HORMONAL CONTROL OF

CALCIUM METABOLISM

Dr. M. Anbarasi, MD (Physiology)

HORMONES INVOLVED…

1,25 Dihydrocholecalciferol

Parathyroid hormone

Calcitonoin

Parathyroid hormone related protein

{ PTHrP}

Miscellaneous hormones :

Glucocorticoids, Growth hormone, Estrogen

CALCIUM & PHOSPHATE METABOLISM

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}

FUNCTIONS OF CALCIUM

Blood coagulation

Muscle contraction

Transmission of nerve impulses

Formation of skeleton ,etc.

FREE IONIZED CALCIUM

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.

SIGNS OF MANIFEST TETANY

CARPOPEDAL SPAM

Obstetric hand /

Main d’ acconcheur hand

• Laryngeal stridor• Convulsions • Visceral features like

intestinal spasm, bronchospasm and profuse sweating.

LATENT TETANY

• CHVOSTEK’S SIGN

• TROUSSEAU’S SIGN

HYPERCALCEMIA

CALCIUM LEVEL > 12 mg / dL

• Nervous system is depressed

• Reflex activities are sluggish

• Decreased QT interval

• Lack of appetite

CALCIUM IN BONE

Two types

1. Readily exchangeable reservoir

{500 mmol of Ca2+ is exchanged}

2. Stable calcium

{7.5 mmol of Ca2+ is exchanged}

CALCIUM IN KIDNEYS

• 98 % - 99 % is reabsorbed

60 % in PCT

40 % in Ascending limb of LOH

Distal tubule

PARATHYROID HORMONE

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 D3

GLOMERULAR FILTRATE

250 mmol

DIET25mmol (1000 mg)

GIT

FECES22.5mmol

ABSORPTION

15 mmol

SECRETION

12.5 mmol

REABSORPTION247.5 mmol

ECF35 mmol

URINE2.5 mmol

BONE

EXCHANGEABLE100 mmol

STABLE27,200 mmol

RAPID EXCHANGE

500 mmol

REABSORPTION

7.5 mmol

PHOSPHATE METABOLISM

NORMAL VALUES

• Total body phosphate – 500 to 800 g.• 85 – 90 % in skeleton• Plasma phosphate – 12 mg / dL

2/3rd – organic

1/3rd – inorganic {Pi}

ex. PO43- , HPO4

2-, H2PO42-

FUNCTIONS

ATPase , c AMP , 2-3, DPG

Phosphorylation and Dephosphorylation

BONE:

3 mg of PO4 enters and is again reabsorbed.

KIDNEYS:

85 % - 90 % of filtered Pi is reabsorbed by Active Transport in PCT

PTH

Overflow mechanism

G I T

• Absorbed in duodenum and small intestine by Active transport and passive diffusion.

• Absorption is linear to dietary intake.

• All PO4 excreted in urine.

BONE PHYSIOLOGY

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

BONE SALTS• Salts of calcium and phosphate.

HYDROXYAPATITE

Ca10(PO4)6. (OH)2

400 Å long

10 – 30 Å thick

100 Å wide

Ca / P ratio – 1.3 to 2.0

Other salts:

Mg2+, Na+ , K+ ions conjugated to bone crystals.

STRUCTURE OF BONE2 types of bones Compact or Cortical bone – 80 %• surface to volume ratio is low• receive nutrients by canaliculiTrabecular or Spongy bone – 20 %• made up of spicules or plates with high

surface to volume ratio• receive nutrients from the ECF through

Haversian canal

BONE GROWTH

Fetus to adults – ENCHONDRAL BONE FORMATION

Exception: clavicles, mandibles and certain skull bones.

INTRAMEMBRANOUS BONE

FORMATION

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

BONE FORMATION & RESORPTION

• Bone formation by OSTEOBLASTS

• Bone resorption by OSTEOCLASTS

CELLS OF BONE

• OSTEOPROGENITOR CELLS

• OSTEOBLASTS

• OSTEOCYTES

• OSTEOCLASTS

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.

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.

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.

CONTINUAL BONE FORMATION :

strength

shape for mechanical support

replace old brittle bone.

BONE STRESS:

• Compressional load – bone in cast

• Shape of the bone

FRACTURE:

• Activates periosteal and intraosseous osteoblasts

• Stimulates osteoprogenitor cells.

• Formation of “ CALLUS ”

VITAMIN D 3

FORMATION OF VITAMIN D3

7 DEHYDROCHOLESTEROL

PREVITAMIN D3 VITAMIN D3CHOLECACIFEEROL

25- HYDROXY CHOLECALCIFEROL

25 HYDROXYLASE LIVER

24, 25 DIHYDROXY CHOLECALCIFEROL 1, 25 DIHYDROXY

CHOLECALCIFEROL

KIDNEY

1 α HYDROXYLASE24 α HYDROXYLASE

SUNLIGHT

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.

ACTIONS OF VITAMIN D3

1. Promotes intestinal calcium absorption BY

1. Formation of calcium binding protein

(calbindin)

2. Formation of calcium stimulated ATPase

3. Formation of alkaline phosphatase

25-HYDROXYLASE

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 PO4 by the renal tubules

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

REGULATION OF SYNTHESIS

25 –OH D31,25 (OH)2 D3 BONE

&INTESTINES

Ca

PO4

PTH

24,25- (OH)2 D3

RICKETS & OSTEOMALACIA

VITAMIN D deficiency in children and adults - defective bone mineralization and calcification

- failure to deliver adequate Ca and PO4 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

Rickety rosary

STRUCTURE

• FOUR parathyroid glands located behind the thyroid gland

• 6 x 3 x 2 mm

• Two types of cells1. Chief cells2. Oxyphil cells

CHEMISTRY

Pre pro PTH ( 115 aa)

Pro PTH ( 90 aa )

PTH ( 84 aa )

Normal plasma PTH 10 -55 pg / mLHalf life – 10 mins

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

I. Ca & PO4 absorption from the bone

Two phases

1. Rapid phase – osteolysis by osteocytes

2. Slow phase – by osteoclasts

RAPID PHASE - OSTEOLYSIS

BONEECF

OSTEOCYTIC MEMBRANE

OCTEOCYTES

BONE FLUID

B.FL BECF O.M

Ca

Ca

Ca

Ca

Ca

Ca

Ca

Ca

Ca

BONEBONE FLUIDOSTEOCYTIC MEMBRANE

ECF

PTH

SLOW PHASE

Done by OSTEOCLASTS…

immediate activation of existing cells formation of new cells

Excess bone resorption

Stimulates osteoblastic activity

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

III. Absorption of Ca & PO4 in GIT…

Enhances absorption of both calcium and phosphate by stimulating

1,25 – dihydroxycholecalciferol.

• cAMP mediated.

• cAMP is in plenty in osteoblasts and osteocytes

MECHANISM OF ACTION

• Binds to PTH receptors – 3 types.

• REGULATION:

stimulus : plasma calcium level.

• 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.

• 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.

DISORDERS OF PTH

• HYPOPARATHYROIDISM

• HYPERPARATHYROIDISM

primary and secondary

• PSEUDOHYPOPARATHYROIDISM

HYPOPARATHYROIDISM

• Body calcium level decreases• Osteoclasts are inactive• Sudden removal – signs of tetany appears• Responds to treatment with PTH or Vitamin D3

PSEUDOHYPOPARATHYROIDISM

PTH is normalDefect is in PTH receptors

Not responsive to hormone therapy

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.

Hypercalcemia:

P. Calcium – 12 – 15 mg / dL

CNS depression, muscle weakness, constipation, abdominal pain, peptic ulcer, lack of appetite etc…

Metastatic calcification:

CaHPO4 crystals are deposited in renal tubules, lung alveoli, thyroid glands etc…

Renal stones: Calcium phosphate and also calcium oxalate stones

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

OSTEOPOROSISDiminished bone matrix due to poor

oeteoblastic activity

Causes:1. Lack of physical stress 2. Malnutrition3. Postmenopausal lack of estrogen4. Old age5. Lack of Vitamin C6. Cushing’s syndrome

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.

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 Po4 from the gut and facilitate its excretion in the kidneys.

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

cytokinesINSULIN Increases bone formation