skeletal system treatments Flashcards
osteoporosis pathology
thinning bone due to excessive reabsorption from osteoclasts
osteoclasts have a ____ border
ruffle
main treatment focuses on
osteoclasts - specialised
also some new focus on osteoblasts
main drug for osteoporosis
bisphosphonates
function of bisphosphonates
prevent bone breakdown, antiresorptive - inhibit osteoclasts
chemical structure of bisphosphonates (2)
two phosphate groups
two r/variable groups
what part of bisphosphonates is most significant and why
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
bioavailability of bisphosphonates
1-4%
how often are bisphosphonates administered
once weekly, often when fasting to inc oral bioavailability
how are bisphosphonates absorbed
intestine
of the absorbed dose, what % of bisphosphonates are taken up by the skeleton
50% (aka 0.5-2% of admin dose)
rest excreted in urine unchanged
do bisphosphonates have a long term or short term retention
long term if dose is maintained
what does the R1 chain determine
drug pharmacokinetics
what does the R2 chain determine
drug potency
bisphosphonates always end in ___
onate
what happens to osteoclast structure once it absorbes bisphosphonate
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
“loses ruffle border, can no longer secrete acid to reabsorb bone” what is the term for this
retraction
what happens to osteoclast structure once it undergoes apoptosis
forms two apoptotic bodies - membrane bound vesicles
controlled mechanism
effect of bisphosphonates on osteoblast function over time
inc effect, bone becomes more dense
dec risk of osteoporotic fractures e.g. hip fractures or vertebral fractures
what are the first generation of bisphosphonates called
simple bisphosphonates
examples of simple/ 1st gen bisphosphonates (2)
etidronate/didronel
clodronate
what are 2nd or 3rd gen bisphosphonates also called
nitrogen containing bisphosphonates
examples of 2nd or 3rd gen/ nitrogen containing bisphosphonates (5)
pamidronate/ aredia
alendronate/ fosamax
ibandronate/ boniva
risendronate/ actonel
zoledronate/ zometa
mechanism of action of 1st gen bisphosphonates
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
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)
the mechanism of action of 2nd/ 3rd gen bisphosphonates is similar to what other drug group
statins for cholesterol disorders
in the mevalonate, HMG-CoA is reduced to mevalonate via _____
HMG-CoA Reductase
in the mevalonate, _____ is reduced to mevalonate via HMG-CoA reductase
HMG-CoA
in the mevalonate, HMG-CoA is reduced to ____ via HMG-CoA Reductase
mevalonate
mevalonate is synthesised via ____ to farnesyl disphosphate
FDDP synthase
mevalonate is synthesised via FDDP synthase to ______
farnesyl disphosphate
role of farnesyl disphosphate
role in prenylating small GTPases
role of small GTPases/ GTP binding proteins
normal cell function/ act as molecular switches
role of small GTPases/ GTP binding protein Ras
cell proliferation
role of small GTPases/ GTP binding proteins Rho and Rop
cell cytoskeleton
role of small GTPases/ GTP binding proteins Art and Rab
membrane trafficking
when small GTPases are bound to GDP are they on or off
off
when small GTPases are bound to GTP are they on or off
on, can activate signalling pathways
how is GDP converted to GTP
GEFs exchange GDP to GTP
role of GTPase activating protein (GAP)
hydrolyse GTP back to GDP (loss of phosphate)
activate intrinsic GTPase activity
aka switch off
N-bisphosphonate function
inhibit farnesyl disphosphate production
what are farnesyl disphosphates
post translational lipid modifications of protein (GTPases)
to allow to interact with cell membrane for activity
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)
what is dysphagia
difficulty swallowing
what is ONJ
rare side effect of bisphosphonates, osteonecrosis of jaw - lack of blood
exposes jaw
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)
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
how can bisphosphates be used in treating hypercalcaemia
reduce calcium mobility from bone to reduce release into blood
restore calcium homeostatic balance
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
cancer cells can form a ___ feedback loop with osteoclasts
positive
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)
what drugs can be used instead of bisphosphonates
human monoclonal antibody - denosumab
(approved 2010)
how does denosumab work
inhibit signals that begin bone reabsorption by binding to cytokine RANKL, prevents it binding to RANK
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
where is receptor activator of nuclear factor KB ligand (RANKL) secreted from
osteocytes
function of receptor activator of nuclear factor KB ligand (RANKL)
RANK agonist - switches it on to begin bone reabsorption
what is OPG
suppresses bone turnover - competes for RANK and prevents RANKL binding
aka RANK antagonist
stops bone resorption
what produces OPG
osteoblasts
denosumab prevents binding of RANK to RANKL by binding to ___ with high affinity/ efficacy- prevents osteoclast activation
RANKL
side effects of denosumab (3)
skin infection
hypocalcaemia
ONJ
longer term affects
risk of discontinuing denosumab treatment
inc risk of multiple vetrebral fractures
less common monoclonal antibody/ biologic used to treat osteoporosis
romosozumab
how does romosozumab work
inhibits sclerostin by binding to it and preventing it affecting osteoblasts
what is sclerostin
protein produced by osteocytes - inhibits osteoblasts, prevents formation of new bone
what is OPG an inhibitor of
RANK (which switches on osteoclasts)
how is OPG produced
in osteoblast following activation of Wnt signalling
sclerostin effect on signalling
inhibits Wnt signalling, inhibits OPG, activates RANK
drives osteoporosis
other function of sclerostin
preventing osteoblasts from producing new fibres to be mineralised and form new bones
side effects of romosozumab (2)
hypocalcaemia
jaw osteonecrosis
what is abaloparatide
new
synthetic peptide analogue of parathyroid hormone-related protein (PTHrP)
manages/ treats osteoporosis
abaloparatide is a ___ amino acid peptide chain with ___ homology to PTHrP
34
76
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
what type of GPCR is parathyroid hormone receptor type 1 (PTH1R) GPCR
g alpha stimulatory coupled
what demographic is abaloparatide recommended for
postmenopausal women at inc risk of fracture
abaloparatide side effects (7)
nausea
dizziness
headache
palpilations
hypercalciuria
hypercalcaemia
postural hypotension
not osteonecrosis of jaw
bisphosphonates have high affinity for ___ and not other tissues, making them specific and idea
bone
bisphosphonates reduce the risk of
osteoporotic fractures
bisphosphonates can also treat
cancers, pagets disease, osetogenesis imperfecta
bisphosphonates are synthetic analogs of ____, an endogenous regulator of bone mineralisation
pyrophosphate
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
the initial dose of bisphosphonate can be associated with
acute phase response
different bisphosphonates can produce different inflammatory cytokines. examples
IL-6 is produced by pamidronate and zoledronate, but not ibandronate
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
out of the bisphosphonates, which seems less likely to lead to renal failure
ibandronate
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
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
med types that are relevant - 3
osteoporosis - bisphosphonates or human monoclonal antibody - denosumab or romosozumab
hypercalacemia - bisphosphonates or human monoclonal antibody - denosumab
examples of med types 3
bisphosphontaes - simple clodronate, nitrogen ibandronate, alendronate
new mfs - 2
osteoporosis - synthetic peptide analogue of parathyroid hormone-related protein (PTHrP) - abaloparatide
anti sclerostin therapy
