PHARM - Drugs Used to Treat Bone Disorders - Week 8 Flashcards
Name three mechanical functions of bone.
Provides structural support
Protects organs
Sites of attachment for muscles
Name two metabolic functions for bone.
Reservoir of calcium (~99%) and phosphate (85%)
Acid-base balance
Name one synthesis function of bone.
Production of white and red blood cells
Are bones metabolically active?
Yesd
Describe the bone strucutr in terms of percentages.
80% cortical bone
20% trabecular bone
What percentage of total bone is remodelled every year in adults?
10%
What four factors affect bone remodelling.
Ageing
Physical factors (exercise/loading)
Hormones (oestrogen)
Drugs (corticosteroids)
Which type of bone do processes affecting bone remodelling preferentially affect? Name two specific bones that are affected.
Trabecular bone
-femoral neck and vertebral bodies
Give three reasons why is bone remodelled (5).
Bone growth during skeletal development
Response to mechanical stress
-mechanical loading
-stress related micro-fractures
Regulation of calcium in the ECM
Name the three constituent cells of bone.
Osteoblasts
Osteocytes
Osteoclasts
What two components form the bone ECM?
Osteoid
Hydroxyapatite
What is calcium phosphate?
Hydroxyapatite
Name 5 components of the osteoid.
Unmineralised bone matrix
Collagen I
Proteoglycans
Osteocalcin
Osteonectin
Name the 5 phases of bone remodelling.
Activation
Resorption
Reversal
Formation
Quiescence
In what phase of bone remodelling does oesteoclastogenesis occur?
Activation
What initiates osteoclastogenesis?
Upstream pro-resorptive cytokines
The balance between the action of what two cells determines bone mineral density?
Modelling osteoblasts and remodelling osteoclasts
What three factors regulate bone mineral homeostasis?
Parathyroid hormone PTH
Vitamin D
Calcitonin
Where are the thyroid and parathyroid glands found?
Found inferior to the larynx, a wing-shaped organ with the lobes on either side of the trachea.
On the posterior surface are four nodes where the parathyroid glands sit, which is small and circular, found at each superior and inferior end of the lobes.
The region of the thyroid connecting the two lobes is called the isthmus.
What hormone is released in response to low blood Ca2+ levels?
Parathyroid hormone
What effects does parathyroid hormone have on the kidney and bones (2)?
Increases Ca2+ uptake in kidneys
Stimulates Ca2+ release from bones
Consider parathyroid hormone’s effect on the kindey. What does it result in the increased synthesis of, what effect does this have, and where?
Increased calcitriol (vitamin D) synthesis which indirectly increases calcium uptake in the GI tract.
What hormone is released in response to high blood Ca2+ levels and by what?
Thyroid gland releases calcitonin
What two effects does calcitonin have on the kidney and bones?
Stimulates Ca2+ deposition in bones
Reduces Ca2+ uptake in kidneys
Calcitonin decreases the activity of which bone cell?
Osteoclast
What is ergocalciferol, where does it come from, and what happens to it once it is uptaken (3)?
It is vitamin D2 - or vitamin D sourced from plants.
It is modified first in the liver and then again in the kidney into the active form of vitamin D3.
What is the active form of vitamin D3?
Calcitriol
What is cholecalciferol, where does it come from (2), and what happens to it when it is uptaken (4)?
It is vitamin D3 - or vitamin D sourced from eggs, fish, and cheese. It is also made by the skin.
It is modified first by UVB light in the skin, then again in the liver, and a final time in the kidney, into the active form of vitamin D3.
What are precursors of vitamin D converted to in the liver?
Calcifediol
In what three ways does calcitriol increase plasma calcium?
Increased intenstinal absorption
Decreased renal excretion
Increased osteoclast activity in bones
Define osteoporosis.
Reduction in bone mass more than 2.5 standard deviations below the normal for healhy 30 year old women
What happens to the trabeculae with osteoporosis (2)?
Loss and thinning
In what three circumstances can osteoporosis occur?
Post-menopausal
With ageing
Following glucocorticoid therapy
How do glucocorticoids induce osteoporosis?
They upregulate osteoclast activity, inducing bone resorption
Name five anti-resporptive drug classes to treat bone disorders.
Bisphosphonates
Selective oestrogen receptor modulators (SERMs)
RANK ligand inhibitors
Calcitonin
Calcimimetics
Name five anabolic drug classes to treat bone disorders.
Parathyroid hormone
Oral calcium
Oral vitamin D analogues
What drug class is the first line of treatment for post-menopausal women at risk of fractures?
Bisphosphonates
Briefly describe the mechanism of bisphosphonates (3).
It has a high affinity for bone mineral as it binds to hydroxyapatite.
It is incorporated into the bone matrix and remains for long periods.
When ingested by osteoclasts, apoptosis occurs.
Name and describe the three generations of bisphosphonates and briefly mention their action.
Non-nitrogen containing - 1st generation
-metabolised to a cytotoxic ATP analogue
Nitrogen containing - 2nd and 3rd generation
-impaired osteoclast attachment, formation of a ruffled border
Name four modalities by which bisphosphonates can exert their effect.
-Cytotoxic or metabolic injury of mature osteoclasts
-Inhibition of osteoclast attachment to bone
-Inhibition of osteoclast differentiation or recruitment
-Interference with osteoclast structural features necessary for bone resorption
What three conditions are bisphosphonates indicated for, how is it administered (2), and its bioavailability (including percentage).
Osteoporosis
Paget’s disease
Hypercalcaemia
Given orally or IV once yearly
Poorly absorbed orally - 1-2%
Name 5 side effects of bisphosphonates.
Nausea
Discomfort
Vomiting
Diarrhoea
Headache
What effect does oestrogen have on bone?
Protective effect from PTH induced bone resorption
Why is there a greater risk of osteoporosis in women post-menopause?
Descreased oestrogen production
Name a treatment therapy for women post-menopause who have osteoporosis and whether it increases or maintains bone mass.
Name two risks associated with this.
Hormone replacement therapy, which maintains mass and slows bone loss.
Increased risk of cardiovascular disease and breast cancer.
What therapy has replaced hormone replacement therapy for treating osteoporosis?
Selective oestrogen receptor modulators (SERMs)
What are SERMs (6)?
Agonist at oestrogen receptors in bone and cardiovascular tissue
Antagonist at oestrogen receptors in mammary tissue and the uterus
What is the preferred treatment for osteoporosis in women who have breast cancer or a family history of breast cancer?
SERMs
How are SERMs administered and what is its bioavailability?
Once daily orally with 2% bioavailability
Name 7 side effects of SERMs.
Hot flushes
Sweating
Leg cramps
Oedema
Sleep disorders
Increased risk of DVT and pulmonary embolism
Describe how RANK ligand inhibitors work.
Human monoclonal antibodies that bind to RANK ligands, inhibiting them.
Name three outcomes of RANK ligand inhibitors.
Reduces osteoclast differentation, survival, and activity.
Name two side effects of RANK ligand inhibitors.
Eczema
Hypercholesterolaemia
Describe how pharmacologically administered calcitonin works, name 4 outcomes, and what two diseases it is used for.
Binds to calcitonin receptors on osteoclasts
Decreases osteoclastic resorption and mobilisation of calcium from bone
Increases urinary excretion of calcium and phosphate
It is used in Paget’s disease and hypercalcaemia associated with neoplasia
Is pharmacologically administered calcitonin a 1st line therapy for oesteoporosis?
No
How is calcitonin administered (3)?
Subcutaneous injection
Intramuscular injection
Nasal spray
Name four side effects of calcitonin.
Flushing
Nausea
Vomiting
Diarrhoea
Briefly describe how calcimimetics work.
Allosteric modulators of the calcium sensing receptor on the parathyroid cells, increasing its sensitivity to blood Ca2+, and suppressing PTH.
What two diseases are calcimimetics indicated for?
Hypercalcaemia in parathyroid carcinoma
Primary hyerthyroidism when parathyroidectomy isnt an option
Name 9 side effects of calcimimetics.
Hypocalcaemia
Nausea
Vomiting
Anorexia
Dizziness
Parasthaesia
Weakness
Myalgia
Rash
What must patients taking calcimimetics be monitored for?
Hypocalcaemia
What is given for severe osteoporosis (an alternatives are unsuitable)?
Bone anabolic agents
Give an example of a pharmaceutical bone anabolic agent and name 5 side effects.
Teriparatide
Nausea
Headaches
Dizziness
Cramping
Joint pain
What kind of onset and duration of action does orally administered cholecalciferol have? Is there a risk of hypercalcaemia?
Slow onset (4-8 weeks) and prolonged duration of action (8-16 weeks)
No risk of hypercalcaemia at physiological doses
What kind of onset and duration of action does orally administered calcitriol have? Is there a risk of hypercalcaemia?
Rapid onset (1-3 days) and short duration of action (<1 week)
Higher risk of hypercalcaemia
Is calcitriol used for osteoporosis? Can it be taken with calcium like cholecalciferol can?
Calcitriol is rarely used.
Shouldnt be taken with calcium supplements due to the risk of hypercalcaemia.
