96 - Drugs Affecting Bone

Question 1

Proportions of trabecular and cortical bone

Answer 1

Bones are 20% trabecular, 80% cortical

Question 2

Effect of tetracycline on teeth

Answer 2

When consumed during tooth development, binds to calcium ions. Leads to yellow/brown discolouration of dentine.

Question 3

Amount of bone remodelled each year in adults

Answer 3

25% of trabecular bone remodelled each year
3% of cortical bone remodelled each year
~10% of total bone remodelled each year

Question 4

Five phases of bone remodelling

Answer 4

– Activation
– Resorption
– Reversal
– Formation
– Quiescence

Question 5

How can growth factors be released in bone remodelling?

Answer 5

Embedded in bone, released during bone resorption.

Recruit, activate osteoblasts to begin making new osteoid over resorbed bone.

Question 6

Osteoclastogenesis

Answer 6

Upstream pro-resorptive cytokines promote stromal cell RANKL (membrane associated or soluble).
RANKL stimulates osteoclastic precursors (in conjunction with M-CSF) to differentiate into mature osteoclasts

Question 7

Factors regulating bone remodelling

1-5

Answer 7

1) Parathyroid hormone
2) Oestrogen
3) Glucocorticoids
4) Sequestered cytokines in bone
5) Calcitonin

Question 8

Parathyroid hormone role

Answer 8

Increased osteoblast activity, increased osteoclast activity

Question 9

Oestrogen role, with respect to bone

Answer 9

Decreased osteoclast activity

Question 10

Glucocorticoid effect on bones

Answer 10

Increased osteoclast activity

Decreased osteoblast activity

Question 11

Calcitonin effect on bones

Answer 11

Decreased osteoclast activity

Question 12

Effect of dexamethasone on bones

Answer 12

Increases RANKL and decreases OPG

Question 13

Things regulating serum calcium concentration

1-3

Answer 13

Parathyroid hormone
Vitamin D
Calcitonin

Question 14

How does PTH increase serum Ca2+?

Answer 14

Increased vitamin D synthesis
Mobilises Ca2+ from bone
Reduces renal Ca2+ excretion

Question 15

How does calcitonin decrease serum Ca2+?

Answer 15

Decreases osteoclast activity and Ca2+ resorption from bone.

Inhibits Ca2+ resorption in the kidney

Question 16

Where does calcitonin come from?

Answer 16

C cells of the thyroid gland

Question 17

Vitamin D synthesis

Answer 17

Cholesterol metabolised in the skin, catalysed by UV exposure.
This results in liver producing calcifediol in the liver.
Calcifediol is metabolised to calcitriol in the kidney.
Calcitriol is the active part of vitamin D

Question 18

Effect of calcitriol on plasma Ca2+

Answer 18

Increases plasma Ca2+.
Increased intestinal absorption
Decreased renal excretion
Increased osteoclast activity

Question 19

Blood Ca2+ homeostasis

Answer 19

Thyroid gland detects high Ca2+, releases calcitonin.

Parathyroid glands detect low Ca2+, release PTH.

Question 20

Disorders of bone

1-5

Answer 20

Hypocalcaemia
Hypercalcaemia
Hypophosphataemia
Hyperphosphateaemia
Osteoporosis

Question 21

What can cause hypocalcaemia?

Answer 21

Vitamin D deficiency

Question 22

What can cause hypercalcaemia?

Answer 22

Malignancies

Question 23

What can cause hypophosphataemia?

Answer 23

Nutritional deficiency

Question 24

What can cause hyperphosphataemia?

Answer 24

Renal failure

Question 25

Definition of osteoporosis

Answer 25

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

Question 26

Definition of osteopaenia

Answer 26

Reduction in bone mass more than 1-2.5 standard deviations below the normal for healthy 30 year old woman

Question 27

When is peak bone density?

Answer 27

20s to 30s.

Question 28

When does bone density begin decreasing?

Answer 28

Age 35-40 (decrease about 0.5-1% per year)

Question 29

Effect of osteoporosis on bone

Answer 29

Loss of trabeculae and thinning leads to reduced cross-sectional area, so that loads on bone are relatively greater.

Question 30

Anti-resorptive agents for bone disorders | 1-3

Answer 30

Bisphosphonates Selective oestrogen receptor modulators (SERM) RANK-L inhibitors

Question 31

Anabolic agents for bone disorders | 1-4

Answer 31

PTH Oral Ca2+ Oral vitamin D analogues Calcitonin

Question 32

Bisphosphonate structure

Answer 32

Enzyme resistant analogues of pyrophosphate (pyrophosphate is essential for binding to bone mineral).

Question 33

Bisphosphonate mechanism of action

Answer 33

Inhibit binding of osteoclasts to bone surface, promote osteoclast apoptosis. Inhibit osteoclast recruitment. Promote osteoclast apoptosis Inhibit osteoclast binding to bone. Accumulate at sites of bone mineralisation, stay for long periods

Question 34

Bisphosphonate administration and side effects

Answer 34

Oral administration daily/weekly IV administration Poorly absorbed. Adverse GIT effects (osteophagitis)

Question 35

How does oestrogen affect bones?

Answer 35

Decreases osteoclast proliferation, differentiation, activation Promotes osteoclast apoptosis Increases life span of osteoblasts and osteocytes Doesn't increase bone mass, but maintains mass, slows bone loss.

Question 36

Problem with oestrogen for slowing bone loss

Answer 36

A lost of side effects, can lead to cancers

Question 37

Drug replacement for oestrogen (for bones)

Answer 37

Selective oestrogen receptor modulators (SERMS)

Question 38

Selective oestrogen receptor modulators (SERMS) mechanism

Answer 38

Agonist at oestrogen receptors in bone and cardiovascular tissue Antagonist at oestrogen receptors in mammary tissue and uterus (decreases cancer risk)

Question 39

Side effects of SERMS

Answer 39

Increased DVT risk, pulmonary embolism risk

Question 40

Human MAb that binds RANK-L

Answer 40

Denosumab

Question 41

Denosumab action

Answer 41

Human MAb that binds RANK-L Inhibits RANKL activity Reduces osteoclastic differentiation, survival , activity

Question 42

Antiresorptive and anabolic drug

Answer 42

Strontium ranelate

Question 43

Side effects of strontium ranelate

Answer 43

Increased incidence of MI. | For this reason, is a last line of treatment for severe osteoporosis.

Question 44

Drug based on PTH

Answer 44

Teriparatide

Question 45

Effect of PTH administration on bones

Answer 45

At low levels, is anabolic. | Long-term, high exposure to PTH leads to bone catabolism.

Question 46

Common adjunctive therapy for osteoporosis

Answer 46

Oral Ca2+

Question 47

What is vitamin D administered for?

Answer 47

Deficiency states, EG rickets, osteomalacia, endocrine dysfunction (hypoparathyroidism), chronic renal disease (where calcitriol can't be produced by kidney)

Question 48

Effect of calcitonin on bones

Answer 48

Decreases osteoclastic resorption and mobilisation of Ca2+ from bone.

Question 49

How is calcitonin administered?

Answer 49

Synthetic salmon calcitonin (salcatonin) given as an injection.

Question 50

What is calcitonin used to treat?

Answer 50

Paget's disease, hypercalcaemia associated with neoplasia