CA Metabolism

7/28/2019 CA Metabolism

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GOOD MORNING


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CALCIUM METABOLISM


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CONTENTS INTRODUCTION

IMPORTANCE OF CALCIUM SOURCES OF CALCIUM

DISTRIBUTION OF CALCIUM

DIETARY REQUIREMENTS

ABSORPTION OF CALCIUM

OVERALL CALCIUM HOMEOSTASIS

EXCRETION OF CALCIUM

PARATHYROID GLANDS AND PARATHORMONE

1,25-DIHYDROXYVITAMIN D(CALCITRIOL)

CALCITONIN

REFERENCE


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INTRODUCTION

Minerals constitute a small proportion of the body weight.

Calcium is a macro element. These are required in

amounts greater than 100mg/ day.

Calcium is the most abundant among the minerals in the

body. It is the main constituent of hard tissues and is animportant inorganic ion for many physiologic functions.

It is vital for us to have a complete understanding of the

general metabolism of calcium and phosphorous as it is

these minerals that help in the formation and maintenance

of the teeth and their supporting bony structure.


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IMPORTANCE OF CALCIUM

1. Development of bones and teeth.

2. Unique binding ability--stabilize the 3 dimensional

structure of many enzymes and other proteins.

3. Muscle contraction.

4. Blood Coagulation

5. Nerve transmission

6. Cell membrane integrity and permeability

7. Activation of enzymes


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SOURCES OF CALCIUM

MILK

MILKPRODUCTSBEST

SOURCE

BEANS

LEAFYVEGETABLE

FISH

EGG YOLK

CABBAGE

GOODSOURCE


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Adult men and women

Women during pregnancy,

lactation and post-menopause

Children (1- 18 yrs)

Infants ( 1 year)

800mg/day

1.5 g /day

0.8- 1.2 g/day

300 500 mg/day


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DISTRIBUTION OF CALCIUM IN PLASMA


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PLASMA LEVEL

Normal level is 9.4 mg/dl = 2.4 mmol/liter.

Range = 9-11 mg/dl


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FACTORS AFFECTING CALCIUM ABSORPTION

Factors Favoring

PTH

Vitamin D

High protein diet

Acidic pH Bile salts

Negative Ca balance

Pregnancy, lactation and

growth

Calcium Deficiency

Factors Decreasing

Oxalates, phylates, phytic

acids

Excess of phosphates in diet

Excess of intestinal lipids

Alkaline pH

High body stores of calcium

Menopause

Rapid Intestinal Transit Time


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Serum [Ca2+] is determined by the interplay

of intestinal absorption, renal excretion

and bone remodeling (bone resorption and

formation). Each component is hormonally

regulated.

To maintain Ca2+ balance, net intestinalabsorption must be exactly balanced by

urinary excretion:


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1. Positive Ca2+ balance

Seen in growing children, where intestinal Ca2+

absorption exceeds urinary excretion and the difference isdeposited in the growing bones.

2. Negative Ca2+ balance

Seen in women during pregnancy or lactation, where

intestinal Ca2+ absorption is less than urinary excretion .


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PARATHYROID

PARATHORMONE

BONE:Increase in

resorption and releaseof calcium

KIDNEY

1,25-DIHYDROXY

CHOLECALCIFEROL

INTESTINE: Increase

in absorption ofcalcium

THYROID

CALCITONIN

BONE: Inhibition of

bone resorption anddeposition ofcalcium

INCREASED BLOOD

CALCIUM LEVEL

DECREASED BLOOD

CALCIUM LEVEL

NORMAL BLOOD CALCIUM LEVEL


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EXCRETION OF CALCIUM AND PHOSPHATE

About 60% of plasmacalcium is filtered by thekidneys.

60% of reabsorptionoccurs in the PCT andremaining 40% occurs inthe loop of Henle and

distal tubules.

DCT reabsorption isregulated by

parathormone.

80% in Feaces Remaining Urine


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PRECIPITATION OF CALCIUM IN

BONE-The initial stage in bone formation is osteoid matrix

formation by osteocytes.

Within a few days after the osteoid is formed, calcium salts

begin to precipitate on the surfaces of the collagen fibers.

The precipitates first appear at intervals along each collagen

fiber, forming minute nidi that rapidly multiply and grow

over a period of time into hydroxyapatite crystals.


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BONE REMODELLING:

Remodeling is the major pathway of bony changes in

shape, resistance to forces, repair of wounds, and calcium

and phosphate homeostasis in the body. Indeed, the

coupling of bone resorption with bone formation

constitutes one of the fundamental principles by which

bone is necessarily remodeled throughout its life.


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Bone contains 99% of the body's calcium ions. A decrease in

blood calcium is mediated by receptors on the chief cells of the

parathyroid glands, which then release parathyroid

hormone(PTH). PTH stimulates osteoblasts to release Il-1 and

Il-6 which stimulate monocytes to migrate into the bone area.

Leukemia inhibiting factor (LIT), secreted by osteoblasts,

coalesces monocytes into multinucleated osteoclasts, which

then resorb bone, releasing calcium ions from hydroxyapatite

into the blood.


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A feedback mechanism of normal blood levels of calcium

turns off the secretion of PTH. Meanwhile, osteoclasts have

resorbed organic matrix along with hydroxyapatite. The

breakdown of collagen from the organic matrix releases

various osteogenic substrates, which are covalently bound to

collagen, and this in turn stimulates the differentiation of

osteoblasts, which ultimately deposit bone. This

interdependency of osteoblasts and osteoclasts in remodeling

is called coupling.


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When osteoclasts are active rather than resting, they

possess an elaborately developed ruffled border from

which hydrolytic enzymes are believed to be secreted.

These enzymes digest the organic portion of bone. The

activity of osteoclasts and morphology of the ruffled

border can be modified and regulated by hormones such

as PTH (indirectly) and calcitonin, which has receptors on

the osteoclast membrane.


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BONE REMODELLING CYCLE:


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HARMONAL CONTROL OF CALCIUM

AND PHOSPHORUS

VITAMIN D

PTH

CALCITONIN


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PARATHORMONE

Secreted by chief cells of parathyroid gland. The major hormone for regulation of the serum [Ca2+].

PTH can be referred to as the bodys defense against

hypocalcemia.

The main function is to increase the level of calcium inplasma

Target sites

Bone

Kidney

Intestine

i i f


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Activity of PTH

BONE PTH promotes the resorption of bones by activating the

osteoclasts and also, by the formation of new osteoclasts,followed by their activation.

Releases calcium & phosphate into blood.

PTH acts on osteoblastic cells to express RANKL ( ReceptorActivator of Nuclear Factor B Ligand), an inducer ofosteocalstic bone resorption.

KIDNEY PTH increases reabsorption of calcium & reduces reabsorption

of phosphate.

Net effect of its action is increased calcium & reducedphosphate in plasma.

INTESTINE Increases calcium reabsorption via vitamin D.


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REGULATION OF PTH SECRETION

Controlled by the serum [Ca2+] by negative feedback.

Decreased serum [Ca2+] increases PTH secretion.

Mild decrease in serum [Mg2+] also stimulate PTH

secretion.


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HYPERPARATHYROIDISM

Parathyroid hypersecretion produces generalized

demineralization of the skeleton, increased osteoclasis

with proliferation of the connective tissue in the enlarged

marrow spaces, and formation of bone cysts and giant cell

tumors. The disease is called osteitis fibrosra cystica, or

von Recklinghausen's bone disease.


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ORAL CHANGES-

Malocclusion and tooth mobility,

Radiographic evidence of alveolar osteoporosis with closely

meshed trabeculae,

Widening of the periodontal ligament space,

Absence of the lamina dura, and

Radiolucent cystlike spaces. Bone cysts become filled with

fibrous tissue with abundant hemosiderin laden

macrophages and giant cells. These cysts have been called

brown tumors, although they are not really tumors but

Reparative giant cell granulomas.

In some cases these lesions appear in the periapical region

of teeth and can lead to a misdiagnosis of a lesion ot

endodontic origin.


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Loss of the lamina dura and giant cell tumors in the jaws

are late signs of hyperparathyroid bone disease, which initself is uncommon. Complete loss of the lamina dura does

not occur often.

Loss of lamina dura may also occur in Paget's disease,

fibrous dysplasia, and osteomalacia.


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Acccording to the studies done by rosenberg and

Guralnick(1962), silverman et al(1962) and strock

MS(1945), 25%, 45%, and 50% of patients with

hyperparathyroidism have associated oral changes.

A relationship has been suggested between periodontal

disease in dogs and hyperparathyroidism secondary to

calcium deficiency in the diet, (Henrikson 1962), but this

has not been confirmed by other studies (Svanberg,

Lindhe, Hugosonm et al 1973).


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METASTATIC CALCIFICATION

Ectopic calcification in soft tissue is the most common feature

of hyperparathyroidism.

A reported 45% to 80% of the patients have nephrolithiasis and

/ornephrocalcinosis.

Other soft tissues involved are the subcutaneous tissues, walls

of blood vessels, articular cartilages, and joint capsules.

The pancreas and the salivary glands frequently develop

lithiasis.


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HYPOCALCEMIA

Hypocalcemia is often asymptomatic.

This leads to muscular and mental manifestations that

include paresthesia of hands, feet and circumoral muscles,

anxiety, confusion and depression.

Spasm of the laryngeal muscles can lead to asphyxia and

death.


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Painful muscular spasms affect oral and laryngeal muscles.

If hypoparathyroidism is part of an autoimmune

polyendocrinopathy syndrome, oral mucocutaneous candidiasis

may be present in an acute or chronic form.

If hypoparathyroidism occur when teeth are still developing,

there will be abnormalities in the appearance and eruptionpattern.


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Malformed, anodontia, short blunt root apices, elongated

pulp chambers (some occluded by pulp stones, even in the

primary dentition), impacted teeth and mandibular

exostoses.

There may be enamel hypoplasia, single or parallel

horizontal bands on the enamel, and poorly mineralized

dentin.


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Laboratory Findings

Hypocalcemia is characterized by the following:

serum [Ca2+] and tetany

serum [phosphate]

urinary phosphate excretion


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VITAMIN D

VITAMIN D 1,25- dihydroxycholecalciferol the active form of vitaminD. It behaves like a true harmone.

Vitamin D containing food includes liver, eggs, milk and

other food of animal origin.

The sources of vitamin D in the body are dietary intake,

and more importantly, cutaneous synthesis of vitamin D (

cholecalciferol).


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ACTION

The intestine, kidney and the bone are the chief target organs.

Increasing the synthesis of calcium channels and a carrier protein

for ca2+ called CALCIUM BINDING PROTEIN (CaBP) or

CALBINDIN in many tissues, particularly the intestine.

It promotes the reabsorption of calcium and phosphate from the

renal tubules.

The active pump which transfers calcium ions out of the

osteocytic membrane into the ECF is vitamin D mediated.


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VITAMIN D Deficiency

Embrace a group of disorders characterized by failure in the

mineralization of bones.

Rickets is failure of mineralization of endochondral new bone

formed at the growth plates in children, whereas osteomalacia is

failure of mineralization of newly formed organic bone matrix

at site of bone turnover.


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CAUSES

Dermal synthesis of vitamin D can be impaired by inadequate

sunlight in geographic regions of extreme latitude or in cultural

regions that wear extensive clothing to cover the whole body.

Calcium-deficient diets, as well as malabsorption states such as

those encountered after gastric resection .

Biliary obstruction may also produce a calcium deficiency by

preventing bile salts from reaching the intestine.


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Prolonged administration ofanticonvulsant drugs ( eg:

phenobarbitol, primidone) can result in calcium deficiencybecause these drugs enhance liver enzyme activity, which leads

to an increased breakdown of vitamin D to biologically inert

products.

A variety of renal diseases, which may be congenital or may

result from a chronic nephritis.


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RICKETS


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DENTAL FINDINGS IN RICKETS

Developmental anomalies

of enamel and dentin

Delayed eruption

Misalignment of teeth

Increase caries index

Wide predentin zone and

more interglobular dentin


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Vitamin D, or calcilerol, is essential for the absorption of

calcium from the gastrointestinal tract and themaintenance of the calcium-phosphorus balance.

Deficiency in vitamin D and imbalance in calcium-

phosphorus intake result in rickets in young children and

osteomalacia in adults.

No studies demonstrate a relationship between vitamin D

deficiency and periodontal disease.


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The effect of vitamin D deficiency or imbalance on the

periodontal tissues of young dogs results in osteoporosisof alveolar bone; osteoid that forms at a normal rate but

remains uncalcified; failure of osteoid to resorb, which

leads to its excessive accumulation; reduction in the width

of the periodontal ligament space; a normal rate of

cementum formation, but defective calcification and some

cementum resorption; and distortion of the growth pattern

of alveolar bone. - Becks et al 1946 and

Weinmann and Schour 1945


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In osteomalacic animals, there is rapid, generalized, severe

osteoclastic resorption of alveolar bone; proliferation of

fibroblasts that replace bone and marrow; and new boneformation around the remnants of unresorbed bony

trabeculae.(Dreizen et al 1967)

Radiographically, there is generalized partial to complete

disappearance of the lamina dura and reduced density of thesupporting bone, loss of trabeculae, increased radiolucency of

the trabecular interstices, and increased prominence of the

remaining trabeculae.

Microscopic and radiographic changes in the periodontium arealmost identical with those seen in experimentally induced

hyperparathyroidism.


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OSTEOPOROSIS:

Seen in old age

Results from diminished organic bone matrix rather than

abnormal bone calcification.

With the increased rate of remodelling in older age, there is

uncoupling of the remodeling cycle, that is, rate of

resorption exceeds the rate of formation. This results in a

remodeling imbalance with net bone loss, lower bone mass,

and ultimately increased risk for fractures.


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CALCITONIN

Calcitonin is a peptide hormonesecreted by the parafollicular or

C cells of the thyroid gland.

Also called as thyrocalcitonin.

It is released in response to high

plasma calcium.

Calcitonin acts on bone

osteoclasts to reduce bone

resorption.


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ACTION OF CALCITONIN

Net result of its action is a decline in plasma calcium & phosphate .

Calcitonin is a physiological antagonist to PTH with respect to

Calcium.

With respect to phosphate it has the same effect as PTH i.e.

plasma phosphate level.

Osteoclast cells

Lose their ruffled borders

Undergo cytoskeletal rearrangement

mobility

Detach from bone


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Other Hormones Regulating

Calcium GROWTH HORMONE

INSULIN

TESTOSTERONE & OTHER HORMONES

OESTROGENS

STEROIDS

THYROID HORMONES


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GROWTH HORMONE

Increases the intestinal absorption of calcium and decreasesits excretion from urine.

Stimulates production of insulin like growth factor in bone

which stimulates protein synthesis in bone.

.


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TESTOSTERONE Acts on cartilage & increase the bone growth.

INSULIN

It is an anabolic hormone which favors bone formation.


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GLUCOCORTICOSTEROIDS

Anti vitamin D action, decrease absorption of calcium in

intestine.

Inhibit protein synthesis and so decrease in boneformation.

Inhibit new osteoclast formation & decrease the activity of

old osteoclasts.


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Exogenous cortisone may have an adverse effect on bone

quality and physiology. The systemic administration of

cortisone in experimental animals results in osteoporosis

of alveolar bone; capillary dilation and engorgement, with

haemorrhage in the periodontal ligament and gingival

connective tissue; degeneration and reduction in the

number of collagen fibres of the periodontal ligament; and

increased destruction of the periodontal tissues, associated

with inflammation.Glickman et al 1953


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Stress increases circulating cortisol levels through

stimulation of the adrenal glands (hypothalamic-pituitary

adrenal axis). This increased exposure to endogenous

cortisol may have adverse effects on the periodontium by

diminishing the immune response to periodontal bacteria.

Drugs affecting calcium


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Drugs affecting calcium

metabolism:

Steroids

Antiepileptics (phenytoin)

Anticoagulants

Proton pump inhibitors


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REFERENCE

Guyton and hall- textbook of medical physiology.

Davidsons Principles and practice of Medicine.

Sembulingam and sembulingam- Essentials of MedicalPhysiology.

Satyanarayan- Essentials of Biochemistry.

Shafers- Oral Pathology.

Rose- Periodontal Medicine.


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GOOD MORNING!!!

CONTENTS


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CONTENTS INTRODUCTION

IMPORTANCE OF CALCIUM

SOURCES OF CALCIUM DISTRIBUTION OF CALCIUM


ABSORPTION OF CALCIUM


EXCRETION OF CALCIUM

PARATHYROID GLANDS AND PARATHORMONE

1,25-DIHYDROXYVITAMIN D(CALCITRIOL) CALCITONIN

PERIODONTIUM AND CALCIUM

REFERENCE


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PERIODONTIUM AND CALCIUM

INCREASED BLOODDECREASED BLOOD


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PARATHYROID

PARATHORMONE

BONE:Increase in

resorption and releaseof calcium

KIDNEY

1,25-DIHYDROXY

CHOLECALCIFEROL

INTESTINE: Increase

in absorption ofcalcium

THYROID

CALCITONIN

BONE: Inhibition ofbone resorption and

deposition ofcalcium

CALCIUM LEVELCALCIUM LEVEL

NORMAL BLOOD CALCIUM LEVEL


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BONE REMODELLING:

Remodeling is the major pathway of bony changes in

shape, resistance to forces, repair of wounds, and calcium

and phosphate homeostasis in the body. Indeed, thecoupling of bone resorption with bone formation

constitutes one of the fundamental principles by which

bone is necessarily remodeled throughout its life.


61/112

Bone contains 99% of the body's calcium ions. A decrease in

blood calcium is mediated by receptors on the chief cells of theparathyroid glands, which then release parathyroid

hormone(PTH). PTH stimulates osteoblasts to release Il-1 and

Il-6 which stimulate monocytes to migrate into the bone area.Leukemia inhibiting factor (LIF), secreted by osteoblasts,

coalesces monocytes into multinucleated osteoclasts, which

then resorb bone, releasing calcium ions from hydroxyapatite

into the blood.


62/112

A feedback mechanism of normal blood levels of calcium

turns off the secretion of PTH. Meanwhile, osteoclasts haveresorbed organic matrix along with hydroxyapatite. The

breakdown of collagen from the organic matrix releases

various osteogenic substrates, which are covalently bound tocollagen, and this in turn stimulates the differentiation of

osteoblasts, which ultimately deposit bone. This

interdependency of osteoblasts and osteoclasts in remodeling

is called coupling.


63/112

When osteoclasts are active rather than resting, they

possess an elaborately developed ruffled border from

which hydrolytic enzymes are believed to be secreted.

These enzymes digest the organic portion of bone. The

activity of osteoclasts and morphology of the ruffled

border can be modified and regulated by hormones such

as PTH (indirectly) and calcitonin, which has receptors on

the osteoclast membrane.


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BONE REMODELLING CYCLE:


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HYPERPARATHYROIDISM

Parathyroid hypersecretion produces generalized

demineralization of the skeleton, increased osteoclasis

with proliferation of the connective tissue in the enlarged

marrow spaces, and formation of bone cysts and giant cell

tumors. The disease is called osteitis fibrosra cystica, or

von Recklinghausen's bone disease.


66/112

Loss of the lamina dura and giant cell tumors in the jaws

are late signs of hyperparathyroid bone disease, which in

itself is uncommon. Complete loss of the lamina dura does

not occur often.

Loss of lamina dura may also occur in Paget's disease,

fibrous dysplasia, and osteomalacia.


67/112

Acccording to the studies done by rosenberg and

Guralnick(1962), silverman et al(1962) and strock

MS(1945), 25%, 45%, and 50% of patients with

hyperparathyroidism have associated oral changes.

A relationship has been suggested between periodontal

disease in dogs and hyperparathyroidism secondary to

calcium deficiency in the diet, (Henrikson 1962), but this

has not been confirmed by other studies (Svanberg,

Lindhe, Hugosonm et al 1973).



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Embrace a group of disorders characterized by failure in the

mineralization of bones.

Rickets is failure of mineralization of endochondral new boneformed at the growth plates in children, whereas osteomalacia is

failure of mineralization of newly formed organic bone matrix

at site of bone turnover.


69/112

The effect of vitamin D deficiency or imbalance on the

periodontal tissues of young dogs results in osteoporosisof alveolar bone; osteoid that forms at a normal rate but

remains uncalcified; failure of osteoid to resorb, which

leads to its excessive accumulation; reduction in the widthof the periodontal ligament space; a normal rate of

cementum formation, but defective calcification and some

cementum resorption; and distortion of the growth pattern

of alveolar bone. - Becks et al 1946 and

Weinmann and Schour 1945


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In osteomalacic animals, there is rapid, generalized, severe

osteoclastic resorption of alveolar bone; proliferation of

fibroblasts that replace bone and marrow; and new boneformation around the remnants of unresorbed bony

trabeculae.(Dreizen et al 1967)

Radiographically, there is generalized partial to complete

disappearance of the lamina dura and reduced density of thesupporting bone, loss of trabeculae, increased radiolucency of

the trabecular interstices, and increased prominence of the

remaining trabeculae.

Microscopic and radiographic changes in the periodontium are

almost identical with those seen in experimentally induced

hyperparathyroidism.


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Periodontitis can be considered an abnormal inflammatory

response to periodontal flora, in which hard and soft

tissues are destroyed by auto-degradative mechanisms.(Birkedal-Hansen H. 1993, Graves DT, Cochran D 2003.)

As part of this process, monocytes respond to bacterial

invasion and secrete cytokines, which in turn cause

lymphocytic infiltration, bone resorption, and dissolution

of the extracellular matrix.


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Cytokines (cell proteins) regulate the bodys inflammatory

response by transmitting signals between cells. Cytokines

such as IL-1, IL-6, and TNF- are potent osteoclastogenic

signaling agents, which result in the resorption of alveolar

bone. (Birkedal-Hansen H. 1993, Salvi GE. 1997)

IL-1 also stimulates the release of metalloproteinases(MMP), which degrade the extracellular matrix and

prostaglandin E2 (PGE2), which causes vasodilation,

edema, and bone resorption.


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Hypertension, diabetes mellitus, cardiovascular diseases,

and periodontal diseases are associated with obesity and,because vitamin D and 25(OH)D are stored in adipose

tissue, obese subjects have low serum levels of 25(OH)D.

(Ralston SH, 2004, Nishimura F 2003)

Moreover, specific vitamin D-receptor genotypes have

been shown to be associated with localized aggressive

periodontal disease, with oral bone loss, clinical

attachment loss, and tooth loss. (Hennig BJ et al 1999,

Inagaki K et al 2003)


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In a study (Krook L et al 1972), 10 subjects with

periodontal disease received 1,000 mg/day of calciumsupplementation and were followed for 6 months. The

investigators reported that at the end of 6 months of

treatment, gingival inflammation was improved, probing

depth and tooth mobility decreased, and new bone

appeared to have formed as observed radiographically.


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A more recent 3-year hormone replacement study (Civitelli R,

2002) in which 67 periodontally healthy post-menopausal

women received only 1,000 mg of calcium and 400 IU ofvitamin D per day. Over a 3-year period, there were significant

increases in both alveolar bone mass and alveolar crest height.

The apparent increase in crestal bone height was attributed to a

reduction or complete refilling of the remodeling space. After 3years, this increase in crestal density (decrease in crestal

porosity) would have been most pronounced in subjects with

vitamin D deficiency and radiographically would appear as an

increase in alveolar crest height.


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In an examination of data on 12,000 adults who took part inthe Third National Health and Nutrition Examination Survey

(NHANES III), (Nishida M et al, 2000). it was found thatlower dietary intake of calcium increased attachment loss in a

dose-dependent fashion.

The investigators suggested that the increased risk ofperiodontal disease could be related to decreased alveolar

bone density associated with inadequate calcium intake. The

major limitations of the study are that it was cross-sectional

and lacked exact data on calcium supplementation.


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References:

Carranza 10 th edition

Charles F. Hildebolt, Effect of Vitamin D and Calcium on

Periodontitis. J Periodontol 2005;76:1576-1587.

Nishida M, Sara G, et al Calcium and the risk for periodontal

disease J Periodontol 2000;71:1057-1066

Guyton and hall- textbook of medical physiology.

Davidsons Principles and practice of Medicine.

Sembulingam and sembulingam- Essentials of Medical

Physiology. Satyanarayan- Essentials of Biochemistry.



REFERENCE


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REFERENCE

Guyton and hall- textbook of medical physiology. Davidsons Principles and practice of Medicine.

Sembulingam and sembulingam- Essentials of MedicalPhysiology.

Satyanarayan- Essentials of Biochemistry.




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THANK YOU!


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OSTEOPOROSIS

Meaning- Porous Bone.

Too little bone to provide mechanical support.

Osteopenia- reuction in bone mineral density (BMD) below

a predefined level.

Osteoporosis is characterised by a reduction in BMD to a

level below what is required for mechanical support.


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Definition:

a systemic skeletal disease characterized by low bone

mass and microarchitectural deterioration with a

consequent increase in bone fragility and susceptibility tofracture.

A World Health Organization panel has operationally

defined osteoporosis as a BMD that is 2.5 SD below themean peak value in young adults.


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The pathophysiology of osteoporosis is poorly understood.

Bone mass at any given time is related to peak bone mass

and bone loss that has occurred since peak mass was

attained. Bone is continuously remodelled throughout the

life of an individual, and the rate of remodelling isincreased in older adults. With the increased rate of

remodelling in older age, there is uncoupling of the

remodelling cycle, that is, the rate of resorption exceedsthe rate of formation.


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This results in a remodelling imbalance with net bone loss,

lower bone mass, and ultimately increased risk for

fractures. Such an imbalance would be even greater if the

rate of initiation of new bone remodelling cycles were to

increase. Therefore, genetically determined bone mass and

age constitute the major determinants of risk of

osteoporosis and osteoporotic fractures.


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It has long been postulated that mandibular bone density

may be indicative of systemic bone mineral density. In a

classic series of studies, done by Kribbs and colleagues

they addressed this relationship in both normal and

osteoporotic women.

In a study, (Kribs PJ 1983), total body calcium as assessed

by neutron activation analysis, was found to be associated

with mandibular density as measured by quantitative

analysis of intraoral radiographs.

In another study (Kribs PJ 1990), done in normal,

nonosteoporotic women, revealed that bone mass was not

affected by age but was significantly associated withskeletal bone mass at the spine and wrist.

T th L d O t i


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Tooth Loss and Osteoporosis

Several studies have demonstrated a relationship between

tooth loss and systemic osteoporosis in both dentate and

edentulous individuals.

Daniell and colleagues (1983) suggested that systemic

bone loss was a risk factor for edentulism. Women with

severe osteoporosis, were three times more likely (44%

versus 15%) to have no teeth compared with healthy, age-

matched controls.


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In a 7-year longitudinal study, rate of systemic bone loss

was a predictor of tooth loss in postmenopausal women.

(Krall EA et al 1996).. For each 1% per year decrease in

whole body BMD, the risk for tooth loss more than

quadrupled. Decreases in BMD at the femoral neck and

spine resulted in a 50% and 45% increased risk of tooth

loss respectively.


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Collectively, evidences indicate that osteoporotic women

have lost significantly more teeth, and more are

edentulous compared with nonosteoporotic women.(daniell HW 1983, Taguchi A 1995, Krall EA 1994, 1996)

Thus, women that are at risk for or suffer from

osteoporosis are also at risk for tooth loss.

P i d t l Di d O t i /


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Periodontal Disease and Osteopenia/

Osteoporosis

Unlike the clear relationship between osteoporosis and

tooth loss, controversy still exists concerning the

association between osteopenia/osteoporosis and

periodontal disease. Different studies have given

conflicting results accounting for much of the controversy.


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In a study done by Wactawski-Wende and colleagues,45

including 70 postmenopausal women, a significant

relationship was found between alveolar crestal bone

height as a measure of periodontitis and skeletal

osteopenia (femur and lumbar spine) measured by DXA.

This relationship was seen after controlling for possible

confounders such as dental plaque, years of menopause,

and smoking. In addition, there was a relationship between

osteopenia at the hip and probing attachment loss in thissame group.

Th l i hi b i d i f


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The relationship between osteopenia and severity of

periodontal disease was also examined in a sample from the

Third National Health and Nutrition Examination Survey

(NHANES III) of 11,247 individuals 20 to 90 years of age.46

Osteopenia of the hip was significantly associated with

severity of periodontal disease (mean attachment loss > 1.5

mm) in females and males alike, independently of the

confounding effects of age, gender, smoking, or intake ofdietary calcium.

This association was increased even further in

postmenopausal females. Hence, though limited, the evidencesuggests an association between osteopenia, osteoporosis, and

periodontal disease.

CORISK FACTORS FOR OSTEOPOROSIS


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AND PERIODONTAL DISEASE

Osteoporosis and periodontal disease are chronic,

multifactorial diseases. Therefore, both diseases share

common risk factors.

Risk factors common to both osteoporosis and periodontal

disease are listed under the categories of genetic, dietary,

environmental, and systemic factors.


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Estrogen Deficiency


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Estrogen Deficiency

Estrogen deficiency is the factor most closely associated

with postmenopausal osteoporosis.

Estrogen regulates bone remodeling by modulating the

production of cytokines and growth factors, especially IL-1b, TNF-a, GM-CSF, and M-CSF from bone cells.

IL-1, TNF-a, and GM-CSF contribute to bone resorption

by promoting osteoclast recruitment and differentiationfrom bone marrow precursors. Osteoblast precursors

respond to the loss of estrogen by secreting IL-6, which

then induces osteoclastogenesis.


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Three studies have directly examined the relationship of

estrogen status/deficiency and periodontal disease.

Norderyd and colleagues (1993) reported lower, although

not statistically significant, levels of clinical attachment

loss in postmenopausal women receiving estrogen

supplementation compared with estrogen-deficientpostmenopausal women. In addition, gingival bleeding

was statistically significantly reduced in the estrogen-

treated postmenopausal women compared with the

estrogen-deficient group, after controlling for levels of

supragingival plaque and frequency of dental treatment.


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In a 5-year longitudinal study (Jacobs et al 1996) of 69 women

with surgical or natural menopause receiving hormonereplacement therapy compared lumbar spine BMD, measured by

dual photon absorptiometry, with mandibular bone mass

assessed by quantitative measures of standardized intraoral

radiographs. A statistically significant but moderate correlation

was observed between mandibular and lumbar spine bone mass

and that estrogen replacement therapy after surgical or natural

menopause had a positive effect on bone mass not only of the

lumbar spine but the mandible as well.

l i di l d f l


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In a 1-year longitudinal study of 24 postmenopausal

women,(Payne and colleagues (1997)) it was seen that

estrogen-deficient women displayed a mean net loss inalveolar bone density compared with estrogen sufficient

women, who displayed a mean net gain in alveolar bone

density. The authors proposed estrogen deficiency as a risk

factor for alveolar bone density loss. Thus, in the estrogen

deficient state, the governor controlling cytokines andbone remodelling is lost, resulting in increased bone

resorption and net skeletal and alveolar bone loss.

Vitamin D Genotypes


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Vitamin D Genotypes

Activated form of vit D molecules bind to the vitamin Dreceptor (VDR), a nuclear receptor that is highlyexpressed in the target organs of calcium metabolism.

Activated form of vit. D exhibits its physiologic andpharmacologic effects by activating the vitamin Dreceptor.


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VDR belongs to nuclear recptor super family of

transcription factor.

VDR responds to endocrine signal (vit D3) and

metabolites (lithocholic acid)

VDR is localised in both cytosol and nucleus and


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accumulates in the nucleus in response to 1,25(OH)2 D3

binding.

DR3 VDR binding elements.. In regulatory regions of

many target genes, including 25-hydroxyvitamin D 24-

hydroxylase (CYP24A1), calbindin D9k. Cathelicidin

antimicrobial peptide (CAMP) and transient receptor

potential vanilloid type 6 (TRPV6).


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Nuclear receptors including VDR undergo a

confirmational change in the cofactor binding site andactivation function AF2 domain upon ligand binding, a

structural rearrangement that results in the dynamic

exchange of cofactor complexes.

Dynamic and co-ordinated interaction of co factor

complexes and VDR is required for efficient regulation of

transcription.


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VDR mutations have been identified in HVDRR

.(Malloy PJ 1999).

Ligand activated VDR induces the expression of

genes involved in calcium metabolism, such as

calbindin D9k, TRPV6, and TRPV5.


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Activation of VDR by pharmacological doses ofvit D regulates osteoblasts by inducing thebone remodelling proteins osteocalcin and

osteopontin and upregulates the RANKL, aparacrine signal for osteoclastogenesis.

VDR mediated induction of osteoblast RANKL may


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account for enhanced bone resorption. Chondrocyte

specific VDR- ablated mice have reduced RANKLexpression and reduced osteoclastogenesis.

VDR regulates bone homeostasis through actions in

osteoblasts and chondrocytes.

Vitamin D deficiency is a risk factor for osteoporotic


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y p

fractures, and treatment of osteoporotic women with

1,25(OH)2D3 increases BMD and decreases the incident

of vertebral compression fractures. Vitamin D supresses

pro inflammatory responses and enhances innate

immunity. Therefore VDR ligands can be clinically useful

in the treatment of osteoporosis associated periodontal

disease.


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Along with the loss of function VDRmutations responsible for HVDRR,associations of several VDR restriction

fragment length polymorphisms with severaldiseases including DM, cancer, osteoporosisand periodontal disease have been reported.

The RFLPs Bsml, Tru91, Taq1, EcoRV andApal may infulence mRNA stability.


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Insufficient clearence of periodontopathic bacteria andsubsequent bone destruction are suggested to causeaggressive periodontitis.

VDR ligands stimulate innate immunity by inducingantimicrobial peptides and have bone anabolicsuggesting that VDR ligands can be applied forprevention of aggressive periodontitis .


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A dysregulated release of proinflammatorycytokines by the monocye/macrophages andlymphocytes is considered to induce chronic

periodontitis.

Since Vit D has potent immunomodulatory

effects that is by inhibiting theproinflammatory cytokine release VDRligands may be effective in the treatment.


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REFERENCES


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REFERENCES

Periodontal Medicine- Rose LF and Genco RJ.

Amano Y, et al. Vitamin D and periodontaldisease. J Oral Sci 2009;51:11-20.


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CA Metabolism