Chapter 80
ABSORPTION AND EXCRETION OF CALCIUM AND PHOSPHATE
OVERVIEW OF CALCIUM AND PHOSPHATE REGULATION IN THE ECF AND PLASMA
• ECF calcium concentration is normally regulated precisely
• normal value = 9.4 mg/dl (2.4 millimoles of calcium per liter)
• Hypercalcemia = progressive depression of nervous system
• Hypocalcemia = increases excitability of nervous system
• only about 1% of total body calcium is found in ECF
• about 1% in cells; the rest is stored in the bones
CALCIUM IN THE PLASMA AND INTERSTITIAL FLUID
calcium in plasma is present in three forms:
1. 41% = combined with plasma proteins
• non-diffusible through the capillary membrane
2. 9% = diffusible through capillary membrane
• combined with anionic substances of plasma and interstitial fluids
→ citrate
→ phosphate
3. 50% = both diffusible through capillary membrane and ionized.
INORGANIC PHOSPHATE IN THE EXTRACELLULAR FLUIDS
PHOSPHATE IN BODY
→ 85% = stored in bones
→ 14% to 15% = in the cells
→ less than 1% = extracellular fluid
inorganic phosphate is mainly in two forms:
→ HPO4 = 1.05 mmol/L
→ H2PO4 = 0.26 mmol/L
average total quantity of inorganic phosphorus = 4mg/dl
→ 3-4mg/dl in adults
→ 4-5mg/dl in children
NONBONE PHYSIOLOGICAL EFFECTS OF ALTERED CALCIUM
AND PHOSPHATE CONCENTRATIONS IN THE BODY FLUIDS
*Change in level of phosphate in ECF below 2-3x normal = do not cause major immediate effects
→ slight increases or decreases of Ca ion in ECF = cause extreme immediate effects
HYPOCALCEMIA CAUSES NERVOUS SYSTEM EXCITEMENT AND TETANY
• increased permeability of neurons to Na ions
HYPERCALCEMIA DEPRESSES NERVOUS SYSTEM AND MUSCLE ACTIVITY
• blood level of calcium rises above about 12 mg/dl
• can become marked as the calcium level rises above 15 mg/dl
PRECIPITATION AND ABSORPTION OF CALCIUM AND PHOSPHATE IN BONE
• calcium and phosphorus intake = 1000 mg per day
• VITAMIN D = promotes Ca absorption by intestines
→ ~ 35% (350 mg/day) of ingested calcium is absorbed
→ remaining calcium in the intestine is excreted in the feces
• ++250 mg/day of Ca enters intestines via secreted GI juices and sloughed mucosal cells
• ~10% (100 mg/day) of ingested Ca = excreted in urine.
• Renal phosphate excretion = controlled by an overflow mechanism
→ when phosphate concentration in plasma is below critical value of ~1mmol/L
→ all phosphate in glomerular filtrate is reabsorbed
→ no phosphate is lost in the urine
BONE AND ITS RELATION TO EXTRACELLULAR CALCIUM AND PHOSPHATE
BONE
• composed of a tough organic matrix
• greatly strengthened by deposits of calcium salts
• Average compact bone contains by weight about 30 percent matrix and 70 percent salts
• Newly formed bone = higher percentage of matrix in relation to salts
ORGANIC MATRIX OF BONE
• organic matrix of bone = 90 to 95 percent collagen fibers,
→ remainder is called homogeneous gelatinous medium = ground substance
• Collagen Fibers
→ extend primarily along the lines of tensional force
→ give bone its powerful tensile strength
• Ground Substance
→ composed of ECF +++ proteoglycans (chondroitin sulfate and hyaluronic acid
→ help control the deposition of calcium salts
BONE SALTS
• crystalline salts deposited in organic matrix of bone composed principally of:
→ calcium and phosphate
• formula for the major crystalline salt:
→ hydroxyapatite = Ca10 (PO4)6 (OH)2
• Magnesium, sodium, potassium, and carbonate ions
→ also present among bone salts
→ conjugated to hydroxyapatite crystals rather than into distinct crystals of their own.
• strontium, uranium, plutonium, other transuranic elements, lead, gold, other heavy metals.
→ also conjugate to bone crystals
• Deposition of radioactive substances in the bone
→ cause prolonged irradiation of the bone tissues
• if a sufficient amount is deposited
→ osteogenic sarcoma (bone cancer) may eventually develop
—EQUILIBRIUM WITH THE EXTRACELLULAR FLUIDS
• Hydroxyapatite doesn’t Precipitate in ECF Despite Supersaturation of Ca and PO4 Ions
• concentrations of Ca and PO4 ions in ECF
→ considerably greater than those required to cause precipitation of hydroxyapatite
• inhibitors such as pyrophosphate present = prevent precipitation
MECHANISM OF BONE CALCIFICATION
• initial stage in bone production = osteoblasts secretion of:
→ collagen molecules (called collagen monomers)
→ ground substance (mainly proteoglycans)
• formation of osteoid
• importance of the amorphous salts that are not converted in hydroxyapatite
→ fall in extracellular calcium and absorption of amorphous compounds
• Precipitation of calcium in nonoxious tissues under abnormal conditions,
→ form arteriosclerosis and precipitate in blood clots
CALCIUM EXCHANGE BETWEEN BONE AND EXTRACELLULAR FLUID
• bone contains a type of exchangeable calcium that is always in equilibrium with Ca ions
• small portion are found in liver, in GI tract (highly permeable types of cell)
• most of exchangeable Ca can be found in the bone
→ normally amounts to about 0.4% to 1% of total bone Ca in form of readily mobilizable salts
calcium phosphate
→ other amorphous calcium salts.
IMPORTANCE
• provides rapid buffering mechanism
→ keep Ca ion concentration in ECF from rising to excessive levels
→ falling to low levels under transient conditions of excess or decreased availability of Ca
DEPOSITION AND RESORPTION OF BONE—REMODELING OF BONE
DEPOSITION OF BONE BY THE OSTEOBLASTS
Bone
• continually being deposited by osteoblast
• continually being resorbed where osteoclasts are active
OSTEOBLASTS
• outer surfaces of the bones and in the bone cavities
• small amount of osteoblastic activity occurs continually in all living bones
→ 4% of all surfaces at any given time in an adult
• at least some new bone is being formed constantly
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RESORPTION OF BONE—FUNCTION OF THE OSTEOCLASTS
Osteoclasts
→ large, phagocytic, multinucleated cells (containing as many as 50 nuclei)
→ derivatives of monocytes or monocyte-like cells formed in bone marrow
→ normally active on less than 1% of bone surfaces of an adult
• PTH stimulates osteoclast activity and bone resorption indirectly
• osteoblasts signal osteoclast precursors
→ form mature osteoblasts thru RANKL and M- CSF
• RANKL binds to its receptors on preosteoclast cells
→ causing them to differentiate into mature osteoclasts that promote bone resorption
• Osteoblasts also produce PG that inhibits bone resorption
• Vitamin D and PTH - stimulate production of mature osteoclasts
• Glucocorticoids promote osteoclast activity
• Estrogen - stimulates PG production
BONE DEPOSITION AND RESORPTION ARE NORMALLY IN EQUILIBRIUM
• Except in growing bones; rates of bone deposition and resorption are normally equal
• Osteoclasts usually exist in small but concentrated masses
→ usually eat away at the bone for about 3 weeks
→ create a tunnel (diameter = 0.2-1 several m)
→ disappear and tunnel is invaded by osteoblasts and new bone begins to develop
• Bone deposition continues for several months
→ new bone being laid down in successive layers
→ layers are called = LAMELLAE
• Deposition of new bone ceases
→ when bone begins to encroach on the blood vessels supply in the area
• The canal through which these vessels run = Haversian Canal
→ all that remains of the original cavity
→ each area of the bone deposited = OSTEON
VALUE OF CONTINUAL BONE REMODELING
1. bone ordinarily adjusts its strength in portion to degree of bone stress
→ bone thickens when subjected to heavy loads
→ those in athletes, the weightlifting athletes; they have bigger bone and stronger bones
2. shape of the bone can be rearranged for proper support of mechanical forces
→ by deposition and resorption of bone in accordance with stress patterns
3. old bone becomes relatively brittle and weak, new organic matrix is needed
→ how the normal toughness of bone is contained
• bones of children with rapid rates of deposition and absorption = show little brittleness
→ in comparison with bones of elderly in whom rates of deposition and resorption are slow
CONTROL OF THE RATE OF BONE DEPOSITION BY BONE “STRESS”
1. Bone is deposited in proportion to the compressional load that the bone is carrying
2. Bone stress also determines the shape of bones under certain circumstances.
VITAMIN D
Cholecalciferol
• is formed in skin as a result of irradiation of 7-dehydrocholesterol by UV rays.
• vitamin D compounds we ingest in food = identical to vitamin D3 formed in skin.
• cholecalciferol is activated to convert it to 25 hydroxycholecalciferols = occurs in liver.
→ 25-hydroxycholecalciferol directly inhibits its own information
• PTH acts on 25-dihydroxycholecalciferol =occurs in kidney
• 125-dihydroxycholecalciferol is formed which is the most active form of vitamin D
• Calcium levels in versatile affects its formation
→ calcium increases = inhibits PTH
ACTIONS OF VITAMIN D
1. “Hormonal” Effect of Vitamin D to Promote Intestinal Calcium Absorption
→ Increasing (about 2 days) = formation of CALBINDIN; calcium-binding protein
2. Vitamin D Promotes Phosphate Absorption by the Intestines
3. Vitamin D Decreases Renal Calcium and Phosphate Excretion
4. Vitamin D Decreases Renal Calcium and Phosphate Excretion
PARATHYROID HORMONE
• four parathyroid glands = located behind thyroid gland
→ 1 behind each of the upper and the lower poles of the thyroid
→ each gland is about 6x3x2 mm
→ macroscopic appearance of apparent dark brown fats
• difficult to locate during thyroid operations = often look like just another lobule
• total or subtotal thyroidectomy = they are frequently removed as well
• removal of half of parathyroid glands = no major physiological abnormalities
• removal of 3 out of 4 normal glands = transient hypoparathyroidism
• even a small quantity of remaining parathyroid tissue
→ usually capable of hypertrophying to satisfactorily perform
• parathyroid gland of adult human being
→ contains chief cells and a small amount of oxyphil cells.
• oxyphil cells are absent in many animals
• in young humans
→ chief cells = believed to secrete most, if not all, of PTH
• function of oxyphil cells
→ not certain
→ believed to modify or deplete chief cells that no longer secrete hormones
EFFECT OF PTH ON CALCIUM AND PHOSPHATE CONCENTRATIONS IN THE ECF
• calcium and phosphate concentrations in response to introduction of a PTH
• start of infusion calcium levels begins to rise and reaches a plateau in about 4 hours
→ phosphate falls more rapidly and reaches a depressed level within an hour or 2 hours.
• rise in calcium concentration is caused mainly by two effects:
1. an effect of PTH to increase calcium and phosphate absorption from the bone
2. a rapid effect of PTH to decrease the excretion of calcium by the kidneys
PARATHYROID HORMONE MOBILIZES CALCIUM AND PHOSPHATE FROM THE BONE
RAPID PHASE
• begins in minutes and increases progressively for several hours
• results from activation of the already existing bone cells (mainly osteocytes)
→ = to promote calcium and phosphate release
SLOW PHASE
• requires several days or even weeks to become fully developed
• results from proliferation of osteoclasts
• followed by greatly increased osteoclastic resorption of bone itself
• bone and the activation of osteoclasts occurs in two stages:
1. immediate activation of the osteoclasts that are already formed
2. formations of the osteoclast
*Several days of excess PTH = osteoclastic system become well developed
→ but it can continue to grow for months under the influence of strong PTH stimulation
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PTH DECREASES CA EXCRETION AND INCREASES PHOSPHATE EXCRETION BY KIDNEYS Calcitonin has a weak effect on plasma calcium concentration in the adult human because: EFFECTS OF HYPERCALCEMIA IN HYPERPARATHYROIDISM

PTH: 1. initial reduction of the calcium ion concentration caused by calcitonin leads within hours • Hyperparathyroidism = cause the plasma calcium level to rise to 12 to 15 mg/dl
before powerful stimulation of PTH secretion, which overrides the calcitonin effect
• decreases proximal tubular reabsorption of phosphate ions. 1. depression of the central and peripheral nervous systems
2. daily rates of absorption and deposition of calcium are small and even after the rate of 2. muscle weakness
• increases tubular reabsorption of calcium absorption is slowed by calcitonin, this still only has a very small effect on plasma calcium 3. constipation
→ while decreasing phosphate reabsorption ion concentration 4. abdominal pain
5. peptic ulcer
• increases the absorption of magnesium ions hydrogen ions SUMMARY OF CONTROL OF CALCIUM ION CONCENTRATION 6. lack of appetite
→ while decreasing absorption of sodium, potassium and amino acids 7. depressed relaxation of the heart during diastole
• Amount of calcium used is as much as 0.3 grams/hour
• increased calcium reabsorption occurs mainly in: → addition or subtraction of this = serious hyperkalemia or hypocalcemia. PARATHYROID POISONING AND METASTATIC CALCIFICATION
→ distal tubules
→ collecting tubules FIRST LINE OF DEFENSE: BUFFERING FUNCTION OF EXCHANGEABLE CALCIUM IN BONES KIDNEYS cannot excrete all phosphate being absorbed from bone rapidly enough
→ collecting ducts • calcium salts are easily deposited and easily resolved that any change in the calcium 
→ ascending loop of Henle concentration causes a rapid response to maintain the equilibrium calcium and phosphate in the body fluids = greatly supersaturated

PTH INCREASES INTESTINAL ABSORPTION OF CALCIUM AND PHOSPHATE SECOND LINE OF DEFENSE: HORMONAL CONTROL OF CALCIUM ION CONCENTRATION calcium phosphate crystals begin to deposit in:
• PTH greatly enhances both calcium and phosphate absorption • PTH and calcitonin: Increase calcium concentration, PTH decreases, calcitonin increases
• increasing formation in kidneys of 1,25-dihydroxycholecalciferol from vitamin D causing rapid deposition of calcium in bones 1. alveoli of the lungs
2. kidneys
CONTROL OF PARATHYROID SECRETION BY CALCIUM ION CONCENTRATION PATHOPHYSIOLOGY OF PARATHYROID HORMONE, VITAMIN D, AND BONE DISEASE 3. thyroid gland
4. stomach
• PTH secretion is controlled by plasma concentrations of calcium HYPOPARATHYROIDISM 5. walls of the arteries throughout the body

• Increased activity of the parathyroid glands in pregnancy and lactation • parathyroid glands do not secrete sufficient PTH • extensive metastatic deposition of calcium and phosphate = develop within a few days
→ causes increase in gland size • osteocytic resorption of exchangeable calcium decreases → form = kidney stones
→ osteoclasts become almost totally inactive.
• increase plasma Ca levels = decreased activity and reduced size of glands FORMATION OF KIDNEY STONES IN HYPERPARATHYROIDISM
→ activities such as: • Hypoparathyroidism = Hypocalcemia
1. excess quantities of calcium in the diet • excess calcium and phosphate absorbed from intestines or mobilized from bones
2. increased vitamin D in the diet treatment of hypoparathyroidism with PTH and vitamin D → cause an increase in concentration in the urine
3. bone resorption (such as misuse of the bones) → PTH is occasionally used to treat hypoparathyroidism
• crystals of calcium and calcium phosphate and calcium oxalate precipitate in kidneys
SUMMARY OF EFFECTS OF PARATHYROID HORMONE PRIMARY HYPERPARATHYROIDISM → form kidney stones
• cause = tumor of one of the parathyroid glands;
1. PTH stimulates bone resorption, causing release of calcium into the extracellular fluid • occur much more frequently in women than in men or children • calcium oxalate stones = 60% to 80% of all kidney stones
→ mainly because pregnancy and lactation stimulate parathyroid glands • calcium phosphate stones = 10% of all kidney stones.
2. PTH increases reabsorption of calcium and decreases phosphate reabsorption by the renal → therefore, predispose to the development of such a tumor
tubules, leading to decreased excretion of calcium and increased excretion of phosphate SECONDARY HYPERPARATHYROIDISM
BONE DISEASE IN HYPERPARATHYROIDISM.
3. Necessary for conversion of 25-hydroxycholecalciferol to 1,25 dihydroxycholecalciferols, • high levels of PTH occur = compensation for hypocalcemia rather than as a primary
which, in turn, increases calcium absorption by the intestines • new bone can be deposited rapidly enough to compensate for increased osteoclastic abnormality of parathyroid gland
resorption of bone in persons with mild hyperparathyroidism
• It can be caused by vitamin D deficiency chronic renal disease in which the damaged
CALCITONIN • severe hyperparathyroidism kidneys are unable to produce sufficient amounts of the active form of vitamin D, 1,25
• peptide hormone secreted by parafollicular or C cells in thyroid gland → osteoclastic absorption outstrips osteoblastic deposition dihydroxycholecalciferols
• tends to decrease plasma calcium concentration → bone may be eaten away almost entirely
RICKETS
CALCITONIN DECREASES PLASMA CALCIUM CONCENTRATION • cystic bone disease of hyperparathyroidism = OSTEITIS FIBROSA CYSTICA
→ bone where we see large holes or the bubble • Vitamin D deficiency results from calcium or phosphate deficiency in ECF
1. The immediate effect → bones that are eaten away • plasma Ca concentration only slightly depressed; level of phosphate is greatly depressed
decrease the absorptive activities of the osteoclasts and possibly the osteolytic effect of
the osteocytic membrane throughout the bone • Osteoblastic activity in the bones • Prolonged cases = weaker bones; marked physical stress = rapid osteoblastic activity
• increases to form new bone to make up for old bone absorbed by osteoclastic activity
2. The more prolonged effect of calcitonin • Tetany almost never occurs early in the disease
decrease the formation of new osteoclasts. • When the osteoblasts become active = secrete large quantities of alkaline phosphatase. = bones become exhausted of calcium = level of calcium may fall rapidly = tetany develops
• important diagnostic finding = high plasma alkaline phosphatase
• Treatment: calcium & phosphate in the diet; vitamin D

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OSTEOMALACIA CEMENTUM DEVELOPMENT OF THE PERMANENT TEETH.

• Adult rickets • Bony substance secreted by cells of the periodontal membrane; lines the tooth socket • During embryonic life
• Adults seldom have a dietary deficiency of it D or calcium → tooth-forming organ develops in deeper dental lamina
• Serious deficiency of vit D or calcium = result of steatorrhea (failure to absorb fat) • When teeth are exposed to excessive strain → for each permanent tooth that will be needed after the deciduous teeth are gone
→ layer of cementum becomes thicker and stronger → slowly form the permanent teeth throughout the first 6 to 20 years of life
• Osteomalacia caused by renal diseases
→ Renal rickets • It increases in thickness and strength with age • When each permanent tooth becomes fully formed:
→ Congenital hypophosphatemia → causing teeth to become more firmly seated in the jaws by adulthood and later → like the deciduous tooth, pushes outward through the bone.
→ erodes the root of the deciduous tooth = causes it to loosen and fall out
OSTEOPOROSIS PULP
METABOLIC FACTORS INFLUENCE DEVELOPMENT OF THE TEETH
• Most common of all bone diseases in adults, especially in old age • Composed of connective tissue
• Accelerated by both thyroid and growth hormones.
• Different from osteomalacia and rickets • Has an abundant supply of nerve fibers, blood vessels, and lymphatics
• Deposition of salts in the early forming teeth affected by:
• results from diminished organic bone matrix rather than from poor bone calcification. • The cells lining the surface of the pulp cavity = ODONTOBLASTS 1. availability of calcium and phosphate in the diet
→ lay down the dentin 2. amount of vitamin D present
• osteoblastic activity in the bone is usually less than normal → at the same time encroach more and more on the pulp cavity, making it smaller 3. rate of PTH secretion
→ rate of bone osteoid deposition is depressed
→ cause of the diminished bone = osteoclastic activity. • Odontoblasts are still viable and send projections into small dentinal tubules that • When all these factors are normal = dentin and enamel will be correspondingly healthy
penetrate all the way through the dentin; they are of importance for exchange of calcium, • When they are deficient = calcification of teeth also may be defective and abnormal
Common causes of osteoporosis are: phosphate, and other minerals with the dentin
(1) lack of physical stress MINERAL EXCHANGE IN TEETH
(2) malnutrition DENTITION
(3) lack of vitamin C. • Deposition and absorption occur mainly in dentin and cementum; limited extent in enamel
(4) post-menopausal • first teeth = deciduous teeth, or milk teeth; number 20 in humans
(5) old age → erupt between the seventh month and the second year of life • The rate of absorption and deposition of minerals in the cementum
(6) Cushing syndrome → last until the sixth to the 13th year → equal to that in the surrounding bone of the jaw

PHYSIOLOGY OF THE TEETH
• functional parts of the tooth
• divided into the:
→ CROWN = visible part
→ ROOT = one embedded in the gums
ENAMEL
• outer layer; composed of large and dense crystals of hydroxyapatite
→ embedded in a fine meshwork of strong and almost insoluble protein fibers
→ similar in physical characteristics but not chemically identical to the keratin in hair
• crystalline structure of the salt makes the enamel extremely hard; much harder than dentin
• protein fiber meshwork about 1% of the enamel masks
→ makes the enamel resistant to acids, enzymes, and other corrosive agents
• this protein is one of the most insoluble and resistant proteins known
DENTIN
• main body of the tooth; strong bony structure
• made up principally of hydroxyapatite crystals
→ similar to those in bone, but much denser
→ these crystals are also embedded in a strong meshwork of collagen fibers
• Adult: 28-32 permanent teeth (4 wisdom teeth appear or not)
FORMATION OF TEETH
invagination of the oral epithelium into the dental lamina

followed by the development of a tooth producing organ
• epithelial cells above form ameloblasts
→ form the enamel on the outside of the tooth
• epithelial cells below invaginate upward into middle of tooth
→ form pulp cavity and the odontoblasts that secrete dentin
• enamel is formed on the outside of the tooth
• dentin is formed on the inside
ERUPTION OF TEETH
• During early childhood:
→ teeth begin to protrude outward from bone through oral epithelium into mouth
• cause of "eruption" is unknown = most likely theory is that growth of tooth root and bone
underneath tooth progressively shoves tooth forward
• The rate of deposition and absorption of minerals in the dentin
→ one third that of bone
In summary, continual mineral exchange occurs in the dentin and cementum of teeth, although
the mechanism of this exchange in dentin is unclear. However, enamel exhibits extremely slow
mineral exchange, so it maintains most of its original mineral complement throughout life
DENTAL ABNORMALITIES
CARIES
• Caries result from the action of bacteria Streptococcus mutans.
• Plaque deposition, a film of precipitated products of saliva and food, on the teeth is
inhabited by bacteria
• Fluorine makes the teeth about 3x as resistant to caries
MALOCCLUSION
• Usually caused by a hereditary abnormality that causes teeth of one jaw to grow to
abnormal positions
• The teeth do not interdigitate properly and therefore cannot perform their normal grinding
or cutting action adequately

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