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HOMEOSTASIS CALCIUM and PARATHYROID HORMONIntegrative Teaching
Bloc 9Prof. dr. Hardi Darmawan, MPH&TM, FRSTMDr. Swanny,
MSc
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Learning Objectives After studying this section, you will be
able to :1.Learn how the body controls the calcium
level.2.Understand the inter - action of Parathyroid hormone,
vitamin D3 and calcitonin in homeostatic regulation of extra and
intracellular calcium level.
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Learning Objectives3.Recognize the clinical manifestations of
calcium homeostatic disturbances.4.Recognize and understand the
pathophysiology of the diseases related to disturbances of
endocrine control of calcium homeostasis.
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CALCIUM BALANCE99% of calcium in the body is found in
BONES.Calcium pool in bone is relatively stable.1% of non bone
calcium that is most critical to physiological functioning.
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FUNCTION of Calcium1. Extracellular calcium : 99% of total
calcium in the body. located in the bone. Function : calcified
matrix of bone
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CA AS BONE MATRIX
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FUNCTION of Calcium2. Extracellular fluid: 0,1 % Function :-
Cement for tight junctionsMyocardial and smooth muscle
contractionRelease of neurotransmitters at synapsesExcitability of
neurons due to effect on Na permeabilityCofactor for coagulation
cascade
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FUNCTION of Calcium3. Intracellular : 0,9 % Function :Signal in
second messenger pathways.Muscle contraction.
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1. Calcium is a signal moleculeCa is most concentrated in ECF
and inside organelles; endoplasmic reticulum and sarcoplasmic
reticulum.If membrane channels for Ca open, Ca moves into
cytoplasma, creating a signal that initiates exocytosis of synaptic
& secretory vesicles, altered activity of enzymes or
transporters.
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2. CEMENT
Calcium is part of the intercellular cement that holds cells
together at tight junctions
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3. Cofactor in the coagulation cascadeAt each step in cascade,
an enzyme converts an inactive precursor into an active enzyme,
with the help of calcium, such as converting of in active factor
XI, IX, X to an active factor XI, IX, X.Although Ca is essential
for coagulation, body Ca level never decrease to the point that
coagulation is inhibited.
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4. Excitability of neuronsClinically relatedHypocalcemia :
neuronal permeability to Na increases, neurons depolarizes, and the
nervous system become hyperexcitable.It will cause sustained
contraction (Tetany) of hand: carpopedal spasm , of respiratory
muscles, resulting in asphyxiation.Hypercalcemia : causes
depressing neuromuscular activity.
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Homeostasis of CalciumCalcium is critical to many physiological
functions.Calcium level must very closely regulated.Principle of
calcium homeostasis : TOTAL BODY CALCIUM = INTAKE - OUTPUT
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INTAKE of calciumRequired daily amounts of Ca : 1,2 gramIntake
is dietary ingestion and uptake in small intestine ( duodenum ).
Calcium absorption is active transport and hormonally regulated.
Absorption is exactly controlled in relation to the need of the
body for calcium.
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OUTPUT of calciumCalcium loss : primarily through Kidney. small
amounts in fecesIonized Ca is freely filtered at
glomerulus.Reabsorbed along the length of nephron. Hormonally
regulated reabsorption occurs in distal nephron.
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Normal distribution and movements of calcium in the body. (ICF,
intracellular fluid; ECF, extracellular fluid)
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EXTRACELLULAR CALCIUM1. PLASMA CALCIUM. Ca concentration : 9 10
mg/dl. Equivalent to 2,4 mmol Ca / liter.40% (1 mmol/ l ) is
combined with plasma protein. This form is nondiffusible to
capillary membrane.10% (0,2 mmol/ l ) is combined with other
substances of plasma and interstitial fluid (citrate , phosphate).
Diffusible to capillary membrane.50% is ionized and diffusible.
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INTRACELLULAR CALCIUMThe concentration of free calcium in
cytosol is about 0,001 mM. Calcium is concentrated inside
mitochondria and sarcoplasmic reticulum.These electrochemical
gradients favor movement of Ca++ into cytosol when Ca++ channels
open.
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EXTRACELLULAR MATRIX (BONE)Bone is the largest reservoir of Ca++
in the body. Most bone Ca++ in the form of HYDROXYAPATITE
crystals.Bone Ca++ in equilibrium with Ca++ of the interstitial
fluid.Only small fraction is ionized and readily exchangeable.Bone
is constantly remodelling.
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Osteoblast controls deposition of Ca++ into bone.Osteoclast
controls movement of Ca++ out of hydroxyapatite and into ionized
Ca++ pool. Osteoclast are responsible for dissolving bone or
RESORPTION.
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PHOSPHATE HOMEOSTASISClosely links to Calcium homeostasis.Most
found in bone, especially in hydroxyapatite of bone ,
Ca10(PO4)6(OH)2 .Phosphate homeostasis parallels that of
Ca++.Absorbed in intestines, filtered, reabsorbed in
kidneys.Divided between bones, ECF, and intracellular.
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FUNCTION of PHOSPHATE
Energy transferStorage in high energy-phosphate bondsActivation
and deactivation of enzymes, transporters, and ion channels.Part of
the DNA and RNA backbone.
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Sites of control of extracellular calcium concentration1.
PLASMA
2. INTESTINE
3. KIDNEY
4. BONE
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HORMONAL CONTROL of CALCIUM BALANCE1. Parathyroid hormone2.
Vitamin D3 ( Calcitriol, 1,25 dihydroxycholecalciferol )3.
Calcitonin4. Cortisol5. Growth Hormone6. Sex steroid ( estrogen,
testosteron )
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Parathyroid hormoneEssential for life.Cell of origin :
parathyroid glandsChemical nature : 84-amino acids
peptideBiosynthesis : continuous production, little storedTransport
: dissolved in plasmaHalf life : less than 20 minutes
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Parathyroid hormoneFactor affecting release : decrease plasma
Ca++Target cell : Kidney, bone, intestineTarget receptor : membrane
receptor acts via cAMPWhole body or tissue action : increase plasma
Ca++
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Actions of parathyroid hormone (PTH) on the kidney and bone
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Parathyroid hormoneAction at cellular level :Increase vit.D3
synthesisIncrease renal reabsorption of Ca++Increase bone
resorption
Action at molecular level :Rapidly alters Ca++ transport but
also initiates protein synthesis in osteoclasts.
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Activation of vitamin D (25 (OH) vitamin D3, 25 - hydroxyvitamin
D3; 1,25(OH)2 vitamin D3, 1,25-dihydroxyvitamin D3)
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Parathyroid hormoneOnset of action :2 3 hours for bone, with
increased osteoclast activity requiring 1 2 hours; 1 2 days for
intestinal absorption; within minutes for kidney transport.
Feed back regulation : Negative feed back by increasing plasma
Ca++
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Other informationOsteoclast have no PTH receptors, so are
affected by PTH induced paracrines.
PTH is ESSENTIAL FOR LIFE.Absence of PTH causes hypocalcemic
tetany, which may lead to death.
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How PTH raises Ca++ concentration 1. PTH mobilizes calcium from
bone.Increased bone resorption by osteoclasts takes about 12 hours
to become measurable.Osteoclasts do not have PTH receptors.PTH
effects are mediated by paracrines, such as osteoprotegerin (OPG)
and osteoclast differentiation factor called RANKL.
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PTH raises Ca++2. PTH enhances renal reabsorption of
calcium.Takes place in the distal nephron.PTH simultaneously
enhances renal excretion of phosphate by reducing its
reabsorption.
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Actions of parathyroid hormone (PTH) on the kidney and bone
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PTH raises Ca++
3. PTH indirectly increases intestinal absorption of calcium by
its influence on vit.D3.
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Calcitriol ( 1,25-dihydroxycholecalciferol) or vitamin
D3Chemical nature : SteroidBiosynthesis : formed by sunlight on
precursor molecules or ingested in food; converted in 2 steps
(liver & kidney) to 1,25-(OH)2 D3.Transport in circulation :
bound to plasma proteins
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Actions of vitamin D on the gastrointestinal tract, bone, and
kidney
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CalcitriolStimulus for synthesis : decrease of Ca++; indirectly
via PTH, prolactin also stimulates synthesis.Target cells/tissues :
Intestine, bone, kidneyTarget receptor : nuclearWhole body or
tissue action : increase of plasma calcium
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Calcitriol
Action at molecular level : stimulates production of calbindin,
a Ca++ -binding protein; associated with intestinal transport by
unknown mechanism.Feed back regulation : plasma Ca++ shuts off PTH
secretion
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CalcitoninCell of origin : C cells of thyroid gland
(parafollicular cells)Chemical nature : 32-amino acid
peptideBiosynthesis : typical peptideTransport : dissolved in
plasmaHalf life : less than 10 minutesFactor affecting release :
increase plasma Ca++.
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CalcitoninTarget cell/tissues : bone and kidneyTarget receptor :
G-protein-coupled membrane receptorWhole body action : prevents
bone resorption; enhances kidney excretion.Action at molecular
level : signal transduction pathways appear to vary during cell
cycle.
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CalcitoninOther information :Experimentally decreases plasma
Ca++, but has little apparent physiological effect in adult humans;
possible effect on skeletal development; possible protection of
bone Ca++ stores during pregnancy and lactation.
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CalcitoninPlays a minor role in daily calcium balance in adult
human.Medically, used to treat patients with PAGET disease, a
genetic disorder in which osteoclasts are overactive and bone is
weakened by resorption.Speculation : most important during
childhood growth, pregnancy and lactation
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Actions of calcitonin on the kidney and bone
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Cortisol Minor role.At low levels : necessary for normal bone
growth.At high levels : inhibits bone formation, that may leads to
osteoporosis.
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Growth HormoneMinor roleIncrease the formation of bone at normal
level. Action of GH on bone is mediated via Somatomedin.
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Sex SteroidsMinor role.Estrogen and testosteron causes closure
of epiphyse of bone.After menopause, estrogen level decreases, bone
resorption increases which is may cause osteoporosis.
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Integrated control of extracellular calcium In HYPOCALCEMIA :1.
PTH increases :- increase bone resorption. - increase renal
reabsorption - increase phosphate excretion - increase renal
synthesis of vit. D3
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2. Increase synthesis of vit.D3 :-increase absorption of Ca++ in
intestine-increase renal reabsorption-increase PTH action on
bone.
NET RESULT: plasma Ca++ increases hypocalcemia is restore back
to calcium balance again.
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HYPOCALCEMIACauses :1. Hypoparathyroidsm : caused by : a.
autoimmune atrophy. b. inadvertent removal of parathyroid glands at
thyroidectomy PTH level low Ca++ level low Phosphate level high
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2. Pseudohypoparathyroidism. a rare hereditary disorder.failure
of target cells to response to PTH.PTH levels high.Ca++
lowPhosphate levels high
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3. Vitamin D deficiency.Causes : a. inadequate enzymatic
conversion. b. increase rate of metabolism c. insufficient sun or
intakePTH levels high.Ca++ levels lowPhosphate levels low
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4. Renal disease. Failure to excrete phosphate and reabsorp
Ca++.Ca++ levels lowPhosphate levels highPTH level high
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Symptoms and signs of hypocalcaemia
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HYPERCALCEMIA1. HyperparathyroidismCaused by : tumor of
parathyroid glandPTH levels highCa++ levels highPhosphate levels
low
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2. Vitamin D toxicity. Ca++ levels high Phosphate levels high
PTH levels low
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Symptoms and signs of hypercalcaemia
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Parathyroid and Bone diseases1. Hypoparathyroidism. PTH level
low---osteocytic reabsorption of exchangeable calcium decreases.
Osteoclasts become inactive. Bone resorption decreases, so that
plasma Ca++. Phosphate in blood increases.Symptoms : muscle
weakness, increase of neuromuscular activity, such as hyperactive
reflex, seizures and tetany.
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HyperparathyroidismCaused by tumor of parathyroid glands.Occurs
more frequently in women, because pregnancy and lactation
stimulates the glands.Osteoclastic activity increases elevates Ca++
concentration in ECF, depressed phosphate concentration due to
increased renal excretion.
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Bone disease in hyperparathyroidismDue to increased activity of
osteoclasts ; bone undergoes extensive decalcification cystic areas
easily fracture : Osteitis fibrosa cystica.Activity of osteoblast
increases also secrete alkaline phosphatase.One of important
diagnostic finding in hyperparathyroidism is a high level of plasma
alkaline phophatase.
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Effects of hypercalcemia in hyperparathyroidismPlasma calcium
level : 12 -15 mg/ dl.Cause depression of CNS and peripheral
nervous system --- muscle weakness, constipation, abdominal pain,
peptic ulcer, lack of appetite, depressed relaxation of heart
during diastole.
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Parathyroid poisoning and Metastatic calcificationIf PTH level
extremely increased; level of calcium in body rises rapidly.
Phosphate level often rises also. Calcium and phosphate in ECF
becomes supersaturated--CaHPO4 crystals deposited in alveoli of
lung, tubules of kidney, thyroid gland, acid producing area of
stomach mucosa, walls of arteries throughout body.Extensive
metastatic deposition of calcium phosphate ----death.
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Kidney stonesCrystals of calcium phosphate tend to precipitate
in kidney forming kidney stones.Tendency for forming renal calculi
is greater in alkaline urine, because the solubility of renal
stones is slight in alkaline media.
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RICKETSOccur mainly in children.Caused by : deficiency of vit.
D.Plasma level of calcium and phosphate decreases.Ordinarily,
plasma calcium is slightly depressed, but phosphate concentration
is greatly depressed.
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Effects of Rickets on bonesProlonged Rickets PTH increased
(compensatory mechanism) osteoclastic absorption of bone increases
bone becomes weaker easily fractured.Lack of calcium and phosphate
new bone is uncalcified, and weak osteoid takes place of the older
bone that is being reabsorbed.
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Tetany in RICKETSTetany occurs when the blood concentration of
calcium falls below 7 mg%.The child may die of tetanic respiratory
spasm. Treatment of tetany : intravenous calcium.
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Signs and symptoms caused by ricketsRickets (Childhood)Knock-
knees or bow-legs caused by bending of the long bones.Chest
deformities, back deformities (e.q. kyphosis) and protruding
forehead.Features of hypocalcaemia.
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OsteomalaciaAdult Rickets.Deficiency of vit. D or calcium is
caused by steatorrhea ( failure to absorb fat).Prolonged kidney
damage renal rickets.Caused by renal failure to form 1,25-(OH)2
vit.D3. Often a serious problem for patients whose kidneys have
been removed or destroyed and are being treated by
hemodialysis.
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Signs and symptoms caused by osteomalaciaOsteomalacia
(adulthood)Bone painBones appear thin on X-ray, with localized
lucencies (called Loosers zones)Fractures (common in the neck of
the femur)Features of hypocalcaemia (e.q. proximal myopathy causes
waddling gait)
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OSTEOPOROSISMost common bone diseases in adults, especially in
old age.Disease of bone loss, due to bone resorption exceeding bone
deposition. The result is fragile, weakened bones that are easily
fractured.Particularly affect spongy trabecular bone, in vertebrae,
hip and wrist.
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A complex disease with genetic and environmental components.Risk
factors include small, thin body type, postmenopausal age, smoking
and low dietary Calcium intake.Most common in women after menopause
when estrogen level falls.
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Causes of Osteoporosis1. Inactivity lack of physical stress on
bone.2. Malnutrition.3. Lack of vit. C necessary for making
osteoid.4. Postmenopausal lack of estrogen.5. Old age GH, growth
factors diminish protein anabolic function decreases poor bone
matrix deposition.6. Cushings diseases cortisol increases increased
protein catabolism depressing osteoblastic activity.
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Calcium Regulation
The regulation of Ca++ involves 3 tissues
:BoneIntestineKidneyThe regulation of Ca++ involves 3 hormones
:ParathormoneCalcitoninActivated vitamin D3 (activated
calciferols)
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The regulation of Ca++ involves 3 cell types
:OsteoblastsOsteocytesOsteoclasts
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Hormonal ControlPituitary gld does not play a major role in the
regulation of the cells that produce parathormons, calcitonin,
vitamin D3
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ParathormonePolypeptide : 84 amino acid residuesSecreted by :
chief cells of 4 parathyroid gldsHypercalcemic hormone of the
bodyEffect on the : bone, intestine, kidneyRegulates only : plasma
concentration of ionic form of Ca++
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Inverse linear relationship between [Ca++] and parathormons
secretion.[Ca++] and parathormons secretion [Ca++] and parathormons
secretion
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Calcitonin32 amino acid residue polypeptideSecreted by
parafollicular cells (c cells) of the thyroid gldHypocalcemic
hormoneEffect on the: bone, intestine, kidneyPositive linear
relationship between [Ca++] and calcitonin secretion
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[Ca++] , calcitonin secretion [Ca++] , calcitonin secretion
Calcitonin release : stimulate by pentagastrin
Vitamin D3 (Cholecalciferol)Vitamin hormone : secosteroid (27
carbonatomes) largest (steroid hormone)
Active metabolites of this hormone : exert biologic activity
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Calcidiol (25 hydroxyvitamin D3 or 25 hydroxycholecalciferol)One
of active metabolite of Vitamin DMajor blood form2-5 > more
effective than Vitamin D3 in preventing rickets.Calcitriol
(1.25-dihydroxyvitamin D3 or 1.25 dihydroxycholecalciferol)Another
active metabolite of vitamin D3On weight basis : 100x > potent
than calcidiol.
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The synthesis of active vitamin D37-dehydrocholesterol vitamin
D3 (skin) uv light
Vitamin D3 25 hydroxyvitamin D3 25-hydroxylase (in the
liver)
25 hydroxyvitamin D3 1.25 dihydroxy 1 = hydroxylase vitamin D3
(kidney)
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Cellular Aspects of Bone MetabolismOsteoblastsHighly
differentiated cellsNon mitotic in their differentiated stateBone
forming cellsLocated on the bone forming surface
OsteoblastsSynthesize and secrete collagenThey contain abundant
alkaline phoshatase activity
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OsteocytesAre osteoblasts that have become burried in bone
matrixEach cell is surrounded by its own lacunaExtensive
canalicular system connects osteocytes and surface osteoblasts,
forming a functional syncytium in the osteocyticform : no longer
synthesize collagenOsteocytes : have an osteolytic activity
stimulated by performanceOsteocytic osteolysis :In the bone matrix
providerRapid movement of Ca++ from bone ECF space
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OsteolaclastsLarge, multinucleated cellsNumerous
lysosomesMediate bone resorption at bone surfacesContain acid
phosphataseForm significant amounts of lactic and hyaluromic
acidsCause bone dissolution via increasedLocal concentration of H+
which solubilizes bone mineral activity of enzymes that degrade
matrix
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Physiologic actions of ParathormoneOsseous TissueParathormone
action on bone : increased Ca++ phosphate mobilization (bone
dissolution) from non readily exchangeable Ca++ pool.Long term
effects of PTH on bone : release of Ca ++ from bone : related to
bone remodelling, involves bone resorption & accretionPTH:
stimulate bone synthesisPTH effects on osteogenesis can be both
anabolic and catabolic in term of collagen metabolism
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Parathormone has 3 important effects on bone account for its
overall osteolytic activityIt stimulates osteoclastic &
osteolytic activityIt stimulates fusion of progenitor cells to form
multinucleated osteoclastic cellsParathormone causes transcient
suppresion of osteoblastic activity
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References.1. Guyton and Hall, Text book of Medical
Physiology.2. Ganong, W.F. , Review of Medical Physiology.3.
Silverthorn, D.U., Human Physiology, An integrated approach.
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