Bone Abnormalities

Question 1

What are the functions of bone as a metabolic tissue?

Answer 1

1. Acts as mineral buffer
2. Needs to be able to repair damage and maintain integrity
3. Quality of bone
4. Coordination between bone cells

Question 2

What are the protective and load-bearing functions of bone?

Answer 2

1. Cortical versus trabecular bone = weight versus strength

2. Rigidity:resilience = hydroxyapatite:collagen

Question 3

Why can fractures occur?

Answer 3

1. Too much force

2. Problem with the bone

Question 4

What is osteogenesis imperfecta?

Answer 4

Group of disorders characterised by defective production (processing) of type I collagen due to genetic mutations in collagen genes leading to loss of bone flexibility making bones brittle which is why it is called BRITTLE BONE DISEASE

Question 5

What is Pagets disease?

Answer 5

When there is rapid turnover of overactive osteoclasts so there is poor quality woven bone

Question 6

What blood tests can be done to assess bone structure?

Answer 6

Routine: ALP + albumin

Others: Ca2+, phosphate, vitamin D + PTH

Question 7

What imaging can be done to assess bone structure?

Answer 7

1. Plain X-ray
2. Radionuclide scans: radioactive material e.g. technetium (Tc) is put into body to pick up an overactive cell type
3. CT/MRI/US

Question 8

How should we assess bone structure?

Answer 8

1. Blood tests
2. Imaging
3. Bone biopsy (histology)
4. Bone mineral density (BMD) via a Dual Energy X-ray Absorptiometry (DEXA) scan

Question 9

What problems with the bone can cause fractures?

Answer 9

1. Quantity of bone:
   - Too little bone (osteoporosis)
   - Too much bone (osteopetrosis)
2. Quality of bone:
   - Defective/loss of mineralisation (rickets, osteomalacia or hyperparathyroidism)
   - Change in structure (osteogenesis imperfecta, Paget’s disease or tumours)

Question 10

What is osteoporosis?

Answer 10

A complex skeletal disease, most common in post-menopausal older women, characterised by low bone density and micro-architectural defects in bone tissue resulting in increased bone fragility and susceptibility to fracture esp. of the neck of femur, vertebral bodies and wrist

Question 11

What does FOOSH stand for?

Answer 11

Fall On OutStretched Hand

Question 12

Why do some older adults demonstrate a hunched-over appearance?

Answer 12

The natural lumbar kyphosis can become exaggerated as the intervertebral (IV) discs become compressed and smaller (can impinge nerves too)

Question 13

What are the wider implications of osteoporosis?

Answer 13

Future fractures
Pain
QoL
Loss of confidence
Long-term admission
Permanent disability
Mortality

Question 14

What are the risk factors for osteoporosis?

Answer 14

Old age
Sex (females > males)
Ethnicity
Low BMI
Family Hx
Fragility fracture
Post-menopausal
Smoking
Excessive alcohol use
Long-term steroid use
Immobility 
Vit D + Ca2+ deficiency
Etc...

Question 15

When are patients most commonly assessed for osteoporosis?

Answer 15

If an elderly patient has had a fall and a fracture

Question 16

What is the pathophysiology of osteoporosis?

Answer 16

1. Genetic factors, nutrition and physical activity make up an individuals peak bone mass
2. During aging, there is:
   - Decreased replicative activity of osteoprogenitor cells
   - Decreased synthetic activity of osteoblasts
   - Decreased biologic activity of matrix-bound GFs
   - Reduced physical activity
3. During menopause there is:
   - Decreased serum oestrogen
   - Increased IL-1, IL-6 + TNF levels
   - Increased expression of RANK + RANKL
   - Increased osteoclast activity
4. Balance disruption between bone formation and resorption due to decreased osteoblast activity and increased osteoclast activity cause a net bone loss = osteoporosis

Question 17

When does peak bone mass deteriorate?

Answer 17

Men: achieve a higher peak bone mass that plateaus and gradually declines at around 50 years old
Women: peak bone mass deteriorates rapidly post-menopausal

Question 18

What can be done for fracture patients?

Answer 18

1. Secondary prevention of injury e.g. home changes
2. FRAX tool to evaluate fracture risk
3. DEXA scan if indicated by the FRAX tool and other factors to diagnose osteoporosis clinically

Question 19

How is osteoporosis diagnosed?

Answer 19

DEXA scan that outputs a T-score:

• Normal = hip BMD < 1 SD below young adult mean (T-score equal to/> -1)
• Osteopenia = hip BMD 1-2.5 SDs below young adult mean (T-score < -1 but > 2.5)
• Osteoporosis = hip BMD 2.5 SDs or > below young adult mean (T-score fragility fractures

Question 20

How do you manage osteoporosis?

Answer 20

Diet
Exercise
Supplements 
Fall prevention
Pharmacological treatment

Question 21

What pharmacological treatments are used to treat osteoporosis?

Answer 21

1. Oral/IV bisphosphonates (1st line): Alendronic acid (Alendronate), Risedronate + Zoledronic acid
2. SERMs: Raloxifene
3. PTH: recombinant fragment of PTH e.g. Teriparatide (Forteo) SC injection
4. Denosumab: SC injection

Question 22

How do bisphosphonates work?

Answer 22

Primarily:
1. Absorbed onto hydroxyapatite crystals and slow rate of bone remodelling as they are taken up by osteoclasts and interfere with their function by reducing their attachment to bone via their ruffled surface meaning that they do not release acids/enzymes to resorb bone
Some:
2. Inhibit mevalonate pathway or form toxic ATP analogues
3. Decrease osteoclast progenitor development/recruitment
4. Promote osteoclast apoptosis

Used orally most commonly (OD/OW) in osteoporosis, Pagets disease, hypercalcaemia or malignancy

Question 23

Why are the side effects of bisphosphonates?

Answer 23

• Asymptomatic hypocalcaemia
• Oesophageal reactions + general GI disturbance (patients need to take it in morning on empty stomach with a glass of water + sit up for a while = unpopular)
• Osteonecrosis of jaw
• Possible long-term effects e.g. atypical femur fracture

Question 24

What considerations must be taken into account when prescribing bisphosphonates?

Answer 24

1. Poorly absorbed and absorption decreased if taken with Ca2+
2. Not metabolised but excreted unchanged in urine so must be given with caution in patients with CKD
3. Patients dental hygiene if giving big doses e.g. Zoledronic acid as osteonecrosis of jaw can occur in rare cases

Question 25

How do Selective Estrogen Receptor (ER) Modulators (SERMs) work?

Answer 25

Mixed antagonist/agonist function that is tissue specific: antagonist of uterine/breast tissue but agonist in bone so there is no cancer risk but treatment of osteoporosis - used commonly in postmenopausal osteoporosis if bisphosphonates not tolerated

Question 26

How does Parathyroid Hormone (PTH) work?

Answer 26

Intermittent peaks (doses) promote production of trabecular bone (anabolic) by: - Increasing osteoblast differentiation and activity - Decreasing osteoblast apoptosis and secretion But continuous PTH will cause bone loss so max duration of treatment is 24 months

Question 27

What are the side effects of Parathyroid Hormone (PTH)?

Answer 27

Hypercalcaemia Muscle cramp N+V

Question 28

How does Denosumab work?

Answer 28

Monoclonal Ab acts like OPG as a natural decoy for RANKL mopping it up decreasing formation, function, activation and survival of osteoclasts subsequently slowing down bone remodelling and resorption

Question 29

What are the side effects of Denosumab?

Answer 29

Hypocalcaemia Diarrhoea Dyspnoea Constipation

Question 30

What are rickets and osteomalacia?

Answer 30

Disorders characterised by inadequate mineralisation of bone where bone remains as chrondrocytes instead of being mineralized to bone so they have the SAME pathological process, depending on whether or not growth plates are fused, but DIFFERENT manifestations - most common cause if vitamin D deficiency usually resulting low Ca2+ and phosphate levels

Question 31

What is the difference between rickets and osteomalacia?

Answer 31

Rickets: defective mineralisation at the GROWTH PLATE so affects CHILDREN Osteomalacia: defective mineralisation of OSTEOID so affects ADULTS as well as CHILDREN

Question 32

What are the signs and symptoms of rickets?

Answer 32

Growth retardation Bony deformities Fractures Widening/splaying of epiphyseal growth plate/metaphysis (as shown by imaging)

Question 33

What are the signs and symptoms of osteomalacia?

Answer 33

May be asymptomatic Muscle weakness (proximal) Bone pain Fractures

Question 34

How should you test for rickets and osteomalacia? What is the treatment?

Answer 34

Blood test: vitamin D, Ca2+ and phosphate will be low whereas ALP will be high Management: DEXA scan/X-ray by specialist but mostly education, diet advice and supplements

Question 35

What types of bone cancers exist?

Answer 35

1. Primary: arisen from bone tissue (rare) 2. Secondary: metastasis from breast, lung or prostate cancers for example as bone has a good blood supply Which can both be either benign or malignant

Question 36

How can you tell what cancer might have metastasized to the bone?

Answer 36

Lytic lesions: bone will be less dense and more translucent on X-ray as bone has been broken down and replaced by tissue from cancer e.g. breast or lung - release of Ca2+ too (hypercalcaemia) Sclerotic lesions: woven bone production is stimulated but this is unstructured so you get dense bone appearing more opaque and bright on X-ray e.g. prostate cancer

Question 37

What is Paget's disease of the bone?

Answer 37

Disease characterised by increased bone turnover as osteoclasts are overactive due to genetic/environmental factors so osteoblasts start to react by laying down more weak woven (immature) bone resulting in overgrowth, bowing, pain, fractures, deformity and even visual/hearing disturbances if skull is affected (focal or multifocal lytic AND sclerotic lesions) - occurs in 1-3% of > 55 year olds

Question 38

How do you investigate Paget's disease?

Answer 38

1. Bloods: serum Ca2+, PTH and ALP - ALP will be only high result 2. X-rays 3. Radionuclide bone scans to look for overactive osteoclasts 4. Bone biopsy if malignant change is suspected as patients are more susceptible to mutations due to high bone turnover so need to be reviewed regularly - rapid growth and erythema can indicate malignancy

Question 39

How do you treat Paget's disease?

Answer 39

1. Walkers, sticks and orthotics 2. Analgesia if required 3. Supplements 4. Bisphosphonates: decrease OC recruitment and cause OC apoptosis decreasing depth of resorption site which in turn calms down osteoblasts 5. Surgery

Question 40

What are the symptoms of osteogenesis imperfecta?

Answer 40

Systemic disease: - Brittle bones -> multiple fractures - Hearing loss - Sclera may have a blue, purple or grey tint (collagen so thin vascular underneath can be seen) - Teeth problems i.e. brownish teeth - Growth retardation

Question 41

What are the different types of osteogenesis imperfecta?

Answer 41

Type 1: mildest form where patients can live their life but more susceptible to fractures Type II: more severe where bones are so brittle they fracture during labour giving babies severe kyphosis that can restrict respiration so they only live for a few weeks after birth if they survive birth

Question 42

What can osteogenesis imperfecta often get confused for?

Answer 42

Child abuse as the child may have multiple fractures in many limbs all at different stages of repair

Question 43

What is the treatment for osteogenesis imperfecta?

Answer 43

No cure but it can be helped with: - Braces - Orthotics - Surgery - Bisphosphonates to stabilise bone remodelling process