Bone Disorders

Question 1

Bone physiology

Answer 1

• is living, dynamic tissue, subject to continuous remodelling
• balance between osteoclasts and osteoblasts
  Osteoclasts: break down bone
  Osteoblasts: build up bone

Question 2

Most common disorder involving bone

Answer 2

Osteoporosis

Question 3

Osteoporosis characteristics

Answer 3

• loss of bone mineral density (BMD) and increased fracture risk
• tends to be associated with aging, but can occur in relatively young individuals

Question 4

Drugs used to treat Osteoporosis

Answer 4

Drugs that inhibit Osteoclasts: anti-resorptive

Drugs that promote osteoblasts: anabolic

Question 5

Drugs that inhibit osteoclasts (4)

Answer 5

• Bisphosphonates
• Hormone therapies
• RANKL inhibitors
• Calcitonin

Question 6

Bisphosphonates example

Answer 6

Alendronate

Question 7

Mechanism of Bisphosphonates

Answer 7

Promote apoptosis of osteoclasts

• inhibit mevalonate pathway
• this inhibits generation of prenylated proteins
• prenylated proteins promote osteoclasts function and promote apoptosis
• therefore BPs inhibit osteoclasts function and promote apoptosis

Question 8

Other uses of BPs (Alendronate)

Answer 8

Hypercalcemia: inhibit bone reabsorption, reduces release of Calcium into the blood

Question 9

BPs unusual distribution

Answer 9

Concentrate in bone: can remain attached to bone for several months, Osteoclasts activity (release of acids) releases BPs slowly over time, can take weekly: One formulation, zolendronic acid, administered IV once/year

Question 10

Administration of BP’s

Answer 10

Most administered Orally
- low oral bioavailability, food and mineral like calcium reduce absorption
- take on empty stomach
Other than Zolendronic acid: intravenous infusion

Question 11

BPs adverse effects

Answer 11

• irritating to the GI tract
• Nausea, vomiting, diarrhea
• abdominal pain
• Osteonecrosis of the jaw: bone become necrotic and exposed to the oral cavity, painful and increased risk of fracture
• key factor is a previous dental extraction

Question 12

Main serious Issue with BPs

Answer 12

• Esophageal damage: may be due to direct irritant effect or increased acid production
• should remain upright for at least 30 minutes after taking

Question 13

Hormone therapy

Answer 13

Estrogens promote bone

• inhibit osteoclasts
• may promote osteocytes survival
• this is why as estrogen levels decline with age, so does bone health

Question 14

Negative effects of Estrogen

Answer 14

• increased risk to some cancers

- increased risk to thrombosis

Question 15

Raloxifene

Answer 15

Acts as an estrogen agonist in bone

- inhibits reabsorption

Question 16

Adverse effects of Raloxifene

Answer 16

Hot flashes
Leg cramps
Increases risk of thrombosis

Question 17

Role of RANKL

Answer 17

Receptor Activator of Nuclear factor Kappa-B Ligand

• binds to the RANK receptor
• stimulates osteoclasts

Question 18

RANKL inhibitor example

Answer 18

Denosumab

Question 19

Denosumab mechanism

Answer 19

• binds to the RANK receptor, prevents RANKL binding

- inhibits osteoclasts activity

Question 20

Denosumab characteristics

Answer 20

• monoclonal antibody

- administered by injection

Question 21

RANKL inhibitors adverse effects

Answer 21

• may increase risk of infection: RANKL plays a role in the immune system
• Osteonecrosis of jaw: Mechanism unclear

Question 22

Calcitonin mechanism

Answer 22

• inhibits osteoclasts activity by activating G-protein coupled receptor: decreases bone reabsorption, decrease calcium in blood
• therefore can also be used in treatment of hypercalcemia
• receptor desensitization can occur over time, reducing efficacy of Calcitonin

Question 23

Calcitonin uses

Answer 23

More commonly for treating pain from osteoporotic fractures

Administered as an injection

Question 24

Calcitonin adverse effects

Answer 24

• Nausea
• Hives
  Serious: Cancer - Calcitonin nasal spray withdrawn from market over cancer concerns

Question 25

Promoting bone formation drug example

Answer 25

Teriparatide - human recombinant parathyroid hormone (PTH) - high levels of PTH stimulates osteoclasts - low intermittent PTH stimulates osteoblasts

Question 26

Intermittent use Human recombinant parathyroid hormone

Answer 26

- increase osteoblasts numbers | - prevents osteoblasts apoptosis

Question 27

Administration of teriparatide

Answer 27

Subcutaneous injection

Question 28

Adverse effects of Teriparatide

Answer 28

Cramping Hypercalcemia Safety issue: Teriparatide promotes bone formation/osteoblasts - animal studies show link to osteosarcoma - treatment duration limited to 18 months

Question 29

Calcium Supplements available

Answer 29

- Calcium carbonate (TUMS) - Calcium citrate - Carbonate has higher Calcium content than citrate

Question 30

Adverse effects of calcium supplements

Answer 30

- Gastrointestinal: constipation | - excess intake can lead to problems: hypercalcemia, renal stones

Question 31

Calcium supplements in certain stages of life

Answer 31

Early: contributes to bone growth Elderly: reduces bone turnover - no clear evidence that supplementation reduces fractures

Question 32

Role of Vitamin D

Answer 32

Improves Calcium absorption - Natural sources: Sunshine, dairy, fish Elderly at increased risk of deficiency due to reduced time outdoors

Question 33

Various forms of Vitamin D

Answer 33

Vitamin D2: Ergocalciferol Vitamin D3: Cholecalciferol - synthetic form: calciferol

Question 34

Vitamin D adverse effects

Answer 34

Gastrointestinal: Nausea, constipation | Hypercalcemia

Question 35

Drugs that reduce BMD

Answer 35

Tobacco (smoking) Corticosteroids - both promote osteoclasts activity