Osteoporosis

Question 1

What is osteoporosis?

Answer 1

This is the loss of bone mass due to the reduction in organic bone matrix and mineral content.
-decreased mechanical strength of the bones
-increased incidences of fractures
-more common in females as oestrogen controls the balance between osteoblast and clasts.

Question 2

What do osteoclasts and osteoblasts do?

Answer 2

Osteoclast- degrade bone
Osteoblast- formation of bone

There is a balance of these. A balance is required.

Question 3

Why are women at a higher risk of osteoporosis?

Answer 3

This is due to the loss of oestrogen levels this helps to maintain the balance of osteoblast and osteoclasts.

RANKL is not suppressed when a women is oestrogen deficient

Question 4

What is rank L ?

Answer 4

Receptor activated NFkb ligand- this is a osteoclast activator.

It’s main role is to activate osteoclasts

Question 5

What is OPG and what is the job?

Answer 5

Osteoprotegerin- this inhibits bone resorption (breakdown of bone)

Binds to rankL to stop the formation of osteoclasts.
Increased bone formation via the osteoblasts.

Question 6

What pharmacological treatments are available for osteoporosis?

Answer 6

BISPHOSPHONATES: ANTI RESORPTIVE THERAPIES
-ORAL(Alendronic acid and risedronate)
-parental( zoledronic acid)
-RALOXIFENE AND OESTROGEN
-Denosumab ( sub injection)

Less commonly used:
-HRT ( early menopause)

BONE FORMING ANABOLIC THERAPIES:
-Calcitonin
-teriparatide

Question 7

What is primary osteoporosis?

Answer 7

Menopause - increased bone reabsorption
Age associated - decrease in bone formation

Question 8

What is secondary osteoporosis?

Answer 8

-Drug or disease induced.
-Malnutrition (anorexia)
-Lack of vitamin D
-Hyperparathyroidism
-Cancer

Question 9

What is RANK?

Answer 9

Rank is the receptor activated NFkB, this is found on the surface of pre osteoclasts.

Question 10

What can cause the bone to release RANK L?

Answer 10

Parathyroid hormone
If there is a stimulation of PTH then more RANK L to be released.

Question 11

Why is oestrogen important for bone?

Answer 11

Oestrogen promotes the formation of osteoblasts.
Oestrogen will inhibit the T cell formation/activation thus inhibits the release of RANK L.

Question 12

WHAT HAPPENS IF THERE IS AN ABSENCE OF OESTROGEN FOR BONE ?

Answer 12

Increased activation of T cells which can go onto promote the release of RANK L to form osteoclasts that can again promote bone reabsorption.

Question 13

What does calcified bone contain?

Answer 13

-25% organic matrix
-5% water
-70% hydroxyapatite (holds the bone together)

Question 14

Why can’t we give pyrophosphate and what would we give instead?

Answer 14

This is because it is hydrolysed when taken orally by the GI tract, into two phosphate groups, thus we would use a biphosphonate, e.g. alendronic acid

Question 15

How does the pyrophosphate and bisphosphatonates differ in structure?

Answer 15

The bisphosphonate replaces the oxygen of the pyrophosphate with a carbon with two functional groups. Therefore they cannot be hydrolysed.

They bind and stabilise calcium phosphate in the bone.

Question 16

What is the job of bisphosphonates?

Answer 16

They work like pyrophosphate, like a glue to hold the bones together.
-inhibit osteoclast proliferation
-inhibit osteoclast activity
-inhibit the malaveonate pathway of osteoclasts

THEY ALLOW OSTEOBLASTS TO FUNCTION.

Question 17

Why is it effective to have a hydroxyl group as R1 functional groups in bisphosphonates?

Answer 17

This is because it maximises the effects to bind to hydroxyapatite and increases the calcium affinity.

Question 18

What happens if we add an amino acid residue on functional group R2 in bisphosphonates?

Answer 18

This will increase the potency (concentration)

Question 19

Bisphosphonates and the pharmacology?

Answer 19

-absorption is poor due to being polar
-50% incorporated into bone the rest is excreted via the kidneys
-serum half life is 4-6 hr the tissue half life is 10 years

Question 20

What is 1st line treatment for osteoporosis and what is the drugs job?

Answer 20

ALENDRONIC ACID (second generation)
- it strengthens the bone lattice
-decreases osteoclast formation
-impacts the malaveonate pathway.
-reduces fracture risks by 50%

Question 21

What is the second line drug used in osteoporosis?

Answer 21

Risedronate

Question 22

What is the bisphosphonate that requires to be adminstrated via IV route?

Answer 22

Zolendronic acid and it is given every 12 months or annually.
-it is give if oral route are not tolerated.

Question 23

What does the renal function of a patient require to be if they take Alendronic acid and risedronate?

Answer 23

Alendronic acid = <35ml/min

Risedronate= <30ml/min

Question 24

What do we need to look out for when a patient is on an osteoporosis medication?

Answer 24

Hypocalcaemia= this is when the calcium levels are too low in the body.

Dysphagia= patient unable to swallow properly

Question 25

Why is a patient advised to take bisphosphonates on an empty stomach?

Answer 25

To avoid binding by calcium in the food.

Question 26

What adverse effects are experienced with bisphosphonates?

Answer 26

-GI disturbances -nausea -abdominal pain -diarrhoea -constipation. -headaches -dizziness -vertigo -musculoskeletal pain -oesophagitis -I.V can cause osteonecrosis of the jaw.

Question 27

What is denosumab and how does it work?

Answer 27

Denosumab is a monoclonal antibody that mimics OPG, it is seen as a synthetic version. -thus it binds to RANK L to prevent osteoclast activation.

Question 28

How often is denosumab injected?

Answer 28

6 monthly injections

Question 29

What are selective estrogen receptor modulators and give examples?

Answer 29

Raloxifene This is seen as an antagonist in breast tissue, thus stops the formation of breast cancer In osteoclasts it is an ER agonist, thus it will switch on the estrogen receptors in bones and switches off the estrogen in the breast tissue. -reduces the osteoclast activity

Question 30

What are the disadvantages to taking SERMS?

Answer 30

-It doesnt prevent: Hot flushes And other symptoms of menopause

Question 31

What is the job of raloxifene?

Answer 31

-it decreases fracture risk -promotes bone formation -excreted in bile -stimulates estrogen receptor and reduces osteoclast activity.

Question 32

Why is HRT less favoured in the treatment of osteoporosis?

Answer 32

This is because there is an increased risk of breast cancer and thrombosis.

Question 33

How does raloxifene differ depending on where it is in the body?

Answer 33

In breast tissue= antagonist thus switches the genes off here. Bones/osteoclasts=agonist

Question 34

HOW IS RALOXIFENE EXCRETED?

Answer 34

VIA BILE

Question 35

What are the 2nd generation SERMS and grove an example?

Answer 35

Lasofoxifene -prevents bone loss -impoirves bone density by 3%

Question 36

What is a SERM?

Answer 36

A serm stands for a selective estrogen receptor modulator

Question 37

What causes the SERM effect?

Answer 37

Raloxifene binds to the estrogen receptor, moves into the nucleus of the bone environment, and then binds to raloxifene response element that is only found in bone, and not in the breast. Helper proteins in the bone environment will help and aid the binding into the receptors, this isn’t present in the breast environment thus activating the genes.

Question 38

What is teriparatide and what is its job in the treatment of osteoporosis?

Answer 38

This is an anabolic treatment, it stimulates osteoblasts -it is a synthetic version of the PTH hormone, which means that continuous use of it will promote bone formation. -activates osteoblasts and OPG stimulation -decreases osteoclasts NEEDS TO BE INJECTED DAILY

Question 39

What does the parathyroid hormone do?

Answer 39

It indirectly stimulates intestinal absorption of calcium and promotes bone reabsorption, it does this by: -osteoprogenitor cells becoming osteoclasts in the presence of PTH. -PTH promotes the deep osteocytes to mobilise calcium -surface osteocytes are stimulated by PTH to increase the flow of calcium out of the bone. -PTH decreases renal excretion of calcium

Question 40

What function does PTH obtain in bones?

Answer 40

PTH effects bones as it can: 1.promote bone reabsorption, it does this by increasing osteoclast activity, through the up regulation of RANK L and down regulation of OPG secretion by osteoblasts. 2.promotes bone formation, it does this by autocrine and paracrine pathways through release of growth factors . THIS OCCURS ONLY IF PTH IS GIVEN EVERYDAY.

Question 41

What are the risk factors of osteoporosis?

Answer 41

-post menopausal women -being a women -old age -repeated steroid use -excessive alcohol consumption -underweight -eating disorders -smoking -early menopause