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MSK Week 7 > 2.7.2. Biphosphonates and Vitamin D > Flashcards

2.7.2. Biphosphonates and Vitamin D Flashcards

1
Q

What does the drug Raloxifene do?

A

It is a type of SERM or selective estrogen receptor modulators

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2
Q

What does the drug Alendronate do?

A

a type of bisphosphonate

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3
Q

What does the drug Denosumab do?

A

a type of RANKL antibody

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4
Q

What does the drug Teriparatide do?

A

a type of synthetic PTH (just the active portion of the peptide)

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5
Q

Explain the synthetic pathway by which Vitamin D increases serum Calcium levels

A
  1. sunlight (UV) converts 7-dehydrocholesterol to cholecalciferol (Vit D) in the skin
  2. in the liver, Vit D is hydroxylated at the 25 position by 25-hydroxylase (clever, eh?)
  3. in the kidney, PTH stimulates 1-alpha-hydroxylase activity and increases the formation of the hormonally-active form of Vitamin D, called “calcitriol” (1,25-dihydroxycholecalciferol)
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6
Q

In the kidney, PTH stimulates 1-alpha-hydroxylase activity and increases the formation of the hormonally-active form of Vitamin D, called “calcitriol” (1,25-dihydroxycholecalciferol).

How does this occur specifically in the kidneys?

A
  1. in renal tubular cells, PTH binds to a surface GPCR, increasing intracellular [cAMP] and PKA activity
  2. activated PKA then activates 1-alpha-hydroxylase
  3. increased hormonally active Vit D production is observed
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7
Q

PTH stimulates synthesis of Ca-binding transport protein in mucosal cells of the intestine.

How does this occur and what is the result?

A
  1. Vit D travels through blood, diffuses to intestinal cell where it binds to its receptor
  2. Receptor/ligand pair diffuses into nucleus, where transcription begins
  3. Ca transport binding protein is synthesized and expressed on cell surfaces

Leads to increased Ca absorption

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8
Q

PTH at low vs. high concentrations

A

at LOW concentrations, PTH STIMULATES bone growth

at HIGH concentrations, PTH increases serum Ca by STIMULATING OSTEOCLASTS

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9
Q

2 effects of calcitonin

A

inhibits Oclast activity while decreasing renal Ca resorption

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10
Q

Where is Calcitonin made?

A

produced by C cells in the thyroid

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11
Q

THROWBACK - Briefly describe Paget’s Disease

A

Paget’s disease results from osteoclast overactivity, leading to abnormally-restructured bone.

Pts are more prone to painful compression frx

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12
Q

What can we do to treat Paget’s?

A
  1. Calcitonin injections

2. Orally-active bisphosphonates

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13
Q

What is the leading orally-active bisphosphonate we need to know in regards to treating Paget’s, and what suffic should we look for for Paget’s treatment?

A 
alendronate (daily and once per wk) *** KNOW THIS ONE ***
if a drug has “-dronate” or “-dronic acid” as a suffix, it’s probably in the same drug class and can be used to trx Paget’s
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14
Q

What is the structure behind Bisphosphonates?

A

Structure: functional group is similar to the pyrophosphate structure

may or may not contain Nitrogen, depending on the generation

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15
Q

What are our non-nitrogen containing Bisphosphonates?

A

Etidronate
Clodronate
Tiludronate

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16
Q

What are our nitrogen containing bisphosphonates?

A

2nd generation
Pamidronate
Alendronate
Ibandronate

3rd generation
Risedronate
Zoledronate

17
Q

Side effects of BisphosphonateS?

A

GI - esophageal irritation

osteonecrosis of the jaw (rare, but usually ass’d w/dental work)

after 5 yrs, there’s a small increased risk of femur frx w/o trauma

18
Q

Overall benefit of bisphosphonates

A

increase bone mineral density (BMD) and can prevent osteoporosis

19
Q

Bisphosphonates, denosumab, calcitonin, and SERMS all have what in common?

A

They are antiresorptive drugs

20
Q

What does it mean to be antiresorptive or anticatabolic?

A

what anti-resorptive drugs do is DECREASE osteoclast activity while sparing osteoblast activity

21
Q

What do anti-resorptive drugs specifically do to cells?

A

inhibition of hematopoietic stem cell differentiation into mature osteoclasts

stimulates apoptosis of mature osteoclasts

22
Q

How is the bioavailability of antiresorptive drugs?

A

they have very poor bioavailability because they’re deposited directly within the bone matrix

23
Q

Since they are deposited directly on the bone matrix, how are antiresorptive drugs able to have an effect?

A

when the Oclasts reach bone matrix that harbors these drugs, the drugs are released and can exert their effects

24
Q

How does Teriparatide work?

A

this drug is the active portion of endogenous PTH (this hormone normally stimulates both osteoclasts and osteoblasts)

it stimulates osteoblast differentiation (from pre-Oblast to mature Oblast) and reduces osteoblast apoptosis

25
Q

How is Teriparatide delivered and what risks are associated with it?

A

given by daily SQ injection, but permitted for only 2 yrs b/c of risk of osteosarcoma

26
Q

How is osteoporosis clinically defined?

A

Osteoporosis - clinically defined when Pt’s BMD is -2.5 SD from the age-specific reference

27
Q

How does estrogen contribute to bone strength?

A

E reduces levels of pro-resorptive cytokines

E causes increased production of OPG (osteoprotegerin)

28
Q

How does Denosumab work?

A

denosumab (a monoclonal antibody) binds RANKL, thus neutralizing it & preventing it from binding to RANK on osteoclasts

29
Q

How do SERMs work?

A

differential recruitment of co-repressors or co-activators to estrogen receptors

30
Q

How do Estrogen receptors work?

A

The E receptor is an xscription factor (nuclear receptor, thus has delayed effect compared to cytosolic receptors)

The receptor binds to its ligand (E), then DIMERIZES w/another ligand+receptor

Dimerized receptor complex then binds to the HRE on the particular gene sequence

Add’l cofactors/etc must bind before transcription can finally occur

31
Q

How does Raloxifene work?

A

partial bone agonist, and a breast antagonist

significantly reduces recurrence of breast cancer and protects against osteoporosis

32
Q

What is TSEC?

A

when SERMS are combined w/ Estrogen, the treatment is called TSEC (Tissue-Selective Estrogen Complexes)

33
Q

Who do we use TSECs on and why?

A

Particularly important for women who have bad symptoms of menopause

Blocking Estrogen’s action in the bone, but kind of like weaning the Pt off Estrogen during menopause to alleviate their symptoms (hot flashes, etc)

34
Q

What stem cells do osteoblasts arise from? Osteoclasts?

A

Osteoclasts: multi-nuclear bone resorbing cells that are derived from hematopoietic stem cells

Osteoblasts: bone forming cells derived from mesenchymal stem cells.

35
Q

Main secretions of osteoblasts and osteoclasts?

A

Main secretion osteoblast: osteoid

Main secretion osteoclast: cathepsin K

36
Q

5 stages of bone remodeling

A

Quiescence

Preosteoclast recruitment and osteoclast differentiation

Bone resorption by osteoclasts

Preosteoclast recruitment and osteoblast differentiation

Bone formation by osteoblasts

MSK Week 7 (13 decks)

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