B6-052 CBCL Osteoporosis Flashcards
characterized by loose arrangement of collagen fibers
forms during fracture repair and remodeling
primary (woven) bone
regular parallel arrangement of collagen
only visible on dried/ground sections
lamellar bone
inner layer of bone with spaces for marrow
trabecular bone
outer solid cortex of bone which encloses an inner layer of spongey bone
cortical bone
contains osteoprogenitor cells that can help with bone repair/remodeling [2]
periosteum
endosteum
organic matrix of bone is composed primarily of
type 1 collagen fibers
inorganic matrix of bone is composed primarily of
calcium hydroxypatite
99% of the bodies […] and […] is stored in bone
calcium
phosphate
osteoblasts come from what stem cell line?
mesenchymal
osteoclasts come from what stem cell line?
hematopoietic (monocyte/macrophages)
found in growing portion of bone, including periosteum and endosteum
osteoblasts
stimulates osteoclastogenesis
RANKL
decoy receptor of RANKL
ostoprotegerin
noncollagenous protein required for bone mineralization
osteocalcin
noncollagenous protein required for formation of sealing zone
osteopontin
**allow osteoblasts to have tight grip on bone
entrapped in matrix
osteocytes
function to maintain mineral concentration of matrix
osteocytes
primary function is bone formation
osteoblasts
mechanosensory sensors of bone
osteocytes
synthesize sclerostin which inhibits osteoblastic activity
osteocytes
found at bone surface and at sites of old, injured, or unneeded bone
osteoclasts
giant, mutlinucleate cells derived from monocytes
osteoclasts
genetic factors that influence peak bone mass
polymorphisms in vitamin D-R
LRP5/6 (males)
RANK, OPG, RANKL
how does menopause lead to osteoporosis?
decreased serum estrogen increases RANK/RANKL expression and stimulation of osteoclasts
compact bone remodeling occurs within the
osteon
trabecular bone remodeling occurs on
bone surface
inhibits osteoclastic activity
calcitonin
how does PTH stimulate bone reabsorption?
PTH binds to osteoblasts
osteoblasts release RANKL
RANKL binds to RANK on preosteoclasts
activates osteoclasts
what factors lead to the activation of osteoclasts? [2]
vitamin D
PTH
what factors lead to the inhibition of osteoclasts? [3]
estrogen
calcintonin
TGF-b
how does estrogen inhibit osteoclasts?
estrogen induces the secretion of OPG
OPG binds to RANKL and interferes with RANKL/RANK interaction
inhibits bone resorption
if OPG is greater than RANKL…
osteoclast apoptosis –> more bone formation
if OPG is less than RANKL…
osteoclast activation –> bone resorption
monoclonal antibody that binds to RANKL and competitively inhibits RANK binding
denosumab
can be used to treat osteoporosis
estrogen inhibits differentiation and promotes apoptosis of […]
osteoclasts
estrogen promotes differentiation and inhibits apoptosis of […]
osteoblasts
what does vitamin D do during positive calcium balance?
promotes intestinal calcium transport
what does vitamin D do during negative calcium balance?
induce osteoblastic expression of RANKL
suppresses bone matrix mineralization
WNT binds to LRP5/6 to stimulate [2]
osteoblastic activity
OPG
produced by osteocytes and has a negative effect on the WNT LRP5/6 pathway inhibiting osteoblasts
sclerostin
mechanical stress leads to the downregulation of […]
sclerostin
reduced muscle activity and reduced mechanical stress will lead to
higher slerostin
inhibition of ostoblasts
top genes associated with the development of osteoporosis [3]
RANK
OPG
RANKL
calcium nutritional state is key to […]
peak bone mass
**calcium deficiency in young life restricts PBM
vitamin D absorption and metabolism […] with age
decline
decreased estrogen after menopause increases
bone resorption and formation
**but bone resorption is greater
what cytokines increase as a result of low estrogen?
IL 6
TNF-a
IL-1
**any disease state/drug that reduces estrogen in premenopausal women will also have this effect and cause net bone loss
inflammation primarily promotes […] activity
osteoclast
TNF-a, IL-1, and IL-6 inhibits […]
osteoblasts
high doses of glucocorticoids […] RANKL and […] OPG
increase RANKL
decrease OPG
prednisone doses of […]/day can increase fracture risk
5 mg/day
why do males have a decreased risk of developing osteoporosis [2]
higher PBM
no sudden loss of estrogen
most accurate and standardized way to measure bone mineral density
DEXA
indications for BMD testing
women and men over 65
postmenopausal women and men aged 50-64 with risk factors
compares bone density with that of healthy young adult
T score
**0 means equal
a t score less than […] indicates osteoporosis
-2.5
used to calculate 10 year risk of fracture
FRAX
reversible causes of osteoporosis [5]
hyperparathyroidism
celiac disease
multiple myeloma
cushings
hypogonadism
what is considered adequate intake of calcium and vitamin D for osteoporosis therapy?
1200-1500 mg Ca/day
800-1000 IU of vitamin D3
indications for FDA meds treatment of osteoporosis
- hx of osteoporotic fracture
- T score less than -2.5
- FRAX score greater what 20% (3% in hip)
selective estrogen receptor modulator
raloxifene
medication often given to postmenopausal women with osteopenia/porosis and an increased risk of breast cancer
raloxifene
bisphosphonates [4]
alendronate
ibandronate
risendronate
zolendronic acid
considered first line for prevention/treatment of osteoporosis
bisphophonates
administration instructions of bisphosphate
first thing in the morning, on empty stomach with a full glass of water
sit up for a while after
most common side effect of bisphosphonates
esophageal reflux
inhibit osteoclast-mediated bone resorption
bisphosphonates
monoclonal antibody against RANKL that reduces osteoclastogenesis
denosumab
what osteoporosis medications have evidence of fracture reduction in all three types? [4]
alendronate
risedronate
zoledronic acid
denosumab
recombinant form of parathyroid hormone that is administered as a once daily injection
teriparatide
previously had a black box warning for causing the side effect of osteosarcoma
teriparatide
monoclonal antibody that binds/inhibits sclerostin
romosozumab
main function of sclerostin
inhibit bone formation
if oral bisphosphates are contraindicated, what medications can be used?
IV bisphosphonate (zoledronic acid)
teriparatide
denosumab
romosozumab
with bisphosphonates there is evidence of plateau after […]
5 years
options when you are approaching the 5 year mark of bisphosphonates
drug holiday (2 years)
switch to another class
bone is classified as […] tissue
specialized connective
outer, solid layer of bone
cortex
inner layer of bone
cancellous
immature bone that forms during fracture repair and remodeling
woven bone
what part of bone contains the epiphyseal plate?
metaphysis
ends of long bone that contain spongy bone covered by a thin layer of compact bone
epiphysis
shaft of bone that contains compact bone around the medullary cavity
diaphysis
outer layer of connective tissue that covers bone
periosteum
inner layer of connective tissue that covers bone
endosteum
arise from monocyte precursors
osteoclasts
osteoid makes up the bulk of the organic matrix in bone and consists of [2]
proteoglycans
type 1 collagen
have a ruffled border
osteoclasts
opposes osteoclasts differentiation and activity
OPG
prevents RANKL from binding to RANK on osteoclasts precursors
OPG
opposes WNT signaling by binding to receptor LRP5/6 to
scelorstin
net effect is promote osteoclasts and inhibit osteoblasts
increases the number of osteoclasts and the ruffled border activity of existing osteoclasts
PTH
calcitonin receptors are found on
osteoclasts
t score for osteopenia
-1 to -2.4
factors associated with lower risk of osteoporosis in post-menopausal women
elevated BMI
former estrogen use
why is elevated BMI thought to offer a protective factor for osteoporosis?
lower sclerostin production due to mechanical stress of increased load bearing
concentrate at sites of active remodeling and remain in the matrix until bone is remodeled
bisphosphonates
demonstrates greater percent change in lumbar spine BMD over treatment [2]
teriparatide
romosozumab
drug that is functionally analogous to OPG
denosumab
most significant challenge in management of osteoporosis after a fracture
treatment adherance
what classes of drugs reduce all three fracture types
bisphosphonates
denosumab
considered an option for primary drug in a patient with prior fractures or high risk,
but not considered first line in a patient with moderate risk or no prior fracture
teriparatide
diagnostic definition of osteoporosis
history of atraumatic osteoporotic fracture
T score in any part of the body lower than -2.5
FRAX score greater than 20% in any part of the body, or 3% in the hip
first line therapy for osteoporosis
bisphosphonates
describe what happens to bone density following menopause
rapid decline for 3-5 year, then slower decline
treatment for an individual with low fracture risk
calcium and vitamin D
[…] can be used in adjunct to denosumab to help maintain gains in bone mineral density
bisphosphonates
used to both treat osteoporosis and serve as prophylaxis in women with breast cancer
raloxifene
**unless patient currently taking aromatase inhibitor
decoy receptor that binds RANKL
OPG
secrete RANKL and OPG
osteoblasts
monocytes/macrophages can bind M-CSF which will cause them to differentiate into
preosteoclasts
once RANKL binds to RANK, it causes the differentiation of […] into […]
preosteoclasts
osteoclasts
phase 1 of bone loss occurs when
in women in 3-5 years following onset of menopause
what type of bone is most affected in phase 1 bone loss?
trabecular
phase II of bone loss occurs when
in both men and women, with age
what type of bone is lost in phase II bone loss?
cortical and trabecular
calcitonin inhibits the activity of
osteoclasts
T score of -1 to -2.4
osteopenia
best next step for a patient who has a high risk of fracture?
get a bone density test
why do bisphosphonates have such a long half life?
they get incorporated into hydroxyapatite crystals of bone
used in metastatic cancer to prevent pathologic fractures
bisphosphonates
IL-1, IL-6, and TNF-a promote the activity of
osteoclasts
suppresses RANKL-induced osteoclast activation
denosumab
