Drugs Affecting Bone Mineralization

Question 1

key molecule that causes formation, activation and maintenance of osteoclasts

Answer 1

NF-kB ligand RANKL

Question 2

The three MAJOR regulators of calcium homeostasis

Answer 2

PTH, vitamin D and FGF-23

Question 3

PTH action in gut, kidney, and overall (on Ca and phosphorus)

Answer 3

PTH acts on the kidneys to increase calcium reabsorption and but it decreases phosphorous reabsorption in the kidney.

PTH works in the gut to increase BOTH calcium and phosphorous to reabsorption.

The net effect of PTH is to increase serum calcium and decrease serum phosphorous.

Question 4

What is Teriparatide (Forteo)

Answer 4

a subunit of amino acids 1-34 of human PTH

Question 5

Mechanism of action of Teriparatide (Forteo)

Answer 5

PTH has been shown to stimulate osteoblastic bone formation with intermittent PTH treatment. Teriparitide stimulates osteoblastic bone formation although the mechanism is not well understood. Thus Teriparatide has an anabolic effect on bone by increasing bone mass, structural integrity and strength.

Question 6

Side effects of Teriparatide (Forteo)

Answer 6

mild hypercalcemia, and orthostatic hypotension.

Question 7

What is the drug of choice for osteoporosis?

Answer 7

Teriparatide

Question 8

Steps in Vitamin D activation

Answer 8

Vitamin D is hydroxylated in the liver to form 25-hydroxyvitamin D which is also called calcifediol calcidiol. Next, in kidney, 25-hydroxyvitamin D is further converted to 1,25-hydroxyvitamin D. This activated form of vitamin D is called calcitriol.

Question 9

What is inactivated vitamin D and where is it stored?

Answer 9

vitamin D is stored in the liver as 25 -hydroxyvitamin D

Question 10

What is the active form of vitamin D and what enzyme creates it

Answer 10

the active form of vitamin D occurs by 1-a hydroxylase in the kidney to form 1,25 -hydroxy vitamin D.

Question 11

How does vitamin D lead to reabsorption in the GI system

Answer 11

Vitamin D metabolites increase absorption of dietary calcium and phosphorous by stimulating the synthesis of many brush border proteins that increase uptake across the GI mucosa, leading to an increase in serum calcium concentration.

Question 12

Disorders where treatment is vitamin D

Answer 12

One of the primary treatment indications is vitamin D deficiency. It also is effective in the treatment of rickets and osteomalacia. Vitamin D is also used in the treatment of hypocalcemia. and hypoparathyroidism.

Question 13

What is the main role of FGF-23

Answer 13

The main role of FGF-23 is to inhibit 1,25 hydroxy vitamin D formation in the kidney and phosphate reabsorption in the kidney.

Question 14

What are the main functions of calcitonin

Answer 14

Question 15

What is calcitonin used for clinically

Answer 15

Calcitonin is used to lower plasma calcium and phosphorous concentrations in patients with hypercalcemia due to decreased bone resorption. However, the use of calcitonin is limited for this purpose long-term due to the “calcitontin escape” occurs within a few days and likely due to downregulation of receptors. Calcitonin is also effective in disorders of increased skeletal remodeling, such as Paget’s disease and osteoporosis

Question 16

What impact do glucocorticoids have one bone

Answer 16

Excess glucocorticoid levels decrease renal calcium reabsorption, interfere with intestinal calcium absorption, stimulate PTH secretion and stimulate osteoclastogenesis through RANKL.

Question 17

Main use of estrogen

Answer 17

The principal therapeutic application for estrogen is in the treatment and/or prevention of postmenopausal osteoporosis.

Question 18

What are SERMs and which is the most common

Answer 18

Selective estrogen receptor modulators, raloxifene

Question 19

How does raloxifene work

Answer 19

SERMs work by stimulating certain estrogen receptors and inhibiting other estrogen receptors. Raloxifene stimulates bone estrogen receptors and inhibits breast and uterine estrogen receptors. Raloxifene also increases bone mineral density by inhibiting bone resorption through effects on cytokines and RANKL.

Question 20

Side effects of raloxifene

Answer 20

raloxifene increases the risk of stroke, pulmonary emboli, and deep vein thrombosis.

Question 21

Mechanism of bisphosphonates

Answer 21

They form a three-dimensional structure capable of chelating divalent cations such as calcium. Bisphosphonates have a strong affinity for bone and especially target bone surfaces undergoing remodeling.

The enzyme-resistant analogues of pyrophosphate inhibit osteoclast function. Bisphosphonatesincrease bone density by inhibiting bone resorption, and osteoclastic function. Bisphosphonates become incorporated into the bone matrix and ingested by osteoclasts, promoting osteoclasts apoptosis.

Question 22

When is bisphosphanate indicated

Answer 22

Current guidelines recommend oral bisphosphonates first line for primary and secondary prevention of fractures. Additionally, bisphosphonates are indicated for osteoporosis and postmenopausal osteoporosis, glucocorticoid-induced osteoporosis, paget’s disease, and bone metastases and cancer-induced hypercalcemia

Question 23

Bisphosphonates side effects

Answer 23

Bisphosphonates cause gastric and esophageal irritation. A very rare, but quite serious, side effect of bisphosphonates is osteonecrosis of the jaw.

Question 24

Contraindications for bisphosphonates

Answer 24

Contraindications to the administration and use of bisphosphonates include decreased renal function, esophageal motility disorder and peptic ulcers.

Question 25

Mechanism of denosumab

Answer 25

Denosumab (Prolia or XGEVA) is a monoclonal antibody. Its primary mechanism of action is that it binds to and **prevents the action of RANKL.** If you need to review the action of RANKL, go back to PAGE 2 of this learning activity. Remember since RANK ligand stimulates bone resorption, inhibition of RANK ligand would **favor overall bone building** as osteoclast activity would be less than osteoblast activity.

Question 26

Indications for denosumab

Answer 26

dications for the use of denosumab include the treatment of **postmenopausal women or men with osteoporosis at high risk for fracture.** Treatment is also indicated to increase bone mass in men at high risk for fracture receiving androgen deprivation therapy for nonmetastatic prostate cancer or in women at high risk for fracture receiving adjuvant aromatase inhibitor therapy for breast cancer.

Question 27

Contraindications for denosumab

Answer 27

Contraindications to denosumab includes hypocalcemia.

Question 28

Side effects of denosumab

Answer 28

Hypocalcemia can occur with treatment. Like bisphosphonates, osteonecrosis of the jaw has been reported with denosumab (Prolia).

Question 29

Mechanism of gallium nitrate

Answer 29

Gallium nitrate acts by inhibiting resorption through the inhibition of osteoclast activity. By preventing the activity of osteoclasts, gallium nitrate can successfully decrease serum levels of calcium. Gallium nitrate is given as an IV infusion.

Question 30

Clinical indications for gallium nitrate

Answer 30

Gallium nitrate is currently FDA approved for the management of hypercalcemia of malignancy.

Question 31

Side effect of gallium nitrate

Answer 31

nephrotoxicity

Question 32

Contraindication for gallium nitrate

Answer 32

severe kidney disease.

Question 33

Mechanism of calcimetics - Cinacalcet (Sensipar)

Answer 33

Cinacalcet activates the Calcium-sensing receptor (CaSR) in the parathyroid gland. Recall that the calcium sensing receptor is expressed on parathyroid cells, bone and kidneys and senses the fluctuations of calcium. Activation of the CaSR increases intracellular calcium resulting in inhibition of PTH secretion via negative feedback. Ultimately inhibits PTH

Question 34

Indications for cinacalcet

Answer 34

Cinacalcet is approved for the treatment of secondary **hyperparathyroidism in chronic kidney disease**. It is also indicated for the treatment of parathyroid carcinoma and primary hyperparathyroidism in patients who are unable to undergo surgical resection of the parathyroid.

Question 35

Contraindications for cinalcalcet

Answer 35

patients with hypocalemia

Question 36

Side effects of cinalcalcet

Answer 36

dizziness, myalgia, nausea, vomiting, and hypoparathyroidism.

Question 37

Mechanism for calcylitics

Answer 37

Calcilytics are a calcium sensing receptor (CaSR) antagonist. By inhibiting the action of the CaSR, PTH secretion is stimulated

Question 38

Indication for calcylitics

Answer 38

have potential use for the short term stimulation of PTH secretion to have increase in bone formation, similar to the intermittent use of Teriparatide.

Question 39

Mechanism for Furosemide (Lasix)

Answer 39

Furosemide inhibits sodium reabsorption in the ascending limb of the loop of henle. Calcium reabsorption is coupled to sodium reabsorption in the loop. Sodium infusion leads to increase sodium loss and increase calcium loss. **T****he net effect of furosemide is to decrease serum calcium levels by excreting calcium in the urine.**

Question 40

Indications for furosemide

Answer 40

Hypercalcemia

Question 41

Example of thiazide diuretic

Answer 41

Hydrochorothiazide (Diurel)

Question 42

Mechanism of hydrochlorothiazide

Answer 42

Primary function is **reducing renal calcium excretion.** Calcium reabsorption occurs at the distal tubule in the kidney. Thiazides diuretics may increase the effectiveness of PTH in stimulating reabsorption of calcium by the renal tubules. They may also act on calcium reabsorption secondarily by increasing sodium reabsorption in the proximal tubule. The net effect is a decrease in calcium excretion in the urine. This could cause an increase in serum calcium levels since urine calcium excretion is reduced.

Question 43

Indications for hydrochlorothiazide

Answer 43

Hydrochlorothiazide is indicated for idiopathic hypercalciuria since they effectively reduce the hypercalciuria and incidence of stone formation.

Question 44

Contraindications for hydroxycholorthiazide

Answer 44

Since thiazide diuretics decrease urine calcium excretion, they are contraindicated in the treatment of hypercalcemia.