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calcium 2024.pdf

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Calcium and phosphate balance 12/6/24 1 Suzanne.Dickson@gu.se Calcium Homeostasis Suzanne Dickson 1 Suzanne.Dickson@gu.se Functions of calcium ØStructural: bone, teeth, connective tissue ØExcitation-contraction coupling (muscles) ØExcitation-secretion coupling (neurotransmitters, hormones) ØStability of excitable membranes ØCardiac & smooth muscle potentials ØEnzyme activity ØBlood clotting 2

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Calcium and phosphate balance 12/6/24 2 Suzanne.Dickson@gu.se Calcium homeostasis The issues:

  1. Maintaining adequate amounts of calcium in bone. If fails à osteoporosis. د bone mineral content & ¯ bone matrix ØIncreasing in the Western World ØRisk increases with age ØMore common in post- menopausal women than in men ØOestrogen helps prevent progression of disease Normal matrix Severe osteoporotic matrix 3 Suzanne.Dickson@gu.se Calcium homeostasis The issues:

Maintaining adequate amounts of calcium in bone. If fails à osteoporosis. 2. Maintenance of a stable concentration of ionized calcium (Ca2+) in the plasma. If fails à tetany, seizures (+ death). Short term. Tetany: The point at which action potentials are arriving to skeletal muscle rapidly enough in succession to cause a steady contraction, and not just a series of individual twitches. Larynx: spasm can cause airway obstruction and asphyxia à death 4

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Calcium and phosphate balance 12/6/24 3 Suzanne.Dickson@gu.se Distribution of calcium Total body content is approx 1.3 kg 99% in bone 1% intracellular 0.1% extracellular Normal range: 2.00 – 2.5 mmol/l. Calcium in blood 5 Suzanne.Dickson@gu.se Distribution of calcium in the plasma 44% ionized 1.18 mM 11% complexed as bibarbonate, citrate, phosphate 0.16 mM 31.5% albumin- bound: 0.92 mM 13.5% globulin- bound: 0.24 mM 55% free (filterable) 1.54 mM 45% bound (non- filterable) 1.16 mM ØNote: measurements of total serum calcium include both ionised (metabolically active) calcium (Ca2+) and bound calcium. ØWhen protein (eg. albumin) concentrations fluctuate, total Ca levels may vary whereas Ca2+ remains relatively stable. 6

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Calcium and phosphate balance 12/6/24 4 Suzanne.Dickson@gu.se Blood pH important Ionised fraction (Ca2+) depends on blood pH Protein binding decreases as pH decreases. Alkalosis: pH 7.45 pH 7.35 Acidosis: If H+ decreases (eg hyperventilating) à­ calcium binding to protein ௠ionised fraction (Ca2+) àRisk of tetany (if total Ca is <1.5 mmol/l) More H+ Less H+ If H+ increases ௠calcium binding to protein à­ ionised fraction (Ca2+) 7 Suzanne.Dickson@gu.se Calcium balance Normally: intake=loss Positive balance (intake>loss) in growing young, pregnancy, bone healing. Negative balance (loss>intake) in old age, prolonged weightlessness, prolonged bed rest. Bone mass (g calcium) 8

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Calcium and phosphate balance 12/6/24 5 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 1000 mg Intracellular 10,000 mg Body fluid compartments Regulatable calcium flux Unregulated calcium flux 300 mg 300 mg
  3. Exchange 9 Suzanne.Dickson@gu.se Ways to increase blood calcium • Ingest/absorb more (GUT) • Lose less (KIDNEY) • Release from stores (last defense) (BONE) 10

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Calcium and phosphate balance 12/6/24 6 Suzanne.Dickson@gu.se Calcium absorption 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 1000 mg Intracellular 10,000 mg Body fluid compartments Regulatable calcium flux Unregulated calcium flux 300 mg 300 mg
  3. Exchange Most important hormone is CALCITRIOL (from Vit D) 11 Suzanne.Dickson@gu.se Calcium absorption by the gut About 40-50% ingested calcium is absorbed Duodenum (& upper jejunum) Active process regulated by vitamin D metabolite (CALCITRIOL) Low uptake Ileum and lower jejunum Passive process (ie no hormones involved) Uptake higher Absorption rate also influenced by: Acidity of stomach (­ absorption) Fatty acids form insoluble soaps (¯ absorption) 12

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Calcium and phosphate balance 12/6/24 7 Suzanne.Dickson@gu.se Calcitriol summary ØAlso called 1,25- dihydroxycholecalciferol (1,25-DHCC). ØA steroid hormone derived from vitamin D ØNormal plasma – 0.03 ng/ml ØNuclear receptors that regulate transcription of RNA. Located in intestine, bone, kidney. ØAction:

  • DIRECT Primary action: ­ intestinal absorption of calcium and phosphate.
  • (Facilitates Ca2+ reabsorption in kidneys)
  • (­ Synthetic activity of osteoblasts. Required for normal calcification of matrix). ØDeficiency à rickets in children; osteomalaci in adults 13 Suzanne.Dickson@gu.se Rickets (vit D deficiency - children) Articular cartilage bone Epiphyseal plate Calcifying cartilage or metaphyseal bone Osteoid tissue bone Bone marrow cavity Ø Soft bones Ø Bowing of tibiae Ø Cupping of metaphyses Ø Epiphyseal cartilage is enlarged. Ø Osteoid tissue (in adults vit D deficiency = osteomalacia) 14

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Calcium and phosphate balance 12/6/24 8 Suzanne.Dickson@gu.se . van de Graaf S F J et al. Am J Physiol Renal Physiol 2006;290:F1295-F1302 ©2006 by American Physiological Society Vitamin D metabolite (calcitriol, 1,25 DHCC) Ca ABSORPTION (duodenum & upper jejunum) VITAMIN D metabolite (calcitriol, 1,25 DHCC) 15 Suzanne.Dickson@gu.se By what mechanism does calcitriol increase calcium absortion in the duodenum? Brush border – uptake into epithelial cell ­ expression of TRPV6* (also TRPV5**), a membrane calcium channel. Inside epithelial cell ­ expression of calbindin-D9K which binds calcium and acts as a calcium buffer (ie stops it from impacting on the cell function eg excitability etc). Basolateral membrane – delivery to blood. ­ expression of NCX1 (a Na+/Ca2+ exchanger) ­ expression of PMCA1b (a plasma membrane Ca2+- ATPase) *TRPV = Transient receptor potential cation channel subfamily V **TRPV5 More important in kidney 16

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Calcium and phosphate balance 12/6/24 9 Suzanne.Dickson@gu.se Important: Absorption is controllable. When calcium intake is high, Ø active transport mechanism becomes saturated. Ø calcitriol (vit D derivative) levels fall (as plasma Ca levels increase) Absorption of Calcium (gut) 17 Suzanne.Dickson@gu.se SKIN VIT D3 (1 –OH) DIET VIT D2 VIT D3 SUNSHINE (UV) 25-OH-cholecalciferol (2 –OH) If Ca2+ low 24,25-dihydroxy- cholecalciferol (inactive) 1,25-dihydroxy- cholecalciferol (active) = calcitriol (3 –OH) Production of 1,25-DHCC (calcitriol)

  • only when calcium low Stimulates Ca transport mechanism ­ Ca2+ absorption If Ca2+ high 18

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Calcium and phosphate balance 12/6/24 10 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 1000 mg Intracellular 10,000 mg Body fluid compartments Regulatable calcium flux Unregulated calcium flux 300 mg 300 mg
  3. Exchange THE MOST IMPOSTANT HORMONE IS PTH 19 Suzanne.Dickson@gu.se Renal excretion and reabsorption of calcium Reabsorption (controllable): Ø 98-99% filtered calcium is reabsorbed Ø low blood calcium à ­reabsorption Ø 60% occurs in the proximal kidney tubule (an active transport mechanism) Ø 25% occurs in the thick ascending limb of the loop of Henle Ø 15% occurs in distal tubule and collecting ducts (involves TRP5 channel). Only this 15% is under parathyroid hormone (PTH) control. PTH regulates expression of TRP5 in the distal tubule. Excretion in glomeruli (unregulated): Increased by high circulating calcium concentrations. 20

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Calcium and phosphate balance 12/6/24 11 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 1000 mg Intracellular 10,000 mg Body fluid compartments Regulatable calcium flux Unregulated calcium flux 300 mg 300 mg
  3. Exchange THE MOST IMPOSTANT HORMONE IS PTH 21 Suzanne.Dickson@gu.se Parathyroid hormone (PTH) ØSecreted by the chief cells of the (usually 4) parathyroid glands. ØPlasma: 10-55 pg/ml; Half-life <10 min. ØPeptide hormone. 84 amino acids. ØTwo receptors: PTHR1 and PTHR2. ØPrimary physiological role: ­ blood calcium and ¯ blood phosphate ØEssential for life. ØSecretion rate increased when blood calcium levels fall. thyroid 22

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Calcium and phosphate balance 12/6/24 12 Suzanne.Dickson@gu.se PTH secretion is regulated by blood calcium 15 Time (hrs) 1 0 3 2 4 6 Ca 2+ 24 12 18 6 0 PTH secretion ng/min 0 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

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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

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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

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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

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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

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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+
  2. 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

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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

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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

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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

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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

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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

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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

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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

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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
  1. 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
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