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

2. Skeleton * Bone tissue

3. Regulation of calcium and phosphate levels in the extracellular fluid and plasma
Extracellular fluid calcium concentration normally is regulated very precisely.
Normal plasma value is about 9.4 mg/dl
Hypercalcemia, progressive depression 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

4. Calcium in the Plasma and Interstitial Fluid
The calcium in the plasma is present in three forms:
About 41% of the calcium is combined with the plasma proteins and in this form is indiffusible thorugh the capillary membrane
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)
The remaining 50% of the calcium in the plasma is both diffusible and ionized

5. Calcium in the Plasma and Interstitial Fluid

6. Inorganic phosphate in the extracellular fluids
About 85% of the body phosphate is found in the bones; % in the cells and less than 1% in the extracellular fluid
Inorganic phosphate in the plasma is mainly in two forms:
HPO4-
H2PO4-
The average total quantity of inorganic phosphorus for both ions is about 4 mg/dl

7. 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
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
Hypercalcemia depresses nervous system and muscle activity. These effects become marked as the calcium level rises above 15 mg/dl

8. Absorption and Excretion of Calcium and Phosphate
Intestinal absorption and fecal excretion of calcium and phosphate
Renal excretion of calcium and phosphate
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
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…

9. Absorption and Excretion of Calcium and Phosphate

10. 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
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.
Hydroxyapatite = collagen + Ca(PO4)2 + OH + bicarbonate
Metals, radioactive and toxic substances can also be deposited in the bone

11. 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
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
Formation of osteoid…
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.

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

13. skeleton is not only important for locomotion, but protects the soft parts of the body like the brain, produces blood cells in the bone marrow of certain bones and is needed, with the muscles, to give the body shape and support.
Some bone is built up in layers between or beneath specialized tissue layers. That tissue is typically tough and not too unlike canvas in thickness and toughness. The plates of the skull are made wholly from bone layered between two such membranes. The shafts of long bones get thicker by deposition of bone beneath an encircling tube of similar tissue. Bone gets strength from two things.
1) What it is made from (kind of bone), and 2) How it is shaped and organized.

14. A coronal section of bone tissue

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

16. Vitamin D
Vitamin D has a potent effect to increase calcium absorption from the intestinal tract
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
Cholecalciferol (Vitamin D3) is formed in the skin: UV and 7-dehydroxycholesterol
Cholecalciferol that we ingest in food
Vitamin D is lipid soluble and can be stored in fat tissue

17. Synthesis and Functions of 1,25-dihydroxycholecalciferol

18. Calcium ion concentration controls the formation of 1,25-dihydroxycholecalciferol
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
Instead, Vitamin D is converted to an inactive form, 24,25-dihydroxycholecalciferol

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

20. Synthesis and Functions of 1,25-dihydroxycholecalciferol

21. Actions of Vitamin D
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
Vitamin D promotes phosphate absorption by the intestines
Vitamin D decreases renal calcium and phosphate excretion
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
In the absence of Vit D, bone resoptive action of PTH is greatly reduced

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

23. Parathyroid Glands

24. Parathyroid Glands

25. Parathyroid Glands and Histology

26. Effect of PTH on calcium and phosphate concentrations in the extracellular fluid
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
Slow phase of bone absorption and calcium phosphate release: Activation of the osteoclasts
Osteoclasts do not themselves have membrane receptors for PTH

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

28. Control of PTH Secretion by Calcium
PTH secretion is controlled by plasma concentrations of calcium
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

29. CALCITONIN
Calcitonin is a peptide hormone secreted by parafollicular (C type) cells in the thyroid gland
High plasma calcium concentrations increase calcitonin release
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

30. 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

31. Regulation of PTH Secretion

32. HYPOPARATHYROIDISM
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
In its treatment, Vitamin D and calcium are administered
Hypoparathyroidism is usually not treated with PTH administration

33. PRIMARY HYPERPARATHYROIDISM
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
And the bone may be eaten away entirely
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
Effects of hypercalcemia
Parathyroid poisoning and metastatic calcification
CaHPO4 crystals become deposited in the alveoli of the lungs, kidneys, thyroid gland, arteries and stomach
Formation of kidney stones in hyperparathyroidism

34. SECONDARY HYPERPARATHYROIDISM
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
Rickets – Vitamin D deficiency
Mainly occurs in children
It results from calcium or phosphate deficiency in the extracellular fluid
Usually caused by vitamin D deficiency

35. 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
Rickets weakens bones
Tetany in rickets
Treatment of rickets:
Supplying adequate calcium and phosphate in the diet
Administering large amount of Vit D

36. 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

37. SECONDARY HYPERPARATHYROIDISM
Osteomalacia (adult rickets)
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)
Osteomalacia caused by renal rickets:

38. OSTEOPOROSIS
Osteoporosis: decreased bone matrix
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

40. Estrogen and Osteoporosis
Role of cytokines in the bone tissue
Bone resorption increasing effect
Estrogen -
IL-1, IL-6, TGF-b and TNF-a +
Bone resorption

41. PHYSIOLOGY OF TEETH