Pharmacology of the Parathyroids and Bone

Question 1

What effect does PTH have on kidney?

Answer 1

decreased phosphate reabsorption
activation of VD3 via upregulation of 1-alpha-hydroxylase
Increased calcium reabsorption

Question 2

What is the effect of PTH on the intestines?

Answer 2

Secondary to activation of D3

Increased calcium and phosphate reabsorption

Question 3

What is the effect of PTH on the bones?

Answer 3

increased calcium and phosphate reabsorption

Question 4

What stimulates PTH secretion?

Answer 4

o Decreased serum ionized calcium

o Mild decrease in magnesium

o Increased serum phosphate (indirect effect through PO4-Ca complexing)

Question 5

What inhibits PTH secretion?

Answer 5

o High ionized serum calcium

o High serum magnesium (causes reversible
hypoparathyroid symptoms and hypocalcemia)

o Vitamin D3 (1,25 dihydroxy)

Question 6

What condition causes these symptoms?

carpo-pedal muscular spasms, cramping, muscle spasms (tetany), generalized seizures, circumoral numbness and tingling

Answer 6

Hypocalcemia

Question 7

Diarrhea, aminoglycosides, loop diuretics and alcohol abuse can trigger what change in PTH secretion?

Answer 7

Decreased PTH secretion

all are major causes of magnesium loss

Question 8

Phosphate excretion is increased by

Answer 8

PTH, 
PTHrP, 
hypercalcemia, 
hypokalemia, 
hypomagnesemia 
calcitonin, 
glucocorticoids 
diuretics

Proximal tubular reabsorption is increased by phosphate depletion, hypoparathyroidism, and hypocalcemia

Question 9

What drugs inhibit magnesium reabsorption?

Answer 9

furosemide and cisplatin

Question 10

When is surgery indicated for primary hyperparathyroidism?

Answer 10

serum calcium of >1mg/dL
BMD T-score mg/day (with stones or risk of stones)
In someone under 50

Question 11

What drug is indicated for pts with
secondary hyperparathyroidism with renal disease,
parathyroid carcinoma,
or primary hyperparathyroidism that don’t have surgery?

Answer 11

cinacalcet

Question 12

What is the MOA of cinacalcet? What indications is it used for?

Answer 12

calcimimetic - reduces PTH and serum calcium levels

secondary hyperparathyroidism with renal failure
parathyroid carcinoma
primary hyperparathyroidism not treated by surgery

Question 13

What drug can be given to patients with his risk osteoporosis that have failed other treatments?

Answer 13

Teriperatide

Question 14

what is the MOA of Teriperatide?

Answer 14

PTH analougue - bolus SQ injections given to stimulate bone resorption and formation (activates RANKL on osteoblasts, inhibits OPG)

terrible because requires multiple SQ injections and contraindicated in pts with increased risk of osteosarcoma (paget’s, radiation treatment)

Question 15

What drug/hormone can be given to rapidly improve hypercalcemia (e.g. in patients with paget’s disease)?

Side effect is rhinitis - nasal spray increases risk of cancer - can only be used effectively for 2-3 days due to rapid diminishing effectiveness

Answer 15

calcitonin

Question 16

What is Raloxifene?

Answer 16

selective estrogen receptor modulator - activates some receptors blocks others - only given to women - used for osteoporosis (INCREASED RISK OF HOT FLASHES AND DVT!)

Question 17

What is Zoledronic acid? what is it used for? Side effects?

Answer 17

I.V. bisphosphonate (only one that doesnt end in “dronate”) - used to treat:

hypercalcemia of malignancy

paget’s disease of the bone

prevention of fractures in osteogenesis imperfecta

Flue like symptoms

Question 18

What is the mechanism of action of bisphosphonates?

Answer 18

reduce osteoclast reabsorption of bone

Question 19

Which bisphosphonate can be used to treat hypercalcemia, osteoporosis, pagets disease of the bone, and prevention of bone fractures in osteogenesis imperfecta?

Answer 19

Residronate - must take sitting up on empty stomach - major side effect is esophogeal iritation

Question 20

What is a possible paraneoplastic side effect of multiple meyloma?

Answer 20

hypercalcemia of malignancy - due to release of local osteolytic factors

Question 21

What is Familial hypercalcemic hypocalciuria?

Answer 21

calcium sensing receptors detect low calcium when there is normal – stimulates inappropriate PTH release – kidneys also have calcium sensing receptors – respond by increasing cacium reabsorption – high blood calcium low urine calcium

Question 22

What is Denosumab?

Answer 22

monoclonal antibody that binds RANKL – inhibits activation of osteoclasts

Question 23

Hypercalcemia of malignancy

Answer 23

oversecretion of PTH related peptide (FROM TUMOR –squamous cell carcinoma of the lung - SMOKER)

Same features as primary hyperparathyroidism except low PTH (low phosphate, high calcium, high VD3)

Question 24

What type of diuretic causes hypercalcemia which type treats it?

Answer 24

thiazide diuretics can cause excessive calcium reabsorption (hypercalcemia) and can be used to treat kidney stones

Loop diuretics (furosumide, bumetinide, torsemide, ethacrynic acid) inhibit Ca2+ reabsorption and can be used to treat hypercalcemia

Question 25

Corticosteroids - decrease production of vitamin D

When can they be useful for treating hypercalcemia?

Answer 25

vitamin D intoxification

granulomatous diseases and hematologic malignancies

Question 26

What are the major types of treatments for hypercalcemia?

Answer 26

Fluids, diuretics (Loop, not thiazide), bisphosphonates, calcitonin, corticosteroids, dialysis (if others fail)

Question 27

What is tertiary hyperparathyroidism?

Answer 27

parathyroid glands exhibit autonomous secretion of PTH

Question 28

How is QT interval affected by calcium levels?

Answer 28

Hypocalcemia = prolonged QT; heart block; CHF
Hypercalcemia = shortened QT; hypertension, bradycardi

Question 29

What is the role of FGF23 in secondary hyperparathyroidism due to chronic kidney disease?

Answer 29

Supresses alpha-1 hydroxilase expression and decreases production of 1,25 dihydroxy vitaminD3

• contributes to increase in PTH levels (high D3

Question 30

How is vitamin D linked to ADH (aka AVP)?

Answer 30

normally calcium is regulated. CaSn cells in PH detect low Ca2+ levels and release PTH => PTH inhibts OPG and stimulates RANKL, also increases Ca2+ reabsorption at distal tubule and increases alpha-1 hydroxylase to increase active D3. Active D3 stimulates Ca/PO4 absorption from the kidneys and reabsorption from bone ==> leads to elevated levels of phosphate and calcium and inhibition of PTH release. D3 feedback inhibits its own production wherease Calcitonin is released when Ca2+ levels are too high which counteracts PTH effect on kidney and bone ==> leads to increased renal Ca2+ excretion and absorption by bone.

Level of ionized calcium in primary hyperparathyroidism leads to hyperosmotic diuresis is elevated which triggers hypothalamous to detect hyperosmolar serum. AVP release is inhibited.

Question 31

What is used to treat secondary hyperparathyroidism?

Answer 31

Active vitamin D (calcitriol) or Vitamin D analogues (paracalcitol or doxercalciferol)

phosphate binders (calcium carbonate, calcium acetate, or sevelamer )

and cacimimetics to decrease PTH secretion (Cinacalcet)

Question 32

What is sevelamer ?

Answer 32

phosphate binder - used for secondary HPTism

Question 33

what are the main side effects of denosumab?

Answer 33

skin infections, hypocalcemia (particularly in those with a lower GFR). (RANKL monoclonal antibody)