الرحمن الله بسمالرحیم

EndocrinologyEndocrinology

Endocrine Endocrine PhysiologyPhysiology

lecture 7lecture 7

Saeed Hajihashemi, PhDSaeed Hajihashemi, PhD

Department of PhysiologyDepartment of Physiology

Arak University of Medical SciencesArak University of Medical Sciences

Calcium homeostasis: Calcium homeostasis:

Parathyroid Hormone, Parathyroid Hormone, Calcitonin and Calcitonin and

Vitamin D3Vitamin D3

Physiological importance of Physiological importance of CalciumCalcium

Calcium salts in bone provide structural Calcium salts in bone provide structural integrity of the skeletonintegrity of the skeleton

Calcium ions in extracellular and cellular Calcium ions in extracellular and cellular fluids is essential to normal function of a fluids is essential to normal function of a host of biochemical processeshost of biochemical processes Neuoromuscular excitabilityNeuoromuscular excitability Blood coagulationBlood coagulation Hormonal secretionHormonal secretion Enzymatic regulationEnzymatic regulation

Regulation of Calcium Regulation of Calcium ConcentrationConcentration

The important role that calcium The important role that calcium plays in so many processes dictates plays in so many processes dictates that its concentration, both that its concentration, both extracellularly and intracellularly, be extracellularly and intracellularly, be maintained within a very narrow maintained within a very narrow range.range.

This is achieved by an elaborate This is achieved by an elaborate system of controlssystem of controls

Control of cellular calcium homeostasis is as Control of cellular calcium homeostasis is as carefully maintained as in extracellular fluidscarefully maintained as in extracellular fluids

[Ca[Ca2+2+]]cytcyt is approximately 1/1000 is approximately 1/1000thth of of extracellular concentrationextracellular concentration

Stored in mitochondria and ERStored in mitochondria and ER ““pump-leak” transport systems control pump-leak” transport systems control

[Ca[Ca2+2+]]cytcyt Calcium leaks into cytosolic compartment and is Calcium leaks into cytosolic compartment and is

actively pumped into storage sites in organelles to actively pumped into storage sites in organelles to shift it away from cytosolic pools. shift it away from cytosolic pools.

Regulation of Intracellular Regulation of Intracellular Calcium ConcentrationCalcium Concentration

Extracellular CalciumExtracellular Calcium

When extracellular calcium falls When extracellular calcium falls below normal, the nervous system below normal, the nervous system becomes progressively more becomes progressively more excitable because of increase excitable because of increase permeability of neuronal membranes permeability of neuronal membranes to sodium.to sodium.

Hyperexcitability causes tetanic Hyperexcitability causes tetanic contractionscontractions Hypercalcemic tetany [CaHypercalcemic tetany [Ca2+2+]]cytcyt

Three definable fractions of calcium Three definable fractions of calcium in serum:in serum: Ionized calcium 50%Ionized calcium 50% Protein-bound calcium 40%Protein-bound calcium 40%

90% bound to albumin90% bound to albumin Remainder bound to globulinsRemainder bound to globulins

Calcium complexed to serum Calcium complexed to serum constituents 10%constituents 10% Citrate and phosphateCitrate and phosphate

Extracellular CalciumExtracellular Calcium

Binding of calcium to albumin is pH Binding of calcium to albumin is pH dependentdependent

Acute alkalosis increases calcium binding Acute alkalosis increases calcium binding to protein and decreases ionized calciumto protein and decreases ionized calcium

Patients who develop acute respiratory Patients who develop acute respiratory alkalosis have increased neural alkalosis have increased neural excitability and are prone to seizures due excitability and are prone to seizures due to low ionized calcium in the extracellular to low ionized calcium in the extracellular fluid which results in increased fluid which results in increased permeability to sodium ionspermeability to sodium ions

Extracellular CalciumExtracellular Calcium

Calcium and phosphorousCalcium and phosphorous

Calcium is tightly regulated with Calcium is tightly regulated with Phosphorous in the body. Phosphorous in the body.

Phosphorous is an essential mineral Phosphorous is an essential mineral necessary for ATP, cAMP second necessary for ATP, cAMP second messenger systems, and other rolesmessenger systems, and other roles

Calcium turnoverCalcium turnover

Calcium in blood and boneCalcium in blood and bone

CaCa2+ 2+ normally ranges from 8.5-10 normally ranges from 8.5-10 mg/dL in the plasma. mg/dL in the plasma.

The active free ionized CaThe active free ionized Ca2+2+ is only is only about 48% 46% is bound to protein about 48% 46% is bound to protein in a non-diffusible state while 6% is in a non-diffusible state while 6% is complexed to salt. complexed to salt.

Only free, ionized CaOnly free, ionized Ca2+2+ is biologically is biologically active. active.

Phosphate TurnoverPhosphate Turnover

Phosphorous in blood and bonePhosphorous in blood and bone

POPO44 normal plasma concentration is normal plasma concentration is

3.0-4.5 mg/dL. 87% is diffusible, with 3.0-4.5 mg/dL. 87% is diffusible, with 35% complexed to different ions and 35% complexed to different ions and 52% ionized. 52% ionized.

13% is in a non-diffusible protein 13% is in a non-diffusible protein bound state. 85-90% is found in bound state. 85-90% is found in bone. bone.

The rest is in ATP, cAMP, and proteinsThe rest is in ATP, cAMP, and proteins

Calcium and boneCalcium and bone

99% of Calcium is found in the bone. 99% of Calcium is found in the bone. Most is found in hydroxyapatite Most is found in hydroxyapatite crystals. Very little Cacrystals. Very little Ca2+2+ can be can be released from the bone– though it is released from the bone– though it is the major reservoir of Cathe major reservoir of Ca2+2+ in the in the body.body.

Structure of bonesStructure of bones

Haversian canals within lamellae

Calcium turnover in bonesCalcium turnover in bones

80% of bone is mass consists of cortical bone– 80% of bone is mass consists of cortical bone– for example: dense concentric layers of for example: dense concentric layers of appendicular skeleton (long bones)appendicular skeleton (long bones)

20% of bone mass consists of trabecular 20% of bone mass consists of trabecular bone– bridges of bone spicules of the axial bone– bridges of bone spicules of the axial skeleton (skull, ribs, vertebrae, pelvis) skeleton (skull, ribs, vertebrae, pelvis)

Trabecular bone has five times greater Trabecular bone has five times greater surface area, though comprises lesser mass.surface area, though comprises lesser mass.

Because of greater accessibility trabecular Because of greater accessibility trabecular bone is more important to calcium turnoverbone is more important to calcium turnover

BonesBones 99% of the Calcium in our bodies is found in our 99% of the Calcium in our bodies is found in our

bones which serve as a reservoir for Cabones which serve as a reservoir for Ca++++ storage. storage. 10% of total adult bone mass turns over each year 10% of total adult bone mass turns over each year

during remodeling processduring remodeling process During growth rate of bone formation exceeds During growth rate of bone formation exceeds

resporption and skeletal mass increases. resporption and skeletal mass increases. Linear growth occurs at epiphyseal plates.Linear growth occurs at epiphyseal plates. Increase in width occurs at periosteumIncrease in width occurs at periosteum Once adult bone mass is achieved equal rates of Once adult bone mass is achieved equal rates of

formation and resorption maintain bone mass until formation and resorption maintain bone mass until age of about 30 years when rate of resportion age of about 30 years when rate of resportion begins to exceed formation and bone mass slowly begins to exceed formation and bone mass slowly decreases.decreases.

Bone cell typesBone cell types

There are three types of bone cells: There are three types of bone cells: OsteoblastsOsteoblasts are the differentiated bone are the differentiated bone forming cells and secrete bone matrix on forming cells and secrete bone matrix on which Cawhich Ca++++ and PO precipitate. and PO precipitate.

OsteocytesOsteocytes, the mature bone cells are , the mature bone cells are enclosed in bone matrix. enclosed in bone matrix.

OsteoclastsOsteoclasts is a large multinucleated cell is a large multinucleated cell derived from monocytes whose function is derived from monocytes whose function is to resorb bone. Inorganic bone is to resorb bone. Inorganic bone is composed of hydroxyapatite and organic composed of hydroxyapatite and organic matrix is composed primarily of collagen.matrix is composed primarily of collagen.

Bone formationBone formation

Active Active osteoblastsosteoblasts synthesize and synthesize and extrude collagenextrude collagen

Collagen fibrils form arrays of an Collagen fibrils form arrays of an organic matrix called the organic matrix called the osetoidosetoid. .

Calcium phosphate is deposited in the Calcium phosphate is deposited in the osteoid and becomes mineralized osteoid and becomes mineralized

Mineralization is combination of Mineralization is combination of CaP0CaP044, OH, OH--, and H, and H33COCO33

–– hydroxyapatite. hydroxyapatite.

MineralizationMineralization

Requires adequate Calcium and Requires adequate Calcium and phosphatephosphate

Dependent on Vitamin DDependent on Vitamin D Alkaline phosphatase and Alkaline phosphatase and

osteocalcin play roles in bone osteocalcin play roles in bone formationformation

Their plasma levels are indicators of Their plasma levels are indicators of osteoblast activity.osteoblast activity.

CanaliculiCanaliculi

Within each bone unit is a minute fluid-Within each bone unit is a minute fluid-containing channel called the containing channel called the canaliculicanaliculi..

Canaliculi traverse the mineralized bone.Canaliculi traverse the mineralized bone. Interior osteocytes remain connected to Interior osteocytes remain connected to

surface cells via syncytial cell processes. surface cells via syncytial cell processes. This process permits transfer of calcium This process permits transfer of calcium

from enormous surface area of the from enormous surface area of the interior to extracellular fluid.interior to extracellular fluid.

Bones Bones cellscells

Control of bone formation and Control of bone formation and resorptionresorption

Bone resorption of CaBone resorption of Ca++++ by two mechanims: by two mechanims: osteocytic osteolysis is a rapid and transient osteocytic osteolysis is a rapid and transient effect and osteoclasitc resorption which is effect and osteoclasitc resorption which is slow and sustainedslow and sustained. .

Both are stimulated by PTH. CaPOBoth are stimulated by PTH. CaPO44 precipitates out of solution id its solubility is precipitates out of solution id its solubility is exceeded. The solubility is defined by the exceeded. The solubility is defined by the equilibrium equation: Ksp = [Caequilibrium equation: Ksp = [Ca2+2+]]33[PO[PO44

3-3-]]22.. In the absence of hormonal regulation In the absence of hormonal regulation

plasma Caplasma Ca++++ is maintained at 6-7 mg/dL by is maintained at 6-7 mg/dL by this equilibrium.this equilibrium.

Osteocytic osteolysisOsteocytic osteolysis

Transfer of calcium from canaliculi Transfer of calcium from canaliculi to extracellular fluid via activity of to extracellular fluid via activity of osteocytes.osteocytes.

Does not decrease bone mass.Does not decrease bone mass. Removes calcium from most recently Removes calcium from most recently

formed crystalsformed crystals Happens quickly. Happens quickly.

Bone resorptionBone resorption

Does not merely extract calcium, it Does not merely extract calcium, it destroys entire matrix of bone and destroys entire matrix of bone and diminishes bone mass.diminishes bone mass.

Cell responsible for resorption is the Cell responsible for resorption is the osteoclastosteoclast. .

Bone remodelingBone remodeling

Endocrine signals to resting osteoblasts Endocrine signals to resting osteoblasts generate paracrine signals to osteoclasts and generate paracrine signals to osteoclasts and precursors.precursors.

Osteoclasts resorb and area of mineralized Osteoclasts resorb and area of mineralized bone.bone.

Local macrophages clean up debris.Local macrophages clean up debris. Process reverses when osteoblasts and Process reverses when osteoblasts and

precursors are recruited to site and generate precursors are recruited to site and generate new matrix. new matrix.

New matrix is minearilzed.New matrix is minearilzed. New bone replaces previously resorbed bone.New bone replaces previously resorbed bone.

Osteoclasts and CaOsteoclasts and Ca++++ resorption resorption

Calcium, bones and Calcium, bones and osteoporosisosteoporosis

The total bone mass of humans peaks The total bone mass of humans peaks at 25-35 years of age.at 25-35 years of age.

Men have more bone mass than Men have more bone mass than women.women.

A gradual decline occurs in both A gradual decline occurs in both genders with aging, but women genders with aging, but women undergo an accelerated loss of bone undergo an accelerated loss of bone due to increased resorption during due to increased resorption during perimenopause. perimenopause.

Bone resorption exceeds formation.Bone resorption exceeds formation.

Reduced bone density and mass: Reduced bone density and mass: osteoporosis osteoporosis

Susceptibility to fracture. Susceptibility to fracture. Earlier in life for women than men but Earlier in life for women than men but

eventually both genders succumbeventually both genders succumb.. Reduced risk:Reduced risk:

Calcium in the diet Calcium in the diet habitual exercisehabitual exercise avoidance of smoking and alcohol intake avoidance of smoking and alcohol intake avoid drinking carbonated soft drinksavoid drinking carbonated soft drinks

Calcium, bones and Calcium, bones and osteoporosisosteoporosis

Vertebrae of 40- vs. 92-year-old Vertebrae of 40- vs. 92-year-old women women

Note the marked loss of trabeculae with preservation of cortex.

Hormonal control of

bones

Hormonal control of CaHormonal control of Ca2+2+

Three principal hormones regulate CaThree principal hormones regulate Ca++++ and three organs that function in Caand three organs that function in Ca++++ homeostasis. homeostasis.

Parathyroid hormone (PTH)Parathyroid hormone (PTH), , 1,25-1,25-dihydroxy Vitamin D3 (Vitamin D3)dihydroxy Vitamin D3 (Vitamin D3), , and and CalcitoninCalcitonin, regulate Ca, regulate Ca++++ resorption, resorption, reabsorption, absorption and excretion reabsorption, absorption and excretion from the bone, kidney and intestine. In from the bone, kidney and intestine. In addition, many other hormones effect addition, many other hormones effect bone formation and resorption.bone formation and resorption.

Vitamin DVitamin D

Vitamin D, after its activation to the Vitamin D, after its activation to the hormone 1,25-dihydroxy Vitamin D3 hormone 1,25-dihydroxy Vitamin D3 is a principal regulator of Cais a principal regulator of Ca++++. .

Vitamin D increases CaVitamin D increases Ca++++ absorption absorption from the intestine and Cafrom the intestine and Ca++ ++

resorption from the bone .resorption from the bone .

Synthesis of Vitamin DSynthesis of Vitamin D

Humans acquire vitamin D from two sources.Humans acquire vitamin D from two sources. Vitamin D is produced in the skin by Vitamin D is produced in the skin by

ultraviolet radiation and ingested in the diet. ultraviolet radiation and ingested in the diet. Vitamin D is not a classic hormone because it Vitamin D is not a classic hormone because it

is not produce and secreted by an endocrine is not produce and secreted by an endocrine “gland.” Nor is it a true “vitamin” since it can “gland.” Nor is it a true “vitamin” since it can be synthesized be synthesized de novode novo. .

Vitamin D is a true hormone that acts on Vitamin D is a true hormone that acts on distant target cells to evoke responses after distant target cells to evoke responses after binding to high affinity receptorsbinding to high affinity receptors

Vitamin D3 synthesis occurs in Vitamin D3 synthesis occurs in keratinocytes in the skin. keratinocytes in the skin.

7-dehydrocholesterol is photoconverted to 7-dehydrocholesterol is photoconverted to previtamin D3, then spontaneously previtamin D3, then spontaneously converts to vitamin D3. converts to vitamin D3.

Previtamin D3 will become degraded by Previtamin D3 will become degraded by over exposure to UV light and thus is not over exposure to UV light and thus is not overproduced. overproduced.

Also 1,25-dihydroxy-D (the end product of Also 1,25-dihydroxy-D (the end product of vitamin D synthesis) feeds back to inhibit vitamin D synthesis) feeds back to inhibit its production.its production.

Synthesis of Vitamin DSynthesis of Vitamin D

PTH stimulates vitamin D synthesis. In the PTH stimulates vitamin D synthesis. In the winter or if exposure to sunlight is limited winter or if exposure to sunlight is limited (indoor jobs!), then dietary vitamin D is (indoor jobs!), then dietary vitamin D is essential. essential.

Vitamin D itself is inactive, it requires Vitamin D itself is inactive, it requires modification to the active metabolite, 1,25-modification to the active metabolite, 1,25-dihydroxy-D. dihydroxy-D.

The first hydroxylation reaction takes place The first hydroxylation reaction takes place in the liver yielding 25-hydroxy D. in the liver yielding 25-hydroxy D.

Then 25-hydroxy D is transported to the Then 25-hydroxy D is transported to the kidney where the second hydroxylation kidney where the second hydroxylation reaction takes place. reaction takes place.

Synthesis of Vitamin DSynthesis of Vitamin D

The mitochondrial P450 enzyme 1The mitochondrial P450 enzyme 1--hydroxylase converts it to 1,25-dihydroxy-hydroxylase converts it to 1,25-dihydroxy-D, the most potent metabolite of Vitamin D, the most potent metabolite of Vitamin D.D.

The 1The 1-hydroxylase enzyme is the point of -hydroxylase enzyme is the point of regulation of D synthesis. regulation of D synthesis.

Feedback regulation by 1,25-dihydroxy D Feedback regulation by 1,25-dihydroxy D inhibits this enzyme. inhibits this enzyme.

PTH stimulates 1PTH stimulates 1-hydroxylase and -hydroxylase and increases 1,25-dihydroxy D. increases 1,25-dihydroxy D.

Synthesis of Vitamin DSynthesis of Vitamin D

25-OH-D3 is also hydroxylated in the 24 25-OH-D3 is also hydroxylated in the 24 position which position which inactivatesinactivates it. it.

If excess 1,25-(OH)If excess 1,25-(OH)22-D is produced, it can -D is produced, it can

also by 24-hydroxylated to remove it. also by 24-hydroxylated to remove it. Phosphate inhibits 1Phosphate inhibits 1-hydroxylase and -hydroxylase and

decreased levels of POdecreased levels of PO44 stimulate 1 stimulate 1--

hydroxylase activityhydroxylase activity

Synthesis of Vitamin DSynthesis of Vitamin D

Synthesis of Vitamin D

Vitamin DVitamin D

Vitamin D is a lipid soluble hormone that Vitamin D is a lipid soluble hormone that binds to a typical nuclear receptor, binds to a typical nuclear receptor, analogous to steroid hormones. analogous to steroid hormones.

Because it is lipid soluble, it travels in the Because it is lipid soluble, it travels in the blood bound to hydroxylated blood bound to hydroxylated -globulin.-globulin.

There are many target genes for Vitamin There are many target genes for Vitamin D. D.

Vitamin D actionVitamin D action

The main action of 1,25-(OH)The main action of 1,25-(OH)22-D is to -D is to

stimulate absorption of Castimulate absorption of Ca2+2+ from the from the intestineintestine. .

1,25-(OH)1,25-(OH)22-D induces the production of -D induces the production of

calcium binding proteins which sequester calcium binding proteins which sequester CaCa2+2+, buffer high Ca, buffer high Ca2+2+ concentrations that concentrations that arise during initial absorption and allow arise during initial absorption and allow CaCa2+2+ to be absorbed against a high Ca to be absorbed against a high Ca2+2+ gradientgradient

Vitamin D promotes intestinal Vitamin D promotes intestinal calcium absorptioncalcium absorption

Vitamin D acts via steroid hormone Vitamin D acts via steroid hormone like receptor to increase like receptor to increase transcriptional and translational transcriptional and translational activityactivity

One gene product is calcium-binding One gene product is calcium-binding protein (CaBP)protein (CaBP)

CaBP facilitates calcium uptake by CaBP facilitates calcium uptake by intestinal cellsintestinal cells

Clinical correlateClinical correlate

Vitamin D-dependent rickets type IIVitamin D-dependent rickets type II Mutation in 1,25-(OH)2-D receptorMutation in 1,25-(OH)2-D receptor Disorder characterized by impaired Disorder characterized by impaired

intestinal calcium absorptionintestinal calcium absorption Results in rickets or osteomalacia Results in rickets or osteomalacia

despite increased levels of 1,25-despite increased levels of 1,25-(OH)2-D in circulation(OH)2-D in circulation

Vitamin D Actions on BonesVitamin D Actions on Bones

Another important target for 1,25-(OH)Another important target for 1,25-(OH)22-D -D is the bone. is the bone.

Osteoblasts, but not osteoclasts have Osteoblasts, but not osteoclasts have vitamin D receptors. vitamin D receptors.

1,25-(OH)1,25-(OH)22-D acts on osteoblasts which -D acts on osteoblasts which produce a paracrine signal that activates produce a paracrine signal that activates osteoclasts to resorb Caosteoclasts to resorb Ca++++ from the bone from the bone matrix. matrix.

1,25-(OH)1,25-(OH)22-D also stimulates osteocytic -D also stimulates osteocytic osteolysis. osteolysis.

Vitamin D and BonesVitamin D and Bones

Proper bone formation is stimulated Proper bone formation is stimulated by 1,25-(OH)by 1,25-(OH)22-D. -D.

In its absence, excess osteoid In its absence, excess osteoid accumulates from lack of 1,25-(OH)accumulates from lack of 1,25-(OH)22-D -D

repression of osteoblastic collagen repression of osteoblastic collagen synthesis. synthesis.

Inadequate supply of vitamin D results Inadequate supply of vitamin D results in in ricketsrickets, a disease of bone , a disease of bone deformationdeformation

Parathyroid HormoneParathyroid Hormone

PTH is synthesized and secreted by PTH is synthesized and secreted by the parathyroid gland which lie the parathyroid gland which lie posterior to the thyroid glands. posterior to the thyroid glands.

The blood supply to the parathyroid The blood supply to the parathyroid glands is from the thyroid arteries. glands is from the thyroid arteries.

The Chief Cells in the parathyroid The Chief Cells in the parathyroid gland are the principal site of PTH gland are the principal site of PTH synthesis. synthesis.

Synthesis of PTHSynthesis of PTH

PTH is translated as a pre-PTH is translated as a pre-prohormone. prohormone.

Cleavage of leader and pro-Cleavage of leader and pro-sequences yield a biologically active sequences yield a biologically active peptide of 84 aa. peptide of 84 aa.

Cleavage of C-terminal end yields a Cleavage of C-terminal end yields a biologically inactive peptide.biologically inactive peptide.

Regulation of PTHRegulation of PTH

The dominant regulator of PTH is The dominant regulator of PTH is plasma Caplasma Ca2+2+. .

Secretion of PTH is inversely related Secretion of PTH is inversely related to [Cato [Ca2+2+]. ].

Maximum secretion of PTH occurs at Maximum secretion of PTH occurs at plasma Caplasma Ca2+2+ below 3.5 mg/dL. below 3.5 mg/dL.

At CaAt Ca2+2+ above 5.5 mg/dL, PTH above 5.5 mg/dL, PTH secretion is maximally inhibited. secretion is maximally inhibited.

Calcium regulates PTHCalcium regulates PTH

PTH secretion responds to small alterations in PTH secretion responds to small alterations in plasma Caplasma Ca2+2+ within seconds. within seconds.

A unique calcium receptor within the A unique calcium receptor within the parathyroid cell plasma membrane senses parathyroid cell plasma membrane senses changes in the extracellular fluid concentration changes in the extracellular fluid concentration of Caof Ca2+2+. .

This is a typical G-protein coupled receptor that This is a typical G-protein coupled receptor that activates phospholipase C and inhibits activates phospholipase C and inhibits adenylate cyclase—result is increase in adenylate cyclase—result is increase in intracellular Caintracellular Ca2+2+ via generation of inositol via generation of inositol phosphates and decrease in cAMP which phosphates and decrease in cAMP which prevents exocytosis of PTH from secretory prevents exocytosis of PTH from secretory granules. granules.

Regulation of PTHRegulation of PTH

When CaWhen Ca2+2+ falls, cAMP rises and falls, cAMP rises and PTH is secreted. PTH is secreted.

1,25-(OH)1,25-(OH)22-D inhibits PTH gene -D inhibits PTH gene expression, providing another level expression, providing another level of feedback control of PTH. of feedback control of PTH.

Despite close connection between Despite close connection between CaCa2+ 2+ and POand PO44, no direct control of , no direct control of PTH is exerted by phosphate levels. PTH is exerted by phosphate levels.

Regulation of PTHRegulation of PTH

Calcium Calcium regulates regulates

PTH PTH secretionsecretion

PTH actionPTH action

The overall action of PTH is to increase The overall action of PTH is to increase plasma Caplasma Ca++++ levels and decrease plasma levels and decrease plasma phosphate levels. phosphate levels.

PTH acts directly on the bones to PTH acts directly on the bones to stimulate stimulate CaCa++++ resorption resorption and kidney to stimulate Ca+ and kidney to stimulate Ca++ reabsorption in the distal tubule of the + reabsorption in the distal tubule of the kidney and to kidney and to inhibit reabosorptioin of inhibit reabosorptioin of phosphatephosphate (thereby stimulating its excretion). (thereby stimulating its excretion).

PTH also acts indirectly on intestine by PTH also acts indirectly on intestine by stimulating 1,25-(OH)stimulating 1,25-(OH)22-D synthesis. -D synthesis.

Calcium vs. PTHCalcium vs. PTH

Primary HyperparathyroidismPrimary Hyperparathyroidism

Calcium homeostatic loss due to excessive PTH Calcium homeostatic loss due to excessive PTH secretionsecretion

Due to excess PTH secreted from adenomatous Due to excess PTH secreted from adenomatous or hyperplastic parathyroid tissueor hyperplastic parathyroid tissue

Hypercalcemia results from combined effects Hypercalcemia results from combined effects of PTH-induced bone resorption, intestinal of PTH-induced bone resorption, intestinal calcium absorption and renal tubular calcium absorption and renal tubular reabsorptionreabsorption

Pathophysiology related to both PTH excess Pathophysiology related to both PTH excess and concomitant excessive production of 1,25-and concomitant excessive production of 1,25-(OH)2-D. (OH)2-D.

Hypercalcemia of MalignancyHypercalcemia of Malignancy

Underlying cause is generally excessive Underlying cause is generally excessive bone resorption by one of three bone resorption by one of three mechanismsmechanisms

1,25-(OH)2-D synthesis by lymphomas 1,25-(OH)2-D synthesis by lymphomas Local osteolytic hypercalcemiaLocal osteolytic hypercalcemia

20% of all hypercalcemia of malignancy20% of all hypercalcemia of malignancy Humoral hypercalcemia of malignancyHumoral hypercalcemia of malignancy

Over-expression of PTH-related protein Over-expression of PTH-related protein (PTHrP)(PTHrP)

PTHrPPTHrP

Three forms of PTHrP identified, all Three forms of PTHrP identified, all about twice the size of native PTHabout twice the size of native PTH

Marked structural homology with Marked structural homology with PTHPTH

PTHrP and PTH bind to the same PTHrP and PTH bind to the same receptorreceptor

PTHrP reproduce full spectrum of PTHrP reproduce full spectrum of PTH activitiesPTH activities

PTH receptor defectPTH receptor defect

Rare disease known as Jansen’s Rare disease known as Jansen’s metaphyseal chondrodysplasiametaphyseal chondrodysplasia

Characterized by hypercalcemia, Characterized by hypercalcemia, hypophosphotemia, short-limbed hypophosphotemia, short-limbed dwarfismdwarfism

Due to activating mutation of PTH Due to activating mutation of PTH receptorreceptor

Rescue of PTH receptor knock-out with Rescue of PTH receptor knock-out with targeted expression of “Jansen’s targeted expression of “Jansen’s transgene”transgene”

HypoparathyroidismHypoparathyroidism

Hypocalcemia occurs when there is Hypocalcemia occurs when there is inadequate response of the Vitamin inadequate response of the Vitamin D-PTH axis to hypocalcemic stimuliD-PTH axis to hypocalcemic stimuli

Hypocalcemia is often multifactorialHypocalcemia is often multifactorial Hypocalcemia is invariably Hypocalcemia is invariably

associated with hypoparathyroidismassociated with hypoparathyroidism Bihormonal—concomitant decrease Bihormonal—concomitant decrease

in 1,25-(OH)2-Din 1,25-(OH)2-D

PTH-deficient hypoparathyroidism PTH-deficient hypoparathyroidism Reduced or absent synthesis of PTHReduced or absent synthesis of PTH Often due to inadvertent removal of Often due to inadvertent removal of

excessive parathyroid tissue during excessive parathyroid tissue during thyroid or parathyroid surgerythyroid or parathyroid surgery

PTH-ineffective hypoparathyroidism PTH-ineffective hypoparathyroidism Synthesis of biologically inactive PTHSynthesis of biologically inactive PTH

HypoparathyroidismHypoparathyroidism

PseudohypoparathyroidismPseudohypoparathyroidism

PTH-resistant hypoparathyroidism PTH-resistant hypoparathyroidism Due to defect in PTH receptor-Due to defect in PTH receptor-

adenylate cyclase complexadenylate cyclase complex Mutation in GMutation in Gs subunits subunit Patients are also resistant to TSH, Patients are also resistant to TSH,

glucagon and gonadotropinsglucagon and gonadotropins

Calcium homeostasisCalcium homeostasis

PTH, PTH, Calcium & Calcium & PhosphatePhosphate

CalcitoninCalcitonin

Calcitonin acts to decrease plasma CaCalcitonin acts to decrease plasma Ca++++ levels. levels.

While PTH and vitamin D act to increase While PTH and vitamin D act to increase plasma Caplasma Ca++++-- -- only calcitonin causes a only calcitonin causes a decrease in plasma Cadecrease in plasma Ca++++..

Calcitonin is synthesized and secreted by Calcitonin is synthesized and secreted by the parafollicular cells of the thyroid the parafollicular cells of the thyroid gland. gland.

They are distinct from thyroid follicular They are distinct from thyroid follicular cells by their large size, pale cytoplasm, cells by their large size, pale cytoplasm, and small secretory granules. and small secretory granules.

The major stimulus of calcitonin The major stimulus of calcitonin secretion is a rise in plasma Casecretion is a rise in plasma Ca++++ levelslevels

Calcitonin is a physiological Calcitonin is a physiological antagonist to PTH with regard to antagonist to PTH with regard to CaCa++++ homeostasis homeostasis

CalcitoninCalcitonin

The target cell for calcitonin is the The target cell for calcitonin is the osteoclast. osteoclast.

Calcitonin acts via increased cAMP Calcitonin acts via increased cAMP concentrations to inhibit osteoclast concentrations to inhibit osteoclast motility and cell shape and motility and cell shape and inactivates them. inactivates them.

The major effect of calcitonin The major effect of calcitonin administration is a rapid fall in Caadministration is a rapid fall in Ca2+2+ caused by inhibition of bone caused by inhibition of bone resorption. resorption.

CalcitoninCalcitonin

Role of calcitonin in normal CaRole of calcitonin in normal Ca2+2+ control is not control is not understood—may be more important in control of understood—may be more important in control of bone remodeling. bone remodeling.

Used clinically in treatment of hypercalcelmia Used clinically in treatment of hypercalcelmia and in certain bone diseases in which sustained and in certain bone diseases in which sustained reduction of osteoclastic resorption is reduction of osteoclastic resorption is therapeutically advantageous.therapeutically advantageous.

Chronic excess of calcitonin does not produce Chronic excess of calcitonin does not produce hypocalcemia and removal of parafollicular cells hypocalcemia and removal of parafollicular cells does not cause hypercalcemia. PTH and Vitamin does not cause hypercalcemia. PTH and Vitamin D3 regulation dominate. D3 regulation dominate.

May be more important in regulating bone May be more important in regulating bone remodeling than in Caremodeling than in Ca2+2+ homeostasis. homeostasis.

CalcitoninCalcitonin

Nutrition and CalciumNutrition and Calcium

Heaney RP, Refferty K Am J. Clin Nutr Heaney RP, Refferty K Am J. Clin Nutr 200120017474:343-7:343-7 Excess calciuria associated with consumption Excess calciuria associated with consumption

of carbonated beverages is confined to of carbonated beverages is confined to caffeinated beverages. caffeinated beverages.

Acidulant type (phosphoric vs. citric acid) has Acidulant type (phosphoric vs. citric acid) has no acute effect. no acute effect.

The skeletal effects of carbonated beverage The skeletal effects of carbonated beverage consumption are due primarily to milk consumption are due primarily to milk displacement.displacement.

Nutrition and CalciumNutrition and Calcium

See Nutrition 2000 Vol 16 (7/8) in particularSee Nutrition 2000 Vol 16 (7/8) in particular:: Calvo MS “Dietary considerations to Calvo MS “Dietary considerations to

prevent loss of bone and renal functionprevent loss of bone and renal function”” ““overall trend in food consumption in the US is to drink overall trend in food consumption in the US is to drink

less milk and more carbonated soft drinks.”less milk and more carbonated soft drinks.” ““High phosphorus intake relative to low calcium intake”High phosphorus intake relative to low calcium intake” Changes in calcium homeostasis and PTH regulation Changes in calcium homeostasis and PTH regulation

that promote bone loss in children and post-menopausal that promote bone loss in children and post-menopausal women.women.

High sodium associated with fast-food consumption High sodium associated with fast-food consumption competes for renal reabsorption of calcium and PTH competes for renal reabsorption of calcium and PTH secretion.secretion.

Nutrition and CalciumNutrition and Calcium

See Nutrition 2000 Vol 16 (7/8) in particular:See Nutrition 2000 Vol 16 (7/8) in particular: Harland BF “Caffeine and Nutrition”Harland BF “Caffeine and Nutrition”

Caffeine is most popular drug consumed world-Caffeine is most popular drug consumed world-wide.wide.

75% comes from coffee75% comes from coffee Deleterious effects associated with pregnancy Deleterious effects associated with pregnancy

and osteoporosis.and osteoporosis. Low birth-rate and spontaneous abortion with Low birth-rate and spontaneous abortion with

excessive consumptionexcessive consumption For every 6 oz cup of coffee consumed there was a net For every 6 oz cup of coffee consumed there was a net

loss of 4.6 mg of calcium loss of 4.6 mg of calcium However, if you add milk to your coffee, you can However, if you add milk to your coffee, you can

replace the calcium that is lost. replace the calcium that is lost.

Ill effects of soft drinksIll effects of soft drinks

Intake of carbonated beverages has been Intake of carbonated beverages has been associated with increased excretion and associated with increased excretion and loss of calciumloss of calcium

25 years ago teenagers drank twice as 25 years ago teenagers drank twice as much milk as soda pop. Today they drink much milk as soda pop. Today they drink more than twice as much soda pop as milk.more than twice as much soda pop as milk.

Another significant consideration is obesity Another significant consideration is obesity and increased risk for diabetes.and increased risk for diabetes.

For complete consideration of ill effects of For complete consideration of ill effects of soft drinks on health and environment see:soft drinks on health and environment see: http://www.saveharry.com/bythenumbers.htmlhttp://www.saveharry.com/bythenumbers.html

Excessive sodium intakeExcessive sodium intake

Excessive intake of sodium may cause Excessive intake of sodium may cause renal hypercalciuria by impairing calcium renal hypercalciuria by impairing calcium reabsorption resulting in compensatory reabsorption resulting in compensatory increase in PTH secretion.increase in PTH secretion.

Stimulation of intestinal calcium Stimulation of intestinal calcium absorption by PTH-induced 1,25-(OH)2-D absorption by PTH-induced 1,25-(OH)2-D production compensates for excessive production compensates for excessive calcium excretioncalcium excretion

Post-menopausal women at greater risk Post-menopausal women at greater risk for bone loss due to excessive sodium for bone loss due to excessive sodium intake due to impaired vitamin D intake due to impaired vitamin D synthesis which accompanies estrogen synthesis which accompanies estrogen deficiency.deficiency.

Exercise and CalciumExercise and Calcium

Normal bone function requires Normal bone function requires weight-bearing exerciseweight-bearing exercise

Total bed-rest causes bone loss and Total bed-rest causes bone loss and negative calcium balancenegative calcium balance

Major impediment to long-term Major impediment to long-term space travelspace travel