Drugs Of Bone Metabolism

Question 1

How does estrogen deficiency result in bone dysfunction

Answer 1

Increases bone resorption via increases in osteoclast lifespan and activity and loss of osteoblasts via apoptosis
- starts 3-5 years after menopause

Clincial features:
- low bone mass and bone strength

Treatments

• SERM
• stronger
• bisphosphonates
• RANKL antagonists
• calcitonin
• vitamin D and calcium supplementation

Question 2

How does osteoporosis result in bone dysfunction

Answer 2

Increase osteoclast production causes increased bone resorption vs formation
- causes decrease trabecular bone density and overall BMD which increases risk for fractures in hip, spine, neck and hips

Clinical features

• low bone mass and strength
• fragile bones increased risk for fracture

Treatments

• same as estrogen loss except also:
• Daily PTH IM injections
• cathepsin K inhibitors and Sclerostin antibodies (investigational only)

Question 3

How does CDK affect bone dysfunction?

Answer 3

Decreased excretion of phosphate an decreased formation of 1,25-OH. Also increases PTH levels in the blood.

Clinical features

• ectopic calcification
• hypocalcemia
• osteomalacia

Treatment

• phosphate restriction
• chelators to calcitriol

Question 4

Affects of (1,25-OH)

Answer 4

Increases calmodulin production in the GI tract which increases calcium and phosphate absorption

Inhibits PTH synthesis due to increases in calcium levels in the blood

Question 5

What types of vitamin D preparations are most importaint for poor renal function and poor liver function respectively?

Answer 5

Renal = calcitriol (1,25-OH)
- this way we can skip the final step of vitamin D activation

Liver = calcifediol (25,OH)
- this way we can skip the second to last step in vitamin D synthesis, but not skip the renal step (to prevent hypervitaminosis D)

Question 6

Steps of vitamin D synthesis

Answer 6

1) 7-dehydrocholesterol gets absorbed via skin with UV light to make cholecalciferol (vitamin D3)
2) vitamin D3 moves to liver along with any plant based vitamin D2 (ergocalciferol) consumed where it is stored until needed
3) when needed, vitamin D is hydroxylated into 25-OH (calcifediol) by 25-hydroxylase enzymes
4) calcifediol moves to kidney where it is hydroxylated into 1,25-OH (calcitriol) by 1a-hydroxylase enzymes

Question 7

What does adding vitamin D3 to calcium do?

Answer 7

Increases GI tract absorption of calcium by adding more calmodulin

Question 8

What does adding magnesium to calcium supplements do?

Answer 8

Is a cofactor needed to activate the enzyme that activates vitamin D in liver and kidneys

Question 9

What are the main biological factors in play for calcium/phosphate homeostatic control?

Answer 9

PTH

Vitamin D3

FGF-23

Calcitonin

Glucocorticoids

Thyroid hormone

Gonadal steroids

in order of most effect to least effect

Question 10

How does parathyroid hormone effect change based on how often it is given?

Answer 10

Continuously = increases osteoclast activity

Given once-daily = paradoxically increases osteoblast activity

**this is why we only give daily doses for decreased BMD

Question 11

Estrogen effects in therapy

Answer 11

Suppresses cytokine IL-6

Promotes apoptosis of osteoclasts and decreases activity

Inhibits apoptosis of osteoblasts and osteocytes

however estrogen therapy by itself does increase risks for breast cancer so is not often used

Question 12

How does pyrophosphate/bisphosphonates work biologically?

Answer 12

Concentrate in bone matrix and chelates hydroxyapatite preventing hydroxyapatite solubility and make osteoblast job easier

**also can get internalized by osteoclasts and induce apoptosis

Question 13

How does denosumab and RANKL work biologically

Answer 13

RANKL = released by osteoblasts to induce fusion and generation of multi-nucleated active osteoclasts

Denosumab = chelates RANKL and prevents it to bind to osteoclasts