in an adult man having a calcium intake of 900 mg/day and a phosphorus intake of 900 mg/day. All numerical values are milligrams per day. All entries relating to phosphate are calculated as phosphorus, and are enclosed in ovals. Entries related to calcium are enclosed in rectangles. Modified by permission from Norman, A. W. (1979) "Vitamin D: The Calcium Homeostatic Steroid Hormone," p. 278. Academic Press, New York.

FIGURE 9-1 Schematic model of calcium and phosphorus metabolism in an adult man having a calcium intake of 900 mg/day and a phosphorus intake of 900 mg/day. All numerical values are milligrams per day. All entries relating to phosphate are calculated as phosphorus, and are enclosed in ovals. Entries related to calcium are enclosed in rectangles. Modified by permission from Norman, A. W. (1979) "Vitamin D: The Calcium Homeostatic Steroid Hormone," p. 278. Academic Press, New York.

biological function of oxyphil cells is not known. Under some circumstances of the pathological dysfunction hyperparathyroidism (e.g., parathyroid adenomas and chief cell hyperplasia), the oxyphil cells are believed to secrete PTH.

B. Calcitonin-Secreting Cells

Calcitonin (CT) is secreted by the parafollicular or C cells, which are located in the thyroid glands of higher animals. The anatomical relationship of the C cells to the thyroid follicles varies with the species. The thyroid C cells have been established as being embryologically derived from the neural crest.

In lower vertebrates, including the teleost fish, elasmobranchs, anurans, urodeles, and aves, the calcitonin-secreting C cells are localized in the anatomically distinct ultimobranchial body. The ultimo-branchial body persists as a separate gland in all jawed vertebrates except mammals.

C. Intestine

The morphology and cellular organization of the intestine are superbly adapted to efficiently effect the absorption of dietary constituents, including calcium and phosphorus. The anatomical organization of the intestinal mucosa, which optimizes the surface/volume ratio of the cell and thereby facilitates the intestinal absorptive processes, is discussed in Chapter 8 (see Figure 8-3).

D. Kidney

The kidney is responsible not only for indispensable homeostatic actions with regard to the electrolytes of the body and filtration and removal of nitrogenous wastes, but also as an endocrine gland for several classes of hormones, including the hormonally active forms of vitamin D. The anatomical organization of the kidney is presented in Chapter 15. Shown in Figure 15-4 is the principal site of reabsorption of calcium and phosphorus, as well as the putative sites of action of parathyroid hormone and of vitamin D and/or its metabolites.

The concentration of calcium in the blood, particularly its ionized form, is regulated stringently through complex interactions among (1) the movement of calcium in and out of the bone, (2) its absorption by the intestine, and (3) the renal tubular reabsorption of calcium lost into the renal tubule by glomerular filtration. The kidneys of a typical adult male transfer some 11,000 mg (275 mmol) of calcium per day from the plasma into the glomerular filtrate. However, only 0.5-1.0% of this large amount of filtered calcium is lost into the urine; this is a reflection of the remarkably effective tubular reabsorption mechanism(s) for calcium. Humans normally lose 100-200 mg of calcium daily in the urine. It is known that several nonhormonal factors, as well as parathyroid hormone, vitamin D, and its metabolites, may alter the renal handling and excretory rate of calcium.

From consideration of the fluid dynamics of the kidney, it is possible to postulate that an increase in the urinary excretion of calcium may arise from either decreased tubular reabsorption, increased filtered load of calcium, or both. An increase in the filtered load produced by an elevation in the rate of glomerular filtration normally has only a small effect on calcium excretion. However, an increase in the filtered load produced by hypercalcemia usually will result in a more marked reduction in the tubular reabsorption of this cation.

The concentration of phosphorus in the blood is not regulated as stringently as that of calcium. In the case of phosphate, 40-60% of that available in the diet is absorbed by the intestine. The inorganic phosphate in the blood is also very efficiently filtered at the glomerulus, so that in a typical day «=6000-10,000 mg is transferred from the blood to the glomerular filtrate. Of this amount, the renal tubule reabsorbs 80-90%. Humans normally lose 700-1500 mg of phosphate daily in the urine. Thus, in comparison to calcium, a significantly larger amount of phosphate is excreted on a daily basis (see Figure 9-1). As will become evident later, both parathyroid hormone and vitamin D metabolites play important roles in modulating the amount of phosphate actually excreted in the urine. Under circumstances of dietary phosphate restriction, the kidney becomes very efficient in its tubular reabsorption of phosphate from the glomerular filtrate, thus conserving this important anion for the body. In contrast, in situations of dietary excess, the plasma phosphorus concentrations may become elevated, ultimately resulting in a significant increase in the amount of phosphorus excreted in the urine.

E. Bone

Bone is a complex tissue made up of cells and extracellular material; it is composed of organic and mineral components. The cells are of a wide variety of morphological and functional types, but all have a common origin in the mesenchymal tissue. The principal cell types are the (1) chondrocytes or cartilage cells, which secrete the collagen matrix of the cartilage region, (2) osteoblasts or bone-forming cells, (3) osteoclasts, which are multinucleated giant cells responsible for both bone resorption and bone remodeling at specific sites, and (4) osteocytes, which represent osteoblasts trapped in a mineralized matrix. On a dry weight basis, bone consists of =65-70% inorganic crystals of the salt hy-droxyapatite and 30-35% organic matrix known as osteoid. Of the osteoid, 40% is composed of the extracellular protein collagen.

Figure 9-2 shows a schematic representation of bone organization at both the macro (A) and cellular (B) levels. There are two major categories of bone. Cortical bone is composed of densely packed columns of mineralized collagen laid down in layers and is the major component of tubular bones. Trabecular or cancellous bone is spongy in appearance, providing both strength and elasticity, and is present in the axial (vertebrae) skeleton.

The formation of functional bone tissue can be divided into two phases: (1) that concerned with the production and secretion of the extracellular collagen bone matrix and (2) the deposition of the mineral calcium hydroxyapatite crystals in the matrix. It should be emphasized that bone is a dynamic tissue and that both of these processes occur continuously throughout the life of the skeletal system.

Neither the collagen matrix, the extracellular mineral crystals, nor the several different cell types associated with bone exclusively determine the behavior of the bone tissue. It is a unique combination of the organic and inorganic phases, as well as the particular biochemical properties of these various cell types, that collectively confers on bone both its unusual mechanical properties (to support the weight of the soft tissues

Resorption spaces

Trabecular (cancellous) bone

Lacunae

Cortical (compact) bone

Resorption spaces

Trabecular (cancellous) bone

Lacunae

Articular cartilage zone

Epiphyseal zone

Epiphyseal plate (non-hypertrophic zone)

Epiphyseal plate (hypertrophic cartilage zone)

- Subchondral trabeculae

Articular cartilage zone

Epiphyseal zone

Epiphyseal plate (non-hypertrophic zone)

Epiphyseal plate (hypertrophic cartilage zone)

- Subchondral trabeculae

Cortical (compact) bone

FIGURE 9-2 Schematic representation of bone at the macro and cellular levels of organization. (A) Diagram of some of the main features of the structure of bone seen in both the transverse (top) and longitudinal sections. Areas of cortical (compact) and trabecular (cancellous) bone are indicated. The central area in the transverse section simulates a microradiograph, with the variations in density reflecting variations in mineralization (see also Figure 9-18). Note the distribution of the osteocytic lacunae, Haversian canals, and resorption spaces and the different views of the structural basis of bone Iamellation. Reproduced with permission from "Gray's Anatomy" (R. Warwick and P. L. Williams, eds.), 35th edition, Longman, Philadelphia, 1973. (B) Schematic sagittal section of the proximal portion of a typical long bone. Cartilage cell (chondrocytes) proliferation occurs in the nonhypertrophic zone of the epiphyseal plate. In the bottom portion of the hypertrophic zone, the chondrocytes undergo hypertrophy and degeneration (apoptosis) at the same time as the region becomes vascularized. Calcification first occurs after the invasion of bone-forming osteoblasts, which in turn produces the typical osseous tissue within the template created by the hypertrophic cartilage cells. Reproduced with permission from Norman, A. W., and Hurwitz, S. (1993). /. Nutr. 123,310-316.

of the body) and its ability to serve as a dynamic reservoir for the calcium and phosphate ions needed for mineral homeostasis in the whole organism. Table 93 presents an outline of the elements of bone structure and metabolism.

Bone matrix is biosynthesized, secreted, organized, mineralized, and finally destroyed by reabsorption, all in accordance with the physiological and hormonal signals operative at any particular time. The production of organic matrix by osteoblast cells first involves the intracellular synthesis of protocollagen molecules by the ribosomal system through conventional protein biosynthetic pathways. The protocollagen is then polymerized to yield a three-stranded triple helix, each strand of which has a separate unique amino acid sequence. Next, approximately half of the proline residues and a small number of lysine residues of the protocollagen helix are enzymatically hydroxylated, and these new hydroxyamino acid residues are then glycosylated to yield the macromolecule known as procollagen. The procollagen is secreted into the extracellular space around the osteoblast cells, where it undergoes further conversion to yield tropocollagen via cleavage of an N-terminal fragment of 20,000 Da from each of the three individual peptide genes of the macromolecule. After proteolysis, the tropocollagen molecule is some 15 A in diameter. It immediately undergoes polymerization to yield microfibrils several centimeters in length and consisting of five tropocollagen molecules across the diameter. These microfibril pentamers further polymerize to yield the final form of collagen fibers, which range in diameter from 150 to 1300 A. The polymerization process, although spontaneous, is highly ordered and principally in-

9. Calcium-Regulating Hormones TABLE 9-3 Outline of the Elements of Bone Structure and Metabolism"

I. Structure of bone

A. Macroscopic level

1. Spongiosa or cancellous

2. Cortical bone

B. Microscopic level

1. Collagen fiber distribution a. Woven bone b. Lamellar bone

2. Three-dimensional collagen fiber network a. Trabecular b. Haversian

C. Types of bone cells

1. Osteoprogenitor

2. Osteoblasts

3. Osteoclasts

4. Osteocytes

5. Chondrocytes

II. Inorganic phase of bone

A. Components

1. Crystalline calcium hydroxy apatite

2. Amorphous calcium phosphate

B. Ionic composition

III. Organic phase of bone

A. Collagen

1. Biosynthetic steps a. Intracellular phase i. Protocollagen biosynthesis ii. Protocollagen hydroxylation iii. Glycosylation of protocollagen to yield procollagen b. Extracellular phase i. Conversion of procollagen to tropocollagen ii. Tropocollagen polymerization into microfibrils iii. Polymerization of microfibrils into collagen fibrils iv. Cross-linking of strands of collagen fibers

B. Ground substance

1. Mucopolysaccharide

2. Mucoproteins

C. Bone matrix proteins 1. Osteocalcin

2. Matrix Gla protein (MGP)

3. Osteopontin

4. Bone sialoprotein (BSP)

5. Osteonectin

Occurs in metaphyseal region of long bone and is composed of spicules known as trabeculae; is the most metabolically active region Occurs in cortex and diaphysis of long bone

Composed of loosely and randomly arranged collagen bundles;

predominant in young bones Composed of highly ordered bundles of collagen fibers arranged in layers interspersed between osteocytes; is characteristic of adult bone

Principally characteristic of adult bone

Synonymous with cancellous bone

Occurs as a consequence of remodeling of cortical bone

Synonymous with mesenchymal cells Cells that synthesize and secrete bone matrix Cells that resorb bone; are multinucleate Precise function not known

Cartilage cells; they synthesize and release collagen On a dry-weight basis bone is 65-70% inorganic material

Constitutes 55-60% of bone mineral; molecular formula

[(Ca2+)10.,(H3OK+y(PO43-)6(OH-)2] Constitutes 40-45% of bone mineral; may be formed before crystalline calcium hydroxyapatite, which is then produced with time Other ions include K+, Na+, Mg2+, Sr2+, CI", CO;, F", and citrate3" and many trace constituents On a dry-weight basis bone is 30-35% organic material, often referred to as bone matrix or osteoid

Occurs on ribosome; composed of 20% proline and 33% glycine Specific hydroxylation of 50% of proline and a small number of lysines Procollagen molecular weight is 360,000; is secreted into extracellular space

An N-terminal fragment of procollagen of 20,000 Da is removed;

tropocollagen molecule is 3000 X 15 A 44-A diameter X several centimeters length 150-1300-A diameter X several centimeters length Formation of Schiff bases, followed by aldol condensation 5% bone matrix is ground substance

Major extracellular cellular protein of bone (the sixth most abundant protein in the body); produced by osteoblasts; molecular weight = 13,000; contains -y-carboxyglutamic residues (Gla) A Gla-containing protein; molecular weight = 15,000 Molecular weight = 41,000; contains N- and O-linked oligosaccharides Protein = 33 kDa; contains 50% carbohydrate An acidic glycoprotein; molecular weight = 44,000

a Modified with permission from Norman, A. W. (1979). "Vitamin D: The Calcium Homeostatic Hormone." Academic Press, New York.

volves hydrophobic interactions between adjacent peptide chains. The final phase of formation of mature collagen molecules is the generation of covalent chemical bonds, either by an aldol condensation or by a Schiff base conjugation.

In the normal process of human bone formation, there is usually a delay of 5-10 days between the synthesis of the extracellular organic matrix and its ultimate mineralization. It is believed that the normal coupling time between matrix formation and subsequent mineralization depends on the presence of vitamin D metabolites. After the final secretion of protocollagen by the osteoblasts and the ultimate formation of mature collagen, the osteoblasts differentiate and are incorporated into the bone matrix as osteocytes.

As yet a detailed molecular description of the total calcification process cannot be provided. However, in the final mineralization steps, an extracellular accumulation of calcium and phosphate occurs, which ultimately results in the appearance of amorphous calcium phosphate. This in turn is crystallized into the formal hydroxyapatite structure of bone within the matrix of the mature collagen fibers.

In understanding the hormonal regulation of calcium and phosphorus homeostasis, it is important to appreciate that bone tissue is dynamic, in terms both of the metabolic activity of the various cell populations present and of the kinetics of mineral flux into and out of the various bone compartments. As summarized in Figure 9-1, there are three "compartments" of bone mineral; they represent the various fractions of the total calcium present in bone that can be identified on the basis of radioactive tracer studies (utilizing either radioactive 45Ca2+ or 47Ca2+). These compartments include the readily exchangeable bone mineral compartment, which has both a rapid (20,000 mg/day) and a slow (300 mg/day) component of calcium. The term rapid implies the capability of exchange on a minute-by-minute basis. The third compartment is stable bone mineral and in adult men is composed of approximately 1 kg of calcium. However, the stable bone mineral compartment is not biologically inert, and it is that pool of calcium that participates in the bone remodeling processes associated with bone mineralization (accretion, as in growth) and/or resorption. Both the accretion and resorption processes are those that are affected by the hormonal regulators of calcium metabolism, whereas the rapid and slow exchange pools largely represent chemical equilibria between the bone and the bathing extracellular fluids.

In a normal adult, a remodeling of the stable bone mineral is occurring continuously, such that, on any given day, approximately 300 mg of calcium is resorbed and another 300 mg of calcium is replaced by accretion. Thus, in the normal state there is a balance in the extent of daily bone resorption and bone accretion, leading to no net change in total skeletal calcium content. In contrast, in certain disease states, such as osteoporosis, there can be an imbalance in the daily bone remodeling rates so that there is a small net daily loss of calcium from the skeleton. For example, if bone resorption exceeds bone accretion by only 10 mg/day, when extended for 20 years (e.g., from menopause at age «50 to age «70) there will be 10 mg/day X 365 days X 20 years = 73,000 mg of calcium lost from the skeleton or about 7.3% of the total skeletal calcium content.

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