Week 2 - MSK

Question 1

What is osteoarthritis?

Answer 1

A chronic, progressive, irreversible, degenerative disease of articular cartilage.
Characterised by the inflammation or loss of cartilage in the joints.

Question 2

Where does osteoarthritis affect?

Answer 2

hands, knees, hips and spine.

Question 3

What causes osteoarthritis?

Answer 3

The active biological process of matrix degradation mediated by cells within the joint.

Question 4

What are the signs and symptoms of osteoarthritis?

Answer 4

Pain and stiffness in one or more load bearing joints.
Swelling/tenderness, limited ROM, imbalance, muscle wasting, joint deformity and restricted physical activity.

Question 5

In osteoarthritis what happens to the joint?

Answer 5

The cartilage thins and the surface becomes rough.
The meniscus is damaged or missing.

Question 6

4 stages of osteoarthritis

Answer 6

1 - minimum disruption, 10% cartilage loss, may experience pain and stiffness.
II - joint space narrowing, occurrence of osteophytes - cracks start to develop.
III - moderate joint space reduction, gaps in cartilage expand until reaches the bone, more stiffness/pain.
IV - joint space greatly reduced, 60% cartilage lost, larger osteophytes.

Question 7

Osteoarthritis mechanism 1: Proteoglycan breakdown

Answer 7

1. Enzymatic breakdown of the cartilage matrix - proteoglycans and collagen broken down into fragments via enzymes e.g. IL-1.
   IL-1 is a potent inflammatory cytokine which induces cytokines and synovial cells to release MMPs (involved in degradation of cartilage). Inhibits collagen synthesis.
2. Fragments secreted into fluid and serve no further purpose.
3. Fewer proteoglycans - disrupts pumping action of regular movement of synovial fluid in and out of the joint.

Question 8

Osteoarthritis mechanism 2: Inflammation

Answer 8

IL-1 with TNF-alpha induces release of IL6 and 8.
Inhibit anabolic processes and promote catabolic processes.
Reduces tensile strength.

Question 9

Potential mechanism of osteoarthritis: obesity

Answer 9

Obese adipose tissue releases pro-inflammatory cytokines (IL5 TNF-alpha).
And…
1. OA chondrocytes accumulate lipids. 2. Oxidises LDL induces joint inflammation –> cartilage destruction in OA and RA.

Question 10

What are the main drugs/treatment methods for osteoarthritis?

Answer 10

Analgesics & NSAIDS (non-steroidal anti-inflammatory drugs).

Surgery may be considered if the drugs have not been successful.

Question 11

Analgesics ladder

Answer 11

Mild to moderate pain: non-opioid analgesics. Aspirin, paracetamol, ibuprofen.
Moderate pain: weak opioid. Codeine, tramadol with/without non-opioid.
Severe pain: strong opioid analgesics. Morphine, oxycodone.

Question 12

What do COX-1 and COX-2 do?

Answer 12

COX-1 = produces prostaglandins that help to maintain gastric mucosal integrity and platelet initiated blood clotting.

COX-2 = produces prostaglandins that mediate pain and inflammation. COX-2 is produced in response to inflammatory cytokines e.g. IL-1. Increase pain and inflammation.

Question 13

What do classical NSAIDS do?

Answer 13

Inhibit COX-1 but mainly COX-2. Therefore inhibit prostaglandin synthesis, reducing pain and inflammation.

Question 14

What is rheumatoid arthritis?

Answer 14

A systemic, chronic, inflammatory auto-immune disease of the synovial membrane (lining of the joint).

Question 15

Which joints are affected by rheumatoid arthritis?

Answer 15

Small joints of hands and feet, larger joints later in disease progression.
Symmetrical effects.

Question 16

How is rheumatoid arthritis identified?

Answer 16

Detection of rheumatoid factor autoantibodies
X-ray.
Observation of symptoms.

Question 17

Pathophysiology of Rheumatoid arthritis

Answer 17

1. Endothelial dysfunction causes inflammatory cells (CD4+ and T cells) to infiltrate the synovial membrane.
2. T cells induce macrophages to release pro-inflammatory cytokines (IL-1, IL-6 and TNF-alpha).
3. Endothelial cells express adhesion molecules e.g. NF-kB.
4. These induce fibroblasts, chondrocytes and release MMPs.
5. Cartilage breaks down. Activates osteoclasts

Question 18

What do DMARDS do?

Answer 18

They interfere with the cascade, inhibiting TNF-alpha and IL1.
Stops the T cells turning into macrophages that release the cytokines.

Question 19

What is osteoporosis?

Answer 19

A skeletal condition characterised by decrease in bone mass and BMD, enlargement of bone spaces producing brittleness and porosity.

Question 20

What is the main issue with osteoporosis?

Answer 20

Increase in fracture risk in the hip, spine and wrist.

Question 21

How is osteoporosis identified?

Answer 21

DXA scan. It gives a BMD T-score which categorises patients into normal (-1 and above), osteopenia (-1 to -2.5) and osteoporotic (less than -2.5).

Question 22

Impact of parathyroid hormone on bones

Answer 22

Stimulates release of calcium stores from bones to the bloodstream.
Increases bone destruction and decreases formation of new bone.

Question 23

Osteoporosis mechanism 1: disrupted bone remodelling cycle

Answer 23

Bone loss (OC) > bone formation (OB).
Caused by increased parathyroid hormone and decreased insulin like growth factor (IGF) - has anabolic effects so usually helps with fracture healing, collagen synthesis and bone mineralisation.

Question 24

Osteoporosis mechanism 2: inflammation

Answer 24

Inflammatory cytokines control osteoclast activity.
1. Immune cells are attracted to the adhesion molecules (NF-kB)
2. These immune cells release cytokines (IL6 and TNF-alpha).
3. These cytokines regulate OC survival and activation.
This process keeps repeating - the cytokines then bind to the NF-kB and cause the release of more cytokines and so more osteoclast activity.

Question 25

Mechanism of action for bisphosphonates

Answer 25

1. Binds to surface of bone (hydroxyapatite crystals)​
2. OC resorb bone containing bisphosphonates​
3. Bisphosphonates then released during resorption​
4. Impairs OC ability to form ruffled border and to adhere to bone surface ​
5. Triggers apoptosis (programmed cell death) of OC​
6. Inhibits osteoclast-mediated bone resorption​
7. Osteoblast activity and bone mineralisation preserved​
8. Reduce rate of bone turnover ​

Question 26

Give an example of a bisphosphonates

Answer 26

Alendronic acid
Risedronate sodium