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Parathyroid Hormone, Calcitonin, Calcium and Phosphate Metabolism, Vitamin D and Bone Prof. Dr. Bayram Yılmaz Faculty of Medicine Department of Physiology.

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Presentation on theme: "Parathyroid Hormone, Calcitonin, Calcium and Phosphate Metabolism, Vitamin D and Bone Prof. Dr. Bayram Yılmaz Faculty of Medicine Department of Physiology."— Presentation transcript:

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2 Parathyroid Hormone, Calcitonin, Calcium and Phosphate Metabolism, Vitamin D and Bone Prof. Dr. Bayram Yılmaz Faculty of Medicine Department of Physiology YEDİTEPE UNIVERSITY

3 Skeleton * Bone tissue Skeleton * Bone tissue

4 Regulation of calcium and phosphate levels in the extracellular fluid and plasma Extracellular fluid calcium concentration normally is regulated very precisely. Extracellular fluid calcium concentration normally is regulated very precisely. Normal plasma value is about 9.4 mg/dl Normal plasma value is about 9.4 mg/dl Hypercalcemia, progressive depression of the nervous system Hypercalcemia, progressive depression of the nervous system Hypocalcemia, increased excitability of the nervous system Hypocalcemia, increased excitability of the nervous system 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 bones 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 bones

5 Calcium in the Plasma and Interstitial Fluid The calcium in the plasma is present in three forms: 1) About 41% of the calcium is combined with the plasma proteins and in this form is indiffusible thorugh the capillary membrane 2) About 9% of the calcium is diffusible through the capillary membrane but is combined with anionic substances of the plasma and interstitial fluid (such as citrate and phosphate) 3) The remaining 50% of the calcium in the plasma is both diffusible and ionized

6 Calcium in the Plasma and Interstitial Fluid

7 Inorganic phosphate in the extracellular fluids About 85% of the body phosphate is found in the bones; 14-15 % in the cells and less than 1% in the extracellular fluid About 85% of the body phosphate is found in the bones; 14-15 % in the cells and less than 1% in the extracellular fluid Inorganic phosphate in the plasma is mainly in two forms: Inorganic phosphate in the plasma is mainly in two forms: HPO 4 HPO 4 - H 2 PO 4 H 2 PO 4 - The average total quantity of inorganic phosphorus for both ions is about 4 mg/dl The average total quantity of inorganic phosphorus for both ions is about 4 mg/dl

8 Non-bone physiologic effects of altered calcium and phosphate concentrations in the body fluids Changing the level of phosphate in the extracellular fluid from far below normal or two or three times normal does not cause major immediate effects on the body Changing the level of phosphate in the extracellular fluid from far below normal or two or three times normal does not cause major immediate effects on the body In contrast, even a slight increase or decrease of calcium ion in the extracellular fluid can cause extreme immediate physiologic effects. In contrast, even a slight increase or decrease of calcium ion in the extracellular fluid can cause extreme immediate physiologic effects. Hypocalcemia causes nervous system excitement and tetany. Increased permeability of neurons to sodium ions Hypocalcemia causes nervous system excitement and tetany. Increased permeability of neurons to sodium ions Hypercalcemia depresses nervous system and muscle activity. These effects become marked as the calcium level rises above 15 mg/dl Hypercalcemia depresses nervous system and muscle activity. These effects become marked as the calcium level rises above 15 mg/dl

9 Absorption and Excretion of Calcium and Phosphate Intestinal absorption and fecal excretion of calcium and phosphate Intestinal absorption and fecal excretion of calcium and phosphate Renal excretion of calcium and phosphate Renal excretion of calcium and phosphate Approximately 10% (100 mg/day) of the ingested calcium is excreted in urine Approximately 10% (100 mg/day) of the ingested calcium is excreted in urine Normally, the renal tubules reabsorb 99% of the filtered calcium, and only 100 mg/day is excreted in urine Normally, the renal tubules reabsorb 99% of the filtered calcium, and only 100 mg/day is excreted in urine Renal phosphate excretion is controlled by an over-flow mechanism, when phosphate level is below 1 mmol/lt, all phosphate in the glomerular filtrate is reabsorbed… Renal phosphate excretion is controlled by an over-flow mechanism, when phosphate level is below 1 mmol/lt, all phosphate in the glomerular filtrate is reabsorbed…

10 Absorption and Excretion of Calcium and Phosphate

11 Bone and its relation to extracellular calcium and phosphate Organic matrix of the bone: 90-95% collagen fibers, and the remaining is homogenous gelatinous medium called ground substance Organic matrix of the bone: 90-95% collagen fibers, and the remaining is homogenous gelatinous medium called ground substance The ground substance is composed of extracellular fluid plus proteoglycans, especially chondroitin sulfate and hyaluronic acid The ground substance is composed of extracellular fluid plus proteoglycans, especially chondroitin sulfate and hyaluronic acid Bone salts: The crystalline salts deposited in the organic matrix of the bone are composed principally of calcium and phosphate. Bone salts: The crystalline salts deposited in the organic matrix of the 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 bone Metals, radioactive and toxic substances can also be deposited in the bone

12 Precipitation and absorption of calcium and phosphate in bone Concentrations of calcium and phosphate in extracellular fluid are greater than those required to cause precipitation of hydroxyapatite Concentrations of calcium and phosphate in extracellular fluid are greater than those required to cause precipitation of hydroxyapatite Role of inhibitors: pyrophosphate Role of inhibitors: pyrophosphate Mechanism of bone calcification: The initial stage in bone production is secretion of collagen molecules and the ground substance (mainly proteoglycans) by the osteoblasts Mechanism of bone calcification: The initial stage in bone production is secretion of collagen molecules and the ground substance (mainly proteoglycans) by the osteoblasts Formation of osteoid… Formation of osteoid… Importance of amorphous salts that are not converted in hydroxyapatite: fall in extracellular calcium and reabsorption of amorphous compounds Importance of amorphous salts that are not converted in hydroxyapatite: fall in extracellular calcium and reabsorption of amorphous compounds Precipitation of calcium in nonosseous tissues under abnormal conditions: formation of arteriosclerosis, precipitation in blood clots. Precipitation of calcium in nonosseous tissues under abnormal conditions: formation of arteriosclerosis, precipitation in blood clots.

13 Calcium exchange between bone and extracellular fluid Importance of exchangeable calcium; a rapid buffering mechanism Importance of exchangeable calcium; a rapid buffering mechanism Deposition of bone by the osteoblasts Deposition of bone by the osteoblasts Absorption of bone – function of the osteoclasts Absorption of bone – function of the osteoclasts Bone deposition and absorption are normally in equlibrium Bone deposition and absorption are normally in equlibrium Value of continual bone remodeling Value 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 osteoblasts Repair of a fracture activates osteoblasts

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15 A coronal section of bone tissue

16 RANK: Osteoclast procursor cells produce a surface receptor protein RANK Ligand Ostaoblasts produce osteoprotegerin which interferes with RANKL

17 Vitamin D Vitamin D has a potent effect to increase calcium absorption from the intestinal tract Vitamin D has a potent effect to increase calcium absorption from the intestinal tract Vitamin D itself is not the active substance Vitamin D itself is not the active substance It must first be converted through a succession of reactions in the liver and kidneys to the final active product; 1,25- dihydroxycholecalciferol It must first be converted through a succession of reactions in the liver and kidneys to the final active product; 1,25- dihydroxycholecalciferol Cholecalciferol (Vitamin D3) is formed in the skin: UV and 7- dehydroxycholesterol Cholecalciferol (Vitamin D3) is formed in the skin: UV and 7- dehydroxycholesterol Cholecalciferol that we ingest in food Cholecalciferol that we ingest in food Vitamin D is lipid soluble and can be stored in fat tissue Vitamin D is lipid soluble and can be stored in fat tissue

18 Synthesis and Functions of 1,25-dihydroxycholecalciferol

19 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 secretion is inhibited, conversion of 25-hidroxycalciferol to 1,25-dihydroxycholecalciferol is prevented When plasma calcium levels rise, parathyroid hormone secretion is inhibited, conversion of 25-hidroxycalciferol to 1,25-dihydroxycholecalciferol is prevented Instead, Vitamin D is converted to an inactive form, 24,25-dihydroxycholecalciferol Instead, Vitamin D is converted to an inactive form, 24,25-dihydroxycholecalciferol

20 Calcium ion concentration controls the formation of 1,25-dihydroxycholecalciferol

21 Synthesis and Functions of 1,25-dihydroxycholecalciferol

22 Actions of Vitamin D Hormonal effect of vitamin D to promote intestinal calcium absorption Hormonal effect of vitamin D to promote intestinal calcium absorption It does this by increasing formation of a calcium-binding protein in the intestinal epithelial cells It does this by increasing formation of a calcium-binding protein in the intestinal epithelial cells Vitamin D promotes phosphate absorption by the intestines Vitamin D promotes phosphate absorption by the intestines Vitamin D decreases renal calcium and phosphate excretion Vitamin D decreases renal calcium and phosphate excretion Effect of Vitamin D on bone and its relation to parathyroid hormone activity Effect of Vitamin D on bone and its relation to parathyroid hormone activity Vitamin D in smaller quantities promotes bone calcification, whereas in extreme quantities causes bone absorption Vitamin D in smaller quantities promotes bone calcification, whereas in extreme quantities causes bone absorption In the absence of Vit D, bone resoptive action of PTH is greatly reduced In the absence of Vit D, bone resoptive action of PTH is greatly reduced

23 PARATHYROID HORMONE (PTH) Physiologic anatomy of the parathyroid glands Physiologic anatomy of the parathyroid glands The chief cells in the parathyroid glands secrete PTH The chief cells in the parathyroid glands secrete PTH Chemistry of parathyroid hormone: protein Chemistry of parathyroid hormone: protein

24 Parathyroid Glands

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26 Parathyroid Glands and Histology

27 Effect of PTH on calcium and phosphate concentrations in the extracellular fluid PTH increases plasma calcium concentrations PTH increases plasma calcium concentrations 1- It increases calcium and phosphate absorption in the bone 2- With the fast action of PTH, it decreases renal excretion of calcium Rapid phase of calcium and phosphate absorption: Osteolysis Rapid phase of calcium and phosphate absorption: Osteolysis Slow phase of bone absorption and calcium phosphate release: Activation of the osteoclasts Slow phase of bone absorption and calcium phosphate release: Activation of the osteoclasts Osteoclasts do not themselves have membrane receptors for PTH Osteoclasts do not themselves have membrane receptors for PTH

28 PTH decreases calcium excretion and increases phosphate excretion by the kidneys PTH causes rapid loss of phosphate in urine, by decreasing its tubular reabsorption PTH causes rapid loss of phosphate in urine, by decreasing its tubular reabsorption In contrast, PTH increases tubular reabsorption of calcium In contrast, PTH increases tubular reabsorption of calcium The increased calcium absorption occurs mainly in the late distal tubule and collecting tubules The increased calcium absorption occurs mainly in the late distal tubule and collecting tubules PTH increases intestinal absorption of calcium and phosphate PTH increases intestinal absorption of calcium and phosphate Role of Vitamin D Role of Vitamin D

29 Control of PTH Secretion by Calcium PTH secretion is controlled by plasma concentrations of calcium PTH secretion is controlled by plasma concentrations of calcium Increased activity of parathyroid glands in pregnancy and lactation Increased activity of parathyroid glands in pregnancy and lactation Conditions that increase plasma calcium levels above normal cause decreased activity and reduced size of the parathyroid glands Conditions that increase plasma calcium levels above normal cause decreased activity and reduced size of the parathyroid glands

30 CALCITONIN Calcitonin is a peptide hormone secreted by parafollicular (C type) cells in the thyroid gland Calcitonin is a peptide hormone secreted by parafollicular (C type) cells in the thyroid gland High plasma calcium concentrations increase calcitonin release High plasma calcium concentrations increase calcitonin release In turn, calcitonin reduces plasma calcium concentrations In turn, calcitonin reduces plasma calcium concentrations 1- The immediate effect is to decrease the absorptive activities of the osteoclasts and possibly the osteolytic effect of the osteolytic membrane 2- The second and more prolonged effect of calcitonin is to decrease the formation of new osteoclasts Calcitonin has a weak effect on plasma calcium concentration in the adult human Calcitonin has a weak effect on plasma calcium concentration in the adult human

31 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

32 Regulation of PTH Secretion

33 HYPOPARATHYROIDISM When the parathyroid glands do not secrete sufficient PTH, osteocytic reabsorption of exchangable calcium decreases and the osteoclasts become almost totally inactive When the parathyroid glands do not secrete sufficient PTH, osteocytic reabsorption of exchangable calcium decreases and the osteoclasts become almost totally inactive Hypoparathyroidism causes hypocalcemia Hypoparathyroidism causes hypocalcemia In its treatment, Vitamin D and calcium are administered In its treatment, Vitamin D and calcium are administered Hypoparathyroidism is usually not treated with PTH administration Hypoparathyroidism is usually not treated with PTH administration

34 PRIMARY HYPERPARATHYROIDISM The cause of primary hyperparathyroidism is usually a tumor of one of the parathyroid glands The cause of primary hyperparathyroidism is usually a tumor of one of the parathyroid glands Bone disease in hyperparathyroidism: In severe hyperparathyroidism, increased osteoclastic reabsorption far exceeds osteoblastic deposition Bone disease in hyperparathyroidism: In severe hyperparathyroidism, increased osteoclastic reabsorption far exceeds osteoblastic deposition And the bone may be eaten away entirely And the bone may be eaten away entirely In addition to absorption of the old bones, osteoblastic activity to form new bone also increases In addition to absorption of the old bones, osteoblastic activity to form new bone also increases When osteoblasts become active, they secrete large quantities of alkaline phosphatase When osteoblasts become active, they secrete large quantities of alkaline phosphatase Effects of hypercalcemia Effects of hypercalcemia Parathyroid poisoning and metastatic calcification Parathyroid poisoning and metastatic calcification CaHPO4 crystals become deposited in the alveoli of the lungs, kidneys, thyroid gland, arteries and stomach CaHPO4 crystals become deposited in the alveoli of the lungs, kidneys, thyroid gland, arteries and stomach Formation of kidney stones in hyperparathyroidism Formation of kidney stones in hyperparathyroidism

35 SECONDARY HYPERPARATHYROIDISM In secondary hyperparathyroidism, high levels of PTH occur as a compensation for hypocalcemia rather than a primary tumor of the parathyroid gland In secondary hyperparathyroidism, high levels of PTH occur as a compensation for hypocalcemia rather than a primary tumor of the parathyroid gland It can be caused by Vit D deficiency or failure to form active Vit D in chronic renal disease It can be caused by Vit D deficiency or failure to form active Vit D in chronic renal disease Rickets – Vitamin D deficiency Rickets – Vitamin D deficiency Mainly occurs in children Mainly occurs in children It results from calcium or phosphate deficiency in the extracellular fluid It results from calcium or phosphate deficiency in the extracellular fluid Usually caused by vitamin D deficiency Usually caused by vitamin D deficiency

36 SECONDARY HYPERPARATHYROIDISM Rickets: Plasma concentration of calcium and phosphate decrease in Rickets: The plasma calcium concentration is rickets is only slightly depressed, but the level of phosphate is greatly decreased Plasma concentration of calcium and phosphate decrease in Rickets: The plasma calcium concentration is rickets is only slightly depressed, but the level of phosphate is greatly decreased Rickets weakens bones Rickets weakens bones Tetany in rickets Tetany in rickets Treatment of rickets: Treatment of rickets: Supplying adequate calcium and phosphate in the diet Supplying adequate calcium and phosphate in the diet Administering large amount of Vit D Administering large amount of Vit D

37 Rickets ► Deficiency of Vit D in childhood – Lack of sun exposure – Deficiency in diet ► Decreased plasma calcium ► Increased PTH secretion ► Increased bone resorption – O or X legs

38 SECONDARY HYPERPARATHYROIDISM Osteomalacia (adult rickets) Adults seldom have a dietary deficiency of vit D or calcium Adults seldom have a dietary deficiency of vit D or calcium Serious deficiency of vit D or calcium occasionally occur as a result of steatorrhea (failure to absorb fat) Serious deficiency of vit D or calcium occasionally occur as a result of steatorrhea (failure to absorb fat) Osteomalacia caused by renal rickets: Osteomalacia caused by renal rickets:

39 OSTEOPOROSIS Osteoporosis: decreased bone matrix Osteoporosis: decreased bone matrix Osteoporosis is the most common of all bone diseases in adults. Most common causes are: Osteoporosis is the most common of all bone diseases in adults. Most common causes are: 1- Inactivity (lack of physical stress) 2- Malnutrition, lack of protein in diet 3- Deficiency of Vit C (reduced osteoblastic activity) 4- In older ages, markedly decreased growth hormone and other factors 5- Cushing Syndrome 6- Reduced secretion of estrogen in menopause

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41 Estrogen and Osteoporosis Role of cytokines in the bone tissue Role of cytokines in the bone tissue Bone resorption increasing effect Bone resorption increasing effect Estrogen IL-1, IL-6, TGF-  and TNF-  Bone resorption + -

42 PHYSIOLOGY OF TEETH


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