Calcium

Question 1

Describe the role of PTH in calcium and phosphate homeostasis and bone remodeling:

Answer 1

• PTH increases Ca in extracellular fluid which leads to…
• Increased Ca reabsorption from collecting tubules (TrpV5)
• Increased Ca resorption from bone (increased osteoclast # and activity)
• Increased phosphate loss in urine
• Increased 1,25(OH)2D3 production in kidney

Question 2

What is PTH secretion triggered by?

Answer 2

low serum Ca levels

Question 3

Explain the biosynthesis of Vitamin D:

Answer 3

• UV irradiation of skin converts 7-dehyrocholesterol into cholecalciferol (Vitamin D3)
• Vitamin D3 gets hydroxylated in the liver by Vit D 25-hydroxylase, thus turning it into 25-hydroxyvitamin D3
• From here, it can undergo two different hydroxylase reactions.
• 1-a-hydroxylase will convert it into the active form (1,25 dihydroxy Vit D3) (calcitriol)
• 24-hydroxylase will convert it into the significantly less active form (24,25 dihydroxy vit D3) (secalciferol)

Question 4

Fibroblast Growth Factor 23 (FGF23)

Answer 4

• secreted by osteocytes and osteoblasts in response to elevated serum phosphate
• stims phosphate excretion
• inhibits PTH secretion
• inhibits 1,25(OH)2D3 synth

Question 5

What do the auto/paracrine effects of FGF23 on osteocytes do?

Answer 5

inhibits bone mineralization

Question 6

Explain the concentrations that inhibits PTH secretion:

Answer 6

• 1,25(OH)2D#
• FGF23
• High Ca

Question 7

What stimulates calcitonin?

Answer 7

Calcitonin is stimulated by high serum calcium levels

Question 8

What are the effects of calcitonin?

Answer 8

• inhibits osteoclastic bone resorption
• increases Ca and phosphate loss in urine (less is reabsorbed)

Question 9

Explain the rationale for the use of 1,25 (OH)-vitamin D3 or its precursors in osteoporosis and vitamin D deficiency:

Answer 9

• can slightly reduce fracture risk

Question 10

Estrogens and SERMS

Answer 10

• prevention and control of postmenopausal bone resorption
• increase osteoblasts, decrease osteoclasts

Question 11

Calcitonin

Answer 11

• a negative regulator of serum (extracellular) Ca
• not used for osteoporosis much anymore
• 4th line treatment
• used for paget’s

Question 12

Actions of Vitamin D

Answer 12

• increased Ca and phosphate absorption from small intestine
• increases Ca and phosphate reabsorption
• Feedback inhibition of PTH

Question 13

Bisphosphonates

Answer 13

• 1st line treatment
• inhibit bone resorption
• may lead to hypocalcemia
• gastric irritation
• only 10% absorbed orally

Question 14

Teriparatide/Abaloparatide

Answer 14

• used for high fracture risk
• amino acids of PTH

Question 15

Risk factors for osteoporosis:

Answer 15

• physical inactivity
• age
• low ca intake in early years
• long term glucocorticoid therapy

Question 16

Romosozumab

Answer 16

• reserved for high fracture risk
• mab against sclerostin

Question 17

Deniszumab

Answer 17

• 1st line treatment
• humanized mab against RANKL

Question 18

Explain the mechanism of action for bisphosphonates based on their molecular structure:

Answer 18

• reduce formation and dissolution of hydroxyapatite crystals
• 50% of absorbed dose ends up in bone
• disrupt cytoskeleton, induce apoptosis, inhibit farnesyl-PP synthesis of osteoclasts

Question 19

How does teriparatide increase bone mass?

Answer 19

• occurs with intermittent dosing
• preferentially stimulates osteoblast activity when administered with Ca and vit D
• Activates Gs and Gq (Adenylyl cyclase and PLC)

Question 20

Explain the mechanism of denosumab:

Answer 20

• binds to RANKL and prevents activation of RANK on osteoclast precursors, preventing differentiation of osteoclasts

Question 21

Explain the mechanism of romosozumab:

Answer 21

• inhibits sclerostin
• sclerostin is responsible for decreasing blasts and increasing clasts

Question 22

Explain the rationale for the use of inhibitors of PTH secretion in patients with CDK on dialysis:

Answer 22

• in CDK with dialysis, the Ca-sensing receptor can become less responsive to Ca
• cinacalcet is a PAM of the Ca-sensing receptor
• when cinacalcet is bound to the receptor, its more responsive to Ca, and will better inhibit PTH secretion

Question 23

Explain the mechanism of Zemplar/Hectorol

Answer 23

• inhibit secretion of PTH with less effect on serum Ca than 1,25(OH)2VitD3

Question 24

Explain the mechanism of etelcalcetide:

Answer 24

• PAM of CaR
• decreases PTH and calcium

Question 25

Explain the rationale for the use of phosphonate binders in patients with CDK on dialysis:

Answer 25

- CDK often includes loss of phosphate excretion in response to PTH and FGF23 - phosphate binders complex with dietary phosphate and prevent absorption from GI

Question 26

Differentiate the mechanisms of action of Fosrenol and Renagel:

Answer 26

- Fosrenol decreases serum phosphate and calcium levels - Renagel selectively decreases serum phosphate

Question 27

Osteoblasts

Answer 27

- bone forming cells - incorporate Ca and Phosphate from plasma into bone

Question 28

Osteoclasts

Answer 28

- bone resorption cells - release Ca2+ and phosphate from bone into plasma

Question 29

Osteocytes

Answer 29

release factors that regulate osteoblast/clast activity

Question 30

Which factors decrease bone mineral density (BMD)?

Answer 30

- sclerostin - DKK-1 - RANKL

Question 31

Effects of hyperparathyroidsim:

Answer 31

increased bone resorption and decreased Ca excretion

Question 32

Effects of malignant tumors:

Answer 32

some produce a peptide with PTH activity

Question 33

Effects of hypocalcemia:

Answer 33

- hypoparathyroidism - vit d deficiencies - neuromuscular disturbances, paresthesia, tetany muscle cramps

Question 34

Effects of Rickets (Vit D deficit)

Answer 34

- weight bearing bone deformities in children - hypocalcemia in adults

Question 35

Pros of teriparatide compared to bisphosphonates:

Answer 35

- more effective in preventing fractures - builds bone mass at higher rate - may allow better bone healing after fracture

Question 36

What is the black box warning for teriparatide?

Answer 36

- risk of bone cancer

Question 37

Cons of teriparatide:

Answer 37

- injected daily - not recommended beyond 2 years