parathyroid hormone, calcitonin, calcium and phosphate metabolism, vitamin d and bone prof. dr....
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Parathyroid Hormone, Calcitonin,
Calcium and Phosphate Metabolism,
Vitamin D and Bone
Prof. Dr. Bayram YılmazProf. Dr. Bayram Yılmaz
Faculty of MedicineFaculty of Medicine
Department of PhysiologyDepartment of Physiology YEDİTEPE UNIVERSITY
• SkeletonSkeleton
* * Bone tissueBone tissue
Regulation of calcium and phosphate levels in the Regulation of calcium and phosphate levels in the extracellular fluid and plasmaextracellular fluid and plasma
Extracellular fluid calcium concentration normally is regulated very Extracellular fluid calcium concentration normally is regulated very
precisely.precisely.
Normal plasma value is about 9.4 mg/dlNormal plasma value is about 9.4 mg/dl
Hypercalcemia, progressive depression of the nervous systemHypercalcemia, progressive depression of the nervous system
Hypocalcemia, increased excitability of the nervous systemHypocalcemia, increased excitability of the nervous system
Only about 0.1% of total body calcium is found in the extracellular Only about 0.1% of total body calcium is found in the extracellular
fluid, about 1 % in the cells and the rest is stored in the bonesfluid, about 1 % in the cells and the rest is stored in the bones
Calcium in the Plasma and Interstitial FluidCalcium in the Plasma and Interstitial Fluid
The calcium in the plasma is present in three forms:The calcium in the plasma is present in three forms:
1)1) About 41% of the calcium is combined with the plasma About 41% of the calcium is combined with the plasma
proteins and in this form is indiffusible thorugh the capillary proteins and in this form is indiffusible thorugh the capillary
membranemembrane
2)2) About 9% of the calcium is diffusible through the capillary About 9% of the calcium is diffusible through the capillary
membrane but is combined with anionic substances of the membrane but is combined with anionic substances of the
plasma and interstitial fluid (such as citrate and phosphate)plasma and interstitial fluid (such as citrate and phosphate)
3)3) The remaining 50% of the calcium in the plasma is both The remaining 50% of the calcium in the plasma is both
diffusible and ionizeddiffusible and ionized
Calcium in the Plasma and Interstitial FluidCalcium in the Plasma and Interstitial Fluid
Inorganic phosphate in the extracellular fluidsInorganic phosphate in the extracellular fluids
About 85% of the body phosphate is found in the About 85% of the body phosphate is found in the bones; 14-15 % in the cells and less than 1% in the bones; 14-15 % in the cells and less than 1% in the extracellular fluidextracellular fluid
Inorganic phosphate in the plasma is mainly in two Inorganic phosphate in the plasma is mainly in two
forms:forms: HPOHPO44
-
HH22POPO44-
The average total quantity of inorganic phosphorus for The average total quantity of inorganic phosphorus for both ions is about 4 mg/dlboth ions is about 4 mg/dl
Non-bone physiologic effects of altered calcium Non-bone physiologic effects of altered calcium and phosphate concentrations in the body fluidsand phosphate concentrations in the body fluids
Changing the level of phosphate in the extracellular Changing the level of phosphate in the extracellular fluid from far below normal or two or three times normal fluid from far below normal or two or three times normal does not cause major immediate effects on the bodydoes not cause major immediate effects on the body
In contrast, even a slight increase or decrease of In contrast, even a slight increase or decrease of calcium ion in the extracellular fluid can cause extreme calcium ion in the extracellular fluid can cause extreme immediate physiologic effects.immediate physiologic effects.
Hypocalcemia causes nervous system excitement and Hypocalcemia causes nervous system excitement and tetany. Increased permeability of neurons to sodium tetany. Increased permeability of neurons to sodium ionsions
Hypercalcemia depresses nervous system and muscle Hypercalcemia depresses nervous system and muscle activity. These effects become marked as the calcium activity. These effects become marked as the calcium level rises above 15 mg/dllevel rises above 15 mg/dl
Absorption and Excretion of Calcium and Absorption and Excretion of Calcium and PhosphatePhosphate
Intestinal absorption and fecal excretion of calcium and Intestinal absorption and fecal excretion of calcium and phosphatephosphate
Renal excretion of calcium and phosphateRenal excretion of calcium and phosphate Approximately 10% (100 mg/day) of the ingested Approximately 10% (100 mg/day) of the ingested
calcium is excreted in urine calcium is excreted in urine Normally, the renal tubules reabsorb 99% of the filtered Normally, the renal tubules reabsorb 99% of the filtered
calcium, and only 100 mg/day is excreted in urinecalcium, and only 100 mg/day is excreted in urine
Renal phosphate excretion is controlled by an over-flow Renal phosphate excretion is controlled by an over-flow mechanism, when phosphate level is below 1 mmol/lt, mechanism, when phosphate level is below 1 mmol/lt, all phosphate in the glomerular filtrate is reabsorbed…all phosphate in the glomerular filtrate is reabsorbed…
Absorption and Excretion of Calcium and PhosphateAbsorption and Excretion of Calcium and Phosphate
Bone and its relation to extracellular calcium and Bone and its relation to extracellular calcium and phosphatephosphate
Organic matrix of the bone:Organic matrix of the bone: 90-95% collagen fibers, and the remaining 90-95% collagen fibers, and the remaining is homogenous gelatinous medium called ground substanceis homogenous gelatinous medium called ground substance
The ground substance is composed of extracellular fluid plus The ground substance is composed of extracellular fluid plus proteoglycans, especially chondroitin sulfate and hyaluronic acid proteoglycans, especially chondroitin sulfate and hyaluronic acid
Bone salts:Bone salts: The crystalline salts deposited in the organic matrix of the The crystalline salts deposited in the organic matrix of the bone are composed principally of calcium and phosphate.bone are composed principally of calcium and phosphate.
Hydroxyapatite = collagen + Ca(PO4)2 + OH + bicarbonate
Metals, radioactive and toxic substances can also be deposited in the Metals, radioactive and toxic substances can also be deposited in the bonebone
Precipitation and absorption of calcium and phosphate in Precipitation and absorption of calcium and phosphate in bonebone
Concentrations of calcium and phosphate in extracellular fluid are Concentrations of calcium and phosphate in extracellular fluid are greater than those required to cause precipitation of hydroxyapatite greater than those required to cause precipitation of hydroxyapatite
Role of inhibitors: pyrophosphateRole of inhibitors: pyrophosphate
Mechanism of bone calcification: The initial stage in bone production Mechanism of bone calcification: The initial stage in bone production is secretion of collagen molecules and the ground substance is secretion of collagen molecules and the ground substance (mainly proteoglycans) by the osteoblasts(mainly proteoglycans) by the osteoblasts
Formation of osteoid…Formation of osteoid…
Importance of amorphous salts that are not converted in Importance of amorphous salts that are not converted in hydroxyapatite: fall in extracellular calcium and reabsorption of hydroxyapatite: fall in extracellular calcium and reabsorption of amorphous compoundsamorphous compounds
Precipitation of calcium in nonosseous tissues under abnormal Precipitation of calcium in nonosseous tissues under abnormal conditions: formation of arteriosclerosis, precipitation in blood clots.conditions: formation of arteriosclerosis, precipitation in blood clots.
Calcium exchange between bone and extracellular fluidCalcium exchange between bone and extracellular fluid
Importance of exchangeable calcium; a rapid buffering Importance of exchangeable calcium; a rapid buffering mechanismmechanism
Deposition of bone by the osteoblastsDeposition of bone by the osteoblasts
Absorption of bone – function of the osteoclastsAbsorption of bone – function of the osteoclasts
Bone deposition and absorption are normally in equlibriumBone deposition and absorption are normally in equlibrium
Value of continual bone remodelingValue of continual bone remodeling
Control of the rate of bone deposition by bone “stress”Control of the rate of bone deposition by bone “stress”
Repair of a fracture activates osteoblastsRepair of a fracture activates osteoblasts
A coronal section of
bone tissue
RANK: Osteoclast procursor cells produce a surface receptor protein
RANK Ligand
Ostaoblasts produce osteoprotegerin which interferes with RANKL
Vitamin DVitamin D
Vitamin D has a potent effect to increase calcium absorption from Vitamin D has a potent effect to increase calcium absorption from the intestinal tractthe intestinal tract
Vitamin D itself is not the active substanceVitamin D itself is not the active substance It must first be converted through a succession of reactions in the It must first be converted through a succession of reactions in the
liver and kidneys to the final active product; 1,25-liver and kidneys to the final active product; 1,25-dihydroxycholecalciferoldihydroxycholecalciferol
Cholecalciferol (Vitamin D3) is formed in the skin: UV and 7-Cholecalciferol (Vitamin D3) is formed in the skin: UV and 7-dehydroxycholesteroldehydroxycholesterol
Cholecalciferol that we ingest in foodCholecalciferol that we ingest in food
Vitamin D is lipid soluble and can be stored in fat tissueVitamin D is lipid soluble and can be stored in fat tissue
Synthesis and Functions of 1,25-dihydroxycholecalciferol
Calcium ion concentration controls the formation of
1,25-dihydroxycholecalciferol
Formation of Formation of 1,25-dihydroxycholecalciferol is controlled
inversely proportional to plasma levels of calcium
When plasma calcium levels rise, parathyroid hormone When plasma calcium levels rise, parathyroid hormone
secretion is inhibited, conversion of 25-hidroxycalciferol secretion is inhibited, conversion of 25-hidroxycalciferol
to 1,25-dihydroxycholecalciferol is prevented to 1,25-dihydroxycholecalciferol is prevented
Instead, Vitamin D is converted to an inactive form, Instead, Vitamin D is converted to an inactive form,
24,25-dihydroxycholecalciferol24,25-dihydroxycholecalciferol
Calcium ion concentration controls the formation of
1,25-dihydroxycholecalciferol
Synthesis and Functions of 1,25-dihydroxycholecalciferol
Actions of Vitamin D
Hormonal effect of vitamin D to promote intestinal calcium Hormonal effect of vitamin D to promote intestinal calcium
absorptionabsorption It does this by increasing formation of a calcium-binding protein in the It does this by increasing formation of a calcium-binding protein in the
intestinal epithelial cellsintestinal epithelial cells
Vitamin D promotes phosphate absorption by the intestinesVitamin D promotes phosphate absorption by the intestines
Vitamin D decreases renal calcium and phosphate excretionVitamin D decreases renal calcium and phosphate excretion
Effect of Vitamin D on bone and its relation to parathyroid Effect of Vitamin D on bone and its relation to parathyroid
hormone activityhormone activity Vitamin D in smaller quantities promotes bone calcification, whereas in Vitamin D in smaller quantities promotes bone calcification, whereas in
extreme quantities causes bone absorptionextreme quantities causes bone absorption
In the absence of Vit D, bone resoptive action of PTH is greatly reducedIn the absence of Vit D, bone resoptive action of PTH is greatly reduced
PARATHYROID HORMONE (PTH)PARATHYROID HORMONE (PTH)
Physiologic anatomy of the parathyroid glandsPhysiologic anatomy of the parathyroid glands
The chief cells in the parathyroid glands secrete PTHThe chief cells in the parathyroid glands secrete PTH
Chemistry of parathyroid hormone: proteinChemistry of parathyroid hormone: protein
ParatParathyroid Glandshyroid Glands
ParatParathyroid Glandshyroid Glands
ParatParathyroid Glands and Histologyhyroid Glands and Histology
Effect of PTH on calcium and phosphate
concentrations in the extracellular fluid
PTH increases plasma calcium concentrationsPTH increases plasma calcium concentrations
1- It increases calcium and phosphate absorption in the bone1- It increases calcium and phosphate absorption in the bone
2- With the fast action of PTH, it decreases renal excretion of 2- With the fast action of PTH, it decreases renal excretion of
calciumcalcium
Rapid phase of calcium and phosphate absorption: OsteolysisRapid phase of calcium and phosphate absorption: Osteolysis
Slow phase of bone absorption and calcium phosphate release: Slow phase of bone absorption and calcium phosphate release:
Activation of the osteoclastsActivation of the osteoclasts
Osteoclasts do not themselves have membrane receptors for PTHOsteoclasts do not themselves have membrane receptors for PTH
PTH decreases calcium excretion and increases PTH decreases calcium excretion and increases phosphate excretion by the kidneysphosphate excretion by the kidneys
PTH causes rapid loss of phosphate in urine, by decreasing its PTH causes rapid loss of phosphate in urine, by decreasing its
tubular reabsorptiontubular reabsorption
In contrast, PTH increases tubular reabsorption of calciumIn contrast, PTH increases tubular reabsorption of calcium
The increased calcium absorption occurs mainly in the The increased calcium absorption occurs mainly in the
late distal tubule and collecting tubuleslate distal tubule and collecting tubules
PTH increases intestinal absorption of calcium and phosphatePTH increases intestinal absorption of calcium and phosphate
Role of Vitamin DRole of Vitamin D
Control of PTH Secretion by CalciumControl of PTH Secretion by Calcium
PTH secretion is controlled by plasma concentrations of PTH secretion is controlled by plasma concentrations of
calciumcalcium
Increased activity of parathyroid glands in pregnancy and Increased activity of parathyroid glands in pregnancy and
lactationlactation
Conditions that increase plasma calcium levels above normal Conditions that increase plasma calcium levels above normal
cause decreased activity and reduced size of the parathyroid cause decreased activity and reduced size of the parathyroid
glandsglands
CALCITONINCALCITONIN
Calcitonin is a peptide hormone secreted by parafollicular (C type) Calcitonin is a peptide hormone secreted by parafollicular (C type)
cells in the thyroid glandcells in the thyroid gland
High plasma calcium concentrations increase calcitonin releaseHigh plasma calcium concentrations increase calcitonin release
In turn, calcitonin reduces plasma calcium concentrationsIn turn, calcitonin reduces plasma calcium concentrations1- The immediate effect is to decrease the absorptive activities of the osteoclasts 1- The immediate effect is to decrease the absorptive activities of the osteoclasts
and possibly the osteolytic effect of the osteolytic membraneand possibly the osteolytic effect of the osteolytic membrane
2- The second and more prolonged effect of calcitonin is to decrease the 2- The second and more prolonged effect of calcitonin is to decrease the
formation of new osteoclastsformation of new osteoclasts
Calcitonin has a weak effect on plasma calcium concentration in the Calcitonin has a weak effect on plasma calcium concentration in the
adult humanadult human
Control of calcium concentrations in the extracellular fluid
1- The first line of defense: Fuffer function of exchangable calcium in the bone
2- The second line of defense: Hormonal control
Regulation of PTH SecretionRegulation of PTH Secretion
HYPOPARATHYROIDISMHYPOPARATHYROIDISM
When the parathyroid glands do not secrete sufficient PTH, When the parathyroid glands do not secrete sufficient PTH,
osteocytic reabsorption of exchangable calcium decreases and the osteocytic reabsorption of exchangable calcium decreases and the
osteoclasts become almost totally inactiveosteoclasts become almost totally inactive
Hypoparathyroidism causes hypocalcemiaHypoparathyroidism causes hypocalcemia
In its treatment, Vitamin D and calcium are administeredIn its treatment, Vitamin D and calcium are administered
Hypoparathyroidism is usually not treated with PTH administrationHypoparathyroidism is usually not treated with PTH administration
PRIMARY HYPERPARATHYROIDISM The cause of primary hyperparathyroidism is usually a tumor of one of the The cause of primary hyperparathyroidism is usually a tumor of one of the
parathyroid glandsparathyroid glands
Bone disease in hyperparathyroidism: In severe hyperparathyroidism, Bone disease in hyperparathyroidism: In severe hyperparathyroidism,
increased osteoclastic reabsorption far exceeds osteoblastic depositionincreased osteoclastic reabsorption far exceeds osteoblastic deposition
And the bone may be eaten away entirelyAnd the bone may be eaten away entirely
In addition to absorption of the old bones, osteoblastic activity to form new In addition to absorption of the old bones, osteoblastic activity to form new
bone also increases bone also increases
When osteoblasts become active, they secrete large quantities of alkaline When osteoblasts become active, they secrete large quantities of alkaline
phosphatasephosphatase
Effects of hypercalcemiaEffects of hypercalcemia
Parathyroid poisoning and metastatic calcificationParathyroid poisoning and metastatic calcification
CaHPO4 crystals become deposited in the alveoli of the lungs, CaHPO4 crystals become deposited in the alveoli of the lungs,
kidneys, thyroid gland, arteries and stomachkidneys, thyroid gland, arteries and stomach
Formation of kidney stones in hyperparathyroidismFormation of kidney stones in hyperparathyroidism
SECONDARY HYPERPARATHYROIDISMSECONDARY HYPERPARATHYROIDISM
In secondary hyperparathyroidism, high levels of PTH occur as a In secondary hyperparathyroidism, high levels of PTH occur as a
compensation for hypocalcemia rather than a primary tumor of the compensation for hypocalcemia rather than a primary tumor of the
parathyroid glandparathyroid gland
It can be caused by Vit D deficiency or failure to form active Vit D in chronic It can be caused by Vit D deficiency or failure to form active Vit D in chronic
renal diseaserenal disease
Rickets – Vitamin D deficiencyRickets – Vitamin D deficiency
Mainly occurs in childrenMainly occurs in children
It results from calcium or phosphate deficiency in the extracellular fluidIt results from calcium or phosphate deficiency in the extracellular fluid
Usually caused by vitamin D deficiencyUsually caused by vitamin D deficiency
SECONDARY HYPERPARATHYROIDISMSECONDARY HYPERPARATHYROIDISM
Rickets:Rickets:
Plasma concentration of calcium and phosphate decrease in Rickets: Plasma concentration of calcium and phosphate decrease in Rickets:
The plasma calcium concentration is rickets is only slightly The plasma calcium concentration is rickets is only slightly
depressed, but the level of phosphate is greatly decreaseddepressed, but the level of phosphate is greatly decreased
Rickets weakens bonesRickets weakens bones
Tetany in ricketsTetany in rickets
Treatment of rickets:Treatment of rickets: Supplying adequate calcium and phosphate in the dietSupplying adequate calcium and phosphate in the diet
Administering large amount of Vit DAdministering large amount of Vit D
RicketsRickets►Deficiency of Vit D in Deficiency of Vit D in
childhoodchildhood
Lack of sun exposureLack of sun exposure
Deficiency in dietDeficiency in diet
► Decreased plasma calciumDecreased plasma calcium
► Increased PTH secretionIncreased PTH secretion
► Increased bone resorptionIncreased bone resorption
O O oror X X legslegs
SECONDARY HYPERPARATHYROIDISMSECONDARY HYPERPARATHYROIDISM
Osteomalacia (adult rickets) Osteomalacia (adult rickets)
Adults seldom have a dietary deficiency of vit D or calciumAdults seldom have a dietary deficiency of vit D or calcium
Serious deficiency of vit D or calcium occasionally occur as a Serious deficiency of vit D or calcium occasionally occur as a
result of steatorrhea (failure to absorb fat)result of steatorrhea (failure to absorb fat)
Osteomalacia caused by renal rickets: Osteomalacia caused by renal rickets:
OSTEOPOROSISOSTEOPOROSIS
Osteoporosis: decreased bone matrixOsteoporosis: decreased bone matrix
Osteoporosis is the most common of all bone diseases in Osteoporosis is the most common of all bone diseases in
adults. Most common causes are:adults. Most common causes are:
1- Inactivity (lack of physical stress)1- Inactivity (lack of physical stress)
2- Malnutrition, lack of protein in diet2- Malnutrition, lack of protein in diet
3- Deficiency of Vit C (reduced osteoblastic activity)3- Deficiency of Vit C (reduced osteoblastic activity)
4- In older ages, markedly decreased growth hormone and other 4- In older ages, markedly decreased growth hormone and other
factorsfactors
5- Cushing Syndrome5- Cushing Syndrome
6- Reduced secretion of estrogen in menopause6- Reduced secretion of estrogen in menopause
Estrogen and OsteoporosisEstrogen and Osteoporosis
Role of cytokines in the bone tissueRole of cytokines in the bone tissue Bone resorption increasing effectBone resorption increasing effect
Estrogen
IL-1, IL-6, TGF- and TNF-
Bone resorption
+
-
PHYSIOLOGY OF TEETH