Hormonal Control of Calcium &

Phosphate Metabolism
M. Djauhari Widjajakusumah

Faculty of Medicine
University of Indonesia

Introduction
Three hormones are primarily concerned with the regulation of
calcium
metabolism:
1,25-Dihydroxycholecalciferol
o a steroid hormone formed from vitamin D
o increases calcium absorption from the intestine.
Parathyroid hormone (PTH)
o mobilizes calcium from bone, increases urinary phosphate
excretion.
Calcitonin,
o secreted primarily by cells in the thyroid gland
o inhibits bone resorption
All three hormones operate in concert to maintain the constancy of
the
Ca2+ level in the body fluids

Calcium Homeostasis Control

Control of intestinal Ca absorbtion ( by vit D3)

Control of bone Ca
PTH & Calcitonin

Control of renal Ca reabsorbtion

PTH : reabsorbtion
1,25 DHC : reabsorbtion
Calcitonin : reabsorbtion

Calcium Metabolism
o The body of a young adult human contains about 1100 g
(27.5 mol) of calcium
o 99% of the calcium is in the skeleton
o The plasma calcium, normally about 10 mg/dL (5 meq/L,
2.5 mmol/L), is partly bound to protein and partly
diffusible
o Free, ionized calcium in the body fluids:
a vital second messenger
necessary for blood coagulation, muscle contraction,
and nerve function
o The extent of Ca2+ binding by plasma proteins is
proportionate to the plasma protein level it is
important to know the plasma protein level when
evaluating the total plasma calcium.
o Other electrolytes and pH also affect the free Ca2+ level.
Ganongs Review of Medical Physiology, 23rd
ed, 2010

Calcium
Calcium Distribution
Distribution
Total Calcium
1100 g 1.5% BW

Bone Calcium
99% total

Plasma Calcium
1% total
10 mg/dL-2.5 mmol/l

Diffusible
1.34 mmol/l
59% plasma calcium
calcium

Nondiffusible
1.16 mmol/l
41% plasma
(protein-bound)

Ionized (Ca++)
1.18 mmol/l
Bound to
50% plasma calcium
globulin

Complexed to HCO3, citrate

0.16 mmol/l
9% plasma calcium

Ganongs Review of Medical Physiology,

23rd ed, 2010

Bound to
albumin

0.92 mmol/l

0.24 mmol/l

Fig 23-14. Total body calcium, an index of bone mass, at various ages in
men and women. Note the rapid increase to young adult levels (phase I)
followed by the steady loss of bone with advancing age in both sexes (phase III)
and the superimposed rapid loss in women after menopause (phase II).
Ganongs Review of Medical Physiology,

Calcium in Bone
o The calcium in bone is of two types:
a readily exchangeable reservoir and ,
a much larger pool of stable calcium that is only
slowly exchangeable.
o Two independent but interacting homeostatic systems
affect the calcium in bone.

The system that regulates plasma Ca2+, providing

for the movement about 500 mmol of Ca2+ per day
into and out of the readily exchangeable pool in the
bone (Figure 231).

The system that involves bone remodeling by the

constant interplay of bone resorption and deposition.

The Ca2+ interchange between plasma and this

stable pool of bone calcium is only about 7.5 mmol/d.
Ganongs Review of Medical Physiology,
23rd ed, 2010

(1000 mg)

25 mmol (1000 mg)

Figure 231
Calcium metabolism in an adult human. A typical daily intake of 25 mmol Ca2+
(1000 mg) moves through many body compartments.

Ganongs Review of Medical Physiology,

Calcium metabolism in an adult

human

Robert M. Berne,
Matthew N. Levy,
Bruce M. Koeppen,
Bruce A. Stanton:
Physiology, 5th
ed, 2007

Figure 42-1 Average daily calcium turnover in humans. Note both the external
balance between intake and excretion and the internal balance between entry into
and exit from bone.

Phosphorus
Metabolism

Robert M. Berne,
Matthew N. Levy,
Bruce M. Koeppen,
Brice A. Stanton:
Physiology, 5th ed, 2007

Figure 42-2 Average daily phosphate turnover in humans. Note both the external
balance between intake and excretion and the internal balance between entry into
and exit from bone.

Parathyroid Gland

Figure 219.

Figure 219.

Humans usually have four

parathyroid glands: two embedded
in the superior poles of the thyroid
and two in its inferior poles.

The human parathyroid glands, viewed from behind.

Review of Medical Physiology,
Ganongs Review of Medical Physiology, 22nd Ganongs
rd
23 ed, 2010

Parathyroid Gland

Each parathyroid gland is a

richly vascularized disk, about
3 x 6 x 2 mm, containing two
distinct types of cells: (a) The
abundant chief cells, which
contain a prominent Golgi
apparatus plus endoplasmic
reticulum and secretory
granules, synthesize and
Section of human parathyroid. Small cells are chief
cells; large stippled cells (especially prominent in
secrete parathyroid hormone
the lower left of picture) are oxyphil cells.
(PTH).
(b) The less abundant and
larger oxyphil cells contain
oxyphil granules and large
Ganongs Review of Medical Physiology,
23rd numbers
ed, 2010 of mitochondria in

PTH Actions

PTH acts directly on bone to increase bone resorption and

mobilize Ca2+.

In addition to increasing the plasma Ca2+, PTH increases

phosphate excretion in the urine and thereby depresses
plasma phosphate levels.

This phosphaturic action is due to a decrease in

reabsorption of phosphate via effects on NaPi-IIa in the
proximal tubules.

PTH increases reabsorption of Ca2+ in the distal tubules

PTH increases the formation of 1,25dihydroxycholecalciferol, and this increases Ca2+

absorption from the intestine.

On a longer time scale, PTH stimulates both osteoblasts and

osteoclasts.
Ganongs Review of Medical Physiology,
23rd ed, 2010

PTH Mechanism of Action

Figure 237
Signal transduction pathways activated by PTH or PTHrP binding to the
hPTH/hPTHrP receptor. Intracellular cAMP is increased via Gs and adenylyl
cyclase (AC). Diacylglycerol and IP3 (1,4,5-InsP3) are increased via Gq and
phospholipase C (PLC).

OSTEOBLASTOGENESIS - OSTEOCLASTOGENESIS
Bone Marrow Culture
Fibroblast ColonyForming Unit
(Osteoprogenitor cells)
Osteoblast, Fibroblast
Chondrocytes, Adipocytes
Progenitors
PTH
Calcitriol
RANK-L
Osteoblastic
precursor cells
(+)
Late pre-osteoclast
Estrogen
(+)
(+)
Androgen
Osteoblast
IGF-1

Granulocyte-Macrophag
Colony Forming Unit
(Hematopoetic cells)
Osteoclast, Monocytes
Macrophage Progenitors

(-)
Early pre-osteoclast

(+)

Osteoclast
Bone Resorption

Bone Forming (RANK: receptor activator of nuclear factor kappa B) =

(ODF: osteoclast differentiation factor)

Osteoblast
Osteoblast Osteoclast
Osteoclast Communication
Communication
osteoblast (& osteoblast precursors)
estrogens

glucocorticoids
PTH
osteoprotegerin (OPG)
free-floating decoy receptor

osteoclast precursors
RANK receptor
+

estrogens

OPG-ligand
(RANK ligand)

osteoclast +
RANK receptor
osteoclast activity

RANK ligand
(osteoblast) +

bone resorption
PTH, DHC (vit D3), IL 1- 4 - 6-11-17, TNF-alfa

Regulation of Secretion
o Circulating ionized calcium acts directly on the parathyroid
glands in a negative feedback fashion to regulate the
secretion of PTH.
o Activation of this G-protein coupled receptor, a cell
membrane Ca2+ receptor, CaR, inhibits PTH secretion.
when the plasma Ca2+ level is high, PTH secretion is
inhibited and the Ca2+ is deposited in the bones.
when the plasma Ca2+ level is low, secretion is increased
and Ca2+ is mobilized from the bones.
o 1,25-dihydroxycholecalciferol acts directly on the parathyroid
glands to decrease preproPTH mRNA.
o Increased plasma phosphate stimulates PTH secretion by
lowering plasma levels of free Ca2+ and inhibiting the
formation of 1,25-dihydroxycholecalciferol.
o Magnesium is required to maintain normal parathyroid
secretory responses.
o Impaired PTH release along with diminished target organ
responses to PTH account for the hypocalcemia that
occasionally occurs in magnesium deficiency.

Diseases of Parathyroid Excess

o Hyperparathyroidism is characterized by hypercalcemia and
hypophosphatemia.
o Humans with PTH-secreting adenomas are usually
asymptomatic, with the condition detected when plasma
Ca2+ is measured in conjunction with a routine physical
examination.
o There may be minor changes in personality, and calciumcontaining kidney stones occasionally form.
o In conditions such as chronic renal disease and rickets, in
which the plasma Ca2+ level is chronically low, stimulation
of the parathyroid glands causes compensatory parathyroid
hypertrophy and secondary hyperparathyroidism.
o The plasma Ca2+ level is low in chronic renal disease
primarily because the diseased kidneys lose the ability to
form 1,25-dihydroxycholecalciferol.

Effects of Parathyroidectomy

Occasionally, inadvertent parathyroidectomy

occurs in humans during thyroid surgery a

steady decline in the plasma Ca2+ level.

Signs of neuromuscular hyperexcitability appear,

followed by full-blown hypocalcemic tetany

Plasma phosphate levels usually rise as the

plasma calcium level falls

Symptoms usually develop 2 to 3 d

postoperatively but may not appear for several

weeks or more

Injections of PTH can be given to correct the

chemical abnormalities, and the symptoms then

disappear

Injections of Ca2+ salts can also give temporary

relief

Effects of Parathyroidectomy

The signs of tetany in humans include

Chvostek's sign, a quick contraction of the

ipsilateral facial muscles elicited by tapping
over the facial nerve at the angle of the jaw,

Trousseau's sign, a spasm of the muscles of

the upper extremity that causes flexion of the
wrist and thumb with extension of the fingers.
In individuals with mild tetany in whom spasm
is not yet evident, Trousseau sign can
sometimes be produced by occluding the
circulation for a few minutes with a blood
pressure cuff.

Vitamin D & the

Hydroxycholecalciferols

Chemistry

o The active transport of Ca2+ and PO43 from the

intestine is increased by a metabolite of vitamin D
o Vitamin D3 (cholecalciferol) is produced in the skin of
mammals from 7-dehydrocholesterol by the action of
sunlight
o Vitamin D3 is also ingested in the diet
o Vitamin D3 25-hydroxycholecalciferol (calcidiol,
25-OHD3) [in the liver] the more active metabolite
1,25-dihydroxy-cholecalciferol (calcitriol or 1,25(OH)2D3) [in the proximal tubules cells of the kidneys,
in the placenta, in keratinocytes in the skin, and in
macrophages]
o The normal plasma level of 1,25dihydroxycholecalciferol + 0.03 ng/mL (+ 100 pmol/L).
Ganongs Review of Medical Physiology,

Regulation of Synthesis
o The formation of 1,25-dihydroxycholecalciferol in the kidneys,
catalyzed by the renal 1 -hydroxylase, is regulated in a
feedback fashion by plasma Ca2+ and PO43+.
o This effect of Ca2+ on production of 1,25dihydroxycholecalciferol is the mechanism that brings about
adaptation of Ca2+ absorption from the intestine.
o Expression of 1 -hydroxylase is stimulated by PTH, and when
the plasma Ca2+ level is low, PTH secretion is increased.
o The production of 1,25-dihydroxycholecalciferol is also
increased by low and inhibited by high plasma PO43 levels, by
a direct inhibitory effect of PO43 on the 1 -hydroxylase.
o Additional control
a direct negative feedback effect of the metabolite on 1hydroxylase,
a positive feedback action on the formation of 24,25dihydroxycholecalciferol,
a direct action on the parathyroid gland to inhibit PTH
expression.

Figure 232
Formation and hydroxylation of vitaminD3. 25-hydroxylation takes place in the
liver, and the other hydroxylations occur primarily in the kidneys. The formulas of 7dehydrocholesterol, vitamin D3, and 1,25-dihydroxycholecalciferol are also shown
below.
Ganongs Review of Medical Physiology,
23rd ed, 2010

Figure 796
Activation of vitamin D3 to form 1,25-dihydroxycholecalciferol and the role of vitamin D in
controlling the plasma calcium concentration.
Guyton & Hall: Textbook of Medical Physiology 11th ed

Feedback control of the formation of 1,25-dihydroxycholecalciferol (1,25-[OH]2D3)

from 25-hydroxycholecalciferol (25-OHD3) in the kidneys. Solid arrows indicate
stimulation, and dashed arrows indicate inhibition.
Ganongs Review of Medical
Physiology, 22nd ed

Fig 23-3.
Effects of PTH and 1,25-dihydroxycholecalciferol on whole body calcium
homeostasis. Note that these hormones are also involved in the regulation of
circulating phosphate levels.
Ganongs Review of Medical Physiology,

Parathormone and 1.25 (OH)2Cholecalciferol

7-dehydrocholesterol cholecalciferol (vit D3)

Prolactin

25(OH)D3
PTH

24.25(OH)2D3

1.25(OH)2 D3

Intestine Ca++ absorption

Kidney PO4 ion

Bone resorption

Kidney Ca++

reabsorbtion

plasma Ca++

+
--

plasma PO4 ion

reabsorption

Figure 798
Effect of plasma calcium concentration on the plasma concentration of 1,25dihydroxycholecalciferol. This figure shows that a slight decrease in calcium
concentration below normal causes increased formation of activated vitamin D,
which in turn leads to greatly increased absorption of calcium from the intestine.
Guyton & Hall: Textbook of Medical Physiology 11th ed

Rickets & Osteomalacia

o Vitamin D deficiency causes defective calcification of bone
matrix (rickets in children and osteomalacia in adults).
o It used to be due to inadequate exposure to the sun in
smoggy cities, now it is more commonly due to inadequate
intake of the provitamins on which the sun acts in the skin.
o These cases respond to administration of vitamin D.
o The condition can also be caused by inactivating mutations of
the gene for renal 1-hydroxylase, no response to vitamin
D but a normal response to 1,25-dihydroxycholecalciferol
(type I vitamin D-resistant rickets).
o In rare instances, it can be due to inactivating mutations of
the gene for the 1,25-dihydroxycholecalciferol receptor (type
II vitamin D-resistant rickets), a deficient response to
both vitamin D and 1,25-dihydroxycholecalciferol.

Ganongs Review of Medical Physiology,

23rd ed, 2010

Ca++ vital roles

1.
1.

Neuromuscular
Neuromuscular excitability
excitability
Em
Ca++

Em
muscular
muscular excitability
excitability
Ca++
Em
Ca++

Em
muscular
muscular excitability
excitability
Ca++

cardiac
cardiac arrhythmia
arrhythmia

2.
2.

Excitation-contraction
Excitation-contraction coupling
coupling in
in cardiac
cardiac &
& smooth
smooth muscle
muscle
Ca++
myocardial,
myocardial, and
and smooth
smooth muscle
muscle contractility
contractility
Ca++
(particularly)
(particularly)

3.
3.

Stimulus-secretion
Stimulus-secretion coupling
coupling
Ca++ entry
entry into
into secreting
secreting cells
cells (endocrine
(endocrine cells,
cells, nerve
nerve cells)
cells)
Ca++
in
in response
response to
to stimulation
stimulation
secretory
secretory product
product (peptide
(peptide
hormones,
hormones, catecholamines,
catecholamines, neurotransmitters)
neurotransmitters) exocytosis
exocytosis

4.
4.
5.
5.

Blood
Blood clotting
clotting
Bone
Bone minerals
minerals

Bone
Bone growth
growth and
and maintenance
maintenance

Hydroxyapatite:
Hydroxyapatite: Ca10(PO4)6(OH)2
Ca10(PO4)6(OH)2

6.
6.

Second
Second messenger
messenger

IP3
IP3
endoplasmic
endoplasmic reticulum
reticulum
Ca
Ca ion
ion
enzyme
enzyme activation
activation

Calcitonin

Control of secretion
Secreted by the parafollicular cells
[Ca++] > 9.5 mg/dl calcitonin
Estrogen
calcitonin
Glucagon
calcitonin

Calcitonin
Effects
Effects
Kidneys
Kidneys
Calcitonin
Calcitonin membrane
membrane receptors
receptors on
on renal
renal tubules
tubules cells
cells
Calcium
Calcium reabsorption
reabsorption
Phosphate
Phosphate reabosrption
reabosrption
Bones
Bones
Calcitonin
Calcitonin membrane
membrane receptors
receptors on
on osteoclast
osteoclast
osteoclast
osteoclast activity
activity
bone
bone resorption
resorption
Ca
Ca and
and PO4
PO4 release
release
Blood
Blood
[Ca++]
[Ca++]
[PO4]
[PO4]

Calcitonin
Prevents
Prevents bone
bone resorption
resorption excess
excess in
in pregnancy
pregnancy
estrogen
estrogen

prolactin
prolactin

+
+
calcitonin
calcitonin

1.25
1.25 DHC
DHC

bone
bone resorption
resorption
[Ca
[Ca ++]
++]
+
+
---

Thank You