T5-L4: Bone and New Markers

Question 1

What are the differences between the two types of bone?

Answer 1

Trabecular bone has a large surface exposed to the bone marrow and blood flow, and the turnover is higher than in cortical bone.

Cortical bone: Approximately 80% of the bone mass is in the cortical compartment. Vascular channels occupy about 30% of the volume. It is hard bone that makes up the outer later.

Question 2

Which cells are bone forming?

Answer 2

Osteoblasts.

Osteoblasts create and repair bone. They make osteoid (collagen) and mineralise it to harden it. They are able to communicate with other lines to make hormones such as osteocalcin and alkaline phosphatase.

Question 3

What is the function of osteoclasts?

Answer 3

Bone resorption - process by which osteoclasts break down the tissue in bones and release the minerals, resulting in a transfer of calcium from bone tissue to the blood.

Question 4

What is the function of osteocytes?

Answer 4

Osteocytes derive from osteoblasts, or bone-forming cells, and are essentially osteoblasts surrounded by the products they secreted.

Question 5

What is contained in the extracellular matrix of bone tissue?

Answer 5

• Organic matrix (30%) - mainly collagen (collagen) and ground substrate (made of hyaluronic acids and proteoglycans
  
  • Inorganic components (70%) - minerals - Hydroxyapatite (calcium and phosphate); Minerals (magnesium, sodium, potassium)

Question 6

Give examples of enzymes used in the maturation of osteoclasts.

Answer 6

• RANKL
• Osteoprotegrin

This leads to mature osteoclasts which create resorption bays (pits in the bone) to dissolve the bone and break it down with enzymes that the osteoclasts make . It is under endocrine control as well as PTH, calcitonin and IL6 that cause bone resorption

Question 7

What methods can we use to investigate bone disease?

Answer 7

• Structure - MRI, CT, X-Ray
• Density - DEXA
• Cellular function/turnover using Biochemistry such as ALK
• Microstructure and cellular function using biopsy

Question 8

Give examples of biochemical markers of bone turnover.

Answer 8

• ALK
• Osteocalcin
• Procollagen Type 1 Properties (PT1P)
• CTX, NTX (cross linked telopeptides of type 1 collagen). This is released in the of breakdown collagen. We can also measure enzymatic activity such as TRACP-5b and Cathepsin K. Another enzyme used is Tartrate-resistant acid.

Question 9

During what instances is CTX raised?

Answer 9

Periods of high turnover such as hyperthyroidism, puberty and menopause.

Question 10

When is bone ALK released?

Answer 10

Released by osteoblasts - release is stimulated by bone remodelling. Examples include puberty, fractures, hyperthryodisism and Paget’s disease.

Question 11

What T score defines osteoporosis?

Answer 11

-2.5T

Question 12

What is Osteoporosis? Give common primary causes.

Answer 12

Osteoporosis is a decrease quantity of bone and a decreased quality of bone leading to failure of structural integrity. We rarely measure quality.

The most common causes: aging, menopause, steroid use etc.

Question 13

What are risks of a fragility fracture?

Answer 13

Risk fractures of fracture:
	• Age*
	• Sex*
	• Recent fragility fracture*
	• Vertebral fractures – number and severity*
	• Smoking
	• Alcohol*
	• Falls
	• Drugs*
	• Inflammatory conditions*
	• Malabsorption
	• T1 DM
	• Family history*
* Independent of BMI

Question 14

Why can long term steroid use lead to Osteoporosis?

Answer 14

Corticosteroids tend to both reduce the body’s ability to absorb calcium and increase how fast bone is broken down. The more of these drugs you take and the longer you take them, the greater your risk of developing osteoporosis.

Question 15

What methods can we use to investigate secondary causes of Osteoporosis?

Answer 15

• Coeliac Test
• Vitamin D Levels
• Testosterone/Oestrogen Levels
• Plasma screen (+/- myeloma screen)
• FBC
• TFTs
• U&Es
• PTH issues

Question 16

What is the most common treatment for Osteoporosis?

Answer 16

Antiresorpitive treatments - most common is Bisphosphates. They stop osteoclasts from working. The bisphosphate destroy osteoclast when ingested by the osteoclasts. Mimic pyrophosphate structure

Question 17

What are complications of Bisphosphates?

Answer 17

Complications of treatment:

- Osteonecrosis of the jaw 
- Atypical femurs fracture - particularly if they have been on the drug for too long

Question 18

What can we use to evaluate whether treatement is being taken appropriately?

Answer 18

Bone markers e.g. in bisphosphates we would check CTX

Question 19

What are the two types of bone metastases? What primary cancers are they associated with?

Answer 19

• Lytic bone mets - destruction of the bone (high osteoclastic activity) - associated with hypercalcaemia. Caused by often breast/kidney thyroid
  
  • Sclerotic/osteoblastic mets. - deposition of new bone. This is not often associated with hypercalcaemia. Due to metastases from often prostate, lymphoma and breast/lung (15/25%)

Usual sites of spread is via the spine, pelvis femur and humerus, skull.

Question 20

What are common presenting symptoms of bone mets.?

Answer 20

• Pain - Often worse at night and gets better with movement initially that usually becomes constant.
  
  • Broken bones - Pathological fractures. Commonly femur, humerus, vertebral.
  • Numbness, paralysis, trouble urinating - Spinal cord compression from bone metastases
  • Loss of appetite, nausea, thirst, confusion, fatigue - Symptoms of hypercalcaemia
    - Anaemia - due to disruption of bone marrow

Question 21

What are symptoms of hypercalaemia?

Answer 21

• Polyuria, polydipsia
• Mood disturbance
• Anorexia
• Nausea
• Fatigue
• constipation

It can lead to vomiting, coma, pancreatitis dehydration, cardiac arrhythmia and even death.

Question 22

What is the next line blood test you would do in anyone with high calcium levels?

Answer 22

PTH

When the blood calcium level becomes low, the calcium receptor on the gland senses this. PTH increases which leads to restoration of blood calcium levels - takes calcium from the bone, reabsorption from the kidneys, increased from the intestines, increases Vitamin D levels. PTH is the predominant control from blood calcium levels.

Question 23

Other than a hyperparathyrodisim, what is the second most common cause of hypercalaemia?

Answer 23

Malignancy

Question 24

Give an example of a secondary cause of hyperparathyrosiism.

Answer 24

CKD and Vitamin D deficiency. In this was either PTH is appropriately high and calcium is normal or low.

Question 25

What is Paget’s disease?

Answer 25

Thickening of the bone and lytic lesions and sclerotic lesions. There is chaotic breakdown. It affects certain bones - sometimes one or many. It leads to progressive thickening and deformity. Rapid bone turnover and formation. Leading to abnormal bone remodelling.

Due to abnormal bearing we can get arthritis.

- Mainly over 50 years old
- Higher prevalence in men
- Probable genetic and environmental triggers
- Elevated alkaline phosphatase reflecting increased bone turnover
- Presents with bone pained deformity, fractures and arthritis. If in the cranium we can get hearing and vision loss.

Question 26

What is the treatment for Paget’s disease?

Answer 26

Bisphosphate - due to high bone turnover it is similar to that in osteoporosis. Can use P1NP, CTX or ALK to monitor activity.

Question 27

What is Osteomalacia?

Answer 27

“adult rickets”
- Lack of mineralisation of bone - in kids you get bowing of the bone due to soft bones
In adults we get widened osteoid seams with lack of mineralisation - causes bone pain (usually symmetrical), muscle pain and weakness and fractures.

Question 28

For HyperPTH and Osteomalacia, what changes in of ALK, Ca, Phosphate and PTH would you expect?

Answer 28

HyperPTH: Raised PTH, causing raised Ca, and raised ALK (due to high turnover) but decreased phosphate due to kidney loss.

Osteomalacia: Low calcium and phosphate. this leads to secondary hyperPHT (and so raised PTH). This means we get raised ALK (due high turnover)