3 - osteoperosis Flashcards
what is osteoporosis
skeletal disorder in which deterioration of bone density and bone quality increases the risk of fracture
how does oseoperosis effect more (men or women)
women (4:1)
what is the role of hydroxyapatite
calcium and phosphate in a 3d matrix, provides compression and resistance and hardness
it is 65% of bone mass
what does hydroxyapatite associate with
collagen fibre
what is the role of osteoclasts
bone reabsorption (break down)
what is the role of osteoblasts
bone deposition (both collagen and hydroxyapatite)
what happens when osteoclasts do their thing
they break down bone, releasing growth factors and acid and collegenase
what do the growth factors released from osteoclasts cause
stimulate osteoblast formation from progenitor cells
what is collagenase
enzyme that degrades collagen
what are biphosphonates structure
two phosphate groups attached to a central carbon
what do the phosphonate groups do in biphosphonates
act as anchors to bone and are essential for both binding to hydroxyapatite and for biochemical actions
what happens when R1=OH in biphosphates
there is an improved binding to bone via interaction with calcium
what does the R2 group in biphosphonates determine
antiresorptive potency and affects binding to hydroxyapatite
when do biphosphonates have the highest affinity for bone
bone undergoing remodeling (this happens more in osteoperosis)
are biphosphonates natural in the body or drugs
drugs
they mimic the pyrophosphate that circulates in the blood
what are the names for 1st gen BPs
non-nitrogen BPs
what is an example of first gen BPs
medronate
what is the R groups of medronate
H
what are the R groups in first gen
they are minimally modifies, no nitrogen or OH
what is an example of 2nd gen
alendronate
what are the R groups in alendronate
R1=OH
R2=nitrogen after a carbon chain
how much more potent is gen 2 than gen 1
10-100X
why are gen 2 more potent than gen 1
more affinity to bone
what are the general structure of 2nd gen
nitrogen containing with alkyl-amino structure
what are the general structure of 3rd gen
nitrogen containing BP with heterocyclic structure
what is an example of 3rd gen
zoledronate
what is the R in zoledronate
R1=OH
R2=nitrogen incorporated in rigid ring structure
how much are gen 3 more potent than gen 1
10 000X
where do biphosphonates bind
hydroxyapatite
what causes differences in potency
different abilities of binding to hydroxyapatite
what is the main role of OH in the biphosphonates
initial binding to the bone
what happens to osteoclasts when people are on biphosphonates
the osteoclasts taken up the biphosphonates
along with the calcium phosphate and collagen
how do non nitrogen biphosphonates interfere with osteoclasts (2)
they interfere with ATP production, making non-hydrolysable ATP analogues
also the ATP analogues inhibit the mitochondrial ADP/ATP translocase protein which exports ATP and imports ADP
what is the net effect of non nitrogen biphosphonates in osteoclasts
they are starved of energy cause they have no ATP causing apoptosis
what is the mechanism of action of nitrogen containing biphosphonates
they inhibit the mevalonate pathway which is involved in cholesterol synthesis
(and other sterols)
what is the major target of nitrogen containing biphosphonates
FPPS enzyme in osteoclasts
what does FPPS do
produce essential lipids that are linked to proteins in prenylation
what does prenylation allow
proteins to associate with membranes
what is prenylation
when you add fatty acid tail to protein
what are 4 roles of Ras protein
cytoskeletal arrangement, membrane ruffling, trafficking of vesicles, apoptosis
what are Ras proteins known as / referred to as
“molecular switches”
what is Ras protein (what kind of protein)
GTPase protein
what happens if Ras is not prenylated
they are not able to go to the membrane, they become dysfunctional and kills the osteoclasts
how does it prevent prenylation at FPPS (mechanism of action at FPPS)
phosphate groups bind to two magnesium atoms
what causes high affinity binding to FPPS
interaction with nitrogen on R2 with lysine and threonine in the binding site
what must the distance between nitrogen and oxygen be for optimal binding
3 angstroms
are the actions at FPPS competitive or non competitive
mix of both
what is common between biphosphonates and statins
they both inhibit the mevalonate pathway
where do statins inhibit in the mevalonate pathway
HMG-CoA reductase
are statins of biphosphonates more potent in inhibiting osteoclasts and bone resoption in cultures
statins
do statins work in vivo on bones and why (2 things)
no
they are transported into liver tissue via specific transporters not present in bone
no affinity for hydroxyapatite
do statins affect liver cholesterol production and why
no because they are not transported into the liver
which biphosphonates can cause flu symptoms and why
nitrogen biphosphonates because inhibition of FPPS results in accumulation of precursors (IPP)
which precursor is accumulated that causes the flu like symptoms
IPP which is immediately upstream from FPPS
what happens with extra IPP
agonist at receptors on circulating immune cells
what does activation of immune cell receptors cause (from IPP)
release of tumor necrosis factor alpha
TNF_alpha) which is a signalling molecule which initiates inflammation (acute phase reaction
