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Flashcards in Musculoskeletal System Deck (277):

What are the five common metabolic bone disorders?

- Primary hyperparathyroidism
- Rickets / osteomalacia
- Osteoporosis
- Paget's disease
- Renal osteodystrophy


What are the symptoms of metabolic bone disease?

- Hypo/hypercalcaemia
- Hypo/hyperphosphataemia
• Low phosphate→renal damage
• High phosphate→precipitation with calcium to form calcium phosphate causing widespread tissue damage

- Pain
- Deformity
- Fractures


How is calcium stored in bone?

As inorganic hydroxyapatite


What makes a bone strong?

1) Mass
2) Material properties (matrix and mineral)
3) Microarchitecture
- Trabecular thickness
- Trabecular connectivity
- Cortical porosity
4) Macroarchitecture


What are the different ways of assessing bone structure and function?

1) Bone histology
2) Biochemical tests
3) Bone mineral densitometry (e.g. osteoporosis)
4) Radiology


What are the age related changes in bone mass?

Men always have higher bone mass than women.
Attainment of peak bone mass <30
Consolidation ∼30-40
Age related bone loss >40
Women have a faster loss of bone mass during the menopause


What biochemical investigations are performed in bone disease?

- Bone profile
(calcium, corrected calcium [albumin], phosphate, alkaline phosphatase)
- Renal function
(creatinine, parathyroid hormone, 25-hydroxy vitamin D)
- Urine
(calcium/phosphate, NTX)


What are the biochemical changes in osteoporosis?

Calcium: normal
Phosphate: normal
Alkaline Phosphatase: normal
Bone Form: ↑⟷
Bone Resorption: ↑↑


What are the biochemical changes in osteomalacia?

Calcium: normal or ↓
Phosphate: ↓
Alkaline Phosphatase: ↑


What are the biochemical changes in Paget's disease?

Calcium: normal
Phosphate: normal
Alkaline Phosphatase: ↑↑↑
Bone Form: ↑↑


What are the biochemical changes in primary hyperparathyroid?

Calcium: ↑
Phosphate: ↓
Alkaline Phosphatase: normal or ↑
Bone Resorption: ↑↑


What are the biochemical changes in renal osteodystrophy?

Calcium: normal or ↓
Phosphate: ↑
Alkaline Phosphatase: ↑


What are the biochemical changes that occur in metastases (metabolic bone disease)?

Calcium: ↑
Phosphate: ↑
Alkaline Phosphatase: ↑
Bone Resorption: ↑


How is normal calcium homeostasis maintained?

1) Calcium is absorbed (mainly in the jejunum and ileum); either passive (not controlled; inefficient) or active (vitamin D controlled)
2) Exchange of Ca with bone
3) Kidneys filter blood and have compulsary loff of Ca per day


What is a normal total calcium in the serum?



What is the total calcium in serum comprised of? What percentage are these of total calcium? What causes a shift in the percentages?

46% is protein bound
47% is free (ionized)
7% is complexed
Alkalosis causes a shift from free to protein bound calcium


What causes PTH to be released? What effect does the release of PTH have?

↓ plasma Ca²⁺ = ↑ PTH
↑ resorption = release of Ca and phosphate
↑ phosphate excretion
↑ calcium reabsorption
↑ calcitriol formation → ↑ intestinal CaHPO₄ absorption


What is the rapid response system for low serum Ca?

PTH release


What also binds to the PTH receptor? Why is this clinically relevant?

A lot of this is produced during breastfeeding and by some tumours (which induces hypercalcaemia)


How is PTH release controlled?

The parathyroid gland monitors serum Ca through the calcium sensing receptor
Even at high calcium levels there is a base-line PTH secretion
There is a set-point (half of the maximal suppression of PTH)


What effect does PTH have on the kidney?

1) Internalises the Na/phosphate transporter from the membrane of the PCT to prevent reabsorption
2) Binds to receptor, activating Ca transport protein. Ca then binds to an intracellular protein which is transported through the cell and into the interstitial space by either a Ca²⁺ATPase or a Ca exchanger


How does PTH induce bone resorption?

PTH activates osteoblasts/stromal cells to express RANKL on their surface.
RANKL binds to RANK receptors on macrophages which stimulates osteoclasts to initiate bone resorption


What age and gender is primary hyperparathyroidism most common in?

Female 3:1 Male


What are the causes of primary hyperparathyroidism?

Parathyroid adenoma 80%
Parathyroid hyperplasia 20%
Parathyroid CA <1%
Familial syndromes
MEN1 2%
MEN2A rare
HPT-IT rare


How is primary hyperparathyroidism diagnosed?

Elevated total/ionized calcium with PTH levels elevated or in the upper half of the normal range


What are the clinical features of primary HPT?

Thirst, polyuria, tiredness, fatigue and muscle weakness
Stones, moans and psychic groans
Renal colic, dyspepsia, pancreatitis, constipation, nausea, anorexia, depression, drowsy, coma


At what point is a calcium level a medical emergency? Why?

Kidney will shut down
Transporter will shut down so the patient will get rapidly dehydrated


What effect does acute and chronic PTH elevation have on bone resorption?

Acute (pulsatile): anabolic- builds bone
Chronic: catabolic- resorption


What are the actions of vitamin D?

- 1,25(OH)₂ vitamin D activates Ca and phosphate absorption in duodenum
- Synergises with PTH, acting on osteoblasts to increase formation of osteoclasts through RANKL
- Increases osteoblast differentiation and bone formation
- Facilitates PTH action to increase Ca reabsorption in distal tubule


What is Rickets? What are the signs and symptoms?

Inadequate vitamin D activity leads to defective mineralisation of the cartilaginous growth plate
- Bone pain and tenderness
- Muscle weakness
- Lack of play
- Age dependent deformity
- Myopathy
- Hypotonia
- Short stature
- Tenderness on percussion


What are the causes of Rickets/osteomalacia?

Vitamin D related:
- Dietary
- Gastrointestinal
• Small bowel malabsorption / bypass
• Pancreatic insufficiency
• Liver/biliary disturbance
• Drugs (phenytoin, phenobarbitone)
- Renal
• Chronic renal failure
- Rare hereditary
• Vitamin D dependent rickets
→ Type I - deficiency of 1α-hydroxylase
→ Type II- defective VDR for calcitriol


What hormone also causes phosphate loss in the PCT, as well as PTH? What metabolic bone disorder does this cause?



What two hormones control phosphate homeostasis? What is the duration of action of these hormones?

PTH: Fast-acting hormone
FGF-23: Slow, long lasting hormone


What is osteoporosis?

Low bone density


What are the causes of osteoporosis?

1) High bone turnover
Increased bone resorption greater than increased bone formation
2) Low bone turnover
Decreased bone formation more pronounced than decreased bone resorption
3) Increased bone resorption and decreased bone formation


Deficiency in what hormone causes menopausal bone loss? What effect does it have?

- Increases number of remodelling units
- Causes remodelling imbalance with increased bone resorption (90%) compared to bone formation (45%)
- Remodelling errors- deeper and more resorption pits lead to:
• Trabecular perforation
• Cortical excess excavation
- Decreased osteocyte sensing


Why would high urine calcium not be diagnostic of osteoporosis?

Because urine calcium will be high when a woman is post-menopausal


How is osteoporosis diagnosed? Explain this.

DEXA (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


What is a FRAX? What does it measure and why?

Fracture Risk Assessment Tool
Uses hip bone
The commonest fractures in osteoporosis are vertebral fractures followed by hip fractures.


What propeptides can be measured in the blood and used to indicate bone formation?

P1NP = Procollagen type I N-terminal propeptide


What markers indicate bone resorption?

Serum CTX
Urine NTX


What is the process of collagen synthesis involved in bone formation?

1) 2 'Alpha 1' and 1 'Alpha 2' chain of type 1 collagen is produced by the osteoblast join
2) Extension peptides are cut off
3) 3 hydroxylysine molecules on adjacent tropocollagen fibrils condense to form a pyridinium ring linkage


Following treatment with anti-resorptive drugs, how long would it take to see results in an osteoporosis patient?

Bone resorption markers fall in 4-6 weeks
Expect a 50% drop of urine NTX by 3 months
Bone mineral density change in 18 months


What is alkaline phosphatase used to diagnose and monitor?

Boney metastases


What is Chronic Kidney Disease Mineral Bone Disorder?

Skeletal remodelling disorders caused by CKD which contributes directly to vascular calcification
Contributes to excess mortality in CKD
CKD impairs skeletal anabolism, decreasing osteoblast function and bone formation rates


What in renal osteodystrophy? What is the progression of this disease?

Increased serum phosphate and reduction in calcitriol
Secondary Hyperparathyroidism develops to compensate
Unsuccessful and hypocalcaemia develops
Parathyroids autonomous (tertiary)


What happens to the parathyroid gland in secondary hyperparathyroidism?

Parathyroid hyperplasia causing huge increase in parathyroid hormone


What are the functions of bone?

1) Mechanical
- support and site for muscle attachment
2) Protective
- vital organs and bone marrow
3) Metabolic
- reserve of calcium


What is the composition of bone, and their proportions?

Inorganic - 65%
Organic - 35%


What is contained within the inorganic portion of bone?

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


What is contained within the organic portion of bone?

- Bone cells
- Protein matrix


What are cortical bones?

- Long bones
- 80% of the skeleton
- Appendicular
- 80-90% calcified
Mainly mechanical and protective


What are cancellous bones?

- Vertebrae and pelvis
- 20% of skeleton
- Axial
- 15-25% calcified
- Mainly metabolic- Large surface


What are the two types of bone biopsy?

- needle - core biopsy usually taken from ASIC (Jamshidi needle)
- For sclerotic or inaccessible lesions perfored under general anaesthetic (e.g. inner aspect of the pelvis)


What are the different types of bone cells?

1) Osteoblasts
2) Osteoclasts
3) Osteocytes


What are osteoblasts?

Build bone by laying down osteoid.


What are osteoclasts?

Multinucleate cells of macrophage family.
Reabsorb bone or chew bone


What are osteocytes?

Osteoblast-like cells, which sit in lacunae in bone


What is RANK?

Receptor Activator for Nuclear Factor κβ


What inhibits osteoclastogenesis? How?

OPG = Osteoprotegerin
Inhibits RANK/RANKL binding by competing with RANK for RANKL


What turns on the RANK/RANKL system causing osteoclast differentiation?

- Cytokines
- Mechanical influences


Anatomically, what are the different types of bones? Give examples of each.

Flat (Intramembranous ossification)
- Shoulder blades
Long (Endochondral ossification)
- Femur
- Vertebrae


What are the different classifications of bones? Explain the function of each.

1) Trabecular bone (cancellous)
The ends of long bones; porous, contains bone marrow
2) Compact bone (cortical)
Thick, dense, white bone; protective. Forms the hard exterior of bone
3) Woven bone (immature)
Abnormal, except in the base of teeth
4) Lamellar bone (mature)
Forms in response to gravity; thickens/makes bone strong


What is osteopaenia?

Reduced bone mass
Often results in fractures with little of no trauma


What are the three main categories of metabolic bone disease?

1) Related to endocrine abnormality (↓ Vit D; ↑ PTH)
2) Non-endocrine (e.g. age-related osteoporosis)
3) Disuse osteopaenia (lack of gravity)


What do you reach your peak bone mass?



What are the different types of osteoporosis?

Primary: age, post-menopause
Secondary: drugs, systemic disease (long-term steroids, some chemotherapy, anti-epileptics, thyroid treatment)


What is osteomalacia? What are the different types?

Defective bone mineralisation
1) Deficiency of vitamin D
2) Deficiency of PO₄ - usually chronic renal disease. Can't make calcium hydroxyapatite


What are the different causes of low vitamin D?

1) Skin (e.g. culture- veils etc, winter)
2) G.I. disease (small bowel malabsorption)
3) Liver disease
4) Renal disease


What are the sequelae from osteomalacia?

- Bone pain/tenderness
- Fracture
- Proximal weakness
- Bone deformity


What type of labelling is performed to investigate osteomalacia?

Tetracycline labelling
Tetracycline is taken up into bones so bone sample can be taken from ASIC to determine the amount of bone growth in ∼21 days


What skeletal changes are seen in hyperparathyroidism?

Osteitis fibrosa cystica


What organs are affected in hyperparathyroidism?

- Parathyroid gland
- Bones
- Kidneys
- Proximal small intestine


What are the different types of hyperparathyroidism?

- Parathyroid adenoma (85-90%)
- Chief cell hyperplasia within the parathyroid (rare)
- Chronic renal deficiency
- Vitamin D deficiency (due to feedback mechanism)


What would be shown on a hand X-ray of a patient with hyperparathyroidism? Why?

Lesions within the phalanges (Brown cell tumours)
Bone is broken down and replaced by fibrous tissue


What are the skeletal changes associated with chronic renal disease?

Can have one or a mixture:
1) Increased bone resorption (osteitis fibrosa cystica)
2) Osteomalacia
3) Osteosclerosis (thick bone)
4) Growth retardation
5) Osteoporosis


What are the features of renal osteodystrophy?

1) PO₄ retention (hyperphosphataemia)
2) Hypocalcaemia as a result of ↓ vitamin D
3) Secondary hyperparathyroidism
4) Metabolic acidosis
5) Aluminium deposition


What is Paget's disease? What are the stages of this disease?

A disorder of bone turnover
Divided into 3 stages:
1) Osteolytic (bone is broken down rapidly)
2) Osteolytic-osteosclerotic (bone built again-mixed)
3) Quiescent osteosclerotic (cycle of break down→reformed)


Who is typically affected by Paget's disease?

Onset >40y (3% Caucasians >55y)
Rare in Asians and Africans
Mono-ostotic 15% - remainder polyostotic


What are the main sites affected by Paget's disease?

Spine 76%
Skull 65%
Pelvis 43%


What are the clinical symptoms of Paget's disease?

- Pain
- Microfractures
- Nerve compression (including spinal nerve and cord)
- Skull changes may put medulla at risk
- Deafness
- ± haemodynamic changes, cardiac failure (↑ cardiac output to bone)
- Hypercalcaemia
- Development of sarcoma in area of involvement (1%- usually young people <30)


What is the haversian canal?

Space in mature bone where vessels run


What is Howship's lacunae?

The bite mark left by osteocytes


What is Rheumatoid Arthritis?

Chronic joint inflammation that can result in joint damage
- Site of inflammation is the synovium
- Associated with atuoantibodies
- Rheumatoid factor
- Anti-cyclic citrullinated peptide (CCP) antibodies


What is Ankylosing Spondylitis?

Chronic spinal inflammation that can result in spinal fusion and deformity
- Site of inflammation is the enthesis
- No autoantibodies ('seronegative')


What are the different types of seronegative Spondyloarthropathies?

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


What is Systemic Lupus Erythematosus?

Chronic tissue inflammation in the presence of antibodies directed against self antigens
- Multi-site inflammation but particularly the joints, skin and kidney
- Associated with autoantibodies:
- Antinuclear antibodies
- Anti-double stranded DNA antibodies


What are the different types of connective tissue diseases?

- Systemic lupus erythamatosus
- Inflammatory muscle disease: polymyositis, dermatomyositis
- Systemic sclerosis
- Siogren's syndrome
- A mixture of the above: 'Overlap syndromes'


What HLA is associated with Rheumatoid arthritis?



What HLA is associated with Systemic Lupus Erythematosus?



What HLA is associated with Ankylosing Spondylitis?



Where are MHC class I and class II cells found?

Class I: All cells
Class II: APCs


What antigen is presented by MHC class I? Give examples

Endogenous (intracellular)
- Viral peptides
- Tumour antigens
- Self-peptides


What T cell recognises antigen presented by MHC class I? What is the response?

CD8 +ve T cell
(cytotoxic T cell)
Response: Cell killing


What antigen is presented by MHC class II? Give examples

Exogenous (extracellular)
- Bacterial peptides
- Self-peptides


What T cell recognises antigen presented by MHC class II? What is the response?

CD4 +ve T cell
(helper cell)
Response: Antibody response


What is the MHC peptide binding site made up of?

Walls: α-helical structures
Floor: β-pleated sheet


What is the pathological mechanism of Ankylosing Spondylitis?

Currently thought that the disease is due to abnormalities in both HLA-B27 and the interleukin-23 pathway.
HLA-B27 has a tendency to misfold and this causes cellular stress that trigger interleukin-23 release and triggers interleukin-17 production by
- Adaptive immune cells i.e. CD4 +ve Th17 cells
- Innate immune cells e.g. CD4 -ve CD8 -ve ('double negative') T cells


In what rheumatological conditions do you not see auto-antibodies?

- Osteoarthritis
- Reactive arthritis
- Ankylosing spondylitis
- Gout


What auto-antibodies are present in systemic vasculitis?

Antinuclear cytoplasmic antibodies


What auto-antibodies are present in rheumatoid arthritis?

- Rheumatoid factor
- Anti-cyclic citrullinated peptide antibody


What auto-antibodies are present in systemic lupus erythematosus? What is the significance of each?

- Antinuclear antibodies (ANA)
All cases, non-specific
- Anti-double stranded DNA antibodies (anti-dsDNA) (HIGH)
Specific, serum level correlates with disease activity
- Anti-cardiolipin antibodies (anti-phospholipid antibodies)
Associated with risk of a/v thrombosis in SLE
- Anti-Sm antibodies (ribonucleoprotein antigen)
Specific for SLE

Patient will also have low complement levels


What auto-antibodies are present in diffuse systemic sclerosis?

- Anti-Scl-70 antibody
(also termed antibodies to topoisomerase-1)


What auto-antibodies are present in limited systemic sclerosis?

- Anti-centromere antibodies


What auto-antibodies are present in Dermato-/Polymyositis?

- Anti-tRNA transferase antibodies
e.g. histidyl transferase (also termed anti-Jo-1 antibodies)


What auto-antibodies are present in Sjögren's syndrome?

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


What auto-antibodies are present in Mixed connective tissue disease?

- Anti-U1-RNP antibodies


When would you see anti-Ro antibodies and anti-La antibodies in a patient?

Secondary Sjögren's syndrome
Neonatal lupus syndrome (transient rash in neonate, permanent heart block)


When would you see anti-ribosomal P antibodies in a patient?

Cerebral lupus


If a patient has antinuclear antibodies when would further tests screen for?

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

Cytoplasmic antibodies include:
- Anti-tRNA synthetase antibodies
- Anti-ribosomal P antibodies


What is the pathogenesis of systemic lupus erythematosus?

Apoptosis leads to translocation of nuclear antigens to membrane surface

Impaired clearance of apoptotic cells results in enhanced presentation of nuclear antigens to immune cells

B cell autoimmunity

Tissue damage by antibody effector mechanisms e.g. complement activation and Fc receptor engagement


What cytokines in rheumatology are released by T cells? What effect do they have?

γ-IFN (Th1)
- Activates macrophages
IL-2 (Th1)
- Activates T and B cells
IL-6 (Th2)
- Activates B cells, acute phase response


What cytokines in rheumatology are released by macrophages? What effect do they have?

- Activates T cells, fever, pro-inflammatory
- Similar to IL-1: more destructive


What is the dominant pro-inflammatory cytokine in the rheumatoid synovium?



What are the actions of TNF-α released by an activated macrophage?

- Proinflammatory cytokine release
- Hepcidin induction
- PGE₂ production
- Osteoclast activation
- Chondrocyte activation
- Angiogenesis
- Leukocyte accumulation
- Endothelial cell activation
- Chemokine release


What treatments are available for rheumatoid arthritis in clinic?

- Key treatment is anti-TNF-α
- IL-6 and IL-1 blockade
- Antibodies against B cell surface antigen CD20


What is the role of RANKL in rheumatoid arthritis?

RANKL is produced by T cells and synovial fibroblasts in RA
- Stimulates osteoclast formation (osteoclastogenesis)
- Binds to ligand on osteoclast precursors (RANK)
- Antagonised by decoy receptor- osteoprotegrin (OPG)


What upregulates RANKL?

- IL-1
- TNF-α
- IL-17
- PTH-related peptide


What monoclonal antibody acts against RANKL? What is this used to treat?

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


What is the main treatment target of SLE? Give examples of drugs that use this target.

B cells
- Rituximab → a chimeric anti-CD20 antibody used to deplete B cells
- Belimumab → a monoclonal antibody against a B cell survival factor call BLYS


What is Belimumab? How does it work?

Recombinant fully human IgG1 monoclonal antibody against BLYS
Inhibits activity of BAFF resulting in impaired B cell survival and reduced B cell numbers


What do prostaglandins act on? What treatment inhibits them?

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

Glucocorticoids inhibit phospholipase A₂
- Analgesia
- Anti-pyretic
- Anti-inflammatory
- Anti-platelet


What is rheumatoid arthritis?

Chronic autoimmune disease characterised by pain, stiffness and symmetrical synovitis (inflammation of the synovial membrane) of synovial (diarthrodial) joints


What are the key features of Rheumatoid arthritis?

Chronic arthritis
- Polyarthritis - swelling of the small joints of the hand and wrists is common
- Symmetrical
- Early morning stiffness in and around joints
- May lead to joint damage and destruction - 'joint erosions' on radiographs
Extra-articular disease can occur
- Rheumatoid nodules
- Others rare e.g. vasculitis, episcleritis
Rheumatoid factor may be detected in blood
- IgM autoantibody against IgG


What joints are most commonly affected by rheumatoid arthritis?

- Metacarpophalangeal joints
- Proximal interphalangeal joints
- Wrists
- Knees
- Ankles
- Metatarsophalangeal joints


What are sub-cutaneous nodules in rheumatoid arthritis?

- Central area of fibrinoid necrosis surrounded by histocytes and peripheral layer of connective tissue
- Occur in ≈30% of patients
- Associated with:
- Severe disease
- Extra-articular manifestations
- Rheumatoid factor


What is rheumatoid factor? What is the significance of RF in rheumatoid arthritis?

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 disease onset and further 10-15% become positive over the first 2 years of diagnosis


Why do citrullinated protein antigens develop in rheumatoid arthritis?

Peptidyl arginine deiminases (PADS) convert Arginine → Citrulline
- PADs are present in high concentrations in neutrophils and monocytes and consequently there is increased citrullination of autologous peptides in the inflammed synovium
- ACPA (Anti-cyclic citrullinated peptide antibody) is strongly associated with smoking and HLA 'shared epitope'
- Shared epitope preferentially binds citulline (non-polar) but not arginine (+ve charge) during inflammation- so ACPA more likely to develop among individuals with citrulinated autoantigens who have the shared epitope


What are the extra-articular features of rheumatoid arthritis?

- Fever, weight loss
- Subcutaneous nodules
- Vasculitis
- Ocular inflammation e.g. episcleritis
- Neuropathies
- Amyloidosis
- Lung disease - nodules, fibrosis, pleuritis
- Felty's syndrome - triad of splenomegaly, leukopenia and rheumatoid arthritis


What are the radiographic abnormalities in rheumatoid arthritis?

- Juxta-articular osteopenia
- Joint erosions at margins of the joint
Later still
- Joint deformity and destruction


What are the pathological features of the synovium in rheumatoid arthritis?

- Synovitis
- Bone erosion
- Pannus
- Cartilage degradation (joint space narrowing)


What is synovium? What type of collagen is it made of?

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

Type I collagen


What is synovial fluid?

Hyaluronic acid-rich viscous fluid


What is articular cartilage made of?

Type II collagen
Proteoglycan (aggrecan)


What is the pathogenesis of rheumatoid arthritis?

Synovial membrane is abnormal in rheumatoid arthritis
The synovium becomes a proliferated mass of tissue (pannus) due to:
- Neovascularisation
- Lymphangiogenesis
- Inflammatory cells:
- Activated B and T cells
- Plasma cells
- Mast cells
- Activated macrophages
Recruitment, activation and effector functions of these cells is controlled by a cytokine network
- excess pro-inflammatory vs anti-inflammatory cytokines ('cytokine imbalance')


What are the potential treatments for rheumatoid arthritis?

- TNF-α inhibition: achieved through parenteral administration (most commonly subcutaneous injection) or antibodies or fusion proteins
- IL-6 and IL-1 blockade available
- B cell depletion by IV administration of antibody against B cell surface antigen, CD20


How is joint damage prevented in rheumatoid arthritis?

- Multidisciplinary approach e.g. physiotherapy, occupational therapy, hydrotherapy, surgery
- Medication which includes:
- Drugs that control the disease process (disease-modifying anti-rheumatic drugs: DMARDs)
- Started early in the disease (joint destruction = inflammation x time)
- Biological therapies offer potent and targeted treatment strategies
- Important role of glucocorticoid therapy
- preference to avoid long-term use (side effects)
- useful as short-term treatment options in many settings e.g. to control flare of disease or control inflammation of single joint

DMARDs: steroid sparing agents (e.g. methotrexate)


What are DMARDs? Give examples

Drugs that may induce remission and prevent joint damage
Achieve this by:
- reducing 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 (weeks)
- Methotrexate - commonly used
- Sulphasalazine - commonly used
- Hydroxychloroquine - commonly used
- Leflunomide - uncommon
- Gold (rarely used now)
- Penicillamine (rarely used now)
All have significant adverse effects and therefore require regular blood test monitoring during therapy


Give examples of chimeric antibody biological therapy used to treat rheumatoid arthritis?

- Infliximab
- Rituximab


Give examples of full human antibody biological therapy used to treat rheumatoid arthritis?

- Adalimuman
- Golimumab


What is the main side effect of biological therapy treating rheumatoid arthritis?

Increased infection risk
- Can exacerbate TB
All treatments are expensive so in England their use follows NICE guidance


What is reactive arthritis?

Sterile inflammation in the joints FOLLOWING infection especially urogenital (e.g. Chlamydia trachomatis) and gastrointestinal (e.g. Salmonella, Shigella, Campylobacter) infections
- May be first manifestation of HIV or hepatitis C infection
- 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
- Distinct from infection in joints (septic arthritis)


What are the extra-articular manifestations of reactive arthritis?

- Sterile conjunctivitis
- Sterile urethritis
- Circinate balanitis
- Psoriasis-like rash on hands and feet 'keratoderma blennorrhagicum'

- Enthesopathy


What are the musculoskeletal symptoms of reactive arthritis?

- Asymmetrical
- Oligoarthritis (<5 joints)
- Lower limbs typically affected
- Heel pain (Archilles tendonitis)
- Swollen fingers (Dactylitis)
- Painful feet (Metatarsalgia due to plantar fasciitis)
- Sacroiliitis (inflammation of the sacro-iliac joints)
- Spondylitis (inflammation of the spine)


What are the main differences between rheumatoid arthritis and reactive arthritis?

Rheumatoid: ♀>♂
Reactive: ♂>♀
Rheumatoid: All ages
Reactive: 20-40 years
- Symmetrical
- Polyarticular
- Small and large joints
- Asymmetrical
- Oligoarticular
- Large joints
Rheumatoid: NO
Reactive: YES
Rheumatoid: NO (except atlanto-axial joint because synovial)
Reactive: YES
Rheumatoid: NO
Reactive: YES
Skin Involvement
Rheumatoid: Subcutaneous nodules
Reactive: K. blennorhagicum; Circinate balanitis
Rheumatoid Factor
Rheumatoid: YES
Reactive: NO
HLA Association:
Rheumatoid: HLA-DR4
Reactive: HLA-B27


How is Reactive Arthritis diagnosed?

Clinical diagnosis
Investigations to exclude other causes of arthritis e.g. septic arthritis:
- Microbiology
• Microbial cultures - blood, throat, urine, stool, urethral, cervical
• Serology (e.g. HIV, hepatitis C)
- Immunology
• Rheumatoid factor
• (HLA-B27)
- Synovial fluid examination
• Especially if only single joint affected


How would you differentiate between septic arthritis and reactive arthritis?

Synovial fluid culture
SA: Positive
RA: Sterile
Antibiotic therapy
SA: Yes
RA: No
Joint Lavage
SA: Yes - for large joints
RA: No


How is reactive arthritis treated?

In majority of patients complete resolution occurs within 2-6 months. No role for antibiotics
- Intra-articular corticosteroid therapy
- Typically self-limiting, hence symptomatic therapy
e.g. topical steroids and keratolytic agents in keratoderma
Refractory disease:
- Oral glucocorticoids
- Steroid-sparing agents e.g. sulphasalazine


What is osteoarthritis?

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)


What is typically affected by osteoarthritis?

Joints of the hand
- Distal interphalangeal joints
- Proximal interphalangeal joints
- First carpometacarpal joint
Weight-bearing joints of lower limbs
- Especially knees and hips
- First metatarsophalangeal joint so common it's not reported as a problem


What are Heberden's nodes?

Osteophytes at the distal interphalangeal joints


What are Bouchard's nodes?

Osteophytes at the proximal interphalangeal joints


What symptoms is osteoarthritis associated with?

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


What are the radiographic features of osteoarthritis?

- Joint space narrowing
- Subchondral bony sclerosis
- Osteophytes
- Subchondral cysts


What are the differences between the radiographic changes in rheumatoid arthritis and osteoarthritis?

Joint space narrowing
RA: Yes
OA: Yes
Subchondral sclerosis
RA: No
OA: Yes
RA: No
OA: Yes
RA: Yes
OA: No
Bony Erosions
RA: Yes
OA: No


What are the features of a joint in osteoarthritis? Why does it develop?

There is defective and irreversible articular cartilage and damage to underlying bone
- Worn away cartilage
- Cartilage fragments in fluid
Develops due to:
- Excessive loading on joints
- Abnormal joint components


Describe the pathway in osteoarthritis

Abnormal Abnormal
stress cartilage
↓ ↓
Normal Normal
cartilage cartilage
⤢ ⤡
Loss of ⟷ Collagen
proteoglycans fibril damage

Cartilage fibrillation
Osteophyte formation
Subchondral bone sclerosis


What are the properties of articular cartilage supporting it's function?

Weight-bearing properties of articular cartilage depend on intact collagen scaffold and high aggrecan content
- Avascular and aneural structure
- Collagen >90% is type II
- Chondrocytes
- Proteoglycan monomers (aggrecan)
Central hyaluronic acid and non-covalently linked aggrecan
Negatively charged chemical groups of GAGs attract water


What are proteoglycans? Give examples

Glycoproteins containing one or more sulphates glycosaminoglycan (GAG) chain
GAGs are repeating polymers of disaccharides and include:
- Chondroitin sulphate (glucuronic acid and N-aceyl galactosamine)
- Heparan sulphate
- Keratan sulphate (galactose and N-acetyl glucosamine)
- Dermatan sulphate
- Heparin
Proteoglycan examples:
Intracellular: Serglycin
Cell surface-associated: Betaglycan, Syndecan
Secreted into ECM: Aggrecan, Decorin, Fibromodulin, Lumican, Biglycan


What is the major proteoglycan in articular cartilage?



What is the major component of synovial fluid? What are the disaccharides

Hyaluronic acid
The only-non-sulphated GAG
Maintains synovial fluid viscosity
Disaccharides are: Glucuronic acid and N-acetyl glucosamine


What are the cartilage changes in osteoarthritis?

- Reduces proteoglycan
- Reduced collagen
- Chondrocyte changes e.g. apoptosis


What are the bone changes in osteoarthritis?

Changes in denuded sub-articular bone
- Proliferation of superficial osteoblasts result in production of sclerotic bone (e.g. subchondral sclerosis)
- Focal stress on sclerotic bone can result in focal superficial necrosis
New bone formation at the joints margins (osteophytes)
- Heberden's nodes (DIP joint)
- Bouchard's nodes (PIP joint)


What is the management procedure for osteoarthritis?

- Education
- Physical therapy: physiotherapy, hydrotherapy
- Occupational therapy
- Weight loss where appropriate
- Exercise
- Analgesia
- Paracetamol
- Intra-articular corticosteroid injection
- Joint replacement


What autoimmune diseases affect connective tissue?

- Rheumatoid arthritis
- Sjögren's syndrome
- Systemic lupus erythematosus
- Dermatomyositis
- Polymyositis
- Systemic sclerosis


Who has increased risk of SLE? What is the prevalence?

M:F 1:9
Presentation 15-40 years
Increased in Afro-Caribbean, Asian and Chinese
Prevalence: 4-280/100,000


What is affected by SLE?

Principally affects joints and skin
In severe cases affects lungs, kidneys and haematology


What is the presentation of SLE?

- Malaise
- Fatigue
- Fever
- Weight loss
- Lymphadenopathy


What are the specific features of SLE? What other features are associated?

- Butterfly rash
- Alopecia
- Arthralgia
- Raynaud's phenomenon

Other features:
- Kidney inflammation
- CNS inflammation
- Heart inflammation
- Lung inflammation
- Accelerated atherosclerosis
- Vasculitis


What skin condition is associated with SLE? Why is this important?

Malar rash
Depth of rash is important. It can penetrate into the dermis. This is irreversible and must then be treated cosmetically


What is the pathogenesis of SLE?

Genetic predisposition

Environmental triggers (apoptosis)

Innate immune system activation (macrophages→APC)

Adaptive immune system activation (APC→T cell→B cell→plasma cell=Ab)

Immune complexes (Ab+tissue)
↓←Clinical disease onset
Aberrant amplification pathways

Irreversible tissue damage


What cellular alterations are seen in SLE?

Increased rate:
- Epigenetic deregulation of pro-apoptotic genes
↓ Release of nuclear material
Recognition of autoantigens
- Release of nuclear material with specific epigenetic patterns
- Epigenetic deregulation of genes involved in immune response


What is the pathophysiology of autoantibody formation?

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...


What are the laboratory tests for SLE? What is their significance?

Antinuclear antibodies:
ANA relatively non-specific, pattern important
- Homogenous - Abs to DNA
- Speckled - Abs to Ro, La, Sm, RNP
- Nucleolar - topoisomerase - scleroderma
- Centromere - limited cutaneous scleroderma
Anti-dsDNA and Sm
- More specific but less sensitive
Anti-Ro and/or La
- Common in subacute cutaneous LE
- Neonatal lupus syndrome & Sjögren's
Other tests
- Increased complement consumption
- Anti-cardiolipin antibodies
- Lupus anticoagulant
- β1 glycoprotein
- Lymphopaemia, normochromic anaemia
- Leukopaenia, AIHA, thrombocytopaenia
- Proteinuria, haematuria
- Active urinary sediment


How do you assess disease severity in SLE?

1. Identify pattern of organ involvement
2. Monitor function of affected organs
- Renal- BP, U&E, urine sediment + Prot:Crea ratio
- Lungs/CVS- Lung function, echocardiography
- Skin, haematology, eyes
3. Identify pattern of autoantibodies expressed
- Anti-dsDNA, anti-Sm - renal disease
- Anti-cardiolipin antibodies


What clinical features and laboratory markers are used to pre-empt severe attacks in SLE?

Clinical Features:
- Weight loss
- Fatigue
- Malaise
- Hair loss
Laboratory Markers:
- Increased complement consumption
- Increased anti-dsDNA
- Other Abs e.g. ANA and CRP poor indicators


What is characteristic of mild SLE?

Joint ± skin involvement


What is characteristic of moderate SLE?

Inflammation of other organs; pleuritis, pericarditis, mild nephritis


What is characteristic of severe SLE?

Severe inflammation in vital organs:
- Severe nephritis
- CNS disease
- Pulmonary disease
- Cardiac involvement
- AIHA, thrombocytopaenia, TTP


What is the treatment for mild SLE?

1. Paracetamol ± NSAIDs
- Monitor renal function
2. Hydroxychloroquine
- Arthropathy
- Cutaneous manifestations
- Mild disease activity
3. Topical corticosteroids


What is the treatment for moderate SLE?

- Failure of hydroxychloroquine/NSAIDs
- Organ/life threatening disease
- High initial dose to suppress disease activity


What is the treatment for severe SLE?

- Effective steroid sparing agent
- 20% neutropenia
- Regular FBC and biochemistry monitoring

- Severe organ involvement, I.V. pulsed or oral treatment
- Risk of infertility


What novel treatments are available for treatment of severe SLE?

Mycophenolate Mofetil
- Reversible inhibitor of inosine monophosphate dehydrogenase
- Rate-limiting enzyme in de novo purine synthesis
- Lymphocytes - dependent upon de novo purine synthesis

- Anti-CD20 mAB therapy
- Leads to depletion or B cells - Effective in lupus nephritis


What is the prognosis in SLE?

15 year survival:
- No nephritis 85%
- Nephritis

Prognosis also worse if black male, low socio-economic status


What is the bimodal mortality pattern of SLE?

- Renal failure
- CNS disease
- Infection
- Myocardial infarction


How do you assess gait in a GALS examination? What are you looking for?

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


What does stiffness of joints in the morning indicate?

An inflammatory condition


What does stiffness of joints after exercise indicate?

A mechanical joint problem


How do you assess spine in a GALS examination?

- Lateral cervical spine movement: try to place ear on the shoulder each side
- Normal spine curves
(cervical lordosis, thoracic kyphosis, lumbar lordosis)
- Fibromyalgia: does mild pressure over either mid-point of each supraspinatus or gentle squeezing on skinfold over trapezius muscles elicit tenderness?
- Lumbar and hip flexion: ask patient to bend forward and touch their toes with straight knees


How do you assess arms in a GALS examination?

- Pronation with elbows flexed
- Supination with elbows flexed
- Grip
- Place tip of each finger on to the tip of the thumb to assess normal dexterity and precision grip
- MCP squeeze test: squeeze across 2nd to 5th MCP joints. Discomfort suggests synovitis
- Shoulder movement: Place both hands behind the head, then push elbows back


How do you assess legs in a GALS examination?

- Assess flexion of the hip and knee, whilst supporting the knee, passively internally rotate each hip, in flexion
- Examine each knee for presence of fluid using 'bulge' sign and 'patella tap' sign
- MTP squeeze test: squeeze across the MTP joints. Discomfort suggests synovitis
- Inspect soles of the feet for rashes and/or callosites


What is involved in a locomotor examination?

- Inspection
Swelling, redness, deformity
- Palpation
Warmth, crepitus, tenderness
- Movement
Active, passive, against resistance
- Function
Loss of function


What is arthritis?

Refers to definite inflammation of a joint(s) i.e. swelling, tenderness and warmth of affected joints


What is arthralgia?

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


What is dislocation?

Articulating surfaces are displaced and no longer in contact


What is subluxation?

Partial dislocation


What is a varus deformity?

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


What is valgus deformity?

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


What is gout? What are the signs and symptoms?

Acute gout = arthritis
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)
Gouty arthritis commonly affects the metatarsophalangeal joint of the bog toe
- Abrupt onset
- Extremely painful
- Joint red, warm, swollen and tender
- Resolves spontaneously over 3-10 days


If you have swelling of articular soft tissue what tissue is involved and what is this indicative of?

Tissue: joint synovium or effusion
Indicates: Inflammatory joint disease


If you have swelling of periarticular soft tissue what tissue is involved and what is this indicative of?

Tissue: subcutaneous tissue
Indicates: inflammatory joint disease


If you have swelling of non-articular synovial what tissue is involved and what is this indicative of?

Tissue: bursa/tendon sheath
Indicates: inflammation of structure


If you have swelling of bony areas what tissue is involved and what is this indicative of?

Tissue: articular ends of bone
Indicates: osteoarthritis


What is enthesopathy? Give examples

Pathology at the enthesis i.e. the site where ligament or tendon inserts into bone
Examples include:
- Plantar fasciitis
- Achilles tendinitis


What are the signs of irreversible joint damage from a locomotor examination?

Joint deformity
- Malalignment of two articulating bones
- Audible and palpable sensation resulting from movement of one roughened surface on another
- Classic features of osteoarthritis e.g. patello-femoral crepitus on flexing the knee
Loss of joint range or abnormal movement


What is a swan-neck deformity?

Affect the ring finger- there is hyper-extension at the PIP joint and hyper-flexion at the DIP joint


What is Boutonniére deformity?

Affects the little finger- there is hyper-flexion at the PIP joint


What is Ankylosing Spondylitis?

A chronic condition which may cause joint deformity
A chronic inflammatory disease affecting:
- Sacroiliac joints (sacroiliitis) and deformity: may lead to spinal fusion (ankylosis) and deformity
- Entheses resulting in chronic enthesopathy
- Non-axial joints - hips and shoulders (common), others less frequently involved
- Strong association with HLA-B27
- Rheumatoid factor is negative


What conditions are included in 'sero-negative spondyloarthropathies'?

- Ankylosing spondylitis
- Reiter's syndrome and reactive arthritis
- Arthritis associated with psoriasis (psoriatic arthritis)
- Arthritis associated with gastrointestinal inflammation (enteropathic synovitis)


What are the signs of irreversible joint damage from a locomotor examination?

May be due to inflammation, degenerative arthritis or trauma and 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


What are the different patterns of arthritis?

Determine by the number of joints involved:
- Polyarthritis (>4 joints involved)
- Oligoarthritis (2-4 joints involved)
- Monoarthritis ( single joint affected)


What joints are commonly affected in Rheumatoid arthritis?

- Wrist
- Elbow
- Shoulder
- Cervical spine
- Hip
- Knee
- Ankle
- Tarsal


What joints are commonly affected in osteoarthritis?

- 1st CMC
- Cervical spine
- Thoracolumbar spine
- Hip
- Knee
- 1st MTP
- Toe IP


What joints are commonly affected by polyarticular gout?

- 1st MTP
- Ankle
- Knee


In what condition do you get subcutaneous nodules?

Rheumatoid arthritis


In what condition do you get tophi?



What is the term for an abnormal increase in synovial fluid volume?

Synovial effusion


What is diathroses?

The term for a synovial joint (viscous fluid present in joint space)


What are the different types of synovial lining cells?

Type A: macrophage-like
Type B: fibroblast-like


What cells secrete hyaluronic acid?

Type B cells


What is the composition of a synovial joint in synovitis?

Effusion is inflammatory exudate
- Inflammatory cells and mediators; reduced hyaluronic acid


What is atherocentesis?

Synovial fluid examination using needle aspiration


What crystal is seen in gout? Describe it.

Crystal: Urate
Shape: Needle
Birefringence: Negative


What crystal is seen in pseudogout? Describe it.

Crystal: Calcium pyrophosphate dihydrate ('CPPD')
Shape: Brick-shaped
Birefringence: Positive


What makes synovial fluid viscous?

Hyaluronic acid


What is Sjögren's syndrome? Who is commonly affected? What are the symptoms?

Autoimmune exocrinopathy
- lymphocytic infiltration of especially exocrine glands and sometimes of other organs (extra-glandular involvement)
Typically diagnosed in middle-age females (F:M = 9:1)
Exocrine gland pathology results in:
- Dry eyes (xerophthalmia)
- Dry mouth (xerostomia)
- Parotid gland enlargement
Extraglandular manifestations:
- Non-erosive arthritis
- Raynaud's phenomenon
Associated with autoantibodies:
- Anti-nuclear antibody - Anti-Ro and Anti-La antibodies
- Rheumatoid factor


What is Inflammatory Muscle Disease? What are the associated symptoms?

Proximal muscle weakness due to autoimmune-mediated inflammation either with (dermatomyositis) or without (polymyositis) a rash
Associated with autoantibodies:
- Antinuclear antibody - Anti-tRNA synthetase antibodies (e.g. anti-Jo-1 = histidyl)
Elevated CPK, abnormal electromyography, abnormal muscle biopsy (polymyositis = CD8 T cells; dermatomyositis = CD4 T cells + B cells)
Associated with malignancy (10-15%) and pulmonary fibrosis


What is systemic sclerosis?

Thickened skin with Raynaud's phenomenon
- Dermal fibrosis, cutaneous calcinosis and telangiectasia
Skin changes may be limited or diffuse
- Diffuse systemic sclerosis
- Limited systemic sclerosis


What are the skin changes associated with dermatomyositis?

- Lilac coloured (heliotrope) rash on eyelids, malar region and naso-labial folds
- Red or purple flat or raised lesions on knuckles (Gottron's papules)
- Subcutaneous calcinosis
- Mechanic's hands (fissuring and cracking of skin over finger pads


What is metabolic bone disease?

Systemic disorder of the skeleton resulting from s metabolic disturbance


What are the different types of metabolic bone disease?

- Osteoporosis
- Osteomalacia and Rickets
- Hyperparathyroidism: primary
- Hyperparathyroidism: Secondary / Renal osteodystrophy
- Paget's disease


What are the radiographic signs of metabolic bone disease?

- Osteopenia
- Osteosclerosis


What are the different scans used to detect metabolic bone disease? What do these scans show? What are the main scan that are used?

- X-rays (density)*
- CT scans (density/attenuation)
- MRI scans (chemical/water content)
- Radionuclide Bone Scans (Bone turnover NOT density
- Bone Densitometry (density/attenuation)*
*main scans used


What is osteopenia? What conditions is it observed in?

"Poverty" of bone
- a sign not a disease
Seen in:
- Osteoporosis
- Osteomalacia


What is osteoporosis?

Decreased quantity of bone overall (bone mass), microstructure normal
- Normal biochemistry
- Fragility fractures / deformity / pain
- Loss of cortical bone
- Loss of trabeculae
- Insufficiency fractures


What is osteomalacia?

- Vitamin D deficiency
- Biochemistry: Vit D deficiency, Calcium normal/low, parathyroid hormone high, inadequate/delayed mineralisation
- Radiology (age/growth plate closure)
- Too little mineral: osteopenic and soft bone bends and deforms
- Too much osteoid (Looser's zones/pseudofracture)
- If Ca stays low secondary hyperparathyroidism may be superimposed
- 'Codfish' vertebra


What areas of the body are at risk of Looser's zones in osteomalacia?

Narrow lucency, perpendicular to bone cortex
- pubic rami
- proximal femer, scapula
- lower ribs


What are Codfish vertebrae?

- Biconcave loss of height
- Osteopenic
- Pencilled-in margin


What is the difference between osteomalacia and osteoporosis?

Osteomalacia: less mineral
- osteopenia
- bend and bow before break
- Codfish vertebrae: uniform spine deformity
Osteoporosis: less bone
- osteopenia
- break
- anterior wedging


What is the difference between osteomalacia and rickets?

Osteomalacia: changes in mature bone
- Osteopenia
- Looser's zone's
- Codfish vertebrae
- Bending deformities
Rickets: before growth plate closure
- changes related to growth plates dominate
- changes of osteomalacia coexist


What is Rickets?

Metaphysis most rapid growth = most obvious change
- indistinct frayed matephyseal margin
- widens growth plate (no calcifiction)
- metaphysis indistict / frayed margin
- cupping / splaying metaphyses - due to weight bearing
- Rickety rosary
- osteopenia


What is Rickety Rosary?

Splayed and cupped anterior ends of ribs


What are the PTH, Ca and phosphate changes in primary, secondary and tertiary hyperparathyroidism?

Primary HPT: ↑PTH ↑Ca ↓P
Secondary HPT: ↑PTH ↓Ca N/↓P
Tertiary HPT: ↑PTH ↑Ca ↓P


What are the radiological changes in primary hyperparathyroidism?

Bone resorption


What are the radiological changes in secondary hyperparathyroidism?

Renal osteodystophy
Resorption and increased density (anabolic and resorptive features of PTH)


What bone resorption occurs in hyperparathyroidism? Describe each

- Subperiosteal
Radial aspect of middle and ring finger phalanges
- Subchondral (distal clavical, pubis
- Intracortical
- Brown tumours (osteoclastic activity

e.g. pepper-pot skull


What causes slow bone loss?

Involutional osteoporosis
Bone has time to remodel/bone loss occurs according to mechanical needs


What causes fast bone loss?

Hyperparathyroidism/disuse osteoporosis
Bone loss is too rapid. Loss does not cater to mechanical needs


What radiological changes occur in renal osteodystrophy (chronic renal failure)?

- Osteomalacia and osteoporosis
- Secondary HPTH (sub-periosteal erosions, brown tumours, sclerosis-axial skeleton/vertebral end plates, rugger jersey spine, soft tissue calcification (arteries/cartilage)
- Bone resorption
- Bone sclerosis


What are the mediators of bone metabolism?

- Ca / P / vitamin D / Calcitonin
- Other hormones: Tyroxine, growth hormone, glucocorticoids, oestrogens, androgens, insulin
- Other factors: vitamin C and other nutrients, cytokines, prostaglandins, several growth factors


What are the functions of collagen and mineral in bone?

Collagen provides the flexibility
Mineral provides the strength


How often is skeletal tissue replaced?

Every 120 days


What is the process of normal bone turnover?

Resorption- Ruffle border on osteoclasts releases enzymes to break down bone
Reversal- Osteoclasts apoptose and preosteoblasts form where bone must be formed
Formation- Osteoblasts build more osteoid tissue than osteoclasts broke down. Mineralisation of the bone


What are bisphosphonates? What is the half life of bisphosphonates?

They destroy the cytoskeleton of osteoclasts, causing the ruffle border to break down so they can't release enzymes and destroy bone
Half life is 10 years so even if the patient is taken off the drug it is still active in the body for 10 years


What is the main side effect of bisphosphonates?

Drug actually causes fractures as bone ages and becomes more brittle
Microcracks form due to load on the bone, which are normally repaired. If they are not they build up and lead to a fracture
People taking bisphosphoates


What is Denosumab? How does it work?

Monoclonal antibody
RANK-RANKL determines the osteoclast response that occurs
Denosumab is an antiresorpative, stronger than bisphosphonates which interferes with RANK-RANKL


What is the mortality rate 30 days after a hip fracture?



What is Wolff's Law?

Bone remodels according to the stress applied to it

Means that during child development you need to load the bones properly for them to develop correctly
If patients are not active the bone will start to resorb


What is the process of fracture healing?

Week 1- Haematoma (or inflammation)
- Macrophages, leukocytes, IL-6, BMP etc
- Granulation tissue forms
- Progenitor cells invade
Weeks 2-3- Soft callus
- Chondroblasts and fibroblasts differentiate and form collagen (II) and fibrous tissue
- Proteoglycans produced → prevent mineralisation
- Chondrocytes release calcium into ECM and degrading enzymes to break down proteoglycans → allows mineralisation
Weeks 4-16- Hard callus
- soft callus invaded by blood vessels
- chondroclasts break down calcified callus
- replaced by osteoid (Type I collagen) from osteoblasts
- Osteoid calcifies → woven bone)
Weeks 17+- Remodelling
- Woven bone to lamella bone
- Shape relative to stress = Wolff's law
- Medullary canal reforms


What happens to the bone healing process in children?

It is much faster
Woven bone produced in 2 weeks


What is a fracture?

A soft tissue injury with an underlying break in the bone


What is a bone infection called?

Difficult to get antibiotics to penetrate bone


What are the different type of fracture?

- Spiral fracture
- Oblique fracture
- Butterfly fragment
- Transverse fracture


What is a spiral fracture?

Fracture that goes diagonally across the bone, and occurs as a result of rotating the bone in the opposite direction to muscle force


What causes an oblique fracture?

Normally a result of compressive forces


What causes a butterfly fragment fracture?

Caused by a direct blow on the opposite side to the fragment


What causes a transverse fracture?

Usually caused by a traction injury


What is a Greenstick fracture? Who does it commonly occur in?

Occurs when the bone breaks but one side stays intact with the membrane. Much easier to treat as it is still quite stable
Occurs most commonly in children as their bones are more bendy


What effect does exercise have on arthritis?

Sport makes you more likely to injure yourself and therefore more likely to get arthritis
Exercise is the most effective treatment for arthritis


What did Hueter-Volkmann discover about growing bones?

Increased compression at the growth plate slows down longitudinal growth
Increased tension at the growth plate speeds up longitudinal growth


What are the different types of varus alignment?

Neutral alignment: weight is passed straight through the middle of the knee joint so the load is spread evenly
Varus deformity: Weight is loaded onto the medial part of the knee joint resulting in a bowlegged appearance
Valgus deformity: Weight is loaded onto the lateral part of the knee joint resulting in a "knock-kneed" appearance


Who is more likely to get varus deformity?

Football (and rugby) player
People who do a lot of sport


Who is more likely to get a valgus deformity?

Tall thin women


What effect does varus deformity have on arthritis?

More likely to develop arthritis


What treatment is there for a varus deformity?

X-ray to look at alignment and joint space
Straighten leg to get neutral alignment
Make a cut in the bone (so it remains attached laterally) and gently hinge it open then fix with a plate

Corrects alignment


What causes developmental dysplasia of the hip? What is the treatment?

In utero the hip becomes malformed
- Steep slope on the acetabulum on one side compared to the other

Currently perform surgery after birth; if it is picked up really early the hips can be kept very abducted and the problem will resolve


What are Cam and Pincer hips?

Cam impingement: (pistol grip deformity) extra bone forming a bump on the head of the femur
Pincer impingement: extra bone on the socket of the pelvis- hip socket is too deep

Both deformities prevent flexion of the thigh