Pathophysiology of Osteoporosis

Question 1

What are the determinants of bone strength?

Answer 1

Geometry + BMD

Question 2

What regulates calcium?

Answer 2

Parathyroid hormone (PTH)
Calcitonin

Question 3

How does PTH regulate calcium?

Answer 3

Increases calcium by stimulating osteoclasts, increasing intestinal absorption + decreases calcium excretion by kidneys

Question 4

How does Calcitonin regulate calcium?

Answer 4

Decreases calcium by inhibiting osteoclast activity + increasing calcium excretion via kidneys

Question 5

How does calcium regulation work overall?

Answer 5

Homeostasis remained by PTH + calcitonin
Rise in blood Ca = thyroid release calcitonin = stimulates Ca salt deposit in bone
Falling blood Ca = parathyroid gland release PTH = signals osteoclasts to degrade bone + release Ca into blood

Question 6

What is osteoporosis?

Answer 6

Skeletal disorder where bone strength is compromised with an increased risk of fracture

Question 7

What is osteomalacia + rickets?

Answer 7

Abnormal bone formation due to inadequate mineralisation

Question 8

What are the causes of osteomalacia?

Answer 8

Severe, prolong VitD deficiency
Long term anticonvulsant therapy (eg. phenobarbital)

Question 9

What is the pathophysiology of osteomalacia?

Answer 9

Normal bone resorption + formation
But body unable to fully mineralise newly formed osteoid tissue = decreased bone strength

Question 10

What is the treatment of osteomalacia?

Answer 10

High dose of VitD

Question 11

How does osteoporosis develop?

Answer 11

Osteoclast recruitment increased
Osteoblast-osteoclast coupling interrupted
= factors don’t adequately recruit osteoblasts
Lack of oestrogen = less bone stimulation + deposition = reduced later osteoblast recruitment

Question 12

What does hormone dysregulation do to osteoporosis?

Answer 12

Accelerate it
= oestrogens + androgens help maintain bone mass

Question 12

What happens in postmenopausal osteoporosis?

Answer 12

Increases proliferation + activation of osteoclasts
Prolongs survival of osteoclasts

Question 12

What is type I osteoporosis?

Answer 12

Postmenopausal osteoporosis
= oestrogen deficiency

Question 13

What is type II osteoporosis?

Answer 13

Senile osteoporosis
= bone loss due to increased bone turnover

Question 14

How does long-term glucocorticoids cause osteoporosis?

Answer 14

Alteration in Ca absorption = secondary hyperparathyroidism
Inhibitory effect of sex hormone production
Inhibition of osteoblast function

Question 15

How do anticoagulants (heparin) cause reversible osteoporosis?

Answer 15

Increased osteoclast activity
Decreased osteoblast activity
Antagonist effect on VitK

Question 16

What other drugs may cause osteoporosis?

Answer 16

GnRH
Antiepileptics (eg. Phenytoin)
Loop diuretics (eg. Furosemide)

Question 17

How is osteoporosis diagnosed?

Answer 17

BMD

Question 18

What is the non-pharmacological treatment of osteoporosis?

Answer 18

Stop alcohol + smoking
Increase calcium in diet
Regular exercise
Avoid drugs that induce it

Question 19

What are the pharmacological therapies for osteoporosis?

Answer 19

Bisphosphonates
Ca
VitD
Oestrogen
Oestrogen receptor modulators (SERM)

Question 20

How much calcium should the average healthy adult receive?

Answer 20

1000mg

Question 21

How much calcium should someone over 65/osteoporosis/post-menopausal need?

Answer 21

1500mg

Question 22

How is total daily Ca achieved?

Answer 22

Diet + diet supplements

Question 23

What are the drug interactions for calcium?

Answer 23

Fe therapy impairs absorption Tetracyclines 2hrs apart = avoid intestinal chelation

Question 24

What are the adverse effects of calcium?

Answer 24

Nausea Constipation Abdominal distension Excess Ca = kidney stones

Question 25

What is given fir VitD?

Answer 25

Cholecalciferol

Question 26

How does Cholecalciferol work?

Answer 26

Improves Ca absorption in GI tract

Question 27

What are the adverse effects of Cholecalciferol?

Answer 27

Hypercalcemia (symptoms: anorexia, nausea + weakness)

Question 28

What are the drug interactions of Cholecalciferol?

Answer 28

Thiazide diuretics = increase risk of hypercalcemia

Question 29

What is the mechanism of action of Calcitonin?

Answer 29

Inhibits bone resorption by inhibiting osteoclast activity

Question 30

How is Calcitonin administrated?

Answer 30

Given by injection (SC/IM)

Question 31

What must patients do during the treatment of Calcitonin?

Answer 31

Ingest adequate Ca + VitD

Question 32

What are the adverse effects of Calcitonin?

Answer 32

Nausea + GI discomfort Initial face flushing + dermatitis Pruritis at site of injection

Question 33

What is the adverse effect of nasal Calcitonin?

Answer 33

Rhinitis

Question 34

What is the indication of Calcitonin?

Answer 34

2nd line treatment for osteoporotic patients who cannot tolerate other antiosteoporotic agents

Question 35

What is the indication of bisphosphonates?

Answer 35

1st line treatment for prevention of osteoporotic fractures

Question 36

How do bisphosphonates work?

Answer 36

Reduce bone absorption by inhibiting osteoclasts By binding to hydroxyapatite on bone mineral surface Taken up by osteoclast + modify activity Induce apoptosis

Question 37

Where are bisphosphonates excreted from?

Answer 37

Kidneys = not recommended for patients with impaired renal function

Question 38

What are the adverse effects of bisphosphonates?

Answer 38

Oesophagitis, gastritis + peptic ulcer Mild fever Aches following parentals

Question 39

What is the mechanism of action of oestrogen?

Answer 39

Supress bone resorption

Question 40

What are the adverse effects of oestrogen?

Answer 40

Increase incidence of breast + endometrial cancers Increase risk of DVT + gall bladder disease

Question 41

What are the indications of SERMs?

Answer 41

Postmenopausal women at risk for osteoporosis who cannot take bisphosphonates Post menopausal women at increased risk for breast cancer

Question 42

What is the indication of Teriparatide (recombinant PTH)?

Answer 42

Severe osteoporosis in men + postmenopausal women

Question 43

What is the mechanism of action of Teriparatide (recombinant PTH)?

Answer 43

Supplements production of parathyroid hormone Regulates calcium-phosphate balance + stimulates new bone growth

Question 44

What is the administration of Teriparatide (recombinant PTH)?

Answer 44

Injected daily S/C Use limited to 2-year duration

Question 45

What are the adverse effects of Teriparatide (recombinant PTH)?

Answer 45

Postural hypertension Hypercalcemia Associated with osteosarcoma

Question 46

What are the contraindications of Teriparatide (recombinant PTH)?

Answer 46

Untreated hyperthyroidism Recurrent urolithiasis

Question 47

What is RANKL?

Answer 47

Mediator of osteoclast differentiation, activation + survival = primary mediator of bone resorption

Question 48

What is osteoprotegerin?

Answer 48

Alternative binding site for RANKL (decoy receptor), which cannot activate cellular signalling

Question 49

What is Denosumab?

Answer 49

Monoclonal Ab to RANKL

Question 50

What does Denosumab do?

Answer 50

Reduces osteoclast development = increases BMD = reduces risk of fractures

Question 51

What is the mechanism of action of Denosumab?

Answer 51

RANKL to surface of pre-osteoclast Activation of RANK by RANKL = maturation of osteoclast Denosumab inhibits maturation by inhibiting RANKL NO osteoclast = no bone resorption