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Human Diseases > W8 35 bisphosphonates > Flashcards

W8 35 bisphosphonates Flashcards

1
Q

What are the different structured groups of bisphosphonates?

A
  1. Non-nitrogen bisphosphonate
  2. Alkyl-amino bisphosphonates
  3. Heterocyclic nitrogen bisphosphonates
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2
Q

Give examples of non-nitrogen bisphosphonates and describe the mode of action

A

Clodronate, etidronate, tiludronate
Incorporates into ATP, resulting osteoclast apoptosis

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3
Q

Give examples of alkyl-amino bisphosphonates and describe the mode of action

A

Pamidronate, alendronate, ibandronate
Inhibits the enzyme FPPS

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4
Q

Give examples of heterocyclic nitrogen bisphosphonates and describe the mode of action

A

Risedronate, zoledronate
Inhibits the enzymes FPPS

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5
Q

How can you increase absorption of bisphosphonates?

A

Absorption can be increased by adding cyclic nitrogen or an amino terminal onto the R2 side

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6
Q

Which bisphosphonates are not really used anymore?

A

Non-nitrogen bisphosophonates are less potent and not used that often - they do not cause MRONJ!

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7
Q

What is the affinity of bisphosphonates for bone?

A

Bisphosphonates have a high affinity for calcium ions and are strongly attracted to bone. They are released from the surface of bone (which is acidified) and taken up by osteoclasts. Osteoclasts can take up a lot of bisphosphonates.

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8
Q

What is protein prenylation?

A

Protein prenylation is important in osteoclastic activities and for the osteoclasts to survive. Bisphosphonates target protein prenylation.

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9
Q

What is the mevalonate pathway?

A

Key in cellular processes like cholesterol/cell growth
HMG CoA -> mevalonate -> FPP -> GPP
Mevalonate to FPP requires FPP synthase

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10
Q

How do nitrogen bisphosphonates inhibit bone resorption?

A

They attach to bone so that when an osteoclast comes along, they are internalised by the osteoclast. Once inside, the bisphosphonate induces a series of changes that cause the osteoclasts to detach from the bone (so can no longer adhere to bone) and undergo apoptosis of the osteoclast.

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11
Q

Bisphosphonates inhibit farnesyl pyrophosphate (FPP) synthase. How does this affect and help inhibit bone resorption?

A

FPP synthase allows cholesterol formation in the mevalonate pathway. Inhibiting FPPS means the lipids needed by the osteoblasts to manufacture and maintain its cell membrane are not available.
These lipids are needed for normal osteoclast functions allowing it to adhere and migrate along the bone surface. Hence blocks bone resorption.

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12
Q

Which bisphosophates are taken orally and how often?

A

Alendronate - daily/weekly
Risedronate - weekly
Clodronate - daily
Ibandronate - monthly

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13
Q

Which bisphosphonates are administered via IV and how often?

A

Zolendronate - 1x a year for osteoporosis, or for cancer
Ibandronate - 3x monthly
Pamidronate - given as required usually for hypercalcaemia as required (not licensed for osteoporosis, also poorly absorbed orally)

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14
Q

What’s the difference between zoledronate for osteoporosis and for cancer?

A

Zoledronate dose is much highly monthly doses in cancer patients

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15
Q

What bisphosphonates are used in Paget’s?

A

Zoledronate and Pamidronate

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16
Q

Which bisphosphonate is the most potent?

A

Zolendronate - cautious monitoring this and be aware of MRONJ

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17
Q

What is zeta potential and what does this mean for bisphosphonates?

A

Zeta potential is how positively charged the bisphosphonate is
- the more positively charged means there will be deeper infiltration into bone so attach more bisphosphonates onto the molecules (increasing max binding capacity of bisphosphonates to bone)

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18
Q

What is the nitrogen bisphosphonate triangle?

A

Binding to bone
Zeta potential
Inhibition of enzyme FPPS

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19
Q

Individual properties of each type of bisphosphonate mean differing potencies and resulting effects on bone. Give examples of this.

A

Risedronate has a lower kinetic binding to bone but high FPPS inhibition ability, do can be used in similar clinical doses to alendronate
Zolendronate has high kinetic binding to bone and high inhibition to FPPS, so highly effective anti-resorption drug

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20
Q

What is another property of bisphosphonayes that use used for cancer patients?

A

Bisphosphonayes have an anti-angiogenesis property. Useful because sometimes (eg Zolendronate) in high doses to cancer patients will stop tumour growth and blood vessels to the tumour.

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21
Q

Bone remodelling brief description

A

A balance between osteoclast and osteoblast activity
Tipped in favour of osteoclasts in osteoporosis, with net bone loss

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22
Q

What is osteoporosis?

A

Osteoporosis is a skeletal disorder characterised by compromised bone strength, predisposing a person to an increased risk of fracture.

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23
Q

What is bone strength determined by?

A

Bone quality (architecture, damage accumulation and bone turnover) AND bone density

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24
Q

How might bone quality be deteriorated and what does this cause?

A

Architectural abnormalities, trabecular thinning and loss of trabecular connectivity
This microarchitectural deterioration may particularly increase the risk of vertebral fracture, since trabecular bone dominates in the vertebra

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25
Q

What are the consequences of osteoporosis?

A

Osteoporosis can result in fracture such as hip, wrist, vertebrae

26
Q

What is the relationship between bone turnover and bone strength (GRAPH PG363)

A

An inverted ‘U’ shaped curve - accelerated (excessive) turnover (far RHS) and absent (insufficient) bone turnover (far LHS)

27
Q

Why is accelerated/excessive turnover of bone bad?

A

It increases bone fragility because of osteoid matrix accumulation, decreased time for adequate mineralisation, and increased remodeling sites that cause temporarily weakened focal lesions in the trabeculae.
Associated with osteonecrosis of the external auditory canal.

28
Q

Why is absent/insufficient turnover (far LHS) bad?

A

Some minimal amount of remodeling is necessary to repair taigue micro damage, replace old or dead osteocytes and restore bone hydration. Can decrease bone strength potentially causing MRONJ.

29
Q

What are the uses of bisphosphonates?

A

Osteoporosis
Skeletal events associated with metastatic cancer eg breast/prostate/lung/multiple myeloma
Osteogenesis imperfects
Paget’s disease
Hypercalcaemia
Skeletal complications in cystic fibrosis
Primary hyperparathyroidism
Bone cancers eg ewings sarcoma

30
Q

What category of people have a higher risk of osteoporosis?

A

Higher in post-menopausal women as the oestrogen is less. Oestrogen keeps osteoclasts in check.

31
Q

How do bisphosphonates help cancers?

A

A lot of cancers metastasise to the skeleton, which can cause nerve compression and pain associated with this. Secondary osteoporosis needs to be prevented as can cause fractures.

32
Q

What is MRONJ?

A

MRONJ is defined as exposed bone, or bone that can be probed through an intraoral or extra oral fistula, in the maxillofacial region that has persisted for more than eight weeks in patients with a history of treatment with anti-resorptive or anti-angiogenic drugs, and where there has been no history of radiation therapy to the jaw or no obvious metastatic disease to the jaws.

33
Q

What areas are more at risk of MRONJ (exostoses-increased bone mineral density)?

A

Lingual tori
Mylohyoid ridge
Palatal tori
Familial
Mandible > maxilla
Possibly at a higher risk of MRONJ due to poor blood supply to these areas if taking bisphosphonates

34
Q

What is denosumab?

A

Denosumab is a monoclonal antibody. Can target specific antigens. (Doses are much higher in cancer patients). Does same job as OPG (osteoprotegerin)

35
Q

What is the RANK/RANKL/OPG concept?

A

On the surface of the osteoclasts is a RANK receptor. For the osteoclasts to function, RANK receptor has to be stimulated by the RANK ligand.
The body has a decoy receptor called OPG which mops up excess ligand to stop the osteoclasts from over functioning.
Denosumab does the same job as OPG, so inhibits osteoclasts.

36
Q

What is the difference between denusomab and bisphosphonates?

A

Denusomab doesn’t bind to bone like bisphosphonates, effect is lost quickly after 9 months.
Bisphosphonates stay in bone longer eg alendronate (10yrs half life) and zoledronate can bind to the bone for many years
(thus need full history of drugs even if taken years ago)

37
Q

What is the speed of effect of IV vs oral bisphosphonates?

A

IV bisphosphonates enter quickly into the target and are highly effective. Oral bisphosphonates will gradually accumulation into the bone.

38
Q

Who is at a higher risk of MRONJ - patients taking oral bisphosphonates for osteoporosis or cancer patients taking IV?

A

Risk of MRONJ is lower in patients taking oral bisphosphonates for osteoporosis than in cancer patients taking IV bisphosphonates.

39
Q

What are some monoclonal Abs associated with MRONJ? - pg366 for uses of each

A

(Names end in mabs)
Denusomab
Bevacizumab, adalimumab, rituximab, infliximab

40
Q

What are some tyrosine kinase inhibitors that are associated with MRONJ? - pg367 for uses

A

(Named end in nib)
Sunitinib, sorafenib, imatinib
Mainly for cancers

41
Q

What do tyrosine kinase inhibitors do?

A

Affect tumour regulatory proteins, cell signals, proliferation and metastasis. They are anti-angiogenic (stopping tumour growth)

42
Q

What are some MTOR inhibitors associated with MRONJ?

A

(Names end in limus)
Sirolimus, everolimus
Mainly for cancers

43
Q

What do MTOR inhibitors do?

A

These effect cell growth/blood vessels of tumours

44
Q

What are some fusion proteins associated with MRONJ?

A

(Names end in cept)
Aflibercept for cancer

45
Q

What action do fusion proteins have?

A

Anti-antigenic action, and target the blood supply to the growing tumour blood vessels

46
Q

Which patients are MRONJ risks higher in?

A

Doses of bisphosphonates and denusomab are much higher in malignancy compared to osteoporosis patients so MRONJ risk is higher.

47
Q

What can the addition of corticosteroids to the medication regime do?

A

Other patient factors in malignancy are immune compromised, poorer healing etc. so might add corticosteroids to the medication regime, but these can give secondary osteoporosis, weakening the bone structure further. Bisphosphonates are useful in helping prevent secondary osteoporosis.

48
Q

What are the signs and symptoms of MRONJ?

A

Delayed healing
Pain
Swelling/tissue infection
Numbness/tingling/altered sensation/parasthesia
Exposed bone
(the above occur following dental extraction or oral surgery procedure but can rarely be spontaneous)

49
Q

What are the 4 stages of MRONJ?

A

0 - no exposed bone (1-3 all have exposed bone)
1 - exposed bone and no symptoms
2 - pain and infection
3 - more severe and extensive case of MRONJ, bone loss can extend to the floor of the maxillary sinus or inferior border of the mandible - may need jaw resection/reconstruction.

50
Q

What is stage 0, the non-exposed variant of MRONJ?

A

Where MRONJ does not show the classical definition of MRONJ (ie 8 week time frame of exposure). There have been cases where MRONJ has taken over 4 months to occur from the time of trauma.

51
Q

What are the differential diagnosis’s of MRONJ (that need to be ruled out first)?

A

Metastasis
Osteomyelitis arising from dental origin
Periodontal infection
Alveolar osteitis (dry socket)
Sinusitis (if upper tooth)
Temporomandibular joint disorder
Idiopathic benign sequestration of the mandible (rare)

52
Q

What is osteomyelitis?

A

Marrow space infection

53
Q

What timeframe puts someone at higher risk of developing MRONJ?

A

Taking oral bisphosphonates for more than 5 years becomes higher risk

54
Q

What should you try to do dentally for patients on bisphosohonates or denusomab?

A

Try to maintain dentition and avoid extractions with patients. Do as much of this treatment needed before patients start these drugs.

55
Q

Should you give implants in patients with high dose antiresorptives or antiangiogenic medication?

A

Avoid implants in patients being treated for cancer with high dose antiresoprtives or antiangiogenic medications. Can get MRONJ due to implant placement. (fine if placing before treatment starts).

56
Q

Should you use antibiotics in patients at a high risk of MRONJ?

A

Do not use antibiotic cover, because if you have MRONJ, immunity is lower and resistance might occur

57
Q

In bisphosphonate patients you should review the XLA site. What should you do if the extraction site is not healing at 8 weeks?

A

Refer!

58
Q

What should you do if your risk assessment shows that an extraction is necessary eg in malignancy patients?

A

Refer it.
(refer to SDCEP guidelines)

59
Q

To summarise, which patients are at a higher risk of MRONJ?

A
  1. Previous diagnosis of MRONJ
  2. On systemic corticosteroids in addition to bisphosphonate / or 9 months plus denosumab therapy
  3. On anti-resorptives or anti-angiogenic drugs for cancer management
  4. On oral bisphosphonates for >5yrs
    (?diabetes, ?smoking reduced healing - blood flow affected)
60
Q

Why is it essential to use bisphosphonayes and anti-angiotensin drugs?

A

Essential in reduction of nerve compression pain as well as possible reduction in the spread of metastic cancer in bone, and prevention of fragility fractures.

Human Diseases (75 decks)

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