Bone Mineral Homeostasis

Question 1

What is the relation of Mg to PTH?

Answer 1

Moderate Mg decline leads to Increased PTH secretion, but SEVERE Mg decline leads to decreased PTH secretion.

*common causes of Mg decline are chronic diarrhea, diuretics, alcohol abuse, chronic PPI and aminoglycoside use

Question 2

Action of calcitonin?

Answer 2

Elevated plasma calcium leads to release of calcitonin from the parafollicular cells. Elevated calcitonin causes decreased phosphate and calcium reabsorption in the kidneys leading to increased urinary excretion and decreased plasma concentrations. Calcitonin also works on the bone where it decreases bone resorption to decrease calcium release.

Question 3

Fibroblast growth factor-23?

Answer 3

Produced by osteoblasts and osteoclasts. FGF-23 inhibits calcitriol (activated vit D) production decreasing calcium and phosphate reabsorption in the kidneys and intestines.

*PTH stimulates calcitriol (1a-hydroxylase) activity in kidney whereas FGF-23 inhibits it

Question 4

Teriparatide?

Answer 4

PTH analog that stimulates PTH receptors to produce a net increase in bone formation/mineralization.

Used to treat osteoporosis. - At physiological dose this gives the best change in bone mineral density compared to any other medication.

Teriparatide is administered subcutaneously at low, intermittent levels to exert an anabolic effect (building bone) on osteoblasts and osteoclasts (indirect). Chronic administration causes a massive increase in PTH levels leading to a catabolic effect on the bone (osteitisfibrosa cystica)

AE - hypercalcemia, hypercalciuria, osteosarcoma

Question 5

Cholecalciferol and Ergocalciferol?

Answer 5

Vitamin D analogs usually added to calcium supplement and dairy products and require metabolism in the kidney or liver to be activated. These analogs regulate gene transcription via the vitamin D receptors.

Cholecalciferol = vitamin D3
Ergocalciferol = vitamin D2

Uses – vit D deficiency (Rickets and osteomalacia) [Type I is due to defective 1a-hydroxylase enzyme and Type II is due to defective Vit D receptor so not binding well in the nucleus]

AE - hypercalcemia, hyperphosphatemia, hypercalciuria

Question 6

Calcitriol?

Answer 6

Active vitamin D [1,25-dihydroxyvitamin D3] that does not require activation by the kidney.
Used in the management of secondary hyperparathyroidism in pts with chronic kidney disease and management of hypocalcemia in pts with hypoparathyroidism.

Question 7

Doxercalciferol?

Answer 7

1a-hydroxyvitamin D2

Used for management of secondary hyperparathyroidism in pts with chronic kidney disease.

Question 8

Paricalcitol?

Answer 8

19-nor-1,25 - dihydroxyvitamin D2

Analog of calcitriol used for management of secondary hyperparathyroidism in pts with chronic kidney disease.

Question 9

Calcipotriol?

Answer 9

Calcipotriene - approved for topical treatment of psoriasis

Question 10

Calcitonin?

Answer 10

Peptide hormone that acts through calcitonin receptors to inhibit bone resorption.

Used - Pagets disease and osteoporosis

Salmon calcitonin - nasal spray or subcutaneous injections

AE - rhinitis with nasal spray

Question 11

Bisphosphonates (Alendronate)?

Answer 11

Suppresses activity of osteoclasts and inhibits bone resorption. It inhibits osteoclastic activity via decreasing farnesyl pyrophosphate synthesis by disrupting mevalonate pathway decreasing osteoclast H+ ATPase.

Uses - osteoporosis and Paget’s disease

AE - adhynamic bone, esophageal irritation (risk reduced by drinking water and remaining in upright position for 30 minutes after taking medication), osteonecrosis of jaw

Ex. Risedronate, Ibandronate, Pamidronate, Zoledronate – all very similar to aledronate

Question 12

Estrogens (ethinyl estradiol)?

Answer 12

Activates estrogen receptors leading to changes in the rate of transcription of estrogen regulating genes.

Uses - prevents osteoporosis, HRT, OCP, hypogonadism

Oral, parenteral or transdermal admin and its metabolism is dependent on cytochrome P450 enzymes

AE..
Moderate toxicity - breakthrough bleeding, nausea, breast tenderness
Serious toxicity - thromboembolism, gallbladder disease, hypertriglyceridemia, migraine headache, hypertension, depression
In post menopausal women - breast cancer, endometrial hyperplasia (unopposed estrogen)

Question 13

Raloxifene?

Answer 13

Selective estrogen-receptor modulator (SERM)
Estrogen agonist in bone and estrogen antagonist in breast and endometrium.

Uses - osteoporosis in postmenopausal women

Oral admin

AE - hot flushes, thromboiembolism

Question 14

Denosumab?

Answer 14

Monoclonal antibody that binds RANKL (rank ligand). Binding to the RANKL leads to inhibition of osteoclastic activity.

Uses - osteoporosis

Subcutaneous every 6 months

AE - increase risk of infections

Question 15

Cinacalcet?

Answer 15

Calcimemtic that stimulates the calcium-sensing receptors (CaSR) in parathyroid to circulating Calcium leading to decrease in PTH. When the receptors is activated by cinaclcet or free ionized calcium, it activates a signaling pathway to suppress PTH synthesis and release.

Uses - hyperparathyroidism

Oral admin

AE - nausea, vomiting, hypocalcemia, adynamic bone

Question 16

Calcium preprs?

Answer 16

Oral - calcium carbonate, calcium citrate, calcium lactate

IV - calcium gluconate for tx of hypocalcemic tetany or counteract magnesium suflate overdose used in eclampsia tx

AE - IM injection leads to necrosis and abscess formation or IV admin leads to thrombophlebitis

Question 17

Prednisone?

Answer 17

Glucocorticoid agonist that leads to activation of glucocorticoid receptors that alter gene transcription.

Uses - inflammatory conditions, organ transplants, hematologic cancers

IV or oral admin, long half life due to change in gene transcription in the nucleus

AE - osteoporosis, adrenal suppression, growht inhibition, muscle wasting, salt retention, glucose intolerance, behavioral changes

Question 18

What is the effect of Fluoride on the bone?

Answer 18

Chronic exposure leads to new bone synthesis with is denser but brittle.

Question 19

What is the effect of Callium nitrate on bone?

Answer 19

Inhibits bone resportion and useful in cancer-related hypercalcema.

AE - nephrotoxic

Question 20

Plicamycin (Mithracin)?

Answer 20

This is a cytotoxic anticancer drug used in cancer-related hypercalcemia.

AE - thrombocytopenia, hepatic and renal toxicity

Question 21

What drugs cause osteoporosis?

Answer 21

1. corticosteroids
2. heparin
3. lithium
4. anastrozole
5. alcohol

Question 22

What drugs cause osteomalacia?

Answer 22

1. phenytoin

2. Etidronate (when used for more than 12 months)

Question 23

Sevelamer?

Answer 23

Hyperphosphatemia occurs due to renal failure, PTH or vitamin D issue.

Sevalamer treats hyperphosphatemia by decreasing dietary absorption of phosphate by binding phosphate in the GI tract.

Question 24

Tx of osteoporosis?

Answer 24

1. stop smoking, alcohol abuse, corticosteroid
2. HRT
3. calcium and vitamin D supplementation
4. bisphosphonate
5. SERMs
6. Teriparatide

Question 25

How do Thiazides effect bone?

Answer 25

Thiazide diuretics decrease calcium excretion increases its reabsorption within the kidney. It is useful in prevention of renal stone formation and treat HTN in osteoporosis pts.

Question 26

How do you treat hypercalcemia?

Answer 26

1. Furosemide and saline infusion
2. bisphosphonate
3. calcitonin
4. parathyroidectomy (if pt is symptomatic)