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Treatment of Major Rheumatic Diseases Dr Tanya Potter Consultant Rheumatologist.

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1 Treatment of Major Rheumatic Diseases Dr Tanya Potter Consultant Rheumatologist

2 Aims 1 To pass your exam 2 Encourage safe prescribing (and remember that have an exam in this also)

3 Rheumatoid arthritis (RA) or osteoarthritis (OA) most common types seen in clinics (& exams) Dramatically improved treatments in past 20 yrs

4 Osteoarthritis most common 75% people > 70 radiographic OA F: M 2.5:1

5 Osteoarthritis Joint space narrowing Osteophytes Subchondral sclerosis Bone cysts

6 Management Pain relief is key Seek improvement in joint mobility or walking time –e.g. how long it takes for pt to walk to end of corridor Quality of life- can use functional measures to see how well person is doing. Use several simple questions: –How well can dress or wash? –Can make own meals everyday? –Gives good reliable data

7 OA - Goals of Treatment No cure –Meds can improve function by reducing pain Can limit final impairment Non-pharmacological and pharmacological Non-pharmacological Patient education (education leaflets/ websites) –Wt loss (10-15 lb weight loss can reduce pain 100%) –Every lb gained, X four across weight bearing joint –PT: Muscle strengthening important -esp. quads muscle –OT: Use devices for joint protection (canes, walkers etc)

8 Drugs Mild to moderate –Paracetamol; –Topical agents: non steroidals, rubefacients Moderate to severe –As above, plus –NSAIDs –combination analgesics (paracet +opiods) / Opiods/ Tramadol

9 Paracetamol –Analgesic/ antipyretic –Unknown mechanism of action –combo with opiods better response when cant use NSAIDs (gu / du/ renal/ warfarin) –Doesnt alter platelet function (bleeding/ surgery) –Safer for elderly –1g qds max –Caution with chronic liver dz (hepatotoxicity, > 2 gm) –Thrombocytopaenia, neutropaenia rare

10 Tramadol Centrally acting analgesic –Use in addition to NSAID –Effects mu receptors; Same potency as opiods –Can use as adjunctive therapy –Less opiod SE; esp constipation/ nausea/ vomiting Balance problems smaller potential of abuse or dose acceleration, (pt needs more drug in shorter time period) c.f. opiods

11 Strong opiods –Use in pt with limited options loss of function due to pain renal or heart disease preventing operation Select pt carefully –Use during period of disease flare, then decrease use –Limitations Nausea, vomiting, constipation, ***urinary retention Chronic use leads to physical dependence –Can use with anti-inflammatory –Lots of choice (short or long acting, patches)

12 NSAIDS 25 million NSAID prescriptions/ yr in UK Non selective –Aspirin –Ibuprofen –Naproxen –Indomethacin –Piroxicam Selective cox 2 inhibiters –Celecoxib –Etoricoxib –Meloxicam –etodolac

13 NSAID risk How many GI bleed admissions annually in the uk? What percentage are likely to due to NSAIDs? How many deaths annually?

14 65,000 emergency upper GI admissions p.a. in UK 12,000 of these admissions (including 2,230 deaths) attributable to NSAID use Further 330 attributable deaths occur in community ~2% of NSAID users admitted annually for GI emergencies Upper GI complications


16 42% 19% Many patients asymptomatic prior to serious NSAID- associated GI event (bleeding, perforation) GI event may be devoid of warning symptoms 58%81% without symptomswith symptoms n = 141n = 1,921

17 prostoglandins

18 blocked Asthma NSAIDs: Inhibit cox enzymes

19 Action Reduce prostaglandin production- less inflammatory mediators Unopposed leukotrione action Antipyretic effects – partly due to a decrease in prostaglandin that is responsible for elevating the hypothalamic set point for temp control in fever

20 COX enzyme Cyclo-oxygenase (COX) has two forms COX-1 : protects the stomach lining from harsh acids and digestive chemicals. It also helps maintain kidney function COX-2 : is produced when joints are inflamed or injured

21 Action Different NSAIDs inhibit the enzyme by different mechanisms Aspirin – binds covalently with a serine residue of the enzyme (irreversible) Ibuprofen/Piroxicam – reversible competitive inhibitors of COX non selective Paracetamol – acts partly by reducing cytoplasmic peroxidase

22 Older nonselective NSAIDs (Ibuprofen, Naproxen) Block both COX-1 and COX-2, GI upset, bleeding as well as decreasing inflammation Advice patients to take them with food or a glass of milk and should avoid alcohol. Pros: –OTC version of these drugs are inexpensive –Low doses of aspirin taken over long term helps to prevent heart attacks, strokes and bowel cancer Cons: –GI upset ie nausea, ulcers –Kidney problems from overuse –Interacts with warfarin


24 COX-2 inhibitors (Celecoxib, meloxicam, etorocoxib) Target only the COX-2 enzyme that stimulates the inflammatory response Pros : –less likely to cause GI upset compared to the older NSAIDs –longer lasting drug – longer relief –do not thin the blood therefore can consider co- prescription with warfarin Cons: –More expensive compared to traditional NSAIDs –Results not as good as endoscopic drug studies suggest

25 Indications Commonest use – arthritis ie RA or OA and gout Back pain, sciatica, sprains and strains and rheumatism Dental pain Post op pain Period pain Renal/ureteric colic Fever migraines

26 CAUTIONS Elderly Pregnancy- miscarriage, early closure of ductus arteriosus Breast feeding Coagulation defects Renal, cardiac (heart failure/ hypertension/ IHD) or hepatic impairment

27 Contraindications Severe heart failure COX-2 : IHD, stroke, PVD and moderate to severe heart failure CSM advice – previous or active peptic ulceration hypersensitivity to aspirin or any NSAID – which includes those in whom attacks of asthma, angioedema, urticaria or rhinitis have been precipitated.

28 SIDE EFFECTS GI – N&D, dyspepsia bleeding and ulceration, Hypersensitivity Headaches, dizziness, nervousness, depression, drowsiness, insomnia, hearing disturbances Photosensitivity Fluid retention (heart failure), raise blood pressure Hepatic damage, pancreatitis Eye and lung changes (alveolitis) Stevens-Johnson syndrome & toxic epidermal necrolysis (rare)

29 GI Similar anti inflammatory effects of selective and non selective NSAIDs Non selective: –15-40% dyspepsia, nausea, abdo pain –10% discontinue –Severe GI toxicity 4.5/100pt years Selective Cox 2 inhibiters –Similar GI symptoms –< 6% discontinue –Severe toxicity 2.1/100 pt years NNT 42 to prevent 1 serious GI event

30 Cardiovascular toxicity Increased cardiovascular risk of selective NSAIDs is a problem unopposed pro-thrombotic effects of COX- 1-mediated production of thromboxane A2 Also, coxibs effects on blood pressure and renal function could turn out to be more detrimental than those of conventional NSAIDs.

31 prostoglandins

32 CV risk It is a real risk APPROVE study Data obscured by clinical trials not recruiting normal pts Data obscured by drug company manipulation of the results of clinical trials Up to 42% higher risk of MI with selective –0.6%/yr vs 0.3%/yr

33 All NSAID/ CVS Rise in BP 3-5mm Equate with an increase –CCF 10-20% –CVA 20% –Angina 12% Lowest risk of all with naproxen (aspirin like effects)

34 Naproxen Pain and inflammation in rheumatic disorders 0.5-1g / day in 1-3 divided doses In high risk pts, give with PPI Which one?

35 NSAIDs - past strategies Enteric Coating Pro-drugs; hepatic metabolism Gastro-protective agents:PPIs, misoprostol, H 2 blockade

36 OA- Adjunctive therapy Intra articular steroids plus local anesthetic for joint inflammation Decrease production of inflammatory mediators Can last a 3-6 months; use with physio Probably can be done safely up to four times a year –not too frequently; can effect the cartilage

37 Visco-supplementation Crosslinked hyaluronic acid polymers OA (knee) Intra-articular injections X 3-5 Change viscosity in joint Pain relief with improved mobility Success rate is 50-70% for up to 4-6 months no systemic SE

38 Visco-supplementation OA, where physio, weight loss, simple analgesia +/- NSAIDs insufficient & IA steroids not helpful /not lasting Awaiting/ unfit for surgery

39 Capcaisin cream 0.025% preparation (Zacin) Depletes Substance P from nerve endings Slow to act (1/12 to max effect) More effective than topical NSAIDs May reduce analgesic requirement

40 What are the alternatives? Cod liver oil & other fishy oils Evening primrose oil Borage or Starflower oil Change in balance of cell membrane fatty acids

41 Alternatives? Glucosamine 1.5 gram/day –substrate for glucosaminoglycans –Pain relief & mobility Possible 10-25% analgesic effect -disease modifier ? ? Nutrition for cartilage ? Stimulate metabolism Vitamin C Framingham study results show reduced pain OA of knee & hip may improve integrity of cartilage

42 Approximately how many upper GI admissions are attributable to NSAID use in the UK per annum? of of 120


44 Gout Joint inflammation caused by uric acid crystal deposits in the joint space

45 Gout Primary –Over production (10%) –Under secretion (90%) –Enzyme mutations Predominantly secondary –Overproduction (mutations, heavy exercise, obesity) –Under excretion severe renal diseases, drugs, alcohol, HBP

46 2-17% of population are hyperuricaemic The higher the uric acid the higher the chance of gout Self reported adult prevalence of 8/ M:1F Increase in blacks may reflect increased rates of hypertension

47 Figure 4 Simplified diagram of uric acid production and excretion Roddy E et al. (2007) The changing epidemiology of gout Nat Clin Pract Rheumatol 3: 443–449 doi: /ncprheum0556 2/31/3 2/3 1/3


49 Epidemiology Middle aged men Dietary purine consumption Alcohol Drugs:Low dose aspirin, diuretics Inherited metabolic abnormalities

50 Clinical features Gouty Tophi on pinnae Olecranon bursitis Gouty tophi on hands Gouty nephropathy& stones Large joint oligoarthritis 1 st metatarsophalangeal joint arthritispodagra


52 Management Prevent occurrence! Diagnose Treat acute flare Reduce risk of further flare Reduce associated morbidity secondary to HBP, hypercholesterolaemia

53 Aspirate joint Differential diagnosis monoarthritis?

54 Management of Acute Gout (1) Goal is to rapidly resolve pain and inflammation Non pharmacological- ice packs etc High doses of NSAID used: Naproxen. 500mg bd until the attack has passed Indomethacin, diclofenac, etoricoxib also used

55 Management of Acute gout(2) Alternative to NSAIDs Colchicine inhibits microtubule polymerization by binding to tubulin, inhibition of neutrophil motility and so produces an anti-inflammatory response.

56 Treatment Colchicine 500mg bd to tds –DO NOT USE BNF DOSE OF COLCHICINE –2/3 will respond cf 1/3 placebo –peak plasma concentration 1-2 hrs and a half life of 4 hrs –Metabolised by the liver with possible enterohepatic circulation –20% excreted unchanged in urine –Avoid IV –Good alternative for patients receiving anticoagulants/patients in heart failure (doesnt induce fluid retention) or those who cannot tolerate NSAIDs for any other reason

57 Side effects colchicine GI Haemorrhagic gastroenteritis neuropathy on prolonged course

58 Acute gout treatment cont. Glucocorticoids –Intra-articular –Oral pred –IM pred

59 Management of Chronic Gout(1) When is gout chronic? Recurrence of acute attacks, presence of tophi, or signs of gouty arthritis may call for preventative treatment. Urate lowering therapy has been shown to be cost effective in patients with 2/more acute attacks/ year

60 Management of chronic gout Decision to treat –Number of attacks –The uric acid level –Presence of reversible risk factors –Tophi –Renal impairment Aim to reduce uric acid to below 0.36mmol/l or lower in the presence of tophi

61 Choice of drug Decrease uric acid production by inhibiting xanthine oxidase –Not used in a history of hypersensitivity Promote renal excretion of urate: uricosurics –Not useful if decreased GFR or history of renal colic

62 Management of Chronic Gout Allopurinol Allopurinol: 1 st line therapy for Chronic Gout Xanthine Oxidase inhibitor Uric acid formation Not to be started in the acute phase Start 2-3 weeks following acute phase. Initiation of allopurinol treatment may trigger acute attack start with NSAID or colchicine & continue for 1 month after hyperuricaemia is corrected

63 Management of chronic gout Allopurinol Dose Initial 100mg OD ( Preferably after food) Then adjusted accordingly to plasma/urinary uric acid levels: Mild: mg daily Moderately severe: mg daily Severe: mg daily Doses> 300mg should be given in divided doses

64 Management of Chronic Gout Allopurinol ctd Caution: Hepatic impairment Renal Impairment Pregnancy Breast Feeding Contraindications: Acute gout ! Side effects ( extensive list in BNF) Rashes: Withdraw therapy(if mild re start but withdraw immediately if reccurs) Neuropathy Blood disorders Renal impairment Hepatoxicity

65 febuxostat Inhibits xanthine oxidase Used if allopurinol not tolerated More expensive!

66 Uricosurics High dose aspirin (note low dose retains urate) Sulfinpyrazone Probenecid Benzbromarone –Use colchicine prophylaxis –Slowly increase dose –Alkaline diuresis with water loading and oral bicarb

67 Management of Chronic gout (5)Sulfinpyrazone A uricosuric drug – increases the excretion of uric acid Used instead of allopurinol, or in conjunction. Dose mg daily, increasing over2-3 weeks to 600mg(rarely 800mg) daily, until serum uric acid levels normal. Cautions: Hepatic impairment Renal impairment Pregnancy Contraindications: in patients with a history of hypersensitivity to aspirin or any other NSAIDwhich includes those in whom attacks of asthma, angioedema, urticaria or rhinitis have been precipitated by aspirin or any other NSAIDs) coagulation defects Hx of MI/Stroke or PAD moderate or severe heart failure active pepticulceration

68 Also address… Obesity Triglycerides Alcohol Hypertension Thiazide therapy- consider alternative

69 At what point should you start allopurinol in a patient with recurrent acute gout? 1.At the beginning of the attack 2.When symptoms lessen 3.When symptoms have subsided 0 of of 120

70 Questions?

71 RA (& Psoriatic Arthritis) 600,000 people in UK many unable to work 42% registered disabled within 3 years 80% moderate to severe disability in 20 years


73 Management MDT Physiotherapy & OT very important –must see early or lose mobility quickly –Range of motion, exercise & how to protect joints NSAIDs consider low-dose corticosteriods (suppress symptoms while DMARDSs have time to work)

74 5-10% very aggressive disease severe disability, co-morbidity, reduced life expectancy, despite conventional therapy Large burden on hospital & social services, carers Successful reduction disease progression may reap long term cost savings e.g. Reduction in need for joint replacement

75 DMARDS: What are they? Disease -modifying antirheumatic drugs DMARDs influence the disease process, unlike NSAIDs which just alleviate symptoms varying and sometimes poorly understood mechanisms of action e.g. methotrexate, sulfasalazine, gold compounds, penicillamine, chloroquine and biologic agents- which target the action of TNF alpha or cd20 or IL6

76 Current Treatment –Early & Aggressive Sulphasalazine, Methotrexate, hydroxychloroquine, Cyclosporin, Leflunomide, (IM Gold) Single or combination Rx (NICE)

77 RA/ PsA Others -D-penicillamine, azathioprine More aggressive (cyclophosphamide, mycophenolate) Any/ all may be ineffective + /or toxic Difficult to predict who will benefit

78 Methotrexate dihydrofolate reductase inhibitor/ folate antagonist – purine antagonist –dihydrofolate reductase reduces folate to FH4, the latter being an essential co-factor in DNA synthesis) uses: RA (1st line DMARD), psoriasis (if severe/ resistant to topical treatments), cancer, Crohns disease

79 CI: severe blood disorders, active infections, immunodeficiency, kidney or liver failure, pregnancy (females and males must avoid conception for at least 3/12 after stopping treatment), breast- feeding cautions: effusions (especially ascites and pleural effusions as these act as storage for the drug thereby increasing its toxicity), UC, peptic ulcer, decreased immunity and prophyria

80 Se: mucositis/ GI upset, myelosuppression, skin reactions. Rarely: pulmonary fibrosis/ pneumonitis, hepatotoxicity, neurotoxicity, seizures, renal failure (due to precipitation of the drug in the renal tubules) interactions: NSAIDs (caution), trimethoprim, co-trimoxazole. These increase toxicity levels

81 dose: methotrexate is usually given orally but can be given im or subcut (intrathecally- only in oncology) Usually 10mg once WEEKLY po Always prescribe folic acid 5mg once weekly max 25mg/week.

82 Pre-tx assessment: FBC, U&E's, creatinine, LFT's, CXR. Monitoring: FBC fortnightly- until 6/52 after last dose increase, and provided it is stable monthly thereafter. LFT's fortnightly U&E's 6-12 monthly (more frequently if there is any reason to suspect deteriorating renal function).

83 Action to be taken (i.e. discuss with rheumatologist) if: WBC <4.0x10^9/l, neutrophils<2.0x10^9 Platelets<150x10^9 /l >2-fold rise in AST, ALT (from upper limit of reference range) fall in albumin Rash or oral ulceration New or increasing dyspnoea or cough MCV>105fl (investigate and if B12 or folate low start appropriate supplementation) Significant deterioration in renal function Abnormal bruising or sore throat

84 note that in addition to absolute values for haematological indices a rapid fall or a consistent downward trend in any value should prompt caution and extra vigilance.

85 Sulphasalazine (EN) 1 st or 2nd choice in UK; mild to moderate or combination not teratogenic or strong immunosupressant Up to three months to take effect GI upset, elevated LFTs, bone marrow depression Monitoring bloods 3 monthly first introduced for antibiotic action in colon, for inflammatory bowel disease. mode of action unclear - ?anti-inflammatory, immunomodulatory and/or antibacterial

86 Corticosteriods start early to tide over or adjunct e.g. to MTX Prednisolone –Modest dose ( mg/day) & decrease –Long term < 10 mg/day –Treat acute flares IA, IM or IV SE: ?

87 start early to tide over or adjunct e.g. to MTX Prednisolone –Modest dose ( mg/day) & decrease –Long term < 10 mg/day –Treat acute flares IA, IM or IV SE: –Wt gain, Cushings, bruising, osteoporosis, infection risk –Discontinuation may be difficult

88 Gold therapy Established> 50 yrs as effective treatment weekly painful injection for 6/52 then 2-4 /52 freq lab monitoring; BM suppression; nephritis Decreases phagocytosis & monocyte activation Inhibits lymphocyte responses SE –35% discontinue –rash & stomatitis –proteinuria –glomerulonephritis

89 Hydroxcloroquine (Plaquinal) Least toxic, no blood tests 6 month response mild RA/ skin or joint lupus Use in increasing methotrxate efficacy decreases antigen processing by macrophages & dendritic cells ocular toxicity (rare- high cumulative dose) –retinal deposits (useful in SLE)

90 Cyclosporin A Nephrotoxicity espec with NSAIDs causes hypertension usually in combination Azathiaprine moderate efficacy, three months to reach efficacy purine antagonist, & interferes with nucleotide synthesis SEs liver toxicity, bone marrow toxicity, monitoring 3/12 –Cyclosporin & azothiaprine used in 2-5% of pts

91 Leflunomide pyrimidine antagonist comparable efficacy to SZP probably comparable toxicity may be tolerated/ effective where other drugs not suitable after methotrexate, before CyA

92 Mycophenolate Mofetil Reversible inhibitor inosine monophosphate dehydrogenase inhibition lymphocyte proliferation/ antibody formation/ adhesion molecule expression Improved safety cf. other immunosupressants SLE nephritis;refractory to cyclophosphamide Scleroderma. (RA)

93 Biologic therapies Evolving group of drugs which more dramatically act as immunomodulaters All increase infection risk List is growing quickly Cost impact huge

94 Anti-TNFs anticytokine therapy specifically target TNF-alpha, which is an important mediator of rheumatoid inflammation uses: RA, psoriatic arthritis and ankylosing spondylitis (crohns, psoriasis, behcets) current guidelines (developed by the British Society for Rheumatology in 2003) restrict their use in the UK to patients who fail two or more conventional second-line agents

95 Pre-administration Disease Activity Score (DAS) of joint count on two occasions (one month apart) before treatment Pre-tx: bloods (FBC, U&E, LFT, ANA and DNA binding, hepatitis), check for TB, do not administer live vaccines, check cardiac function and demyelinating diseases (b/c these are all side-effects of medication) for subcutaneous self-administration – assess patients ability to self-administer; include training plan

96 Adalimumab, Infliximab & Etanercept, certolizumab monoclonal antibody against TNF-alpha or fusion protein (etanercept) against soluble TNF alpha MOA/ a TNF receptor joined to the Fc domain of a human IgG molecule (basically acts to mop up TNF molecules taking them out of circulation). CI/ pregnancy, breastfeeding, severe infections. Severe infections- TB, septicaemia

97 Biological therapy: B-cell depletion, e.g. Rituximab a monoclonal antibody against CD20 which causes lysis of B-cells uses/ lymphoma chemotherapy, RA. used with methotrexate in patients who have had an inadequate response to the anti-TNFs. MOA/ binds to CD20 molecule on the B- cell.

98 Newer biologics Tocilizumab- anti IL6 Abatacept- inhibits costimulation T cells

99 Methotrexate acts as a 1.Purine antagonist 2.Pyramidine antagonist 3.HMG CoA Reductase inhibitor 4.Xanthine Oxidase Inhibitor 0 of of 120

100 References BNF various pharmacology books and websites..

101 Psoriatic arthritis 10% with psoriasis get psoriatic arthritis. Often asymmetrical inflammatory arthropathy NSAIDs & Sulphasalazine in early stages, but neither affects the psoriasis. Methotrexate, CyA & anti-TNF drugs treat both the arthritis & the psoriasis

102 Ankylosing spondylitis DMARDS dismal in treating axial disease NSAIDs for pain & stiffness Exercise & physio Sulphasalazine, & Methotrexate particularly useful with peripheral disease Anti-TNF drugs for axial disease

103 Questions?

104 OSTEOPOROSIS Common, preventable, potentially disabling Worth treating to prevent further #, & improve quality of life Primary Care


106 Socioeconomic Costs Osteoporotic Fractures 200,000 osteoporotic fractures each year cost NHS an estimated £1.5 billion 1 in 2 women experience a fracture by the age in 12 men at risk of fracturing due to osteoporosis at some time in their life. D1202

107 Bone Mass Age (years) Attainment of Peak Bone Mass ConsolidationAge Related Bone Loss Men Women Menopause Fracture threshold 1. Compston JE. Clinical Endocrinology 1990; 33: Age Related Changes in Bone Mass 1 D1202


109 Osteopaenia: T score <-1-<2.5 Osteoporosis ; T score <-2.5 T score means comparing the pts density to a 25 year old female.

110 Risk Factors?

111 Identifying those at risk Predisposing factors- –alcohol, smoking –liver or renal disease –malabsorption, poor Ca intake –Low BMI –thyroid disease, DM, Cushings, hyperparathyroidism –immobility, inflammatory disease, RA –hypogonadism in men

112 Identifying those at risk drugs –Current or planned medium or long term oral corticosteroid use –Anticonvulsants –heparin

113 Management 1. Patient Education Lifestyle Changes: Diet Weight bearing exercise Habits: smoking & excess alcohol Falls Prevention home assessment hip protectors

114 NICE guidance 1 Primary prevention Complex >70 with a risk factor for fracture or an indicator for fracture and t score <-2.5

115 NICE 2 Secondary prevention ie at least 1 fracture Ca + vit D >75yrs bisphosphonate DEXA< and if <2.5 then bisphos <65 treat if T score < -3, or -2.5 plus a risk factor

116 NICE 3 Prevention of steroid induced OP: Lifestyle advice Ca & vit d <65 yrs DEXA, bisphosphonate if osteopaenic >65bisphosphonate

117 Osteoporosis Pharmacology Osteoporosis Bisphosphonates Calcitonin Vitamin D Calcium salts Raloxifene & Teriparatide

118 Calcium Indications: Osteoporosis, Ca 2+, PO 4 Contraindications: Conditions associated with Ca 2+ Side effects: GI disturbances, arrhythmias, bradycardia Interactions: effects potentiated by thiazides and decreased by corticosteroids. Decreases absorption of tetracyclines and biosphosphonates. In osteoporosis, calcium intake double recommended amount reduces rate of bone loss. Dose: 800mg/ day -Adcal D3 forte, calcichew D3 Forte

119 Vit D Examples: ergocalciferol, calciferol, cacitriol Mechanism of action: stimulates absorption of calcium and phosphate from intestine and decreases renal excretion of calcium Indications: Osteoporosis, CRF, osteomalacia, hypoparathyroidism SE: Vascular calcification, nephrocalcinosis, soft- tissue calcification

120 Bisphosphonates Pharmacology Alendronate and residronate orally, pamidronate, ibandronate and zoledronate IV Mechanism of action: inhibit osteoclastic mediated bone resorption (mimics pyrophosphate). Reduces the resorption and formation of hydroxyapatite crystals. Indications: postmenopausal osteoporosis, pagets disease of bone, malignancy-associated hypercalcaemia Adverse effects: bone pain, osteomalacia (etidronate), oesophagitis, nausea, diarrhea 70mg alendronate once a week with ca and vit d

121 Strontium ranelate (Protelos) oral suspension postmenopausal osteoporosis As good as bisphosponates & well tolerated (even in very elderly) Increases bone formation & decreased bone resorption Absorption affected by food & milk/derivatives. Suspension given at bedtime, at least two hours after any food or drink cost per month comparable with branded bisphosphonates & raloxifene.

122 Calcitonin Synthesised and secreted by parafoliicular C cells of thyroid gland Mechanism of action: decreases osteoclastic bone resorption and calcium and phosphate resorption from kidney. Indications: painful osteoporotic fracture osteoporosis, pagets disease of bone, malignancy- associated hypercalcaemia Adverse effects: allergic reaction (flushing, redness or tingling of face), nausea, increased urinary frequency

123 teriparatide rDNA (Forsteo) Synthetic parathyroid hormone; 5X greater BMD in lumbar spine than alendronate after 6/12 BUT daily injections with 20mg Forteo for 18/12 –Teriparatide 20mcg daily - 1 prefilled pen = £750 –Strontium £25.60/month –alendronate once weekly 70mg £1.44/ month stimulates new bone formation

124 Teriperatide cont animal studies increased incidence osteosarcoma Can use for secondary prevention if >65 and bisphosphates not helpful and T score <-4

125 Denosumab Fully human monoclonal antibody to RANK ligand RANK is expressed by pre-osteoclasts, and induces their conversion into mature osteoclasts There for inhibits clasts, reducing bone resorption Sub cut every 6 months Cost similar to branded bisphosphonates

126 Alendronate can commonly cause 1.Lower GI Disturbance 2.Upper GI disturbance 3.LFT Dysfunction 4.Myalgia 0 of of 120

127 So Plenty of hope with new treatments BUT Also plenty of a) COST & b) scope for causing harm

128 Questions?

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