osteoporosis (Steve Darby) Flashcards
What is osteoporosis?
loss of bone mass due to reduced organic bone matrix and mineral content
causes of osteoporosis
increased bone resorption (osteoclasts)
decreased bone formation (osteoblasts)
both
causes of primary osteoporosis
menopause (inc bone resorption) age associated (dec bone formation)
causes of secondary osteoporosis
drug/disease induced
- severe malnutrition (anorexia, lack of Vit D)
- endocrine (hypogonadism, hyperparathyroidism)
- cancer
- drug use
What hormones control the homeostatic regulation of Ca?
calcitonin
PTH
Vit D
RANKL
receptor activated NF kappa B ligand
How does an osteoclast precursor become an active osteoclast?
pre-osteoclast has RANK (receptor) on its surface
PTH stimulates release of RANKL
RANKL binds to RANK
causes the osteoclast precursor to become active
these then degrade bone
What is bone resorption?
degradation of bone
What substances cause bone resorption (degradation)?
RANKL
PTH
What is OPG?
oseteoprotegerin
What does OPG do?
inhibits bone resorption
How does inhibition of bone resorption occur?
bone releases OPG (oesteoprotegerin)
OPG binds to RANKL
this prevents RANKL from binding to RANK on the osteoclast precursor
How do oestrogens help in bone formation?
promote formation of pre-osteoblasts
prevent activation of T cells (T cells release RANKL)
prevent generaion of osteoclasts
What happens when oestrogen levels are decreased?
T cells become activated
RANKL increased (from T cells)
activates pre-osteoclasts, inc in bone resportion - bone loss
preventative measures for osteoporosis
- oral Ca supplements (inc BMD in spine in postmenopause)
- Vit D
- HRT in peri/post menopause
- smoking cessation
- increased exercise (promotes bone remodelling)
pharmacological treament options for osteoporosis
bisphosphonates denosumab HRT raloxifene teriparatide
2 types of therapies for established osteoporosis
- anti-resorptive therapies - dec markers of bone formation and bone resorption
bisphosphonates, raloxifene, oestrogen, denosumab - bone forming therapies (anabolic) - inc markers of bone formation over bone resorption
calcitonin, teriparatide
composition of calcified bone
25% organic matrix
5% water
70% hydroxyapatite
What is hydroxyapetite?
crystalline complex of Ca and P
What does pyrophosphate do?
binds and stabilises Ca and P in bone
Why can’t pyrophosphate be given orally?
it’s hydrolyses in GIT
ester bond broken into 2 phosphate groups
difference between pyrophosphate and bisphosphonates?
oxygen replaced with a carbon with 2 functional groups
P-C-P can’t be hydrolysed
R1 side chain of bisphosphonates
hydroxyl group
- maximises effects to bind hydroxyapatite
- increases Ca affinity
R2 side chain on bisphosphonates
amino residue
- increaes potency
How do bisphosphonates work?
- stabilise the hydroxyapatite matrix
- inhibit bone resorption
- inhibit osteoclast proliferation
- inhibit osteoclast activity
- inhibit malaveonate pathway -> to regulate osteoclast fxn
- > reduce bone turnover and allow osteoblasts to function
Why do bisphosphonates have poor absorption?
their polar nature
How much bisphosphonate is absorped into bone?
50%
the rest excreted via kidneys
half life of bisphosphonates
serum half life - 4-6hrs
tissue half life - 10yrs
2nd generation of bisphosphonates
amino-bisphosphonates
- > nitrogen containing drugs
- > alendronic acid
How often is alendronic acid taken?
once a week
3rd generation bisphosphonates
amino-bisphosphonates
- > nitrogen containing
- > risedronate sodium (once a week)
What is given if oral bisphosphonates not tolerated?
IV bisphosphonates
-> Zoledronic acid (annually)
cautions with zoledronic acid
osteonecrosis of the jaw
renal function and bisphosphonates
alendronic acid eGFR <35
ridedronate eGFR < 30
How to take bisphosphonates?
taken once weekly
empty stomach to avoid binding to Ca in food
oral forms of bisphosphonates
alendronic acid
risedronate
IV formulations of bisphosphonates
pamidronate disodium
zoledronic acid
s/e of bisphosphonates
GI disturbance - nausea, abdominal pain, diarrhoea/constipation
severe oesophagitis (oral)
headache
dizziness
MSK pain
transient pyrexia, flu-like symptons (IV)
osteonecrosis of the jaw (esp IV)
How does Denosumab mimick natural inhibition of bone resorption?
it mimicks OPG
How does denosumab work?
binds to RANKL to prevent osteoclast activation
How often is denosumab given?
6 monthly injection
How is the oestrogen receptor activated?
- HRT casuses helix H12 to fold over the E2 binding site
- conformational change enables ER to bind to trascriptional cofactors and DNA
- initiates ER target gene transcription
- promotes cellular growth and bone formation
Why is HRT not used as much for osteoporosis teratment today?
risk of breask cancer and thrombosis
What HRTs are used?
SERMs - selective estrogen receptor modulators
example of SERM
raloxifene
Is raloxifene an ER agonist/antagonist in osteoclasts?
ER agonist (turns on the receptor, activates bones to reform/remodel)
-> ER antagonist in breast tissue, turns off the receptor
What does raloxefine do?
reduces osteoclast activity
advantages/diasdvantages with SERMs (raloxifene)
- doesn’t inc risk of breast cancer
- doesn’t prevent hot flushes/menopause symptoms
2nd generation SERM
Lasofoxifene
What does raloxifene bind to in the nucleus of bone cells?
RRE - Raloxifene response element (bone)
difference betwen estradiol and raloxifene
ESTRADIOL (antagonist) - binds to ER - moves into nucleus - binds to ERE in breast tissue and switches on genes RALOXIFENE (agonist) - binds to ER - moves into nucleus of bones - binds to RRE (not present in breast tissue), helper proteins help with this
What does PTH do with bones?
stimulates intestinal absorption of Ca and promotes bone resorption
How does PTH stimulate resorption?
- osteoprogenitor cells become osteoclasts in presence of PTH (activates osteoclasts)
- promotes deep osteocytes to mobilise Ca
- surface of osteocytes are stimulated by PTH to increase the flow of Ca out of bone
biphasic effect of PTH
promotes bone resorption by binding to PTH1R
if given daily, promotes bone formation
How does PTH stimulate bone resorption?
increases osteoclastic activity through upregulation of RANKL
downregulation of OPG secretion by osteoblasts
How does PTH increase bone formation?
indirectly via autocrine and paracrine pathways through release of IGF-1, FGF-2 and amphiregulin from osteoblasts
PTH given intermittently (naturally)
binds to PTH1R on osteoclasts
-> breakdown of bone
PTH given continuously/daily
binds to PTH1R on osteoblasts
-> bone formation (osteogenesis)
How does Teriparatide work?
- activates PTHR
- activates osteoblasts - OPG stimulation, natural RANKL inhibitor
- decreases osteoclasts
When is Teriparatide used?
severe cases
brand name of teriparatide
Forteo
What does teriparatide do?
stimulates new bone formation
increased BMD
How is teriparatide given?
daily injections
not ORAL because it’s a hormone so it’s degraded by GIT
