2.7.2. Biphosphonates and Vitamin D

Question 1

What does the drug Raloxifene do?

Answer 1

It is a type of SERM or selective estrogen receptor modulators

Question 2

What does the drug Alendronate do?

Answer 2

a type of bisphosphonate

Question 3

What does the drug Denosumab do?

Answer 3

a type of RANKL antibody

Question 4

What does the drug Teriparatide do?

Answer 4

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

Question 5

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

Answer 5

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)

Question 6

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?

Answer 6

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

Question 7

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

How does this occur and what is the result?

Answer 7

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

Question 8

PTH at low vs. high concentrations

Answer 8

at LOW concentrations, PTH STIMULATES bone growth

at HIGH concentrations, PTH increases serum Ca by STIMULATING OSTEOCLASTS

Question 9

2 effects of calcitonin

Answer 9

inhibits Oclast activity while decreasing renal Ca resorption

Question 10

Where is Calcitonin made?

Answer 10

produced by C cells in the thyroid

Question 11

THROWBACK - Briefly describe Paget’s Disease

Answer 11

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

Pts are more prone to painful compression frx

Question 12

What can we do to treat Paget’s?

Answer 12

1. Calcitonin injections

2. Orally-active bisphosphonates

Question 13

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?

Answer 13

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

Question 14

What is the structure behind Bisphosphonates?

Answer 14

Structure: functional group is similar to the pyrophosphate structure

may or may not contain Nitrogen, depending on the generation

Question 15

What are our non-nitrogen containing Bisphosphonates?

Answer 15

Etidronate
Clodronate
Tiludronate

Question 16

What are our nitrogen containing bisphosphonates?

Answer 16

2nd generation
Pamidronate
Alendronate
Ibandronate

3rd generation
Risedronate
Zoledronate

Question 17

Side effects of BisphosphonateS?

Answer 17

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

Question 18

Overall benefit of bisphosphonates

Answer 18

increase bone mineral density (BMD) and can prevent osteoporosis

Question 19

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

Answer 19

They are antiresorptive drugs

Question 20

What does it mean to be antiresorptive or anticatabolic?

Answer 20

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

Question 21

What do anti-resorptive drugs specifically do to cells?

Answer 21

inhibition of hematopoietic stem cell differentiation into mature osteoclasts

stimulates apoptosis of mature osteoclasts

Question 22

How is the bioavailability of antiresorptive drugs?

Answer 22

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

Question 23

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

Answer 23

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

Question 24

How does Teriparatide work?

Answer 24

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

Question 25

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

Answer 25

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

Question 26

How is osteoporosis clinically defined?

Answer 26

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

Question 27

How does estrogen contribute to bone strength?

Answer 27

E reduces levels of pro-resorptive cytokines E causes increased production of OPG (osteoprotegerin)

Question 28

How does Denosumab work?

Answer 28

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

Question 29

How do SERMs work?

Answer 29

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

Question 30

How do Estrogen receptors work?

Answer 30

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

Question 31

How does Raloxifene work?

Answer 31

partial bone agonist, and a breast antagonist significantly reduces recurrence of breast cancer and protects against osteoporosis

Question 32

What is TSEC?

Answer 32

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

Question 33

Who do we use TSECs on and why?

Answer 33

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)

Question 34

What stem cells do osteoblasts arise from? Osteoclasts?

Answer 34

Osteoclasts: multi-nuclear bone resorbing cells that are derived from hematopoietic stem cells Osteoblasts: bone forming cells derived from mesenchymal stem cells.

Question 35

Main secretions of osteoblasts and osteoclasts?

Answer 35

Main secretion osteoblast: osteoid Main secretion osteoclast: cathepsin K

Question 36

5 stages of bone remodeling

Answer 36

Quiescence Preosteoclast recruitment and osteoclast differentiation Bone resorption by osteoclasts Preosteoclast recruitment and osteoblast differentiation Bone formation by osteoblasts