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skeletal system treatments Flashcards

1
Q

osteoporosis pathology

A

thinning bone due to excessive reabsorption from osteoclasts

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2
Q

osteoclasts have a ____ border

A

ruffle

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3
Q

main treatment focuses on

A

osteoclasts - specialised

also some new focus on osteoblasts

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4
Q

main drug for osteoporosis

A

bisphosphonates

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5
Q

function of bisphosphonates

A

prevent bone breakdown, antiresorptive - inhibit osteoclasts

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6
Q

chemical structure of bisphosphonates (2)

A

two phosphate groups
two r/variable groups

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7
Q

what part of bisphosphonates is most significant and why

A

phosphates as they interact with calcium ions, embed calcium and bisphosphonate in bone

leaves bone more stable

can be absorbed by osteocyte and then has its effect

this means no accumulation, drug is specialised to target

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8
Q

bioavailability of bisphosphonates

A

1-4%

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9
Q

how often are bisphosphonates administered

A

once weekly, often when fasting to inc oral bioavailability

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10
Q

how are bisphosphonates absorbed

A

intestine

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11
Q

of the absorbed dose, what % of bisphosphonates are taken up by the skeleton

A

50% (aka 0.5-2% of admin dose)

rest excreted in urine unchanged

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12
Q

do bisphosphonates have a long term or short term retention

A

long term if dose is maintained

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13
Q

what does the R1 chain determine

A

drug pharmacokinetics

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14
Q

what does the R2 chain determine

A

drug potency

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15
Q

bisphosphonates always end in ___

A

onate

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16
Q

what happens to osteoclast structure once it absorbes bisphosphonate

A

loses ruffle border, can no longer secrete acid to reabsorb bone

cell undergoes apoptosis (not programmed cell death)

thus no more bone resorption until new osteocytes formed

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17
Q

“loses ruffle border, can no longer secrete acid to reabsorb bone” what is the term for this

A

retraction

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18
Q

what happens to osteoclast structure once it undergoes apoptosis

A

forms two apoptotic bodies - membrane bound vesicles

controlled mechanism

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19
Q

effect of bisphosphonates on osteoblast function over time

A

inc effect, bone becomes more dense

dec risk of osteoporotic fractures e.g. hip fractures or vertebral fractures

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20
Q

what are the first generation of bisphosphonates called

A

simple bisphosphonates

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21
Q

examples of simple/ 1st gen bisphosphonates (2)

A

etidronate/didronel

clodronate

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22
Q

what are 2nd or 3rd gen bisphosphonates also called

A

nitrogen containing bisphosphonates

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23
Q

examples of 2nd or 3rd gen/ nitrogen containing bisphosphonates (5)

A

pamidronate/ aredia

alendronate/ fosamax

ibandronate/ boniva

risendronate/ actonel

zoledronate/ zometa

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24
Q

mechanism of action of 1st gen bisphosphonates

A

metabolise to compounds that replace the terminal phosphate group in ATP

forms non-hydrolysable analogue of ATP

means no high energy third phosphate bond that can be hydrolysed to release energy for osteoclast function

depleted cellular ATP causes cell death/ apoptosis

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25
mechanism of action of 2nd/ 3rd gen bisphosphonates
via mevalonate pathway HMG-CoA reduced to mevalonate via HMG-CoA Reductase synthesised via FDDP synthase to farnesyl disphosphate bisphosphonates inhibit FDDP synthase (not ATP)
26
the mechanism of action of 2nd/ 3rd gen bisphosphonates is similar to what other drug group
statins for cholesterol disorders
27
in the mevalonate, HMG-CoA is reduced to mevalonate via _____
HMG-CoA Reductase
28
in the mevalonate, _____ is reduced to mevalonate via HMG-CoA reductase
HMG-CoA
29
in the mevalonate, HMG-CoA is reduced to ____ via HMG-CoA Reductase
mevalonate
30
mevalonate is synthesised via ____ to farnesyl disphosphate
FDDP synthase
31
mevalonate is synthesised via FDDP synthase to ______
farnesyl disphosphate
32
role of farnesyl disphosphate
role in prenylating small GTPases
33
role of small GTPases/ GTP binding proteins
normal cell function/ act as molecular switches
34
role of small GTPases/ GTP binding protein Ras
cell proliferation
35
role of small GTPases/ GTP binding proteins Rho and Rop
cell cytoskeleton
36
role of small GTPases/ GTP binding proteins Art and Rab
membrane trafficking
37
when small GTPases are bound to GDP are they on or off
off
38
when small GTPases are bound to GTP are they on or off
on, can activate signalling pathways
39
how is GDP converted to GTP
GEFs exchange GDP to GTP
40
role of GTPase activating protein (GAP)
hydrolyse GTP back to GDP (loss of phosphate) activate intrinsic GTPase activity aka switch off
41
N-bisphosphonate function
inhibit farnesyl disphosphate production
42
what are farnesyl disphosphates
post translational lipid modifications of protein (GTPases) to allow to interact with cell membrane for activity
43
side effects of bisphosphonates (4)
hypocalcaemia (lack of calcium in blood as trapped in bone) gastrointestinal (oesophageal irritation, dysphagia, heartburn) nephrotoxicity acute-phase response (most common if iv admin)
44
what is dysphagia
difficulty swallowing
45
what is ONJ
rare side effect of bisphosphonates, osteonecrosis of jaw - lack of blood exposes jaw
46
what side effect is most common when bisphosphonate is administered IV
acute phase response (due to initial dose) lasts less than 72 hrs (thus oral is preferred)
47
what is involved in acute phase response
non-specific symptoms - flu like inc inflammatory cytokine levels - IL-1 and TNF-alpha fever fatigue nausea joint pain muscle pain
48
how can bisphosphates be used in treating hypercalcaemia
reduce calcium mobility from bone to reduce release into blood restore calcium homeostatic balance
49
how can bisphosphates be used in treating cancers (especially breast cancers)
some cancers prefer to metastasise bone, causing imbalance in bone remodelling - osteoporosis and osteolytic lesions bisphosphates prevent or manage lesions/ porosis
50
cancer cells can form a ___ feedback loop with osteoclasts
positive
51
positive feedback loop of cancers with osteoclasts
cancer cells release cytokines, growth factors, etc which act on osteoclasts osteoclasts cause bone resorption which releases growth factors from bone which help cancer cells grow and divide, which release inc cytokines, growth factors, etc (bisphosphonates can switch this feedback off)
52
what drugs can be used instead of bisphosphonates
human monoclonal antibody - denosumab (approved 2010)
53
how does denosumab work
inhibit signals that begin bone reabsorption by binding to cytokine RANKL, prevents it binding to RANK
54
what is activation of bone reabsorption regulated through (normal conditions) aka activate osteoclasts
receptor activator of nuclear factor KB (RANK) which are expressed by osteoblasts
55
where is receptor activator of nuclear factor KB ligand (RANKL) secreted from
osteocytes
56
function of receptor activator of nuclear factor KB ligand (RANKL)
RANK agonist - switches it on to begin bone reabsorption
57
what is OPG
suppresses bone turnover - competes for RANK and prevents RANKL binding aka RANK antagonist stops bone resorption
58
what produces OPG
osteoblasts
59
denosumab prevents binding of RANK to RANKL by binding to ___ with high affinity/ efficacy- prevents osteoclast activation
RANKL
60
side effects of denosumab (3)
skin infection hypocalcaemia ONJ longer term affects
61
risk of discontinuing denosumab treatment
inc risk of multiple vetrebral fractures
62
less common monoclonal antibody/ biologic used to treat osteoporosis
romosozumab
63
how does romosozumab work
inhibits sclerostin by binding to it and preventing it affecting osteoblasts
64
what is sclerostin
protein produced by osteocytes - inhibits osteoblasts, prevents formation of new bone
65
what is OPG an inhibitor of
RANK (which switches on osteoclasts)
66
how is OPG produced
in osteoblast following activation of Wnt signalling
67
sclerostin effect on signalling
inhibits Wnt signalling, inhibits OPG, activates RANK drives osteoporosis
68
other function of sclerostin
preventing osteoblasts from producing new fibres to be mineralised and form new bones
69
side effects of romosozumab (2)
hypocalcaemia jaw osteonecrosis
70
what is abaloparatide
new synthetic peptide analogue of parathyroid hormone-related protein (PTHrP) manages/ treats osteoporosis
71
abaloparatide is a ___ amino acid peptide chain with ___ homology to PTHrP
34 76
72
how does abaloparatide work
acts on parathyroid hormone receptor type 1 (PTH1R) GPCR in osteoblasts g alpha stimulatory coupled pathway switches on adenylate cyclase switches on cAMP and PKA promotes osteoblasts
73
what type of GPCR is parathyroid hormone receptor type 1 (PTH1R) GPCR
g alpha stimulatory coupled
74
what demographic is abaloparatide recommended for
postmenopausal women at inc risk of fracture
75
abaloparatide side effects (7)
nausea dizziness headache palpilations hypercalciuria hypercalcaemia postural hypotension not osteonecrosis of jaw
76
bisphosphonates have high affinity for ___ and not other tissues, making them specific and idea
bone
77
bisphosphonates reduce the risk of
osteoporotic fractures
78
bisphosphonates can also treat
cancers, pagets disease, osetogenesis imperfecta
79
bisphosphonates are synthetic analogs of ____, an endogenous regulator of bone mineralisation
pyrophosphate
80
compare effects of accumulation of both types of bisphosphonates
simple - cytotoxic analogue of ATP accumulation, causes apoptosis of ostoclasts eventually nitrogen - not metabolised, excreted unchanged
81
the initial dose of bisphosphonate can be associated with
acute phase response
82
different bisphosphonates can produce different inflammatory cytokines. examples
IL-6 is produced by pamidronate and zoledronate, but not ibandronate
83
how to offset bisphosphonate treatment adverse reactions in general - 2
preclinical data suggests combination therapy of clodronate (simple bp) with nitrogren - simple can reverse proinflammatory effects of nitrogen containing bp but keep potency of nitrogen containing bp or, statins can inhibit coenzymes in mevalonate pathway and prevent production of proinflammatory metabolites linked to ADRs
84
out of the bisphosphonates, which seems less likely to lead to renal failure
ibandronate
85
anti sclerostin therapy
promotes bone formation and has shown beneficial effects in increasing bone mineral density (BMD) in osteoporotic patients, helping to strengthen bones and reduce the risk of fractures but, therapy's effects dec over time, liekly due to body's adaptove response return to pretreatment levels after discontinuation, so need to be routinely administered
86
Sclerostin in Cancer-Induced Bone Loss
preclinical models show sclerostin level is altered in bone cancers. inhibiting sclerostin prevented cancer-caused bone loss. blocking sclerostin might help prevent or reduce cancer-induced bone destruction, offering a potential new treatment approach neutralizing antibodies against sclerostin is being explored as a possible therapeutic strategy for cancers that target the bone studies needed to test
87
med types that are relevant - 3
osteoporosis - bisphosphonates or human monoclonal antibody - denosumab or romosozumab hypercalacemia - bisphosphonates or human monoclonal antibody - denosumab
88
examples of med types 3
bisphosphontaes - simple clodronate, nitrogen ibandronate, alendronate
89
new mfs - 2
osteoporosis - synthetic peptide analogue of parathyroid hormone-related protein (PTHrP) - abaloparatide anti sclerostin therapy

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