Osteoporosis - L6

Question 1

Name functions of healthy bones.

Answer 1

• Movement
• Weight baring / shape
• Calcium reservoir
• Phosphate reservoir
• Hematopoiesis / stem cell niche
• Protection of vital organs
• Endocrine function

Question 2

Bones must be as light as possible, while being as strong as possible. What is the problem in osteoporosis?

Answer 2

That bones no longer are able to withstand the loads placed upon it, even whet they are relatively light (e.g. getting up from a chair).

Question 3

How is quality of life affected by osteoporosis?

Answer 3

Fractures, pain, immobility, difficulty breathing, death.

Question 4

What determines bone strenght, i.e. fracture resistance?

Answer 4

• Amount of bone material
• Quality of bone material
• Structural organization

Question 5

What happens when bone is lost (e.g. does it grow back the same)?

Answer 5

When bone is lost, it will not come back exactly the same. The general consensus here is that completely destroyed bnones will not grow back even when stimulated with exercise or anabolic agents. Remaining bone may become stronger and thicker, but resistance to loading is lowered, especially in loading directions not encountered in everyday life.

Question 6

Describe how bone mass changes throughout life and take into account the sex differences.

Answer 6

Around 20 years of age, both men and women reach their peak bone mass. However, peak bone mass is higher in men than women. After peak bone mass has been reached in men, there is a steady decline of bone mass throughout life. However, this decline in bone mass is more rapid in women once they reach menopause. This will stimulate the process of bone mass loss even further.

Question 7

Why do women get osteoporosis earlier compared to men?

Answer 7

• They lose more bone during menopause
• They have less bone to begin with

Question 8

What are two processes that enhance the progression of osteoporosis in women?

Answer 8

• Menopause is associated with higher cytokine levels, thus there is low grade systemic inflammation.
• Menopause is associated with loss of estrogen.

Question 9

Describe the function of the following cells:
- osteoblast
- osteocyte
- osteoclast

Answer 9

• osteoblast → responsible for the formation of bone by synthesizing dense, crosslinked collagen and specialized proteins, which compose the organic matrix of bone.
• osteocyte → type of bone cell commonly found in mature bone tissue responsible for mechanosensing and regulation of bone turnover
• osteoclast → type of bone cell that breaks down bone tissue (critical for maintenance, repair and remodleing of bones) via bone resorption (disassembly and digestion of hydrated protein and mineral by the secretion of collagenase)

Question 10

Fill in the right word:

Bone mass is determined by the balance between bone … and bone ….

Answer 10

Bone mass is determined by the balance between bone formation and bone resorption.

Question 11

Explain how the balance between bone formation and resorption determines the amount of bone mass.

Answer 11

There are three types of bone remodeling cycles:

• coupled and balanced bone remodeling → the amount of active osteoblasts (responsible for bone formation) and active osteoclasts (responsible for bone resorption) is equal.
• coupled and unbalanced bone remodeling → the amount of active osteoblasts is less than the amount of active osteoclasts, which results in bone mass loss.
• uncoupled bone remodeling → there are no (or far less) active osteoblasts and there are a lot more active osteoclasts, which results in (massive) bone mass loss → i.e. arrested reversal phase.

Question 12

Name two molecules produced by osteocytes that support the fact that osteocytes are the key regulators of bone resorption and formation.

Answer 12

Osteocytes produce RANKL and sclerostin.

• RANKL is a ligand of RANK that is found on osteoclasts. Since osteoclasts are involved in bone resorption, RANK-RANKL interaction results in the initiation of bone resorption by osteoclasts.
• Sclerostin inhibits the function of osteoblasts of bone formation by inhibiting Wnt signaling.

Question 13

What is the function of OPG in bone (re)modeling?

Answer 13

OPG is able to bind to RANKL produced by osteocytes and prevents RANKL from binding to RANK that is found on osteoclasts. Therefore, osteoclasts are not activated to initiate the process of bone resorption.

Question 14

What happens to the amount and activity of osteoblasts during the menopause?

Answer 14

Osteoblast amont and activity increases during the menopause. However, the bone resorption activity of osteoclasts increases even more. This results in a net loss of bone mass and more fragile bones in women.

Question 15

Answer the following questions regarding actue osteoporosis:

• Does bone formation increase or decrease?
• Does bone resorption increase or decrease?
• How does this explain the loss of bone mass?

Answer 15

• Bone formation increases.
• Bone resorption increases even more.
• This is due to loss of estrogen levels.

Question 16

A finding of a study: targeted ablation of osteocytes induces osteoporosis with defective mechanotransduction. With this, these osteocytes showed resistance to unloading-induced bone loss.
What does this say about the role of osteocytes?

Answer 16

That osteocytes are essential for bone turnover and control unloading-induced bone loss (bone mass declined in tibiae of wild type mice upon hind limb suspension, but not in mice without osteocytes).

Question 17

Explain how adaptation of bone mass and structure to mechanical loading is driven by osteocytes.

Answer 17

Mechanical load is sensed by osteocytes (mechanosensing). Osteocytes produce signaling molecules that induce bone remodelling by osteoclasts and osteoblasts, resulting in adaptation of bone mass and structure driven by osteocytes.

Question 18

What would happen to bone mass if cytokines affect the mechanosensitivity of osteocytes?

Also think of this scenario in patients with chronic inflammation (and therefore high amounts of cytokines).

Answer 18

If cytokines affect the mechanosensitivity of osteocytes, leading to reduced mechanosensitivity of osteocytes, this could mean that osteocytes wrongly perceive unloading even when the bone is under mechanical stress, while unloading typically signals the need for bone resorption. Therefore, the may may undergo excessive resorption even when it should be experciencing loading and requiring bone formation.

Question 19

• How does serum obtained from patients with rheumatoid arthritis (RA), characterized by elevated levels of cytokines, influence osteoclastogenesis by osteocytes?
• What happens to osteoclastogenesis by osteocytes when mechanical loading in the form of pulsatile fluid flow (PFF) is applied?
• And how does the latter translate to exercise?

Answer 19

• The serum of patients with RA enhances osteoclastogenesis by osteocytes.
• The application of mechanical loading in the form of PFF prevents osteoclastogenesis by osteocytes.
• Physical exercise may have a protective effect on bone health in patients with RA.

Question 20

• What are prostaglandins in the context of bone metabolism?
• What happens to bone metabolism when you take NSAIDs?

Answer 20

• Bone cells produce prostaglandins in response to mechanical loading, which are important molecules for bone formation.
• Bone formation in response to mechanical loading is reduced if you take NSAIDs.