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LCRS2- Musculoskeletal > Musculoskeletal > Flashcards

Musculoskeletal Flashcards

1
Q

What is the function of bone?

A

Mechanical= support and site for muscle attachment

Protective= vital organs and bone marrow

Metabolic= reserve of calcium

(Bone is dynamic/communicative but looks inert)

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2
Q

Outline the composition of bone

A

INORGANIC- 65%
Calcium hydroxyapatite
Storehouse for 99% of Ca in the body
85% of the phosphorous, 65% Na and Mg

ORGANIC- 35%
Cartilage on edge of bone
Bone cells and protein matrix

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3
Q

Describe the bone geography of a long bone (e.g. arms, legs, hands and feet)

A

DIAPHYSIS= BONE SHAFT
Medulla (endosteum) surrounded by cortex and periosteum (outside)

METAPHYSIS
Flared (children get infections here because blood rich)

EPIPHYSIS= GROWTH PLATE
Epiphyseal line
Subchondral bone
Articular cartilage (to prevent friction)

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4
Q

What is the medulla of bone comprised of?

A

High surface area bone (cancellous bone) with bone marrow

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5
Q

What is cortical bone?

A 
Long bones (outside where muscles attach) 
80% of skeleton
Appendicular 
80-90% calcified
Mainly mechanical and protective
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6
Q

What is cancellous bone?

A

Vertebrae and pelvis
20% of skeleton
High surface area, sits within bone marrow
Axial
15-25% calcified
Mainly metabolic (can be dissolved quickly to release calcium phosphate when you need it)
Large surface

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7
Q

Outline cortical bone microanatomy

A

Circumferential lamellae

Concentric lamellae (blood supply that makes bone strong and allows communication with surface via canniculi)

Interstitial lamellae

Trabecular lamellae (thin- doesn’t have blood vessels in it)

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8
Q

Outline when bone biopsies are used

A

Painful so not often used (but maybe when someone has a metabolic bone disease)

Used for:
Evaluate bone pain or tenderness
Investigate an abnormality seen on X-ray
To determine the cause of an unexplained infection
To evaluate therapy
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9
Q

Where are bone biopsies taken from?

A

Normally from anterior superior ileac crest

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10
Q

What are the types of bone biopsy?

A

Closed- needle, core biopsy (Jamshidi needle) NB. can;t use this needle near vessels (e.g. not for sternum because near aorta)

Open- for sclerotic or inaccessible lesions

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11
Q

What bone cells are there?

A

Osteoblasts
Osteoclasts
Osteocytes

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12
Q

What are osteoblasts?

A

Build bone by laying down osteoid (calcium hydroxyapatite)

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13
Q

What are osteoclasts?

A

Multinucleate cells of macrophage family

Resorb or chew bone

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14
Q

What are osteocytes?

A

Osteoblast-like cells which sit in lacunae in bone

Sits in BM and communicate with osteoblasts and osteoclasts

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15
Q

How are osteoclasts converted to active osteoblasts?

A

Osteoclast-> liberated matrix bound growth factors-> osteoprogenitor cells-> active osteoblasts

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16
Q

Outline what happens when RANKL binds to RANK?

A

RANKL binds to RANK
Then cell becomes osteoclast and resorbs bone

To turn this off.. (triggered by PTH, cytokines and mechanical stimuli)

OPG binds to RANK (competes with RANK)
Stops bone resorption

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17
Q

What is OPG?

A

Osteoprotegerin

Inhibits RANK/RANKL binding and therefore inhibits osteoclastogenesis

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18
Q

How do osteoblasts become osteoclasts?

A

Active osteoblasts-> surface osteoblasts (input from mechanical factors, hormones and cytokines)-> OPG competes with RANK for RANKL-> osteoclast activated

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19
Q

What are the classifications of bone?

A

Anatomically- flat/long/cuboid bones

Trabecular bone (cancellous)= metabolically active

Compact bone= cortical (skull and pelvis)

Woven bone= immature (abnormal in adult apart from base of teeth in mandible and maxilla)

Lamellar bone= mature (like concentric lamellae, forms in response to gravity-> thickens and strengthens bone)

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20
Q

Give examples of cuboid bones

A

Wrists and ankles

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21
Q

What kind of ossification happens in flat and long bones?

A 
Intramemebranous ossification (flat)
Endochondral ossification (long)
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22
Q

True or false: you can track development where bone has been remodelled in trabecular lamellar bone

A

True

Prominent reversal lines can be seen

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23
Q

How does the layer of osteoid on the surface of normal trabecular bone look with a special histological stain?

A

Red layer

NB. Green dark= calcified bone
Surface different

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24
Q

What are the main reasons for metabolic bone disease?

A

Disordered bone turnover due to imbalance of various chemicals in the body (vitamins, hormones, minerals etc)

Overall effect is reduced bone mass (osteopaenia) often resulting in fractures with little or no trauma

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25
Q

What causes osteoporosis?

A 
Primary= age, post-menopause
Secondary= drugs, systemic disease

Oestrogen falls after menopause
OPG levels fall too
Can’t find RANKL as well
Mineralization still ok but not enough bone

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26
Q

How does osteoporosis present?

A

Present with bone pain and difficulty walking/carrying or pathological fracture e.g. from walking

Bone becomes thin and widely spaced

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27
Q

What causes osteomalacia?

A

Defective bone mineralisation unlike osteoporosis

Deficiency of vitamin D
Deficiency of PO4 (usually from chronic renal disease)

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28
Q

How is vitamin D activated?

A

SEE DIAGRAM

Hypocalcaemia-> PTH secretion

PTH-> kidney-> GI tract
PTH-> liver

Skin and diet-> vitamin D-> liver

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29
Q

How do bones appear in osteomalacia?

A

Bones appear very thin on X ray
Weak bones

Proximal weakness, pain, pathological fracture, maybe bone deformity

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30
Q

How does osteomalacia present?

A 
Sequelae
Bone pain/tenderness
Fracture
Proximal weakness
Bone deformity

Rickets in children= Bow legs due to bone not being able to handle soft tissue weight
Expanded growth plate

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31
Q

What kind of fractures aren’t common?

A

Horizontal fractures

E.g. in looser’s zone

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32
Q

What is tetracycline labelling used for? How is it good for?

A

To investigate bone mineralisation

Tetracycline (not for children because turns teeth black) with fluoro labelling

Given 2s (2 weeks apart) shows mineralisation fronts which should reveal how much mineralisation in 2 weeks

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33
Q

What is hyperparathyroidism caused by?

A

Excess PTH

Increased Ca and PO4 excretion in urine
Hypercalcaemia
Hypophosphataemia
Skeletal changes of osteitis fibrosa cystica

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34
Q

What organs are affected in hyperparathyroidism?

A

4 organs directly or indirectly affected by PTH and between them control Ca metabolism

Parathyroid glands
Bones
Kidneys
Proximal small intestine

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35
Q

What does hyperparathyroidism look like in an x-ray?

A

Holes in bone in X ray
Cysts in bone and fibrous tissue where bones broken down (features of osteitis fibrosa cystic affecting tibia)

Best to look at hand X ray= lesions on thumb aspect, small brown tumours

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36
Q

What is primary hyperparathyroidism?

A 
Parathyroid adenoma (85-90%)
Chief cell hyperplasia
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37
Q

What is secondary hyperparathyroidism?

A

Chronic renal deficiency
Vit D deficiency
Possibly by drugs

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38
Q

What are the symptoms of hyperparathyroidism?

A

Symptoms mnemonic

Stones= Ca oxalate renal stones (also renal colic, nephrocalcinosis, CRF)

Bones= osteitis fibrosa cystic, bone resorption (and fractures secondary to bone resorption)

Abdominal groans= acute pancreatitis (and dyspepsia, constipation, nausea, anorexia)

Psychic moans= psychosis and depression (and impaired concentration, drowsy. coma)

Mainly caused by calcium too high

Also, thirst, polyuria, tiredness, fatigue, muscle weakness

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39
Q

What is renal osteodystrophy?

A

Spectrum of bone disease
Can have 1, all or a combo

Comprises all the skeletal changes of chronic renal disease:

  • Increased bone resorption (osteitis fibrosa cystica)
  • Osteomalacia
  • Osteosclerosis
  • Growth retardation
  • Osteoporosis
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40
Q

What stain can be used to see features of osteitis fibrosa cystica e.g. affecting a femur?

A

H&E

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41
Q

What causes renal osteodystrophy?

A 
PO4 retention- hyperphosphataemia
Hypocalcaemia as a result of decreased vit D
Secondary hyperparathyroidism
Metabolic acidosis
Aluminium deposition
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42
Q

What are the stages of Paget’s disease?

A

Disorder of bone turnover

  1. Osteolytic (phase where osteoblasts fight back)
  2. Osteolytic-osteosclerotic
  3. Quiescent osteosclerotic
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43
Q

Why does Paget’s disease cause an odd mosaic of bone?

A

Broken down and reformed constantly

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44
Q

Who is affected by Paget’s disease?

A 
Onset >40y (affects 3% caucasians >55y)
M=F
Rare in Asians and Africans
Mono-ostotic 15%
Remained polyostotic (more than one bone affected)
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45
Q

What causes Paget’s disease?

A

Unknown

Familial cases show autosomal pattern of inheritance with incomplete penetrance (mutation 5q35-qter - sequestosome 1 gene)

Parvomyxovirus type particles have been seen on EM in Pagetic bone

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46
Q

Outline site predilection in Paget’s disease

A

Usually not in hands, feet or arms

Lots in skull, lower spine and pelvis

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47
Q

What are the clinical symptoms of Paget’s disease?

A

Pain
Microfractures
Nerve compression (incl. spinal N and cord)
Skull changes may put medulla at risk
Deafness
+/- haemodynamic changes, cardiac failure
Hypercalcaemia
Development of sarcoma in area of involvement 1%

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48
Q

Why do haemodynamic changes affect the bone in Paget’s disease?

A

Bone supply to bone changes (can affect heart because more cardiac output to bone)

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49
Q

What are the 5 common metabolic bone disorders?

A

Primary hyperparathyroidism

Rickets/ Osteomalacia

Osteoporosis

Paget’s Disease

Renal osteodystrophy

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50
Q

How can you investigate bone disease biochemically?

A

SERUM
Bone profile- Ca, corrected Ca (albumin), phosphate, alkaline phosphatase
Renal function- creatine

PTH
25-hydroxy vit D

URINE- ca/phosphate, NTX

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51
Q 
How are the following affected in osteoporosis?
Ca
P
Alk P
Bone formation
Bone resorption
A 
Ca= N
P= N
Alk P= N
Bone formation= increases/same
Bone resorption= increases a lot
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52
Q 
How are the following affected in osteomalacia?
Ca
P
Alk P
Bone formation
Bone resorption
A

Ca= N or decreases
P= decreases
Alk P= increases

Bone formation=
Bone resorption=

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53
Q 
How are the following affected in Pagets?
Ca
P
Alk P
Bone formation
Bone resorption
A 
Ca= N (increase)
P= N
Alk P= increases A LOT!! 
Bone formation= increases a lot
Bone resorption=
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54
Q 
How are the following affected in primary HPT?
Ca
P
Alk P
Bone formation
Bone resorption
A 
Ca= increases
P= N or decreases
Alk P= N or increases
Bone formation= 
Bone resorption= increases a lot
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55
Q 
How are the following affected in renal osteodystrophy?
Ca
P
Alk P
Bone formation
Bone resorption
A 
Ca= decreases or N
P= increases
Alk P= increases
Bone formation= 
Bone resorption=
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56
Q 
How are the following affected in metastases?
Ca
P
Alk P
Bone formation
Bone resorption
A 
Ca= increases
P= increases
Alk P= increases
Bone formation= 
Bone resorption= increases
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57
Q

What 3 main systems are involved in Ca balance?

A

GUT what’s coming in; 1g day recommended intake

KIDNEY what’s going out

BONE flux; your compensatory mechanism

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58
Q

True or false: cancellous bone doesn’t have a blood supply?

A

Cancellous bone has a huge blood supply

Surface area for gas exchange is enormous

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59
Q

Why do you compensate serum calcium measurements?

A

Compensates for protein level; if protein levels are HIGH they compensate down; 0.02 for each g/l of albumin

Corrected calcium = [calcium] + 0.02( 45 – [albumin])

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60
Q

What is total calcium made up of?

A

46% protein-bound (mostly to albumin)

47% free ionized

7% complexed (to P and citrate)

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61
Q

What is the name of the process when free calcium goes to protein-bound calcium?

A

Alkalosis

E.g. If HYPERVENTILATE; get alkalosis which causes more ca to bind to protein so that free levels drop (tingling)

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62
Q

How much is total calcium?

A

Total calcium 2.15-2.56 mmol/L

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63
Q

What is the predominant regulator (min by min) of serum calcium levels?

A

PTH

Low plasma Ca-> increased PTH

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64
Q

What affect does increased PTH have on bone?

A

Bone resorption (by increased osteoclast activity)

Release of Ca and phosphate (acute release not in hydrozyapatite crystals)

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65
Q

What affect does increased PTH have on the kidney?

A

INCREASED PHOSPHATE EXCRETION
Decreased P excretion by inhibiting the NAP cotransporter in the proximal tubule

INCREASED CA REABSORPTION
Increased ca re-absorption in the distal convoluted tubule= the only site where Ca re-absorption is under active hormonal control

INCREASED CALCITRIOL FORMATION (-> INCREASED INTESTINAL CALPO4 ABSORPTION)
Stimulation of 1alpha hydroxylase activity , so increasing activated vit D production, which leads to increased gut re-absorption of Ca

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66
Q

What part of the PTH is used to build bone?

A

N1-34 is active

The whole peptide is 84 AAs

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67
Q

How does hypomagnesium affect PTH?

A

Hypo Mg-> low PTH and hypocalcaemia especially in alcoholics

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68
Q

Why is the short half life of PTH useful?

A

Allows intraoperative sampling

T1/2= 8 mins

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69
Q

What do you expect PTH to be in primary hyperparathyroidism?

A

Doesn’t have to be high, can be in upper half or normal

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70
Q

Describe the relationship between PTH levels and calcium ions outside the cell in vivo?

A

Steep inverse sigmoidal functions

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71
Q

Where does calcium absorption due to PTH occur?

A

PTH drives active calcium absorption in the distal tubule of the kidney

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72
Q

How does PTH cause bone resorption?

A

Through the RANK system

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73
Q

Who is commonly affected by primary hyperparathyroidism (HPT)?

A

50s
Female 3x more than male
2% post menopausal develop

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74
Q

What are the main causes of primary hyperparathyroidism?

A

Parathyroid adenoma= 80%

Parathyroid hyperplasia= 20%

Parathyroid CA= <1%

Familial Syndromes

  • MEN 1= 2%
  • MEN 2A= rare
  • HPT-JT= rare
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75
Q

How can HPT be diagnosed?

A

An elevated total/ionised calcium with PTH levels frankly elevated
or in the upper half of the normal range

i.e. Corrected calcium >2.6mmol/l with pTH > 3.9 pmol/l (nr 1.0-6.8)

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76
Q

How can high calcium become a medical emergency?

A

High calcium causes a diuresis

High Ca shuts down transporter (like the drug frusemide)-> excess dehydration (and go into renal failure)-> medical emergency because can become vicious cycle

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77
Q

How does calcium affect risk of kidney stones?

A

Calcium-> diuresis-> hypercalciuria-> increased stone risk

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78
Q

How does calcium affect cortical bone resorption?

A

Calcium-> increased bone turnover

Acute (or pulsed) increase in PTH can build anabolic bone
Chronic increase in PTH can have catabolic bone (mainly cortical)

THIS MEAN CORTICAL > CANCELLOUS

Mainly cortical-> increased fractures

i.e. chronically elevated PTH increases fracture risk

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79
Q

Why are rickets and osteomalacia increasingly common again?

A

Chronic vit D deficiency

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80
Q

How is vitamin D metabolised?

A

SEE DIAGRAM

UV light on skin leads to conversion of 7-dehydrocholesterol to cholecalciferol (also from diet)

Liver converts cholecalciferol to 25-cholecalciferol

Kidney converts 25-cholecalciferol with PTH to calcitriol (1,25 (OH)2 vit D)

1,25 (OH)2 vit D needed by intestine bone and kidney

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81
Q

What does 1,25 (OH)2 vit D do in the intestine?

A

Activates Ca and P absorption

In duodenum- TRPV6, calbindin

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82
Q

What does 1,25 (OH)2 vit D do in the kidney?

A

Facilitates PTH action in distal tubule to increase Ca reabsorption (inducing TRPV5, calbindin)

Proximal tubule reaborbs vitamin D and activates it

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83
Q

What does 1,25 (OH)2 vit D do in the bone?

A

Synergises with PTH to increase osteoclastic osteolysis differentiation agent for osteoclast precursors

Increases osteoblast differentiation and bone formation

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84
Q

How does activated vitamin D increase gut calcium absorption?

A

Vitamin D increases active calcium transport in the gut

Active: up to 40% saturable duodenum 1,25 Vit D

20 – 60% load
Duodenum/ jejenum
also colon
Passive: Paracellular linear

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85
Q

How does 1,25 (OH)2 vit D affect feedback?

A

Parathyroid directly reduces PTH secretion bone to increase FGF-23 production

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86
Q

What is the functional definition of vitamin D deficiency?

A

At a nadir 25 OH D = 30 ng/ml (75nmol/l) PTH levels start to rise

Muscle function optimal >70nmol/l

Gut Ca absorption increases up to 80 nmol/l

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87
Q

What is rickets?

A

Inadequate vit D activity leads to defective mineralisation of the cartilagenous growth plate (before a low calcium)

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88
Q

What are the signs and symptoms of rickets?

A

SYMPTOMS
Bone pain and tenderness (axial)
Muscle weakness (proximal)
Lack of play

SIGNS
Age dependent deformity
Myopathy
Hypotonia
Short stature
Tenderness on percussion
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89
Q

What are the causes of rickets/osteomalacia?

A

VITAMIN D RELATED
Lack of sunlight
Decreased production with age
Dietary (not added to foods except USA)

GI= small bowel malabsoprtion/bypass (v. common in gastrectomies and coeliacs), pancreatic insufficiency, liver/biliary disturbance

Drugs= phenytoin, phenobarbiton (drugs increase p450 cytochrome activity that inactivates vit D)

Renal= chronic renal failure

Rare hereditary= vit D dependent rickets

  • Type 1= deficiency of 1 alpha hydroxylase
  • Type 2= defective VDR for calcitriol
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90
Q

What is the biochemistry of rickets/osteomalacia?

A 
SERUM
Calcium= N/low
Phosphate= N/low
Alk phos= High 
25(OH)Vit D= Low
PTH= High (secondarily to compensate)

URINE
Phosphate= High
?Glycosuria, aminoaciduria, high pH, proteinuria

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91
Q

What does FGF-23 do?

A

FGF-23 produced by osteoblast lineage cells in long bones

LIKE PTH= Causes PCT (proximal convoluted tubule) phosphate loss

UNLIKE PTH= inhibits activation of vit D by 1 alpha hydroxylase

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92
Q

How is phosphate loss related to osteomalacia?

A

In osteomalacia, can also get renal phosphate loss when Ca and Vit D levels are usually normal

Kidney forced to lose phosphate

E.g. in ‘isolated” hypophosphataemia (X-linked hyphophataemic Rickets or autsomal dominant hypophasphataemic rickets (ADRR) and oncogenic osteomalasia

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93
Q

What is ‘isolated’ hypophosphataemia?

A

X-linked hypophosphataemic Rickets

  • 1;20,000
  • Mutations in PHEX; high levels of FGF-23
  • Toddlers with leg deformity, enthesopathy, dentin anomalies

Autosomal dominant hypophosphataemic rickets (ADRR)

  • Variable age of onset; may improve
  • Cleavage site for FGF-23 mutated, so high FGF-2
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94
Q

What is oncogenic osteomalacia?

A

Mesenchymal tumours

Produce FGF-23, causes phosphaturia and stops 1 alpha hydroxylase

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95
Q

How does FGF-23 excess cause rickets/ostemalacia?

A

Mesenchymal tumour-> active FGF-23-> renal phosphate wasting

(NB. NORMALLY= normal tissues, active FGF-23 cleaved-> inactive which -> normal phosphate levels for cartilage and bone mineralization)

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96
Q

What happens as a results of the kidney proximal tubule damage in osteomalacia?

A

Kidney proximal tubule damaged-> causes phosphaturia and stops 1 alpha hydroxylation of vit D

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97
Q

What are the causes of Fanconi Syndrome?

A

Multiple myeloma
Heavy metal poisoning: lead, mercury
Drugs- tenofovir, gentamycin
Congenital diseases e.g. Wilsons, glycogen storage diseases

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98
Q

What causes osteoporosis?

A

High turnover- increased bone resorption greater than increased bone formation

Low turnover- decreased bone formation more pronounced than decreased bone resorption

Increased bone resorption and decreased bone formation

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99
Q

How does high turnover of bone lead to osteoporosis?

A 
Estrogen deficiency- primarily in postmenopausal women
Hyperparathyroidism
Hyperthyroidism
Hypogonadism in young women and in men
Cyclosporine
Heparin
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100
Q

How does low turnover of bone lead to osteoporosis?

A

Liver disease- primarily primary biliary cirrhosis
Heparin
Age >50 years

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101
Q

How does increased bone resoprtion lead to osteoporosis?

A

Glucocorticoids

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102
Q

What is metabolic bone disease?

A

A group of diseases that cause a change in bone density and bone strength by:

  • Increasing bone resorption
  • Decreasing bone formation
  • Altering bone structure

May be associated with disturbances in mineral metabolism

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103
Q

What are the metabolic and bone-specific symptoms of metabolic bone diseases?

A

Metabolic= hypocalcaemia, hypercalcaemia, hypophosphataemia, hyperphosphataemia

Bone pain= deformity, fractures

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104
Q

How is cancellous bone metabolically active?

A

Remodelling= 5% anytime, total skeleton over 7 years

Continuous exchange of ECF with bone fluid reserve

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105
Q

What makes bone strong?

A

MASS

MATERIAL PROPERTIES
Collagen, cross-linking, isomerization
Women vs lamellar
Mineralization
Microcracks
MICROARCHITECTURE
Trabecular thickness
Trabecular connectivity
Cortical porosity 
(Particularly relevant in trabecular bone i.e. spine post menopause lose thickness and connection, which cannot be reformed)

MACROARCHITECTURE
Hip axis length
Diameter
(Hip/femoral neck inferiorly under particular strain)

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106
Q

How can bone structure and function be assessed?

A

Bone histology
Biochemical tests
Bone mineral densitometry e.g. osteoporosis
Radiology

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107
Q

Outline age related changes in bone mass

A

Peak bone mass in mid 20s (after attainment of peak bone mass)
Stable until around 40 (consolidation)
Men slow loss (age-related bone loss)
Women fast loss in early menopause (age-related bone loss)

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108
Q

How do growth and exercise change peak bone mass?

A

Change in bone dimensions and bone shape

Change in trabecular volumetric BMD

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109
Q

In growth of the tibia, how is bone remodelled?

A

More bone placed anteriorly and posteriorly
OPTIMISE DEPOSITION SO AS NOT TO WASTE MASS

Increase in bending strength ratio; AP to ML

PERIOSTEAL apposition; essentially only when young (greater diameter has greater bone strength)

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110
Q

What is bone remodelling?

A

The process by which these areas are repaired

each osteon essentially represents a previous remodelling event

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111
Q

What is bone structure designed for?

A

Bone has a structure designed to absorb energy

Irreversible plastic deformation does occur (-> microfractures)

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112
Q

Outline the bone remodeling cycle?

A

Bone remodelling occurs in the basic multicellular unit

ACTIVATION
Activation occurs
A microcrack crosses canaliculi, so severing the osteocyte processes causing osteocytic apoptosis

This acts as a signal to the connected surface lining cells (which are osteoblast lineage), which along with the osteocytes release local factors that attract cells from blood and marrow into the remodeling compartment

RESORPTION
For the resorption phase to start osteoclasts are generated locally and resorb matrix and the offending microcrack, then successive teams of osteoblasts deposit new lamellar bone

REVERSAL
Osteoblasts that are trapped in the matrix become osteocytes; others die or form new, flattened osteoblast lining cells

FORMATION
New lining cells formed

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113
Q

How does estrogen deficiency causes menopausal bone loss?

A

Increases the number of remodelling units

Causes remodelling imbalance with increased bone resorption (90%) compared to bone formation (45%)

Enhanced osteoclast survival and activity

-> Remodelling errors
Deeper and more resorption pits lead to:
-Trabecular perforation
- Cortical excess excavation

Decreased osteocyte sensing

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114
Q

What kind of bone loss is marked early in menopause?

A

Cancellous bone

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115
Q

What biochemistry in osteoporosis can be used to exclude other causes?

A

Serum biochem should be normal if primary:

  1. Check for vit D deficiency
  2. Chek for secondary endocrine causes *
  3. Exclude multiple myeloma
  4. May have high urine calcium
* E.g. 
HIV where chronic inflam process-> bone loss
Primary hyperphrathyroidism (PTH high)
Primary hyperthryoidism (free T3 high)
Hypogonadism (testosterone low)
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116
Q

What is the main tool for assessing osteoporosis?

A

BMD
Single best predictor of fracture risk
(BMD represents 70% of total risk)

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117
Q

What is DEXA?

A

Dual energy X ray absorptiometry
Measures transmission through the body of X rays of two different photon energies
Enables densities of two different tissues to be inferred i.e. bone mineral, soft tissue

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118
Q

How is osteoporosis defined on BMD?

A

T-score = (measured BMD – young adult mean BMD) OVER (young adult standard deviation)

T score (standard deviations)
-2.5= osteoporosis
- 1 to -2.5= osteopaenia
>-1= normal

(I SD reduction= 2.5 increase in risk of fracture)

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119
Q

What is FRAX?

A

Fracture risk assessment tool

Uses hip BMD

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120
Q

What are the central measurements taken to study BMD?

A 
VERTEBRAL
Commonest fracture
Increasing incidence after aged 60
Measure of cancellous bone
Metabolic bone; quickest response to treatment

HIP
2nd commonest
>70
Costs and mortality

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121
Q

What are the bone markers?

A

In most bone diseases the bone cycle is disrupted

Markers of bone formation and resorption give us insight into activity

Unlike BMD they are dynamic

Divided into markers of formation and resorption

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122
Q

Outline collagen synthesis in bone formation?

A

2 alpha 1 and 1 alpha 2 chain of type I collagen produced by the osteoblast join

Extension peptides cut off these propeptides can be measured in blood

3 hydroxylysine molecules on adjacent tropocollagen fibrils condense to form a pyridinium ring linkage

These can be used to measure bone resorption (serum CTX, urine NTX)

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123
Q

How are bone resorption markers used in monitoring osteoporosis treatment?

A

Monitoring of response to treatment with anti- resorptive drugs (BMD change 18mnths)

Bone resorption markers fall in 4-6 weeks

Expect a 50% drop of urine NTx by 3 months

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124
Q

What are the problems with cross-links?

A
  1. Reproducibility: CV 20%
  2. Positive association with age
  3. Need to correct for Cr
  4. Diurnal variation in urine markers

Peak 4-8am
Measure 24h or 2nd urine

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125
Q

What is a common usage of alkaline phosphatase?

A

Clinical use as a bone formation marker

TYPES= Tissue-specific form (liver vs bone), intestine, germ cell and placental forms

ROLE= Essential for mineralisation, regulates concentrations of phosphocompounds

USES= consistent within an individual (t1/2 40 hours)
Used in diagnosis and monitoring of pagets, osteomalcia and bone metastases (prostate with PSA)

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126
Q

How is P1NP used as a bone formation marker?

A

As a predictor of response to anabolic treatments

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127
Q

What is CKD-MBD?

A

Chronic kidney disease mineral bone disorder (2006)

Skeletal remodeling disorder caused CKD contribute directly to heterotopic calcification, especially vascular

The disorders in mineral metabolism that accompany CKD are key factors in the excess mortality caused by CKD

CKD impairs skeletal anabolism, decreasing osteoblast function and bone formation rates

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128
Q

How does renal osteodystrophy develop?

A

Increasing serum phosphate and reduction in 1,25 vit D (calcitriol)

So…
Secondardary hyperparathyroidism develops to compensate

But…
Unsuccessful and hypocalcaemia deelops

Later... 
Parathyroids autonomous (tertiary) causing hypercalcaemia
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129
Q

What is the progression of secondary HPT: parathryoid hyperplasia?

A

Parathyroid hyperplasia develops in tandem with the progressive decline in renal function

(By increasing continuous functional demand and increasing gland volume-> these drive cell proliferation)

Normal
Secretory cells
Diffuse
Early nodularity
Nodular
Single nodule

Parathyroid glands with nodular hyperplasia therefore become less responsive to serum calcium levels and resistant to the medical treatment of SHPT

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130
Q

List 3 main autoimmune musculoskeletal disorders

A

Rheumatoid arthritis
Ankylosing spondylitis
Systemic lupus erythematosus (SLE)

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131
Q

What happens in rheumatoid arthritis?

A

Chronic joint inflammation that can result in joint damage

Site of inflammation is the synovium (synovitis)

Associated with autoantibodies

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132
Q

What autoantibodies are involved in rheumatoid arthritis?

A

Rheumatoid factor

Anti-cyclic citrullinated peptide (CCP) antibodies

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133
Q

What is ankylosing spondylitis?

A

Chronic spinal inflammation-> can result in spinal fusion and deformity-> exaggerated kyphosis, patient strains neck to see

Primarily rheumatoid (can be associated by either IBD and psoriasis)

Site of inflammation is the enthesis

No autoantibodies (seronegative)

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134
Q

What site of inflammation in ankylosing spondylitis?

A

Enthesis

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135
Q

What are the kinds of seronegative spondyloarthropathies?

A

Ankylosing spondylitis

Reiters syndrome and reactive arthritis

Arthritis associated with psoriasis (psoriatic arthritis)

Arthritis associated with GI inflammation (enteropathic synovitis)

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136
Q

What is systemic lupus erythematosus (SLE)?

A

Chronic tissue inflammation in the presence of antibodies directed against self antigens (deposit-> inflammation)

Multi-site inflammation but particularly the joints, skin and kidney (clinical features depend on organs affected)

Associated with autoantibodies

Rare (female preponderance)

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137
Q

Which autoantibodies are involved in SLE?

A

Antinuclear antibodies (ANA)= in all cases, not specific for SLE

Anti-double stranded DNA antibodies (anti-dsDNA)= specific for SLE (ab serum level correlates with disease activity)

Anti-cardiolipid antibodies= associated with risk of arterial and venous thrombosis in SLE

Anti-Sm antibodies= specific for SLE (ab serum level doesn’t correlate with disease activity)

Anti-Ro/Anti-La antibodies= secondary Sjogren syndrome/Neonatal lupus syndrome

Anti-ribosomal p antibodies= cerebral lupus

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138
Q

List examples of connective tissue diseases

A

Systemic lupus erythematosus (SLE)

Inflammatory muscle disease: polymyositis, dermatomyositis

Systemic sclerosis

Sjogren’s syndrome

A mixture of the above:
‘Overlap syndromes’

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139
Q

How do HLA molecules contribute to rheumatology?

A

MHC and disease are associated:

  • The genes within the MHC class I and II regions encode cell surface proteins
  • Function of mHC molecules is to present antigen to T cells

Rheumatoid arthritis= hLA-DR4
SLE= HLA-DR3
Ankylosing spondylitis= HLA-B27

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140
Q

What is the peptide-binding site on MHC made up of?

A

Made up of walls (A-helical structures) and floor (B-pleated sheet)

Sequence in peptide-binding groove determines which antigens can bind

T cells only see antigen-bound to MHC (‘MHC restriction’)

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141
Q

What happens in HLA-associated rheumatology disease?

A

Possibly due to a peptide antigen (exogenous or self) that is able to bind to HLA molecule and trigger disease (‘arthritogenic antigen’)

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142
Q

What autoantibodies are involved in systemic vasculitis?

A

Antinuclear cytoplasmic antibodies (ANCA)

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143
Q

What rheumatological diseases don’t involve auto-antibodies?

A

Osteoarthritis
Reactive arthritis
Gout
Ankylosing spondylitis

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144
Q

What autoantibodies are involved in diffuse systemic sclerosis?

A

Anti-Scl-70 antibodies

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145
Q

What autoantibodies are involved in limited systemic sclerosis?

A

Anti-centromere antibodies

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146
Q

What autoantibodies are involved in Dermato/Polymyositis?

A

Anti-tRNA transferase antibodies

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147
Q

What autoantibodies are involved in Sjogren’s syndrome?

A

No unique antibodies but typically see:
Antinuclear antibodies (Anti-Ro and Anti-La)
Rheumatoid factor

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148
Q

What autoantibodies are involved in mixed connective tissue disease?

A

Anti-U1-RNO antibodies

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149
Q

If there are antinuclear antibodies, further tests will be used to work out what kind of ANA it is. These include:

A 
Anti-Ro
Anti-La
Anti-centromere
Anti-Sm
Anti-RNP
Anti-ds-DNA antibodies 
Anti-Scl-70
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150
Q

What kind of cytoplasmic antibodies are there?

A

Anti-tRNA synthetase antibodies

Anti-ribosomal P antibodies

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151
Q

What complement levels and serum levels of anti-ds-DNA antibodies are present in a sick lupus patient?

A

Low complement levels

High serum levels of anti-ds-DNA antibodies

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152
Q

What cytokines appear in rheumatology?

A

Cytokine γ-IFN on T cells
-> Activates macrophages

Cytokine IL-1 on Macrophages
-> Activates T cells, fever, pro-inflammatory

Cytokine IL-2 on T cells
-> Activates T and B cells

Cytokine IL-6 on T cells -> Activates B cells, acute phase response

Cytokine TNF-α on Macrophages
(Similar to IL-1)-> more destructive

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153
Q

What cytokine is dominant in rheumatology?

A

TNF alpha

Dominant pro-inflammatory cytokine in the rheumatoid synovium and its pleotropic actions are detrimental in this setting

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154
Q

What does TNF alpha do that is important in rheumatology?

A

Activated macrophage-> TNF-a

LEADS TO:
Proinflammatory cytokine release 
Hepcidin induction
PGE2 production
Osteoclast activation
Chondrocyte activation
Angiogenesis
Leukocyte accumulation
Endothelial cell activation
Chemokine release
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155
Q

What cytokines can be blocked to treat rheumatology?

A

IL-6 and IL-1 currently used in clinic

Others under investigation

(Can also deplete B cells by IV admin of an antibody against a B cell surface antigen, CD20)

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156
Q

Why is RANKL important in bone destruction in rheumatoid arthritis?

A

RANKL (receptor activator of nuclear factor B ligand)

Binds to RANK (antagonized by OPG)-> Acts to stimulate osteoclast formation (osteoclastogenesis)

Upregulated by IL-1 (TNFa), iL-17 nad PTH-related peptide

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157
Q

What is RANKL produced by in rheumatoid arthritis?

A

T cells and synovial fibroblasts

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158
Q

What is denosumab?

A

Monoclonal antibody against RANKL

Indicated for treatment of osteoporosis, bone metastases, multiple myeloma and Giant cell tumours

159
Q

What is a key feature of systemic lupus erythematosus that has become a useful drug target?

A

B cell hyper-reactivity= key feature

So biological therapies targeting B cells have been used in the treatment of SLE

E.g. rituximab (chimeric anti-CD20 ab to deplete B cells) and belimumab (monoclonal ab against B cell survival factor called BLYS)

160
Q

What is the role of prostaglandins in rheumatology?

A

Lipid mediators of inflammation that act on platelets, endothelium, uterine tissue and mast cells

Synthesized from essential fatty acids: phospholipase A2 generates arachidonic acid from diacylglycerol in cell membranes

Arachidonic acid enters two pathways:

  • Cycloxygenase pathway
  • Lipoxygenase pathway
161
Q

Which isoform of cyclooxygenase is inducible and which is constitutive?

A

COX-1 (constitutive)

COX-2 (inducible)

162
Q

What is rheumatoid arthritis?

A

Chronic, autoimmune disease characterised by pain, stiffness and symmetrical synovitis of synovia (diarthrodial) joints

163
Q

What are the key features of chronic rheumatoid arthritis?

A

Polyarthritis (especially in small joints of hand and wrists)
Symmetrical
Early morning stiffness in and around joints
May lead to joint damage and destruction (joint erosions)

Extra-articular disease can occur (rheumatoid nodules, vasculitis, episcleritis)

Rheumatoid ‘factor’ may be detected in blood (IgM autoantibody against IgG)

164
Q

Outline the epidemiology of rheumatoid arthritis

A

1% of population affected

3x more in females

165
Q

What is the genetic component of rheumatoid arthritis?

A

Disease concordance rates for twins are 15-30% (monozygotic) and 5% (dizygotic)

Heritability estimates of up to 60%

Specific HLA-DRB gene variants involved
- There is a region encoding conserved AA sequence in HLA-DR ag-binding groove which is common to rheumatoid arthritis-associated DR alleles (shared epitope)

166
Q

What environmental factors contribute to rheumatoid arthritis?

A

Smoking increases risk

167
Q

What joints are most commonly affected by rheumatoid arthritis?

A 
Metacarpophalangeal joints (MCP)
Proximal interphalangeal joints (PIP)
Wrists 
Knees
Ankles
Metatarsophalangeal joints (MTP)
168
Q

True or false; polyarthritis is usually unsymmetrical in rheumatoid arthritis?

A

False

Symmetrical polyarthritis

169
Q

Where do calouses form in rheumatoid arthritis?

A

Under heads of metatarsals due to joint deformity

170
Q

What kind of joint damage and destruction happens in the hand in rheumatoid arthritis?

A

Swan-neck deformity (e.g. ring finger)= hyper-extension at the PIP join and hyper-flexion at DIP joint

Boutonniere deformity (e.g. little finger)= hyper-flexion at PIP joint

171
Q

What is the primary site of pathology in rheumatoid arthritis?

A

In the synovium (synovial joints, tenosynovium surround tendons, bursa)

172
Q

Where does fusiform swelling happen in rheumatoid arthritis?

A

Fusiform swelling limited to joint

173
Q

Where does swelling in extensor tenosynovitis happen?

A

Swelling is not above either the wrist or MCP joints

174
Q

What are sub-cutaneous nodules in rheumatoid arthritis?

A

Central area of fibrinoid necrosis surround by histiocytes and peripheral layer of connective tissue

Occur in 30% of patients

Associated with severe disease, extra-articular manifestations and rheumatoid factor

175
Q

Where are rheumatoid nodules found in rheumatoid arthritis?

A

Ulnar border of forearm

In hands

176
Q

What is rheumatoid factor?

A

Antibodies that recognise the Fc portion of IgG as their target antigen

Typically IgM antibodies i.e. IgM anti-IgG antibody

Positive in 70% at rheumatoid disease onset and further 10-15% become positive over the first 2 years

177
Q

What are the antibodies to citrullinated protein antigens (ACPA)?

A

Highly specific for rheumatoid arthritis (anti-cyclic citrullinated peptide antibody ‘anti-CCP antibody’)

Cirtullination of peptides is mediated by enzymes that convert arginine to citrulline

178
Q

What enzymes convert arginine to citrulline?

A

Peptidyl arginine deiminases (PADs)

179
Q

Why do ACPAs develop in rheumatoid arthritis?

A

PADs are present in high concentrations in neutrophils and monocytes and consequently there is increased citrullination of autologous peptides in the inflammed synovium

ACPA is strongly associated with smoking and HLA ‘shared epitope’

The shared epitope preferentially binds non-polar amino acids like citrulline but not positively charged amino acids like arginine- so ACPA more likely to develop among individuals with citrulinated autoantigens who have the shared eptiope

Smoking – increases ACPA-positive rheumatoid arthritis risk (enhances citrullination in lungs)

180
Q

What is the shared epitope of rheumatoid arthritis?

A

Amino acids 70-74 of the HLA-DRB-chains associated with rheumatoid arthritis

This is why multiple different HLA serotypes were associated with disease (all contain the shared epitope)

The shared epitode preferentially binds non-polar AAs e.g. citrulline and citrulline-containing peptide antigens increased during inflammation

181
Q

What are the extra-articular features of rheumatoid arthritis?

A

COMMON
Fever, weight loss
Subcutaneous nodules

UNCOMMON
Vasculitis
Ocular inflammation e.g. episcleritis
Neuropathies
Amyloidosis
Lung disease- nodules, fibrosis, pleuritis
Felty’s syndrome- traid of splenomegaly, leukopenia and rheumatoid arthritis

182
Q

What radiographic abnormalities are present in rheumatoid arthritis?

A

Scan= US and MRI scanning
NB. Articular cartilage can’t be seen on normal X ray

EARLY
Juxta-articular osteopenia
Bone looks less dense

LATER
Joint erosions at margins of the joint

LATER STILL
Joint deformity and destruction

183
Q

How can you see articular cartilage on an X-ray?

A

Can’t be seen on normal X ray

Can see gap (bit of air between bones) if normal bone- if that’s lost then osteoarthritis

184
Q

Describe a synovial joint

A

SHOULD BE ABLE TO DRAW DIAGRAM

Synovium
Synovial fluid
Articular cartilage

185
Q

Describe the synovium in synovial joint

A

1-3 cell deep lining containing macrophage-like phagocytic cells (type A synoviocyte) and fibroblast-like cells that produce hyaluronic acid (type B synoviocyte)

Type I collagen

(bONE= type 1)

186
Q

Describe synovial fluid

A

Hyaluronic acid-rich viscous fluid

187
Q

Describe articular cartilage

A

Type II collagen

Proteoglycan (aggregan)

188
Q

Outline the pathogenesis at the synovial membrane in rheumatoid arthritis

A

The synovium becomes a proliferated mass of tissue (pannus)

Recruitment, activation and efffector functions of these cells is controlled by a cytokine network

(There is an excess of pro-inflammatory vs anti-inflammatory cytokines= cytokine imbalance)

189
Q

What causes the synovium to become a pannus (proliferated mass of tissue)?

A

Neovascularisation

Lymphangiogenesis

Inflammatory cells:

  • Activated B and T cells
  • Plasma cells
  • Mast cells
  • Activated macrophages
190
Q

What does a healthy synovial membrane look like/contain?

A

1 to 3 cell layer that lines synovial joints

Contains macrophage-like (type A synoviocyte) and fibroblast-like (type B synoviocyte) cells and type I collagen

Functions include the maintenance of synovial fluid, the hyaluronate-rich viscous fluid within joint space

191
Q

How can you achieve TNFa inhibition?

A

Through parenteral administration

Most commonly sub-cutaneous injection of antibodies or fusion proteins

192
Q

How can you manage rheumatoid arthritis?

A

Treatment goal is to prevent joint damage

Multidisciplinary approach e.g. physiotherapy, occupational therapy, hydrotherapy, surgery

Medication

193
Q

What medication can be used to manage rheumatoid arthritis?

A

‘DMARDs’= drugs that control the disease process
termed disease- modifying anti-rheumatic drugs

Biological therapies offer potent and targeted treatment strategies

Important roles for glucocorticoid therapy (‘steroids’, ‘prednisolone’)

DMARDs offer safer and more effective long-term treatment than ‘steroids’ so DMARDs= ‘steroid-sparing agents’ (don’t need steroids or need lower doses)

194
Q

Why are DMARDs started early?

A

Started early in the disease because:

Joint destruction = inflammation x time

195
Q

Why are glucocorticoid therapies avoided long-term?

A

Preference to avoid long-term use because of side-effects

Useful as short-term treatment options in many settings e.g. to control flare of disease or control inflammation of single joint

196
Q

How do DMARDs work?

A

Drugs that may induce remission (not cure) and prevent joint damage

Reduce the amount of inflammation in the synovium

Slow or prevent structural joint damage e.g. bone erosions

Complex mechanisms of action and all have relatively slow onset of action i.e. weeks

All have significant adverse effects and therefore require regular blood test monitoring during therapy

197
Q

Give examples of DMARDS

A

Methotrexate- commonly used

Sulphasalazine- commonly used

Hydroxychloroquine-commonly used

Leflunomide - uncommon

Gold (rarely used now)

Penicillamine (rarely used now)

198
Q

What is the downside to biological therapy?

A

Expensive

SEs= include increased infection risk

Especially:

  • TNFα inhibition is associated with increased susceptibility to mycobacterial infection e.g. tuberculosis so need to screen all patients for tuberculosis before starting treatment and may use prophylactic antibiotics in those at high risk
  • B cell depletion therapy can be associated with hepatitis B reactivation so need to screen all patients for hepatitis B before treatment
  • B cell depletion therapy can be associated with JC virus infection and progressive multifocal leukoencephalopathy (PML)- rare
199
Q

What is reactive arthritis?

A

Sterile inflammation in joints following infection (especially urogenital e.g. chlamydia trachomatis) and GI (e.g. salmonella, shigella, campylobacter) infections

200
Q

What are the important extra-articular manifestations of reactive arthritis?

A

Enthesopathy
Skin inflammation
Eye inflammation

201
Q

What can reactive arthritis be the first manifestation of?

A

HIV

Hep C infection

202
Q

What can cause reactive arthritis in young adults?

A

Commonly young adults with genetic predisposition (e.g. HLA-B27) and environmental trigger (e.g. Salmonella infection)

Symptoms follow 1-4 weeks after infection and this infection may be mild

203
Q

What are the musculoskeletal symptoms of reactive arthritis?

A

ARTHRITIS
Asymmetrical
Oligoarthritis (<5 joints)
Lower limbs typically affected

ENTHESITIS
Heel pain (Achilles tendonitis)
Swollen fingers (dactylitis)
Painful feet (metatasalgia due to plantar fascitis)

SPONDYLITIS
Sacroiliitis (inflammation of sacro-iliac joints)
Spondylitis (inflammation of spine)

204
Q

What are the extra- articular symptoms of reactive arthritis?

A

OCULAR
Sterile conjuncitivitis

GENITO-URINARY
Sterile urethritis

SKIN
Circinate balanitis
Psoriasis-like rash on hands and feet (keratoderma blenmorrhagicum)

205
Q

What is the triad that was the original description of reactive arthritis?

A

Arthritis
Urethritis
Conjunctivitis following infectious dysentery

(Reiter’s syndrome)

206
Q

Who does reactive arthritis affect?

A

M>F

20-40 years

207
Q

Do rheumatoid and reactive arthritis have enthesopathy?

A 
Rheum= no
React= yes
208
Q

Do rheumatoid and reactive arthritis have spondylitis?

A 
Rheum= no (except atlanto-axial joint in cervical spine)
React= yes
209
Q

Do rheumatoid and reactive arthritis have urethritis?

A 
Rheum= no
React= yes
210
Q

Do rheumatoid and reactive arthritis have skin involvement?

A 
Rheum= subcutaneous nodules
React= k.blennorhagicum, circinate balantis
211
Q

Do rheumatoid and reactive arthritis have rheumatoid factor?

A 
Rheum= yes
React= no
212
Q

Do rheumatoid and reactive arthritis have HLA association?

A 
Rheum= HLA-DR4
React= HLA-B27
213
Q

What kind of arthritis happens in rheumatoid and reactive arthritis?

A 
Rheum= symmetrical, polyarticular, small and large joints
React= asymmetrical, oligoarticular, large joints
214
Q

How is reactive arthritis diagnosed?

A

Clinical diagnosis
Investigations to exclude other causes of arthritis e.g. septic arthritis

Microbiology= cultures from blood, throat, urine, stool, urethra, cervical
Serology= HIV, hep C

Immunology= rheumatoid factor, (HLA-B27)

Synovial fluid exam= especially if only single joint affected

215
Q

What are the main differences between septic and reactive arthritis?

A

SEPTIC
Synovial fluid culture= positive
Antibiotic therapy= yes
Joint lavage= yes (for large joints)

REACTIVE
Synovial fluid culture= sterile
Antibiotic therapy= no
Joint lavage= no

216
Q

How is reactive arthritis treated?

A

In majority of patients complete resolution occurs within 2-6 months
No role for antibiotics

Articular= NSAIDs, intra-articular corticosteroid therapy

Extra-articular= typically self-limiting, hence symptomatic therapy

Refractory disease= oral glucocorticoids, steroid-sparing agents e.g. sulphasalazine

217
Q

What is osteoarthritis?

A

Chronic slowly progressive disorder due to failure of articular cartilage that typically affecting joints of the hand (especially those involved in pinch grip), spine and weight-bearing joints (hips and knees)

218
Q

Where does osteoarthritis usually affect?

A

JOINTS OF THE HAND
Distal interphalangeal joints (DIP)
Proximal interphalangeal joints (PIP)
First carpometacarpal joint (CMC)

SPINE

WEIGHT-BEARING JOINTS OF LOWER RLIMBS
Esp. knees and hips
First metatarsophalangeal joint (MTP)

219
Q

What are Heberden’s nodes?

A

In osteoarthritis

Osteophytes at the DIP joints

220
Q

What are Bouchard’s nodes?

A

In osteoarthritis

Osteophytes at the PIP joints

221
Q

What symptoms can osteoarthritis be associated with?

A

Joint pain= worse with activity, better with rest

Joint crepitus= creaking, cracking grinding sound on moving affected joint

Joint instability

Joint enlargement= e.g. Heberden’s nodes

Joint stiffness after immobility (‘gelling’)

Limitation of motion

222
Q

What are the radiographic features of osteoarthritis?

A

Joint space narrowing
Subchondral bony sclerosis
Osteophytes
Subchondral cysts

223
Q

Do rheumatoid and osteoarthritic arthritis have joint space narrowing (articular cartilage loss)?

A 
Rheum= yes
Osteo= yes
224
Q

Do rheumatoid and osteoarthritic arthritis have subchondral sclerosis?

A 
Rheum= no
Osteo= yes
225
Q

Do rheumatoid and osteoarthritic arthritis have osteophytes?

A 
Rheum= no
Osteo= yes
226
Q

Do rheumatoid and osteoarthritic arthritis have osteopenia?

A 
Rheum= yes (juxta-articular osteopenia common)
Osteo= no
227
Q

Do rheumatoid and osteoarthritic arthritis have bony erosions?

A 
Rheum= yes (erosions initially at the margins of the joint where the synovium is in direct contact with bone)
Osteo= no
228
Q

What does lack of space on X rays of bones indicate?

A

Loss of articular cartilage-> bone in contact with bone

See bone spurs

229
Q

Why does osteoarthritis develop?

A

Defective and irreversible articular cartilage and damage to underlying bone

Develops due to excessive loading on joints and/or abnormal joint components

230
Q

What factors can contribute to osteoarthritis?

A

GENETIC (contributes to abnormal stress and abnormal cartilage)

ABNORMAL STRESS
Trauma]Dysplasia
Obesity
Misalignment
Muscle weakness 
Loss of proprioception
ABNORMAL CARTILAGE
Ageing
Inflammation
Metabolic changes
Endocrine factors

These contribute to:
Chondrocyte apoptosis
Loss of proteoglycans
Colagen fibril damage

231
Q

What is the function of articular cartilage?

A

Weight-bearing

Depends on intact collagen scaffold and high aggrecan contect

232
Q

Outline the components of the articular cartilage

A

Avascular and aneural structure

Collagen - >90% is type II

Chondrocytes

Proteoglycan monomers (aggrecan)
- Monomers arranged into supreamolecular aggregates consisting of central hyaluronic acid filament and non-covalently linked aggrecan
233
Q

Give examples of proteoglycans

A

Intra-cellular
- Serglycin

Cell surface-associated

  • Betaglycan
  • Syndecan

Secreted into ECM

  • Aggrecan
  • Decorin
  • Fibromodulin
  • Lumican
  • Biglycan
234
Q

What are proteoglycans?

A

Glycoproteins containing one or more sulphates glycosaminoglycan (GAG) chains

235
Q

What is the role of hyaluronic acid in synovial fluid?

A

Hyaluronic acid is the only non-sulphated GAG

Is a major component of synovial fluid where it has an important role in maintaining synovial fluid viscosity

236
Q

What are GAGs?

A

Repeating polymers of disaccharides

Including:
Chondroitin sulphate 
Heparan sulphate
Keratan sulphate 
Dermatan sulphate
Heparin
237
Q

What are the cartilage changes in osteoarthritis?

A

Reduced proteoglycan
Reduced collagen
Chondrocyte changes e.g. apoptosis

238
Q

What are the bone changes in osteoarthritis?

A

DENUDED SUB-ARTICULAR BONE
Proliferation of superficial osteoblasts results in production of sclerotic bone e.g. subchondral sclerosis

Focal stress on sclerotic bone can result in focal superficial necrosis

NEW BONE FORMATION (OSTEOPHYTES/AT JOINT MARGINS)
Heberden’s nodes (DIP)
Bouchard’s nodes (PIP)

239
Q

How is osteoarthritis managed?

A

Education

Physical therapy= physiotherapy, hydrotherapy

Occupational therapy

Weight loss where appropriate

Exercise

Analgesia= paracetamol, NSAIDs, intra-articular corticosteroid injection

Joint replacement

240
Q

What are the therapeutic approaches for treating osteoarthritis that aren’t approved in the UK?

A

Glucosamine and chondroitin sulphate

Intra-articular injections of hyaluronic acid
hyaluronic acid to increase lubrication (viscosupplementation)
NB. Knee only

241
Q

What is in the family of chronic overlapping AI connective disease that SLE is in?

A

Rheumatoid arthritis

Sjögren’s syndrome

Systemic lupus erythematosus

Dermatomyositis

Polymyositis

Systemic sclerosis

242
Q

What does SLE commonly affect?

A

Joints and skin principally

Lungs, kidneys and haematology

243
Q

What is the epidemiology of SLE?

A

9x more common in women

Presentation 15 - 40 yrs

Increased in Afro-Caribbean, Asian, Chinese

244
Q

Are there genetic associations in SLE?

A

Multiple genes implicated

Complement deficiency e.g. C1q and C3

Fc receptors, IRF5, CTLA4, MHC class II HLA genes

245
Q

How does SLE present?

A

Malaise, fatigue, fever, weight loss

Lymphadenopathy

SPECIFIC FEATURES:
Butterfly rash, alopecia
Malar rash/photosensitive rash
Arthralgia
Raynaud's phenomenon
Serositis
OTHER FEATURES:
Inflammation 
Disease of kidney, CNS, heart and/or lungs
Accelerated atherosclerosis
Vasculitis
246
Q

What causes SLE?

A

Unknown

Genetic predisposition
Environmental triggers (e.g. EBV?)
Chronic innate immune system activation
Adaptive immune system activation

Deposition of immune complexes

Disease expression seems to follow flares of these

Aberrant amplification pathways (increases in severity-> can lead to tissue damage e.g. renal failure)

247
Q

How does apoptosis relate to SLE?

A

Apoptosis is increased (increased rate of epigenetic deregulation of pro-apoptotic genes)

Clearance of apoptotic cells is impaired (normally done by phagocytes)

-> Release of nuclear material and chronic exposure of nuclear material

Recognition of autoantigens

  • Release of nuclear material with specific epigenetic patterns
  • Epigenetic deregulation of genes involved in immune response
248
Q

How are autoantibodies in pathology formed?

A

Abnormal clearance of apoptotic cell material

  • > Dendritic cell uptake of autoantigens and activation of B cells
  • > B cell Ig class switching and affinity mutation
  • > IgG autoantibodies
  • > Immune complexes
  • > Complement activation, cytokine generation etc.
249
Q

What lab tests are used to diagnose SLE?

A 
Antinuclear antibodies
Anti-dsDNA and Sm
Anti-Ro and/or La
Haematology
Renal
250
Q

How are antinuclear antibodies used to detect SLE?

A

Patient serum put onto cells or fixed nuclear antigen

Antibodies if present will bind

Detect those with antibodies with fluorescence bound (indirect immunofluroscence)

ANA relatively non-specific, pattern important (homogenous, speckled, nucleolar and centromere)

Not diagnostic on its own

251
Q

Why can Anti-dsDNA and SM be used with ANA in SLE?

A

More specific but less sensitive

252
Q

Why can Anti-Ro and/or Labe used withANA in SLE?

A

Common in subacute cutaneous LE

Neonatal lupus syndrome and Sjögren’s

253
Q

What tests can be used to determine how active SLE is?

A 
Level of dsDNA
Increased complement consumption 
Anti-cardiolipin antibodies
Lupus anticoagulant
B1 glycoprotein
254
Q

What haematological tests are needed with diagnosis of SLE?

A

Lymphopaenia, normochromic anaemia

Leukopaenia, AIHA, thrombocytopaenia

255
Q

What renal tests are needed with diagnosis of SLE?

A

Proteinuria, haematuria
Active urinary sediment

Looking for glomerular nephritis

256
Q

How can you assess SLE disease severity?

A

Identify pattern of organ involvement

Monitor function of affected organs

  • Renal= BP, U and E, urine sediment and Prot:Crea ratio
  • Lungs/CVS=lung function, echocardiography
  • Skin, haematology, eyes

Identify pattern of autoantibodies expressed

  • Anti-dsDNA, anti-Sm- renal disease
  • Anti-cardiolipin antibodies
257
Q

What features can pre-empty severe SLE attacks?

A

CLINICAL FEATURES
Weight loss, fatigue, malaise, hair loss
Alopecia
Rash

LAB MARKERS
ESR (drift up)
Increased complement consumption (falling C3 and C4)
Increased anti-dsDNA
Other Abs e.g ANA and CRP poor indicators (doesn’t link to active disease)

258
Q

How is SLE divided into 3 groups?

A

MILD
Joint +/- skin involvement
Lethargy and tiredness

MODERATE
Inflammation of other organs
Pleuritis, pericarditis, mild nephritis

SEVERE 
Severe inflammation in vital organs:
- Severe nephritis		          
- CNS disease
- Pulmonary disease
- Cardiac involvement
- AIHA, Thrombocytopaenia, TTP
259
Q

How is mild SLE treated?

A

Paracetamol +/- NSAID
Monitor renal function

Hydroxychloroquine

  • Arthropathy
  • Cutaneous manifestations
  • Mild disease activity

Topical corticosteroids (to scalp)

260
Q

How is moderate SLE treated?

A

E.g. if hydroxychloroquine/ NSAID fails
Organ/life threatening disease

CORTICOSTEROIDS
High initial dose to suppress disease activity
IV methylprednisolone
Reduce dose slowly over 2-3 months
Reduce slowly to manage symptoms with minimal SEs

261
Q

How is severe SLE treated?

A

AZATHIOPRINE
Effective steroid-sparing agent
Need to monitor FBC and biochem (be aware of neutropenia)

CYCLOPHOSPHAMIDE
For more severe disease (leads to risks- BM suppression, infertility, cystitis (acrolein))
IV pulsed or oral

262
Q

What are novel ways of treating severe SLE?

A

MYCOPHENOLATE MOFETIL
Reversible inhibitor of inosine monophosphate dehydrogenase
Rate-limiting enzyme in de novo purine synthesis and lymphocyte proliferation
Lymphocytes- dependent upon de novo purine synthesis

RITUXIMAB
Anti-CD20 mAb therapy
Leads to depletion of B cells
Effective in lupus nephritis

263
Q

What is the prognosis for SLE?

A

15 year survival= 85% no nephritis or 60% nephritis

Worse if black, male and low socio-economic status

264
Q

What is the bimodal mortality pattern of SLE?

A

Chronic autoimmune inflammatory diseases drive other harmful processes

EARLY
Renal failure
CNS disease
Infection

LATE
Myocardial infarction

265
Q

When doing a locomotor examination- what main questions should be asked?

A

GALS screening for musculoskeletal disease

Are any of the joints abnormal?

What is the nature of the joint abnormality? (inflammation, irreversible, mechanical)

What is the extent (distribution) of the joint involvement? (number, symmetry, size, axial involvement)

Are any other features of diagnostic importance present?

266
Q

What are the first questions before performing the GALS examination?

A

Have you any pain or stiffness in your muscles, joints or back?
Can you dress yourself completely without any difficulty?
Can you walk up and down stairs without any difficulty?

267
Q

What are the components in GALS?

A

Gait
Arms
Legs
Spine

268
Q

How do you examine gait in GALS?

A

Observe patient walking, turning and walking back
look for:
- Smoothness and symmetry of leg, pelvis and arm movements
- Normal stride length
- Ability to turn quickly

269
Q

How do you examine the spine in GALS?

A 
Is paraspinal and shoulder girdle muscle bulk symmetrical?
Is the spine straight?
Are the iliac crests level?
Is the gluteal muscle bulk normal?
Are the popliteal swellings?
Are the Achilles tendons normal?
Are there signs of fibromyalgia? 
Are spinal curvatures normal?
Is lumbar spine and hip flexion normal?
Is cervical spine normal?
270
Q

How can you detect fibromyalgia in GALS?

A

Does mild pressure over either mid-point of each supraspinatus or gentle squeezing of skinfold over trapezius muscles elicit tenderness?

271
Q

How can you tell if someone has normal lumbar and hip flexion in GALS?

A

Ask patient to bend forward and touch their toes with knees straight

272
Q

What are the normal curves of the spine?

A

Cervical lordosis
Thoracic kyphosis
Lumbar lordosis

273
Q

How can you confirm normal neck movement in GALS?

A

Lateral cervical spine movement= try to place ear on the shoulder each side

274
Q

How do you examine the arms in GALS?

A

Look for normal girdle muscle bulk and symmetry
Look to see if there is full extension at the elbows
Are shoulder joints normal?
Examine hands palms down with fingers straight
Observe supination, pronation, grip and finger movements
Test for synovitis at the metacarpo-phalangeal joints (MCP joints)

275
Q

How can you assess shoulder movement in the GALS exam?

A

Patient places both hands behind head and pushes elbows back

Gleno-humeroid joints

276
Q

How can you test normal dexterity and and precision grip in GALS?

A

Place tip of each finger on to the tip of the thumb

277
Q

What is the MCP/MTP squeeze test? What does discomfort suggest?

A

Squeeze across 2nd to 5th MCP/MTP joints

Discomfort suggests synovitis

(Hands and feet)

278
Q

How do you examine the legs in GALS?

A 
Look for knee or foot deformity
Assess flexion of hip and knee
Look for knee swellings
Test for synovitis at the metatarso-phalangeal joints (MTP joints)
Inspect soles of the feet
279
Q

How do you assess flexion of hip and knee in GALS?

A

Whilst supporting the knee- passively internally rotate each hip, in flexion

280
Q

How do you assess knee for fluid in GALS?

A

Presence of fluid using ‘bulge’ sign and ‘patella tap’ sign

281
Q

Why should you inspect soles of feet in the GALS test?

A

For rashes and/or callosities

282
Q

What is the overall aim of the GALS screen?

A

Detailed exam of any abnormal joint(s)

Inspection: swelling, redness, deformity
Palpation: warmth, crepitus, tenderness
Movement: active, passive, against resistance
Function: loss of function

283
Q

What are the signs of inflammation?

A

Swelling= tumor

Warmth= calor

Erythema= rubor

Tenderness= dolor

Loss of function= functio laesa

284
Q

Define: arthritis

A

Definite inflammation of a joint(s)

I.e. swelling, tenderness and warmth of affected joints

285
Q

Define: arthralgia

A

Refers to pain within a joint(s) without demonstrable inflammation by physical examination

286
Q

Define: dislocation

A

Articulating surfaces are displaced and no longer in contact

287
Q

Define: subluxation

A

Partial dislocation

288
Q

Define: varus deformity

A

Lower limb deformity whereby distal part is directed towards the midline

E.g. varus knee with medial compartment osteoarthritis

289
Q

Define: valgus deformity

A

Lower limb deformity whereby whereby distal part is directed away from the midline

E.g. hallux valgus

290
Q

True or false; acute gout is a good example of arhtritis?

A

True

291
Q

What is gout?

A

A disease in which tissue deposition of monosodium urate (MSU) crystals occurs as a result of hyperuricaemia and leads to one or more of the following:
Gouty arthritis
Tophi (aggregated deposits of MSU in tissue)

292
Q

Where does gouty arthritis commonly affect?

A

Metatarsophalangeal joint of big toe (1st MTP joint)= podagra

293
Q

What are the symptoms of gout?

A

Abrupt onset
Extremely painful (cytokine involvement)
Joint red, warm, swollen and tender
Resolves spontaneously over 3-10 days

294
Q

If there is joint swelling involved at the articular softer tissue…
Tissue involved=
Indicative of=

A

Tissue involved= joint synovium or effusion

Indicative of= inflammatory joint disease

295
Q

If there is joint swelling involved at the periarticular soft tissue…
Tissue involved=
Indicative of=

A

Tissue involved= subcutaneous tissue

Indicative of= inflammatory joint disease

296
Q

If there is joint swelling involved at non-articular synovial…
Tissue involved=
Indicative of=

A

Tissue involved= bursa/tendon sheath

Indicative of= inflammation of structure

297
Q

If there is joint swelling involved at bony areas…
Tissue involved=
Indicative of=

A

Tissue involved= articular ends of bone

Indicative of= osteoarthritis

298
Q

What is enthesopathy?

A

Pathology at the enthesis i.e. the site where ligament or tendon inserts into bone

E.g. plantar fasciitis and Achilles tendinitis

299
Q

What are the signs of irreversible joint damage?

A

JOINT DEFORMITY
Malalignment of two articulating bones

CREPITUS
Audible and palpable sensation resulting from movement of one roughened surface on another
Classic feature of osteoarthritis e.g. patello-femoral crepitus on flexing the knee

LOSS OF JOINT RANGE OR ABNORMAL MOVEMENT

300
Q

What is ankylosing spondylitis?

A

Chronic inflammatory disease affecting sacroiliac joints (sacroiliitis) and spine

Sero-negative spondyloarthropathis (not associated with rheumatoid factor)

Strong association with HLA-B27

301
Q

What can ankylosing spondylitis cause?

A

May lead to spinal fusion (ankylosis) and deformity

  • Lumbar spine straight (loss of lordosis due to fusion)
  • Exaggerated thoracic kyphosis (patient can’t put head back straight)

Entheses resulting in chronic enthesopathy

Non-axial joints e.g. hips and shoulders commonly involved

302
Q

What can cause mechanical defects of a joint and how are they identified?

A

May be due to inflammation, degenerative arthritis or trauma

Identified by:

  • Painful restriction of motion in absence of features of inflammation
    (e. g. knee ‘locking’ due to meniscal tear or bone fragment)
  • Instability
    (e. g. side-to-side movement of tibia on femur due to ruptured collateral knee ligaments)
303
Q

How do you name arthritis based on number of joints involved?

A 
Polyarthritis= > 4 joints involved
Oligoarthritis=  2-4 joints involved
Monoarthritis= Single affected joint
304
Q

Is rheumatoid arthritis symmetrical or asymmetrical?

A

Bilateral and symmetrical involvement of large and small joints is typical of rheumatoid arthritis

305
Q

What is lower limb asymmetrical oligoarthritis and axial involvement typical of?

A

Reactive arthritis

Others in that family

306
Q

What joints are commonly affected in rheumatoid arthritis?

A 
PIP
MCP
Wrist
Elbow
Shoulder
Cervical spine
Hip 
Knee
Ankle
Tarsal
MTP
307
Q

What joints are commonly affected in rheumatoid arthritis?

A

DIP
Thoracic spine
Lumbar spine

308
Q

What joints are commonly involved in osteoarthritis?

A 
1st CMC
DIP
PIP
Cervical spine
Thoracolumbar spine
Hip
Knee
1st MTP
Toe IP
309
Q

What joints are commonly spared in rheumatoid arthritis?

A 
MCP
Wrist
Elbow 
Shoulder
Tarsal joints
310
Q

What joints are commonly affected in polyarticular gout?

A

1st MTP
Ankle
Knee

311
Q

What joints are commonly spared in polyarticular gout?

A

Axial

312
Q

What does normal synovial fluid look like?

A

Like egg

Viscous fluid present in joint space of synovial joints (diarthroses)

Colourless or pale yellow transparent viscous film covering synovium and cartilage with few cells

313
Q

Where is synovial fluid synthesised?

A

Synovial lining cells (1-3 cells deep in a matrix mainly containing type I collagen and proteoglycans)

Type B cells secrete the hyaluronic acid which results in the increased viscosity of synovial fluid

314
Q

What are the types of synovial lining cells

A

Two types of synovial lining cells

Type A = macrophage-like

Type B = fibroblast-like

315
Q

What is synovial effusion?

A

Abnormal increase in synovial fluid volume

E.g. due to abnormal mechanical stimulation (in osteoarthritis) and synovitis (due to inflammation)

316
Q

How does osteoarthritis lead to synovial effusion?

A

Abnormal mechanical stimulation e.g. in osteoarthritis with damage to cartilage and bone

Increase production of hyaluronic acid by synovial fibroblasts due to mechanical forces

Excess hyaluronic acid increases oncotic pressure and increases synovial volume (normal composition)

317
Q

How does synovitis lead to synovial effusion?

A

Inflammatory exudate with abnormal composition (inflammatory cells and mediators, reduced hyaluronic acid

318
Q

What is the difference between synovial effusions?

A

Normal = clear or pale yellow and viscous

Non-inflammatory (due to osteoarthritis/mechanical defects) = slightly turbid, more WCCs and neutrophils than normal

Inflammatory (gout, rheum arth) = turbid, lots more WCCs and neutrophils than normal

Infection (bacterial) = very turbid, LOADS more WCCs and neutrophils than normal

319
Q

When is it useful or important to examine synovial fluid?

A

Mandatory when joint infection is suspected

Useful to confirm diagnosis in suspected crystal arthritis (gout)

320
Q

How is synovial fluid examination performed?

A

Needle aspiration under aseptic conditions (termed arthrocentesis)

321
Q

What are the relative contraindications of arthrocentesis?

A

Conditions and disorders that increase risk of bleeding into joint during/after procedure

e.g. Anticoagulant drugs, low platelet counts, bleeding disorders

Overlying skin infection because of risk of introducing infection into joint

322
Q

What are the possible complications of synovial fluid examination?

A

Rare

Risk of introducing infection (i.e. creating a septic arthritis)
Bleeding into joint (haemarthrosis)
Damage to structures within the joint e.g. cartilage

323
Q

How do you examine synovial fluid samples for pathogens and crystals?

A

Rapid Gram stain followed by culture and antibiotic sensitivity assays

Polarising light microscopy to detect crystals which can be seen in arthritis due to gout or pseudogout

324
Q

What are susceptibility factors to septic arthritis?

A

IMPAIRED HOST DEFENCE
Elderly (>65 years) and young (<5 years)
Chronic illness e.g. diabetes, liver disease, HIV infection
Immunosuppressive medication e.g. corticosteroids

DIRECT PENETRATION
Invasive procedures e.g. arthroscopy
Complication of IV drug abuse
puncture wounds

JOINT DAMAGE
Prosthetic joints
Chronic arthritis e.g. rheumatoid arthritis

325
Q

What do you do to treat a patient with septic arthritis?

A

Aspirated fluid= pus (strong indication of infection)

Antibiotic therapy
Joint washout for large joints (lavage)

Consider why it has happened in this individual

326
Q

What is a big swelling behind elbow likely to be?

A

Sterile olecranon bursitis due to gout

327
Q

Why is synovial fluid viscous?

A

Because of hyaluronic acid (a non-sulphated glycosaminoglycan)

328
Q

What are serum autoantibodies characteristic of?

A

In connective tissue disorders

May aid diagnosis
Correlate with disease activity
May be directly pathogenic

329
Q

Is arthritis present in connective tissue disorders?

A

Sometimes- but non-erosive

Arthralgia= common complaint

330
Q

What is Raynaud’s phenomenon?

A

Common in connective tissue disorders but most commonly isolated and benign condition (Primary Raynaud’s phenomenon)

Intermittent vasospasm of digits on exposure to cold

Doesn’t affect thumb

331
Q

What are the colour changes in Raynaud’s phenomenon?

A

White to blue to red

Vasospasm leads to blanching of digit
Cyanosis as static venous blood deoxygenates
Reactive hyperaemia

332
Q

List the key features of rheumatoid arthritis

A

Symmetrical polyarthritis (typically involving the small joints of the hand and/or wrists)
Subcutaneous nodules
Rheumatoid factor
Morning stiffness in and around joints (inflammatory arthritis)
Joint erosions on radiographs

333
Q

Define rheumatoid factor

A

Antibodies that recognize another antibody (recognize the Fc portion of IgG as their target antigen)

Typically IgM antibodies i.e. IgM anti-IgG antibody

334
Q

Define: reaction arthritis

A

Sterile inflammatory synovitis following an infection with extra-articular manifestations

These may include:
Enthesopathy
Skin inflammation (circinate balanitis, keratoderma blennorrhagicum)
Eye inflammation (conjunctivitis)

NOT ONGOING INFLAMMATION

335
Q

What infections may be associated with reactive arthritis?

A

Urogenital e.g. chlamydia trachomatis

Enterogenic e.g. Salmonella, Shigella, Campylobacter infections

May be first manifestation of HIV or hep C infection

336
Q

Give 4 examples of enthesopathy (where?)

A 
Achilles tendonitis (painful heel)
= inflammation at insertion of Achilles tendon into calcaneum
Plantar fasciitis (painful feet)
= inflammation at insertion of plantar fascia

Dactylitis (swollen digits)
= inflammation at insertion of capsule and ligaments in digits

Spondylitis (spinal inflammation) in Ankylosing Spondylitis
= inflammation where the outer part (annulus fibrosis) of the inter-vertebral disc inserts into the vertebral body

337
Q

What is the key pathological finding in osteoarthritis?

A

Irreversible loss of articular cartilage

Osteophytosis (new bone formation at joint margins)

Sclerosis (changes in subchondral bone)

338
Q

Define: proteoglycan (and give example)

A

Glycoproteins containing sulphated glycosaminoglycan chains e.g. aggrecan

339
Q

Define: glycosaminoglycan (and give 3 examples)

A

Repeating polymers of disaccharides

e.g.
Chondroitin sulphate
Keratan sulphate
Hyaluronic acid (= hyaluronate)

340
Q

What is the major collagen found in articular cartilage?

A

Type II collegen (two t’s in articular cartilage)

341
Q

What is the major proteoglycan found in articular cartilage?

A

Aggrecan

342
Q

The major HLA associations for:
Ankylosing spondylitis and reactive arthritis
SLE
Rheumatoid arthritis

A

Ankylosing spondylitis and reactive arthritis= HLA-B27
SLE= HLA-DR3
Rheumatoid arthritis= HLA-DR4

SLE has 3 letters so HLA-DR3

U will remember that U is fourth letter in rheumatoid so HLA-DR4

Average of 2 words in ‘Ankylosing Spondylitis’ and ‘Reactive Arthritis’ and average of 7 syllables (Ankylosing spondylitis = 8, Reactive Arthritis = 6, average = 7) so HLA-B27

343
Q

Summarise the composition of bone

A

Bone is comprised of protein matrix (osteoid) and mineral (hydroxyapatite)
Osteoclasts resorb bone, osteoblasts form bone

344
Q

Define: osteoporosis

A

Predisposition to skeletal fractures resulting from reduction in regional or total bone mass

Bone chemistry is normal (serum calcium, phosphate, PTH, alkaline phosphatase)

Osteoporosis is assessed by ‘dual energy X-ray absorptiometry’ DEXA scanning

T score less than -2.5

345
Q

What is the T score?

A

T-score is comparison of patient’s bone mass to the mean of young normal subjects

Mean of young normal subjects represents ‘peak bone mass’

T-score calculates how many standard deviations (SD) the patient’s score is above/below peak bone mass

346
Q

Define: osteomalacia

A

‘Soft bones’
Impaired mineralisation in mature bones

(Rickets is kids)

347
Q

What is the most common cause of osteomalacia?

A

Most frequently due to inadequate EC fluid concentration of phosphate and/or calcium

Causes include:
Vitamin D deficiency or abnormal metabolism (e.g. liver or kidney disease)
Hypophosphataemia

Associated with:
Low or normal serum calcium
Low phosphate
Secondary hyperparathyroidism i.e. high PTH and high serum alkaline phosphatase

348
Q

Define: Paget’s disease

A

Disorder of bone remodelling of unknown cause where there is increased bone resorption followed by increased bone formation

This results in disorganised mosaic pattern of woven and lamellar bone-> pain and bone deformity (sometimes-> fracture)

349
Q

How can Paget’s disease be diagnosed?

A

High alkaline phosphatase in bone chemistry

Increased cortical bone thickness on radiographys

350
Q

What musculoskeletal disorders are in chronic renal failure?

A

Renal osteodystrophy

Secondary and tertiary hyperparathyroidism
Osteomalacia
Soft tissue and vascular calcification

351
Q

What is the problem with DEXA?

A

Diagnosis is barrier to care
- Most people only receive treatment after osteoporotic fractures (not before diagnosis)

BUT problems with DEXA= Structure determines strength not material (mineral density doesn’t change if material is same)

DEXA scans don’t measure estrogen-> osteoclasts-> perforated trabeculae-> fractures

352
Q

Where is a lot of bone lost in osteoporosis?

A

Femoral site

Leads to lots of fractures

353
Q

What is the overall composition of bone?

A

Collagen matrix:
ORGANIC (collagen, mucopolysaccharides, non-collagenous proteins)
INORGANIC (calcium, phosphorous)

Cells:
Osteoprogenitor, osteocytes, osteoblasts, osteoclasts

354
Q

How long does it take for bone tissue to be replaced itself?

A

Approximately every 120 days skeletal tissue gets replaced

Bone is living and self-reppairing

355
Q

Outline normal bone turnover

A

RESTING
Lining cells on surface of bone

RESORPTION
Osteoclasts digest bone within a sealed resorption vacuole

REVERSAL
Apoptotic osteoclasts
Prosteoblasts

FORMATION
Mature osteoblasts building ostoid tissue
Mineralization

356
Q

What are bisphosphonates for? How do they work?

A

Frontline treatment for osteoporosis
1/10th UK population on this drug
Destroy the cytoskeleton in osteoclasts-> ruffle border breaks down-> osteoclasts can’t release enzymes so can’t resorb bone

357
Q

Outline the half life of bisphosphonates

A

10 years

Drugs given for 3-5 years so can stay in system long after stopping them

358
Q

What is the problem with bisphosphonates?

A

1 in 10,000 who take drug have fractures increase

Suppressing bone cell activity-> bone ages, weaker and more brittle bone-> full of microcracks-> accumulate and aren’t repaired-> atypical fractures (stress-> whole fractures)

359
Q

What does denosumab do?

A

Mimick osteoprotegerin

Suppresses remodelling (stronger than bisphophonates)

Same risks as bisphosphonates

Should be given with vitamin D and calcium

360
Q

What is the mortality associated with hip fractures?

A

Mortality 30 days after hip fracture =10%

Mortality a year after hip fracture =30%

NB. May be due to other morbidities associated with weakness

361
Q

What is Wolff’s law?

A

States that bone grows and remodels in response to the forces that are placed upon it

After injury to bone, placing specific stress in specific directions to the bone can help it remodel and become normal healthy bone again

Bedrest= bone starts to fracture and resorb

(Trajectorial therapy= bone adapts to meet the load)

362
Q

When does peak bone mass occur?

A

Around 20 years

Exercise and healthy diet in young-> builds up good bone for future

363
Q

What makes bone quality strong?

A 
Gross structure
Microstructure (of trabeculae and thickness of cortex)
Nanostructure 
Microcracks and perforation
Bone metabolism
364
Q

What is the difference between a fracture and a break?

A

No difference

365
Q

What is a fracture associated with?

A

Soft tissue injury with underlying break in bone

Risk if there is an infection

366
Q

What happens in the fracture healing process?

A

WEEK 1= Haematoma (or inflammation)
Involves macrophages, leukocytes, IL1-6, BMPs etc.
Granulation tissue forms, progenitor cells invade

WEEKS 1-4= Soft callus
Chondroblasts and fibroblasts differentiate and form collage and fibrous tissue 
Proteoglycans produced (to prevent mineralisation)
Chondrocytes release calcium into ECM and degrading enzymes to break down proteoglycans (to allow mineralisation)

MONTH 1-4= Hard callus
Soft callus invaded by blood vessels
Chrondroclasts break down calcified callus
Replaced by osteoid (type I collagen) from osteoblasts
Osteoid calcifies-> woven bone (disorganised)

UP TO SEVERAL YEARS
Remodelling
Woven to lamellar bone
Wolff's law
Medullary canal reforms
367
Q

What happens when a child’s bone heals

A

Heals much quicker

Bits at edges don’t get stressed (Wolff’s law) so gradually slim down

368
Q

What are the types of fracture patterns?

A

Spiral fracture
Oblique fracture
Butterfly fracture
Transverse fracture

History is important

369
Q

What causes a spiral fracture?

A

Torsion

E.g. arm wrestle

370
Q

What causes an oblique fracture?

A

Compressive forces

371
Q

What causes a butterfly fracture?

A

Direct blow leads to sideways Y shape

372
Q

What causes a transverse fracture?

A

Usually traction

373
Q

What is a greenstick fracture?

A

Child fracture

Snaps, one side remained attached by membrane (doesn’t happen in adults)

374
Q

How can osteoarthritis and sport be linked?

A

Not a direct link
But sport-> more injuries and injuries-> osteoarthritis

BUT effective, cheapest and safest treatment for arthritis is exercise

More problematic in children

375
Q

What did Hueter-Volkmann show?

A

Compressing growing bone-> slows down its growth

Traction on bone-> increases growth

376
Q

How can Hueter-Volkmann’s theory be applied to treatment?

A

Eight growth plate
If there is uneven bone growth
Compress one side and this allows other side to catch up

377
Q

What are the types of alignment of legs?

A

Neutral= straight

Varus (bow legs)= distal bone towards midline, load passes to inside of knee (lots of pressure)

Valgus (lock knee), distal bone away from midline, load passes outside knee (lots of pressure)

Normally= people slightly varus

378
Q

How can varus legs become exaggerated?

A

Naturally slightly varus
Compress medial growth plate constantly so grows less
Becomes varus

379
Q

Who gets malalignment?

A

Footballers go varus

Tall, thin models and front row rugby players (props) have valgus

380
Q

What happens when you’re an adult to wear out the inside part of the knee?

A

Unequal loading on varus knees

More likely to wear out inside part of knee

381
Q

What is the relationship between knee shape and osteoarthritis?

A

Neutral= lower risk to advance to osteoarthritis

2x OA risk with varus
1.4x OA risk with valgus

382
Q

What is an osteotomy?

A

Cut in bone, leave one corner in tact, fix with plate and it heals and straightens

E.g. Find young, retired footballer and X-ray
Realign and look at joint space
Straightening leg could prevent them getting arthritis

383
Q

How does Wolff’s law explain surfer’s knuckles?

A

Wolff’s law in adults
Surfers knuckles and knobs
Constantly loading usual areas

384
Q

How does Wolff’s law explain what happens to astronauts?

A

Bones lose density because bones aren’t loading correctly

385
Q

How does Wolff’s law explain tennis players bones?

A

Thicken bones in dominant arm

386
Q

What is DDH?

A

Developmental dysplasia of the hip

Starts in utero

387
Q

What happens in DDH?

A

Malformed hip in utero
Hip dislocated

ELDERLY= on ileum (where acetabular joint attaches)- steep slope so hip dysplasia forms shallow hip joint-> doesn’t align with femur (femoral head moves along acetabulum and bumps into labrum)-> labrum thick cartilage breaks down-> osteophytes break down-> osteoarthritic hip

Femur higher in unhealthy leg-> hip dislocation

Could do surgery in utero to avoid problems in elderly

388
Q

What kind of impingements can happen to the hip?

A

Cam impingement= head of femur

Pincer impingement= acetabulum

389
Q

Why should join shape problems be treated early?

A

Likely to lead to osteoarthritis

E.g. pelvis, posture, leg

390
Q

What does intact hyaline cartilage look like?

A

Smooth glossy surface

391
Q

What happens in an ACL injury?

A

E.g. from football or skiing
ACL under maximum tension (nearly straight) and then some tension (twisted)

ACL injury allows tibia to slide forward
Load from femur passes on to small area of tibia
Meniscal tears

392
Q

What causes miniscal tears?

A 
ACL injury allows tibia to slide forward
Load from femur passes on to small area of tibia
Meniscal tears (caused by menisci shock absorbers try to resist sliding)
393
Q

Can you do a partial knee replacement?

A

Yes

Keep cruciate ligaments etc. in tact- replace small parts with metal

LCRS2- Musculoskeletal (1 decks)

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