Week 4: Calcium and phosphate homeostasis

Question 1

Circulating levels of Calcium and phosphate

Answer 1

• plasma calcium: 45% free ionized form, 45% protein bound, and 10% complexed with phosphate
• free ionized form is active form
• circulating concentrations of Ca must be tightly regulated, only vary by 10%
• plasma phosphate: 80% ionized form. More variation in extracellular concentrations

Question 2

Bone physiology and metabolism

Answer 2

1. bone formation
   - by osteoblasts
2. bone resorption
   - by osteoclasts regulated by a cytokine released by osteoblasts: RANKL
   - RANKL acts on RANK receptors on osteoclasts precursors to promote development into mature osteoclasts
   - osteoblasts/others release OPG which binds to RANK L and prevents it from acting (decoy receptor for RANK L)

Question 3

what effects RANKL and OPG balance?

Answer 3

• estrogen deficiency results in relative increase in RANKL over OPG: post menopausal osteoporosis
• inflammatory cytokines such as TNFa can do the same
• denosumab: drug that is a monoclonal antibody against RANKL

Question 4

Vitamin D synthesis

Answer 4

• Vit D2 (ergocalciferol) or Vit D3 (caholcalciferol) can be converted by liver to 25(OH)-Vit D (by 25- hydroxylase)
• Kidneys can convert 25(OH)-VitD to either 24,25 (inactive) or 1,25(OH)2-VitD (highly regulated)
• 1,25(OH)2-VitD is the active form
• Vitamin D and 25(OH)-vit D circulate bound to DBP (vit D binding protein)

Question 5

Vitamin D deficiency

Answer 5

• Rickets
• most normal persons will have lower plasma levels of 25(OH)-Vit D but usually doesn’t have lowered active form 1,25(OH2)-VitD
• VitD deficiency leads to compensatory rise in PTH, which promotes conversion of 25(OH)VitD to 1,25(OH)2VtD

Question 6

Regulation of 1,25(OH)2 Vitamin D synthesis

Answer 6

• fall in plasma phosphate: promotes formation of 1,25(OH)2VitD via 1-hydroxylase
• fall in plasma Ca: promotes PTH which acts on kidney by doing same as above
• estrogen and prolactin increase 1-hydroxylase activity to form more active VitD because of increase need during pregnancy and lactation.

Question 7

Effects of Vitamin D on body

Answer 7

-intestines: increases Ca2+ absorption by increasing transcription of a gene coding for a calcium binding protein
-kidney: facilitate PTH mediated reabsorption of calcium in the distal renal tubules
-kidneys: retains phosphate
-bone: promotes bone resorption
-parathyroid: suppresses synthesis and release of PTH
VITAMIN D only mainly increases the phosphate levels in plasma, but it helps PTH increase plasma Ca

Question 8

Regulation of PTH release

Answer 8

1. plasma Ca2+ concentration is principle regulator
   - decrease in plasma Ca increases PTH secretion
   - Ionic Ca binds to cell surface Ca sensing receptor CaSR, coupled to G protein, which leads to increase in internal cellular Ca, and inhibition of PTH release
2. Sigmoidal relationship between PTH and Ca
   - set point: concentration of Ca that produces 50% PTH secretion
3. Set point can move
   - prolonged hypocalcemia leads to hyperplasia of PT gland and can shift set point to left. Meaning less Ca produces more PTH

Question 9

Effects of PTH

Answer 9

1. Bones: Increases bone resorption
   - acts of osteoblasts to release RANKL
2. Kidneys: increase phosphate excretion and decrease Ca excretion in urine
   - so that less phosphate will complex with Ca, increasing ionic Ca levels in plasma
3. Kidneys: increases formation of 1,25(OH)2-Vit D

Question 10

Hyperparathyroidism

Answer 10

• primary: can be from PTH secreting tumors- hypercalcemia, hypophophatemia, demineralization of bones, hypercalcuria, formation of kidney stones
• secondary: deficiency of Vit D (results in low Ca from low absorption from gut).

Question 11

Pharmacologics for hyperparathyroidism and hypoparathyroidism

Answer 11

• calcimimetics: increase affinity of CaSR for Ca2+ so that it can be used to decrease PTH release from parathyroid hormones. shifts set point left.
• calcilytics: decrease affinity of CaSR for Ca2+. Shifts set point to the right, increases release of PTH.

Question 12

Pseudohypoparathyroidism (PHP)

Answer 12

• genetic condition that resembles mild hypoparathyroidism
• normal amounts of PTH are present
• however, patients don’t respond to PTH
• test for cAMP in urine. PTH produces increase in urinary cAMP in normal individuals and in true hypoparathyroidism.
• patients may express only 50% of Gs alpha protein that mediates hormone stimulation of adenylate cyclase

Question 13

Calcitonin

Answer 13

• produced by parafollicular cells of thyroid gland
• secretion is stimulated by hypercalcemia, b agonists, other hormones
• can inhibit bone resorption
• importance of calcitonin is unclear

Question 14

phosphatonins

Answer 14

• factors that oppose 1,25(OH)2VitD
• FGF23 (fibroblast growth factor): lowers 1a-hydroxylase activity and promotes 24 hydroxyls, shunting 25(OH)VitD to inactive form
• reduces phosphate reabsorption in kidney
• FGF23 normally produced in bone, also some tumors, where it contributes to tumor induced osteomalacia