Overview of Calcium and Phosphate
Regulation in the Extracellular Fluid
and Plasma
Dr. Shafali Singh
Objectives
• Explain primary physiological actions of calcium
and phosphate.
• Understand the importance of maintaining
homeostasis of bodily calcium and phosphate
concentrations, and how this is accomplished.
• Describe the bodily pools of calcium, their rates
of turnover, and the organs that play central
roles in regulating movement of calcium
between stores.
• Define the basic anatomy of bone.
• Delineate cells and their functions in bone
formation and resorption
Calcium
• Calcium plays a key role
in many physiologic
processes,
• contraction of skeletal,
cardiac, and smooth
muscles; blood clotting,
transmission of nerve
impulses etc
• 0.1% –ECF
• 1 %- inside CELLS
• 99%-BONES
Plasma Ca : 9.4mg%
Phosphate
Phosphate have role in ATP
formation, act as biological
buffers, modifiers of protein.
• <1 %-ECF .
• 14 to 15 %-inside cells,
• 85 %- bones,
Plasma Phosphate: 3-5 mg%
Inorganic phosphate in the
plasma is mainly in two
forms:
HPO4- and H2PO4-
• Plasma calcium represents 45% ionized free,
40% attached to protein, 15% associated with
anions such as phosphate and citrate.
• The free calcium is the physiologically active
and precisely regulated form.
• The most accurate determination of free
calcium is via a calcium-selective electrode
Factors that may alter the ionized
Ca2+concentration
1. Acid-base abnormalities alter the ionized Ca2+
concentration by changing the fraction of Ca2+
bound to plasma albumin.
1. Changes in plasma protein concentration:
3. Changes in anion concentration alter the ionized
Ca2+ concentration:
Non-Bone Physiologic Effects
of Altered Calcium
Concentrations in the Body
Fluids
• Hypocalcemia Causes Nervous
System Excitement and Tetany.
Signs and Symptoms of Hypocalcemia
• Extensive spasms of skeletal muscle, involving
especially the muscles of the extremities and the
larynx.
Neurol Trousseau’s (carpopedal spasm)
Chvostek’s (CN VII spasm)
Paresthesias
Lethargy, seizures
Respiratory arrest
Cardio Heart block, CHF
Derm
Dry skin, brittle hair
Trousseau’s (carpopedal spasm)
Symptoms of tetany appear at higher total
calcium levels if the patient hyperventilates,
thereby increasing plasma pH.
Plasma proteins are more ionized when the
pH is high, providing more protein anion to
bind with Ca2+.
• Hypercalcemia Depresses
Nervous System and Muscle
Activity
Signs and Symptoms of Hypercalcemia
• If calcium is > 12 mg/dl, one may see:
Neurol Lethargy, confusion, coma
Psych
Depression, psychosis
Cardiol decreases the QT interval of heart
Nephrol nephrolithiasis (>17mg/dl)
GI
Nausea/emesis, anorexia
Constipation,
Intestinal Absorption and Fecal
Excretion of Phosphate
• Except for the portion of phosphate that is
excreted in the feces in combination with non
absorbed calcium, almost all the dietary
phosphate is absorbed into the blood from the
gut and later excreted in the urine.
• Phosphate excretion by the kidneys is controlled
primarily by an overflow mechanism : When less
than this amount of phosphate is present in the
glomerular filtrate, essentially all the filtered
phosphate is reabsorbed.
When more than this is present, the excess is
excreted.
Relationship Between Calcium and
Phosphate
• Whether calcium and phosphate are laid down
in bone (precipitate from solution) or are
resorbed from bone (go into solution) depends
on the product of their concentrations rather
than on their individual concentrations.
• When the product exceeds a certain number
(solubility product or ion product),
bone is laid down:
[Ca2+] x [P04] > solubility product = bone
deposition
Relationship Between Calcium and
Phosphate
• Under normal conditions the ECF product of calcium
times phosphate is close to the solubility product.
• Thus, an increase in the interstitial fluid concentration
of either Ca2+ or phosphate increases bone
mineralization.
• For example,
• an increase in plasma phosphate would increase the
product of their concentrations, promote precipitation,
and lower free calcium in the interstitial fluid.
• A malignant increase in the concentration of calcium or
phosphate due to chronic renal disease or
rhabdomyolysis can cause the precipitation of calcium
phosphate within tissues.
• When the product is below the solubility
product, bone is resorbed:
[Ca2+]x [P04] < solubility product = bone resorption
• Thus, a decrease in the interstitial concentration
of either Ca2+ or phosphate promotes the
resorption of these salts from bone
(demineralization).
• For example, a decrease in plasma phosphate
alone would promote bone demineralization.
Increasing renal excretion of phosphate would
promote bone demineralization and a rise in
interstitial free calcium.
BONE PHYSIOLOGY
Bone is involved in overall Ca2+ and PO43–
homeostasis. It protects vital organs, and the rigidity
it provides permits locomotion and the support of
loads against gravity
Bone formation:
Bone is a special form of connective tissue with a
collagen framework impregnated with Ca2+ and
PO43– salts, particularly hydroxyapatites
Mechanism of Bone Calcification
Secretion of collagen molecules and ground
substance by osteoblasts
collagen fibers form;the resultant tissue becomes
osteoid,
Ground substance is an amorphous, gel-like matrix of
glycosaminoglycans, proteoglycans, glycoproteins, salts, and
water that fills the space between cells in all tissues. Bone
ground substance is saturated with Ca2+ and PO4- .
OSTEOID
The combination of
colla-gen fibrils
and
ground substance
is called osteoid
Initial calcium salts to be deposited are amorphous compounds
(noncrystalline), then by a process of substitution and addition
of atoms, or reabsorption and reprecipitation, these salts are
converted into the hydroxyapatite crystals (Crystal Seeding)
•
Maturation
few per cent salt may remain permanently in the amorphous
form. These amorphous salts can be absorbed rapidly when
there is need for extra calcium in ECF
• Bone contains a type of exchangeable calcium
that is always in equilibrium with the calcium
ions in the extracellular fluids.
• This amounts to 0.4% to 1% of the total bone
calcium.
• This calcium is deposited in the bones in a form
of readily mobilizable salt such as CaHPO4 and
other amorphous calcium salts.
• Exchangeable calcium is that it provides a rapid
buffering mechanism
• Hydroxyapatite Does Not Precipitate in
Extracellular Fluid Despite Supersaturation
of Calcium and Phosphate Ions.
inhibitor pyrophosphate
• Precipitation of Calcium in Nonosseous
Tissues Under Abnormal Conditions:Arterial wall, degenerating tissue, old blood clot
REMODELLING OF BONE
Is a continuous process
BONE CELLS: Osteocytes, Osteoblasts and
Osteoclasts
Osteocytes & Osteoblasts: Bone deposition
Osteoclasts:
Bone absorption
Is In
equilibrium
Importance of Remodelling of Bone
1.
2.
3.
To adjust the strength: proportionate to degree of
bone stress
Shape of the bone can be rearranged – repair of
fracture
Old bones are replaced by new bones
Causes of Bone remodeling
1. Mechanical Stress
2. Microdamage( Microfissures and microscopic
cracks)
3. Hormones-parathyroid hormone [PTH] from the
parathyroid gland and calcitonin from the thyroid) and by
vitamin D.
Remodeling Sequence
1. Activation
Weight-Bearing Stress
• Though poorly understood, weight-bearing
mechanical stress increases the mineralization of bone.
• The absence of weight-bearing stress (being
sedentary, bedridden, or weightless)
promotes the demineralization of bone.
• Under these conditions, the following occurs:
 Plasma Ca2+tends to be in the upper region
of normal.
 Plasma PTH decreases.
 Urinary calcium increases
Indices can be utilized to detect excess bone
demineralization and remodelling
Resorption
• C-telopeptide (C-terminal
telopeptide of type 1
collagen (CTx))
• Collagen cross-links
(PYD,DPD)
• Tartrate-resistant acid
phosphatase (TRAP)
• Hydroxyproline (OHP)
• Hydroxylysine-glycosides
(Hyl-Glyc)
• Bone Sialoprotein (BSP)
• Gamma Carboxyglutamin
acid (GLA)
Bone formation
• P1NP (Procollagen
type 1 N-terminal
propeptide)
• Bone-specific alkaline
phosphatase (ALP)
• B-ALP
• Osteocalcin (bone gla
protein)
Osteoporosis—Decreased Bone Matrix
• most common of all bone diseases in adults, especially in
old age.
• Diminished organic bone matrix.
• causes of osteoporosis• (1) lack of physical stress on the bones because of inactivity;
• (2) malnutrition to the extent that sufficient protein matrix
cannot be formed;
• (3) lack of vitamin C,
• (4) postmenopausal lack of estrogen secretion
• (5) old age, in which growth hormone and other
growth factors diminish greatly.
(6) Cushing’s syndrome,
Parathyroid hormone(Parathormone)
• PTH is released from parathyroid glands in
response to a decline in circulating Ca2+ and
Mg2+ levels. PTH actions are geared toward
increasing Ca2+ availability.
Regulation of secretion
• In most cells exocytosis depends on a rise in
intracellular free calcium.
• In the parathyroids that role is taken by
magnesium.
• Depletion of magnesium stores can create a
reversible hypoparathyroidism
• Clinical correlation:• Lithium sensitizes the Ca2+ receptor to changes in
plasma Ca2+, causing increased PTH release in
response to a given Ca2+ stimulus. This is the
reason why bipolar patients on lithium salts for
manic episodes can also have hypercalcemia
PARATHYROID HORMONE-RELATED
PEPTIDE
• PTHrP is a paracrine factor secreted by many
tissues; e.g., lung, mammary tissue, placenta.
• The majority of humoral hypercalcemias of
malignancy are due to over-expression of
PTHrP.
• PTHrP has a strong structural homology to PTH
and binds with equal affinity to the PTH
receptor.
Actions on bone, kidney and
intestine
KIDNEY
PTH increases reabsorption of calcium & reduces
reabsorption of phosphate.
increases the rate of reabsorption of magnesium
ions and hydrogen ions while
decreases the reabsorption of sodium, potassium,
and amino acid
Net effect of its action is increased calcium &
reduced phosphate in plasma
BONES
Increases Calcium and Phosphate Absorption from the
bone
RAPID PHASE (min)
SLOW PHASE (days-weeks)
INTESTINE
Increases calcium reabsorption via vitamin D
Actions of PTH
• Rapid actions of PTH –
PTH increases Ca2+reabsorption in the distal
tubule of the kidney and decreases phosphate
reabsorption in the proximal tubule. By
decreasing renal phosphate reabsorption, PTH
lowers plasma phosphate. This causes the
product of the Ca2+and phosphate
concentrations to be less than the solubility
product.
This, in turn, promotes the resorption of these
ions from bone and raises their concentration
in the circulating blood.
Slower actions of PTH
• PTH slowly increases the formation and
activity of osteoclasts, which resorb bone,
releasing Ca2+.
• PTH increases the formation of 1,25 di-OH
D3 (active vitamin D) in the proximal
tubules of the kidney, which leads to
increased absorption of Ca2+and
phosphate from the small intestine.
skin
7- dehydrocholesterol
diet
uv
Vita D induced
incr synt of
proteins--role in
small intestine
Vit D binds to nuclear
Vitamin D receptor
that complexes with
an RXR and induces
transcription from the
Vit D response
elements.
Role of vitamin
D
GI
Stimulates GI absorption of calcium
Promotes Phosphate Absorption by the Intestines.
Effects of vitamin D
Kidney (weak Decreases Renal Calcium and Phosphate Excretion.
effect)
Bones
The resulting high concentrations of Ca2+and phosphate
in the extra-cellular fluid exceed the solubility product,
and precipitation of bone salts into bone matrix occurs.
At abnormally high activity levels Vit D increases bone
resorption and release of Ca2+and phosphate from
bone. Receptors for 1,25 di-OH D3are on the nuclear
membranes of osteoblasts. Through communication
from osteoblasts, activated osteoclasts carry out the
bone resorption.
Rickets—Vitamin D Deficiency
• lack of 1,25-(OH)2D3 can result from
• low exposure to sunlight,
• lack of access to dietary sources of vitamin D
or
• a genetic disorder pro-ducing a low
functioning 25(OH)D1-alpha-hydroxylase.
Rickets—Vitamin D Deficiency
• Vitamin D deficiency results in calcium or
phosphate deficiency in the ECF.
• The plasma Ca concentration in rickets is only
slightly depressed, but the level of PO4 is greatly
depressed.
• Rickets Weakens the BonesCompensatory PTH activity causes – osteoclastic
absorption of the bone, progressively weaker
bones
Rapid osteoblastic activity osteoblasts lay down
large quantities of osteoid, which does not
become calcified.
Chest X – RAY showing promient costochondral joints
bilaterally - a "Rachitic Rosary."
Osteomalacia—“Adult Rickets”
•
•
•
•
Causedietary deficiency
steatorrhea (failure to absorb fat) because
vitamin D is fat-soluble and calcium tends to
form insoluble soaps with fat.
Renal rickets
congenital hypophosphatemia, vitaminD–
resistant rickets.
Excess vitamin D
•
•
•
•
Raises plasma Ca
Secondary hypoparathyroidism
Phosphates levels rise
Bone resorption and bone mass decrease
Exposure to UV light directly facilitates which
of the following?
A) Conversion of cholesterol to 25hydroxycholicalciferol
B) Conversion of 25-hydroxycholicalciferol to
1,25- dihydroxycholicalciferol
C) Transport of calcium into the extracellular
fluid
D) Formation of calcium binding protein
E) Storage of vitamin D3 in the liver
Calcitonin
• Calcitonin is a peptide hormone secreted by
the parafollicular or “C” cells of the thyroid
gland
• It is synthesized as the preprohormone &
released in response to high plasma calcium.
• Calcitonin acts on bone osteoclasts to reduce
bone resorption.
• Net result of its action is a decline in plasma
calcium & phosphate
• Calcitonin is useful in the treatment of Paget’s
disease.
• Calcitonin is not a major controller of Ca2+ in
humans. Removing the thyroid (with the C cells) or
excess of calcitonin via a C cell tumor (medullary
carcinoma of the thyroid) has little impact on plasma
calcium.
Summary
• PTH & calcitonin release are regulated by
plasma Ca levels
• Bone Ca & phosphate serve as a ready reserve
for maintenance of plasma levels
• Bone, kidney & intestine participate in the
regulation of plasma calcium
• PTH, Vitamin D, & calcitonin balance plasma
[Ca++] conc
Effects of Other Hormones & Humoral
Agents on Calcium Metabolism
Positive Ca balance
Negative Ca balance
• Growth hormone
• Insulin
• Insulin-like growth
factor I (IGF-I)
• Estrogen
• Glucocorticoids
• Thyroid hormones
Q. A patient with parathyroid deficiency 10 days
after inadvertent damage to the parathyroid
gland during thyroid surgery would probably
have?
a) Low plasma phosphate and calcium levels and tetany
b) Low plasma phosphate and calcium levels and tetanus
c) A low plasma calcium level, increased muscular
excitability and a characteristic spasm of the muscles of
the upper extremity.
d) High plasma phosphate and calcium levels and bone
demineralization
e) Increased muscular excitability ,a high plasma calcium
level ,bone demineralization
Q. Which of the following is not involved
in regulating plasma calcium levels?
a.
b.
c.
d.
e.
Kidney
Skin
Liver
Lungs
intestine
Q. 1,25dihydroxycholecalciferol affects
intestinal calcium absorption through a
mechanism thata)
b)
c)
d)
e)
Includes alteration in the activity of genes
Activate adenyl cyclase
Decrease cell turnover
Change gastric acid secretion
Is comparable to the action of polypeptide
hormone
Q. Which of the following would you expect to
find in a patient whose diet has been low in
calcium for 2 months?
a) Increased formation of 24,25dihydroxy
cholecalciferol
b) Decreased amount of calcium binding protein in
intestinal epithelial cells
c) Increased parathyroid hormone secretion
d) A high plasma calcitonin concentration
e) Increased plasma phosphates
PATHOPHYSIOLOGY OF
PARATHYROID HORMONE
PATHOLOGIC DISORDERS
• HYPERPARATHYROIDISM
primary
Secondary
( as compensation for hypocalcemia)
• HYPERVITAMINOSIS D
1.Primary Hyperparathyroidism
• Cause - tumor of one of the parathyroid
glands.
• 80% due to a single parathyroid adenoma
• Extreme osteoclastic activity in the bones
• Increased plasma alkaline phosphatase,
osteocalcin and increased excretion of cAMP
(second messenger for PTH in the kidney),
and hydroxyproline.
Effects of Hypercalcemia in
Hyperparathyroidism
• Plasma Ca level to rise to 12 to 15 mg/dl and,
rarely, even higher.
• Elevated Ca levels, cause
• depression of the central and peripheral nervous
systems,
• muscle weakness,
• constipation, abdominal pain, peptic ulcer, lack of
appetite,
• depressed relaxation of the heart during diastole.
Metastatic deposition of calcium
• calcium and phosphate in the body fluids
become greatly supersaturated.
• calcium phosphate (CaHPO4) crystals begin to
deposit in the alveoli of the lungs, the tubules
of the kidneys, the thyroid gland, the acidproducing area of the stomach mucosa, and
the walls of the arteries.
Related causes of hypercalcemia
• Lithium shifts the sigmoid Ca/PTH curve to
the right. Higher calcium levels are thus
needed to suppress PTH. A rare familial
defect which reduces the Ca receptor
sensitivity in a similar way results in
hypercalcemia.
• Sarcidosis and other granulomatous
disorders (10%) due to increased activity of
vitamin D
• Thyrotoxicosis, milk-alkali syndrome
II. Secondary Hyperparathyroidism
• High levels of PTH occur as compensation for
hypocalcemia .
• Caused by vitamin D deficiency or chronic renal
disease in which the damaged kidneys are
unable to produce sufficient amounts of the
active form of vitamin D(1,25dihydroxycholecalciferol).
Differential diagnosis and treatment
• Elevated plasma calcium and PTH normal or
elevated; conclusion is primary
hyperparathyroidism
• Elevated plasma calcium and decreased PTH;
conclusion is something other than primary
hyperparathyroidism
• Treatment is usually surgery; i.e., removing the
adenoma or with hyperplasia removing most
of the parathyroid tissue.
Hypoparathyroidism
• With insufficient PTH, the osteocytic
reabsorption of exchangeable Ca decreases
and the osteoclasts become almost totally
inactive.
• Commonest cause is -thyroidectomy, the Ca
level in the blood falls from the normal of 9.4
mg/dl to 6 to 7 mg/dl within 2 to 3 days, and
the blood phosphate concentration may
double.
• Signs of tetany develop.
Management:
• Administration of extremely large quantities of
vitamin D, along with intake of 1 to 2 grams of
calcium, keeps the calcium ion concentration
in a normal range.
• Treatment with PTH less effective.
Additional causes of hypocalcemia
Acute hypocalcemia can occur even with
intact homeostatic mechanisms.
• Included would be alkalosis via hyperventilation,
transfusions of citrated blood, rhabdomyolysis or
tumor lysis, and the subsequent
hyperphosphatemia
• Hyperphosphatemia of chronic renal failure
• Congenital absence of parathyroids rare (DiGeorge’s
syndrome)
Parathyroid hormone directly
A) controls the rate of 25hydroxycholicalciferol formation
B) controls the rate of calcium transport in
the mucosa of the small intestine
C) controls the rate of formation of calcium
binding protein
D) controls the rate of formation of 1, 25dihydroxycholicalciferol
E) stimulates renal tubular phosphate
reabsorption
A 40-year-old woman comes to the
emergency room with a fracture in the neck
of the femur. Radiographs reveal
generalized demineralization of the bone in
the area. Her plasma calcium ion
concentration is significantly greater than
normal: 12.2 mg/dL. Which of the following
conditions is consistent with this
presentation?
A) Osteoporosis
B) Rickets
C) Hyperparathyroidism
D) Renal failure
The function of which of the following is
increased by an elevated parathyroid
hormone concentration?
A) Osteoclasts
B) Hepatic formation of 25hydroxycholecalciferol
C) Phosphate reabsorptive pathways in the
renal tubules
D) All of the above
A sustained program of lifting heavy weights will
increase bone mass. What is the mechanism of this
effect of weightlifting?
A) Elevated metabolic activity stimulates parathyroid
hormone secretion
B) Mechanical stress on the bones increases the
activity of osteoblasts
C) Elevated metabolic activity results in an increase
in dietary calcium intake
D) Elevated metabolic activity results in stimulation
of calcitonin secretion
Extracellular calcium concentration remains only
slightly below normal for many months even when
dietary calcium intake is minimal. What accounts for
this ability to maintain calcium concentration in the
extracellular fluid?
A) Only a slight reduction in plasma calcium
concentration
stimulates large, sustained increases in parathyroid
hormone secretion
B) Osteoclasts stimulated by high levels of parathyroid
hormone remove calcium from the large quantity
stored in the bone, thereby maintaining the nearnormal extracellular calcium level
C) Renal excretion of calcium is greatly reduced under
the influence of high concentrations of parathyroid
hormone
D) All of the above