Flashcards in Drugs affecting bone metabolism Deck (45):
Describe calcium homeostasis
1 for PTH release from parathyroid glands in response to low plasma Ca2+ levels
3 for 3 effects of circulating PTH (bone - promote osteoclast activity), intestine and kidney absorb Ca2+)
1 for negative feedback (calcitonin)
How do PTH and osteoclast precursors interact?
PTH stimulates recruitment of osteoclast precursors, and differentiation into osteoclasts
How might cytokines such as ILs interact with osteoclast precursors?
Stimulate recruitment of osteoclast precursors, and differentiation into osteoclasts
How might a cytokine such as IGF-1 interact with osteoblast precursors?
Promotes differentiation into osteoblasts
Where might IGF-1 be found?
Circulating in the bloodstream or stored in osteoids
What is RANKL? Describe how it can change blood Ca2+ levels?
RANKL is an activating factor that stimulates transcription, pushing osteoblasts to osteoclasts. RANKL interacts with RANK receptors on osteoclast precursors. These then form multinucleated osteoclasts that resorb bone.
Provide 3 examples that stimulate RANKL pathway and 1 example that inhibits RANKL pathway
Calcitriol, PTH and ILs stimulate, osteoprotogerin inhibits by being a decoy for RANKL - by not allowing interaction with RANK receptors, it inhibits osteoclast activity
3 diseases bisphosphonates are used for?
Osteoporosis, Paget's disease, hypercalcaemia (due to malignancies)
What are bisphosphonates?
Analogues of pyrophosphate
What do bisphosphonates do and how? (3)
Inhibit bone breakdown and resorption
Taken up by osteoclasts in matrix - inhibit recruitment and promote apoptosis
Indirectly stimulate osteoblasts
2 examples of bisphosphonates?
alendronate and risedronate
Can bisphosphonates be taken orally?
Poorly absorbed orally, can be taken with lots of water to prevent gastro-oesophageal irritation
Common adverse effects of bisphosphonates?
GI upset, musculoskeletal pain, headache
Rare adverse effects to bisphosphonates?
Osteonecrosis of the mandible; risk increased by recent dental work or jaw trauma
When are SERMS used?
selective oestrogen receptor modulators used in post-menopausal osteoporosis; a decline in oestrogen leads to a loss in bone-protective effect
Agonist and antagonistic properties of SERMS?
agonist: bone and cardiovascular system (tibolone - vagina, and prosteogenic effect on breasts, common ADRs are headache, dizziness and vaginal bleeding)
antagonist: breast and uterus
Side effects of SERMS?
hot flushes, thromboembolism, dizziness, GI upset, leg cramps
When is Vitamin D used?
treatment in deficiency states, rickets and osteomalacia, hypocalcaemia due to hypoparathyroidism
What is the common clinical form of Vitamin D3 used in treatment?
calcitriol/ 1,25-dihydroxycholecalciferol - most biologically active form of Vitamin D
How might vitamin D be administered?
oral preparations and injectable calciferol
What is Vitamin D's distribution?
Lipid soluble - can be transported to fat stores and remain there for months
A common ADR of vitamin D
Examples of calcium salts and routes of administration
oral: gluconate, carbonate or lactate salts
intravenous: gluconate preferred or chloride
Disadvantage of carbonates?
poorly absorbed and binds to phosphates
Routes of administration of calcium salts to avoid
SC or IM injections are severely irritant
When to use calcium salts?
deficiency states, hypocalcaemia in hypoparathyroidism, prevention and treatment of osteoporosis
Common ADRs of calcium salts
GI disturbances, especially in oral form
What is teriparatide and significance of its structure?
peptide with human parathyroid hormone sequence
- given SC intermittently, stimulates osteoblasts
- given in postmenopausal women in terms of fracture rates and bone density
Side effects of teriparatide
nausea, dizziness, injection site reactions, joint pain
- risk of osteosarcoma limits duration of therapy
In what diseases is it good to use calcitonin?
Paget's disease and osteoporosis
What does calcitonin do?
stimulates calcium uptake into bone and inhibits bone resorption
Duration of effect of calcitonin (relative)?
Rapid, short acting
Types of calcitonin
Porcine (pig) calcitonin or synthetic (salmon) form
How is calcitonin administered?
Injected subcutaneously because it is a peptide
What is cincalcet?
calcium mimetic agent
When is cincalcet used?
in PTH-induced hypercalcaemia, to decrease PTH secretion, lower Ca2+ plasma levels
(works in same way as having high Ca2+ levels)
mechanism of cincalcet?
increase sensitivity of calcium ion sensing receptor on PTH cells
common ADRs of cincalcet?
- nausea and vomiting
- also need to monitor for hypocalcaemia, and calcium and phosphate levels
- drug interactions
What is denosumab, what is it directed at?
a monoclonal antibody
directed to RANKL and its receptor RANK
mechanism of action of denosumab?
decreases osteoclast activity, and consequently bone resorption
common ADRs of denosumab?
hypocalcaemia, hypercholesterolaemia, eczema, osteonecrosis rarely
How is denosumab administered?
What else needs to be taken with denosumab?
concomitant vitamin D and calcium supplementation
What is the significance of bisphosphonates being taken up into the bone?
bisphosphonates can be incorporated into the bone matrix, taken up by osteoclasts causing apoptosis