Parathyroid Hormone, Calcitonin, Calcium and Phosphate Metabolism

Prof. dr. Zoran Valić

Department of Physiology

University of Split School of Medicine

Calcium and Phosphate Regulation in the ECF and Plasma

Ca+2 in extracellular fluid (ECF) – 2,4 mmol/L normally precisely regulated (few %) key role of Ca+2 in many physiologic processes:

muscle contraction, blood clotting, transmission of nerve impulses

hypercalcemia – depression;/ hypocalcemia – excitetion (tetany)

0.1% Ca+2 in ECF, 1% in cells, rest is stored in bones

85% of body's phosphate is stored in bones 14-15% in cells, 1% in ECF concentration is not nearly as well regulated

as calcium same factors that regulate calcium

Calcium in the Plasma and Interstitial Fluid (IF)

present in three forms :

a) 41% - combined with plasma proteins

b) 9% - combined with anionic substances (citrate and phosphate)

c) 50% - ionized

ionic calcium is the form that is important for most functions of calcium in the body

Inorganic Phosphate in the ECF

in the plasma is mainly in two forms : a) HPO4

2- - 1.05 mmol/L

b) H2PO4- - 0.26 mmol/L

concentration depends on pH of plasma total quantity of phosphate is expressed in

terms of phosphorus per liter of blood 1.3 mmol/L (depending on age)

Nonbone Physiologic Effects of Altered Calcium and Phosphate Concentrations

hypocalcemia causes nervous system excitement ( permeability to Na+)

tetany occurs when calcium decreases to 1.5 mmol/L, and death when it is 1 mmol/L

hypocalcemia : dilatation of heart, changes in enzyme activities, increased membrane permeability of some cells, impaired blood clotting – nonphysiological decrease

Hypercalcemia

nervous system becomes depressed lack of appetite and constipation decreases the QT interval of the heart depressive effects begin to appear when

calcium rises above 3.0 mmol/L, they can become marked above 3.8 mmol/L

Absorption and Excretion of Calcium and Phosphate

daily intake is about 1000 mg/day each for calcium and phosphorus (25 mmol) – 1L of milk

90% of daily intake of calcium is excreted in feces

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

kidney filers calcium (ionized and combined with anions)

renal tubules reabsorb 99 percent of the filtered calcium

renal phosphate excretion is controlled by an overflow mechanism (critical value of about 1 mmol/L – no phosphate is lost in the urine)

Bone and Its Relation to ECF Calcium and Phosphate

bone = organic matrix + calcium salts compact bone: 30% matrix, 70% salts organic matrix :

a) 90-95 % collagen fibers (tensile strength)

b) 5-10 % ground substance (ECF + proteoglycans, chondroitin sulfate and hyaluronic acid)

bone salts: calcium and phosphate

Bone Salts

Ca10(PO4)6(OH)2

hydroxyapatite – shaped like long, flat plate relative ratio of Ca/P 1.3-2.0 ions Mg2+, Na+, K+ & HCO3

-

many ions of many types of ions (transuranic elements and heavy metals)

osteogenic sarcoma (bone cancer)

Tensile and Compressional Strength of Bone

compact bone is composed of repeating periodic segments of collagen

hydroxyapatite crystals bound tightly to it – prevents "shear" in the bone

collagen fibers – tensile strength calcium salts – compressional strength

Precipitation and Absorption of Calcium and Phosphate in Bone

concentrations of calcium and phosphate ions in ECF are considerably greater than those required to cause precipitation of hydroxyapatite

pyrophosphate – inhibitor which prevent precipitation

Bone Calcification

osteoblasts produce osteoid (collagen molecules + ground substance)

calcium salts begin to precipitate on the surfaces of the collagen fibers, forming minute nidi

mixture of amorphous compounds (noncrystalline) salts of Ca & P, converted into the hydroxyapatite crystals over a period of weeks or months

few percent may remain permanently in the amorphous form (important role)

mechanism is not fully understood

Precipitation of Calcium in Nonosseous Tissues

arteriosclerosis degenerating tissues old blood clots

Calcium Exchange Between Bone and ECF

fast correction of plasma Ca concentration exchangeable calcium – in equilibrium with

the calcium ions in the ECF – rapid buffering mechanism

in all tissue cells (liver and gastrointestinal tract) & in the bone (amorphous calcium salts)

Deposition and Absorption of Bone osteoblasts (on outer surfaces of bones and in

bone cavities): active on 4% of all surfaces in an adult

osteoclasts : large, multinucleated cells (50 nuclei) derivatives of monocytes, phagocytic active on less than 1% bone surfaces PTH controls bone absorption by

osteoclasts

Absorption of Bone

osteoclasts send out villus-like projections toward the bone (ruffled border) & secrete:

a) proteolytic enzymes – organic matrix

b) acids (citric, lactic acid) – bone salts PTH stimulates osteoclast activity and bone

resorption, but through indirect mechanism

PTH binds to receptors on adjacent osteoblasts

osteoblasts release cytokines: osteoprotegerin ligand (OPGL or RANKL)

OPGL activates receptors on preosteoclast cells mature multinucleated osteoclasts development of ruffled border (release of enzymes and acids)

osteoblasts also produce osteoprotegerin (OPG, also called OCIF)

OPG inhibits bone resorption OPG acts as a "decoy" receptor binding to

OPGL and preventing its actions vitamin D and PTH inhibit OPG production

and stimulate OPGL formation estrogen stimulates OPG production used for treatment

bone deposition and absorption are normally in equilibrium – total mass of bone remains constant.

concentrated mass of osteoclasts tunnel in diameter 0,2-1 mm and several mm long tunnel is invaded by osteoblasts new bone begins to develop

new bone being laid down in successive layers of concentric circles (lamellae)

deposition of new bone ceases when the bone begins to encroach on the blood vessels supplying the area

haversian canal, is all that remains of the original cavity

osteon

Value of Continual Bone Remodeling bone strength in proportion to bone stress shape of the bone can be rearranged replacement of old organic matrix

bone is deposited in proportion to the compressional load (athletes & cast)

repair of fracture activates osteoblasts callus, rings

Gavril Ilizarov

Vitamin D

potent effect to increase calcium absorption from the intestinal tract

vitamin D itself is not the active substance must first be converted into:

1,25-dihydroxycholecalciferol

7-dehydrocholesterol + ultraviolet rays (in the skin) – cholecalciferol (vitamin D)

a) precise controlb) spearing vitamins

Formation of 1,25-Dihydroxycholecalciferol

proximal tubules of the kidneys the most active form of vitamin D in the absence of the kidneys, vitamin D

loses almost all its effectiveness requires PTH

a) precise controlb) spearing vitamins

Actions of Vitamin D

intestines, kidneys, bones intestines : hormone, absorption of Ca by formation of calbindin, a calcium-binding protein

+ Ca ATP-aza & alkaline phosphatase in the brush border

absorption of P by the intestines, direct effect and secondarily from this hormone's action on calcium absorption

kidneys: reabsorption of Ca & P by the epithelial cells of the renal tubules

bone: extreme quantities of vitamin D –

absorption of bone ( Ca transport) smaller quantities of vitamin D – promotes

bone calcification (increase absorption from the intestines; Ca transport in opposite direction)

Parathyroid Hormone

powerful mechanism for controlling ECF Ca & P concentrations

regulates intestinal reabsorption and renal excretion

regulates exchange between the ECF and bone of these ions

increased secretion causes rapid absorption of calcium salts from the bones – hypercalcemia

hypofunction of the parathyroid glands – hypocalcemia (tetany)

normally – 4 parathyroid glands in humans located immediately behind thyroid gland 6 x 3 x 2 mm, appearance of dark brown fat danger of removal during thyroid operations

(2(3) out of 4 – OK) chief cells (majority) and oxyphil cells

(function unknown, absent in many animals and in young humans)

Chemistry of PTH

PTH has been isolated in a pure form preprohormone (110 AA) prohormone

(90 AA) PTH itself (84 AA) smaller compounds have also been isolated

that exhibit full PTH activity kidneys rapidly remove big PTH within

minutes but fail to remove many of the fragments for hours

Effect of PTH on Ca & P Concentrations in ECF

Effect of PTH on Ca & P Concentrations in Plasma

phosphate concentration falls more rapidly than the calcium rises

both reach a plateau in about 4 hours increase Ca & P absorption from bone decrease excretion of Ca by kidneys increase renal P excretion

PTH Increases Ca & P Absorption from Bone

rapid phase: activation of the already existing osteocita (begins in minutes)

much slower phase: proliferation of the osteoclasts (requiring several days or even weeks)

Rapid Phase – Osteolysis

osteocytic membrane system – separates the bone itself from ECF

bone fluid – small amount between osteocytic membrane and bone

pumping of Ca ions from bone fluid into ECF – osteocytic pump

Rapid Phase – Osteolysis

bone fluid calcium concentration falls even lower absorbed of Ca & P from the bone – osteolysis

PTH strongly activates calcium pump ( Ca permeability of the bone fluid side of the osteocytic membrane)

Slow Phase of Bone Absorption

PTH activates osteoblasts and osteocytes which send secondary "signals" to the osteoclasts (OPGL)

1) immediate activation of the osteoclasts that are already formed

2) formation of new osteoclasts osteoclastic resorption of bone can lead to

weakened bones and secondary stimulation of the osteoblasts

PTH Decreases Ca Excretion and Increases P Excretion by Kidneys

increased P excretion is based on diminish proximal tubular reabsorption of P ions

simultaneous increase in renal tubular reabsorption of Ca

PTH increases reabsorption of Mg & H, and diminish reabsorption of Na, K, AA

Control of PTH Secretion by Ca Ion Concentration

PTH increases reabsorption of Ca & P from the intestines

cAMP mediates the effects of PTH Ca concentration controls secretion of PTH

parathyroid glands become greatly enlarged in rickets (5x) in pregnancy, and during lactation

Decrease in PTH Secretion

excess quantities of Ca in the diet increased vitamin D in the diet bone absorption caused by factors other

than PTH (immobilization)

changes in ECF Ca ion concentration are detected by a calcium-sensing receptor (CaSR) in parathyroid cell membranes

CaSR is a G protein-coupled receptor stimulated by calcium ions, activates

phospholipase C ( in IP3 and DAG) stimulation of Ca release from intracellular

stores decreases PTH secretion

Calcitonin

synthesis and secretion of calcitonin occur in the parafollicular cells, or C cells of thyroid gland (0,1% of the human thyroid gland, remnants of ultimobranchial glands)

effects opposite to those of PTH 32-amino acid peptide ECF Ca ion concentration – primary

stimulus for calcitonin secretion

Mechanism of Calcitonin Action

absorptive activities of the osteoclasts osteolytic effect of osteocytic membrane formation of new osteoclasts

minor effects on calcium handling in the kidney tubules and the intestines

calcitonin has bigger effect in children and certain diseases (Paget) than in adult human

Summary of Control of Ca Ions

first line of defense – buffer function of the exchangeable calcium in bones – amorphous compounds (Ca HPO4)

+ mitochondria of the liver and intestine

second line of defense – hormonal control

Pathophysiology

Hypoparathyroidism ( PTH secretion) osteocytic resorption of Ca + osteoclasts

inactivity Ca tetany (laryngeal muscles) extremely large quantities of vitamin D or giving

PTH (expensive, short-acting, antibodies) Hyperparathyroidism (primary & secondary)

ordinarily tumor (in women because pregnancy) extreme osteoclastic activity Ca & P fractures, decalcification, muscle weakness,

metastatic calcification, kidney stones

Rickets Ca (slightly) & P (greatly) in ECF, usually

caused by lack of vitamin D occur in spring months after depletion of stores compensatory increase in PTH secretion causes

extreme osteoclastic absorption of the bone tetany occurs in later stages – death treatment : vitamin D + Ca & P in the food steatorrhea – osteomalacia (adult rickets) renal rickets – failure of the damaged kidneys

to form 1,25-dihydroxycholecalciferol

Osteoporosis most common of all bone diseases in adults especially in old age decreased bone matrix osteoblastic activity is usually less than normal

– osteoid deposition is depressed lack of physical stress on the bones because of

inactivity, malnutrition, lack of vitamin C, postmenopausal lack of estrogen secretion, old age ( hGH), Cushing's syndrome ( glucocorticoids)

treatment: antiresorptive drugs:

bisphosphonates (Fosamax, Actonel & Boniva) estrogen substitution therapy SERMs (raloxifene, Evista) – osteoclasts calcitonin inhibitors of RANKL (monoclonal antibody,

Denosumab) anabolic drugs:

teriparatide (Forteo) – recombinant PTH calcium salts (carbonates, citrates, lactates) sodium-fluoride

Physiology of the Teeth

teeth cut, grind, and mix the food eaten forces: 250-450N & 650-900N occlusion – fitting of upper set of teeth with

the lower

major functional parts: enamel, dentin, cementum and pulp

another division: crown, neck and root

Enamel

outer surface of the tooth; ameloblasts formed before eruption of the tooth composed of large and dense crystals of

hydroxyapatite with adsorbed Mg, Na, K + insoluble protein fibers (similar to keratin)

extremely hard and resistant to acids, enzymes, and other corrosive agents

Dentin

main body of tooth, strong, bony structure hydroxyapatite crystals much denser than in

bone, embedded in a strong meshwork of collagen fibers

does not contain: osteoblasts, osteocytes, osteoclasts, spaces for vessels or nerves

odontoblasts: formation and nurishment calcium salts: compressional forces collagen: toughness and tensional forces

Cementum

bony substance secreted by cells of the periodontal membrane – lines tooth socket

collagen fibers pass directly from jaw bone through periodontal membrane into cementum

increases in thickness and strength with age

Pulp

filling pulp (tooth) cavity composed of connective tissue, nerve fibers,

blood vessels, and lymphatics odontoblasts – cells lining the surface of the

pulp cavity during the formative years lay down dentin send projections into small dentinal tubules

that penetrate all the way through the dentin

Dentition

humans and most other mammals develop two sets of teeth during a lifetime

deciduous or milk teeth (20) erupt between 7th month and 2nd year last until 6 th and 13 th year

permanent teeth (32)

Formation of the Teeth

invagination of the oral epithelium into the dental lamina and development of a tooth-producing organ

epithelial cells above form ameloblasts (enamel)

epithelial cells below invaginate upward into the middle of the tooth to form the pulp cavity and the odontoblasts (dentin)

Eruption of Teeth

cause of "eruption" is unknown most likely theory is that growth of the

tooth root and the bone underneath the tooth progressively shoves the tooth forward

Development of Permanent Teeth

when each permanent tooth becomes fully formed, it pushes outward through the bone

erodes the root of the deciduous tooth and eventually causes it to loosen and fall out

Metabolic Factors

thyroid and growth hormones availability of Ca & P in the diet amount of vitamin D rate of PTH secretion

Mineral Exchange in Teeth

salts composed of hydroxyapatite with adsorbed carbonates and various cations

new salts are constantly being deposited while old salts are being reabsorbed

deposition and reabsorbtion – in dentin and cementum, limited extent in enamel (saliva)

rate of exchange in dentin 3x slower than in bone

Dental Abnormalities

1) caries (erosion of the teeth)

2) malocclusion (failure of the projections of the upper and lower teeth to interdigitate properly)

1) Caries

action of bacteria on the teeth (Streptococcus mutans)

deposit of plaque (film of saliva and food) dependance on carbohydrates (form acids

(lactic) and proteolytic enzymes) acids – slow dissolvement of calcium salts enamel of the tooth is primary and most

important barrier to development of caries

small amounts of fluorine develop enamel that is more resistant to caries

fluorine does not make the enamel harder fluorine ions replace many of hydroxyl ions

in hydroxyapatite crystals, which in turn makes enamel several times less soluble

fluorine may also be toxic to the bacteria fluorine promote deposition of calcium

phosphate to "heal" the enamel surface

2) Malocclusion

hereditary abnormality teeth of one jaw grow to abnormal positions teeth do not interdigitate properly and

therefore cannot perform their normal grinding or cutting action adequately

pain in mandibular joint and deterioration of the teeth

treatment: continuous force on teeth

Copyright ©2009 American Physiological Society

Berndt, T. et al. Physiology 24: 17-25 2009;doi:10.1152/physiol.00034.2008

FIGURE 1. Phosphorus homeostasis in normal humans

Copyright ©2009 American Physiological Society

Berndt, T. et al. Physiology 24: 17-25 2009;doi:10.1152/physiol.00034.2008

FIGURE 4. Adaptations to changes in dietary phosphate