Physiology: Parathyroid Hormone, Calcitonin, Bone Turnover

Intestinal absorption of phosphate

Almost all the dietary phosphate is absorbed into the blood from the gut and later excreted in the urine

CALCIUM EXCHANGE BETWEEN BONE AND EXTRACELLULAR FLUID

If large quantities of Ca2+ are added to or removed from the circulating body fluids, the Ca2+ concentration again returns to normal within 30 minutes to about 1 hour • Bone contains a type of exchangeable calcium that is always in equilibrium with Ca2+ in the ECFs A small portion of the exchangeable calcium is found in all tissue cells, especially in highly permeable types of cells (liver and the GIT) Most of the exchangeable calcium (CaHPO4 and other amorphous calcium salts) is in the bone, comprising about 0.4% to 1% of the total bone calcium Exchangeable calcium provides a rapid buffering mechanism to keep Ca2+ concentration in the ECFs from rising to excessive levels or falling to low levels

Estrogen stimulates

OPG production (inhibits bone resorption)

Administration of extreme quantities of vitamin D cause:

resorption of bone -- effect of 1,25(OH)2 D to increase calcium transport through cellular membranes

Total or subtotal thyroidectomy frequently resulted in removal of the parathyroid glands as well. Effects of removal of parathyroid gland:

- 4 parathyroid glands, immediately behind the thyroid Removal of half the parathyroid glands usually causes no major physiological abnormalities; capable of hypertrophying to perform function even in small quantity Removal of three of the four normal glands causes transient hypoparathyroidism

"Hormonal" Effect of Vitamin D to Promote Intestinal Calcium Absorption

1,25(OH)2 D promotes intestinal absorption of calcium mainly by increasing formation of calbindin (a calcium-binding protein) in intestinal epithelial cells

Repair of a Fracture Activates Osteoblasts

Fracture of a bone maximally activates all the periosteal and intraosseous osteoblasts involved in the break Bone stress accelerates fracture healing by osteoblastic activity at the break and often shortens convalescence

SUMMARY OF CONTROL OF CALCIUM ION CONCENTRATION

In diarrhea, several grams of calcium can be secreted in the intestinal juices and lost into the feces each day After ingestion of large quantities of calcium, particularly when there is also excess vitamin D activity, a person may absorb as much as 0.3 gram in 1 hour The total quantity of calcium in all the ECF of about 1 gram and addition or subtraction of 0.3 gram to or from such a small amount of calcium in the ECF would cause serious hypercalcemia or hypocalcemia

Osteoporosis—Decreased Bone Matrix

MC bone disease - diminished organic bone matrix rather than from poor bone calcification; ↓ Osteoblastic activity → ↓rate of bone osteoid deposition - hyperparathyroidism, the cause of the diminished bone is ↑osteoclastic activity The many common causes of osteoporosis : 1. lack of physical stress on the bones because of inactivity 2. malnutrition →↓ protein matrix 3. lack of vitamin C (necessary for formation of osteoid) postmenopausal lack of estrogen secretion (estrogens decrease the number and activity of osteoclasts) old age, in which GH and other growth factors diminish greatly and many of the protein anabolic functions also deteriorate with age Cushing syndrome, because massive quantities of GCs secreted →↓ deposition of protein and ↑catabolism of protein and depressing osteoblastic activity

Bone-resorbing osteoclast cells do not have PTH receptors; so can't be stimulated by PTH. If PTH indirectly stimulates osteoclasts, how does this occur?

OSTEOBLASTS ARE STIMULATED BY PTH --> OSTEOBLASTS SIGNAL OSTEOCLAST PRECURSORS TO FORM MATURE OSTEOCLASTS MOA: - PTH stimulates synthesis of RANKL by osteoblasts - RANKL binds to its receptors (RANK) on preosteoclast cells→ differentiate into mature multinucleated osteoclasts which then develop a ruffled border and release enzymes and acids that promote bone resorption (STIMULATES OSTEOCLAST TO BE VERY ACTIVE AND SECRETE CHEMICALS RESULTING IN ACCUMULATION OF CALCIUM AND PHOSPHATE = BONE RESORPTION) HOW DOES OSTEOBLAST BALANCE THIS OUT? Osteoblasts produce osteoprotegerin (OPG) or osteoclastogenesis inhibitory factor a cytokine that inhibits bone resorption OPG acts as a "decoy," by binding to RANKL and preventing it from interacting with its receptor, thereby inhibiting differentiation of preosteoclasts into mature osteoclasts that resorb bone

Bone Deposition and Resorption Are Normally in Equilibrium

Once a mass of osteoclasts begins to develop, it usually eats away at the bone for about 3 weeks, creating a tunnel The tunnel is invaded by osteoblasts, and new bone begins to develop Bone deposition continues for several months 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 (haversian canal) is all that remains of the original cavity and each new area of bone deposited is called an osteon

Hyperparathyroidism

Primary: tumor of one of the parathyroid glands; issue is with parathyroid gland itself ; women > men because pregnancy and lactation stimulate the parathyroid glands (when you hypersecrete PTH there's increase growth, cells, PTH = tumor - associated with hypercalcemia - hyperplasia - carcinoma - multiple endocrine neoplasia Hyperparathyroidism causes extreme osteoclastic activity in the bones (resorption)→ ↑Ca2+ concentration (hypercalcemia) in the ECF and ↓the concentration of phosphate ions secondary hyperparathyroidism: high levels of PTH occur as a compensation for hypocalcemia; can be caused by vitamin D deficiency or chronic renal disease in which the active form of vitamin D is insufficient The vitamin D deficiency leads to osteomalacia (inadequate mineralization of the bones), and high levels of PTH cause absorption of the bones

T/F: Calcitonin tends to decrease plasma calcium concentration

True

hypercalcemia causes

depression of NS; inhibit PTH release

Bone Disease in Hyperparathyroidism

• In severe hyperparathyroidism, the bone may be eaten away almost entirely • A broken bone is often the reason a person with hyperparathyroidism seeks medical attention • Bone extensive decalcification and large punched-out cystic areas filled with osteoclasts in the form of giant cell osteoclast "tumors" are seen • The cystic bone disease of hyperparathyroidism is called osteitis fibrosa cystica • 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 which is an important diagnostic finding in hyperparathyroidism

What happens as a result of the NS becoming excited

- NS becomes excited by PTH, which increases neuronal membrane permeability to sodium ions

How does Calcitonin Decreases Plasma Calcium Concentration

(1) decrease the absorptive activities of the osteoclasts and osteolytic effect of the osteocytic membrane; shifting the balance in favor of deposition of calcium in the exchangeable bone calcium salts (2) (prolonged effect) decrease formation of new osteoclasts (inhibit osteoclasts activity; increase osteoblast - and the osteoblast are going to be taking the calcium from the blood and deposit it into the bone) followed by decreased numbers of osteoblasts and little prolonged effect on plasma Ca2+ concentration

The rise in Ca2+ concentration is caused mainly by two effects:

1. PTH - increase Ca2+ and phosphate absorption from the bone 2. decrease excretion of calcium by the kidneys

Two forms of inorganic phosphate in plasma:

HPO4= and H2PO4− *affected by pH; inversely related

Parathyroid Poisoning and Metastatic Calcification

Hyperparathyroidism can cause plasma calcium level to rise to 12 to 15 mg/dl which causes depression of the CNS and PNS, muscle weakness, constipation, abdominal pain, peptic ulcer, lack of appetite, and depressed relaxation of the heart during diastole When extreme quantities of PTH are secreted, the levels of calcium and phosphate in the body fluids rise rapidly to high values The calcium and phosphate in the body fluids become greatly supersaturated, and calcium phosphate (CaHPO4) crystals begin to deposit in the alveoli of the lungs, the tubules of the kidneys, the thyroid gland, the acid-producing area of the stomach mucosa, and the walls of the arteries throughout the body, metastatic calcification (Ca 2+>17 mg/dl ) When Ca 2+ elevation develops along with concurrent elevation of phosphate, death can occur in only a few days

T/F: When Ca2+ concentration is low, almost no Ca2+ is lost in the urine

True

What promotes Ca2+ absorption by intestines?

Vitamin D

Hormonal Control of Calcium Ion Concentration —The Second Line of Defense

While the exchangeable calcium mechanism in the bones is "buffering" the calcium in the ECF, both the parathyroid and the calcitonin hormonal systems are beginning to act Within 3 to 5 minutes after an acute increase in the Ca2+ concentration, the rate of PTH secretion decreases and calcitonin increases • In young children, the calcitonin causes rapid deposition of calcium in the bones In prolonged calcium excess or prolonged calcium deficiency, only the PTH mechanism seems to be important in maintaining a normal plasma Ca2+ concentration When the bone reservoir either runs out of calcium or becomes saturated with calcium, the long-term control of extracellular Ca2+ concentration resides in controlling calcium absorption from the gut and calcium excretion in the urine

What happens to HPO4= and H2PO4− when the pH of the ECF becomes more acidic? alkaline?

acidic relative increase in H2PO4− and a decrease in HPO4= (acidic: increase "2" -- decrease "O" phosphate) alkaline relative decrease in H2PO4− and a increase in HPO4= ("alk": decrease 2 -- increase "O") *does not cause major immediate effects on the body

Bone is deposited in proportion to the compressional load that the bone must carry. Therefore, the rate of bone deposition is controlled by:

bone "stress" *Continual physical stress stimulates osteoblastic deposition and calcification of bone

Why is the effect of Calcitonin so much greater in CHILDREN than ADULT?

bone remodeling occurs rapidly in children, with absorption and deposition of calcium as great as 5 grams or more per day In Paget's disease, in which osteoclastic activity is greatly accelerated, calcitonin has a much more potent effect of reducing the calcium absorption

Types of bone

cortical (compact) bone - denser - 80% of total bone mass - thick in the shaft of long bones (legs) trabecular (spongy) bone - 20% of bone mass - interior of skeletal bones and vertebrae - usually located on ends of bones

Glucocorticoids promote

osteoclast activity and bone resorption by increasing RANKL production and decreasing formation of OPG

Calcitonin synthesis occurs in

parafollicular cells, or C cells of the thyroid gland

The osteoblast secretes:

(1) nucleotide pyrophosphatase phosphodiesterase 1 (NPP1), which produces pyrophosphate outside the cells *NPP1 POOLS IN ECF (2) ankylosis protein (ANK), which contributes to the extracellular pool of pyrophosphate by transporting it from the interior to the surface of the cell *ANK BRINGS TO SURFACE Under abnormal conditions, calcium salts precipitate in arterial walls in arteriosclerosis → arteries become bonelike tubes - calcium salts deposit in degenerating tissues or in old blood clots

Plasma concentration of 1,25(OH)2 D is inversely affected by the concentration of Ca2+ in the plasma:

- Ca2+ has a slight effect in preventing conversion of 25-(OH) D3 to 1,25(OH)2 D - PTH secretion is greatly suppressed when plasma Ca2+ concentration rises above 9 to 10 mg/100 ml Conversely, *low levels of Ca2+ concentrations, increase PTH, which promotes conversion of 25-(OH) D to 1,25(OH)2 D in the kidneys *higher Ca2+ concentrations, *when PTH is suppressed, 25-(OH) D is converted to 24,25(OH)2 D, that has almost no vitamin D effect

PTH Decreases Calcium Excretion and Increases Phosphate Excretion by the Kidneys and Increases Intestinal Absorption of Calcium and Phosphate

Administration of PTH causes rapid loss of phosphate in the urine PTH - increases reabsorption of magnesium ions and hydrogen ions while it - decreases reabsorption of sodium, potassium, and amino acid ions The increased calcium reabsorption occurs mainly in the thick ascending loop of Henle and distal tubules PTH greatly enhances both calcium and phosphate absorption from the intestines by increasing formation in the kidneys of 1,25-(OH)2 D from vitamin D cAMP mediates the effects of PTH. PTH increases the concentration of cAMP in the osteocytes and osteoclasts which is probably responsible for such functions as osteoclastic secretion of enzymes and acids to cause bone resorption and formation of 1,25-(OH)2 D in the kidneys

Highlights

Serum [Ca++] is determined by the rate of Ca absorption by the gastrointestinal tract, bone formation and resorption, and renal excretion. Serum Ca2+ smaller range • Serum [Pi] is determined by the rate of Pi absorption by the gastrointestinal tract, soft tissue influx and efflux, bone formation and resorption, and renal excretion. Serum [Pi] normally fluctuates over a relatively wider range. • The major physiological hormones regulating serum [Ca++] and [Pi] are PTH, 1,25-dihydroxyvitamin D (calcitriol), and FGF23. • Vitamin D is synthesized from 7-dehydrocholesterol in skin in the presence of UVB light or acquired in the diet. It is hydroxylated to 25- hydroxycholecalciferol in the liver and activated by renal 1α-hydroxylase to 1,25-dihydroxyvitamin D. 1,25-Dihydroxyvitamin D promotes intestinal Ca ++ absorption and modestly increases Pi absorption. • The flux of Ca++ and Pi into and out of bone is determined by the relative rates of osteoblastic bone formation and osteoclastic bone resorption. • The PTH/PTHrP receptor is expressed on osteoblasts, • not on osteoclasts. PTH has both anabolic and catabolic actions in bone depending on the dose and timing of administration. PTH promotes bone resorption by upregulation of M- CSF and RANKL in osteoblasts. • 8. 1,25-Dihydroxyvitamin D binds to the VDR in osteoblasts to support osteoclast differentiation via RANKL and promotes bone mineralization by maintaining appropriate serum [Ca++] and [Pi].

Renal reabsorption of calcium

The renal tubules reabsorb 99% of the filtered Ca2 (controlled by PTH); - 90% reabsorbed in the proximal tubules, loops of Henle, and early distal tubules - 10% reabsorbed in late distal tubules and early collecting ducts, depending on the Ca2+ concentration in the blood

Two osteoblast proteins responsible for this signaling OSTEOCLAST

receptor activator for nuclear factor κB ligand (RANKL) and macrophage colony-stimulating factor (MCSF) *both necessary for formation of mature osteoclasts

Importance of continual bone remodeling:

- bones thicken when subjected to heavy loads - shape of the bone can be rearranged for proper support of mechanical forces by deposition and resorption of bone in accordance with stress patterns - new organic matrix is needed as the old organic matrix degenerates

Renal phosphate excretion (reduced tubular reabsorption) is controlled by: *phosphate will excrete in the blood

- overflow mechanism; altering the rate of phosphate excretion - PTH increases phosphate excretion by the kidney ***playing an important role in the control of plasma phosphate and Ca2+ concentrations

The feedback inhibitory effect of 25-(OH) D is extremely important for two reasons:

-regulates concentration of 25-(OH) D in the plasma which prevents excessive action of vitamin D - conserves the vitamin D stored in the liver for future use (vitamin D can be stored in the liver for many months)

Calcium in the plasma :

1. Ca2+ is combined with plasma proteins (non-diffusible through the capillary membrane; 41%) "protein bond calcium" 2. Ca2+ diffusible through the capillary membrane, then combine with anionic substances in plasma and interstitial fluids (citrate and phosphate); non-ionized (9%) 3. the remaining 50% of the Ca2+ in plasma is diffusible through the capillary membrane and ionized - MOST IMPORTANT *ionic calcium most important for functions of Ca2+ in the body, including the effect of Ca2+ on the heart, the nervous system, and bone formation

T/F: Ca2+ ions are greatly absorbed from the intestines

False poorly absorbed; About 35% (350 mg/day) absorbed; the remaining Ca2+ in the intestine is excreted in the feces; 10% excreted in urine

Deficiencies of NPP1 or ANK cause

decreased extracellular pyrophosphate and excessive calcification of bone (bone spurs) or even calcification of tendons and ligaments of the spine, which occurs in people ankylosing spondylitis (a form of arthritis)

Why does Calcitonin Has a Weak Effect on Plasma Calcium Concentration in Adult Humans?

- Calcitonin not secreted when thyroid gland is removed - daily rates of absorption (osteoclastic) and deposition (osteoblastic) is small; small effect on ECF Ca2+ conc.

Tetany or carpopedal spasm (tetany of hand) is caused by

- Hypocalcemia - the peripheral nerve fibers discharge spontaneously, causing tetanic muscle contraction; occurs when the blood concentration of Ca2+< 6 mg/dl, and it is usually lethal at about 4 mg/dl hypocalcemia also causes seizures (on occasion) - increasing excitability in the brain

Excitable cells (neurons) are sensitive to changes in Ca2+ concentrations, therefore hypocalcemia causes

- NS becomes more excitable; strong PTH release - increased permeability to sodium ions (initiation of APs) (decrease CA2+ --> increase PTH --> increase NA+ permeability

What happens during HYPERCALCEMIA?

- Nervous system becomes depressed - Reflex activities of CNS are sluggish - Muscle activity becomes depressed - decreases the QT interval of the heart - cause lack of appetite and constipation *appear when the blood level of Ca2+>12 mg/dl, and they can become marked as the Ca2+ >15 mg/dl *When the Ca2+ >17 mg/dl in the blood, calcium phosphate crystals are likely to precipitate throughout the body

Function of the Osteoclasts

- Resorption of Bone *pull nutrient out into plasma - secrete: 1. proteolytic enzymes 2. several acids, including citric acid and lactic acid

Osteomalacia—"Adult Rickets" (deficiency in BOTH)

- deficiencies of both vitamin D ANDcalcium occasionally occur as a result of steatorrhea (failure to absorb fat), in steatorrhea, vitamin D and calcium tend to pass into the feces Rickets in adults almost never proceeds to the stage of tetany but often is a cause of severe bone disability "Renal rickets" is a type of osteomalacia that results from prolonged kidney damage and failure to form 1,25-(OH)2 D Renal disease can lead to rickets and osteomalacia is congenital hypophosphatemia (due to reduced reabsorption of phosphates by the kidney) vitamin D-resistant rickets

Purpose of Tensile and Compressional Strength of Bone:

- prevents "shear" in the bone - collagen fibers of bone have great tensile strength; collagen fiber of cortical (compact) bone is composed repeating, overlapping segments and hydroxyapatite crystals lie adjacent and overlap as well; tightly bound - the Ca2+ salts have great compressional strength

Deposition of radioactive substances in the bone can cause:

- prolonged irradiation of the bone tissues - osteogenic sarcoma (bone cancer) if longer duration

Mechanism of Bone Calcification

- secretion of collagen molecules (collagen monomers) and ground substance (mainly proteoglycans) by osteoblasts - collagen monomers polymerize rapidly to form collagen fibers --> tissue becomes osteoid (cartilage-like material differing from cartilage in that Ca2+ salts readily precipitate in it) - some osteoblasts become entrapped in the osteoid and become quiescent (osteocytes) - Ca2+ salts begin to precipitate on the surfaces of the collagen fibers - The initial Ca2+ salts to be deposited are amorphous compounds (noncrystalline), a mixture of salts such as CaHPO4 × 2H2O, Ca3(PO4)2 × 3H2O, and others which are converted into the hydroxyapatite crystals over a period of weeks or months - Amorphous form can be absorbed rapidly when there is a need for extra Ca2+ in the ECF

BONE AND ITS RELATIONSHIP TO EXTRACELLULAR CALCIUM AND PHOSPHATE

- trabeculae (in trabecular bones) are filled with red bone marrow where hematopoiesis occurs Bone is composed of a tough organic matrix that is greatly strengthened by deposits of Ca2+ salts; cortical bone contains about 30% matrix and 70% salts Newly formed bone has higher percentage of matrix in relation to salts

The main effects of increased PTH secretion: *PTH regulates calcium

1) PTH stimulates bone resorption, causing release of calcium into the ECF 2) PTH increases calcium reabsorption and decreases phosphate reabsorption by the renal tubules 3) PTH is necessary for conversion of 25-hydroxycholecalciferol to 1,25- dihydroxycholecalciferol, which increases calcium absorption by the intestines

Deposition of Bone by the Osteoblasts

Bone is continually being deposited by osteoblasts, and it is continually being resorbed where osteoclasts are active Osteoclasts are: - large, phagocytic, multinucleated cells - active on <1% of the bone surfaces of an adult Osteoblasts are: - found on the outer surfaces of the bones and in the bone trabecular cavities - A small amount of osteoblastic activity occurs continually - take CA, phosphates etc. and deposit it into bone

The crystalline salts (bone salts) are composed principally of

Ca2+ and phosphate *Other ions that conjugate to bone crystals: strontium, uranium, plutonium, lead, and gold

Calcitonin provides a second (relatively weak) hormonal feedback mechanism for:

ECF calcium ion concentration; Calcitonin tends to decrease plasma calcium concentration

The organic matrix of bone is 90% to 95% collagen fibers, and remainder is ground substance. What is ground substance composed of:

ECF plus proteoglycans (chondroitin sulfate and hyaluronic acid); help control the deposition of Ca2+ salts and are important in bone repair after injury -- The relative ratio of Ca2+ to phosphorus can vary markedly under different nutritional conditions, with the Ca2+ to phosphorus ratio on a weight basis varying between 1.3 and 2.0 • Mg2+, Na+, K+, and carbonate ions are also present among the bone salts

CONTROL OF PARATHYROID SECRETION BY CALCIUM ION CONCENTRATION

Even the slightest decrease in Ca2+ concentration in the ECF causes the parathyroid glands to increase PTH secretion within minutes; if the decreased calcium concentration persists, the glands will hypertrophy The parathyroid glands become greatly enlarged in persons with rickets and during pregnancy and lactation Conditions that increase the Ca2+ concentration cause decreased activity and reduced size of the parathyroid glands: (1) excess quantities of calcium in the diet, (2) increased vitamin D in the diet, and (3) bone resorption caused by factors other than PTH (disuse of the bones) Changes in ECF Ca2+ concentration are detected by CSR in parathyroid cell membranes (a GPCR ), when stimulated by Ca2+, activates phospholipase C and increases intracellular IP3 and DAG, stimulating release of calcium from intracellular stores The acute effect when the calcium concentration is changed over a period of a few hours and even small decreases in calcium concentration from the normal value can double or triple the plasma PTH The approximate chronic effect when Ca2+ concentration changes over a period of many weeks, thus allowing time for the glands to hypertrophy greatly, which demonstrates that a decrease of only a fraction of a milligram per deciliter in plasma calcium concentration can double PTH secretion

Excess calcium and phosphate must eventually be excreted by the kidneys, causing a proportionate increase in the concentrations of these substances in the urine. What can result in the process?

Formation of Kidney Stones in Hyperparathyroidism Crystals of calcium phosphate tend to precipitate in the kidney, forming calcium phosphate stones and calcium oxalate stones The tendency for formation of renal calculi is greater in alkaline urine than in acid urine, acidotic diets and acidic drugs are frequently used to treat renal calculi

Hypoparathyroidism

In Hypoparathyroidism , the osteocytic resorption of exchangeable calcium decreases, and the osteoclasts become almost totally inactive → ↓the level of calcium in the body fluids Sudden removal of parathyroid glands decreases the calcium level in the blood to 6 to 7 mg/dl and the blood phosphate concentration may double Low calcium level causes tetany especially in the laryngeal muscles which obstructs respiration and causes death • PTH is occasionally used to treat hypoparathyroidism PTH is expensive and its effect lasts for a few hours at most, and the tendency of the body to develop antibodies against it makes it progressively less and less effective Administration of extremely large quantities of vitamin D, along with intake of 1 to 2 grams of calcium, keeps the calcium ion concentration in a normal range • Action of 1,25-(OH)2 D is much more potent and much more rapid

Most important factor controlling the reabsorption of Ca2+ concentration in the distal portion of nephron?

PTH

What stimulates osteoclast activity and bone resorption through an indirect mechanism?

PTH *PTH indirectly increases calcium in the body. HOW?

PTH effect on ECF and Phosphate concentrations

Parathyroid Hormone Mobilizes Calcium and Phosphate From Bone • PTH has two effects to mobilize calcium and phosphate from bone: ❖Rapid phase - activation of the already existing bone cells (mainly the osteocytes) to promote calcium and phosphate release = OSTEOLYSIS PTH causes removal of bone salts from two areas in bone: (1) from the bone matrix in the vicinity of osteocytes lying within the bone and (2) in the vicinity of osteoblasts along the bone surface Osteoblasts or osteocytes are normally associated with bone deposition and its calcification The osteoblasts and osteocytes form a system of interconnected cells that spreads all through the bone and over all the bone surfaces except the small surface areas adjacent to the osteoclasts Long, filmy processes extend from osteocyte to osteocyte throughout the bone structure and connect with the surface osteocytes and osteoblasts (osteocytic membrane system), and provides a membrane that separates the bone from the ECF Between the osteocytic membrane and the bone is a small amount of bone fluid The osteocytic membrane pumps Ca2+ from the bone fluid into the ECF, creating a Ca2+ concentration in the bone fluid only one- third that in the ECF When the osteocytic pump becomes excessively activated, the bone fluid calcium concentration falls even lower, and calcium phosphate salts are then released from the bone (osteolysis) and it occurs without resorption of the bone's fibrous and gel matrix • PTH function: The cell membranes of both the osteoblasts and the osteocytes have PTH receptors which activates the calcium pump and rapid removal of calcium phosphate salts from the amorphous bone crystals ❖PTH stimulates the pump by increasing the calcium permeability of the bone fluid side of the osteocytic membrane, thus allowing calcium ions to diffuse into the membrane cells from the bone fluid and then the calcium pump on the other side of the cell membrane transfers the calcium ions the rest of the way into the ECF ❖slower phase - proliferation of the osteoclasts, followed by greatly increased osteoclastic resorption of bone, not merely release of the calcium phosphate salts from the bone The osteoclasts do not themselves have membrane receptors for PTH • The activated osteoblasts and osteocytes send secondary "signals" to the osteoclasts A major secondary signal is RANKL, which activates receptors on preosteoclast cells and transforms them into mature osteoclasts Activation of the osteoclastic system occurs in two stages: (1) immediate activation of the osteoclasts that are already formed and (2) formation of new osteoclasts Chronic osteoclastic resorption of bone can lead to weakened bones and secondary stimulation of the osteoblasts that attempt to correct the weakened state The late effect is to enhance both osteoblastic and osteoclastic activity with more bone resorption than bone deposition in the presence of continued excess PTH Prolonged administration or excess secretion of PTH results in resorption in all the bones and even development of large cavities filled with large, multinucleated osteoclasts

Rickets Caused by Vitamin D Deficiency

Rickets occurs mainly in children and results from calcium or phosphate deficiency in the ECF, usually caused by lack of vitamin D The plasma calcium concentration in rickets is only slightly depressed, but the level of phosphate is greatly depressed, because the parathyroid glands prevent the calcium level from falling by promoting bone resorption whenever the calcium level begins to fall During prolonged cases of rickets, the marked compensatory increase in PTH secretion causes extreme osteoclastic bone resorption which causes the bone to become progressively weaker The osteoblasts lay down large quantities of osteoid, which does not become calcified In the late stages of rickets, when the bones finally become exhausted of calcium, calcium concentration may fall rapidly As the blood level of calcium <7 mg/dl, the usual signs of tetany develop, and the child may die of tetanic respiratory spasm Treatment with supplying adequate calcium and phosphate in the diet and administering large amounts of vitamin D

Buffer Function of the Exchangeable Calcium in Bones —The First Line of Defense

The exchangeable calcium salts in the bones, are amorphous calcium phosphate compounds (mainly CaHPO4) loosely bound in the bone - increase in ECF Ca2+ and phosphate ions above normal causes immediate deposition of exchangeable salt and AND - decrease in ECF Ca2+ and phosphate ions causes immediate absorption of exchangeable salt About one-half of any excess calcium that appears in the ECF is removed by the buffer function of the bones in about 70 minutes The mitochondria of many of the tissues of the body, especially of the liver and intestine, contain a significant amount of exchangeable calcium (an additional buffer system )

Vitamin D in smaller quantities promotes

calcification -- by increasing calcium and phosphate absorption from the intestines

What is stored in bones?

calcium phosphate *Phosphate is controlled by many of the same factors that regulate calcium

The parathyroid gland of the adult human being contains mainly

chief cells (secrete most PTH) and a small # oxyphil cells

Roles of calcium

contraction of skeletal cardiac contraction of smooth muscle blood clotting transmission of nerve impulses

Function of proteolytic enzymes: (and acids)

digest or dissolve the organic matrix of the bone, and the acids cause dissolution of the bone salts

ACTIONS OF VITAMIN D

effects on the intestines, kidneys, and bones that increase absorption of calcium and phosphate into the ECF and contribute to feedback regulation of these substances The vitamin D receptor forms a complex with another intracellular receptor, the retinoid-X receptor, and this complex binds to DNA and activates transcription Vitamin D receptor affinity for 1,25(OH)2 D is roughly 1000 times that for 25(OH) D Vitamin D promotes phosphate absorption by the intestines Vitamin D decreases renal calcium and phosphate excretion. **vitamin D increase calcium absorption in blood, increase calcium in blood, via increase 1-alpha-hydroxylase expression**********

When are Bone Deposition and Resorption not at Equilibrium?

growing bones

Calcitonin stimulated by

high levels of CA2+ levels in ECF

Pyrophosphate inhibits

hydroxyapatite crystallization and calcification of the bone *INHIBITS BOTH *this is rich mineralized calcium phosphate ground substance; what is it inhibited by? TNAP what secretes it? Osteoblast

The decline in phosphate concentration is caused by

increase renal phosphate excretion

Lack of 1,25(OH)2 D decreases absorption of Ca2+ from:

intestines bones renal tubules, thus causing the Ca2+ ion concentration to fall back toward its normal level

Vitamin D and PTH stimulate production of:

mature osteoclasts through the dual action of inhibiting OPG production and stimulating RANKL formation

Tissue-nonspecific alkaline phosphatase (TNAP) is secreted by osteoblasts into the osteoid to neutralize pyrophosphate, and the natural affinity of the collagen fibers for calcium salts causes hydroxyapatite crystallization . Tissue-nonspecific alkaline phosphatase (TNAP) breaks down:

pyrophosphate and decreases its levels to allow calcification of bones and hydroxyapatite crystallization

Where is calcium stored?

rest in BONES *large reservoirs ECR (9.4 mg/dl (2.4 millimoles per liter - concentration) Organelles of cells (1%) blood muscle tissue

Conversion of 25-(OH) D to 1,25(OH)2 D requires PTH. Where does the conversion of 25-(OH) D ---> TO --> 1,25(OH)2 D occurs in:

the proximal tubules of KIDNEY *PTH acts on kidney to increase 1-alpha-hydroxylase expression - activated 25 (OH) into active 1,25 (OH) and then it works on GI tracts *1,25(OH)2 D is the most active form of vitamin D *In the absence of the kidneys, vitamin D loses almost all its effectiveness