Johan Dahlin
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# calcium 2024.pdf
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**OCR Transcript**
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- Pages: 25
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- OCR Engine: pymupdf
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- Quality Score: 1.00
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---
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## Page 1
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Calcium and phosphate balance
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12/6/24
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1
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Suzanne.Dickson@gu.se
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Calcium Homeostasis
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Suzanne Dickson
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1
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Suzanne.Dickson@gu.se
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Functions of calcium
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ØStructural: bone, teeth, connective tissue
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ØExcitation-contraction coupling (muscles)
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ØExcitation-secretion coupling (neurotransmitters,
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hormones)
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ØStability of excitable membranes
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ØCardiac & smooth muscle potentials
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ØEnzyme activity
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ØBlood clotting
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2
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---
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## Page 2
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Calcium and phosphate balance
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12/6/24
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2
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Suzanne.Dickson@gu.se
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Calcium homeostasis
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The issues:
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1. Maintaining adequate amounts of calcium in bone. If fails à
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osteoporosis.
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د bone mineral content &
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¯ bone matrix
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ØIncreasing in the Western
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World
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ØRisk increases with age
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ØMore common in post-
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menopausal women than
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in men
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ØOestrogen helps prevent
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progression of disease
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Normal
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matrix
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Severe
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osteoporotic
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matrix
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3
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Suzanne.Dickson@gu.se
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Calcium homeostasis
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The issues:
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1.
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Maintaining adequate amounts of calcium in bone. If fails à
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osteoporosis.
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2.
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Maintenance of a stable concentration of ionized calcium (Ca2+) in
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the plasma. If fails à tetany, seizures (+ death). Short term.
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Tetany: The point at which
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action potentials are arriving
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to skeletal muscle rapidly
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enough in succession to cause
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a steady contraction, and not
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just a series of individual
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twitches.
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Larynx: spasm can cause airway
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obstruction and asphyxia à
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death
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4
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---
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## Page 3
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Calcium and phosphate balance
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12/6/24
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3
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Suzanne.Dickson@gu.se
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Distribution of calcium
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Total body content is approx 1.3 kg
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99% in bone
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1% intracellular
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0.1% extracellular
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Normal range: 2.00 – 2.5 mmol/l.
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Calcium in blood
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5
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Suzanne.Dickson@gu.se
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Distribution of calcium in the plasma
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44% ionized
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1.18 mM
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11% complexed as
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bibarbonate, citrate,
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phosphate 0.16 mM
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31.5% albumin-
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bound: 0.92 mM
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13.5% globulin-
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bound: 0.24 mM
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55% free
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(filterable)
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1.54 mM
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45% bound
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(non-
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filterable)
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1.16 mM
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ØNote: measurements
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of total serum calcium
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include both ionised
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(metabolically active)
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calcium (Ca2+) and
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bound calcium.
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ØWhen protein (eg.
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albumin)
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concentrations
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fluctuate, total Ca
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levels may vary
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whereas Ca2+ remains
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relatively stable.
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6
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---
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## Page 4
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Calcium and phosphate balance
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12/6/24
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4
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Suzanne.Dickson@gu.se
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Blood pH important
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Ionised fraction (Ca2+) depends on blood pH
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Protein binding decreases as pH decreases.
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Alkalosis:
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pH 7.45
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pH 7.35
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Acidosis:
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If H+ decreases (eg hyperventilating)
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à calcium binding to protein
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௠ionised fraction (Ca2+)
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àRisk of tetany (if total Ca is <1.5 mmol/l)
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More H+
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Less H+
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If H+ increases
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௠calcium binding to protein
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à ionised fraction (Ca2+)
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7
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Suzanne.Dickson@gu.se
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Calcium balance
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Normally: intake=loss
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Positive balance (intake>loss) in
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growing young, pregnancy, bone
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healing.
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Negative balance (loss>intake) in
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old age, prolonged
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weightlessness, prolonged bed
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rest.
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Bone
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mass
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(g
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calcium)
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8
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---
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## Page 5
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Calcium and phosphate balance
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12/6/24
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5
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Suzanne.Dickson@gu.se
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Calcium exchange (per day)
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Intestinal
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secretions
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400 mg
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1. Absorption
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500 mg
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Faecal
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excretion
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900 mg
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Dietary intake
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(1000 mg)
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Filtered
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10,000 mg
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Renal
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excretion
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100 mg
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2. Reabsorption
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9,900 mg
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Extracellular
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1000 mg
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Intracellular
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10,000 mg
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Body fluid compartments
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Regulatable calcium flux
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Unregulated calcium flux
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300 mg
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300 mg
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3. Exchange
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9
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Suzanne.Dickson@gu.se
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Ways to increase blood calcium
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• Ingest/absorb more (GUT)
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• Lose less (KIDNEY)
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• Release from stores (last defense) (BONE)
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10
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---
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## Page 6
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Calcium and phosphate balance
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12/6/24
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6
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Suzanne.Dickson@gu.se
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Calcium absorption
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Intestinal
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secretions
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400 mg
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1. Absorption
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500 mg
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Faecal
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excretion
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900 mg
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Dietary intake
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(1000 mg)
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Filtered
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10,000 mg
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Renal
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excretion
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100 mg
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2. Reabsorption
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9,900 mg
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Extracellular
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1000 mg
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Intracellular
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10,000 mg
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Body fluid compartments
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Regulatable calcium flux
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Unregulated calcium flux
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300 mg
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300 mg
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3. Exchange
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Most important hormone is CALCITRIOL (from Vit D)
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11
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Suzanne.Dickson@gu.se
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Calcium absorption by the gut
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About 40-50% ingested calcium is absorbed
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Duodenum (& upper jejunum)
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Active process regulated by vitamin D metabolite (CALCITRIOL)
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Low uptake
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Ileum and lower jejunum
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Passive process (ie no hormones involved)
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Uptake higher
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Absorption rate also influenced by:
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Acidity of stomach ( absorption)
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Fatty acids form insoluble soaps (¯ absorption)
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12
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---
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## Page 7
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Calcium and phosphate balance
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12/6/24
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7
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Suzanne.Dickson@gu.se
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Calcitriol summary
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ØAlso called 1,25- dihydroxycholecalciferol (1,25-DHCC).
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ØA steroid hormone derived from vitamin D
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ØNormal plasma – 0.03 ng/ml
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ØNuclear receptors that regulate transcription of RNA. Located in
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intestine, bone, kidney.
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ØAction:
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- DIRECT Primary action: intestinal absorption of calcium
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and phosphate.
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- (Facilitates Ca2+ reabsorption in kidneys)
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- ( Synthetic activity of osteoblasts. Required for normal
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calcification of matrix).
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ØDeficiency à rickets in children; osteomalaci in adults
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13
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Suzanne.Dickson@gu.se
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Rickets
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(vit D deficiency -
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children)
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Articular cartilage
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bone
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Epiphyseal plate
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Calcifying cartilage or
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metaphyseal bone
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Osteoid tissue
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bone
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Bone marrow
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cavity
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Ø Soft bones
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Ø Bowing of tibiae
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Ø Cupping of metaphyses
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Ø Epiphyseal cartilage is
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enlarged.
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Ø Osteoid tissue
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(in adults vit D deficiency
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= osteomalacia)
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14
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---
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## Page 8
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Calcium and phosphate balance
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12/6/24
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8
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Suzanne.Dickson@gu.se
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.
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van de Graaf S F J et al. Am J Physiol Renal Physiol 2006;290:F1295-F1302
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©2006 by American Physiological Society
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Vitamin D metabolite
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(calcitriol, 1,25 DHCC)
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Ca ABSORPTION (duodenum & upper jejunum)
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VITAMIN D metabolite
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(calcitriol, 1,25 DHCC)
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15
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Suzanne.Dickson@gu.se
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By what mechanism does calcitriol increase
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calcium absortion in the duodenum?
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Brush border – uptake into epithelial cell
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expression of TRPV6* (also TRPV5**), a membrane
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calcium channel.
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Inside epithelial cell
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expression of calbindin-D9K which binds calcium and acts
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as a calcium buffer (ie stops it from impacting on the cell
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function eg excitability etc).
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Basolateral membrane – delivery to blood.
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expression of NCX1 (a Na+/Ca2+ exchanger)
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expression of PMCA1b (a plasma membrane Ca2+-
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ATPase)
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*TRPV = Transient receptor potential cation channel subfamily V
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**TRPV5 More important in kidney
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16
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---
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## Page 9
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Calcium and phosphate balance
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12/6/24
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9
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Suzanne.Dickson@gu.se
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Important: Absorption is controllable.
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When calcium intake is high,
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Ø active transport mechanism becomes
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saturated.
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Ø calcitriol (vit D derivative) levels fall (as
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plasma Ca levels increase)
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Absorption of Calcium (gut)
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17
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Suzanne.Dickson@gu.se
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SKIN
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VIT D3 (1 –OH)
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DIET
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VIT D2
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VIT D3
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SUNSHINE
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(UV)
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25-OH-cholecalciferol (2 –OH)
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If Ca2+ low
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24,25-dihydroxy-
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cholecalciferol
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(inactive)
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1,25-dihydroxy-
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cholecalciferol
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(active)
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= calcitriol (3 –OH)
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Production of 1,25-DHCC (calcitriol)
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- only when calcium low
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Stimulates Ca
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transport
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mechanism
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Ca2+
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absorption
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If Ca2+ high
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18
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---
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## Page 10
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|
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Calcium and phosphate balance
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12/6/24
|
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10
|
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Suzanne.Dickson@gu.se
|
||
Calcium exchange (per day)
|
||
Intestinal
|
||
secretions
|
||
400 mg
|
||
1. Absorption
|
||
500 mg
|
||
Faecal
|
||
excretion
|
||
900 mg
|
||
Dietary intake
|
||
(1000 mg)
|
||
Filtered
|
||
10,000 mg
|
||
Renal
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excretion
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100 mg
|
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2. Reabsorption
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9,900 mg
|
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Extracellular
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1000 mg
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Intracellular
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10,000 mg
|
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Body fluid compartments
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Regulatable calcium flux
|
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Unregulated calcium flux
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300 mg
|
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300 mg
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3. Exchange
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THE MOST IMPOSTANT HORMONE IS PTH
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19
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Suzanne.Dickson@gu.se
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Renal excretion and reabsorption of
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calcium
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Reabsorption (controllable):
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Ø 98-99% filtered calcium is reabsorbed
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Ø low blood calcium à reabsorption
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Ø 60% occurs in the proximal kidney tubule (an active
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transport mechanism)
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Ø 25% occurs in the thick ascending limb of the loop of
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Henle
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Ø 15% occurs in distal tubule and collecting ducts (involves
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TRP5 channel). Only this 15% is under parathyroid
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hormone (PTH) control. PTH regulates expression of TRP5
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in the distal tubule.
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Excretion in glomeruli (unregulated):
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Increased by high circulating calcium concentrations.
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20
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---
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## Page 11
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|
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Calcium and phosphate balance
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12/6/24
|
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11
|
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Suzanne.Dickson@gu.se
|
||
Calcium exchange (per day)
|
||
Intestinal
|
||
secretions
|
||
400 mg
|
||
1. Absorption
|
||
500 mg
|
||
Faecal
|
||
excretion
|
||
900 mg
|
||
Dietary intake
|
||
(1000 mg)
|
||
Filtered
|
||
10,000 mg
|
||
Renal
|
||
excretion
|
||
100 mg
|
||
2. Reabsorption
|
||
9,900 mg
|
||
Extracellular
|
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1000 mg
|
||
Intracellular
|
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10,000 mg
|
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Body fluid compartments
|
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Regulatable calcium flux
|
||
Unregulated calcium flux
|
||
300 mg
|
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300 mg
|
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3. Exchange
|
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THE MOST IMPOSTANT HORMONE IS PTH
|
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21
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Suzanne.Dickson@gu.se
|
||
Parathyroid hormone (PTH)
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ØSecreted by the chief cells of the (usually 4) parathyroid
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glands.
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ØPlasma: 10-55 pg/ml; Half-life <10 min.
|
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ØPeptide hormone. 84 amino acids.
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ØTwo receptors: PTHR1 and PTHR2.
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ØPrimary physiological role: blood calcium and ¯
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blood phosphate
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ØEssential for life.
|
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ØSecretion rate increased when blood calcium levels fall.
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thyroid
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22
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---
|
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|
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## Page 12
|
||
|
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Calcium and phosphate balance
|
||
12/6/24
|
||
12
|
||
Suzanne.Dickson@gu.se
|
||
PTH secretion is regulated by blood
|
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calcium
|
||
15
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Time (hrs)
|
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1
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0
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3
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2
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4
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6
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Ca 2+
|
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24
|
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12
|
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18
|
||
6
|
||
0
|
||
PTH
|
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secretion
|
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ng/min
|
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0
|
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5
|
||
10
|
||
5
|
||
EDTA
|
||
Serum
|
||
calcium
|
||
(mg/100 ml)
|
||
Perfusion of goat parathyroid gland.
|
||
EDTA= calcium
|
||
chelating compound ie
|
||
removes calcium
|
||
The parathyroid glands detect changes in serum calcium levels via
|
||
calcium sensing receptors.
|
||
23
|
||
Suzanne.Dickson@gu.se
|
||
How does PTH increase blood calcium?
|
||
DIRECT EFFECTS
|
||
1. Release of calcium from bone ( resorption).
|
||
2. Calcium reabsorption in kidney.
|
||
INDIRECT EFFECTS
|
||
3. Gut calcium absorption by promoting calcitriol
|
||
formation in kidney. It increases expression of 1 alpha
|
||
hydroxylase, the enzyme that converts vitamin D into its
|
||
active form.
|
||
24
|
||
|
||
|
||
---
|
||
|
||
## Page 13
|
||
|
||
Calcium and phosphate balance
|
||
12/6/24
|
||
13
|
||
Suzanne.Dickson@gu.se
|
||
SKIN
|
||
VIT D3 (1 –OH)
|
||
DIET
|
||
VIT D2
|
||
VIT D3
|
||
SUNSHINE
|
||
(UV)
|
||
25-OH-cholecalciferol (2 –OH)
|
||
Ca2+
|
||
¯ Ca2+
|
||
24,25-dihydroxy-
|
||
cholecalciferol
|
||
(inactive)
|
||
1,25-dihydroxy-
|
||
cholecalciferol
|
||
(active)
|
||
= calcitriol (3 –OH)
|
||
Production of 1,25-DHCC (calcitriol)
|
||
Stimulates Ca
|
||
transport
|
||
mechanism
|
||
Ca2+
|
||
(-ve feedback)
|
||
absorption
|
||
1α-hydroxylase
|
||
¯ PTH
|
||
PTH
|
||
+
|
||
+
|
||
+
|
||
25
|
||
Suzanne.Dickson@gu.se
|
||
Bone calcium
|
||
Ø99% of bone calcium is located within the crystal structure
|
||
(stable, slowly exchangeable).
|
||
ØThere are 2 pools of calcium in bone
|
||
- One that readily releases calcium into blood
|
||
- One dedicated to bone remodelling
|
||
Ø1% of bone calcium is found as simple calcium phosphate salts -
|
||
rapidly exchangeable with extracellular calcium pool. (ie provides
|
||
a buffer for maintaining blood calcium).
|
||
ØKey hormone releasing calcium from bone is PTH.
|
||
At low PTH concentrations:
|
||
remodelling. (Ca exchange)
|
||
At high PTH concentrations
|
||
demineralization. (Ca loss)
|
||
26
|
||
|
||
|
||
---
|
||
|
||
## Page 14
|
||
|
||
Calcium and phosphate balance
|
||
12/6/24
|
||
14
|
||
Suzanne.Dickson@gu.se
|
||
Bone remodelling cycle
|
||
70
|
||
60
|
||
50
|
||
40
|
||
30
|
||
20
|
||
10
|
||
0
|
||
0
|
||
50
|
||
100
|
||
150
|
||
200
|
||
Time (days)
|
||
Bone remodelling cycle
|
||
Thickness
|
||
(µm)
|
||
osteoclast
|
||
osteoid
|
||
osteoblast
|
||
lining cell
|
||
osteocyte
|
||
Mineralized
|
||
matrix
|
||
27
|
||
Suzanne.Dickson@gu.se
|
||
Cell types in bone
|
||
Osteoblasts - laying down of bone. They secrete osteoid (non-
|
||
mineralised pre-bone, that has not yet been calcified).
|
||
Osteoblasts become trapped in the bone as it is being laid
|
||
down and become osteocytes.
|
||
Osteoclasts - bone resorption. Release acids and proteolytic
|
||
enzymes.
|
||
Bone lining cells - protect the bone. If they retract, the
|
||
osteoclasts will get access. Osteoclasts only act where there
|
||
are no bone lining cells.
|
||
Remodelling cycle exists because bone is not intert until we
|
||
die - it is dynamic - broken down and built up again.
|
||
28
|
||
|
||
|
||
---
|
||
|
||
## Page 15
|
||
|
||
Calcium and phosphate balance
|
||
12/6/24
|
||
15
|
||
Suzanne.Dickson@gu.se
|
||
PTH increases osteoclast activity but
|
||
this is indirect
|
||
70
|
||
60
|
||
50
|
||
40
|
||
30
|
||
20
|
||
10
|
||
0
|
||
0
|
||
50
|
||
100
|
||
150
|
||
200
|
||
Time (days)
|
||
Thickness
|
||
(µm)
|
||
osteoclast
|
||
osteoid
|
||
osteoblast
|
||
lining cell
|
||
osteocyte
|
||
Mineralized
|
||
matrix
|
||
Retraction.
|
||
Osteoclast-
|
||
stimulating protein
|
||
Indirect actions (no PTH
|
||
receptors): Increased osteoclast
|
||
number and activity
|
||
¯ cell size, ¯ protein
|
||
synthesis, ¯ differentiation
|
||
29
|
||
Suzanne.Dickson@gu.se
|
||
PTH acts on osteoblasts to induce RANK ligand,
|
||
which aids fusion of osteoclast precursors
|
||
70
|
||
60
|
||
50
|
||
40
|
||
30
|
||
20
|
||
10
|
||
0
|
||
0
|
||
50
|
||
100
|
||
150
|
||
200
|
||
Time (days)
|
||
Thickness
|
||
(µm)
|
||
osteoclast
|
||
Mineralized
|
||
matrix
|
||
RANKL (RANK ligand)
|
||
Osteoclast
|
||
Precursor
|
||
cells
|
||
RANK
|
||
Fusion of
|
||
osteoclast
|
||
precursor
|
||
cells
|
||
(receptor)
|
||
Osteoblasts
|
||
PTH
|
||
receptor
|
||
RANK = Receptor activator of nuclear factor kappa-B
|
||
(TRAF6)
|
||
WNT16 – inhibits
|
||
osteoclast formation
|
||
(bone-saving)
|
||
30
|
||
|
||
|
||
---
|
||
|
||
## Page 16
|
||
|
||
Calcium and phosphate balance
|
||
12/6/24
|
||
16
|
||
Suzanne.Dickson@gu.se
|
||
Mechanism of actions of PTH on bone:
|
||
Osteoclasts (bone destruction/resorption):
|
||
-
|
||
indirectly stimulated by PTH.
|
||
1. Osteoblasts (bone creation)
|
||
PTH acts via PTH receptors directly on osteoblasts à
|
||
production of RANKL (RANK ligand)
|
||
2. RANKL bind to osteoclast precursors containing RANK, a
|
||
receptor for RANKL.
|
||
3. The binding of RANKL to RANK stimulates these precursors to
|
||
fuse, forming new osteoclasts which ultimately enhances the
|
||
resorption of bone.
|
||
31
|
||
Suzanne.Dickson@gu.se
|
||
32
|
||
|
||
|
||
---
|
||
|
||
## Page 17
|
||
|
||
Calcium and phosphate balance
|
||
12/6/24
|
||
17
|
||
Suzanne.Dickson@gu.se
|
||
PTH summary
|
||
PARATHYROIDS
|
||
3. Ca2+ release
|
||
IONIZED
|
||
Ca2+
|
||
PTH
|
||
LOW IONISED Ca 2+
|
||
2. Ca2+ reabsorption
|
||
PO4- excretion
|
||
VIT
|
||
D3(sun)
|
||
25-OH D3
|
||
Ca2+, PO4-
|
||
1. absorption
|
||
1,25 (OH)2D3
|
||
DIETARY Ca2+
|
||
1. Calcitriol synthesis
|
||
Negative
|
||
feedback
|
||
33
|
||
Suzanne.Dickson@gu.se
|
||
Endocrine control of calcium homeostasis
|
||
Blood calcium
|
||
Parathormone
|
||
(PTH)
|
||
Calcitonin
|
||
(less important)
|
||
Vitamin D derivative
|
||
calcitriol
|
||
+
|
||
+
|
||
-
|
||
34
|
||
|
||
|
||
---
|
||
|
||
## Page 18
|
||
|
||
Calcium and phosphate balance
|
||
12/6/24
|
||
18
|
||
Suzanne.Dickson@gu.se
|
||
Blood calcium
|
||
Parathormone
|
||
(PTH)
|
||
Calcitonin
|
||
(less important)
|
||
Vitamin D derivative
|
||
Calcitriol (=1,25-DHCC)
|
||
+
|
||
+
|
||
-
|
||
Very
|
||
important
|
||
Endocrine control of calcium homeostasis
|
||
35
|
||
Suzanne.Dickson@gu.se
|
||
Endocrine control of calcium homeostasis
|
||
Blood calcium
|
||
Parathormone
|
||
(PTH)
|
||
Calcitonin
|
||
(less important)
|
||
Vitamin D derivative
|
||
Calcitriol (=1,25 DHCC)
|
||
+
|
||
+
|
||
-
|
||
36
|
||
|
||
|
||
---
|
||
|
||
## Page 19
|
||
|
||
Calcium and phosphate balance
|
||
12/6/24
|
||
19
|
||
Suzanne.Dickson@gu.se
|
||
Calcitonin
|
||
ØMUCH less important than PTH and calcitriol.
|
||
ØRole: Moves Ca2+ into bone after a meal. Also
|
||
prevents bone demineralization during pregnancy and
|
||
lactation.
|
||
ØProduced by parafollicular (or C-cells) of the thyroid
|
||
gland
|
||
ØAction: Lowers blood Ca2+ by inhibiting osteoclasts.
|
||
ØRelease: induced by an increase
|
||
in blood Ca2+, gut hormones
|
||
(gastrin, CCK, secretin).
|
||
37
|
||
Suzanne.Dickson@gu.se
|
||
Slow recovery from changes in plasma
|
||
[Ca2+] after thyro-parathyroidectomy
|
||
120
|
||
140
|
||
100
|
||
160
|
||
80
|
||
Plasma
|
||
[calcium]
|
||
as % of
|
||
control
|
||
value
|
||
0
|
||
12
|
||
24
|
||
Result:
|
||
Thyro-parathyroidectomy caused loss of calcium control.
|
||
Parathyroidectomy (ie no PTH) à slow recovery when Ca removed
|
||
Thyroidectomy (ie no calcitonin)à slow recovery when calcium infused.
|
||
Thyro-
|
||
parathyroidectomy
|
||
controls
|
||
Response
|
||
to calcium
|
||
infusion
|
||
Response
|
||
to EDTA
|
||
infusion
|
||
Experimental model: dogs
|
||
hours
|
||
38
|
||
|
||
|
||
---
|
||
|
||
## Page 20
|
||
|
||
Calcium and phosphate balance
|
||
12/6/24
|
||
20
|
||
Suzanne.Dickson@gu.se
|
||
Hypercalcemia
|
||
Cause:
|
||
Ø hyperparathyroidism, malignancy, excessive vitamin
|
||
D activity.
|
||
Symptoms:
|
||
Ø Kidney stones - calcium deposition in soft tissue.
|
||
Ø Impaired renal function –Ca toxicity to kidneys, thirst,
|
||
large volume of dilute urine.
|
||
Ø CNS: Fatigue, depression
|
||
Ø Muscular aches & pains
|
||
Ø Bone erosion - If too much PTH.
|
||
Ø Gastro-intestinal: nausea, vomiting, constipation
|
||
39
|
||
Suzanne.Dickson@gu.se
|
||
Hypocalcemia
|
||
Cause:
|
||
hypoparathyroidism, (vitamin D deficiency, renal
|
||
disease)
|
||
Symptoms:
|
||
Increased excitability of nervous tissue (pins and
|
||
needles, tetany, epilepsy, cardiac arrhythmias).
|
||
Chvostek’s sign - facial muscles
|
||
(http://www.youtube.com/watch?v=XjtHDhNcXEQ)
|
||
Trousseau’s sign - wrist spasm
|
||
(http://www.youtube.com/watch?v=qHIL3pK_Nao)
|
||
40
|
||
|
||
|
||
---
|
||
|
||
## Page 21
|
||
|
||
Calcium and phosphate balance
|
||
12/6/24
|
||
21
|
||
Suzanne.Dickson@gu.se
|
||
Other hormones in Ca Balance:
|
||
glucocorticoids
|
||
Ølower plasma Ca by inhibiting osteoclast
|
||
formation and activity.
|
||
Ø(longterm) osteoporosis - ¯ bone formation,
|
||
bone resorption
|
||
ØIntestine: ¯ Ca and phosphate absorption
|
||
ØKidney: Ca and phosphate excretion
|
||
41
|
||
Suzanne.Dickson@gu.se
|
||
Other hormones in Ca Balance: PTH-
|
||
related peptide
|
||
ØStructurally related to PTH,
|
||
ØSimilar effects as PTH.
|
||
ØProduced by almost all cells in the body. levels in
|
||
breast milk. Important for cartilage growth in utero.
|
||
ØIdentified as a tumor product that can activate PTH
|
||
receptors à hypercalcemia
|
||
ØCauses 80% of cancer-related hypercalcemia
|
||
(paramalignant symptom)
|
||
Øcauses hypercalcemia by increasing bone resorption
|
||
and renal tubular resorption of calcium.
|
||
ØMost actions mediated by actions at PTH receptor.
|
||
42
|
||
|
||
|
||
---
|
||
|
||
## Page 22
|
||
|
||
Calcium and phosphate balance
|
||
12/6/24
|
||
22
|
||
Suzanne.Dickson@gu.se
|
||
PTH, PTH-rP and their receptors
|
||
Bone, Kidney
|
||
CNS, pancreas, testis, and placenta
|
||
43
|
||
Suzanne.Dickson@gu.se
|
||
Other hormones in Ca Balance:
|
||
oestrogens
|
||
ØPreserves bone mass in both males
|
||
(testosterone àestradiol locally) and females
|
||
ØReduce bone resorption (Direct effect on
|
||
osteoclasts),
|
||
ØPrevent osteoporosis, inhibit the stimulation of
|
||
osteoclasts by cytokines (e g IL-6).
|
||
|
||
osteoporosis
|
||
44
|
||
|
||
|
||
---
|
||
|
||
## Page 23
|
||
|
||
Calcium and phosphate balance
|
||
12/6/24
|
||
23
|
||
Suzanne.Dickson@gu.se
|
||
Other hormones in Ca Balance:
|
||
Thyroid hormones
|
||
ØHyperthyroidism increases risk of osteoporosis and
|
||
bone fracture.
|
||
ØT3 and T4 stimulate the activity of osteoclasts (=the
|
||
bone resorption).
|
||
ØThey increase the production of RANKL which
|
||
promotes the differentiation and activity of
|
||
osteoclasts.
|
||
ØAs a result, osteoclasts break down bone tissue more
|
||
actively, leading to increased bone resorption.
|
||
45
|
||
Suzanne.Dickson@gu.se
|
||
Osteoporosis treatment
|
||
1. Bisfosfanate – binds to hydroxyapatite and
|
||
inhibits osteoclasts
|
||
2. Denosumab – monoclonal antibody that binds to
|
||
RANKL and blocks it.
|
||
3. Teriparatid. PTH analogue given intermittently.
|
||
1 and 2 – anti-resorptive for bone
|
||
3 anabolic for bone.
|
||
46
|
||
|
||
|
||
---
|
||
|
||
## Page 24
|
||
|
||
Calcium and phosphate balance
|
||
12/6/24
|
||
24
|
||
Suzanne.Dickson@gu.se
|
||
Phosphate balance
|
||
• Total body phosphorus is 500-800 g, 90% of which is in
|
||
bone (+ continually exchanged).
|
||
• Reaborption – kidney – proximal tubule
|
||
– Sodium-dependent Pi cotransporters, NaPi-IIa and NaPi-
|
||
IIc.
|
||
– NaPi-IIa powerfully inhibited by PTH à phosphaturea.
|
||
NaPi-IIa also inhibited by FGF23 from bone (next slide)
|
||
• Absorption – duodenum & small intestine.
|
||
– Involves NaPi-IIb
|
||
– Stimulated by calcitriol. (Note FGF23 inhibits formation
|
||
of calcitriol ie less absorption).
|
||
47
|
||
Suzanne.Dickson@gu.se
|
||
FGF-23 is produced by from skeletal osteocytes and
|
||
osteoblasts. Also - high production by tumors, that can
|
||
decrease Ca2+ and phosphate.
|
||
FGF-23 from bone generates a negative
|
||
phosphate balance
|
||
Pi
|
||
Kidney
|
||
ØInhibits the sodium/phosphate
|
||
cotransporter (NaPi-IIa) à
|
||
phosphaturea.
|
||
ØReduces levels of calcitriol (by
|
||
inhibiting 1α-hydroxylase). Less gut
|
||
absorption.
|
||
48
|
||
|
||
|
||
---
|
||
|
||
## Page 25
|
||
|
||
Calcium and phosphate balance
|
||
12/6/24
|
||
25
|
||
Suzanne.Dickson@gu.se
|
||
FGF-23 generates a negative phosphate balance
|
||
1. PO4- loss
|
||
- kidneys
|
||
FGF-23 produced
|
||
by bone
|
||
2. Reduces production
|
||
of calcitriol by
|
||
inhibiting the enzyme
|
||
1-alpha hydroxylase.
|
||
49
|
||
Suzanne.Dickson@gu.se
|
||
α-Klotho (enhances FGF23 action)
|
||
u Klotho = daughter of Zeus who spins the
|
||
thread of life.
|
||
u Anti-aging protein (supposedly).
|
||
u Mice that lack it age faster, have decreased
|
||
bone mineral density, calcifications, high
|
||
blood calcium.
|
||
u Actions:
|
||
Required for stabilizing membrane location
|
||
of proteins imp for calcium & phosphate
|
||
(re)absorption.
|
||
Enhances FGF-23 action at its receptor - ie
|
||
less phosphate (re)absorption
|
||
50
|
||
|
||
|
||
---
|
||
|