Bone healing, osteoporosis

Question 1

list the stages of secondary bone repair and how long it lasts for

Answer 1

Fracture hematoma and inflammation = 6-8 hours
Soft (fibrocartilaginous) callus = 3 weeks
Hard (bony callus) = 3-4 months
Bone remodelling = months to years

Question 2

describe hematoma formation and inflammation

Answer 2

Rupture of blood vessels causes blood to pool around them fracture site. Within 6-8 hours, there is formation of a fracture hematoma (mass of clotted blood). The hematoma causes constriction of blood vessels and limits blood flow to the area. Bone cells lacking nutrients lose their function and die, causing inflammation and the area swells up.

Question 3

Describe soft callus formation

Answer 3

New capillaries organise the fracture hematoma into granulation tissue = PROCALLUS
Fibroblasts and osteoprogenitor cells invade the pro callus and make collagen fibres to join the ends together.
Chondrocytes produce fibrocartilage.

Question 4

describe hard callus formation

Answer 4

Osteogenic cells in nearby healthy vasculature develop into osteoblasts and migrate to the fibrocartilaginous callus. They form woven bone.

Question 5

describe bone remodelling

Answer 5

Osteoclasts remodel woven bone into cancellous or compact bone and remove any dead or damaged cells around the callus.

Question 6

List the stages of bone remodelling

Answer 6

Quiescence
Resorption
Reversal
Formation

Question 7

describe the quiescent stage

Answer 7

Bone lining cells (inactive osteoblasts) cover all surfaces of the resting bone. They are activated.

Question 8

describe the resorption stage

Answer 8

Activated bone lining cells separate to form a canopy over the site to be resorbed. The canopy merges with the blood vessels.

Pre-osteoclasts (osteoclast precursor cells) are recruited from circulation to the surface.

Pre-osteoblast cells express RANKL on their surface. Pre-osteoclasts have RANK ligand RECEPTORs on their surfaces.

RANKL binds to RANK and Osteoclast precursor cells are activated and differentiate to form mature, multinucleated osteoclasts.

Osteoclasts break down and resorb bone. It does this by acid secretion to break down minerals and proteases which break down the collagen matrix.

Question 9

Describe reversal

Answer 9

Pre-osteoblast cells mature and stop making RANK ligand. OPG binds to RANK ligand and blocks formation of mature osteoclasts.

Osteoblasts are recruited, they differentiate and are activated. They secrete the collagen matrix.

Question 10

describe bone formation

Answer 10

the bone becomes mineralised

Question 11

list factors the inhibit bone repair

Answer 11

Patient factors:
Peripheral vascular disease
Alcohol
Increasing age
Diabetes
Malnutrition 
Anaemia
Smoking
Hypothyroidism 

Medications:
NSAIDs, especially COX2 inhibitors (reduce vascularity to site)
Steroids
Bisphosphonates - inhibit osteoclast activity which delays fracture healing

Question 12

mention factors that promote bone healing

Answer 12

growth factors and hormones e.g. PTH, VEGF, PDGF, Growth hormone, FGF.

Question 13

discuss the management and rehabilitation of vertebral fractures

Answer 13

Non surgical:
Rest
warm baths/cold pack
Relaxation techniques
Painkillers
Spinal Orthotic brace

Surgical:
Vertebroplasty operation: cement is injected into fractured vertebrae
Kyphoplasty

Question 14

mention some complications of vertebral fractures

Answer 14

Neurological damage 
Kyphosis
More fractures occurring (increased risk)
Reduced mobility
Loss of height
Inability to return to full independence

Question 15

define osteoporosis

Answer 15

A skeletal disorder characterised by decreased bone mineral density, leading to reduced bone strength and increased risk of fractures.

Question 16

How is osteoporosis diagnosed?

Answer 16

DEXA (dual energy X-ray absorptiometry) scan to measure bone mineral density.

Question 17

How are the results from a DXA scan interpreted and what are the BMD ranges that differentiate normal, from osteopenia, from osteoporosis ?

Answer 17

The difference in BMD from the mean is calculated as a standard deviation and is called a T score.
Normal: T score of -1 or above
Osteopenia: T score lower than -1 but higher than -2.5
Osteoporosis: T score or -2.5 or lower

Question 18

describe the pathogenesis of osteoporosis

Answer 18

Osteoblasts and activated T cells in the bone marrow produce RANKL cytokine.

RANKL binds to RANK which is expressed on the surface of osteoclast precursors to promote osteoclast differentiation. Mature, activated osteoclasts form.

OPG (osteoprotegerin),a another protein released by osteoblasts, acts as a decoy receptor that inhibits RANK-RANKL by binding to the RANKL. This prevents osteoclast formation and bone resorption.

In osteoporosis: there is increased expression of RANKL by osteoblasts and decreased release of OPG.

Question 19

List the causes of osteoporosis

Answer 19

Steroids (long term use)
Hyperparathyroidism 
Alcohol + smoking
Thin (low BMI)
Testosterone being low in men (hypogonadism)
Early menopause: lack of oestrogen 
Renal failure
Endocrine problems 
Diet/malnutrition 
(SHATTERED)

Menopause: lack of oestrogen 
Malabsorption problems: coeliac disease
Old age: growth hormone levels reduce 
Females (risk factor)
Lack of physical stress on bones due to inactivity

Question 20

Describe the management of osteoporosis

Answer 20

Modify lifestyle risk factors (smoking cessation, drinking at safe levels)
Oestrogen treatment for post menopausal women
Selective oestrogen receptor modulators: have same effect of oestrogen
Weight bearing + muscle strengthening physical exercise
Calcium + Vitamin D supplements
Bisphosphonates: Alendronate, Ibandronate, Risedronate Zoledronic acid slows the rate of bone resorption
Calcitonin hormone
Testosterone treatment
Denosumab (monoclonal antibody)
Parathyroid hormone: stimulate osteoblast formation

Question 21

what are osteoblast cells derived from?

Answer 21

Mesenchymal stem cells

Question 22

what are the two functions of osteoblasts?

Answer 22

Transport of mineral salts

Deposition of collagen an non-collagenous proteins/ground substance

Question 23

In targeted remodelling (when old/damaged bone needs to be repaired), what vitiates the signal to the osteoblasts to express RANK ligand?

Answer 23

Osteocytes

Question 24

In a quiescent bone surface, what inhibits osteoblast activity?

Answer 24

Osteocytes secrete sclerostin which they use to communicate with one another and inhibit Wnt signalling in cells near the surface. It inhibits bone formation.

Question 25

When a sudden stress causes a micro crack to appear what happens to the signalling and osteocytes near the surface ?

Answer 25

Sclerostin signalling stops.

Osteocytes near the crack undergo apoptosis.

Question 26

In response to bone damage, what signals are released and what cell type releases them?

Answer 26

Osteocytes secrete growth hormone, prostaglandins and nitric oxide.

Question 27

List 4 signals which are promoters of bone remodelling

Answer 27

PTH
1,25 hydroxyvitamin D
Growth hormone
thyroid hormone 
IL1
IL11
Prostaglandins 
TNF alpha
Glucocorticoids

Question 28

List 4 signals which are inhibitors of bone remodelling

Answer 28

Oestrogen
Androgen
Progesterone
Calcitonin

Question 29

what effect does Oestrogen have on OPG secretion?

Answer 29

Increased oestrogen = increased OPG secretion

Question 30

what is alkaline phosphatase a marker of?

Answer 30

Bone mineralisation

Question 31

List the factors affecting bone homeostasis

Answer 31

Diet and lifestyle
Mechanical factors (use/disuse of bones)
Endocrine factors (chemicals in our environment that can change hormone potency/effectiveness)