Antiresorptive-Induced Osteonecrosis Flashcards
Osteoporosis is ____ and ____
preventable
treatable
Stimulators of Bone Formation
PTH 1-34, Action: ____ proliferation and survival, Status: in ____ use, sc ____
Strontium Ranelate (Protelos), Action: ____ action: on ____, Status: in ____ use
Antibody AMG 785 (Sclerostin), Action: ____ proliferation and differentiation, Status: phase ____ ongoing
osteoblast
clinical
injection/daily
dual
osteoblasts (increasing bone formation)/osteoclasts (reducing bone loss)
clinical
osteoblast
III
Development of Targeted Antiresorptives
forming more bone > you want drugs to promote the action of ____; or drugs that prevent the ____ from differentiating into osteoclast
can be explored all the way to 13
osteoblasts
osteoclast precursors
Drugs: Bone Resorption Inhibitors
Sex steroid (estrogen); action: inhibits ____ functions; status: in ____
Selective Estrogen Mimic; action: inhibits ____ function; status: in ____, once ____
Bisphosphonate; action: inhibits ____, status: in ____, once ____
RANKL antibody; action: inhibits osteoclast ____, function; status: in ____, sc injection - ____/year
Cathepsin K inhibitor; action: inhibits ____ function; status: in phase ____ clinical trial
osteoclast
clinical use
osteoclast
clinical use
daily
osteoclasts
clinical use
weekly
development
clinical use
2x
osteoclast
III
Drugs: Bone Resorption Inhibitors
RANK binds to the OCP > becomes activated and differentiates into an osteoclast; drug that binds the ____ and inhibits the formation of osteoclasts
osteoclasts are sealed at the ends so acids do not escape; also secretes ____: which resorbs the bone matrix
drugs that treat osteoporisis > anti-resorptive drugs > have serious ____ (bone necrosis)
RANK receptor
cathepsin K
side effect
Design of Bisphosphonates
• \_\_\_\_ analogue • PO4 ends: – Binding and anchorage to \_\_\_\_ – Form \_\_\_\_ complexes • P-C-P backbone: – Resistance to \_\_\_\_, chemicals and enzymatic hydrolysis •R1 and R2 – \_\_\_\_ potency – \_\_\_\_ binding to HA
All the side radicals (R1) are different which affects the ____ of the drug. Most have Nitrogen in them so they are Nitrogen- containing Bisphosphonates
But the R2 have ____
pyrophosphate HA insoluble heat anti-resorptive long-term
potency
OH
Bisphosphonates
The drugs that have ____ are the more potent bisphosphonates; these are the ones that cause ____
nitrogen
bone necrosis
Mechanism of Action of N-containing Bisphosphonates
Bisphosphonates also inhibits a ____ pathway
N-containing BPs inhibit ____
Absence of FPP, GPP prevent prenylation of ____, small signaling molecules which regulate osteoclast ____, membrane ____, survival
Thioether linkage between ____ and ____ group
cholesterol
farnesyl disphosphate synthase
GTPases
morphology
ruffling
cysteine
prenyl
Bisphosphonates Modulate Bone Remodeling
Directly on ____
As it is resorbing it gets to a part of the bone where BP has been deposited and anchor proteins are not able to be formed through ____. The ruffled borders are disrupted and becomes an ____ OC and is not able to resorb bone
Indirectly through ____
osteoclasts
isoprenylation
inactive
osteoblasts
Role of Osteoblasts/MSCs (mesenchymal stem cell) in Osteoclast Activation
when RANK ligand binds an OC progenitor > committed to become an ____
the osteoblast are able to secrete ____ > a competitor > can bind rankL and prevents it from attaching to OC progenitors
can design another drug that disrupts this interaction
osteoclast
osteoprotegerin
Action of Denosumab (Anti-RANKL mAb)
•RANKL expressed by ____ and ____
•RANK expressed by ____ •Denosumab: Anti-RANKL •Limits RANK-RANKL interaction
•Decreases ____ formation
Acts similarly to ____
MSCs osteoblasts osteoclast precursors osteoclast osteoprotegrin
Denosumab ____ Incidence of Vertebral and Hip Fractures
____ reduction in relative fracture risk
____ decrease in hip fractures
reduced
68%
40%
Odanacatib (Cathepsin K Inhibitor) Prevents Osteoclastic Bone Matrix ____
degradation
Dual Action of Odanacatib (Cathepsin K inhibitor)
Cathepsin K inhibitor (Odanacatib) • Preserve \_\_\_\_ functions • \_\_\_\_ resorption surfaces • Release of osteogenic \_\_\_\_ • Initiate \_\_\_\_ bone formation
makes it superior to ____ (due to the dual action properties)
as bone is resorbed ____ are released from the bone matrix > recruiting the OB to remake bone; howeveer, bisphosphonate kills the ____; but this drug DOES NOT kill the OC, makes it less ____ but it’s still sending to the OB so it can ____
osteoclast
shallow
factors
osteoblast
bisphosphonate cytokines osteoclast effective recruit
Bisphosphonates and Jaw Osteonecrosis
•Bisphosphonates - RxList Top 50 drugs USA •Osteoporosis ---• > \_\_\_\_ million people world wide • Metastatic bone diseases ---•\_\_\_\_ million deaths/year world wide • Paget's disease ---•\_\_\_\_ million people/year in USA • Multiple myeloma ---•\_\_\_\_% of hematological cancers
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