Hormonal control of Calcium Metabolism

1. HORMONAL CONTROL OF
CALCIUM METABOLISM
Dr. M. Anbarasi, MD (Physiology)

2. HORMONES INVOLVED…
1,25 Dihydrocholecalciferol
Parathyroid hormone
Calcitonoin
Parathyroid hormone related protein
{ PTHrP}
Miscellaneous hormones :
Glucocorticoids, Growth hormone,
Estrogen

3. CALCIUM & PHOSPHATE
METABOLISM

4. NORMAL VALUES
Total body calcium – 1100 g {27.5 mol / L}
99 % in bones
Plasma calcium : 9 – 11 mg / dL
{5 m Eq / L or 2.5 mmol / L}
Ionized calcium – 50 % {1.2 mmol / L}
Protein bound – 41 % {1.0 mmol / L}
Complexed with anions – 9 % {0.2 mmol / L}

5. FUNCTIONS OF CALCIUM
Blood coagulation
Muscle contraction
Transmission of nerve impulses
Formation of skeleton ,etc.
FREE IONIZED CALCIUM

6. EFFECTS OF ALTERED CALCIUM
HYPOCALCEMIA
•Nerve and muscle cells becomes hyperexcitable.
increased neuronal membrane
permeability to Na
+
channels
HYPOCALCEMIC TETANY – latent or manifest

Calcium at 6 mg / dL --- TETANY
at 4 mg / dL --- LETHAL
Alkaline pH – tetany at higher values.

7. SIGNS OF MANIFEST TETANY
CARPOPEDAL SPAM
Obstetric hand /
Main d’ acconcheur hand
•Laryngeal stridor
•Convulsions
•Visceral features like
intestinal spasm,
bronchospasm and
profuse sweating.

8. LATENT TETANY
•CHVOSTEK’S SIGN
•TROUSSEAU’S SIGN

9. HYPERCALCEMIA
CALCIUM LEVEL > 12 mg / dL
•Nervous system is depressed
•Reflex activities are sluggish
•Decreased QT interval
•Lack of appetite

10. CALCIUM IN BONE
Two types
1.Readily exchangeable reservoir
{500 mmol of Ca
2+
is exchanged}
2. Stable calcium
{7.5 mmol of Ca
2+
is exchanged}

11. CALCIUM IN KIDNEYS
•98 % - 99 % is reabsorbed
60 % in PCT
40 % in Ascending limb of LOH

Distal tubule

PARATHYROID HORMONE

12. CALCIUM IN GIT
•30 – 80 % of ingested calcium is absorbed
•Actively transported out of the intestinal cells with
the help of
Ca
2+
dependent ATPase
•Increased plasma calcium – decreased absorption
from the gut
•Decreased by phosphates and oxalates and alkalis
•Increased by high protein diet
1,25 Vitamin D
3

13. GLOMERULAR
FILTRATE
250 mmol
DIET
25mmol (1000 mg)
GIT
FECES
22.5mmol
ABSORPTION
15 mmol
SECRETION
12.5 mmol
REABSORPTION
247.5
mmol
ECF
35 mmol
URINE
2.5 mmol
BONE
EXCHANGEABLE
100 mmol
STABLE
27,200 mmol
RAPID
EXCHANGE
500 mmol
REABSORPTION
7.5 mmol

14. PHOSPHATE METABOLISM

15. NORMAL VALUES
•Total body phosphate – 500 to 800 g.
•85 – 90 % in skeleton
•Plasma phosphate – 12 mg / dL
2/3
rd
– organic
1/3
rd
– inorganic {Pi}
ex. PO
4
3-
, HPO
4
2-
, H
2
PO
4
2-
FUNCTIONS
ATPase , c AMP , 2-3, DPG
Phosphorylation and Dephosphorylation

16. BONE:
3 mg of PO
4
enters and is again reabsorbed.
KIDNEYS:
85 % - 90 % of filtered Pi is reabsorbed by
Active Transport in PCT

PTH
Overflow mechanism

17. G I T
•Absorbed in duodenum and small intestine
by Active transport and passive diffusion.
•Absorption is linear to dietary intake.
•All PO
4
excreted in urine.

18. BONE PHYSIOLOGY

19. Made up of organic matrix and salts
COLLAGEN FIBERS
•90 – 95 %
•Type 1 collagen made
up of triple helix
GROUND
SUBSTANCES
•Gelatinous substances
(ECF + proteoglycans)
Chondroitin sulphate
Hyaluranic acid
ORGANIC MATRIX

20. BONE SALTS
•Salts of calcium and phosphate.
HYDROXYAPATITE
Ca
10
(PO
4
)
6
. (OH)
2
400 Å long
10 – 30 Å thick
100 Å wide
Ca / P ratio – 1.3 to 2.0
Other salts:
Mg
2+
, Na
+
, K
+
ions conjugated to
bone crystals.

21. STRUCTURE OF BONE
2 types of bones
Compact or Cortical bone – 80 %
• surface to volume ratio is low
• receive nutrients by canaliculi
Trabecular or Spongy bone – 20 %
• made up of spicules or plates with high
surface to volume ratio
• receive nutrients from the ECF through
Haversian canal

23. BONE GROWTH
Fetus to adults – ENCHONDRAL BONE
FORMATION
Exception: clavicles, mandibles and certain
skull bones.
INTRAMEMBRANOUS BONE
FORMATION

25. EPIHYSEAL PLATE – bone increases in length
Width is proportionate to growth and influenced by
GH.
EPIPHYSEAL CLOSURE
Cartillage cells hypertropied
Release VEGF
Vascularization and ossification

26. BONE FORMATION &
RESORPTION
•Bone formation by OSTEOBLASTS
•Bone resorption by OSTEOCLASTS

27. CELLS OF BONE
•OSTEOPROGENITOR CELLS
•OSTEOBLASTS
•OSTEOCYTES
•OSTEOCLASTS

29. OSTEOBLASTS
•Modified fibroblasts developed from
mesenchymal cells
•Secrete collagen monomers and ground
substances
•Finally forms an ‘OSTEOID’
•Calcium salts are deposited in the collagen
fibers and forms hydroxyapatite crystals.

30. OSTEOCYTES
•Mature bone cells – imprisoned osteoblasts
in the lacunae of osteon.
•Sends processes throughout bone matrix
•Maintains the metabolic activity of bone
• Opens the channels for distribution of
nutrients
•Exchanges calcium between bone and ECF.

31. OSTEOCLASTS
•MEMBER OF MONOCYTE FAMILY
•Attach its ruffled border to bone via integrins in the
“sealing zone”
•Proton pumps secrete acid and acidify the isolated area
•Proteolytic enzymes breaks down the organic matrix
•Eats away the bone in 3 wks - tunnel
•Osteoblasts are activated - forms a new Haversian
canal.

34. CONTINUAL BONE FORMATION :
strength
shape for mechanical support
replace old brittle bone.
BONE STRESS:
•Compressional load – bone in cast
•Shape of the bone

35. FRACTURE:
•Activates periosteal and intraosseous
osteoblasts
•Stimulates osteoprogenitor cells.
•Formation of “ CALLUS ”

36. VITAMIN D
3

37. FORMATION OF VITAMIN D
3

38. 7 DEHYDROCHOLESTEROL
PREVITAMIN D3
VITAMIN D3
CHOLECACIFEEROL
25- HYDROXY CHOLECALCIFEROL
25 HYDROXYLASE
LIVER
24, 25 DIHYDROXY
CHOLECALCIFEROL
1, 25 DIHYDROXY
CHOLECALCIFEROL
KIDNEY
1 α HYDROXYLASE
24 α HYDROXYLASE
SUNLIGHT

39. MECHANISM OF ACTION
•1,25 – dihydroxycholecalciferol is a steroid
compound (secosteroid)
•Acts via the steroid receptor superfamily
•Exposes the DNA – binding domain and
results in increased transcription of some
mRNAs.

40. ACTIONS OF VITAMIN D
3
1. Promotes intestinal calcium absorption
BY
1. Formation of calcium binding protein
(calbindin)
2. Formation of calcium stimulated ATPase
3. Formation of alkaline phosphatase

41. 25-HYDROXYLASE

43. 2. Promotes phosphate absorption by the
intestines
• As a direct effect
• Calcium acts as a transport mediator for
phosphate.
3. Decreases renal excretion of calcium &
phosphate
•Increases reabsorption of Ca and PO
4
by the
renal tubules

44. 4. Increases both bone resorption and bone
mineralization
BONE RESORPTION – by stimulating PTH.
Calcitriol receptors are present in osteobasts
Receptor – calcitriol complex – stimulate osteoblasts
--- activation & differentiation of osteoclasts.
BONE MINERALIZATION – by stimulation
osteoblasts and alkaline phosphatase secretion

45. REGULATION OF SYNTHESIS

25 –OH D
3
1,25 (OH)
2
D3
BONE
&
INTESTINES
Ca
PO
4
PTH
24,25- (OH)
2
D3

46. RICKETS & OSTEOMALACIA
VITAMIN D deficiency in children and adults
- defective bone mineralization and calcification
- failure to deliver adequate Ca and PO
4

FEATURES:
Weakness and bowing of weight bearing bones,
dental defects and hypocalcemia.
Responsive to Vitamin D therapy.
VITAMIN D RESISTANT RICKETS:
mutations in the gene coding for the enzyme
1 α HYDROXYLASE

47. Rickety rosary

49. STRUCTURE
•FOUR parathyroid
glands located behind
the thyroid gland
•6 x 3 x 2 mm
•Two types of cells
1.Chief cells
2.Oxyphil cells

50. CHEMISTRY
Pre pro PTH ( 115 aa)
Pro PTH ( 90 aa )
PTH ( 84 aa )
Normal plasma PTH
10 -55 pg / mL
Half life – 10 mins

51. ACTIONS OF PTH
I.Increases calcium and phosphate
absorption from the bones
II.Decreases excretion of calcium by the
kidneys
III.Increases the excretion of phosphate by
the kidneys
IV.Increases intestinal absorption of calcium
and phosphate.
INCREASED PLASMA CALCIUM

52. I. Ca & PO
4
absorption from the bone
Two phases
1.Rapid phase – osteolysis by osteocytes
2.Slow phase – by osteoclasts

53. RAPID PHASE - OSTEOLYSIS
BONE
ECF
OSTEOCYTIC MEMBRANE
OCTEOCYTES
BONE FLUID
B.FLBECFO.M

54. Ca
Ca
Ca
Ca
Ca
Ca
Ca
Ca
Ca
BONEBONE FLUID
OSTEOCYTIC
MEMBRANE
ECF
PTH

55. SLOW PHASE
Done by OSTEOCLASTS…
immediate activation of existing cells
formation of new cells
Excess bone resorption
Stimulates osteoblastic activity

56. II. Excretion of calcium and phosphate...
•Decreases excretion of calcium
increases reabsorption in CD, DT
and Ascending limb of LOH
•Increases excretion of phosphate
PHOSPHATURIC ACTION
dimishes absorption in PCT

57. III. Absorption of Ca & PO
4
in GIT…
Enhances absorption of both calcium and
phosphate by stimulating
1,25 – dihydroxycholecalciferol.
•cAMP mediated.
•cAMP is in plenty in osteoblasts and
osteocytes

58. MECHANISM OF ACTION
•Binds to PTH receptors – 3 types.
•REGULATION:
stimulus : plasma calcium level.

59. •Produced by the parafollicular cells / C cells
of thyroid gland.
•Remnants of ultimobrachial body.
STRUCTURE:
Molecular weight – 3500 and has 32
aminoacids.
In brain “Calcitonin gene related
polypeptide ( CGrP)” is formed.

60. •STIMULUS : Increased plasma calcium
Others: β adrenergic agonists, dopamine and
estrogen, GASTRIN, CCK, glucagon..
•ACTIONS:
Decreases absorptive action of osteoclasts
Deposits exchangeable Ca in bone salts
Decreases the formation of osteoclasts
•CLINICAL USE:
Used in the treatment of
PAGET’S DISEASE.

61. DISORDERS OF PTH
•HYPOPARATHYROIDISM
•HYPERPARATHYROIDISM
primary and secondary
•PSEUDOHYPOPARATHYROIDISM

62. HYPOPARATHYROIDISM
•Body calcium level decreases
•Osteoclasts are inactive
•Sudden removal – signs of tetany appears
•Responds to treatment with PTH or Vitamin D
3
PSEUDOHYPOPARATHYROIDISM
PTH is normal
Defect is in PTH receptors
Not responsive to hormone therapy

63. PRIMARY
HYPERPARATHYROIDISM
•Tumors – adenoma of parathyroid glands
•More common in women.
•Extreme osteolytic resorption - calcium and

phosphate levels.
Bone :
Punched out cystic areas in the bone filled by osteoclasts
– osteoclast tumors
‘ osteitis fibrosa cystica’
Serum Alkaline phosphatase is elevated.

64. Hypercalcemia:
P. Calcium – 12 – 15 mg / dL
CNS depression, muscle weakness, constipation,
abdominal pain, peptic ulcer, lack of appetite etc…
Metastatic calcification:
CaHPO
4
crystals are deposited in renal tubules, lung
alveoli, thyroid glands etc…
Renal stones:
Calcium phosphate and also calcium oxalate stones

65. SECONDARY
HYPERPARATHYROIDISM
•Increased levels of PTH is the result of
compensatory mechanism to hypocalcemia
•Due to chronic renal disease or deficiency
of Vitamin D
3

66. OSTEOPOROSIS
Diminished bone matrix due to poor
oeteoblastic activity
Causes:
1. Lack of physical stress
2. Malnutrition
3. Postmenopausal lack of estrogen
4. Old age
5. Lack of Vitamin C
6. Cushing’s syndrome

67. OTHER HORMONES
PARATHYROID HORMONE RELATED PROTEIN
( PTHrP)
•Produced by different tissues of our body
•Binds to PTH receptors
•Marked effect on growth and development of cartilage in
utero.
•Cartilage growth is stimulated by a protein called
“Indian hedgehog”
•Other uses :
Brain – prevents excitotoxic damage
Placenta – transports calcium
•Defect in PTHrP – severe skeletal deformities.

68. GLUCOCORTICOIDS
Lowers plasma calcium by inhibiting
osteoclasts.
Over Long periods – osteoporosis
Inhibit protein synthesis in osteoblasts,thereby
synthesis of organic matrix
Inhibit absorption of Ca and Po
4
from the gut
and facilitate its excretion in the kidneys.

69. GROWTH HORMONE
Increases intestinal absorption of Calcium
“Positive calcium balance”
IGF – I
Stimulates protein synthesis in bone.
THYROID HORMONE
Hypercalcemia, Hypercalciuria and
Osteoporosis.
ESTROGENS
Prevents osteoporosis by inhibiting certain
cytokines
INSULIN
Increases bone formation