Bone Pharmacology

Question 1

PTH is a […] hormone

PTH has a […] half-life

PTH binds to […]

[…] also binds to the same receptor as PTH

Answer 1

• Peptide
• Short
• PTHR1
• PTHrP

Question 2

What is the difference between PTH and PTHrP?

Answer 2

• PTH: endocrine hormone secreted by the parathyroid hormone that has various effects on tissues throughout the body
• PTHrP: autocrine/paracrine factor produced locally in certain tissues that shares homology with PTH but does not result in the same effects as PTH

Question 3

Describe the regulation of PTH secretion.

Answer 3

Question 4

Chief cells in the PT gland are responsible for directly gaging the levels of Ca²⁺ in the extracellular environment. Explain how they do this.

Answer 4

They express the Ca²⁺ receptor, which is a GPCR that is G_stimulatory. This GPCR is an exception to the usual pattern of GPCRs because it couples to PLC, which generates IP₃ and DAG from PIP₂ and results in increased intracellular Ca²⁺ which INHIBITS PTH secretion. This is an exception because it is a G_stimulatory subunit that is inhibitory in action.

Question 5

Why does ionized calcium regulate PTH secretion?

Answer 5

Because ionized calcium is biologically active

Question 6

What effect do increased levels of PTH have on the bone?

Answer 6

Increases bone resorption (via increased secretion of RANKL, which helps osteoclasts mature and resorb bone). This leads to an increase in serum Ca²⁺ and PO₄^3-

Question 7

What effect do increased levels of PTH have on the kidney?

Answer 7

• Increases levels of active Vit D (1,25 Dihydroxycholecalciferol)
• Increases Ca²⁺ reabsorption
• Decreases PO₄^3- reabsorption

Question 8

What effect do increased levels of PTH have on the intestines?

Answer 8

PTH does not act directly on the gut. Instead it increases the levels of active VitD which in turn increases Ca²⁺ and PO₄^3- absorption

Question 9

Describe the biosynthesis of VitD and the role of PTH in vitamin D synthesis.

Answer 9

In the skin, UV radiation converts cholesterol to 7-dehydrocholesterol. This is then converted to cholecalciferol in the plasma (VitD3). VitD3 is converted to 25 hydroxyVitD by the liver and that is converted to 1,25 dihydroxyVitD by the kidney. This final conversion to the active form is catalyzed by a cytochrome enzyme that is activated by PTH.

Question 10

PTH increases serum phosphate by increasing release of mineral from bone and increasing phosphate absorption in the gut. High levels of phosphate can be toxic. Why don’t we inadvertently develop hyperphosphatemia from this normal pathway?

Answer 10

In the kidney, PTH inhibits the reabsorption of phosphate and sodium from the urine (lumen). It also stimulates the conversion of 25DHVitD to 1,25DHVitD.

Question 11

Why is it important to have the kidneys absorb more Ca²⁺ in response to PTH?

Answer 11

Because PTH liberates Ca²⁺ from the bones and if we didn’t have a mechanism in place to reabsorb Ca²⁺ we would lose it all from our bones and we would be peeing out our bones in response to PTH.

Question 12

[…] is the major regulator of phosphate levels.

Answer 12

FGF23

Question 13

Describe the effect of serum FGF23 on:

• PTH secretion
• 1,25DHVitD production
• The Kidneys
• The bones

Answer 13

• In general, FGF23 is working to decrease phosphate levels.
• Serum FGF23 inhibits secretion of PTH and production of 1,25DHVitD. FGF23 also causes the kidneys to resorb less phosphate, which can lead to hypophosphatemia, which can inhibit FGF23 in the bone. Additionally, 1,25DHVitD normally stimulates bone FGF23, so reduced levels of 1,25DHVitD will lead to reduced Bone FGF23.

Question 14

In patients with compromised renal function, 1,25DHVitD levels would be expected to […] and PTH levels would be expected to […].

Answer 14

Decrease

Increase

Question 15

What are the effects of PTH if it is administered as a high dose or in a sustained manner?

Answer 15

It will stimulate osteoblasts to produce RANKL, which will promote osteoclast maturation and increase the RANKL/OPG ratio (OPG is decoy receptor for RANKL, increased ratio means that more RANKL is available to exert catabolic effects) and lead to bone resorption. CATABOLIC.

Question 16

What are the effects of low dose or intermittent PTH?

Answer 16

This will decrease expression of the SOST gene, which encodes for sclerostin. Decreased sclerostin leads to increased Wnt signaling, which will promote osteoblastogenesis and the release of mitogens. ANABOLIC.

Question 17

Serum levels of urinary cross-linked C-telopeptide of type 1 collagen would be expected to […] following treatment of Teriparatide for 6 months for the indiciation of osteoporosis.

Answer 17

Decrease - CTX is a measure of bone resorption so if a person is treated with teriparatide you would expect this marker to decrease because this drug is a PTH analog that is being administered intermittently so it will have anabolic effects and decrease the amount of bone resorption.

Question 18

What is prolia (denosumab)?

Answer 18

Humanized monoclonal antibody against RANKL. By scavenging RANKL, this drug prevents maturation to osteoclasts so there is decreased resorption and increased osteoclast apoptosis.

Question 19

What is the effect of PTH/PTHrP on osteoblasts?

Answer 19

If present in a sutained / high dose, will cause osteoblasts to secrete RANKL which will promote the maturation of osteoclasts via binding to RANK on osteoclasts and lead to bone resorption

Question 20

What effect does PTH / PTHrP have on osteocytes?

Answer 20

Binding of PTH to osteocyte receptor (PPR) results in decreased sclerostin, which increases Wnt expression and promotes osteoblastogenesis. This is true both when PTH/PTHrP is present intermittently and continuously.

Question 21

• What is OPG?
• What cell secretes it?
• How is its secretion regulated?

Answer 21

• It is a decoy receptor for RANKL
• Secreted by osteocytes
• Regulated in conjunction with Wnt/Beta-catenin pathway

Question 22

What is romosozumab?

Answer 22

A humanized sclerostin monoclonal antibody for the treatment of osteoporosis. Has potential to be quite novel due to ability to impact both osteoblasts and osteoclasts.

Question 23

When does a person achieve peak bone mass?

Answer 23

30 years old

Question 24

What are the acute effects of glucocorticoids on osteoclasts?

Answer 24

They increase expression of RANKL from osteoclasts and osteoblasts as well as M-CSF from osteoclasts. These effects increase osteoclastogenesis and decrease osteoclast apoptosis, leading to increased bone resorption.

Question 25

What are the chronic effects of glucocorticoids on osteoblasts?

Answer 25

They decrease Wnt signaling and increase activation of caspase 3, leading to decreased osteoblastogenesis and apoptosis.

Question 26

What are the chronic effects of glucocorticoids on osteocytes?

Answer 26

They promote the activation of procaspase 3 which leads to increased apoptosis and thus decreased bone formation.

They can also lead to decreased OPG production, thereby increasing osteoclastogenesis.

Question 27

What is the effect of glucocorticoids on the intestines and kidneys?

Answer 27

They decrease intestinal absorption of calcium and decrease kidney reabsorption of calcium.

Question 28

What is the role of osteoclasts in rheumatoid arthritis?

Answer 28

Osteoclasts secrete TNF, which is a pro-inflammator cytokine. Additinally, there are large numbers of them found within synovial tissues at sites adjacent to one creating resorption pits and lcoal bone destruction.

Question 29

What is humira (adalimumab)?

Answer 29

Humanized anti-TNF monoclonal antibody that is used to treat RA