Musculoskeletal Flashcards

Question

Explain calcium balance.

Answer 1

Uses 3 main systems: GI tract, bone, kidney Total calcium can be complexed, ionised (free) which then undergoes alkalosis to be protein bound PTH - Mg dependent - 8 min T1/2 - PTH receptor activated also by PTHrP PTH drives active calcium absorption in distal tubule of the kidney PTH causes bone resorption through the RANK system

Answer 2

50s, female: male 3:1 Causes: parathyroid adenoma (most common), parathyroid hyperplasia, parathyroid CA Familial syndromes - MEN 1 2% An elevated total/ionised calcium (hypercalcaemia) with PTH levels elevated or in the upper half of normal range Non-suppressed ``` Clinical features: Thirst, polyuria, tiredness, fatigue, muscle weakness “Stones, abdominal moans and psychic groans” Renal colic, nephrocalcinosis, CRF Dyspepsia, pancreatitis Constipation, nausea, anorexia Depression, impaired concentration Drowsy, coma ``` Patients may also suffer fractures secondary to bone resorption High serum calcium causes a diuresis Chronically elevated PTH increases stone risk Chronically elevated PTH causes increased cortical bone resorption (increased bone turnover, acute/pulsed PTH: anabolic, chronic: catabolic, cortical > cancellous (light poreless bone) Chronically elevated PTH increases fracture risk Biochemical findings 1) increased serum calcium by absorption from bone/ gut 2) decraesed serum phosphaterenal excretion in proximal tubule 3) PTH in the upper half of the normal range or elevated 4) increased urine calcium excretion 5) Cr may be elevated

Answer 3

Vitamin D is metabolised by liver and kidney (pathway from endo) Vit D binding protein (DBP): t1/2 3 days filtered by kidney Activated vitamin D increases gut calcium absorption - 1,25(OH)VitD Vit D actions Intestine: activates Ca and P absorption in duodenum Bone: synergies with PTH acting on osteoblasts to increase formation of osetoclasts through RANKL Increases osteoblasts differentiation and bone formation Kidney: facilitates PTH action to increase Ca reabsorption in distal tubule Feedback: parathyroid directly to reduce PTH secretion and increase FGF-23 production in bone Deficiency of Vit D effects: Inadequate Vit D leads to defective mineralisation of the cartilaginous growth plate (before a low calcium) Symptoms Bone pain and tenderness (axial) Muscle weakness (proximal) Lack of play ``` Signs Age depended deformity Myopathy Hypotonia Short stature Tenderness on percussion ```

Answer 4

Vitamin D related Dietary Gastrointestinal: small vowel malabsorption/bypass, pancreatic insufficiency, liver/biliary disturbance, drugs -phenytoin, phenobarbitone Renal: chronic renal failure Rare hereditary: type I: deficient of 1a hydroxylase, II: defective VDR for calcitriol ``` Biochemistry Serum: Calcium N/low Phosphate N/low Alk phos High 25(OH)Vit D Low PTH High (secondarily to compensate) ``` Urine: Phosphate high Glucosuria, aminoaciduria, high pH, proteinuria FGF-23 cause PCT phosphate loss as well as PTH Produced by osteoblasts Like PTH causes P loss, unlike PTH inhibits action of Vit D by 1 a OHase Osteomalacia and phosphate Kidney forced to lose phosphate “Isolated” hypophosphatemia: X-lined hypophosphataemic rickets, high levels of FCF-23 Autosomal dominant hypophosphataemic rickets (ADRR) - cleavage site for FCF-23 mutated so high FGF-2 Oncogenically osteomalacia: mesenchymal tumours produce FGF-23 Therefore FGF-23 excess can cause rickets/ osteomalacia Also: Kidney proximal tubule damage causes phosphaturia and stops 1a hydroxylation of Vit D (normally PCT only reabsorbs P so this is problem because no reabsorption) Fanconi syndrome: multiple myeloma, heavy metal poisoning (lead, Mercury), drugs e.g. gentamicin, congenital disease e.g. Wilsons

Answer 5

Causes: 1) High turnover - increased bone resorption greater than increased bone formation eg. Oestrogen deficiency, hyperparathyroidism, hyperthyroidism, hypogonadism 2) Low turnover - decreased bone formation more than decreased bone resorption: liver disease, heparin, age above 50 3) increased bone resorption and decreased bone formation - glucocorticoids Oestrogen deficiency Causes remodelling balance with increased bone resorption compared to bone formation (enhanced osteoclast survival and activity) Trabecular perforation Increased fracture rates ``` Biochemistry in osteoporosis used to exclude other causes Serum biochemistry should all be normal 1. Check for Vit D deficiency 2. Check for secondary endocrine causes Primary hyperparathyroidism PTH high Primary hyperthyroidism free T3 high, TSH suppressed Hypogonadism Testosterone low 3. Exclude multiple myeloma 4. May have high urine calcium ``` BMD measured in osteoporosis DEXA measures transmissions brought the body of Xrays of two different photon energies Enables densities of two different tissues to be inferred, i.e. bone mineral, soft tissue T-score: Osteoporosis = -2.5 Osteopenia = -1 to 2.5 Normal = > -1 FRAX uses hip BMD (2nd commonest fracture after vertebral) Bone markers Unlike BMD they are dynamic, insight into activity of bone cycle. Divided into markers of formation and resorption Formation markers: o P1NP – Procollagen type 1 N-terminal Propeptide. In production of collagen (2a1, 1a2), extension polypeptides (P1NP) are cleaved. Resorption markers: o Serum CTX – Cross-linked C-telopeptides. o Urine NTX – Cross-linked N-telopeptides. 3 hydroxylysine molecules condense out to form a pyridinium ring linkage on resorption of bone. Resorption markers are used to monitor osteoporosis treatment. o Bone reabsorption markers fall in 4-6 weeks. o Expect a 50% drop of urine NTx by 3 months. o Problems though: -Hard to reproduce. -Positive association with age anyway. -Need to correct for creatinine. -Diurnal variation in urine markers. Formation markers: o Only one formation marker is in common use – ALP. Used in diagnosis/monitoring of: • Paget’s disease of bone. • Osteomalacia. • Bony metastasis. BSAP – Bone-Specific Alkaline Phosphatase: • Types – tissue-specific (bone) form of ALP. • Roles – essential for mineralisation of bone and regulates concentrations of phosphate. • Uses – T1/2 40 hours. Increased in Paget’s, osteomalacia, bone metastasis, HPT, HT. NOTE that ALP varies with age (younger people have more). o P1NP is being used as a predictor of response to anabolic treatments – e.g. PTH treatment.

Answer 6

Chronic kidney disease mineral bone disorder - Skeletal remodeling disorders caused by CKD contribute directly to 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 Biochemistry 1. Increasing serum phosphate 2. Reduction in 1,25 Vit D (calcitriol) SO Secondary Hyperparathyroidism develops to compensate BUT unsuccessful and HYPOCALCAEMIA develops LATER Parathyroids AUTONOMOUS (tertiary) causing HYPERCALCAEMIA o Pathway – secondary hyperparathyroidism develops to compensate —> unsuccessful so hypocalcaemia —> parathyroid become autonomous (tertiary hyperparathyroidism) —> hypercalcaemia. o There is a progressive hyperplasia of the parathyroids. Nephron loss via CKD. Phosphate binds calcium in serum. o Calcium phosphate crystals are deposited causing extra-skeletal calcifications. Acidosis causes demineralisation. In renal osteodystrophy, you can get heterotopic calcification – bone formation at an abnormal anatomical site, usually in soft tissue. o I.E. in MCP joints. (Diagram) Renal osteodystrophy is a CONSEQUENCE of CKD; the results of CKD cause the symptoms of osteodystrophy such as heterotopic calcification.

Answer 7

One of the chronic overlapping autoimmune diseases M:F 1:9, 15-40 years presentation Increased in Afro-Caribbean, Asian and Chinese Principally affects joints and skin Lungs, kidneys, haematology (bone marrow) Genetic associations - multiple genes implicated (polygenic) - complement deficiency e.g. C1q and C3 (these will develop lupus for sure) - Fc receptors, IRF5, CTLA4, MHC class II HLA genes over represented ``` Clinical features Presentation: -malaise, fatigue, fever, weight loss -lymphadenopathy Specific features: -butterfly rash, alopecia (hair loss) -arthralgia -Raynaud’s phenomenon ``` Other features: - inflammation of kidney, CNS, heart (myocarditis), lungs - accelerated atherosclerosis - vasculitis 4 or more of 11 criteria: It’s a multi system chronic autoimmune inflammatory disease * Malar rash * Discoid rash * Photosensitivity * Oral ulcers * Arthritis * Serositis: (a) pleuritis or (b) pericarditis * Renal disorder e.g. proteinuria > 0.5g/24h * Neurological disorder e.g. seizures/ pyschosis * Haematological disorder * Immunologic disorder e.g anti-dsDNA Abs * Antinuclear antibody in raised titre Rash has no pus (distinguish from acne), dermis rash - loss of pigment - permanent scarring Rash spares nasal folds ad other areas, usually on cheeks SLE Pathogensis: Immune complex driven type 3 hypersensitivity reaction Irreversible tissue injury from complement Genetic and environmental e.g. virus SLE also related to abnormal clearance of apoptotic cells by immune system Auto immune antibodies against abnormally cleared apoptotic cells B cell hyper reactivity; exposure to environment antigen; generation of antibodies against apoptotic cells —> immune complexes inside organs e.g. kidneys—> inflammoraory tissue injury B cells - antigen presentation, antibody reproduction, produce cytokines .etc. ``` Pathway: 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. ```

Answer 8

Antinuclear antibodies: ANA relatively non-specific, pattern important (find antibodies that bind to nuclei on glass slide ; indicator of autoantibodies; indirect immunofluorescence used Pattern: homogeneous for SLE • Homogenous - Abs to DNA • Speckled - Abs to Ro, La, Sm, RNP • Nucleolar - topoisomerase - scleroderma • Centromere - limited cutaneous scleroderma Anti-dsDA and Sm (Smith antigen) -more specific but less sensitive Anti-Ro and/or La -common in subacute cutaneous LE -neonatal lupus syndrome and Sjögren’s ``` Other tests: • Increased complement consumption (C3 and C4 complement decrease because deposited in skin, organs and activated) • Anti-cardiolipin antibodies • Lupus anticoagulant • ß1 glycoprotein ``` haematology: • Lymphopaenia, normochromic anaemia (haemolysis) • Leukopaenia, AIHA, thrombocytopaenia (may be due to haemorrhage) Renal: - proteinuria, haematuria - active urinary sediment - presence of casts = ongoing kidney inflammation Assessing disease severity: 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 -myocarditis? Pulmonary hypertension? • Skin, haematology, eyes 3. Identify pattern of autoantibodies expressed - mild? Moderate? Severe? • Anti-dsDNA, anti-Sm - renal disease • Anti-cardiolipin antibodies ``` Signs of disease activity: Try and pre-empt severe attacks Clinical Features in follow up • Wt loss, fatigue, malaise, hair loss • Alopecia • Rash ``` Laboratory markers • ESR (rise) • Increased complement consumption • Increased anti-dsDNA • Other Abs e.g ANA and CRP poor indicators (Lupus one of rare active diseases where ESR increase and CRP decreases, others usually both high)

Answer 9

``` Disease divided into three groups: -mild: joint +/- skin involvement -moderate: inflammation of other organs (pleuritic, pericarditis, mild nephritis) -severe: severe inflammation in vital organs: Severe nephritis CNS disease Pulmonary disease Cardiac involvement AIHA, thrombocytopaenia, TTP ``` ``` Treatment of mild disease: Paracetamol +/- NSAID -Monitor renal fucntion Hydroxychloroquine (rash) -athropathy -cutaneous manifestations -mild disease activity Topical corticosteroids - rash not only on face ``` Moderate disease: Indication - failure of hydroxychloroquine/NSAID -organ/life threatening disease ``` Corticosteroids -high initial dose to suppress disease activity -iv methyprednisolone -initial oral dose for 4 weeks -reduce slowly over 2-3 months Try to control because of side effects: -osteoporosis -weight gain -diabetes -thinking of skin -acne ``` ``` Severe disease: Azathioprine -moderate to severe disease -effective steroid-sparing agent -20% neutropenia -regular FBC and biochemistry monitory -safer in pregnancy and can cause liver failure ``` Cyclophosphamide - for more severe disease -severe organ involvement, iv pulse or oral -nephritis -BM suppression, infertility, cystitis (acrolein) And more severe side effects Mycophenolate mofetil - teratogenic but no effect on patient’s fertility - reversible inhibitor of inosine monophosphate dehydrogenase - rate-limiting enzyme in de novo purine synthesis - lymphocytes - dependent upon de novo purine synthesis Rituximab and bilimumab - monoclonal antibody switches off hyperreactivity - anti CD20 mAb therapy - leads to depletion of B cells - effective in lupus nephritis Belimumab is a fully human IgG1 monoclonal antibody against BLYS (also called BAFF) Inhibits this resulting in impaired B cell survival and reduced numbers

Answer 10

15 year survival: no nephritis (85%), nephritis (60%) Prognosis also worse if black, male, low sociopath-economic status The bimodal mortality pattern of SLE Early = active lupus - Renal failure, CNS disease Infection Late = myocardial infarction Accelerated atherosclerosis Overall SLE = automimmune mutisystem disease Rare disease, female preponderance Severity from mild joint pain to fulminant and life threatening Clinical features depend on organ affected Treatment: Symptomatic Immune-modulating Immunosuppressive

Answer 11

Chronic autoimmune disease characterised by pain, stiffness and symmetrical synovitis ( inflammation of the synovial membrane) of synovial (diarthrodial) joints Can be younger, not only old Key features: Chronic arthritis • Polyarthritis - swelling of the small joints of the hand and wrists is common (one joint - monoarthritis, oligoarthritis = 2-4) • Symmetrical - left and right evenly • Early morning stiffness in and around joints (in osteoarthritis this is for short time) • 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 - should really call this rheumatoid ‘antibody’ not ‘factor’ Important genetic component Specific HLA-DRB gene variants mapping to amino acids 70-74 of the DRb-chains are strongly associated with rheumatoid arthritis • Region encodes conserved amino acid sequence in the HLA-DR antigen-binding groove which is common to rheumatoid arthritis-associated DR alleles – termed ‘shared epitope’ • Other genes identified in genome-wide studies exert modest or weak effects Can be seen in identical twins stronger than non-identical Important environmental component Smoking – contributes 25% of population-attributable risk and interacts with shared epitope to increase risk 1% pop affected - relatively common cause of significant disability in young adults F:M 3:1 Commonest joints: • Metacarpophalangeal joints (MCP) • Proximal interphalangeal joints (PIP) - swan-neck deformity affecting the ring finger - there is hyperextension at the PIP joint and hyperflexion at the DIP; boutonnière (button-like) deformity affecting little finger - there is hyperflexion at the PIP joint Radiographs of hands show evidence of joint damage and deformity - bilateral ulnar deviation of fingers • Wrists • Knees • Ankles • Metatarsophalangeal joints (MTP) - callohys formation under heads of metatarsals due to joint deformity Symmetrical poly arthritis Primary site of pathology is in the synovium which includes (soft tissue swelling, osteoarthritis = bony hard swelling): Synovial joints: proximal inter-phalangeal joint synovitis Tenosynovium surrouding tendons: extensor tensosynovitis - note swelling is not above either the wrist or MCP joints, also incomplete extension of little and ring fingers Bursa: olecranon bursitis - swelling of elbow joint Sub-cutaneous nodules -central area of fibrinoid necrosis surrounded by histiocytes and peripheral layer of connective tissue -occur in around 30% of patients -associated with: Severe disease, extra-articulations manifestations, rheumatoid factor Could be on hand, e.g. fingers Extra-articulations features: Common • Fever, weight loss • Subcutaneous nodules Uncommon • vasculitis • Ocular inflammation e.g. episcleritis • Neuropathies • Amyloidosis - AA protein build up • Lung disease – nodules, fibrosis (methotrexate used to relate RA and can cause this as well), pleuritis • Felty’s syndrome – triad of splenomegaly, leukopenia and rheumatoid arthritis Radiological * Early: juxta-articular osteopenia (thinning of bone) * Later: joint erosions at margins of the joint * Later still: joint deformity and destruction

Answer 12

Rheumatoid factor heumatoid factor • Antibodies that recognize the Fc portion of IgG as their target antigen • typically IgM antibodies i.e. IgM anti-IgG antibody Aggregates of antibodies —> complement —> inflammation Factor +ve = serum positive arthritis • Positive in 70% at disease onset and further 10-15% become positive over the first 2 years of diagnosis Antibodies to citrullinated protein antigens (ACPA) • Antibodies to citrullinated peptides are highly specific for rheumatoid arthritis Anti-cyclic citrullinated peptide antibody ‘anti-CCP antibody’ • Citrullination of peptides is mediated by enzymes termed: Peptidyl arginine deiminases (PADs) Why do they develop in rheumatoid arthritis? -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 [amino acids 70-74 of the HLA-DRb-chains associated with rheumatoid arthritis] 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. ? Smoking enhances citrullination in lungs e.g. change in mcirobiotia, chronic infections ARGININE —> (PADs) CITRULLINE ``` Is the reason that anti-CCP antibodies develop in rheumatoid because of combination of genetic factor (shared epitope) and environmental factor (inflammation resulting in citrullination)? HLA-DRbeta (class 2, MHC) ```

Answer 13

Synovitis, bone erosion, pannus (inflammation), cartilage degrading (joint space narrowing) Synovial joint made up of synovium (1 to 3 cell layer lining synovial joints contains macrophage like phagocytise cells, fibroblast like cells that produce hyaluronic acid, type I collagen), synovial fluid (hyaluronic acid-rich viscous fluid) and articulate cartilage (type II collagen, proteoglycan (aggrecan) 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 there is an excess of pro-inflammatory vs. anti-inflammatory cytokines (‘cytokine imbalance’) The cytokine tumour necrosis factor-alpha (TNFα) is the dominant pro-inflammatory cytokine in the rheumatoid synovium and its pleotropic actions are detrimental in this setting: - proinflammatory cytokine release, angiogenesis, leukocyte accumulation, osteoclast activation - Produced by activated macrophages in synovium

Answer 14

Treatment TNFα inhibition is achieved through parenteral administration (most commonly sub-cutaneous injection) of antibodies or fusion proteins Biological therapy Interleukin 6 and interleukin 1 blockade (TNFa and interleukin 6 inhibition more effective than interleukin 1) In addition to cytokine blockade, we can also deplete B cells in rheumatoid arthritis by parenteral (intravenous) administration of an antibody against a B cell surface antigen, CD20 the antibody in clinical use is termed, rituximab Management Treatment goal is to prevent joint damage This requires: • Multidisciplinary approach e.g. physiotherapy, occupational therapy, hydrotherapy, surgery • Medication includes: drugs that control the disease process are termed disease- modifying anti-rheumatic drugs - ‘DMARDs’ -these are started early in the disease because joint destruction = inflammation x time DMARDs offer safer and more effective long-term treatment than ‘steroids’ so DMARDs are often referred to as ‘steroid-sparing agents’ since they enable us to avoid long-term steroid or at least use much lower doses of steroids than would be possible in their absence New therapies include Janus Kinase inhibitors • Tofacitinib (Xeljanz) • Baricitinib (Olumiant) Important roles for glucocorticoid therapy (‘steroids’, ‘prednisolone’) but • preference is 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 • Biological therapies offer potent and targeted treatment strategies DMARD THERAPY drugs that may induce remission (not cure) and prevent joint damage (can relapse) achieve this by: • reducing the amount of inflammation in the synovium • slow or prevent structural joint damage e.g. bone erosions • complex mechanisms of action and relatively slow onset of action i.e. weeks examples: • methotrexate – commonly used • sulphasalazine – commonly used • hydroxychloroquine – commonly used • leflunomide – uncommon • Janus Kinase inhibitors Tofacitinib (Xeljanz) Baricitinib (Olumiant) * gold (rarely used now) * penicillamine (rarely used now) • all have significant adverse effects and therefore require regular blood test monitoring during therapy BIOLOGICAL THERAPY • Inhibition of tumour necrosis factor-alpha (‘anti-TNF’) antibodies (infliximab, and others) fusion proteins (etanercept) • B cell depletion Rituximab – antibody against the B cell antigen, CD20 • Modulation of T cell co-stimulation Abatacept - fusion protein - extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to modified Fc (hinge, CH2, and CH3 domains) of human immunoglobulin G1 • Inhibition of interleukin-6 Tocilizumab (RoActemra) – antibody against interleukin-6 receptor. Sarilumab (Kevzara) – antibody against interleukin-6 receptor. Downside of using biological therpay: Side-effects for all include increased infection risk Some specific points of note: • 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

Answer 15

• sterile inflammation in joints following infection especially urogenital (e.g. Chlamydia trachomatis) and gastrointestinal (e.g. Salmonella, Shigella, Campylobacter infections) infections • Important extra-articular manifestations include: Enthesopathy -enthesitis - inflamed attachment of red one to bone e.g. plantar fascia, Achille’s tendon Skin inflammation Eye inflammation - uveitis - pus cells in eye • Reactive arthritis may be first manifestation of HIV or hepatitis C infection • Commonly young adults with genetic predisposition (e.g. HLA-B27) -MHC1, CD8 cell and environmental trigger (e.g. Salmonella infection) • Symptoms follow 1-4 weeks after infection and this infection may be mild • Reactive arthritis is distinct from infection in joints (septic arthritis) - this is direct infection of joint, reactive arthritis is part of immune reaction to infection Musculoskeletal - arthritis - asymmetrical, oligoarthritis (<5 joints), lower limbs typically affected - enthesitis - heel pain (Achilles tendinitis), swollen fingers (dactylitis), painful feet (metatarsalgia due to plantar fasciitis) - spondylitis - sacroiliitis (inflammation of the sacro-iliac joints), spondylitis (inflammation of the spine) Extra-articular features: - ocular: sterile conjunctivitis - Genito-urinar: sterile urethritis - pain on urination - skin: circinate balanitis; psoriasis-like rash on hands and feet Original description of Reactive arthritis = triad of arthritis, urethritis and conjunctivitis following infectious dysentery [Reiter’s syndrome]

Answer 16

* Clinical diagnosis * Investigations to exclude other causes of arthritis e.g. septic arthritis - needle take fluid, gran-drain culture, septic only affects one joint usually, reactive look more well Examples of important investigations: • Microbiology: Microbial cultures – blood, throat, urine, stool, urethral, cervical Serology e.g. HIV, hepatitis C • Immunology Rheumatoid factor (HLA-B27) - not very helpful, only minority of pop • Synovial fluid examination Especially if only single joint affected

Answer 17

Diagram Gonorrhoea/ gonococcal arthritis - form of septic arthritis, spread to multiple joint

Answer 18

in majority of patients complete resolution occurs within 2-6 months No role for antibiotics articular: NSAIDs e.g. ibuprofen intra-articular corticosteroid therapy extra-articular: typically self-limiting, hence symptomatic therapy e.g. topical steroids & keratolytic agents (break down keratin deposits) in keratoderma Refractory disease: oral glucocorticoids steroid-sparing agents e.g. sulphasalazine RarerL methotrexate, anti TNF

Answer 19

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) Not autoimmune Wear and tear, gradual wearing, degeneration of joints ``` Slowly progressive disorder that typically affects the: • Joints of the hand Distal interphalangeal joints (DIP) Proximal interphalangeal joints (PIP) First carpometacarpal joint (CMC) • Spine • Weight-bearing joints of lower limbs esp. knees and hips First metatarsophalangeal joint (MTP) ``` Osteophytes at the DIP joints are termed Heberden’s notes Osteophytes at the PIP joints are termed Bouchard’s nodes Can be associated with: • Joint pain worse with activity, better with rest (inflammatory arthritis gets worse with inactivity) • Joint crepitus creaking (cartilage Ron away so bone rubbing on bone), cracking grinding sound on moving affected joint • Joint instability - pain causing atrophy of muscles supporting joint • Joint enlargement - boney swelling e.g. Heberden’s nodes • Joint stiffness after immobility (‘gelling’) • Limitation of motion - hip

Answer 20

Radiographic features of osteoarthritis: • Joint space narrowing - cartilage • Subchondral bony sclerosis • Osteophytes - bony spurs • Subchondral cysts Diagram Spares MCPJ Lack of space indicates loss of articulations cartilage leading to bone in contact with bone.

Answer 21

There is defective and irreversible articular cartilage and damage to underlying bone - break down of cartilage - atrophy of May lets - damage to underlying bone - bone spurs - cartilage fragments in synovial fluid Develops due to excessive loading on joints and/or abnormal joint components Articulate cartilage: Weight-bearing properties of articular cartilage depend on intact collagen scaffold and high aggrecan content - Avascular and aneural structure (no blood supply or innervation) therefore no pain - collagen more than 90% type II - chondrocytes - produce cartilage - proteoglycan monomers (aggrecan) ECM proteoglycans Proteoglycans - glycoproteins containing one or more sulphated glycosaminoglycan (GAG) chains GAGs are repeating polymers of disaccharides and include: • Chondroitin sulphate (disaccharides are: glucuronic acid and N-acetyl galactosamine) • Heparan sulphate • Keratan sulphate (disaccharides are: galactose and N-acetyl glucosamine) • Dermatan sulphate • Heparin Examples of proteoglycans: - intra-cellular: serglycin - cell surface associated: betaglycan, syndecan - secreted into ECM: aggrecan, decorin, fibromodulin, luminance, biglycan • Aggrecan is the major proteoglycan in articular cartilage • Hyaluronic acid is the only non-sulphated GAG and is major component of synovial fluid where it has an important role in maintaining synovial fluid viscosity GAGs attract water Cartilage changes in osteoarthritis • reduced proteoglycan • reduced collagen • chondrocyte changes e.g. apoptosis Bone changes in osteoarthritis • Changes in 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 at the joint margins (termed osteophytes) e.g. Heberden’s and Bouchard’s nodes

Answer 22

Management: • Education • Physical therapy – physiotherapy, hydrotherapy • Occupational therapy • Weight loss where appropriate • Exercise • Analgesia Paracetamol Non-steroidal anti-inflammatory agents Intra-articular corticosteroid injection (try not to do too much because injecting can further damage joint) • Joint replacement - timing important - keep having to replace? Therapeutic approaches not approved in UK -Glucosamine and chondroitin sulphate – commonly taken -Intra-articular injections of hyaluronic acid, hyaluronic acid to increase lubrication Unlike rheumatoid arthritis no disease modifying osteoarthritis drug (DMOAD)

Answer 23

Rheumatoid arthritis • Chronic joint inflammation that can result in joint damage • Site of inflammation is the synovium • Associated with autoantibodies: Rheumatoid factor and Anti-cyclic citrullinated peptide (CCP) antibodies SYNOVITIS Ankylosing spondylitis • Chronic spinal inflammation that can result in spinal fusion and deformity • Site of inflammation is the enthesis - between vertebrae • No autoantibodies (‘seronegative’) Arthritis but no rheumatoid factor, predilection for affecting spine Boney fusion, spinal inflammation Spinal deformity in ankylosing spondylitis: there is increased thoracic kyphosis and loss of the normal lumbar lordosis ENTHESITIS SLE • 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 against self IMMUNE COMPLEXES

Answer 24

Major histocompatibility complex (MHC) There is association between the MHC and disease e.g. Rheumatoid Arthritis HLA-DR4 Systemic Lupus Erythematosus HLA-DR3 Ankylosing Spondylitis HLA-B27 ``` The genes within the MHC class I and class II regions encode cell surface proteins These were first recognised on human white cells – hence termed human leucocyte antigens (‘HLA’) ``` ``` Function of MHC class I & class II molecules is to present antigen to T cells Peptide-binding site made up of walls (α-helical structures) and floor (β-pleated sheet) • Sequence in peptide-binding groove determines which antigens can bind • T cells only see antigen-bound to MHC (‘MHC restriction’) ``` Ankylosing Spondylitis No arthritogenic peptide that binds HLA-B27 identified If you express human HLA-B27 in rats (i.e. transgenic rats) you get a similar disease that develops in the absence of CD8 +ve T cells So need new hypothesis Currently thought that the disease is due to abnormalities in both HLA-B27 and the interleukin- 23 pathway: HLA-B27 has a propensity to misfold and this causes cellular stress that triggers 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 Interestingly these ‘double negative’ T cells have been detected in entheses and this may explain why enthesopathy occurs in Ankylosing Spondylitis

Answer 25

Diagram Antibody bound to antigen —> immune complexes which: 1) bind to immunoglobulin receptors - Fc —> inflammatory cascade 2) complement SLE Low complement levels High serum levels of anti-ds-DNA antibodies 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. tissue damage by antibody effector mechanisms .e.g. complement activation and Fc receptor engagement

Answer 26

Diagram • CD4 +ve T helper cell subsets include: Th1, Th2 and Th17 • Th1 cells secrete IL-2 and γ-IFN and response is important in CD8 +ve cytotoxicity and macrophage stimulation • Th2 cells secrete IL-4 (IgE responses), IL-5 (eosinophils), IL-6 (B cells to plasma cells) and IL-10 (inhibit macrophage response) • Th17 cells develop in response to IL-23 and secrete IL-17, a potent cytokine which triggers IL-6, IL-8, TNFα, matrix metalloproteinases and RANKL in target cells. Important in mucosal immunity but also in disease including arthritis, psoriasis, inflammatory bowel disease and multiple sclerosis The cytokine tumour necrosis factor-alpha (TNFα) is the dominant pro-inflammatory cytokine in the rheumatoid synovium and its pleotropic actions are detrimental in this setting: (refer back to rheumatoid) RANKL is important in bone destruction in rheumatoid arthritis RANKL (receptor activator of nuclear factor KB (kappa beta) ligand) Produced by T cells and synovial fibroblasts in rheumatoid arthritis Acts to stimulate osteoclast formation (osteoclastogenesis) Upregulated by: • Interleukin-1, TNF-a • Interleukin-17 – potent action on osteoclastogenesis via RANKL-RANK pathway • PTH-related peptide Binds to ligand on osteoclast precursors (RANK) Action antagonized by decoy receptor – osteoprotegerin (OPG) DENOSUMAB – monoclonal antibody against RANKL - indicated for treatment of osteoporosis, bone metastases, multiple myeloma and Giant cell tumours

Answer 27

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: Cyclooxygenase pathway: arachidonic acid - - - - prostaglandins • Prostaglandins mediate e.g. vasodilatation (PGI2, also termed prostacyclin, via receptor called IP), inhibit platelet aggregation (PGI2), bronchodilatation (e.g. PGE2 acting via receptor called EP2, PGI2), uterine contraction (PGF2alpha) Lipooxygenase pathway: arachidonic acid - - - - leukotrienes • Leukotrienes mediate e.g. leucocyte chemotaxis (LTB4) and smooth muscle contraction, bronchoconstriction and mucus secretion (LTC4, LTD4, LTE4 via CysLT1 receptors) side note: leukotriene receptor antagonists used in asthma Glucocorticoids inhibit phospholipase A2 Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit cyclooxygenase (‘COX inhibition’) • Benefits: analgesia, anti-pyretic, anti-inflammatory and anti-platelet (thromboxane A2) • Unwanted effects: e.g. asthma exacerbation, gastro-intestinal ulcers, thrombosis, liver and renal problems • Two isoforms of cyclooxygenase – COX-1 (constitutive) and COX-2 (inducible) Used to control symptoms

Answer 28

It is a locomotor examination Aims 1) Are any of the joints abnormal? 2) what is the nature of the joint abnormality? Inflammation/ mechanical e.g. from football 3) what is the extent (distribution) of the joint involvement? E.g. Symmetrical - rheumatoid 4) are any other features of diagnostic importance present? E.g. butterfly rash - lupus Key questions • 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? Gait Arms Legs Spine

Answer 29

GAIT Observe patient walking, turning and walking back and look for: -smoothness and symmetry of leg, pelvis and arm movements -normal stride length -ability to turn quickly ``` SPINE • 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? ``` ARMS • 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) (MCP squeeze test, can feel tenderness) ``` LEGS • 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 ``` Detailed examination of any abnormal joint(s) identified in the GALS screen • Inspection: swelling, redness, deformity • Palpation: warmth, crepitus, tenderness • Movement: active, passive, against resistance • Function: loss of function What is the nature of the joint abnormality? • Is there inflammation? • Is there irreversible joint damage? • Is there a mechanical defect? ``` Signs of inflammation • Swelling (tumor) • Warmth (calor) • Erythema (rubor) • Tenderness (dolor) • Loss of function (functio laesa) ``` Signs of irreversible joint damage • 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 Signs of mechanical defect Signs of mechanical defect • May 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

Answer 30

Arthritis - refers to definite inflammation of a joint(s) i.e. swelling, tenderness and warmth of affected joints Arthralgia - refers to pain within a joint(s) without demonstrable inflammation by physical examination Dislocation - articulating surfaces are displaced and no longer in contact Subluxation - partial dislocation, still some contact with articulating surfaces Varus deformity - lower limb deformity whereby distal part is directed towards the midline e.g. varus knee with medial compartment osteoarthritis Valgus deformity - lower limb deformity whereby distal part is directed away from the midline e.g. hallux vagus

Answer 31

Acute gout is a good example of arthritis A disease in which tissue deposition of monosodium urate (MSU) crystals occurs as a result of hyperuricaemia (diet) 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 big toe (‘1st MTP joint’) (podagra) • Abrupt onset • Extremely painful • Joint red, warm, swollen and tender • Resolves spontaneously over 3-10 days ```

Answer 32

Site of injury; tissue involved; indicative of... Articular soft tissue; joint synovium or effusion; inflammatory joint disease Periarticular soft tissue; subcutaneous tissue; inflammatory joint disease Non-articular synovial; bursa/tendon sheath; inflammation of structure Boney areas; articular ends of bone; osteoarthritis

Answer 33

* pathology at the enthesis i.e. the site where ligament or tendon inserts into bone * examples include: * plantar fasciitis • Achilles tendinitis

Answer 34

Good example of a chronic condition in which joint deformity may occur It is a chronic inflammatory disease affecting: • Sacroiliac joints (sacroiliitis) and spine • 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 It is part of a group of conditions termed ‘sero-negative spondyloarthropathies’ : Ankylosing spondylitis Reiter’s syndrome and reactive arthritis Arthritis associated with psoriasis (psoriatic arthritis) Arthritis associated with gastrointestinal inflammation (enteropathic synovitis) (Rigid fixed kyphosis)

Answer 35

``` • determine number of joints involved: -polyarthritis: > 4 joints involved -oligoarthritis: 2-4 joints involved -monoarthritis: single affected joint • note if involvement is symmetrical • note the size of the involved joints • is there axial involvement? ``` differential diagnosis e.g. • bilateral and symmetrical involvement of large and small joints is typical of rheumatoid arthritis • lower limb asymmetrical oligoarthritis and axial involvement would be typical of reactive arthritis • exclusive inflammation of the first metatarsophalangeal joints is highly suggestive of gout Arthritis; joints commonly involved; joints commonly spared -Rheumatoid arthritis; PIP, MCP, wrist, elbow, shoulder, cervical spine, hip, knee, ankle, tarsal, MTP; DIP, thoracic spine, lumbar spine - Osteoarthritis; 1st CMC, DIP, PIP, cervical spine, thoracolumbar spine, hip, knee, 1st MTP, toe IP; MCP, wrist, elbow, shoulder, ankle, tarsal joints - Polyarticular gout; 1st MTP, ankle, knee; axial (spine)

Answer 36

Rheumatoid arthritis: subcutaneous nodules (immune complexes outside joints) Gout: tophi - subcutaneous deposits of uric acid Systemic lupus erythematosus: malar rash

Answer 37

Viscous fluid present in joint space of synovial joints (diarthroses) • Colourless or pale yellow transparent viscous film covering synovium and cartilage with few cells Synthesized by synovial lining cells • Synovium consists of lining cells 1-3 cells deep in a matrix mainly containing type I collagen and proteoglycans • Two types of synovial lining cells: type A = macrophage-like and type B = fibroblast-like • Type B cells secrete the hyaluronic acid which results in the increased viscosity of synovial fluid Abnormal increase in synovial fluid volume is termed ‘synovial effusion’ • 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 • In synovitis due to inflammation the effusion is inflammatory exudate – abnormal composition: inflammatory cells and mediators, reduced hyaluronic acid (Chronic infections - TB, fungal infections - get biopsy) Confirm/exclude infection Synovial effusions Normal; clear or pale yellow and viscous Non-inflammatory; slightly turbid; osteoarthritis, mechanical defects Infection; very turbid; bacterial

Answer 38

When is it useful or important to examine synovial fluid? • It is mandatory when joint infection is suspected • It is useful to confirm diagnosis in suspected crystal arthritis How is it performed? • needle aspiration under aseptic conditions (termed arthrocentesis) Relative contraindications of arthrocentesis • Conditions / disorders that increase risk of bleeding into joint during/after procedure e.g. Anticoagulant drugs e.g. warfarin, low platelet counts, bleeding disorders like haemophilia • Overlying skin infection because of risk of introducing infection into joint Possible complications are all rare • Risk of introducing infection (i.e. creating a septic arthritis) • Bleeding into joint (haemarthrosis) • Damage to structures within the joint e.g. cartilage Synovial fluid samples are routinely examined for pathogens and crystals • 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 pseudogut Examples - acutely painful right knee: impaired host defence, direct penetration, joint damage - septic arthritis - management: antibiotic therapy, joint washout for large joints (lavage) - swelling behind elbow - sterile olecranon bursitis due to gout * Synovial fluid is viscous fluid rich in hyaluronic acid * It can accumulate (synovial effusions) in joint disease * Examination of the fluid in these circumstances is clinically very useful in crystal arthritis and mandatory when joint infection is suspected

Answer 39

Key points • Arthralgia and arthritis is typically non-erosive • Serum autoantibodies are characteristic and…: -May aid diagnosis -Correlate with disease activity -May be directly pathogenic • Raynaud’s phenomenon is common in these conditions • Intermittent vasospasm of digits on exposure to cold • Typical colour changes – white to blue to red -Vasospasm leads to blanching of digit -Cyanosis as static venous blood deoxygenates -Reactive hyperaemia • Raynaud’s phenomenon is most commonly isolated and benign condition (‘Primary Raynaud’s phenomenon’) SYSTEMIC LUPUS ERYTHEMATOSUS Key points • Prototypic autoimmune disease typically diagnosed in female aged between 15 – 45 years Associated with HLA-DR3 and other genes Clinical manifestations: • Malar rash – erythema that spares the nasolabial fold • Photosensitive rash • Mouth ulcers • Hair loss • Raynaud’s phenomenon • Arthralgia and sometimes arthritis • Serositis (pericarditis, pleuritis, less commonly peritonitis) • Renal disease – glomerulonephritis (‘lupus nephritis’) • Cerebral disease – ‘cerebral lupus’ e.g. psychosis SJOGREN’S SYNDROME Key points • Autoimmune exocrinopathy • lymphocytic infiltration of especially exocrine glands and sometimes of other organs (extra-glandular involvement) • Typically diagnosed in middle-aged female (F:M = 9:1) • Exocrine gland pathology results in -Dry eyes (xerophthalmia) -Dry mouth (xerostomia) -Parotid gland enlargement • Commonest extra-glandular manifestations are non-erosive arthritis and Raynaud’s phenomenon -Termed ‘secondary’ Sjögren’s syndrome if occurs in context of another connective tissue disorder e.g. SLE • Associated with autoantibodies: -Antinuclear antibody - Anti-Ro and Anti-La antibodies -Rheumatoid factor INFLAMMATORY MUSCLE DISEASE Key points • Proximal muscle weakness due to autoimmune-mediated inflammation either with (dermatomyositis) or without (polymyositis) a rash • Skin changes in 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) • Associated with autoantibodies: -Antinuclear antibody – Anti-tRNA synthetase antibodies (e.g. anti-Jo-1 = histidyl) • Elevated CPK, abnormal electromyograpghy, abnormal muscle biopsy (polymyositis = CD8 T cells; dermatomyositis = CD4 T cells in addition to B cells) • Associated with malignancy (10-15%) and pulmonary fibrosis SYSTEMIC SCLEROSIS Key points • Thickened skin with Raynaud’s phenomenon -Dermal fibrosis, cutaneous calcinosis and telangiectasia • Skin changes may be limited or diffuse -Diffuse systemic sclerosis: Fibrotic skin proximal to elbows or knees (excluding face and neck) Anti-topoisomerase-1 (anti-Scl-70) antibodies Pulmonary fibrosis, renal (thrombotic microangiopathy) involvement Short history of Raynaud’s phenomenon • Limited systemic sclerosis* -Fibrotic skin hands, forearms, feet, neck and face -Anti-centromere antibodies -Pulmonary hypertension -Long history of Raynaud’s phenomenon *CREST describes a sub-type of limited systemic sclerosis. It stands for Calcinosis, Raynaud’s phenomenon, Esophageal dysmotility, Sclerodactyly, Telangiectasia OVERLAP SYNDROME Key points • When features of more than 1 connective tissue disorder are present e.g. SLE and inflammatory muscle disease we can use the term overlap syndrome • When incomplete features of a connective tissue disease are present we can use the term undifferentiated connective tissue disease • In one instance a group of patients with features of seen in SLE, scleroderma, rheumatoid arthritis, and polymyositis were identified by the presence of an autoantibody: -Anti-U1-RNP antibody* - ….this condition was termed Mixed Connective Tissue Disease (‘MCTD’)

Answer 40

Exercise when young: growth sensors on both ends affected by how much exercise you do. Hueter-Volkmann Compression on growth plates = stops growing Traction on growth plates = pull on them: grow more Eight growth plate - the distal tibial physis can expand and grow laterally in this case - even out, equally grow

Answer 41

Straight leg, load is equally distributed on inside and outside of knee Varus alignment of knees - weight mostly medial Valgus alignment of knees - weight on lateral People doing sport are significantly more varus constantly loading on medial Arthritis starts either medial or lateral - loss of cartilage Osteotomy can be used for changing bone shape; cut bone - hinge open/shut Wolff’s law -Bone responses to stresses you out on it -if you out more stress, it will lay down more bone and make stronger -if stop using, starts dissolving Can be seen in surfer’s knuckles Start dissolving in space, dominant arm stronger in tennis so more stronger bone

Answer 42

Affects babies Want hip bone to be in hip socket If hip slipped out = dysplastic hip Childbirth - oestrogen causes ligaments to become looser to push up in baby Hip socket not formed because no hip joint Risk of arthritis increases, wear out quickly

Answer 43

Standard hip -slender neck and spherical head in femur CAM impingement - femoral neck bone taking lots of stress - lay down more bone - lots of exercise PINCER impingement -deep socket

Answer 44

1) elderly - wears out, cartilage breaks down, bone nibbling 2) injury - torn structures around, hip impact on cartilage 3) young - activity when young

Answer 45

Anterior cruciate ligament - stops knee from sliding front to back - stability Meniscus - fibrous cartilage - shock absorbers - stability When rupture anterior cruciform ligament, affects: - stability - especially changing direction - protect cartilage - loading correctly - meniscus - back take pressure - meniscal tears Fibrin slides forward, not lined with femur = unstable knee —> arthritis abnormalities - loading cartilage 2 treatments: 1) physiotherapist and modify activity 2) surgery - ACL reconstruction

Answer 46

Describes arrangement of cartilage 1) superficial gliding zone (10-20%) - collagen fibres are flat - resistant to sliding stress from bone above 2) middle transitional zone (40-60%) - resist bit of compression and side to side 3) Deep radial zone (30%) - resist compression 4) tide mark - non-calcified cartilage —> calcified cartilage 4) calcified cartilage - stops blood from outside knee joint entering into joint e.g. infection; nutrition from synovial fluid; downside: if injury, cant repair with inflammatory factors 5) subchondral bone 6) cancellous bone Collagen fibres from bottom to up: Vertical —> oblique —> horizontal

Answer 47

Young - trabeculae is thick As you get older, trabeculae is thinner, holes appearing and bone more fragile Postmenopausal, amputees Amputees don’t load, hips becoming weak Bisphosphates turn active osteoclast into apoptotic osteoclast Denosumab inhibits osteoclast formation, fucntion and survival - bind to RANKL (blocking its interaction with RANK)

Answer 48

Fracture of neck of femur —> mortality risk Milk and exercise lay calcium in young age Help osteoporosis too ``` Fracture healing Stage 1 – Haematoma/Inflammation – up-to 1 week. -Macrophages, leucocytes, IL-1-6, BMPs. -Granulation tissue formation. -Progenitor cell invasion. ``` Stage 2 – Soft callus formation – 1-4 weeks. - Chondroblasts and fibroblasts differentiate and form —> collagen (II) and fibrous tissue. - Proteoglycans produced (prevent mineralisation). - Chondrocytes release calcium + degrading enzymes to break down proteoglycans (allows mineralisation). Stage 3 – Hard callus formation – 1-4 months. - Blood vessel invasion of soft callus. - Chondroclasts break down calcified callus and this is replaced by osteoid (T1 collagen) from osteoblasts. - Osteoid calcified into WOVEN bone. Stage 4 – Remodelling – up-to several years. - Woven to lamellar bone. - Shapes relative to stresses, according to Wolff’s law. - Medullary canal reforms Fracture patterns - soft tissue injury with underlying discontinuity in bone = fracture - nerves and blood vessels affected too - twisted ankle - compression e.g. car crash - butterfly fragment e.g. direct hit - pulling on tension Greenstick fractures - thick periosteum, even if one side cracks, periosteum stays intact and other side bends (in young - paediatrics)