Accurate Regulation of Calcium Ion Concentration Is Essential to Normal Function of the Neuromuscular System and the Skeletal System

If the concentration of calcium in the ECF falls to less than 50% of normal for even brief periods, neuromuscular dysfunction of the skeletal muscles results, initially in the form of hyper-reflexivity and finally as tetanic contractions. If calcium ion concentration increases to 50% greater than normal, central nervous system depression occurs, along with slowing of the contractions of the smooth muscle of the gastrointestinal tract.

Calcium is found normally in the ECF in a total concentration of 2.4 mmol/L, or 9.4 mg/dL. In the ECF, 50% of the calcium is in the free divalent cation form, 40% is loosely bound to proteins, and 10% is in the nonionized form.

Phosphate ion concentration in the ECF can vary rather widely without physiologic impact. Phosphate in the ECF can be either monobasic (H₂PO₄⁻) or dibasic (HPO₄²⁻). The normal concentration of H₂PO₄⁻ is 0.26 mmol/L, whereas HPO₄²⁻ is found at a concentration of 1.05 mmol/L. The relative concentrations of the two are affected by the pH of the ECF, with a reduction in pH increasing the amount of H₂PO₄⁻ and decreasing the concentration of HPO₄²⁻. Clinically, total phosphate concentration is usually expressed in milligrams per deciliter and is normally 3 to 4 mg/dL.

Bone Is Composed Mostly of Calcium and Phosphate Salts along with Organic Matrix

Approximately 70% of bone is calcium salts; most is in the form of large crystals of hydroxyapatite, Ca₁₀(PO4)₆(OH)₂. Bone is about 30% organic matrix, made up of collagen fibers and cells. Some calcium in bone is not in crystalline form and therefore is rapidly exchangeable with calcium in the ECF.

Bone Calcification

Bone formation begins with secretion of collagen fibers by osteoblast cells; the uncalcified collagen structure is referred to as osteoid. Calcification of the osteoid takes place over a period of weeks.

Bone Is Continually Deposited by Osteoblasts and Absorbed by Osteoclasts, a Dynamic Process Referred to as Remodeling

Bone has the capacity to undergo remodeling throughout life, although the process takes place much more rapidly in children and young adults than in the elderly. Osteoclast cells digest bone, after which osteoblasts deposit new bone. The balance between the two processes is affected by the following:

The Calcium and Phosphate Present in Bone Serve as Reservoirs for the Ions in the ECF

About 99% of the total body calcium is in bone, whereas less than 1% is in the ECF. If the calcium ion concentration in the ECF falls below normal, calcium ions move from bone into the ECF. The calcium and phosphate distribution in bone and ECF is affected by PTH and 1,25-dihydroxycholecalciferol, which stimulate movement of calcium and phosphate from bone to the ECF, and by calcitonin, which has the opposite effect. Conversely, when the calcium concentration in the ECF increases above normal, calcium can be deposited in the bone.

Parathyroid Hormone Secretion Increases in Response to Reduction in Extracellular Calcium Concentration

The hormone is formed in the chief cells of the parathyroid glands located immediately behind the thyroid gland. The rate of formation of PTH is strongly regulated by the ECF calcium ion concentration; small decreases in the concentration of the ion result in large increases in the rate of PTH formation. If the reduction below the normal level of calcium concentration persists, the parathyroid glands hypertrophy, as occurs with pregnancy and disease states such as rickets that are characterized by inadequate calcium absorption from the gastrointestinal tract.

Increases in PTH Concentration Decrease Renal Calcium Excretion

Normally, more than 99% of calcium filtered at the glomerulus is reabsorbed along the tubule. Approximately 5% of the filtered calcium is reabsorbed in the collecting tubules, and it is calcium transport in this segment that is stimulated by PTH. Other factors that affect calcium excretion include the following.

Increases in PTH Concentration Elevate Phosphate Excretion

Phosphate excretion is regulated as a tubular maximum (T_m) system (see Chapter 29). Approximately 80% is reabsorbed in the proximal tubule, with additional absorption taking place at more distal sites in the nephron. PTH inhibits phosphate reabsorption in the proximal tubule; other factors that affect phosphate excretion include the following.

Calcitonin Secretion Increases in Response to Elevation of the Extracellular Calcium Concentration

The hormone is a polypeptide with 32 amino acids secreted from the parafollicular cells found in the interstitial tissue of the thyroid gland. In general, its effects are opposite those of PTH in the bone and renal tubule, and the magnitude of its effects is much less than that of PTH.

Hypoparathyroidism Decreases Extracellular Calcium Concentration

With inadequate formation of PTH, osteoclasts become inactive and the formation of 1,25-dihydroxycholecalciferol declines to low levels. Transfer of calcium from bone to the ECF decreases, calcium absorption from the gut decreases to low levels, and calcium excretion by the kidneys is greater than the rate of absorption from the gut. As a result, the calcium concentration in the ECF falls below normal levels, and the phosphate concentration remains normal or is elevated. The condition can be treated with very large doses of vitamin D, which have the effect of stimulating gastrointestinal calcium absorption, or by the administration of 1,25-dihydroxycholecalciferol.

Excessive Formation of PTH by the Parathyroid Gland (Hyperparathyroidism) Causes Loss of Calcium from Bone and Increased Extracellular Calcium Concentration

Excessive PTH levels stimulate osteoclastic activity, renal retention of calcium and excretion of phosphate, and increased formation of 1,25-dihydroxycholecalciferol. Calcium concentration in the ECF is greater than normal, and phosphate levels are below normal. The most serious consequences are related to the damage done by excessive osteoclastic absorption of bone, which results in weakening of the bone.

Rickets Is Caused by Inadequate Absorption of Calcium from the Gastrointestinal Tract

This can be due to inadequate calcium in the diet or failure to form adequate amounts of 1,25-dihydroxycholecalciferol. If the kidneys are damaged or absent, 1,25-dihydroxycholecalciferol cannot be formed. Because of inadequate absorption of calcium, PTH levels are elevated, which stimulates osteoclastic resorption of bone and release of calcium to the ECF. In addition, the elevated PTH levels exert renal effects, causing retention of calcium and excretion of phosphate. The net results of these effects are weakening of the bones, a below-normal phosphate concentration, and for periods of months an only slightly below normal calcium concentration resulting from the transfer of calcium from bone to the ECF.

Osteoporosis Is Caused by Depressed Deposition of New Bone by the Osteoblasts

As a result, the rate of osteoclastic resorption of bone exceeds the rate of deposition of new bone.

The most common causes of the condition are (1) lack of physical stress on the bones because of insufficient physical activity; (2) postmenopausal lack of estrogen, because estrogen normally decreases the number and activity of osteoclasts; and (3) old age, in which growth hormone and other factors that contribute to bone formation diminish greatly.

In men, testosterone levels decline gradually but continue to provide a significant anabolic effect into the seventh and eighth decades of life. In women, estrogen formation falls to near zero at menopause, usually at about 50 years of age. The decline in estrogen concentration shifts the balance between deposition and resorption of bone, although no symptoms are apparent for many years. Starting even before menopause, calcium is continually lost from the skeleton. After years of the gradual wasting of calcium, the bones become weakened to the point that symptoms appear, such as vertebral compression and brittleness of the long bones and pelvis. The condition can be prevented with estrogen replacement therapy beginning at menopause. Calcium supplements after menopause are not effective because the condition is not characterized by inadequate calcium in the ECF.

Enamel Makes Up the Outer Layer of the Crown of the Tooth

It is composed of very large, dense crystals of hydroxyapatite embedded in a tight meshwork of protein fibers similar to keratin in hair. The crystalline structure makes the enamel extremely hard, whereas the protein, which is completely insoluble, provides resistance to enzymes, acids, and other corrosive substances.

Dentine Makes Up the Main Body of the Tooth

It is composed of hydroxyapatite crystals embedded in a strong meshwork of collagen fibers, a structure similar to bone. Dentine has no cellular components; all of the nourishment of the structure is provided from odontoblast cells, which line the inner surface of the dentine along the wall of the pulp cavity.

Cementum Is a Bony Substance That Lines the Tooth Socket

It is secreted by the cells of the periodontal membrane. Collagen fibers pass from the bone of the jaw, through the periodontal membrane, and into the cementum. This arrangement provides the firm attachment between the teeth and jaw.

Pulp Is the Tissue that Fills the Pulp Cavity of the Tooth

It is composed of odontoblasts, nerves, blood vessels, and lymphatic vessels. During formation of the tooth, the odontoblasts lay down new dentine along the lining of the pulp cavity, making it progressively smaller.