Bone & Osteoporosis Flashcards
LO
- Know structural +cellular composition of bone
- Know risk factors for osteoporosis
- Understand fracture risk: clinical diagnosis + epidemiology
- Understand how current + emerging therapeutics work
- Think about challenges in development of novel drugs + learn how these are being addressed
bone is predominantly composed of what fibres that mineralise?
type I collagen woven into fibres
Describe the structure of bone.
- outside: cortical
- inside: trabecular/cancellous/spongy bone tissue
What is the role of trabecular bone?
provides strength w/o weight
cancellous/spongy bone tissue is ….
cellular, highly vascularised and continually remodelled
bone constantly remodelled and get new skeleton every…
10 years
the inner trabecular bone is spongy and allows bone to what?
bone to receive compressive force, then distribute it throughout so bone doesnt break
why is it important that bone tissue is highly vascularised?
as highly cellular
osteoclasts are formed from the fusion of monocytes (always circulating in blood and some enter bone tissue). They have between 12 and 20 nuclei. what is the lifespan?
12 days
osteoblasts produce new bone matrix that is then mineralised. what is this known as?
osteoid
what is the lifespan of an osteoblast?
2-100 days
what is the lifespan of an osteocyte?
up to 25 years
osteocyets are actually hugely interconnected by all what?
long dendrites…
stretch out through cannaliculi tunnels in bone tissue + cna reach each other
OR
cells on either side on bone, all way -> BV
5 stages of bone remodelling process?
- mechanical activation
- resorption
- reversal
- formation
- termination
describe bone remodelling process ()
- OC (cells buried within bone) detect damage… sense load/mciro dmaage + trigger removal of this + reform bone (e.g. running develop stronger bone where needed)
- OC start process + produce signals inc RANKL -> stim monocytes to become OC+ resorb bone
- new bone formed by OB
osteogenesis: balance between what 2 cells?
OB and OClasts
RANKL is secreted by osteoblasts and binds to X to on osteoclasts to activate them?
RANK receptor
osteoblasts also secrete OPG which acts as a decoy receptor for?
RANKL
balance of RANKL/OPG determines the degree of?
bone resorption (oc activity)
what factors/ mols influence Ob activity?
BMP
TGFb
IGF
FGF
PDGF
VEGF
WNT
when is peak bone mass attained?
and when does it start to decline
25
40
loss of bone mass with ageing affects M and F. but who is it accelerated in?
post-menopausal women
age related bone loss= normal until becomes pathological, then called what?
osteopenia/ osteoporosis
describe/ compare Ob vs Oc activity in
attaining bone mass
age related bone loss
more Ob than Oc
more Oc than Ob
whats osteoporosis?
loss of bone mass –> weaker bones
list some of the risk factors for developing osteoporosis?
- Age
- Female (estrogen)
- Menopause (hormone driven)
- Family Hx
- RA + IBD/Crohn’s (chronic inflammation + malabsorption)
- Nutrition: Low intake of calcium and Vitamin D
- Sedentary lifestyle
- Smoking, Alcohol, Caffeine
- corticosteroid treatment
why does menopause cause greater loss in bone mass?
estrogen controls Ob/Oc balance.
Est dec rapidly after menopause…. = Oc genesis = greater period of bone loss
what effect does a lack of bone loading have on bone density?
reduces
loss of bone mass seen in elderly and….
px following immobilisation (bedrest) / disuse following injury/ illness
physical activity causes mechanical loading of the bone. What effect does this have on bone synthesis?
promotes
what effect can increasing load bearing have on bone mineral density BMD and bone mineral content BMC?
increases
how can osteoporosis be diagnosed via examining bone mineral density following a fracture from a low impact fall for example?
DEXA scan
g/cm2
for most px, have osteoporosis without symptoms/ knowledge.
so how would they find out they have it?
most only know if get frcature caused by low impact fall
DEXA T score is the number of SD above or below a reference sample. What is the reference sample?
young healthy adult
What does a T score >1.0 SD indicate?
normal bone density
What does a T score between -1.0 and -2.5 SD indicate?
osteopenia
What does a T score ≤-2.5 SD indicate?
osteoporosis
What does a T score ≤-2.5 SD with 1 or more fragility fractures indicate?
severe osteoporosis
how do the trabecular differ between normal and osteoporotic bone?
osteoporotic bone has fewer and thinner trabecular`
loss of trabecular = loss of?
bone strength
What is the link between calcium absorption and bone mass?
reduced calcium absorption makes bones weaker and susceptible to fracture upon a fall
What are common osteoporosis fracture sites? 3
wrist, vertebrae, hip
what are neck of femur fractures (femoral head) associated with? and can they be repaired?
high morbidity.
no + require joint replacement surgery
What is the decision to treat osteoporosis based on?
Fracture risk scoring tool recommended by WHO known as FRAX
the FRAX tool is used when deciding whether to commence treatment for osteoporosis. What does the algorithm calculate?
based on?2
10 year probability of major osteoporotic fracture
based on BMD and clinical risk factors
What clinical risk factors is the FRAX tool based on?
- Age
- Gender
- BMI
- Previous fracture
- Family Hx
- Current smoker
- Glucocorticoid use
- RA
- Secondary osteoporosis
- Excessive alcohol intake
What are the 2 aims of osteoporosis drug therapy?
- increase BMD
- reduce fracture risk
what are the first line drug class used for the treatment of osteoporosis?
bisphosphonates
rationale behind using HRT for osteoporosis?
estrogen maintains bone mass, so HRT: used to delay loss of bone
HRT. SEs of taking estrogen/ progesterone for >5 years?
increased risk of breast cancer
stroke
CVD in post menopausal women
can be beneficial but due to these, not recommended as 1st line
targeted therapies for osteoporosis requires knowledge of what?
the cellular mechanisms that drive the disease pathology
What are the advantages to targeted therapies for osteoporosis?
- potential improved efficacy w reduced side effects
What are the disadvantages to targeted therapies for osteoporosis?
- requires knowledge of cellular mechanisms that drive disease pathology
- substantial investment, time and risk
What do newer targeted therapies aim to do? 2
- inhibit osteoclasts
- promote osteoblasts
Give some examples of bisphosphonates.
Alendronate
Ibandronate
Risedronate
Zoledronic acid (by IV infusion)
What drug class is alendronate?
Bisphosphonate
How do bisphosponates work?
- have high affinity to bone tissue to stick
- engulfed by osteoclasts during resorption triggering cell death
How long do bisphosphonates work for?
long half-life: 10 years
what is the setback of long term bisphos use?
increase microfracture as bone remodelling + repair prevented -> increased atypical femur fractures
2 possible atypical femur fractures that may be caused by long term bisphos use?
in femoral shaft
subtrochanteric femur fracture (below hip joint)
why do bisphos have horrible SEs?
blocking OC activity = can’t remodel bone + fix damage + remove old/weak bone
What patient advice should be given about oral bisphosphonates?
- taken orally
- how they work
- taken w plain water on empty stomach after overnight fast
- associated w GI/oesophageal irritation
- long-term use: atypical fracture risk, so report thigh, hip or groin pain
how can bisphos lead to osteonecrosis of the jaw? rare SE
reduced repair due to osteoclast inhibition ->tissue necrosis
what is osteonecrosis of the jaw usually triggered by?
oral infection
- tooth extraction -> inflammation/ bacterial infection
- normally cleared by osteoclasts but this inhibited by bisphos -> ONJ + tissue necrosis
What advice would you give a patient undergoing dental treatment on bisphosphonates?
- good oral hygiene: mouthwash, regular teeth brushing, flossing
- routine dental check-ups
- report oral symptoms of dental mobility, pain, swelling
How does osteonecrosis first appear?
as necrotic lesions
What is denosumab and how does it work?
new + emerging therapeutic: targets OC
mab which binds RANKL, similar to OPG + prevents binding to rank so inhibits activity of OC
3 examples of new + emerging therapeutic: targeting OC?
denosumab
saracatinib
odanacatib
How do bisphosphonates -> osteoclast apoptosis?
inhibits FPP synthase -> build up Apppl and which is cytotoxic… kills OC.
-> protein prenylation: ub post-translational modification process
another targeted therapy for osteoporosis = Ob targeting. explain
increase amount of bone mass to protect px from fracture
Overview of osteoblast maturation
proliferation (Ob derived form MSC mesenchymal stem cells)
commitment: early Ob
late Ob: MAR, BFR. can form bone + mineralise that bone
… some mature further -> Ocytes. can have RANKL, OPG + Ob inhibiting factors: DKK1, Sclerostin
How can parathyroid hormone PTH be helpful in bone formation?
encourages MSC to specialise -> osteoblasts, mature, inhibit inhibitors of Ob on osteocytes,
inhibit sclerostin action - inhibits bone formation
very ideal… now become a drug!
How does PTH affect osteogenesis? ie what does it drive
drives osteoblast differentiation process
What is the fate of a mesenchymal stem cell?
Proliferates -> early osteoblasts + commits to form late osteoblasts and some go further -> become osteocytes that can produce RANKL + OPG but also others like sclerostin which can also inhibit osteoblasts from forming bone
PTH encourages what 2 process in osteoblast differentiation process… and inhibit which one?
proliferation + commitment
blokc final extra stage + sclerostin
What drug is based on how PTH affects osteogenesis?
teriparitide
How does teriparitide work? How is it administered?
- synthetic PTH (bone anabolic) that stimulates osteoblast activity
- SC injection
What is the limitation of teriparitide?
- only effective for 18 months
- should be followed by anti-resorptive e.g. bisphosphonate (after bone boost, maintain that)
(also SC saily, hard to amdin and expensive)
why is teriparitide given for 18 months only?
cancer risk
(as with any drug that inc differentn)
Apart from PTH, what else affects the maturation of an osteoblast?
Wnt
How does Wnt compare to PTH in terms of promoting bone formation?
boosts inhibitions of Ob differentiation like sclerostin and Dkk1
problem with Wnt signalloing pathway to target Ob?
has lots of complex effects
can also boost inhibs of Ob differentiation
(so not as helpful as PTH)
2 inhibitors OF Wnt
- sclerostin
- DKK1
cells Wnt inhibits?
adipocyte
chondrocyte
Why is it not helpful to give Wnt as an additional drug when it exists naturally in the body?
Like PTH, it can encourage osteoblast activity but also enhances the inhibitors of osteoblasts like Sclerostin
Summarise the canonical and non-canonical pathway of Wnt.
p242 email if need detail??
Wnt synthesised and secreted from cells, and then:
- non-canonical: binds to FZD enhancing LRP5/6 expression
- canonical: LRP5/6 now can bind to FZD -> upregulation of osteoblast specific genes. induces bone formation )OPG expression + differentiation)
summary: non-canonical pathway upregulates receptor needed for signalling in canonical pathway for bone formation
name 2 developed antibodies to Wnt
AMG-785
(BHQ-880)
AMG 785 / romosozumab is a monoclonal antibody against sclerostin. It prevents the inhibition of wnt. What effect does this have on bone formation?
increased bone formation
name 2 bone repsorption biomarkers ()
PINP
CTX
how is modelling of bone cell in vitro done?
Obs seeded into culture plate
- OPG +RANKL secretion (measured by ELISA) + balance between the 2
- quantification of mineralised bone modules - stained with Alizarin red
how to view resorption pattern of OClast in vitro?
… to see Oc, get monocytes form blood… differentiate in presence of RANKL -> OC
osteocyte funciton = mechanosensing. what 2 things do they sense?
strain and stress
(thorugh dendrites)
Osteoporosis SGT ———————–
does DEXA (bone density/mineral) score of T-score -2.9 ( lumbar spine) and -1.5 (femoral neck) indicate osteoporosis? what do they specifically indicate?
yes
osteopenia in both. femoral neck: -1 to -2.5
what tool used for
diagnosis
treatment
DEXA used for diagnosis
FRAX for treatment, takes other factors into risk too. Calcs predicted risk of major o frac/ hip frac
10 year fracture risk calculated with FRAX algorithm is 17% and 3.9% for major osteoporotic and hip fractures.
is this high?
Above 20% is high for osteoporotic fracture score.
Above 20 for treatment and above 3% or hip fracture score.
What advice should the patient have been given about use of alendronic acid?
bisphosphonate
* Oral bisphosphonates are poorly absorbed so should be taken with plain water on an empty stomach (after overnight fast)
* Oral bisphosphonates often associated with oesophageal irritation/ GI symptoms
* Long term use of bisphosphonates associated with atypical fractures of femur after minimal/ no trauma
* Px on bisphosphonates should have regular dental check ups and dentist should be made aware
* (Renal toxicity= recognised adverse reaction associated with IV bisphosphonates)
what does alendronic do?
Prevents action of osteoclasts (bone breakdown) causes death of oc.
* OsteoClasts: Consume bone
* OsteoBlast: Build bone
reason for osteolytic lesion with periosteal thickening suggestive of osteonecrosis and osteomyelitis. px on bisphos
Osteonecrosis: death of bone tissue
Osteomyelitis: inflammation associated with infection. Specifically bone
Likely (ONJ). possible occurrence for px on bisphosphonates following dental surgery
OC: derived from monocytes. Enter bone then differentiate. Similar role to macrophages (maintain homeostasis in tissue and eat up death of tissue/ infection)
Still have homeostatic function, disrupted by bisphosphonates
ONJ is characterised by what?
difficulty in eating eating/ speaking, mouth pain and bone necrosis
cause of ONJ?
high dose IV bisphosphonates
Alendronate: oral bisphos + rarer for ONJ to occur
Critically though, one of the known risk factors for ONJ is dental treatment. So likely that the combination or dental extraction and oral bisphos therapy -> ONJ.
More likely to be caused by IV bisphosphonates but still possible esp w drug + dental treatment —> osteopathic lesion
what do Bisphosphonates promote ?
osteoclast apoptosis. -> insufficient repair/ remodelling of bone e.g. delayed wound healing, lack of clearance of necrotic tissue and bacteria.
advice for px with ONJ?
Good oral hygiene to prevent it happening again: mouth wash, regular brushing of teeth, flossing
Routine dental check ups while still on med and report issues/ oral symptoms: dental mobility, pain, swelling
Non surgical removal of neurotic tissue
Treat with growth factors to promote healing
Can last many years after taking it. Binds to bone then eaten by OC. Drug
Risk of osteoporosis made worse. Longer action
Better to manage dental problems than stop treatment
DEXA scan showed a T score of -2.8 at the left hip and lumbar spine T score of -2.6.
What is the diagnosis?
even lower = osteoporosis
osteoporotic + pain in mid thigh likely cause?
atypical femoral fracture
Generally without trauma, side effect of alendronate.
difference between Vitamin D and Alendronic Acid , managing OP
Vit D: naturally occurring vitamin.
Aa prevents bone breakdown and Vit D supports formation.
= complementary
Vit D = non-pharmacological therapy, hm units a day are considered safe?
1000-1200 units/ day considered safe
Vit D aids absorption of calcium from gut, so promote…
bone mineralisation and bone strength.
increase of bone mineral density, a decrease of bone turnover and decrease of fracture incidence
Alendronic acid prevents bone resorption by inhibiting what?
osteoclast function
Vit D and Ca often taken alongside bisphosphonates to increase what
drug effectiveness
DEXA informative with regards to biological diagnosis of osteoporosis i.e. determining T score.
But decision to commence pharmacological therapy is based on what?
fracture risk (FRAX tool) which also takes account of other clinical risk factors
how often is DEXA done?
not usually repeated more than once every 2 years.
what drug and conditions may promote OP?
Glucocorticoids and RA etc inflamm conditions
There’s a risk that px who take bisphosphonates for >5 years will develop …
atypical fractures in femur
Given occurrence of an atypical fracture this lady should discuss with her clinician alternative therapies to bisphosphonates, such as ?
Denosumab
what does Lansoprazole do?
PPI decreases acidity as H+ ions Don’t enter stomach
used for gastric reflux
what drug with long term sue is a risk factor for OP?
Corticosteroid eg prednisolone
what does blood test: ESR show?
how quick RBC sediment out
10 = in rnage
2 measures of inflammation
ESR and CRP
Dexa scan T score of -2.6 (left hip) and T score of -3.2 (Lumbar spine).
Is this lady at risk of a fracture?
T of under minus 2.5 and above 3 lumbar spine = OP
3 clinical risk factors for osteoporosis
o Long term use of corticosteroid treatment
o Female gender
o Chronic inflammatory conditions (SLE and rheumatoid arthritis)
Lansoprazole: rare but serious possible SE of developing …
subacute cutaneous lupus erythematosus may worsen symptoms of lupus.
Can increase risk of fractures
high risk of frac from chronic infl. Disease + corticosteroids. Further inc risk of
fracture
