Calcium Homeostasis

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Calcium Homeostasis

• By
• Dr. Khurram Irshad
• Department of
• Physiology

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Calcium HomeostasisKey Players 1. Parathyroid
Hormone 2. Calcitonin 3. and Vitamin D3
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Calcium homeostasis

• Key Organs Involved
• Parathyroid Gland
• Intestines
• Bone
• Kidneys
• And Skin

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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

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Regulation of Calcium Concentration

• The important role that calcium plays in so many
  processes that its concentration, both
  extracellularly and intracellularly, be
  maintained within a very narrow range.
• This is achieved by an elaborate system of
  controls

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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
• Hypocalcemic tetany

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Extracellular Calcium

• Three definable fractions of calcium in serum
• Ionized calcium 50
• Protein-bound calcium 41
• 90 bound to albumin
• Remainder bound to globulins
• Calcium complexed to serum constituents 9
• Citrate and phosphate
• Ca2 normally ranges from 8.5-10 mg/dL in the
  plasma.(9.4 mg/dL or 2.4 mmol/L)

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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

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Calcium turnover
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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.

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Bones cells
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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

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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
  resorption 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 resorption
  begins to exceed formation and bone mass slowly
  decreases.

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Bone cell types

• There are three types of bone cells Osteoblasts
  are the differentiated bone forming cells and
  secrete bone matrix on which Ca and PO
  precipitate.
• Osteocytes, the mature bone cells are enclosed in
  bone matrix.
• Osteoclasts is a large multinucleated cell
  derived from monocytes whose function is to
  resorb bone. Inorganic bone is composed of
  hydroxyapatite and organic matrix is composed
  primarily of collagen.

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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.

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Control of bone formation and resorption?

• Bone resorption of Ca by two mechanims
  osteocytic osteolysis is a rapid and transient
  effect and osteoclasitc resorption which is slow
  and sustained.
• Both are stimulated by PTH. CaPO4 precipitates
  out of solution id its solubility is exceeded.
  The solubility is defined by the equilibrium
  equation Ksp Ca23PO43-2.
• In the absence of hormonal regulation plasma Ca
  is maintained at 6-7 mg/dL by this equilibrium.

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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.

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Bone resorption?

• Does not merely extract calcium, it destroys
  entire matrix of bone and diminishes bone mass.
• Cell responsible for resorption is the
  osteoclast.

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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.

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Calcium, bones and osteoporosis

• 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
• avoid drinking carbonated soft drinks

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Vertebrae of 40- vs. 92-year-old women
Note the marked loss of trabeculae with
preservation of cortex.
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Hormonal control of bones
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Vitamin D

• Vitamin D, after its activation to the hormone
  1,25-dihydroxy Vitamin D3 is one of the principal
  regulator of Ca.
• Vitamin D increases Ca absorption from the
  intestine and Ca resorption from the bone .

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Synthesis of Vitamin D

• Humans acquire vitamin D from two sources.
• Vitamin D is produced in the skin by ultraviolet
  radiation and ingested in the diet.
• Vitamin D is not a classic hormone because it is
  not produce and secreted by an endocrine gland.
  Nor is it a true vitamin since it can be
  synthesized de novo.
• Vitamin D is a true hormone that acts on distant
  target cells to evoke responses after binding to
  high affinity receptors

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Synthesis of Vitamin D

• Vitamin D3 synthesis occurs in keratinocytes in
  the skin.
• 7-dehydrocholesterol is photoconverted to
  previtamin D3, then spontaneously converts to
  vitamin D3.

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Synthesis of Vitamin D

• PTH stimulates vitamin D synthesis. In the
  winter or if exposure to sunlight is limited
  (indoor jobs!), then dietary vitamin D is
  essential.
• Vitamin D itself is inactive, it requires
  modification to the active metabolite,
  1,25-dihydroxy-D.
• The first hydroxylation reaction takes place in
  the liver yielding 25-hydroxy D.
• Then 25-hydroxy D is transported to the kidney
  where the second hydroxylation reaction takes
  place.

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Synthesis of Vitamin D

• The mitochondrial P450 enzyme 1a-hydroxylase
  converts it to 1,25-dihydroxy-D, the most potent
  metabolite of Vitamin D.
• The 1a-hydroxylase enzyme is the point of
  regulation of D synthesis.
• Feedback regulation by 1,25-dihydroxy D inhibits
  this enzyme.
• PTH stimulates 1a-hydroxylase and increases
  1,25-dihydroxy D.
• Phosphate inhibits 1a-hydroxylase and decreased
  levels of PO4 stimulate 1a-hydroxylase activity

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Vitamin D promotes intestinal calcium absorption

• Vitamin D acts via steroid hormone like receptor
  to increase transcriptional and translational
  activity
• One gene product is calcium-binding protein
  (CaBP)
• CaBP facilitates calcium uptake by intestinal
  cells

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Vitamin D action

• The main action of 1,25-(OH)2-D is to stimulate
  absorption of Ca2 from the intestine.
• 1,25-(OH)2-D induces the production of calcium
  binding proteins which sequester Ca2, buffer
  high Ca2 concentrations that arise during
  initial absorption and allow Ca2 to be absorbed
  against a high Ca2 gradient

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Vitamin D Actions on Bones

• Another important target for 1,25-(OH)2-D is the
  bone.
• Osteoblasts, but not osteoclasts have vitamin D
  receptors.
• 1,25-(OH)2-D acts on osteoblasts which produce a
  paracrine signal that activates osteoclasts to
  resorb Ca from the bone matrix.
• 1,25-(OH)2-D also stimulates osteocytic
  osteolysis.

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Vitamin D and Bones

• Proper bone formation is stimulated by
  1,25-(OH)2-D.
• In its absence, excess osteoid accumulates from
  lack of 1,25-(OH)2-D repression of osteoblastic
  collagen synthesis.
• Inadequate supply of vitamin D results in
  rickets, a disease of bone deformation

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Parathyroid Hormone

• Parathyroid Hormone is essential for life

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Parathyroid Hormone

• PTH is synthesized and secreted by the
  parathyroid gland which lie posterior to the
  thyroid glands.
• The blood supply to the parathyroid glands is
  from the thyroid arteries.
• The Chief Cells in the parathyroid gland are the
  principal site of PTH synthesis.

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Synthesis of PTH

• PTH is translated as a pre-prohormone.
• Cleavage of leader and pro-sequences yield a
  biologically active peptide of 84 aa.
• Cleavage of C-terminal end yields a biologically
  inactive peptide.

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Calcium regulates PTH
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Regulation of PTH?

• PTH secretion responds to small alterations in
  plasma Ca2 within seconds.
• When Ca2 falls, cAMP rises and PTH is secreted.
  
• A unique calcium receptor within the parathyroid
  cell plasma membrane senses changes in the
  extracellular fluid concentration of Ca2.
• This is a typical G-protein coupled receptor that
  activates phospholipase C and inhibits adenylate
  cyclaseresult is increase in intracellular Ca2
  via generation of inositol phosphates and
  decrease in cAMP which prevents exocytosis of PTH
  from secretory granules.

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Negative feed back loops

• Calcitonin plays a role in skeletal integrity in
  pregnancy or breast feeding
• Gastrointestinal hormones

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Calcium regulates PTH secretion
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PTH action

• The overall action of PTH is to increase plasma
  Ca levels and decrease plasma phosphate levels.
  
• PTH acts directly on the bones to stimulate Ca
  resorption and kidney to stimulate Ca
  reabsorption in the distal tubule of the kidney
  and to inhibit reabosorptioin of phosphate
  (thereby stimulating its excretion).
• PTH also acts indirectly on intestine by
  stimulating 1,25-(OH)2-D synthesis.

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Primary Hyperparathyroidism

• Calcium homeostatic loss due to excessive PTH
  secretion
• Due to excess PTH secreted from adenomatous or
  hyperplastic parathyroid tissue
• Hypercalcemia results from combined effects of
  PTH-induced bone resorption, intestinal calcium
  absorption and renal tubular reabsorption
• Pathophysiology related to both PTH excess and
  concomitant excessive production of 1,25-(OH)2-D.

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Hypercalcemia of Malignancy

• Underlying cause is generally excessive bone
  resorption by one of three mechanisms
• 1,25-(OH)2-D synthesis by lymphomas
• Local osteolytic hypercalcemia
• 20 of all hypercalcemia of malignancy
• Humoral hypercalcemia of malignancy
• Over-expression of PTH-related protein (PTHrP)

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PTH receptor defect

• Rare disease known as Jansens metaphyseal
  chondrodysplasia
• Characterized by hypercalcemia, hypophosphotemia,
  short-limbed dwarfism
• Due to activating mutation of PTH receptor
• Rescue of PTH receptor knock-out with targeted
  expression of Jansens transgene

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Hypoparathyroidism

• Hypocalcemia occurs when there is inadequate
  response of the Vitamin D-PTH axis to
  hypocalcemic stimuli
• Hypocalcemia is often multifactorial
• Hypocalcemia is invariably associated with
  hypoparathyroidism
• Bihormonalconcomitant decrease in 1,25-(OH)2-D

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Hypoparathyroidism

• PTH-deficient hypoparathyroidism
• Reduced or absent synthesis of PTH
• Often due to inadvertent removal of excessive
  parathyroid tissue during thyroid or parathyroid
  surgery
• PTH-ineffective hypoparathyroidism
• Synthesis of biologically inactive PTH

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-Carpopedal Spasm -Rickets
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Pseudohypoparathyroidism

• PTH-resistant hypoparathyroidism
• Due to defect in PTH receptor-adenylate cyclase
  complex
• Mutation in Gas subunit
• Patients are also resistant to TSH, glucagon and
  gonadotropins

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Calcitonin

• Calcitonin acts to decrease plasma Ca levels.
• While PTH and vitamin D act to increase plasma
  Ca-- only calcitonin causes a decrease in
  plasma Ca.
• Calcitonin is synthesized and secreted by the
  parafollicular cells of the thyroid gland.
• They are distinct from thyroid follicular cells
  by their large size, pale cytoplasm, and small
  secretory granules.

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Calcitonin

• The major stimulus of calcitonin secretion is a
  rise in plasma Ca levels
• Calcitonin is a physiological antagonist to PTH
  with regard to Ca homeostasis

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Calcitonin

• The target cell for calcitonin is the osteoclast.
  
• Calcitonin acts via increased cAMP concentrations
  to inhibit osteoclast motility and cell shape and
  inactivates them.
• The major effect of calcitonin administration is
  a rapid fall in Ca2 caused by inhibition of bone
  resorption.

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Nutrition and Calcium

• Calvo MS Dietary considerations to prevent loss
  of bone and renal function
• overall trend in food consumption in the US is
  to drink less milk and more carbonated soft
  drinks.
• High phosphorus intake relative to low calcium
  intake
• Changes in calcium homeostasis and PTH regulation
  that promote bone loss in children and
  post-menopausal women.
• High sodium associated with fast-food consumption
  competes for renal reabsorption of calcium and
  PTH secretion.

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Nutrition and Calcium

• See Nutrition 2000 Vol 16 (7/8) in particular
• Harland BF Caffeine and Nutrition
• Caffeine is most popular drug consumed
  world-wide.
• 75 comes from coffee
• Deleterious effects associated with pregnancy and
  osteoporosis.
• Low birth-rate and spontaneous abortion with
  excessive consumption
• For every 6 oz cup of coffee consumed there was a
  net loss of 4.6 mg of calcium
• However, if you add milk to your coffee, you can
  replace the calcium that is lost.

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Ill effects of soft drinks

• Intake of carbonated beverages has been
  associated with increased excretion and loss of
  calcium
• 25 years ago teenagers drank twice as much milk
  as soda pop. Today they drink more than twice as
  much soda pop as milk.
• Another significant consideration is obesity and
  increased risk for diabetes.
• For complete consideration of ill effects of soft
  drinks on health and environment see
• http//www.saveharry.com/bythenumbers.html

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Exercise and Calcium

• Normal bone function requires weight-bearing
  exercise
• Total bed-rest causes bone loss and negative
  calcium balance
• Major impediment to long-term space travel

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• Tapping the facial nerve at the angle of jaw in
  a patient with moderate hyposecretion of a
  particular hormone elicits a characteristic
  grimace on that side of the face. Which endocrine
  abnormality could give rise to this so called
  Chvostek sign ?

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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.