CALCIUM METABOLISM

PRESENTED BY-
Dr. MONALISHA BOSE
MDS 1ST YEAR
GUIDED BY-
Dr. D K BAGGA
DEPT OF ORTHODONTICS
 CONTENTS
INTRODUCTION
SOURCES
RDA
ABSORPTION
REGULATION
FUNCTION
FACTORS REGULATING BLOOD CALCIUM LEVEL
DEFICIENCY CONDITIONS
REFERENCES
INTRODUCTION
 Calcium is the most abundant mineral in the body.

 Adult human - 1.0 to 1.2 kg of calcium.

 99% Ca is present in bone & teeth.

 Remaining 1% is present in plasma (muscle & nervous system).

 The plasma calcium is partly bound to protein and partly diffusible.

 SOURCES OF CALCIUM

 Milk & milk products - good source for calcium.

 - Ca in cow's milk is about 100 mg/ 100 ml.
 - human milk is 30 mg/dl.
 Egg
 Fish and
 Vegetables - are medium source for calcium.
 Cereals (wheat, rice) contain only small amount of calcium. But cereals are the staple diet in India.
Therefore, cereals form the major source of calcium in Indian diet.
 DAILY REQUIREMENT OF CALCIUM

Adults – 500-1000 mg/day.

Child – 1,200 mg/day.

Pregnancy & lactation – 1,500 mg/day.

After the age of 50, there is a general

tendency for osteoporosis; which may be
prevented by increased calcium (1500
mg/day) plus vitamin D (20 microgram/day).
 ABSORPTION OF CALCIUM
Transcellular: active transport involving a calcium binding protein, calbindin

 Stimulates calbindin

Paracellular: by diffusion

 A function of calcium content of chyme

Most absorption in ileum

 1,25(OH)2D stimulates synthesis of calbindin in gut cells.

Calcium dependent ATP pump moves calcium into extracellular fluid against the electochemical gradient
Physiologic factors affecting calcium absorption
 Vitamin D adequacy or deficiency
 Mucosal mass
 Calcium deficiency will increase absorption
 Pregnancy will increase absorption
 Menopause will decrease absorption
 Estrogen deficiency will decrease absorption

10
 The following factors increase the absorption rate:

 Vitamin D. Calcitriol induces the synthesis of the carrier protein (Calbindin) in the
intestinal epithelial cells, and so facilitates the absorption of calcium.

Parathyroid hormone increases calcium transport from the intestinal cells.

Acidity favours calcium absorption.

Amino acids, especially lysine and arginine increase absorption.

 The following factors decrease the absorption rate:

Phytic acid, or hexaphosphate of inositol is present in cereals. Fermentation and cooking reduce phytate content.

 Oxalates are present in some leafy vegetables, which cause formation of insoluble calcium oxalates.

In malabsorption syndromes leading to steatorrhea, fatty acid is not absorbed, causing formation of insoluble
calcium salt of fatty acid.

High phosphate content will cause precipitation as calcium phosphate.

The optimum ratio of calcium to phosphorus which allows maximum absorption is

1:2 to 2:1 as present in milk.

EXCRETION
Out of 500 mg of Ca taken orally per day, 400 mg is excreted in stool and 100 mg
is excreted through urine.

Extracellular Ca2+ concentration 2.5 mmol/L

Intracellular Ca2+ concentration < 10 mol/L

 FUNCTIONS OF CALCIUM
1. Activation of enzymes: Calmodulin is a calcium binding regulatory protein.

It is very similar or identical to the muscle protein, Troponin C. Calmodulin is part of various regulatory kinases.

The following enzymes are activated by Ca, mediated by calmodulin:

Adenyl cyclase; protein kinases; Ca -Mg-ATPase; glycerol-3-phosphate dehydrogenase; glycogen synthase;

phosphorylase kinase; pyruvate carboxylase; pyruvate dehydrogenase; pyruvate kinase, etc.
Activation of enzymes

Ca++ + Calmodulin

Ca-bound-Calmodulin

Kinase Active kinase

Enzyme Phosphorylated enzyme

Biological effect
2. Mediates excitation and contraction of muscle fibers.

3. Necessary for transmission of nerve impulses.

4. Ca-Calmodulin complex regulates micro-filament mediated processes. Eg. endocytosis, cell

motility.

5. In myocardium, Ca prolongs systole. In hypercalcemia, cardiac arrest is seen in systole. This

fact should be kept in mind when calcium is administered intravenously. It should be given
very slowly.
6. Used in bone and teeth formation.

7. Ca and cAMP are second messengers in different hormones.

8. Secretion of hormones such as PTH, calcitonin, vasopressin etc.

9. In blood coagulation.

10. Permeability of serum through capillary is decreased by calcium. Thus, calcium is clinically
used to reduce allergic exudates.
 DIETARY CONSIDERATIONS OF CALCIUM
Nutrient-nutrient interactions
 Sodium and calcium share same transport system for excretion in kidney
 High sodium intake can lead to higher calcium excretion in urine

 Protein intake can increase calcium loss in urine

 Mainly due to phosphorus content of protein

 High phosphorus intakes can lower calcium levels

 High caffeine intake can increase urinary calcium losses

 High calcium intake may reduce iron absorption

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PHYSIOLOGICAL IMPORTANCE OF
CALCIUM

Calcium salts in bone provide structural integrity of the skeleton.

Calcium ions in extracellular and cellular fluids is essential to normal

function of a host of biochemical processes.
 Neuoromuscular excitability
 Blood coagulation
 Hormonal secretion
 Enzymatic regulation
REGULATION OF CALCIUM CONCENTRATION

The important role that calcium plays in so many processes dictates that its
concentration, both extracellularly and intracellularly, be maintained within a very
narrow range.

This is achieved by an elaborate system of controls.

REGULATION OF INTRACELLULAR CALCIUM
CONCENTRATION

Control of cellular calcium homeostasis is as carefully maintained as in extracellular

fluids.

 [Ca2+]cyt is approximately 1/1000th of extracellular concentration.

Stored in mitochondria and ER.

“pump-leak” transport systems control [Ca2+]cyt

 Calcium leaks into cytosolic compartment and is actively pumped into storage sites
in organelles to shift it away from cytosolic pools.
EXTRACELLULAR CALCIUM

When extracellular calcium falls below normal, the nervous system becomes
progressively more excitable because of increase permeability of neuronal
membranes to sodium.

Hyperexcitability causes tetanic contractions.

EXTRACELLULAR CALCIUM

Binding of calcium to albumin is pH dependent.

Acute alkalosis increases calcium binding to protein and decreases ionized

calcium.

Patients who develop acute respiratory alkalosis have increased neural

excitability and are prone to seizures due to low ionized calcium in the
extracellular fluid which results in increased permeability to sodium ions.
EXTRACELLULAR CALCIUM

Three definable fractions of calcium in serum:

Ionized calcium 50%
Protein-bound calcium 40%
 90% bound to albumin
 Remainder bound to globulins
Calcium complexed to serum constituents 10%
 Citrate and phosphate
 PLASMA CALCIUM REGULATION
Plasma calcium totals 2.4 mM (9.4 mg/dl)
 Free calcium is 1.2 mM
PLASMA CALCIUM REGULATION
Free calcium is tightly regulated (5%)
 Too low = neuronal hyper-excitability

 Too high = neuronal depression

Control points for calcium

 Absorption – Via intestines

 Excretion – Via urine

 Temporary storage – Via bones

• To maintain Ca2+ balance, net intestinal absorption must be exactly balanced by urinary
excretion:
1. Positive Ca2+ balance
is seen in growing children, where intestinal Ca2+ absorption exceeds urinary excretion and
the difference is deposited in the growing bones.

2. Negative Ca2+ balance

is seen in women during pregnancy or lactation, where intestinal Ca2+ absorption is less than
urinary excretion and the difference comes from the maternal bones.
CALCIUM AND PHOSPHOROUS

Calcium is tightly regulated with Phosphorous in the body.

Phosphorous is an essential mineral necessary for ATP, cAMP second messenger

systems, and other roles.
CALCIUM TURNOVER
CALCIUM IN BLOOD AND BONE

Ca2+ normally ranges from 8.5-10 mg/dL in the plasma.

The active free ionized Ca2+ is only about 48% 46% is bound to protein in a non-
diffusible state while 6% is complexed to salt.

Only free, ionized Ca2+ is biologically active.

CALCIUM AND BONE
99% of Calcium is found in the bone. Most
is found in hydroxyapatite crystals. Very little
Ca2+ can be released from the bone– though
it is the major reservoir of Ca2+ in the body.
 STRUCTURE OF BONES

Haversian canals within lamellae

CALCIUM TURNOVER IN BONES

80% of bone is mass consists of cortical bone– for example: dense concentric layers
of appendicular skeleton (long bones)

20% of bone mass consists of trabecular bone– bridges of bone spicules of the
axial skeleton (skull, ribs, vertebrae, pelvis)

Trabecular bone has five times greater surface area, though comprises lesser mass.

Because of greater accessibility trabecular bone is more important to calcium

turnover.
PHOSPHATE TURNOVER
PHOSPHOROUS IN BLOOD AND
BONE
PO4 normal plasma concentration is 3.0-4.5 mg/dL. 87% is diffusible, with 35%
complexed to different ions and 52% ionized.

13% is in a non-diffusible protein bound state. 85-90% is found in bone.

The rest is in ATP, cAMP, and proteins.

 BONES
99% of the Calcium in our bodies is found in our bones which serve as a reservoir for Ca++ storage.

10% of total adult bone mass turns over each year during remodeling process

During growth rate of bone formation exceeds resporption and skeletal mass increases.

Linear growth occurs at epiphyseal plates.

Increase in width occurs at periosteum

Once adult bone mass is achieved equal rates of formation and resorption maintain bone mass until age
of about 30 years when rate of resportion begins to exceed formation and bone mass slowly decreases.
 TYPES OF CELLS IN BONE
There are three major types of cells in the Bone. They are:
 Osteoblasts
 Osteocytes
 Osteoclasts
Osteoblasts and Osteoclasts are called, Osteoprogenitor
cells as they develop from primitive cells.

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TYPES OF CELLS IN BONE
 Osteoblasts: They are bone forming cells. They are modified
fibroblasts derived from pericytes. They synthesize osteoid. They are
present towards the periphery of the bone.
 Osteoclasts: Osteoblasts surrounded by mineralized osteoid
gradually lose their ability to form bone and they become
Osteocytes.
 Osteoclasts: They develop from precursors such as monocytes and
tissue macrophages. They are large multinucleated cells. They cause
bone resorption by secreating proteolytic enzymes into the
surroundings which degrade the organic matrix. The chemicals
secreted by them create an acidic environment, that enhances the
solubility of bone minerals .

40
 BONE FORMATION

Active osteoblasts synthesize and extrude collagen

Collagen fibrils form arrays of an organic matrix called

the osetoid.

Calcium phosphate is deposited in the osteoid and

becomes mineralized.

Mineralization is combination of CaP04, OH-, and H3CO3–

hydroxyapatite.
MINERALIZATION

Requires adequate Calcium and phosphate.

Dependent on Vitamin D.

Alkaline phosphatase and osteocalcin play roles in bone formation.

Their plasma levels are indicators of osteoblast activity.

 CANALICULI

Within each bone unit is a minute fluid-containing

channel called the canaliculi.

Canaliculi traverse the mineralized bone.

Interior osteocytes remain connected to surface cells

via syncytial cell processes.

This process permits transfer of calcium from enormous

surface area of the interior to extracellular fluid.
 BONE RESORPTION
Bone resorption of Ca++ occurs by two mechanims:

>osteocytic osteolysis is a rapid and transient effect .

>osteoclasitc resorption which is slow and sustained effect.

Both are stimulated by PTH. CaPO4 precipitates out of solution id its solubility is exceeded.
The solubility is defined by the equilibrium equation: Ksp = [Ca2+]3[PO43-]2.

In the absence of hormonal regulation plasma Ca++ is maintained at 6-7 mg/dL by this
equilibrium.
OSTEOCYTIC OSTEOLYSIS

Transfer of calcium from canaliculi to extracellular fluid via activity of osteocytes.

Does not decrease bone mass.

Removes calcium from most recently formed crystals.

Happens quickly.
OSTEOCLASTIC RESORPTION

Does not merely extract calcium, it destroys

entire matrix of bone and diminishes bone
mass.

Cell responsible for resorption is the

osteoclast.
BONE REMODELING
Endocrine signals to resting osteoblasts generate paracrine
signals to osteoclasts and precursors.

Osteoclasts resorb and area of mineralized bone.

Local macrophages clean up debris.

Process reverses when osteoblasts and precursors are

recruited to site and generate new matrix.

New matrix is minearilzed.

New bone replaces previously resorbed bone.

CALCIUM, BONES AND OSTEOPOROSIS

The total bone mass of humans peaks at 25-35 years of age.

Men have more bone mass than women.

A gradual decline occurs in both genders with aging, but women undergo an
accelerated loss of bone due to increased resorption during perimenopause.

Bone resorption exceeds formation.

Reduced bone density and mass: osteoporosis

Susceptibility to fracture.

Earlier in life for women than men but eventually both genders succumb.

Reduced risk:
 Calcium in the diet
 habitual exercise
 avoidance of smoking and alcohol intake
 avoid drinking carbonated soft drinks
 VERTEBRAE OF 40- VS. 92-YEAR-OLD
WOMEN
Note the marked loss of trabeculae with preservation of cortex.
 MAJOR EFFECT OF HORMONES ON BONES
BONE FORMATION BONE RESORPTION

STIMULATED BY INHIBITED BY STIMULATED BY INHIBITED BY

FACTORS REGULATING BLOOD CALCIUM LEVEL

There are effective controls to maintain this narrow range of blood calcium (9-11
mg/dl). But the major factors are:
Vitamin D
Parathyroid hormone and
Calcitonin.
CALCIUM BALANCE
Calcitonin, Calcitriol and PTH Act Together: When blood calcium tends to lower, PTH
secretion is stimulated and calcitonin is inhibited; bone demineralisation leads to entry
of more calcium into blood.

When blood calcium is increased, PTH is inhibited and calcitonin is secreted, causing
more entry of calcium into bone.
VITAMIN D
In liver, it is hydroxylated at the 25th position, and in kidney further hydroxylation is
affected at the 1st position to produce 1,25- dihydroxy-cholecalciferol or calcitriol.
Sites of action are;
(a) intestinal villi cells,
(b) bone osteoblasts and
(c) kidney distal tubular cells.
VITAMIN D AND INTESTINAL ABSORPTION OF CALCIUM

Calcitriol induces a carrier protein in the intestinal mucosa, which increases the
absorption of calcium and phosphorus from the intestine.

In the brush-border surface, calcium is absorbed passively. From the intestinal cell to
blood, absorption of calcium needs energy.

Hence blood calcium level tends to be elevated.

EFFECT OF VITAMIN D ON BONE

Vitamin D acts independently on bone.

 Vitamin D increases the number and activity of osteoblasts.
Secretion of alkaline phosphatase by osteoblasts is increased by vitamin D.
Mineralisation of the bone is increased by increasing the activity of osteoblasts.
Calcitriol co-ordinate the remodelling action of osteoclasts and osteoblasts.
EFFECT OF VITAMIN D ON RENAL TUBULES
Calcitriol increases the reabsorption of calcium and phosphorus by renal tubules,
therefore both minerals are conserved. (PTH conserves only calcium).
REGULATION OF CALCITRIOL
The hormonal level of calcitriol is maintained by the feed-back control.

The rate of production is modulated by serum levels of calcium, phosphorus, PTH ,and
calcitriol itself.

The major site of control is on the 1-alpha-hydroxylase of kidney.

Low dietary calcium and hypocalcaemia increase the rate of production of 1 ,25-
DHCC.
 DEFICIENCY OF VITAMIN D
Rickets: Vit D causes poor absorption of Ca from
intestine, hence leading to Hypocalcemia. Due to Ca
deficiency the protein of new bone fails to mineralize
leading to Rickets.

Osteomalacia: It is similar to rickets but occurs after the

bone growth has completed (i.e. in adults) .

62
 VITAMIN D DEFICIENCY: RICKETS
Inadequate intake and absence of sunlight

The most prominent clinical effect of Vitamin D deficiency is osteomalacia, or the defective
mineralization of the bone matrix

Osteoblasts contain the vitamin D receptor

Vitamin D deficiency in children produces rickets

A deficiency of renal 1α-hydroxylase produces vitamin D-resistant rickets

 Sex linked gene on the X chromosome
 Renal tubular defect of phosphate resorption
 Teeth may be hypoplastic and eruption may be retarded
 PARATHYROID HORMONE (PTH)
Parathyroid Hormone (PTH) is secreted by the chief cells of four parathyroid glands.

The normal PTH level in serum is 10-60 ng/L. In primary hyperparathyroidism, this is increased to 100
ng/L.

This activates adenyl cyclase with consequent increase in intracellular calcium concentration.

The PTH has three major independent sites of action; bone, kidney and intestines.
EFFECT OF PTH ON BONE
 PTH causes demineralisation or decalcification.

It induces pyrophosphatase in the osteoclasts. The number of osteoclasts are also
increased.

Osteoclasts release lactate into surrounding medium which solubilises calcium.

PTH also causes secretion of collagenase from osteoclasts. This causes loss of matrix
and bone resorption.
EFFECT OF PTH ON RENAL TUBULES
 PTH causes decreased renal excretion of calcium. The action is mainly through
increase in reabsorption of calcium from kidney tubules.

PTH increases excretion of phosphates. This phosphaturic action is due to a

decrease in reabsorption of phosphate in the proximal tubules.

PTH stimulates 1-hydroxylation of 25-hydroxycalciferol in kidney to produce

calcitriol.

This indirectly increases calcium absorption from intestine.

 CALCITONIN
 Calcitonin is secreted by parafollicular or clear cells of the thyroid gland.

 Calcitonin secretion is stimulated by serum calcium, gastrin, glucagon and biological amines.

 Calcitonin level is increased in medullary carcinoma of thyroid and therefore used as a tumor marker also.

 The level is also increased in multiple endocrine neoplasia (MEN).

 Hypercalcitoninemia may also result from ectopic calcitonin production from malignant tumors of the lung and
bronchus.

Calcitonin decreases serum calcium level. It inhibits resorption of bone. It decreases the activity of osteoclasts and
increases that of osteoblasts.

Calcitonin and PTH are directly antagonistic. The PTH and calcitonin together promote the bone growth and
remodeling
DISEASES RELATED TO CALCIUM
METABOLISM
 HYPERCALCEMIA
The term denotes that the blood calcium level is more than 11 mg/dl.

The major cause is hyperparathyroidism.

This may be due to

- parathyroid adenoma or
- an ectopic PTH secreting tumor.
Minor Causes

Multiple myeloma,
Paget's disease and
Metastatic carcinoma of bone, there will be bone resorption and mild hypercalcemia.
Milk-alkali syndrome and
Vitamin D toxicity. Increased absorption of calcium from the intestine.
Lithium therapy and
Thiazide diuretics may also cause mild hypercalcemia.
CLINICAL FEATURES
Osteoporosis

X-ray shows punched out areas of bone resorption (Osteitis fibrosa cystica
generalitica or von Recklinghausen's disease).

Pathological fracture of bone may result.

In urine, calcium is excreted, which may cause inhibition of elimination of chloride.

This may lead to hyperchloremic acidosis.

Calcium may be precipitated in urine, leading to recurrent bilateral urinary calculi.

Ectopic calcification may be seen in renal tissue, pancreas (pancreatitis), arterial walls,
and muscle tissues (myositis ossificans).

Anorexia, muscle weakness,

In the blood, calcium and alkaline phosphatase levels are increased, while phosphate
level is lowered.
 HYPOCALCEMIA
When serum calcium level is less than 8.8 mg/dl, it is hypocalcemia.

If serum calcium level is less than 8.5 mg/ dl, there will be mild tremors.

If it is lower than 7.5 mg/dl, tetany, a life-threatening condition will result.

Tetany may be due to accidental surgical removal, of parathyroid glands or by autoimmune

diseases.
 CLINICAL SIGNS OF HYPOCALCEMIA
CHVOSTEK’S SIGN
Elicitation: Tapping on the face at a point just anterior to the ear and just below the
zygomatic bone.
Postitive response: Twitching of the ipsilateral facial muscles, suggestive of neuromuscular
excitability caused by hypocalcemia’
TROUSSEAU’S SIGN
Elicitation: Inflating a sphygmomanometer cuff above systolic blood pressure for several
minutes.
Postitive response: Muscular contraction including flexion of the wrist and
metacarpophalangeal joints, hyperextension of the fingers, and flexion of the thumb on the
palm, suggestive of neuromuscular excitability caused by hypocalcemia.
 CAUSES OF HYPOCALCEMIA
Pseudo-hypoparathyroidism is an X-linked dominant condition.

Although PTH level is normal, there is lack of end organ response to PTH.

This leads to hypocalcemia and hyperphosphatemia.

Shortening of 4th and 5th metacarpal or metatarsal bones may be associated.

HYPOPARATHYROIDISM

• most commonly post thyroid surgery or is congenital

is characterized by the following:
↓ serum [Ca2+] and tetany
↑ serum [phosphate]
↓ urinary phosphate excretion
 PSEUDOHYPOPARATHYROIDISM
Symptoms and signs
 Hypocalcemia

 Hyperphosphatemia

 Characteristic physical appearance: short stature, round face, short thick neck, obesity, shortening of the metacarpals

 Autosomal dominant

Resistance to parathyroid hormone

The patients have normal parathyroid glands, but they fail to respond to parathyroid hormone or PTH injections
The rise in urinary cAMP after parathyroid hormone fails to
occur

The cause of the disease is a 50% deficiency of Gs in all cells

Symptoms begin in children of about 8 years

Tetany and seizures

Hypoplasia of dentin or enamel and delay or absence of

eruption occurs in 50% of people with the disorder

Rx: vitamin D and calcium

CONGENITAL HYPOPARATHYROIDISM

Hypoplasia of the teeth, shortened roots, and retarded eruption

 PRIMARY HYPERPARATHYROIDISM
Calcium excretion > calcium intake
Large regions of bone are replaced by connective
tissue
Two lesions: maxilla and forehead
 HYPERPARATHYROIDISM

Left: Giant Cell Granuloma

Right: Loss of lamina dura, pathognomonic oral change in hyperparathyroidism
FROM THE JOURNALS
Lactation, coupled with a calcium deficient diet will produce decreased bone density
thru 2° hyperparathyroidism. Increased tooth movement was found to correlate
directly with, Increased bone turnover and decreased bone density. Bone resorption
occurs in preference to root resorption- AJODO May 1984
A weekly intraligamentary injection of 1,25-Dihydroxycholecalciferol produces
increased amount of orthodontic tooth movement- AJODO October 1988

84
REFERENCES
 Textbook Of BIOCHEMISTRY – 3rd Edition,DM VASUDEVAN

 Illustrated Reviews: BIOCHEMISTRY – 2nd Edition,LIPPINCOTT

 Review of Medical Physiology – 22nd Edition,W.F.GANONG

 Textbook Of Oral Pathology – 5th Edition,SHAFER

THANK YOU