Drugs Of Bone Metabolism Flashcards
How does estrogen deficiency result in bone dysfunction
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
How does osteoporosis result in bone dysfunction
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)
How does CDK affect bone dysfunction?
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
Affects of (1,25-OH)
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
What types of vitamin D preparations are most importaint for poor renal function and poor liver function respectively?
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)
Steps of vitamin D synthesis
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
What does adding vitamin D3 to calcium do?
Increases GI tract absorption of calcium by adding more calmodulin
What does adding magnesium to calcium supplements do?
Is a cofactor needed to activate the enzyme that activates vitamin D in liver and kidneys
What are the main biological factors in play for calcium/phosphate homeostatic control?
PTH
Vitamin D3
FGF-23
Calcitonin
Glucocorticoids
Thyroid hormone
Gonadal steroids
in order of most effect to least effect
How does parathyroid hormone effect change based on how often it is given?
Continuously = increases osteoclast activity
Given once-daily = paradoxically increases osteoblast activity
**this is why we only give daily doses for decreased BMD
Estrogen effects in therapy
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
How does pyrophosphate/bisphosphonates work biologically?
Concentrate in bone matrix and chelates hydroxyapatite preventing hydroxyapatite solubility and make osteoblast job easier
**also can get internalized by osteoclasts and induce apoptosis
How does denosumab and RANKL work biologically
RANKL = released by osteoblasts to induce fusion and generation of multi-nucleated active osteoclasts
Denosumab = chelates RANKL and prevents it to bind to osteoclasts
