PHARM - Drugs Used to Treat Bone Disorders - Week 8

Question 1

Name three mechanical functions of bone.

Answer 1

Provides structural support
Protects organs
Sites of attachment for muscles

Question 2

Name two metabolic functions for bone.

Answer 2

Reservoir of calcium (~99%) and phosphate (85%)

Acid-base balance

Question 3

Name one synthesis function of bone.

Answer 3

Production of white and red blood cells

Question 4

Are bones metabolically active?

Answer 4

Yesd

Question 5

Describe the bone strucutr in terms of percentages.

Answer 5

80% cortical bone

20% trabecular bone

Question 6

What percentage of total bone is remodelled every year in adults?

Answer 6

10%

Question 7

What four factors affect bone remodelling.

Answer 7

Ageing
Physical factors (exercise/loading)
Hormones (oestrogen)
Drugs (corticosteroids)

Question 8

Which type of bone do processes affecting bone remodelling preferentially affect? Name two specific bones that are affected.

Answer 8

Trabecular bone

-femoral neck and vertebral bodies

Question 9

Give three reasons why is bone remodelled (5).

Answer 9

Bone growth during skeletal development
Response to mechanical stress
-mechanical loading
-stress related micro-fractures
Regulation of calcium in the ECM

Question 10

Name the three constituent cells of bone.

Answer 10

Osteoblasts
Osteocytes
Osteoclasts

Question 11

What two components form the bone ECM?

Answer 11

Osteoid

Hydroxyapatite

Question 12

What is calcium phosphate?

Answer 12

Hydroxyapatite

Question 13

Name 5 components of the osteoid.

Answer 13

Unmineralised bone matrix
Collagen I
Proteoglycans
Osteocalcin
Osteonectin

Question 14

Name the 5 phases of bone remodelling.

Answer 14

Activation
Resorption
Reversal
Formation
Quiescence

Question 15

In what phase of bone remodelling does oesteoclastogenesis occur?

Answer 15

Activation

Question 16

What initiates osteoclastogenesis?

Answer 16

Upstream pro-resorptive cytokines

Question 17

The balance between the action of what two cells determines bone mineral density?

Answer 17

Modelling osteoblasts and remodelling osteoclasts

Question 18

What three factors regulate bone mineral homeostasis?

Answer 18

Parathyroid hormone PTH
Vitamin D
Calcitonin

Question 19

Where are the thyroid and parathyroid glands found?

Answer 19

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.

Question 20

What hormone is released in response to low blood Ca2+ levels?

Answer 20

Parathyroid hormone

Question 21

What effects does parathyroid hormone have on the kidney and bones (2)?

Answer 21

Increases Ca2+ uptake in kidneys

Stimulates Ca2+ release from bones

Question 22

Consider parathyroid hormone’s effect on the kindey. What does it result in the increased synthesis of, what effect does this have, and where?

Answer 22

Increased calcitriol (vitamin D) synthesis which indirectly increases calcium uptake in the GI tract.

Question 23

What hormone is released in response to high blood Ca2+ levels and by what?

Answer 23

Thyroid gland releases calcitonin

Question 24

What two effects does calcitonin have on the kidney and bones?

Answer 24

Stimulates Ca2+ deposition in bones

Reduces Ca2+ uptake in kidneys

Question 25

Calcitonin decreases the activity of which bone cell?

Answer 25

Osteoclast

Question 26

What is ergocalciferol, where does it come from, and what happens to it once it is uptaken (3)?

Answer 26

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.

Question 27

What is the active form of vitamin D3?

Answer 27

Calcitriol

Question 28

What is cholecalciferol, where does it come from (2), and what happens to it when it is uptaken (4)?

Answer 28

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.

Question 29

What are precursors of vitamin D converted to in the liver?

Answer 29

Calcifediol

Question 30

In what three ways does calcitriol increase plasma calcium?

Answer 30

Increased intenstinal absorption Decreased renal excretion Increased osteoclast activity in bones

Question 31

Define osteoporosis.

Answer 31

Reduction in bone mass more than 2.5 standard deviations below the normal for healhy 30 year old women

Question 32

What happens to the trabeculae with osteoporosis (2)?

Answer 32

Loss and thinning

Question 33

In what three circumstances can osteoporosis occur?

Answer 33

Post-menopausal With ageing Following glucocorticoid therapy

Question 34

How do glucocorticoids induce osteoporosis?

Answer 34

They upregulate osteoclast activity, inducing bone resorption

Question 35

Name five anti-resporptive drug classes to treat bone disorders.

Answer 35

``` Bisphosphonates Selective oestrogen receptor modulators (SERMs) RANK ligand inhibitors Calcitonin Calcimimetics ```

Question 36

Name five anabolic drug classes to treat bone disorders.

Answer 36

Parathyroid hormone Oral calcium Oral vitamin D analogues

Question 37

What drug class is the first line of treatment for post-menopausal women at risk of fractures?

Answer 37

Bisphosphonates

Question 38

Briefly describe the mechanism of bisphosphonates (3).

Answer 38

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.

Question 39

Name and describe the three generations of bisphosphonates and briefly mention their action.

Answer 39

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

Question 40

Name four modalities by which bisphosphonates can exert their effect.

Answer 40

- 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

Question 41

What three conditions are bisphosphonates indicated for, how is it administered (2), and its bioavailability (including percentage).

Answer 41

``` Osteoporosis Paget's disease Hypercalcaemia Given orally or IV once yearly Poorly absorbed orally - 1-2% ```

Question 42

Name 5 side effects of bisphosphonates.

Answer 42

``` Nausea Discomfort Vomiting Diarrhoea Headache ```

Question 43

What effect does oestrogen have on bone?

Answer 43

Protective effect from PTH induced bone resorption

Question 44

Why is there a greater risk of osteoporosis in women post-menopause?

Answer 44

Descreased oestrogen production

Question 45

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.

Answer 45

Hormone replacement therapy, which maintains mass and slows bone loss. Increased risk of cardiovascular disease and breast cancer.

Question 46

What therapy has replaced hormone replacement therapy for treating osteoporosis?

Answer 46

Selective oestrogen receptor modulators (SERMs)

Question 47

What are SERMs (6)?

Answer 47

Agonist at oestrogen receptors in bone and cardiovascular tissue Antagonist at oestrogen receptors in mammary tissue and the uterus

Question 48

What is the preferred treatment for osteoporosis in women who have breast cancer or a family history of breast cancer?

Answer 48

SERMs

Question 49

How are SERMs administered and what is its bioavailability?

Answer 49

Once daily orally with 2% bioavailability

Question 50

Name 7 side effects of SERMs.

Answer 50

``` Hot flushes Sweating Leg cramps Oedema Sleep disorders Increased risk of DVT and pulmonary embolism ```

Question 51

Describe how RANK ligand inhibitors work.

Answer 51

Human monoclonal antibodies that bind to RANK ligands, inhibiting them.

Question 52

Name three outcomes of RANK ligand inhibitors.

Answer 52

Reduces osteoclast differentation, survival, and activity.

Question 53

Name two side effects of RANK ligand inhibitors.

Answer 53

Eczema | Hypercholesterolaemia

Question 54

Describe how pharmacologically administered calcitonin works, name 4 outcomes, and what two diseases it is used for.

Answer 54

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

Question 55

Is pharmacologically administered calcitonin a 1st line therapy for oesteoporosis?

Answer 55

No

Question 56

How is calcitonin administered (3)?

Answer 56

Subcutaneous injection Intramuscular injection Nasal spray

Question 57

Name four side effects of calcitonin.

Answer 57

Flushing Nausea Vomiting Diarrhoea

Question 58

Briefly describe how calcimimetics work.

Answer 58

Allosteric modulators of the calcium sensing receptor on the parathyroid cells, increasing its sensitivity to blood Ca2+, and suppressing PTH.

Question 59

What two diseases are calcimimetics indicated for?

Answer 59

Hypercalcaemia in parathyroid carcinoma | Primary hyerthyroidism when parathyroidectomy isnt an option

Question 60

Name 9 side effects of calcimimetics.

Answer 60

``` Hypocalcaemia Nausea Vomiting Anorexia Dizziness Parasthaesia Weakness Myalgia Rash ```

Question 61

What must patients taking calcimimetics be monitored for?

Answer 61

Hypocalcaemia

Question 62

What is given for severe osteoporosis (an alternatives are unsuitable)?

Answer 62

Bone anabolic agents

Question 63

Give an example of a pharmaceutical bone anabolic agent and name 5 side effects.

Answer 63

``` Teriparatide Nausea Headaches Dizziness Cramping Joint pain ```

Question 64

What kind of onset and duration of action does orally administered cholecalciferol have? Is there a risk of hypercalcaemia?

Answer 64

``` Slow onset (4-8 weeks) and prolonged duration of action (8-16 weeks) No risk of hypercalcaemia at physiological doses ```

Question 65

What kind of onset and duration of action does orally administered calcitriol have? Is there a risk of hypercalcaemia?

Answer 65

``` Rapid onset (1-3 days) and short duration of action (<1 week) Higher risk of hypercalcaemia ```

Question 66

Is calcitriol used for osteoporosis? Can it be taken with calcium like cholecalciferol can?

Answer 66

Calcitriol is rarely used. | Shouldnt be taken with calcium supplements due to the risk of hypercalcaemia.