Agents of Bone Metabolism

Question 1

What are the actions of RANKL and how is osteoprotegrin involved?

Answer 1

RANKL is released by osteoblasts after PTH binding. It binds to RANK expressed by osteoclasts and their precursors. Osteoprotegrin is another protein released by osteoblasts which is a decoy ligand for RANKL.

Question 2

Describe how PTH increase osteoblast proliferation?

Answer 2

PTH inhibits the production of sclerostin from osteocytes, which blocks osteoblast proliferation.

Note: The net effect of PTH is still bone resorption

Question 3

What is teriparatide?

Answer 3

Recombinant human PTH

Question 4

What are the MOA and uses of teriparratide? What is the limit of it’s use?

Answer 4

MOA - intermittent PTH induces bone growth

Uses - Women with osteoporotic fractures or risk of fractures, those who have failed other therapies, and men with hypogonadal osteoporosis

Limit - Therapy has not been studied past two years. Must stop at two years.

Question 5

What are the ADRs and CIs of Teriparatide?

Answer 5

ADR - orthostatic hypotension, hypercalcemia, hyper uricemia, and angina

CI - don’t use in those at risk of osteosarcoma: paget’s, open epihpysis, irradiation of skeleton, increased alkaline phosphatase levels

Question 6

What are Vitamin D2 and D3?

Answer 6

D2 = cholecalciferol
D3 = plant-derived ergocalciferol

Question 7

What are the actions of the active form of vitamin D, 1,25-dihydroxy vitamin D (calcitriol)?

Answer 7

Increases intestinal absorption of calcium and phosphate, increased reabsorption of calcium and phosphate from the kidneys, and expression of RANKL by osteoblasts.

Question 8

What is the therapeutic use of Vitamin D Analogs?

Answer 8

1. Can be used to cure nutritional rickets
2. Metabolic Rickets - if patient is in renal failure calcitriol should be used
3. Osteomalacia
4. Hypoparathyroidism
5. Prophylaxis of osteoporosis

Question 9

What are the ADRs of Vitamin D analogs?

Answer 9

hypercalcemia, hyperphosphatemia, constipation, arrhythmias, and pancreatitis

Question 10

What are the actions of FGF-23 and where is it produced?

Answer 10

FGF-23 is produced by osteocytes and osteoblasts. It inhibits the production of vitamin D and the reabsorption of phosphate.

Question 11

What is the MOA, use, and ADR of calcitonin?

Answer 11

MOA - inhibits bone resorption and calcium and phosphate reabsorption

Use - paget’s and osteoporosis

ADR - urticaria and hand swelling

Question 12

What is the therapeutic use of glucocorticoids with reference to hypercalcemia and what are the mechanisms which serve this purpose?

Answer 12

Glucocorticoids can be used to treat hypercalcemia of lymphomas and granulomatous diseases. They inhibit the absoprtion of calcium, increase calcium excretion, and inhibit bone formation. Prolonged use can result in oteoporosis.

Question 13

What is raloxifene? Describe its use, ADR, and CI.

Answer 13

Raloxifene is a selective estrogen receptor modulator

Use - post-menopausal osteoporosis

ADRs - hot flashes, leg cramping, and increased risk of thromboembolism

CI - history of thromboembolism or CAD

Question 14

What is a prototype bisphosphonate and its MOA?

Answer 14

Alendronate

These are analogs of pyrophosphates that have the P-O-P bond replaced by P-C-P. This causes chelation of Ca and decreased formation and dissolution of hydroxyapatite. Leading to increased mineral density.

Question 15

Describe the administration and uses of alendronate.

Answer 15

Must be taken on an empty stomach, with a full glass of water and remaining standing.

Used for the Tx of osteoporosis, paget’s, and hypercalcemia of malignancy

Question 16

What are the ADRs of bisphosphonates?

Answer 16

Gastric and esophageal mucosal irritation, osteonecrosis affecting the jaw and subtrochanteric femur.

Question 17

Describe denosumab with respect to MOA, Use, and ADRs.

Answer 17

MOA - mAb which binds RANKL mimicking osteoprotegrin

Use - post-menopausal osteoporosis

ADR - increased risk of infection, possibility of osteonecrosis, posibility of transient hypocalcemia

Question 18

What are the manifestations of hypercalcemia and the major causes?

Answer 18

Mx - CNS depression progressing towards coma

Etx - Hyperparathyroidism, hypercalcemia of malignancy, thiazide diuretics, vitaminosis D, sarcoidosis, milk-alkali, thyrotoxicosis, and adrenal insufficiency

Question 19

How is hypercalcemia treated?

Answer 19

The mainstay treatment is fluids with furosemide diuretics. Phosphates are a rapid, but dangerous way to decrease calcium. Glucocorticoids can be used to treat the hypercalcemia of chronic disease.

Question 20

Describe the Mx and Etx of hypocalcemia.

Answer 20

Mx - tetany and parasthesias

Etx - HypoPTH, vitamin D deficiency, malabsorption, or chronic renal failure

Question 21

Describe the tx of hypocalcemia.

Answer 21

There are three tx methods of hypocalcemia: IV calcium gluconate (severe), oral calcium carbonate, and calcitriol (rapid action).

Question 22

Describe the Etx and Tx of hyperphosphatemia.

Answer 22

Etx - Chronic renal failure, hypoPTH, vitamin D toxicity

Tx - limit phosphate intake and give phosphate binding agents