Musculoskeletal

Question 1

What is the function of bone?

Answer 1

Mechanical= support and site for muscle attachment

Protective= vital organs and bone marrow

Metabolic= reserve of calcium

(Bone is dynamic/communicative but looks inert)

Question 2

Outline the composition of bone

Answer 2

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

Question 3

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

Answer 3

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)

Question 4

What is the medulla of bone comprised of?

Answer 4

High surface area bone (cancellous bone) with bone marrow

Question 5

What is cortical bone?

Answer 5

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

Question 6

What is cancellous bone?

Answer 6

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

Question 7

Outline cortical bone microanatomy

Answer 7

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)

Question 8

Outline when bone biopsies are used

Answer 8

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

Question 9

Where are bone biopsies taken from?

Answer 9

Normally from anterior superior ileac crest

Question 10

What are the types of bone biopsy?

Answer 10

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

Question 11

What bone cells are there?

Answer 11

Osteoblasts
Osteoclasts
Osteocytes

Question 12

What are osteoblasts?

Answer 12

Build bone by laying down osteoid (calcium hydroxyapatite)

Question 13

What are osteoclasts?

Answer 13

Multinucleate cells of macrophage family

Resorb or chew bone

Question 14

What are osteocytes?

Answer 14

Osteoblast-like cells which sit in lacunae in bone

Sits in BM and communicate with osteoblasts and osteoclasts

Question 15

How are osteoclasts converted to active osteoblasts?

Answer 15

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

Question 16

Outline what happens when RANKL binds to RANK?

Answer 16

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

Question 17

What is OPG?

Answer 17

Osteoprotegerin

Inhibits RANK/RANKL binding and therefore inhibits osteoclastogenesis

Question 18

How do osteoblasts become osteoclasts?

Answer 18

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

Question 19

What are the classifications of bone?

Answer 19

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)

Question 20

Give examples of cuboid bones

Answer 20

Wrists and ankles

Question 21

What kind of ossification happens in flat and long bones?

Answer 21

Intramemebranous ossification (flat)
Endochondral ossification (long)

Question 22

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

Answer 22

True

Prominent reversal lines can be seen

Question 23

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

Answer 23

Red layer

NB. Green dark= calcified bone
Surface different

Question 24

What are the main reasons for metabolic bone disease?

Answer 24

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

Question 25

What causes osteoporosis?

Answer 25

``` 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

Question 26

How does osteoporosis present?

Answer 26

Present with bone pain and difficulty walking/carrying or pathological fracture e.g. from walking Bone becomes thin and widely spaced

Question 27

What causes osteomalacia?

Answer 27

Defective bone mineralisation unlike osteoporosis Deficiency of vitamin D Deficiency of PO4 (usually from chronic renal disease)

Question 28

How is vitamin D activated?

Answer 28

SEE DIAGRAM Hypocalcaemia-> PTH secretion PTH-> kidney-> GI tract PTH-> liver Skin and diet-> vitamin D-> liver

Question 29

How do bones appear in osteomalacia?

Answer 29

Bones appear very thin on X ray Weak bones Proximal weakness, pain, pathological fracture, maybe bone deformity

Question 30

How does osteomalacia present?

Answer 30

``` 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

Question 31

What kind of fractures aren't common?

Answer 31

Horizontal fractures | E.g. in looser's zone

Question 32

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

Answer 32

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

Question 33

What is hyperparathyroidism caused by?

Answer 33

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

Question 34

What organs are affected in hyperparathyroidism?

Answer 34

4 organs directly or indirectly affected by PTH and between them control Ca metabolism Parathyroid glands Bones Kidneys Proximal small intestine

Question 35

What does hyperparathyroidism look like in an x-ray?

Answer 35

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

Question 36

What is primary hyperparathyroidism?

Answer 36

``` Parathyroid adenoma (85-90%) Chief cell hyperplasia ```

Question 37

What is secondary hyperparathyroidism?

Answer 37

Chronic renal deficiency Vit D deficiency Possibly by drugs

Question 38

What are the symptoms of hyperparathyroidism?

Answer 38

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

Question 39

What is renal osteodystrophy?

Answer 39

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

Question 40

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

Answer 40

H&E

Question 41

What causes renal osteodystrophy?

Answer 41

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

Question 42

What are the stages of Paget's disease?

Answer 42

Disorder of bone turnover 1. Osteolytic (phase where osteoblasts fight back) 2. Osteolytic-osteosclerotic 3. Quiescent osteosclerotic

Question 43

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

Answer 43

Broken down and reformed constantly

Question 44

Who is affected by Paget's disease?

Answer 44

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

Question 45

What causes Paget's disease?

Answer 45

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

Question 46

Outline site predilection in Paget's disease

Answer 46

Usually not in hands, feet or arms | Lots in skull, lower spine and pelvis

Question 47

What are the clinical symptoms of Paget's disease?

Answer 47

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%

Question 48

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

Answer 48

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

Question 49

What are the 5 common metabolic bone disorders?

Answer 49

Primary hyperparathyroidism Rickets/ Osteomalacia Osteoporosis Paget’s Disease Renal osteodystrophy

Question 50

How can you investigate bone disease biochemically?

Answer 50

SERUM Bone profile- Ca, corrected Ca (albumin), phosphate, alkaline phosphatase Renal function- creatine PTH 25-hydroxy vit D URINE- ca/phosphate, NTX

Question 51

``` How are the following affected in osteoporosis? Ca P Alk P Bone formation Bone resorption ```

Answer 51

``` Ca= N P= N Alk P= N Bone formation= increases/same Bone resorption= increases a lot ```

Question 52

``` How are the following affected in osteomalacia? Ca P Alk P Bone formation Bone resorption ```

Answer 52

Ca= N or decreases P= decreases Alk P= increases Bone formation= Bone resorption=

Question 53

``` How are the following affected in Pagets? Ca P Alk P Bone formation Bone resorption ```

Answer 53

``` Ca= N (increase) P= N Alk P= increases A LOT!! Bone formation= increases a lot Bone resorption= ```

Question 54

``` How are the following affected in primary HPT? Ca P Alk P Bone formation Bone resorption ```

Answer 54

``` Ca= increases P= N or decreases Alk P= N or increases Bone formation= Bone resorption= increases a lot ```

Question 55

``` How are the following affected in renal osteodystrophy? Ca P Alk P Bone formation Bone resorption ```

Answer 55

``` Ca= decreases or N P= increases Alk P= increases Bone formation= Bone resorption= ```

Question 56

``` How are the following affected in metastases? Ca P Alk P Bone formation Bone resorption ```

Answer 56

``` Ca= increases P= increases Alk P= increases Bone formation= Bone resorption= increases ```

Question 57

What 3 main systems are involved in Ca balance?

Answer 57

GUT what’s coming in; 1g day recommended intake KIDNEY what’s going out BONE flux; your compensatory mechanism

Question 58

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

Answer 58

Cancellous bone has a huge blood supply Surface area for gas exchange is enormous

Question 59

Why do you compensate serum calcium measurements?

Answer 59

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])

Question 60

What is total calcium made up of?

Answer 60

46% protein-bound (mostly to albumin) 47% free ionized 7% complexed (to P and citrate)

Question 61

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

Answer 61

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

Question 62

How much is total calcium?

Answer 62

Total calcium 2.15-2.56 mmol/L

Question 63

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

Answer 63

PTH | Low plasma Ca-> increased PTH

Question 64

What affect does increased PTH have on bone?

Answer 64

Bone resorption (by increased osteoclast activity) Release of Ca and phosphate (acute release not in hydrozyapatite crystals)

Question 65

What affect does increased PTH have on the kidney?

Answer 65

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

Question 66

What part of the PTH is used to build bone?

Answer 66

N1-34 is active | The whole peptide is 84 AAs

Question 67

How does hypomagnesium affect PTH?

Answer 67

Hypo Mg-> low PTH and hypocalcaemia especially in alcoholics

Question 68

Why is the short half life of PTH useful?

Answer 68

Allows intraoperative sampling | T1/2= 8 mins

Question 69

What do you expect PTH to be in primary hyperparathyroidism?

Answer 69

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

Question 70

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

Answer 70

Steep inverse sigmoidal functions

Question 71

Where does calcium absorption due to PTH occur?

Answer 71

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

Question 72

How does PTH cause bone resorption?

Answer 72

Through the RANK system

Question 73

Who is commonly affected by primary hyperparathyroidism (HPT)?

Answer 73

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

Question 74

What are the main causes of primary hyperparathyroidism?

Answer 74

Parathyroid adenoma= 80% Parathyroid hyperplasia= 20% Parathyroid CA= <1% Familial Syndromes - MEN 1= 2% - MEN 2A= rare - HPT-JT= rare

Question 75

How can HPT be diagnosed?

Answer 75

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)

Question 76

How can high calcium become a medical emergency?

Answer 76

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

Question 77

How does calcium affect risk of kidney stones?

Answer 77

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

Question 78

How does calcium affect cortical bone resorption?

Answer 78

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

Question 79

Why are rickets and osteomalacia increasingly common again?

Answer 79

Chronic vit D deficiency

Question 80

How is vitamin D metabolised?

Answer 80

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

Question 81

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

Answer 81

Activates Ca and P absorption | In duodenum- TRPV6, calbindin

Question 82

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

Answer 82

Facilitates PTH action in distal tubule to increase Ca reabsorption (inducing TRPV5, calbindin) Proximal tubule reaborbs vitamin D and activates it

Question 83

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

Answer 83

Synergises with PTH to increase osteoclastic osteolysis differentiation agent for osteoclast precursors Increases osteoblast differentiation and bone formation

Question 84

How does activated vitamin D increase gut calcium absorption?

Answer 84

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

Question 85

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

Answer 85

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

Question 86

What is the functional definition of vitamin D deficiency?

Answer 86

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

Question 87

What is rickets?

Answer 87

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

Question 88

What are the signs and symptoms of rickets?

Answer 88

SYMPTOMS Bone pain and tenderness (axial) Muscle weakness (proximal) Lack of play ``` SIGNS Age dependent deformity Myopathy Hypotonia Short stature Tenderness on percussion ```

Question 89

What are the causes of rickets/osteomalacia?

Answer 89

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

Question 90

What is the biochemistry of rickets/osteomalacia?

Answer 90

``` 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

Question 91

What does FGF-23 do?

Answer 91

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

Question 92

How is phosphate loss related to osteomalacia?

Answer 92

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

Question 93

What is 'isolated' hypophosphataemia?

Answer 93

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

Question 94

What is oncogenic osteomalacia?

Answer 94

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

Question 95

How does FGF-23 excess cause rickets/ostemalacia?

Answer 95

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)

Question 96

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

Answer 96

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

Question 97

What are the causes of Fanconi Syndrome?

Answer 97

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

Question 98

What causes osteoporosis?

Answer 98

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

Question 99

How does high turnover of bone lead to osteoporosis?

Answer 99

``` Estrogen deficiency- primarily in postmenopausal women Hyperparathyroidism Hyperthyroidism Hypogonadism in young women and in men Cyclosporine Heparin ```

Question 100

How does low turnover of bone lead to osteoporosis?

Answer 100

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

Question 101

How does increased bone resoprtion lead to osteoporosis?

Answer 101

Glucocorticoids

Question 102

What is metabolic bone disease?

Answer 102

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

Question 103

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

Answer 103

Metabolic= hypocalcaemia, hypercalcaemia, hypophosphataemia, hyperphosphataemia Bone pain= deformity, fractures

Question 104

How is cancellous bone metabolically active?

Answer 104

Remodelling= 5% anytime, total skeleton over 7 years Continuous exchange of ECF with bone fluid reserve

Question 105

What makes bone strong?

Answer 105

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)

Question 106

How can bone structure and function be assessed?

Answer 106

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

Question 107

Outline age related changes in bone mass

Answer 107

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)

Question 108

How do growth and exercise change peak bone mass?

Answer 108

Change in bone dimensions and bone shape | Change in trabecular volumetric BMD

Question 109

In growth of the tibia, how is bone remodelled?

Answer 109

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)

Question 110

What is bone remodelling?

Answer 110

The process by which these areas are repaired | each osteon essentially represents a previous remodelling event

Question 111

What is bone structure designed for?

Answer 111

Bone has a structure designed to absorb energy Irreversible plastic deformation does occur (-> microfractures)

Question 112

Outline the bone remodeling cycle?

Answer 112

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

Question 113

How does estrogen deficiency causes menopausal bone loss?

Answer 113

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

Question 114

What kind of bone loss is marked early in menopause?

Answer 114

Cancellous bone

Question 115

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

Answer 115

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) ```

Question 116

What is the main tool for assessing osteoporosis?

Answer 116

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

Question 117

What is DEXA?

Answer 117

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

Question 118

How is osteoporosis defined on BMD?

Answer 118

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)

Question 119

What is FRAX?

Answer 119

Fracture risk assessment tool | Uses hip BMD

Question 120

What are the central measurements taken to study BMD?

Answer 120

``` 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

Question 121

What are the bone markers?

Answer 121

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

Question 122

Outline collagen synthesis in bone formation?

Answer 122

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)

Question 123

How are bone resorption markers used in monitoring osteoporosis treatment?

Answer 123

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

Question 124

What are the problems with cross-links?

Answer 124

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

Question 125

What is a common usage of alkaline phosphatase?

Answer 125

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)

Question 126

How is P1NP used as a bone formation marker?

Answer 126

As a predictor of response to anabolic treatments

Question 127

What is CKD-MBD?

Answer 127

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

Question 128

How does renal osteodystrophy develop?

Answer 128

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 ```

Question 129

What is the progression of secondary HPT: parathryoid hyperplasia?

Answer 129

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

Question 130

List 3 main autoimmune musculoskeletal disorders

Answer 130

Rheumatoid arthritis Ankylosing spondylitis Systemic lupus erythematosus (SLE)

Question 131

What happens in rheumatoid arthritis?

Answer 131

Chronic joint inflammation that can result in joint damage Site of inflammation is the synovium (synovitis) Associated with autoantibodies

Question 132

What autoantibodies are involved in rheumatoid arthritis?

Answer 132

Rheumatoid factor | Anti-cyclic citrullinated peptide (CCP) antibodies

Question 133

What is ankylosing spondylitis?

Answer 133

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)

Question 134

What site of inflammation in ankylosing spondylitis?

Answer 134

Enthesis

Question 135

What are the kinds of seronegative spondyloarthropathies?

Answer 135

Ankylosing spondylitis Reiters syndrome and reactive arthritis Arthritis associated with psoriasis (psoriatic arthritis) Arthritis associated with GI inflammation (enteropathic synovitis)

Question 136

What is systemic lupus erythematosus (SLE)?

Answer 136

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)

Question 137

Which autoantibodies are involved in SLE?

Answer 137

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

Question 138

List examples of connective tissue diseases

Answer 138

Systemic lupus erythematosus (SLE) Inflammatory muscle disease: polymyositis, dermatomyositis Systemic sclerosis Sjogren’s syndrome A mixture of the above: ‘Overlap syndromes’

Question 139

How do HLA molecules contribute to rheumatology?

Answer 139

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

Question 140

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

Answer 140

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’)

Question 141

What happens in HLA-associated rheumatology disease?

Answer 141

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

Question 142

What autoantibodies are involved in systemic vasculitis?

Answer 142

Antinuclear cytoplasmic antibodies (ANCA)

Question 143

What rheumatological diseases don't involve auto-antibodies?

Answer 143

Osteoarthritis Reactive arthritis Gout Ankylosing spondylitis

Question 144

What autoantibodies are involved in diffuse systemic sclerosis?

Answer 144

Anti-Scl-70 antibodies

Question 145

What autoantibodies are involved in limited systemic sclerosis?

Answer 145

Anti-centromere antibodies

Question 146

What autoantibodies are involved in Dermato/Polymyositis?

Answer 146

Anti-tRNA transferase antibodies

Question 147

What autoantibodies are involved in Sjogren's syndrome?

Answer 147

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

Question 148

What autoantibodies are involved in mixed connective tissue disease?

Answer 148

Anti-U1-RNO antibodies

Question 149

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

Answer 149

``` Anti-Ro Anti-La Anti-centromere Anti-Sm Anti-RNP Anti-ds-DNA antibodies Anti-Scl-70 ```

Question 150

What kind of cytoplasmic antibodies are there?

Answer 150

Anti-tRNA synthetase antibodies | Anti-ribosomal P antibodies

Question 151

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

Answer 151

Low complement levels High serum levels of anti-ds-DNA antibodies

Question 152

What cytokines appear in rheumatology?

Answer 152

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

Question 153

What cytokine is dominant in rheumatology?

Answer 153

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

Question 154

What does TNF alpha do that is important in rheumatology?

Answer 154

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 ```

Question 155

What cytokines can be blocked to treat rheumatology?

Answer 155

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)

Question 156

Why is RANKL important in bone destruction in rheumatoid arthritis?

Answer 156

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

Question 157

What is RANKL produced by in rheumatoid arthritis?

Answer 157

T cells and synovial fibroblasts

Question 158

What is denosumab?

Answer 158

Monoclonal antibody against RANKL Indicated for treatment of osteoporosis, bone metastases, multiple myeloma and Giant cell tumours

Question 159

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

Answer 159

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)

Question 160

What is the role of prostaglandins in rheumatology?

Answer 160

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

Question 161

Which isoform of cyclooxygenase is inducible and which is constitutive?

Answer 161

COX-1 (constitutive) | COX-2 (inducible)

Question 162

What is rheumatoid arthritis?

Answer 162

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

Question 163

What are the key features of chronic rheumatoid arthritis?

Answer 163

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)

Question 164

Outline the epidemiology of rheumatoid arthritis

Answer 164

1% of population affected | 3x more in females

Question 165

What is the genetic component of rheumatoid arthritis?

Answer 165

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)

Question 166

What environmental factors contribute to rheumatoid arthritis?

Answer 166

Smoking increases risk

Question 167

What joints are most commonly affected by rheumatoid arthritis?

Answer 167

``` Metacarpophalangeal joints (MCP) Proximal interphalangeal joints (PIP) Wrists Knees Ankles Metatarsophalangeal joints (MTP) ```

Question 168

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

Answer 168

False Symmetrical polyarthritis

Question 169

Where do calouses form in rheumatoid arthritis?

Answer 169

Under heads of metatarsals due to joint deformity

Question 170

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

Answer 170

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

Question 171

What is the primary site of pathology in rheumatoid arthritis?

Answer 171

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

Question 172

Where does fusiform swelling happen in rheumatoid arthritis?

Answer 172

Fusiform swelling limited to joint

Question 173

Where does swelling in extensor tenosynovitis happen?

Answer 173

Swelling is not above either the wrist or MCP joints

Question 174

What are sub-cutaneous nodules in rheumatoid arthritis?

Answer 174

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

Question 175

Where are rheumatoid nodules found in rheumatoid arthritis?

Answer 175

Ulnar border of forearm | In hands

Question 176

What is rheumatoid factor?

Answer 176

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

Question 177

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

Answer 177

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

Question 178

What enzymes convert arginine to citrulline?

Answer 178

Peptidyl arginine deiminases (PADs)

Question 179

Why do ACPAs develop in rheumatoid arthritis?

Answer 179

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)

Question 180

What is the shared epitope of rheumatoid arthritis?

Answer 180

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

Question 181

What are the extra-articular features of rheumatoid arthritis?

Answer 181

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

Question 182

What radiographic abnormalities are present in rheumatoid arthritis?

Answer 182

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

Question 183

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

Answer 183

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

Question 184

Describe a synovial joint

Answer 184

SHOULD BE ABLE TO DRAW DIAGRAM Synovium Synovial fluid Articular cartilage

Question 185

Describe the synovium in synovial joint

Answer 185

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)

Question 186

Describe synovial fluid

Answer 186

Hyaluronic acid-rich viscous fluid

Question 187

Describe articular cartilage

Answer 187

Type II collagen Proteoglycan (aggregan)

Question 188

Outline the pathogenesis at the synovial membrane in rheumatoid arthritis

Answer 188

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)

Question 189

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

Answer 189

Neovascularisation Lymphangiogenesis Inflammatory cells: - Activated B and T cells - Plasma cells - Mast cells - Activated macrophages

Question 190

What does a healthy synovial membrane look like/contain?

Answer 190

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

Question 191

How can you achieve TNFa inhibition?

Answer 191

Through parenteral administration | Most commonly sub-cutaneous injection of antibodies or fusion proteins

Question 192

How can you manage rheumatoid arthritis?

Answer 192

Treatment goal is to prevent joint damage Multidisciplinary approach e.g. physiotherapy, occupational therapy, hydrotherapy, surgery Medication

Question 193

What medication can be used to manage rheumatoid arthritis?

Answer 193

‘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)

Question 194

Why are DMARDs started early?

Answer 194

Started early in the disease because: | Joint destruction = inflammation x time

Question 195

Why are glucocorticoid therapies avoided long-term?

Answer 195

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

Question 196

How do DMARDs work?

Answer 196

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

Question 197

Give examples of DMARDS

Answer 197

Methotrexate- commonly used Sulphasalazine- commonly used Hydroxychloroquine-commonly used Leflunomide - uncommon Gold (rarely used now) Penicillamine (rarely used now)

Question 198

What is the downside to biological therapy?

Answer 198

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

Question 199

What is reactive arthritis?

Answer 199

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

Question 200

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

Answer 200

Enthesopathy Skin inflammation Eye inflammation

Question 201

What can reactive arthritis be the first manifestation of?

Answer 201

HIV | Hep C infection

Question 202

What can cause reactive arthritis in young adults?

Answer 202

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

Question 203

What are the musculoskeletal symptoms of reactive arthritis?

Answer 203

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)

Question 204

What are the extra- articular symptoms of reactive arthritis?

Answer 204

OCULAR Sterile conjuncitivitis GENITO-URINARY Sterile urethritis SKIN Circinate balanitis Psoriasis-like rash on hands and feet (keratoderma blenmorrhagicum)

Question 205

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

Answer 205

Arthritis Urethritis Conjunctivitis following infectious dysentery (Reiter's syndrome)

Question 206

Who does reactive arthritis affect?

Answer 206

M>F | 20-40 years

Question 207

Do rheumatoid and reactive arthritis have enthesopathy?

Answer 207

``` Rheum= no React= yes ```

Question 208

Do rheumatoid and reactive arthritis have spondylitis?

Answer 208

``` Rheum= no (except atlanto-axial joint in cervical spine) React= yes ```

Question 209

Do rheumatoid and reactive arthritis have urethritis?

Answer 209

``` Rheum= no React= yes ```

Question 210

Do rheumatoid and reactive arthritis have skin involvement?

Answer 210

``` Rheum= subcutaneous nodules React= k.blennorhagicum, circinate balantis ```

Question 211

Do rheumatoid and reactive arthritis have rheumatoid factor?

Answer 211

``` Rheum= yes React= no ```

Question 212

Do rheumatoid and reactive arthritis have HLA association?

Answer 212

``` Rheum= HLA-DR4 React= HLA-B27 ```

Question 213

What kind of arthritis happens in rheumatoid and reactive arthritis?

Answer 213

``` Rheum= symmetrical, polyarticular, small and large joints React= asymmetrical, oligoarticular, large joints ```

Question 214

How is reactive arthritis diagnosed?

Answer 214

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

Question 215

What are the main differences between septic and reactive arthritis?

Answer 215

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

Question 216

How is reactive arthritis treated?

Answer 216

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

Question 217

What is osteoarthritis?

Answer 217

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)

Question 218

Where does osteoarthritis usually affect?

Answer 218

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)

Question 219

What are Heberden's nodes?

Answer 219

In osteoarthritis | Osteophytes at the DIP joints

Question 220

What are Bouchard's nodes?

Answer 220

In osteoarthritis | Osteophytes at the PIP joints

Question 221

What symptoms can osteoarthritis be associated with?

Answer 221

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

Question 222

What are the radiographic features of osteoarthritis?

Answer 222

Joint space narrowing Subchondral bony sclerosis Osteophytes Subchondral cysts

Question 223

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

Answer 223

``` Rheum= yes Osteo= yes ```

Question 224

Do rheumatoid and osteoarthritic arthritis have subchondral sclerosis?

Answer 224

``` Rheum= no Osteo= yes ```

Question 225

Do rheumatoid and osteoarthritic arthritis have osteophytes?

Answer 225

``` Rheum= no Osteo= yes ```

Question 226

Do rheumatoid and osteoarthritic arthritis have osteopenia?

Answer 226

``` Rheum= yes (juxta-articular osteopenia common) Osteo= no ```

Question 227

Do rheumatoid and osteoarthritic arthritis have bony erosions?

Answer 227

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

Question 228

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

Answer 228

Loss of articular cartilage-> bone in contact with bone See bone spurs

Question 229

Why does osteoarthritis develop?

Answer 229

Defective and irreversible articular cartilage and damage to underlying bone Develops due to excessive loading on joints and/or abnormal joint components

Question 230

What factors can contribute to osteoarthritis?

Answer 230

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

Question 231

What is the function of articular cartilage?

Answer 231

Weight-bearing | Depends on intact collagen scaffold and high aggrecan contect

Question 232

Outline the components of the articular cartilage

Answer 232

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 ```

Question 233

Give examples of proteoglycans

Answer 233

Intra-cellular - Serglycin Cell surface-associated - Betaglycan - Syndecan Secreted into ECM - Aggrecan - Decorin - Fibromodulin - Lumican - Biglycan

Question 234

What are proteoglycans?

Answer 234

Glycoproteins containing one or more sulphates glycosaminoglycan (GAG) chains

Question 235

What is the role of hyaluronic acid in synovial fluid?

Answer 235

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

Question 236

What are GAGs?

Answer 236

Repeating polymers of disaccharides ``` Including: Chondroitin sulphate Heparan sulphate Keratan sulphate Dermatan sulphate Heparin ```

Question 237

What are the cartilage changes in osteoarthritis?

Answer 237

Reduced proteoglycan Reduced collagen Chondrocyte changes e.g. apoptosis

Question 238

What are the bone changes in osteoarthritis?

Answer 238

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)

Question 239

How is osteoarthritis managed?

Answer 239

Education Physical therapy= physiotherapy, hydrotherapy Occupational therapy Weight loss where appropriate Exercise Analgesia= paracetamol, NSAIDs, intra-articular corticosteroid injection Joint replacement

Question 240

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

Answer 240

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

Question 241

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

Answer 241

Rheumatoid arthritis Sjögren’s syndrome Systemic lupus erythematosus Dermatomyositis Polymyositis Systemic sclerosis

Question 242

What does SLE commonly affect?

Answer 242

Joints and skin principally Lungs, kidneys and haematology

Question 243

What is the epidemiology of SLE?

Answer 243

9x more common in women Presentation 15 - 40 yrs Increased in Afro-Caribbean, Asian, Chinese

Question 244

Are there genetic associations in SLE?

Answer 244

Multiple genes implicated Complement deficiency e.g. C1q and C3 Fc receptors, IRF5, CTLA4, MHC class II HLA genes

Question 245

How does SLE present?

Answer 245

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 ```

Question 246

What causes SLE?

Answer 246

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)

Question 247

How does apoptosis relate to SLE?

Answer 247

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

Question 248

How are autoantibodies in pathology formed?

Answer 248

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.

Question 249

What lab tests are used to diagnose SLE?

Answer 249

``` Antinuclear antibodies Anti-dsDNA and Sm Anti-Ro and/or La Haematology Renal ```

Question 250

How are antinuclear antibodies used to detect SLE?

Answer 250

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

Question 251

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

Answer 251

More specific but less sensitive

Question 252

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

Answer 252

Common in subacute cutaneous LE Neonatal lupus syndrome and Sjögren’s

Question 253

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

Answer 253

``` Level of dsDNA Increased complement consumption Anti-cardiolipin antibodies Lupus anticoagulant B1 glycoprotein ```

Question 254

What haematological tests are needed with diagnosis of SLE?

Answer 254

Lymphopaenia, normochromic anaemia Leukopaenia, AIHA, thrombocytopaenia

Question 255

What renal tests are needed with diagnosis of SLE?

Answer 255

Proteinuria, haematuria Active urinary sediment Looking for glomerular nephritis

Question 256

How can you assess SLE disease severity?

Answer 256

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

Question 257

What features can pre-empty severe SLE attacks?

Answer 257

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)

Question 258

How is SLE divided into 3 groups?

Answer 258

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 ```

Question 259

How is mild SLE treated?

Answer 259

Paracetamol +/- NSAID Monitor renal function Hydroxychloroquine - Arthropathy - Cutaneous manifestations - Mild disease activity Topical corticosteroids (to scalp)

Question 260

How is moderate SLE treated?

Answer 260

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

Question 261

How is severe SLE treated?

Answer 261

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

Question 262

What are novel ways of treating severe SLE?

Answer 262

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

Question 263

What is the prognosis for SLE?

Answer 263

15 year survival= 85% no nephritis or 60% nephritis Worse if black, male and low socio-economic status

Question 264

What is the bimodal mortality pattern of SLE?

Answer 264

Chronic autoimmune inflammatory diseases drive other harmful processes EARLY Renal failure CNS disease Infection LATE Myocardial infarction

Question 265

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

Answer 265

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?

Question 266

What are the first questions before performing the GALS examination?

Answer 266

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?

Question 267

What are the components in GALS?

Answer 267

Gait Arms Legs Spine

Question 268

How do you examine gait in GALS?

Answer 268

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

Question 269

How do you examine the spine in GALS?

Answer 269

``` 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? ```

Question 270

How can you detect fibromyalgia in GALS?

Answer 270

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

Question 271

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

Answer 271

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

Question 272

What are the normal curves of the spine?

Answer 272

Cervical lordosis Thoracic kyphosis Lumbar lordosis

Question 273

How can you confirm normal neck movement in GALS?

Answer 273

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

Question 274

How do you examine the arms in GALS?

Answer 274

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)

Question 275

How can you assess shoulder movement in the GALS exam?

Answer 275

Patient places both hands behind head and pushes elbows back Gleno-humeroid joints

Question 276

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

Answer 276

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

Question 277

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

Answer 277

Squeeze across 2nd to 5th MCP/MTP joints Discomfort suggests synovitis (Hands and feet)

Question 278

How do you examine the legs in GALS?

Answer 278

``` 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 ```

Question 279

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

Answer 279

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

Question 280

How do you assess knee for fluid in GALS?

Answer 280

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

Question 281

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

Answer 281

For rashes and/or callosities

Question 282

What is the overall aim of the GALS screen?

Answer 282

Detailed exam of any abnormal joint(s) Inspection: swelling, redness, deformity Palpation: warmth, crepitus, tenderness Movement: active, passive, against resistance Function: loss of function

Question 283

What are the signs of inflammation?

Answer 283

Swelling= tumor Warmth= calor Erythema= rubor Tenderness= dolor Loss of function= functio laesa

Question 284

Define: arthritis

Answer 284

Definite inflammation of a joint(s) | I.e. swelling, tenderness and warmth of affected joints

Question 285

Define: arthralgia

Answer 285

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

Question 286

Define: dislocation

Answer 286

Articulating surfaces are displaced and no longer in contact

Question 287

Define: subluxation

Answer 287

Partial dislocation

Question 288

Define: varus deformity

Answer 288

Lower limb deformity whereby distal part is directed towards the midline E.g. varus knee with medial compartment osteoarthritis

Question 289

Define: valgus deformity

Answer 289

Lower limb deformity whereby whereby distal part is directed away from the midline E.g. hallux valgus

Question 290

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

Answer 290

True

Question 291

What is gout?

Answer 291

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)

Question 292

Where does gouty arthritis commonly affect?

Answer 292

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

Question 293

What are the symptoms of gout?

Answer 293

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

Question 294

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

Answer 294

Tissue involved= joint synovium or effusion Indicative of= inflammatory joint disease

Question 295

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

Answer 295

Tissue involved= subcutaneous tissue Indicative of= inflammatory joint disease

Question 296

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

Answer 296

Tissue involved= bursa/tendon sheath Indicative of= inflammation of structure

Question 297

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

Answer 297

Tissue involved= articular ends of bone Indicative of= osteoarthritis

Question 298

What is enthesopathy?

Answer 298

Pathology at the enthesis i.e. the site where ligament or tendon inserts into bone E.g. plantar fasciitis and Achilles tendinitis

Question 299

What are the signs of irreversible joint damage?

Answer 299

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

Question 300

What is ankylosing spondylitis?

Answer 300

Chronic inflammatory disease affecting sacroiliac joints (sacroiliitis) and spine Sero-negative spondyloarthropathis (not associated with rheumatoid factor) Strong association with HLA-B27

Question 301

What can ankylosing spondylitis cause?

Answer 301

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

Question 302

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

Answer 302

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)

Question 303

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

Answer 303

``` Polyarthritis= > 4 joints involved Oligoarthritis= 2-4 joints involved Monoarthritis= Single affected joint ```

Question 304

Is rheumatoid arthritis symmetrical or asymmetrical?

Answer 304

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

Question 305

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

Answer 305

Reactive arthritis | Others in that family

Question 306

What joints are commonly affected in rheumatoid arthritis?

Answer 306

``` PIP MCP Wrist Elbow Shoulder Cervical spine Hip Knee Ankle Tarsal MTP ```

Question 307

What joints are commonly affected in rheumatoid arthritis?

Answer 307

DIP Thoracic spine Lumbar spine

Question 308

What joints are commonly involved in osteoarthritis?

Answer 308

``` 1st CMC DIP PIP Cervical spine Thoracolumbar spine Hip Knee 1st MTP Toe IP ```

Question 309

What joints are commonly spared in rheumatoid arthritis?

Answer 309

``` MCP Wrist Elbow Shoulder Tarsal joints ```

Question 310

What joints are commonly affected in polyarticular gout?

Answer 310

1st MTP Ankle Knee

Question 311

What joints are commonly spared in polyarticular gout?

Answer 311

Axial

Question 312

What does normal synovial fluid look like?

Answer 312

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

Question 313

Where is synovial fluid synthesised?

Answer 313

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

Question 314

What are the types of synovial lining cells

Answer 314

Two types of synovial lining cells Type A = macrophage-like Type B = fibroblast-like

Question 315

What is synovial effusion?

Answer 315

Abnormal increase in synovial fluid volume E.g. due to abnormal mechanical stimulation (in osteoarthritis) and synovitis (due to inflammation)

Question 316

How does osteoarthritis lead to synovial effusion?

Answer 316

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)

Question 317

How does synovitis lead to synovial effusion?

Answer 317

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

Question 318

What is the difference between synovial effusions?

Answer 318

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

Question 319

When is it useful or important to examine synovial fluid?

Answer 319

Mandatory when joint infection is suspected Useful to confirm diagnosis in suspected crystal arthritis (gout)

Question 320

How is synovial fluid examination performed?

Answer 320

Needle aspiration under aseptic conditions (termed arthrocentesis)

Question 321

What are the relative contraindications of arthrocentesis?

Answer 321

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

Question 322

What are the possible complications of synovial fluid examination?

Answer 322

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

Question 323

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

Answer 323

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

Question 324

What are susceptibility factors to septic arthritis?

Answer 324

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

Question 325

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

Answer 325

Aspirated fluid= pus (strong indication of infection) Antibiotic therapy Joint washout for large joints (lavage) Consider why it has happened in this individual

Question 326

What is a big swelling behind elbow likely to be?

Answer 326

Sterile olecranon bursitis due to gout

Question 327

Why is synovial fluid viscous?

Answer 327

Because of hyaluronic acid (a non-sulphated glycosaminoglycan)

Question 328

What are serum autoantibodies characteristic of?

Answer 328

In connective tissue disorders May aid diagnosis Correlate with disease activity May be directly pathogenic

Question 329

Is arthritis present in connective tissue disorders?

Answer 329

Sometimes- but non-erosive Arthralgia= common complaint

Question 330

What is Raynaud's phenomenon?

Answer 330

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

Question 331

What are the colour changes in Raynaud's phenomenon?

Answer 331

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

Question 332

List the key features of rheumatoid arthritis

Answer 332

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

Question 333

Define rheumatoid factor

Answer 333

Antibodies that recognize another antibody (recognize the Fc portion of IgG as their target antigen) Typically IgM antibodies i.e. IgM anti-IgG antibody

Question 334

Define: reaction arthritis

Answer 334

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

Question 335

What infections may be associated with reactive arthritis?

Answer 335

Urogenital e.g. chlamydia trachomatis Enterogenic e.g. Salmonella, Shigella, Campylobacter infections May be first manifestation of HIV or hep C infection

Question 336

Give 4 examples of enthesopathy (where?)

Answer 336

``` 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

Question 337

What is the key pathological finding in osteoarthritis?

Answer 337

Irreversible loss of articular cartilage Osteophytosis (new bone formation at joint margins) Sclerosis (changes in subchondral bone)

Question 338

Define: proteoglycan (and give example)

Answer 338

Glycoproteins containing sulphated glycosaminoglycan chains e.g. aggrecan

Question 339

Define: glycosaminoglycan (and give 3 examples)

Answer 339

Repeating polymers of disaccharides e.g. Chondroitin sulphate Keratan sulphate Hyaluronic acid (= hyaluronate)

Question 340

What is the major collagen found in articular cartilage?

Answer 340

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

Question 341

What is the major proteoglycan found in articular cartilage?

Answer 341

Aggrecan

Question 342

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

Answer 342

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

Question 343

Summarise the composition of bone

Answer 343

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

Question 344

Define: osteoporosis

Answer 344

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

Question 345

What is the T score?

Answer 345

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

Question 346

Define: osteomalacia

Answer 346

'Soft bones’ Impaired mineralisation in mature bones (Rickets is kids)

Question 347

What is the most common cause of osteomalacia?

Answer 347

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

Question 348

Define: Paget's disease

Answer 348

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)

Question 349

How can Paget's disease be diagnosed?

Answer 349

High alkaline phosphatase in bone chemistry Increased cortical bone thickness on radiographys

Question 350

What musculoskeletal disorders are in chronic renal failure?

Answer 350

Renal osteodystrophy Secondary and tertiary hyperparathyroidism Osteomalacia Soft tissue and vascular calcification

Question 351

What is the problem with DEXA?

Answer 351

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

Question 352

Where is a lot of bone lost in osteoporosis?

Answer 352

Femoral site | Leads to lots of fractures

Question 353

What is the overall composition of bone?

Answer 353

Collagen matrix: ORGANIC (collagen, mucopolysaccharides, non-collagenous proteins) INORGANIC (calcium, phosphorous) Cells: Osteoprogenitor, osteocytes, osteoblasts, osteoclasts

Question 354

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

Answer 354

Approximately every 120 days skeletal tissue gets replaced Bone is living and self-reppairing

Question 355

Outline normal bone turnover

Answer 355

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

Question 356

What are bisphosphonates for? How do they work?

Answer 356

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

Question 357

Outline the half life of bisphosphonates

Answer 357

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

Question 358

What is the problem with bisphosphonates?

Answer 358

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)

Question 359

What does denosumab do?

Answer 359

Mimick osteoprotegerin Suppresses remodelling (stronger than bisphophonates) Same risks as bisphosphonates Should be given with vitamin D and calcium

Question 360

What is the mortality associated with hip fractures?

Answer 360

Mortality 30 days after hip fracture =10% Mortality a year after hip fracture =30% NB. May be due to other morbidities associated with weakness

Question 361

What is Wolff's law?

Answer 361

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)

Question 362

When does peak bone mass occur?

Answer 362

Around 20 years Exercise and healthy diet in young-> builds up good bone for future

Question 363

What makes bone quality strong?

Answer 363

``` Gross structure Microstructure (of trabeculae and thickness of cortex) Nanostructure Microcracks and perforation Bone metabolism ```

Question 364

What is the difference between a fracture and a break?

Answer 364

No difference

Question 365

What is a fracture associated with?

Answer 365

Soft tissue injury with underlying break in bone Risk if there is an infection

Question 366

What happens in the fracture healing process?

Answer 366

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 ```

Question 367

What happens when a child's bone heals

Answer 367

Heals much quicker | Bits at edges don't get stressed (Wolff's law) so gradually slim down

Question 368

What are the types of fracture patterns?

Answer 368

Spiral fracture Oblique fracture Butterfly fracture Transverse fracture History is important

Question 369

What causes a spiral fracture?

Answer 369

Torsion | E.g. arm wrestle

Question 370

What causes an oblique fracture?

Answer 370

Compressive forces

Question 371

What causes a butterfly fracture?

Answer 371

Direct blow leads to sideways Y shape

Question 372

What causes a transverse fracture?

Answer 372

Usually traction

Question 373

What is a greenstick fracture?

Answer 373

Child fracture Snaps, one side remained attached by membrane (doesn't happen in adults)

Question 374

How can osteoarthritis and sport be linked?

Answer 374

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

Question 375

What did Hueter-Volkmann show?

Answer 375

Compressing growing bone-> slows down its growth | Traction on bone-> increases growth

Question 376

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

Answer 376

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

Question 377

What are the types of alignment of legs?

Answer 377

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

Question 378

How can varus legs become exaggerated?

Answer 378

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

Question 379

Who gets malalignment?

Answer 379

Footballers go varus | Tall, thin models and front row rugby players (props) have valgus

Question 380

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

Answer 380

Unequal loading on varus knees | More likely to wear out inside part of knee

Question 381

What is the relationship between knee shape and osteoarthritis?

Answer 381

Neutral= lower risk to advance to osteoarthritis 2x OA risk with varus 1.4x OA risk with valgus

Question 382

What is an osteotomy?

Answer 382

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

Question 383

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

Answer 383

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

Question 384

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

Answer 384

Bones lose density because bones aren't loading correctly

Question 385

How does Wolff's law explain tennis players bones?

Answer 385

Thicken bones in dominant arm

Question 386

What is DDH?

Answer 386

Developmental dysplasia of the hip | Starts in utero

Question 387

What happens in DDH?

Answer 387

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

Question 388

What kind of impingements can happen to the hip?

Answer 388

Cam impingement= head of femur | Pincer impingement= acetabulum

Question 389

Why should join shape problems be treated early?

Answer 389

Likely to lead to osteoarthritis E.g. pelvis, posture, leg

Question 390

What does intact hyaline cartilage look like?

Answer 390

Smooth glossy surface

Question 391

What happens in an ACL injury?

Answer 391

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

Question 392

What causes miniscal tears?

Answer 392

``` 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) ```

Question 393

Can you do a partial knee replacement?

Answer 393

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