HOMEOSTASIS CALCIUM and

PARATHYROID HORMON
Integrative Teaching Bloc 9
Prof. dr. Hardi Darmawan, MPH&TM, FRSTM
Dr. Swanny, MSc
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Learning Objectives
After studying this section, you will be able
to :
1.Learn how the body controls the calcium
level.
2.Understand the inter - action of
Parathyroid hormone, vitamin D3 and
calcitonin in homeostatic regulation of
extra and intracellular calcium level.
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Learning Objectives
3.Recognize the clinical manifestations of
calcium homeostatic disturbances.
4.Recognize and understand the
pathophysiology of the diseases related to
disturbances of endocrine control of
calcium homeostasis.

CALCIUM BALANCE
99% of calcium in the body is found in
BONES.
Calcium pool in bone is relatively stable.
1% of non bone calcium that is most critical
to physiological functioning.

FUNCTION of Calcium
1. Extracellular calcium : 99% of total
calcium in the body.
located in the bone.
Function : calcified matrix of bone

CA AS BONE MATRIX
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FUNCTION of Calcium
2. Extracellular fluid: 0,1 %
Function :
- Cement for tight junctions
- Myocardial and smooth muscle contraction
- Release of neurotransmitters at synapses
- Excitability of neurons due to effect on Na
permeability
- Cofactor for coagulation cascade
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FUNCTION of Calcium
3. Intracellular : 0,9 %
Function :
- Signal in second messenger pathways.
- Muscle contraction.

1. Calcium is a signal molecule

Ca is most concentrated in ECF and inside
organelles; endoplasmic reticulum and
sarcoplasmic reticulum.
If membrane channels for Ca open, Ca
moves into cytoplasma, creating a signal
that initiates exocytosis of synaptic &
secretory vesicles, altered activity of
enzymes or transporters.
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2. CEMENT
Calcium is part of the intercellular cement
that holds cells together at tight junctions

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3. Cofactor in the coagulation

cascade
At each step in cascade, an enzyme
converts an inactive precursor into an
active enzyme, with the help of calcium,
such as converting of in active factor XI,
IX, X to an active factor XI, IX, X.
Although Ca is essential for coagulation,
body Ca level never decrease to the point
that coagulation is inhibited.
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4. Excitability of neurons
Clinically related
Hypocalcemia : neuronal permeability to Na
increases, neurons depolarizes, and the nervous
system become hyperexcitable.
It will cause sustained contraction (Tetany) of
hand: carpopedal spasm , of respiratory
muscles, resulting in asphyxiation.
Hypercalcemia : causes depressing neuromuscular
activity.
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Homeostasis of Calcium
Calcium is critical to many physiological
functions.
Calcium level must very closely regulated.
Principle of calcium homeostasis :
TOTAL BODY CALCIUM = INTAKE - OUTPUT

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INTAKE of calcium
Required daily amounts of Ca : 1,2 gram
Intake is dietary ingestion and uptake in
small intestine ( duodenum ). Calcium
absorption is active transport and
hormonally regulated.
Absorption is exactly controlled in relation to
the need of the body for calcium.
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OUTPUT of calcium
Calcium loss : primarily through Kidney.
small amounts in feces
Ionized Ca is freely filtered at glomerulus.
Reabsorbed along the length of nephron.
Hormonally regulated reabsorption occurs
in distal nephron.

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Normal distribution and

movements of calcium in
the body. (ICF, intracellular
fluid; ECF, extracellular
fluid)

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EXTRACELLULAR CALCIUM
1. PLASMA CALCIUM.
Ca concentration : 9 10 mg/dl. Equivalent to 2,4 mmol Ca
/ liter.
40% (1 mmol/ l ) is combined with plasma protein. This
form is nondiffusible to capillary membrane.
10% (0,2 mmol/ l ) is combined with other substances of
plasma and interstitial fluid (citrate , phosphate).
Diffusible to capillary membrane.
50% is ionized and diffusible.

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INTRACELLULAR CALCIUM
The concentration of free calcium in cytosol
is about 0,001 mM. Calcium is
concentrated inside mitochondria and
sarcoplasmic reticulum.
These electrochemical gradients favor
movement of Ca++ into cytosol when
Ca++ channels open.
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EXTRACELLULAR MATRIX (BONE)

Bone is the largest reservoir of Ca++ in the body.
Most bone Ca++ in the form of HYDROXYAPATITE
crystals.
Bone Ca++ in equilibrium with Ca++ of the
interstitial fluid.
Only small fraction is ionized and readily
exchangeable.
Bone is constantly remodelling.
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Osteoblast controls deposition of Ca++ into

bone.
Osteoclast controls movement of Ca++ out
of hydroxyapatite and into ionized Ca++
pool. Osteoclast are responsible for
dissolving bone or RESORPTION.

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PHOSPHATE HOMEOSTASIS
Closely links to Calcium homeostasis.
Most found in bone, especially in hydroxyapatite of
bone , Ca10(PO4)6(OH)2 .
Phosphate homeostasis parallels that of Ca++.
Absorbed in intestines, filtered, reabsorbed in
kidneys.
Divided between bones, ECF, and intracellular.

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FUNCTION of PHOSPHATE
Energy transfer
Storage in high energy-phosphate bonds
Activation and deactivation of enzymes,
transporters, and ion channels.
Part of the DNA and RNA backbone.

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Sites of control of extracellular

calcium concentration
1. PLASMA
2. INTESTINE
3. KIDNEY
4. BONE
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HORMONAL CONTROL of CALCIUM

BALANCE
1. Parathyroid hormone
2. Vitamin D3 ( Calcitriol, 1,25
dihydroxycholecalciferol )
3. Calcitonin
4. Cortisol
5. Growth Hormone
6. Sex steroid ( estrogen, testosteron )
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Parathyroid hormone
Essential for life.
Cell of origin : parathyroid glands
Chemical nature : 84-amino acids peptide
Biosynthesis : continuous production, little
stored
Transport : dissolved in plasma
Half life : less than 20 minutes
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Parathyroid hormone
Factor affecting release : decrease plasma
Ca++
Target cell : Kidney, bone, intestine
Target receptor : membrane receptor acts
via cAMP
Whole body or tissue action : increase
plasma Ca++
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Actions of
parathyroid
hormone (PTH) on
the kidney and
bone

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Parathyroid hormone
Action at cellular level :
Increase vit.D3 synthesis
Increase renal reabsorption of Ca++
Increase bone resorption
Action at molecular level :
Rapidly alters Ca++ transport but also initiates
protein synthesis in osteoclasts.
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Activation of vitamin D (25 (OH) vitamin D3, 25 hydroxyvitamin D3; 1,25(OH)2 vitamin D3, 1,25dihydroxyvitamin D3)
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Parathyroid hormone
Onset of action :
2 3 hours for bone, with increased
osteoclast activity requiring 1 2 hours; 1
2 days for intestinal absorption; within
minutes for kidney transport.
Feed back regulation : Negative feed back
by increasing plasma Ca++
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Other information
Osteoclast have no PTH receptors, so are
affected by PTH induced paracrines.
PTH is ESSENTIAL FOR LIFE.
Absence of PTH causes hypocalcemic
tetany, which may lead to death.

34

How PTH raises Ca++

concentration
1. PTH mobilizes calcium from bone.
Increased bone resorption by osteoclasts takes
about 12 hours to become measurable.
Osteoclasts do not have PTH receptors.
PTH effects are mediated by paracrines, such as
osteoprotegerin (OPG) and osteoclast
differentiation factor called RANKL.

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PTH raises Ca++

2. PTH enhances renal reabsorption of
calcium.
Takes place in the distal nephron.
PTH simultaneously enhances renal
excretion of phosphate by reducing its
reabsorption.

36

Actions of
parathyroid
hormone (PTH) on
the kidney and
bone

37

PTH raises Ca++

3. PTH indirectly increases intestinal

absorption of calcium by its influence on
vit.D3.

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Calcitriol ( 1,25dihydroxycholecalciferol) or vitamin

D3
Chemical nature : Steroid
Biosynthesis : formed by sunlight on
precursor molecules or ingested in food;
converted in 2 steps (liver & kidney) to
1,25-(OH)2 D3.
Transport in circulation : bound to plasma
proteins
39

Actions of vitamin D on the gastrointestinal tract, bone,

and kidney
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Calcitriol
Stimulus for synthesis : decrease of Ca++;
indirectly via PTH, prolactin also stimulates
synthesis.
Target cells/tissues : Intestine, bone, kidney
Target receptor
: nuclear
Whole body or tissue action : increase of
plasma calcium
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Calcitriol
Action at molecular level : stimulates
production of calbindin, a Ca++ -binding
protein; associated with intestinal
transport by unknown mechanism.
Feed back regulation : plasma Ca++ shuts
off PTH secretion
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Calcitonin
Cell of origin : C cells of thyroid gland
(parafollicular cells)
Chemical nature : 32-amino acid peptide
Biosynthesis : typical peptide
Transport
: dissolved in plasma
Half life
: less than 10 minutes
Factor affecting release : increase plasma
Ca++.
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Calcitonin
Target cell/tissues : bone and kidney
Target receptor
: G-protein-coupled
membrane receptor
Whole body action : prevents bone
resorption; enhances kidney excretion.
Action at molecular level : signal
transduction pathways appear to vary
during cell cycle.
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Calcitonin
Other information :
Experimentally decreases plasma Ca++, but
has little apparent physiological effect in
adult humans; possible effect on skeletal
development; possible protection of bone
Ca++ stores during pregnancy and
lactation.
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Calcitonin
Plays a minor role in daily calcium balance in
adult human.
Medically, used to treat patients with
PAGET disease, a genetic disorder in
which osteoclasts are overactive and bone
is weakened by resorption.
Speculation : most important during
childhood growth, pregnancy and lactation
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Actions of calcitonin on the kidney and bone

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Cortisol
Minor role.
At low levels : necessary for normal bone
growth.
At high levels : inhibits bone formation, that
may leads to osteoporosis.

48

Growth Hormone
Minor role
Increase the formation of bone at normal
level.
Action of GH on bone is mediated via
Somatomedin.

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Sex Steroids
Minor role.
Estrogen and testosteron causes closure of
epiphyse of bone.
After menopause, estrogen level decreases,
bone resorption increases which is may
cause osteoporosis.

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Integrated control of extracellular

calcium
In HYPOCALCEMIA :
1. PTH increases :- increase bone resorption.
- increase renal
reabsorption
- increase phosphate
excretion
- increase renal synthesis of
vit. D3

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2. Increase synthesis of vit.D3 :

-increase absorption of Ca++ in intestine
-increase renal reabsorption
-increase PTH action on bone.
NET RESULT: plasma Ca++ increases
hypocalcemia is restore back to
calcium balance again.

52

HYPOCALCEMIA
Causes :
1. Hypoparathyroidsm :
caused by : a. autoimmune atrophy.
b. inadvertent removal of
parathyroid glands at
thyroidectomy
PTH level low
Ca++ level low
Phosphate level high
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2. Pseudohypoparathyroidism.
a rare hereditary disorder.
failure of target cells to response to PTH.
PTH levels high.
Ca++ low
Phosphate levels high

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3. Vitamin D deficiency.
Causes : a. inadequate enzymatic
conversion.
b. increase rate of metabolism
c. insufficient sun or intake
PTH levels high.
Ca++ levels low
Phosphate levels low
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4. Renal disease.
Failure to excrete phosphate and reabsorp
Ca++.
Ca++ levels low
Phosphate levels high
PTH level high

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Symptoms and signs of

hypocalcaemia

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HYPERCALCEMIA
1. Hyperparathyroidism
Caused by : tumor of parathyroid gland
PTH levels high
Ca++ levels high
Phosphate levels low

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2. Vitamin D toxicity.
Ca++ levels high
Phosphate levels high
PTH levels low

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Symptoms and
signs of
hypercalcaemia

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Parathyroid and Bone diseases

1. Hypoparathyroidism.
PTH level low---osteocytic reabsorption of
exchangeable calcium decreases. Osteoclasts
become inactive. Bone resorption decreases,
so that plasma Ca++. Phosphate in blood
increases.
Symptoms : muscle weakness, increase of
neuromuscular activity, such as hyperactive
reflex, seizures and tetany.
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Hyperparathyroidism
Caused by tumor of parathyroid glands.
Occurs more frequently in women, because
pregnancy and lactation stimulates the
glands.
Osteoclastic activity increases elevates
Ca++ concentration in ECF, depressed
phosphate concentration due to increased
renal excretion.
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Bone disease in hyperparathyroidism

Due to increased activity of osteoclasts ; bone
undergoes extensive decalcification
cystic areas easily fracture : Osteitis fibrosa
cystica.
Activity of osteoblast increases also secrete
alkaline phosphatase.
One of important diagnostic finding in
hyperparathyroidism is a high level of plasma
alkaline phophatase.
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Effects of hypercalcemia in
hyperparathyroidism
Plasma calcium level : 12 -15 mg/ dl.
Cause depression of CNS and peripheral
nervous system --- muscle weakness,
constipation, abdominal pain, peptic ulcer,
lack of appetite, depressed relaxation of
heart during diastole.

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Parathyroid poisoning and

Metastatic calcification
If PTH level extremely increased; level of calcium
in body rises rapidly. Phosphate level often rises
also. Calcium and phosphate in ECF becomes
supersaturated
--CaHPO4 crystals deposited in alveoli of lung,
tubules of kidney, thyroid gland, acid producing
area of stomach mucosa, walls of arteries
throughout body.
Extensive metastatic deposition of calcium
phosphate ----death.
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Kidney stones
Crystals of calcium phosphate tend to
precipitate in kidney forming kidney
stones.
Tendency for forming renal calculi is greater
in alkaline urine, because the solubility of
renal stones is slight in alkaline media.

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RICKETS
Occur mainly in children.
Caused by : deficiency of vit. D.
Plasma level of calcium and phosphate
decreases.
Ordinarily, plasma calcium is slightly
depressed, but phosphate concentration is
greatly depressed.
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Effects of Rickets on bones

Prolonged Rickets PTH increased
(compensatory mechanism) osteoclastic
absorption of bone increases bone
becomes weaker easily fractured.
Lack of calcium and phosphate new bone
is uncalcified, and weak osteoid takes
place of the older bone that is being
reabsorbed.
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Tetany in RICKETS
Tetany occurs when the blood concentration
of calcium falls below 7 mg%.
The child may die of tetanic respiratory
spasm.
Treatment of tetany : intravenous calcium.

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Signs and symptoms caused by rickets

Rickets (Childhood)
- Knock- knees or bow-legs caused by bending
of the long bones.
- Chest deformities, back deformities (e.q.
kyphosis) and protruding forehead.
- Features of hypocalcaemia.

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Osteomalacia
Adult Rickets.
Deficiency of vit. D or calcium is caused by
steatorrhea ( failure to absorb fat).
Prolonged kidney damage renal rickets.
Caused by renal failure to form 1,25-(OH)2 vit.D3.
Often a serious problem for patients whose
kidneys have been removed or destroyed and
are being treated by hemodialysis.
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Signs and symptoms caused by

osteomalacia
Osteomalacia (adulthood)
- Bone pain
- Bones appear thin on X-ray, with localized
lucencies (called Loosers zones)
- Fractures (common in the neck of the femur)
- Features of hypocalcaemia (e.q. proximal
myopathy causes waddling gait)

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OSTEOPOROSIS
Most common bone diseases in adults,
especially in old age.
Disease of bone loss, due to bone resorption
exceeding bone deposition. The result is
fragile, weakened bones that are easily
fractured.
Particularly affect spongy trabecular bone, in
vertebrae, hip and wrist.
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A complex disease with genetic and

environmental components.
Risk factors include small, thin body type,
postmenopausal age, smoking and low
dietary Calcium intake.
Most common in women after menopause
when estrogen level falls.

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Causes of Osteoporosis
1.
2.
3.
4.
5.

Inactivity lack of physical stress on bone.

Malnutrition.
Lack of vit. C necessary for making osteoid.
Postmenopausal lack of estrogen.
Old age GH, growth factors diminish protein
anabolic function decreases poor bone
matrix deposition.
6. Cushings diseases cortisol increases
increased protein catabolism depressing
osteoblastic activity.
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Calcium Regulation
The regulation of Ca++ involves 3 tissues :

1.

Bone
Intestine
Kidney

The regulation of Ca++ involves 3 hormones :

2.

Parathormone
Calcitonin
Activated vitamin D3 (activated calciferols)

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3.

The regulation of Ca++ involves 3 cell

types :

Osteoblasts
Osteocytes
Osteoclasts

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Hormonal Control

Pituitary gld does not play a major role in

the regulation of the cells that produce
parathormons, calcitonin, vitamin D3

81

Parathormone

Polypeptide : 84 amino acid residues

Secreted by : chief cells of 4 parathyroid
glds
Hypercalcemic hormone of the body
Effect on the : bone, intestine, kidney
Regulates only : plasma concentration of
ionic form of Ca++
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Inverse linear relationship between [Ca++]

and parathormons secretion.
[Ca++] and parathormons secretion
[Ca++] and parathormons secretion

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Calcitonin

32 amino acid residue polypeptide

Secreted by parafollicular cells (c cells)
of the thyroid gld
Hypocalcemic hormone
Effect on the: bone, intestine, kidney
Positive linear relationship between [Ca++]
and calcitonin secretion
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[Ca++] , calcitonin secretion

[Ca++] , calcitonin secretion

Calcitonin release : stimulate by pentagastrin

Vitamin D3 (Cholecalciferol)

Vitamin hormone : secosteroid (27 carbonatomes)

largest (steroid hormone)

Active metabolites of this hormone : exert biologic

activity
85

a.

Calcidiol (25 hydroxyvitamin D3 or 25

hydroxycholecalciferol)

b.

One of active metabolite of Vitamin D

Major blood form
2-5 > more effective than Vitamin D3 in
preventing rickets.

Calcitriol (1.25-dihydroxyvitamin D3 or
1.25 dihydroxycholecalciferol)

Another active metabolite of vitamin D3

On weight basis : 100x > potent than
calcidiol.
86

The synthesis of active vitamin D3

a)

7-dehydrocholesterol

vitamin D3

(skin)

b)

uv light

Vitamin D3

25 hydroxyvitamin D3
25-hydroxylase

c)

25 hydroxyvitamin D3

(in the liver)

1.25 dihydroxy
1 = hydroxylase

vitamin D3
(kidney)

87

Cellular Aspects of Bone Metabolism

1.

Osteoblasts

Highly differentiated cells

Non mitotic in their differentiated state

Bone forming cells

Located on the bone forming surface

Osteoblasts

Synthesize and secrete collagen

They contain abundant alkaline phoshatase

activity
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2.

Osteocytes

Are osteoblasts that have become burried in

bone matrix

Each cell is surrounded by its own lacuna

Extensive canalicular system connects

osteocytes and surface osteoblasts, forming a
functional syncytium in the osteocyticform :
no longer synthesize collagen

Osteocytes : have an osteolytic activity

stimulated by performance

Osteocytic osteolysis :

In the bone matrix provider

Rapid movement of Ca++ from bone ECF space
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Osteolaclasts

Large, multinucleated cells

Numerous lysosomes
Mediate bone resorption at bone surfaces
Contain acid phosphatase
Form significant amounts of lactic and hyaluromic
acids
Cause bone dissolution via increased

Local concentration of H+ which solubilizes bone

mineral
activity of enzymes that degrade matrix
90

Physiologic actions of Parathormone

1.

Osseous Tissue
Parathormone action on bone :
increased Ca++ phosphate mobilization
(bone dissolution) from non readily
exchangeable Ca++ pool.

Long term effects of PTH on bone :

release of Ca ++ from bone : related to
bone remodelling, involves bone
resorption & accretion
PTH: stimulate bone synthesis
PTH effects on osteogenesis can be both91

Parathormone has 3 important effects

on bone account for its overall
osteolytic activity
1.

2.

3.

It stimulates osteoclastic & osteolytic

activity
It stimulates fusion of progenitor cells to
form multinucleated osteoclastic cells
Parathormone causes transcient
suppresion of osteoblastic activity
92

References.
1. Guyton and Hall, Text book of Medical
Physiology.
2. Ganong, W.F. , Review of Medical
Physiology.
3. Silverthorn, D.U., Human Physiology, An
integrated approach.

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THANK YOU

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