Bone Metabolisma and Osteoporosis Flashcards
What are the 2 most important mineral for cellular function and where are they mostly found?
calcium (98%) and phosphate (85%) are in bone
Where is there a dynamic exchange between bone and mineral?
in the extracellular fluid
Bone serves as the primary structural framework for the body and provides a space for (blank)
hematopoiesis
What are the three abnormalities that occur with problems of bone metabolism?
cellular dysfunction
defects in structural support
loss of hematopoietic activity
What is an example of cellular dysfunction due to messed up bone mineral metabolism?
muscle weakness, coma and tetany
What is an example of a structural support defect due to messed up bone mineral metabolism?
osteoporosis
What i an example of a loss of hematopoietic activity due to messed up bone mineral metabolism?
infantile osteopetrosis
Tell me about how calcium is regulated
decreased calcium -> Increased PTH-> increased calcium in the blood
Calcitonin reduces plasma calcium levels
What are the three hormones that serve as the principal regulators of calcium and phosphate homeostasis?
PTH, fibroblast growth factor 23 (FGF23), and vitamin D.
What are the stimulators and inhibitors of osteoblast differentiation?
RANKL (+)
M-CSF (+) (macrophage colony stimulating factor i.e. create osteoclasts)
OPG (-) (osteoprogenin)
Explain what RANK and RANKL do?
RANKL (receptor activator ligand) is released by an osteoblast and binds to a RANK (receptor) on an osteoblast precursor to create an osteoclast.
What does OPG do?
it deactivates RANKL to prevent osteoblast differentiation
Describe PTH (structurally)
84 AA, peptide, made in parathyroid glands
What part of the PTH peptide is active?
1-34
How do you regulate PTH?
1) via calcium sensitive protease (limits production)
2) calcium sensing receptor in parathyroid gland reduces PTH production
3) Parathyroid gland has Vit D receptor and CYP27B1 to promote Vit D and suppress PTH
What does PTH do exactly?
mobilizes bone calcium decreases renal excretion of calcium stimulated Vit D synthesis promotes phosphate excretion (i.e wants calcium to be in the blood and wants to get rid of phosphate)
If you have osteoporosis would you want to utilize PTH or vitD3 and calcium?
you can use both but vitD3 and calcium together would be way better
So explain Vit D biosynthesis?
you have 7-DHC in skin gets exposed to UV changes to D3 and goes to liver, liver changes it to 25D3 and gives it to kidney, kidney converts to 1,25 OH D3 to make calcitriol
What is secalciferol?
it is a second pathway that 25 OHD3 can go in the kidney. If you have excess 25 OH D3 or you dont need anymore calcitriol then you will make this instead of calcitriol
What organs are important for calcitriol formation?
skin, liver, kidney
What hormone increases 25OHD3 (calcifediol, i.e the substance that is in kidney waiting to be converted to 1,25 D3) conversion to calcitriol?
PTH :)
How does vit D circulate in the blood?
bound to vit D binding protein
How is vit D cleared from the blood?
rapidly in the liver
What does vit D do?
stimulates absorption of calcium and phosphate in the intestines and mobilization of calcium from bone.
When would you clinically administer Vit D?
osteomalacia (reduced vit D)
hypocalcemia
hypoparathryroidism
What is FGF23 (fibroblast growth factor 23)?
it is a protein (251 AAs) that inhibits 1,25 OH2D production and phosphate reabsorption in the kidney
(i.e inhibits vit D formation)
Where does FGF23 come from?
produced by osteoblast and osteocytes in bone
What inhibits FGF23?
What happens if you have a mutation in this?
DMP1
increased FGF23 and osteomalacia (reduced vit D)
What does FGF23 do?
it keeps vit d from stealing its calcium :)
How do you inactivate FGF23?
What happens if you have a mutation in this resulting in excess FGF23?
via cleavage at an RXXR site
You will get hypophosatemic rickets (osteomalacia)!
How do you stimulate FGF23 production?
Calcitriol, fo real
How does PTH affect the intestine, kidney, bone, and net serum levels?
intestine-> makes calcitriol which stimulates increased Calcium and phosphate
kidney-> decreased calcium excretion, increased phosphate excretion
Bone-> Increased calcium and phosphate resorption (in high doses), increase bone formation (low doses)
Net effect: serum calcium increased, serum phosphate decreased
How does Vit D affect the intestine, kidney, bone, and net effect on serum?
Intestine-> increased calcium and phosphate absorption
Kidney-> reduced calcium and phosphate excretion
Bone-> increased calcium and phosphate resorption via calcitriol, and increased bone formation via calcitriol and secalciferol. i.e. in high calcium concentrations you will increase bone formation, in low concentrations you get bone resorption)
Serum-> calcium and phosphate increase
How does FGF23 affect the intestine, kidney, bone and net effect on serum?
(remember this inhibits Vit D)
Intestine-> decreased calcium and phosphate absorption by decreasing vit D production
Kidney-> increased phosphate excretion
Bone-> decreased mineralization (due to low vit D)
Serum levels-> decreased serum phosphate
How do you regulate PTH, FGF23 and vit D?
Are these major contributors to bone mineral homeostasis?
via secondary regulators
no, their impact is minor however they can be exploited for therapeutic use
What is a protein hormone made up of 32 AA produced by the thyroid gland?
calcitonin
What all does calcitonin do?
inhibits osteoclasts
decreases reabsorption of calcium and phosphate in proximal tubule of kindey
(i.e lower plasma calcium concentrations)
Where does calcitonin inhibit calcium and phosphate reabsorption?
in the proximal tubule of the kidney
What prevents vit D from working its magic on the intestine so you get increased renal excretion of calcium and inhibition of bone formation?
glucocorticoids
Pharmacologically, how can glucocorticoids be used?
to reverse hypercalcemia (ass. w/ lymphomas and granulomatous diseases, sarcodosis) in which Vit D is elevated