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Health 31 > Bone & Osteoporosis > Flashcards

Bone & Osteoporosis Flashcards

1
Q

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

A
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2
Q

bone is predominantly composed of what fibres that mineralise?

A

type I collagen woven into fibres

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3
Q

Describe the structure of bone.

A
  • outside: cortical
  • inside: trabecular/cancellous/spongy bone tissue
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4
Q

What is the role of trabecular bone?

A

provides strength w/o weight

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5
Q

cancellous/spongy bone tissue is ….

A

cellular, highly vascularised and continually remodelled

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6
Q

bone constantly remodelled and get new skeleton every…

A

10 years

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7
Q

the inner trabecular bone is spongy and allows bone to what?

A

bone to receive compressive force, then distribute it throughout so bone doesnt break

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8
Q

why is it important that bone tissue is highly vascularised?

A

as highly cellular

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9
Q

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?

A

12 days

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10
Q

osteoblasts produce new bone matrix that is then mineralised. what is this known as?

A

osteoid

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11
Q

what is the lifespan of an osteoblast?

A

2-100 days

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12
Q

what is the lifespan of an osteocyte?

A

up to 25 years

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13
Q

osteocyets are actually hugely interconnected by all what?

A

long dendrites…
stretch out through cannaliculi tunnels in bone tissue + cna reach each other
OR
cells on either side on bone, all way -> BV

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14
Q

5 stages of bone remodelling process?

A
  1. mechanical activation
  2. resorption
  3. reversal
  4. formation
  5. termination
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15
Q

describe bone remodelling process ()

A
  1. 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)
  2. OC start process + produce signals inc RANKL -> stim monocytes to become OC+ resorb bone
  3. new bone formed by OB
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16
Q

osteogenesis: balance between what 2 cells?

A

OB and OClasts

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17
Q

RANKL is secreted by osteoblasts and binds to X to on osteoclasts to activate them?

A

RANK receptor

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18
Q

osteoblasts also secrete OPG which acts as a decoy receptor for?

A

RANKL

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19
Q

balance of RANKL/OPG determines the degree of?

A

bone resorption (oc activity)

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20
Q

what factors/ mols influence Ob activity?

A

BMP
TGFb
IGF
FGF
PDGF
VEGF
WNT

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21
Q

when is peak bone mass attained?
and when does it start to decline

A

25
40

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22
Q

loss of bone mass with ageing affects M and F. but who is it accelerated in?

A

post-menopausal women

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23
Q

age related bone loss= normal until becomes pathological, then called what?

A

osteopenia/ osteoporosis

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24
Q

describe/ compare Ob vs Oc activity in
attaining bone mass
age related bone loss

A

more Ob than Oc

more Oc than Ob

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25
Q

whats osteoporosis?

A

loss of bone mass –> weaker bones

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26
Q

list some of the risk factors for developing osteoporosis?

A
  • 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
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27
Q

why does menopause cause greater loss in bone mass?

A

estrogen controls Ob/Oc balance.
Est dec rapidly after menopause…. = Oc genesis = greater period of bone loss

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28
Q

what effect does a lack of bone loading have on bone density?

A

reduces

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29
Q

loss of bone mass seen in elderly and….

A

px following immobilisation (bedrest) / disuse following injury/ illness

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30
Q

physical activity causes mechanical loading of the bone. What effect does this have on bone synthesis?

A

promotes

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31
Q

what effect can increasing load bearing have on bone mineral density BMD and bone mineral content BMC?

A

increases

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32
Q

how can osteoporosis be diagnosed via examining bone mineral density following a fracture from a low impact fall for example?

A

DEXA scan
g/cm2

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33
Q

for most px, have osteoporosis without symptoms/ knowledge.
so how would they find out they have it?

A

most only know if get frcature caused by low impact fall

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34
Q

DEXA T score is the number of SD above or below a reference sample. What is the reference sample?

A

young healthy adult

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35
Q

What does a T score >1.0 SD indicate?

A

normal bone density

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36
Q

What does a T score between -1.0 and -2.5 SD indicate?

A

osteopenia

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37
Q

What does a T score ≤-2.5 SD indicate?

A

osteoporosis

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38
Q

What does a T score ≤-2.5 SD with 1 or more fragility fractures indicate?

A

severe osteoporosis

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39
Q

how do the trabecular differ between normal and osteoporotic bone?

A

osteoporotic bone has fewer and thinner trabecular`

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40
Q

loss of trabecular = loss of?

A

bone strength

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41
Q

What is the link between calcium absorption and bone mass?

A

reduced calcium absorption makes bones weaker and susceptible to fracture upon a fall

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42
Q

What are common osteoporosis fracture sites? 3

A

wrist, vertebrae, hip

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43
Q

what are neck of femur fractures (femoral head) associated with? and can they be repaired?

A

high morbidity.

no + require joint replacement surgery

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44
Q

What is the decision to treat osteoporosis based on?

A

Fracture risk scoring tool recommended by WHO known as FRAX

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45
Q

the FRAX tool is used when deciding whether to commence treatment for osteoporosis. What does the algorithm calculate?

based on?2

A

10 year probability of major osteoporotic fracture
based on BMD and clinical risk factors

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46
Q

What clinical risk factors is the FRAX tool based on?

A
  • Age
  • Gender
  • BMI
  • Previous fracture
  • Family Hx
  • Current smoker
  • Glucocorticoid use
  • RA
  • Secondary osteoporosis
  • Excessive alcohol intake
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47
Q

What are the 2 aims of osteoporosis drug therapy?

A
  • increase BMD
  • reduce fracture risk
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48
Q

what are the first line drug class used for the treatment of osteoporosis?

A

bisphosphonates

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49
Q

rationale behind using HRT for osteoporosis?

A

estrogen maintains bone mass, so HRT: used to delay loss of bone

50
Q

HRT. SEs of taking estrogen/ progesterone for >5 years?

A

increased risk of breast cancer
stroke
CVD in post menopausal women

can be beneficial but due to these, not recommended as 1st line

51
Q

targeted therapies for osteoporosis requires knowledge of what?

A

the cellular mechanisms that drive the disease pathology

52
Q

What are the advantages to targeted therapies for osteoporosis?

A
  • potential improved efficacy w reduced side effects
53
Q

What are the disadvantages to targeted therapies for osteoporosis?

A
  • requires knowledge of cellular mechanisms that drive disease pathology
  • substantial investment, time and risk
54
Q

What do newer targeted therapies aim to do? 2

A
  • inhibit osteoclasts
  • promote osteoblasts
55
Q

Give some examples of bisphosphonates.

A

Alendronate

Ibandronate

Risedronate

Zoledronic acid (by IV infusion)

56
Q

What drug class is alendronate?

A

Bisphosphonate

57
Q

How do bisphosponates work?

A
  • have high affinity to bone tissue to stick
  • engulfed by osteoclasts during resorption triggering cell death
58
Q

How long do bisphosphonates work for?

A

long half-life: 10 years

59
Q

what is the setback of long term bisphos use?

A

increase microfracture as bone remodelling + repair prevented -> increased atypical femur fractures

60
Q

2 possible atypical femur fractures that may be caused by long term bisphos use?

A

in femoral shaft
subtrochanteric femur fracture (below hip joint)

61
Q

why do bisphos have horrible SEs?

A

blocking OC activity = can’t remodel bone + fix damage + remove old/weak bone

62
Q

What patient advice should be given about oral bisphosphonates?

A
  • 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
63
Q

how can bisphos lead to osteonecrosis of the jaw? rare SE

A

reduced repair due to osteoclast inhibition ->tissue necrosis

64
Q

what is osteonecrosis of the jaw usually triggered by?

A

oral infection

  • tooth extraction -> inflammation/ bacterial infection
  • normally cleared by osteoclasts but this inhibited by bisphos -> ONJ + tissue necrosis
65
Q

What advice would you give a patient undergoing dental treatment on bisphosphonates?

A
  • good oral hygiene: mouthwash, regular teeth brushing, flossing
  • routine dental check-ups
  • report oral symptoms of dental mobility, pain, swelling
66
Q

How does osteonecrosis first appear?

A

as necrotic lesions

67
Q

What is denosumab and how does it work?

A

new + emerging therapeutic: targets OC

mab which binds RANKL, similar to OPG + prevents binding to rank so inhibits activity of OC

68
Q

3 examples of new + emerging therapeutic: targeting OC?

A

denosumab
saracatinib
odanacatib

69
Q

How do bisphosphonates -> osteoclast apoptosis?

A

inhibits FPP synthase -> build up Apppl and which is cytotoxic… kills OC.

-> protein prenylation: ub post-translational modification process

70
Q

another targeted therapy for osteoporosis = Ob targeting. explain

A

increase amount of bone mass to protect px from fracture

71
Q

Overview of osteoblast maturation

A

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

72
Q

How can parathyroid hormone PTH be helpful in bone formation?

A

encourages MSC to specialise -> osteoblasts, mature, inhibit inhibitors of Ob on osteocytes,

inhibit sclerostin action - inhibits bone formation

very ideal… now become a drug!

73
Q

How does PTH affect osteogenesis? ie what does it drive

A

drives osteoblast differentiation process

74
Q

What is the fate of a mesenchymal stem cell?

A

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

75
Q

PTH encourages what 2 process in osteoblast differentiation process… and inhibit which one?

A

proliferation + commitment

blokc final extra stage + sclerostin

76
Q

What drug is based on how PTH affects osteogenesis?

A

teriparitide

77
Q

How does teriparitide work? How is it administered?

A
  • synthetic PTH (bone anabolic) that stimulates osteoblast activity
  • SC injection
78
Q

What is the limitation of teriparitide?

A
  • 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)

79
Q

why is teriparitide given for 18 months only?

A

cancer risk
(as with any drug that inc differentn)

80
Q

Apart from PTH, what else affects the maturation of an osteoblast?

A

Wnt

81
Q

How does Wnt compare to PTH in terms of promoting bone formation?

A

boosts inhibitions of Ob differentiation like sclerostin and Dkk1

82
Q

problem with Wnt signalloing pathway to target Ob?

A

has lots of complex effects
can also boost inhibs of Ob differentiation
(so not as helpful as PTH)

83
Q

2 inhibitors OF Wnt

A
  • sclerostin
  • DKK1
84
Q

cells Wnt inhibits?

A

adipocyte
chondrocyte

85
Q

Why is it not helpful to give Wnt as an additional drug when it exists naturally in the body?

A

Like PTH, it can encourage osteoblast activity but also enhances the inhibitors of osteoblasts like Sclerostin

86
Q

Summarise the canonical and non-canonical pathway of Wnt.
p242 email if need detail??

A

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

87
Q

name 2 developed antibodies to Wnt

A

AMG-785
(BHQ-880)

88
Q

AMG 785 / romosozumab is a monoclonal antibody against sclerostin. It prevents the inhibition of wnt. What effect does this have on bone formation?

A

increased bone formation

89
Q

name 2 bone repsorption biomarkers ()

A

PINP
CTX

90
Q

how is modelling of bone cell in vitro done?

A

Obs seeded into culture plate

  • OPG +RANKL secretion (measured by ELISA) + balance between the 2
  • quantification of mineralised bone modules - stained with Alizarin red
91
Q

how to view resorption pattern of OClast in vitro?

A

… to see Oc, get monocytes form blood… differentiate in presence of RANKL -> OC

92
Q

osteocyte funciton = mechanosensing. what 2 things do they sense?

A

strain and stress

(thorugh dendrites)

93
Q

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?

A

yes
osteopenia in both. femoral neck: -1 to -2.5

94
Q

what tool used for
diagnosis
treatment

A

DEXA used for diagnosis
FRAX for treatment, takes other factors into risk too. Calcs predicted risk of major o frac/ hip frac

95
Q

10 year fracture risk calculated with FRAX algorithm is 17% and 3.9% for major osteoporotic and hip fractures.
is this high?

A

Above 20% is high for osteoporotic fracture score.
Above 20 for treatment and above 3% or hip fracture score.

96
Q

What advice should the patient have been given about use of alendronic acid?

A

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)

97
Q

what does alendronic do?

A

Prevents action of osteoclasts (bone breakdown) causes death of oc.
* OsteoClasts: Consume bone
* OsteoBlast: Build bone

98
Q

reason for osteolytic lesion with periosteal thickening suggestive of osteonecrosis and osteomyelitis. px on bisphos

A

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

99
Q

ONJ is characterised by what?

A

difficulty in eating eating/ speaking, mouth pain and bone necrosis

100
Q

cause of ONJ?

A

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

101
Q

what do Bisphosphonates promote ?

A

osteoclast apoptosis. -> insufficient repair/ remodelling of bone e.g. delayed wound healing, lack of clearance of necrotic tissue and bacteria.

102
Q

advice for px with ONJ?

A

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

103
Q

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?

A

even lower = osteoporosis

104
Q

osteoporotic + pain in mid thigh likely cause?

A

atypical femoral fracture
Generally without trauma, side effect of alendronate.

105
Q

difference between Vitamin D and Alendronic Acid , managing OP

A

Vit D: naturally occurring vitamin.
Aa prevents bone breakdown and Vit D supports formation.
= complementary

106
Q

Vit D = non-pharmacological therapy, hm units a day are considered safe?

A

1000-1200 units/ day considered safe

107
Q

Vit D aids absorption of calcium from gut, so promote…

A

bone mineralisation and bone strength.

increase of bone mineral density, a decrease of bone turnover and decrease of fracture incidence

108
Q

Alendronic acid prevents bone resorption by inhibiting what?

A

osteoclast function

109
Q

Vit D and Ca often taken alongside bisphosphonates to increase what

A

drug effectiveness

110
Q

DEXA informative with regards to biological diagnosis of osteoporosis i.e. determining T score.
But decision to commence pharmacological therapy is based on what?

A

fracture risk (FRAX tool) which also takes account of other clinical risk factors

111
Q

how often is DEXA done?

A

not usually repeated more than once every 2 years.

112
Q

what drug and conditions may promote OP?

A

Glucocorticoids and RA etc inflamm conditions

113
Q

There’s a risk that px who take bisphosphonates for >5 years will develop …

A

atypical fractures in femur

114
Q

Given occurrence of an atypical fracture this lady should discuss with her clinician alternative therapies to bisphosphonates, such as ?

A

Denosumab

115
Q

what does Lansoprazole do?

A

PPI decreases acidity as H+ ions Don’t enter stomach
used for gastric reflux

116
Q

what drug with long term sue is a risk factor for OP?

A

Corticosteroid eg prednisolone

117
Q

what does blood test: ESR show?

A

how quick RBC sediment out
10 = in rnage

118
Q

2 measures of inflammation

A

ESR and CRP

119
Q

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?

A

T of under minus 2.5 and above 3 lumbar spine = OP

120
Q

3 clinical risk factors for osteoporosis

A

o Long term use of corticosteroid treatment
o Female gender
o Chronic inflammatory conditions (SLE and rheumatoid arthritis)

121
Q

Lansoprazole: rare but serious possible SE of developing …

A

subacute cutaneous lupus erythematosus may worsen symptoms of lupus.
Can increase risk of fractures

122
Q

high risk of frac from chronic infl. Disease + corticosteroids. Further inc risk of

A

fracture

Health 31 (16 decks)

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