3 - osteoperosis

Question 1

what is osteoporosis

Answer 1

skeletal disorder in which deterioration of bone density and bone quality increases the risk of fracture

Question 2

how does oseoperosis effect more (men or women)

Answer 2

women (4:1)

Question 3

what is the role of hydroxyapatite

Answer 3

calcium and phosphate in a 3d matrix, provides compression and resistance and hardness
it is 65% of bone mass

Question 4

what does hydroxyapatite associate with

Answer 4

collagen fibre

Question 5

what is the role of osteoclasts

Answer 5

bone reabsorption (break down)

Question 6

what is the role of osteoblasts

Answer 6

bone deposition (both collagen and hydroxyapatite)

Question 7

what happens when osteoclasts do their thing

Answer 7

they break down bone, releasing growth factors and acid and collegenase

Question 8

what do the growth factors released from osteoclasts cause

Answer 8

stimulate osteoblast formation from progenitor cells

Question 9

what is collagenase

Answer 9

enzyme that degrades collagen

Question 10

what are biphosphonates structure

Answer 10

two phosphate groups attached to a central carbon

Question 11

what do the phosphonate groups do in biphosphonates

Answer 11

act as anchors to bone and are essential for both binding to hydroxyapatite and for biochemical actions

Question 12

what happens when R1=OH in biphosphates

Answer 12

there is an improved binding to bone via interaction with calcium

Question 13

what does the R2 group in biphosphonates determine

Answer 13

antiresorptive potency and affects binding to hydroxyapatite

Question 14

when do biphosphonates have the highest affinity for bone

Answer 14

bone undergoing remodeling (this happens more in osteoperosis)

Question 15

are biphosphonates natural in the body or drugs

Answer 15

drugs

they mimic the pyrophosphate that circulates in the blood

Question 16

what are the names for 1st gen BPs

Answer 16

non-nitrogen BPs

Question 17

what is an example of first gen BPs

Answer 17

medronate

Question 18

what is the R groups of medronate

Answer 18

H

Question 19

what are the R groups in first gen

Answer 19

they are minimally modifies, no nitrogen or OH

Question 20

what is an example of 2nd gen

Answer 20

alendronate

Question 21

what are the R groups in alendronate

Answer 21

R1=OH

R2=nitrogen after a carbon chain

Question 22

how much more potent is gen 2 than gen 1

Answer 22

10-100X

Question 23

why are gen 2 more potent than gen 1

Answer 23

more affinity to bone

Question 24

what are the general structure of 2nd gen

Answer 24

nitrogen containing with alkyl-amino structure

Question 25

what are the general structure of 3rd gen

Answer 25

nitrogen containing BP with heterocyclic structure

Question 26

what is an example of 3rd gen

Answer 26

zoledronate

Question 27

what is the R in zoledronate

Answer 27

R1=OH | R2=nitrogen incorporated in rigid ring structure

Question 28

how much are gen 3 more potent than gen 1

Answer 28

10 000X

Question 29

where do biphosphonates bind

Answer 29

hydroxyapatite

Question 30

what causes differences in potency

Answer 30

different abilities of binding to hydroxyapatite

Question 31

what is the main role of OH in the biphosphonates

Answer 31

initial binding to the bone

Question 32

what happens to osteoclasts when people are on biphosphonates

Answer 32

the osteoclasts taken up the biphosphonates | along with the calcium phosphate and collagen

Question 33

how do non nitrogen biphosphonates interfere with osteoclasts (2)

Answer 33

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

Question 34

what is the net effect of non nitrogen biphosphonates in osteoclasts

Answer 34

they are starved of energy cause they have no ATP causing apoptosis

Question 35

what is the mechanism of action of nitrogen containing biphosphonates

Answer 35

they inhibit the mevalonate pathway which is involved in cholesterol synthesis (and other sterols)

Question 36

what is the major target of nitrogen containing biphosphonates

Answer 36

FPPS enzyme in osteoclasts

Question 37

what does FPPS do

Answer 37

produce essential lipids that are linked to proteins in prenylation

Question 38

what does prenylation allow

Answer 38

proteins to associate with membranes

Question 39

what is prenylation

Answer 39

when you add fatty acid tail to protein

Question 40

what are 4 roles of Ras protein

Answer 40

cytoskeletal arrangement, membrane ruffling, trafficking of vesicles, apoptosis

Question 41

what are Ras proteins known as / referred to as

Answer 41

"molecular switches"

Question 42

what is Ras protein (what kind of protein)

Answer 42

GTPase protein

Question 43

what happens if Ras is not prenylated

Answer 43

they are not able to go to the membrane, they become dysfunctional and kills the osteoclasts

Question 44

how does it prevent prenylation at FPPS (mechanism of action at FPPS)

Answer 44

phosphate groups bind to two magnesium atoms

Question 45

what causes high affinity binding to FPPS

Answer 45

interaction with nitrogen on R2 with lysine and threonine in the binding site

Question 46

what must the distance between nitrogen and oxygen be for optimal binding

Answer 46

3 angstroms

Question 47

are the actions at FPPS competitive or non competitive

Answer 47

mix of both

Question 48

what is common between biphosphonates and statins

Answer 48

they both inhibit the mevalonate pathway

Question 49

where do statins inhibit in the mevalonate pathway

Answer 49

HMG-CoA reductase

Question 50

are statins of biphosphonates more potent in inhibiting osteoclasts and bone resoption in cultures

Answer 50

statins

Question 51

``` do statins work in vivo on bones and why (2 things) ```

Answer 51

no they are transported into liver tissue via specific transporters not present in bone no affinity for hydroxyapatite

Question 52

do statins affect liver cholesterol production and why

Answer 52

no because they are not transported into the liver

Question 53

which biphosphonates can cause flu symptoms and why

Answer 53

nitrogen biphosphonates because inhibition of FPPS results in accumulation of precursors (IPP)

Question 54

which precursor is accumulated that causes the flu like symptoms

Answer 54

IPP which is immediately upstream from FPPS

Question 55

what happens with extra IPP

Answer 55

agonist at receptors on circulating immune cells

Question 56

what does activation of immune cell receptors cause (from IPP)

Answer 56

release of tumor necrosis factor alpha | TNF_alpha) which is a signalling molecule which initiates inflammation (acute phase reaction