Presentation on theme: "Treatment of Major Rheumatic Diseases"— Presentation transcript:
1Treatment of Major Rheumatic Diseases Dr Tanya PotterConsultant Rheumatologist
2Aims1 To pass your exam2 Encourage safe prescribing (and remember that have an exam in this also)
3Rheumatoid arthritis (RA) or osteoarthritis (OA) most common types seen in clinics (& exams) Dramatically improved treatments in past 20 yrs
4Osteoarthritis most common 75% people > 70 radiographic OA F: M 2.5:1
5Osteoarthritis Joint space narrowing Osteophytes Subchondral sclerosis Bone cysts
6Management Pain relief is key Seek improvement in joint mobility or walking timee.g. how long it takes for pt to walk to end of corridorQuality 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
7OA - Goals of Treatment No cure Meds can improve function by reducing painCan limit final impairmentNon-pharmacological and pharmacologicalNon-pharmacologicalPatient education (education leaflets/ websites)Wt loss (10-15 lb weight loss can reduce pain 100%)Every lb gained, X four across weight bearing jointPT: Muscle strengthening important -esp. quads muscleOT: Use devices for joint protection (canes, walkers etc)
8Drugs Mild to moderate Paracetamol; Topical agents: non steroidals, rubefacientsModerate to severeAs above, plusNSAIDscombination analgesics (paracet +opiods) / Opiods/ Tramadol
9Paracetamol Analgesic/ antipyretic Unknown mechanism of action combo with opiods better responsewhen can’t use NSAIDs (gu / du/ renal/ warfarin)Doesn’t alter platelet function (bleeding/ surgery)Safer for elderly1g qds maxCaution with chronic liver dz (hepatotoxicity, > 2 gm)Thrombocytopaenia, neutropaenia rare
10Tramadol Centrally acting analgesic Use in addition to NSAID Effects mu receptors; Same potency as opiodsCan use as adjunctive therapyLess opiod SE; esp constipation/ nausea/ vomitingBalance problemssmaller potential of abuse or dose acceleration, (pt needs more drug in shorter time period) c.f. opiods
11Strong opiods Use in pt with limited options loss of function due to painrenal or heart disease preventing operationSelect pt carefullyUse during period of disease flare, then decrease useLimitationsNausea, vomiting, constipation, ***urinary retentionChronic use leads to physical dependenceCan use with anti-inflammatoryLots of choice (short or long acting, patches)
12NSAIDS 25 million NSAID prescriptions/ yr in UK Non selective AspirinIbuprofenNaproxenIndomethacinPiroxicamSelective cox 2 inhibitersCelecoxibEtoricoxibMeloxicametodolac
13NSAID risk How many GI bleed admissions annually in the uk? What percentage are likely to due to NSAIDs?How many deaths annually?
14Upper GI complications 65,000 emergency upper GI admissions p.a. in UK12,000 of these admissions (including 2,230 deaths) attributable to NSAID useFurther 330 attributable deaths occur in community~2% of NSAID users admitted annually for GI emergenciesThis slide summarises the overall incidence of emergency upper GI admissions in the UK, & shows that about 18% are attributable to NSAIDs.1The authors concluded that “NSAID use is associated with significant morbidity & mortality each year in the UK”.Reference1. Blower AL et al. Aliment Pharmacol Ther 1997;11:
16GI event may be devoid of warning symptoms Many patients asymptomatic prior to serious NSAID-associated GI event (bleeding, perforation)n = 141n = 1,92119%58%42%81%This slide shows results from two studies which indicate that 58-81% of patients with a serious NSAID-associated GI event do not appear to have any prior warning symptoms.References1. Armstrong CP, Blower AL. Gut 1987;28:2. Singh G et al. Arch Intern Med 1996;156:without symptomswith symptoms
19Action Reduce prostaglandin production- less inflammatory mediators Unopposed leukotrione actionAntipyretic effects – partly due to a decrease in prostaglandin that is responsible for elevating the hypothalamic set point for temp control in fever
20COX enzyme Cyclo-oxygenase (COX) has two forms COX-1 : protects the stomach lining from harsh acids and digestive chemicals. It also helps maintain kidney functionCOX-2 : is produced when joints are inflamed or injured
21Action Different NSAID’s 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 selectiveParacetamol – acts partly by reducing cytoplasmic peroxidase
22Older nonselective NSAID’s (Ibuprofen, Naproxen) Block both COX-1 and COX-2, GI upset, bleeding as well as decreasing inflammationAdvice patients to take them with food or a glass of milk and should avoid alcohol.Pros:OTC version of these drugs are inexpensiveLow doses of aspirin taken over long term helps to prevent heart attacks, strokes and bowel cancerCons:GI upset ie nausea, ulcersKidney problems from overuseInteracts with warfarin
24COX-2 inhibitors (Celecoxib, meloxicam, etorocoxib) Target only the COX-2 enzyme that stimulates the inflammatory responsePros :less likely to cause GI upset compared to the older NSAID’slonger lasting drug – longer reliefdo not thin the blood therefore can consider co-prescription with warfarinCons:More expensive compared to traditional NSAID’sResults not as good as endoscopic drug studies suggest
25Indications Commonest use – arthritis ie RA or OA and gout Back pain, sciatica, sprains and strains and rheumatismDental painPost op painPeriod painRenal/ureteric colicFevermigraines
26CAUTIONSElderlyPregnancy- miscarriage, early closure of ductus arteriosusBreast feedingCoagulation defectsRenal, cardiac (heart failure/ hypertension/ IHD) or hepatic impairment
27Contraindications Severe heart failure COX-2 : IHD, stroke, PVD and moderate to severe heart failureCSM advice – previous or active peptic ulcerationhypersensitivity to aspirin or any NSAID – which includes those in whom attacks of asthma, angioedema, urticaria or rhinitis have been precipitated.
29GI NNT 42 to prevent 1 serious GI event Similar anti inflammatory effects of selective and non selective NSAIDsNon selective:15-40% dyspepsia, nausea, abdo pain10% discontinueSevere GI toxicity 4.5/100pt yearsSelective Cox 2 inhibitersSimilar GI symptoms< 6% discontinueSevere toxicity 2.1/100 pt yearsNNT 42 to prevent 1 serious GI event
30Cardiovascular toxicity Increased cardiovascular risk of selective NSAIDs is a problemunopposed pro-thrombotic effects of COX-1-mediated production of thromboxane A2Also, coxibs effects on blood pressure and renal function could turn out to be more detrimental than those of conventional NSAIDs.
32CV 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 trialsUp to 42% higher risk of MI with selective0.6%/yr vs 0.3%/yr
33All 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)
34Naproxen Pain and inflammation in rheumatic disorders 0.5-1g / day in 1-3 divided dosesIn high risk pts, give with PPIWhich one?
36OA- Adjunctive therapy Intra articular steroids plus local anesthetic for joint inflammationDecrease production of inflammatory mediatorsCan last a 3-6 months; use with physioProbably can be done safely up to four times a yearnot too frequently; can effect the cartilage
37Visco-supplementation Crosslinked hyaluronic acid polymersOA (knee)Intra-articular injections X 3-5Change viscosity in jointPain relief with improved mobilitySuccess rate is 50-70% for up to 4-6 monthsno systemic SE
38Visco-supplementation OA, where physio, weight loss, simple analgesia +/- NSAIDs insufficient& IA steroids not helpful /not lastingAwaiting/ unfit for surgery
39Capcaisin cream 0.025% preparation (Zacin) Depletes Substance P from nerve endingsSlow to act (1/12 to max effect)More effective than topical NSAIDsMay reduce analgesic requirement
40What are the alternatives? Cod liver oil & other fishy oilsEvening primrose oilBorage or Starflower oilChange in balance of cell membrane fatty acids
41Alternatives? Glucosamine 1.5 gram/day substrate for glucosaminoglycansPain relief & mobilityPossible 10-25% analgesic effect-disease modifier ?? Nutrition for cartilage? Stimulate metabolismVitamin CFramingham study results show reduced pain OA of knee & hipmay improve integrity of cartilage
42Approximately how many upper GI admissions are attributable to NSAID use in the UK per annum? 300060001200024000of120
44GoutJoint inflammation caused by uric acid crystal deposits in the joint spaceA syndrome of synovitis in response to uric
45Gout Primary Predominantly secondary Over production (10%) Under secretion (90%)Enzyme mutationsPredominantly secondaryOverproduction (mutations, heavy exercise, obesity)Under excretion severe renal diseases, drugs, alcohol, HBP
462-17% of population are hyperuricaemic The higher the uric acid the higher the chance of goutSelf reported adult prevalence of 8/10002-7M:1FIncrease in blacks may reflect increased rates of hypertension
47Figure 4 Simplified diagram of uric acid production and excretion 1/3 2/32/31/3Roddy E et al. (2007) The changing epidemiology of goutNat Clin Pract Rheumatol 3: 443–449 doi: /ncprheum0556
49Epidemiology Middle aged men Dietary purine consumption Alcohol Drugs:Low dose aspirin, diureticsInherited metabolic abnormalitiesCalled the rich man’s disease because urate is a by product of purine metabolism, purines being found in meat and seafood more expensive foodsInherited metabolic abnormalities….. leading to the over-production or under-excretion of uric acid.
50Clinical features Gouty Tophi on pinnae Olecranon bursitis Gouty tophi on handsGouty nephropathy&stonesLarge joint oligoarthritis1st metatarsophalangealjoint arthritis‘podagra’Classic gout – monoarthritis of the first MTPAttacks are agonising and last 7-10 days. Precipitated by trauma, exercise alcohol excess or starvation.
54Management of Acute Gout (1) Goal is to rapidly resolve pain and inflammationNon pharmacological- ice packs etcHigh doses of NSAID used:Naproxen. 500mg bd until the attack has passedIndomethacin, diclofenac, etoricoxib also usedColchicine inhibits microtubule polymerization by binding to tubulin, one of the main constituents of microtubules. This action results in the inhibition of neutrophil motility and so produces an anti-inflammatory response.
55Management of Acute gout(2) Alternative to NSAIDsColchicineinhibits microtubule polymerization by binding to tubulin,inhibition of neutrophil motility and so produces an anti-inflammatory response.See BMJ article ‘colchichine in acute gout’ by Morris et al
56Treatment Colchicine 500mg bd to tds DO NOT USE BNF DOSE OF COLCHICINE 2/3 will respond cf 1/3 placebopeak plasma concentration 1-2 hrs and a half life of 4 hrsMetabolised by the liver with possible enterohepatic circulation20% excreted unchanged in urineAvoid IVGood alternative for patients receiving anticoagulants/patients in heart failure (doesn’t induce fluid retention) or those who cannot tolerate NSAIDs for any other reason
57Side effects colchicine GIHaemorrhagic gastroenteritisneuropathy on prolonged course
58Acute gout treatment cont. GlucocorticoidsIntra-articularOral predIM pred
59Management 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
60Management of chronic gout Decision to treatNumber of attacksThe uric acid levelPresence of reversible risk factorsTophiRenal impairmentAim to reduce uric acid to below 0.36mmol/l or lower in the presence of tophi
61Choice of drugDecrease uric acid production by inhibiting xanthine oxidaseNot used in a history of hypersensitivityPromote renal excretion of urate: uricosuricsNot useful if decreased GFR or history of renal colic
62Management of Chronic Gout Allopurinol Allopurinol: 1st line therapy for Chronic GoutXanthine Oxidase inhibitorUric acid formationNot to be started in the acute phaseStart 2-3 weeks following acute phase.Initiation of allopurinol treatment may trigger acute attackstart with NSAID or colchicine & continue for 1 month after hyperuricaemia is corrected
63Management of chronic gout Allopurinol Dose Initial 100mg OD ( Preferably after food)Then adjusted accordingly to plasma/urinary uric acid levels:Mild: mg dailyModerately severe: mg dailySevere: mg dailyDoses> 300mg should be given in divided doses
64Management of Chronic Gout Allopurinol ctd Caution:Hepatic impairmentRenal ImpairmentPregnancyBreast FeedingContraindications:Acute gout!Side effects ( extensive list in BNF)Rashes: Withdraw therapy(if mild re start but withdraw immediately if reccurs)NeuropathyBlood disordersRenal impairmentHepatoxicity
65febuxostat Inhibits xanthine oxidase Used if allopurinol not tolerated More expensive!
66Uricosurics High dose aspirin (note low dose retains urate) SulfinpyrazoneProbenecidBenzbromaroneUse colchicine prophylaxisSlowly increase doseAlkaline diuresis with water loading and oral bicarb
67Management of Chronic gout (5)Sulfinpyrazone A uricosuric drug – increases the excretion of uric acidUsed 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 impairmentRenal impairmentPregnancyContraindications:in patients with a history of hypersensitivity to aspirin or any other NSAID—which includes those in whom attacks of asthma, angioedema, urticaria or rhinitis have been precipitated by aspirin or any other NSAIDs)coagulation defectsHx of MI/Stroke or PADmoderate or severe heart failureactive pepticulceration
68Also address… Obesity Triglycerides Alcohol Hypertension Thiazide therapy- consider alternative
69At the beginning of the attack When symptoms lessen At what point should you start allopurinol in a patient with recurrent acute gout?At the beginning of the attackWhen symptoms lessenWhen symptoms have subsidedof120
73Management MDT Physiotherapy & OT very important must see early or lose mobility quicklyRange of motion, exercise & how to protect jointsNSAIDsconsider low-dose corticosteriods (suppress symptoms while DMARDSs have time to work)
745-10% very aggressive disease severe disability, co-morbidity, reduced life expectancy, despite conventional therapyLarge burden on hospital & social services, carersSuccessful reduction disease progression may reap long term cost savingse.g. Reduction in need for joint replacement
75DMARDS: What are they? Disease -modifying antirheumatic drugs DMARDs influence the disease process, unlike NSAIDs which just alleviate symptomsvarying and sometimes poorly understood mechanisms of actione.g. methotrexate, sulfasalazine, gold compounds, penicillamine, chloroquine and biologic agents- which target the action of TNF alpha or cd20 or IL6
77RA/ PsA Others -D-penicillamine, azathioprine More aggressive (cyclophosphamide, mycophenolate)Any/ all may be ineffective + /or toxicDifficult to predict who will benefit
78Methotrexatedihydrofolate reductase inhibitor/ folate antagonist – purine antagonistdihydrofolate 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, Crohn’s disease
79CI: 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-feedingcautions: 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
80Se: mucositis/ GI upset, myelosuppression, skin reactions 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
81dose: methotrexate is usually given orally but can be given im or subcut (intrathecally- only in oncology)Usually 10mg once WEEKLY poAlways prescribe folic acid 5mg once weeklymax 25mg/week.
82Pre-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 fortnightlyU&E's 6-12 monthly (more frequently if there is any reason to suspect deteriorating renal function).
83WBC <4.0x10^9/l, neutrophils<2.0x10^9 Platelets<150x10^9 /l Action to be taken (i.e. discuss with rheumatologist) if:WBC <4.0x10^9/l, neutrophils<2.0x10^9Platelets<150x10^9 /l>2-fold rise in AST, ALT (from upper limit of reference range)fall in albuminRash or oral ulcerationNew or increasing dyspnoea or coughMCV>105fl (investigate and if B12 or folate low start appropriate supplementation)Significant deterioration in renal functionAbnormal bruising or sore throat
84note 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.
85Sulphasalazine (EN)1st or 2nd choice in UK; mild to moderate or combinationnot teratogenic or strong immunosupressantUp to three months to take effectGI upset, elevated LFTs, bone marrow depressionMonitoring bloods 3 monthlyfirst introduced for antibiotic action in colon, for inflammatory bowel disease.mode of action unclear - ?anti-inflammatory, immunomodulatory and/or antibacterial
86Corticosteriods start early to tide over or adjunct e.g. to MTX PrednisoloneModest dose ( mg/day) & decreaseLong term < 10 mg/dayTreat acute flares IA, IM or IVSE: ?
87start early to tide over or adjunct e.g. to MTX PrednisoloneModest dose ( mg/day) & decreaseLong term < 10 mg/dayTreat acute flares IA, IM or IVSE:Wt gain, Cushings, bruising, osteoporosis, infection riskDiscontinuation may be difficult
88Gold therapy Established> 50 yrs as effective treatment weekly painful injection for 6/52 then 2-4 /52freq lab monitoring; BM suppression; nephritisDecreases phagocytosis & monocyte activationInhibits lymphocyte responsesSE35% discontinuerash & stomatitisproteinuriaglomerulonephritis
89Hydroxcloroquine (Plaquinal) Least toxic, no blood tests6 month response mild RA/ skin or joint lupusUse in increasing methotrxate efficacydecreases antigen processing by macrophages & dendritic cellsocular toxicity (rare- high cumulative dose)retinal deposits(useful in SLE)
90Cyclosporin A Nephrotoxicity espec with NSAIDs causes hypertension usually in combinationAzathiaprinemoderate efficacy, three months to reach efficacypurine antagonist, & interferes with nucleotide synthesisSEs liver toxicity, bone marrow toxicity, monitoring 3/12Cyclosporin & azothiaprine used in 2-5% of pts
91Leflunomide pyrimidine antagonist comparable efficacy to SZP probably comparable toxicitymay be tolerated/ effective where other drugs not suitableafter methotrexate, before CyA
93Biologic therapiesEvolving group of drugs which more dramatically act as immunomodulatersAll increase infection riskList is growing quicklyCost impact huge
94Anti-TNFs anticytokine therapy specifically target TNF-alpha, which is an important mediator of rheumatoid inflammationuses: 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
95Pre-administrationDisease Activity Score (DAS) of joint count on two occasions (one month apart) before treatmentPre-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 patient’s ability to self-administer; include training plan
96Adalimumab, Infliximab & Etanercept, certolizumab monoclonal antibody against TNF-alpha or fusion protein (etanercept) against soluble TNF alphaMOA/ 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
97Biological therapy: B-cell depletion, e.g. Rituximab a monoclonal antibody against CD20 which causes lysis of B-cellsuses/ 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.
98Newer biologics Tocilizumab- anti IL6 Abatacept- inhibits costimulation T cells
99Methotrexate acts as a Purine antagonist Pyramidine antagonist HMG CoA Reductase inhibitorXanthine Oxidase Inhibitorof120
100References www.rheumatology.org.uk BNF various pharmacology books and websites..
101Psoriatic arthritis 10% with psoriasis get psoriatic arthritis. Often asymmetrical inflammatory arthropathyNSAIDs & Sulphasalazine in early stages, but neither affects the psoriasis.Methotrexate, CyA & anti-TNF drugs treat both the arthritis & the psoriasis
102Ankylosing spondylitis DMARDS dismal in treating axial diseaseNSAIDs for pain & stiffnessExercise & physioSulphasalazine, & Methotrexate particularly useful with peripheral diseaseAnti-TNF drugs for axial disease
106Socioeconomic Costs Osteoporotic Fractures 200,000 osteoporotic fractures each year cost NHS an estimated £1.5 billion1 in 2 women experience a fracture by the age 70.1 in 12 men at risk of fracturing due to osteoporosis at some time in their life.Economic costs of osteoporotic fractures in the UK are a significant burden on the NHS budget. The figure quoted from Torgeson (1999) is £1.5 billion & is likely to rise with age & time. This includes acute hospital & institutional care costs & related social costs such as caring for relatives with a fracture. This huge cost can be explained by the frequency of osteoporotic fractures. Indeed, 1 in 2 women experience a fracture by the age of 70 years, in addition, 1 in 12 men are at risk of fracturing due to osteoporosis at some time in their life.D1202
107Age Related Changes in Bone Mass1 Age (years)Attainment of PeakBone MassConsolidationAge Related Bone LossMenWomenMenopauseFracturethresholdBoneMassThis figure by Compston (1990), illustrates the changes in bone mass throughout life & shows the rapid bone loss that occurs at the menopause. Bone mass in both men & women increases until a peak is attained at around age 30. In both sexes, a slow rate of bone loss starts at around age 40. However, in women, the accelerated postmenopausal phase of bone loss is superimposed on top of this slow loss phase. Rates of bone loss in postmenopausal women can be as great as 5-6% per year. In women, oestrogen deficiency is the major determinant of bone loss after the menopause due to the removal of the ‘brakes’ from osteoclastic activity.The accelerated bone loss is important to remember when looking at preventative therapies for osteoporosis. Unlike treatment for the established disease when relatively large increases in bone mass are observed in response to therapy, a preventative strategy may be said to have been effective if the bone mass is maintained.National Osteoporosis Society, Menopause & osteoporosis therapy - GP manual 1993.National Osteoporosis Society, Priorities for Prevention.Hosking D J et al, J. Bone Miner. Res., 1996: 11 (1); S133, 153.1. Compston JE. Clinical Endocrinology 1990; 33:D1202
111Identifying those at risk Predisposing factors-alcohol, smokingliver or renal diseasemalabsorption, poor Ca intakeLow BMIthyroid disease, DM, Cushings, hyperparathyroidismimmobility, inflammatory disease, RAhypogonadism in men
112Identifying those at risk drugsCurrent or planned medium or long term oral corticosteroid useAnticonvulsantsheparin
113Management 1. Patient Education Lifestyle Changes: Diet Weight bearing exercise Habits: smoking & excess alcoholFalls Prevention home assessment hip protectors
114NICE guidance 1 Primary prevention Complex >70 with a risk factor for fracture or an indicator for fracture and t score <-2.5
115NICE 2 Secondary prevention ie at least 1 fracture Ca + vit D >75yrs bisphosphonate65-74 DEXA< and if <2.5 then bisphos<65 treat if T score < -3, or -2.5 plus a risk factor
116NICE 3 Prevention of steroid induced OP: Lifestyle advice Ca & vit d <65 yrs DEXA, bisphosphonate if osteopaenic>65 bisphosphonate
118Calcium Indications: Osteoporosis, ↓Ca2+, ↑ PO4 Contraindications: Conditions associated with ↑Ca2+Side effects: GI disturbances, arrhythmias, bradycardiaInteractions: 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
119Vit D Examples: ergocalciferol, calciferol, cacitriol Mechanism of action: stimulates absorption of calcium and phosphate from intestine and decreases renal excretion of calciumIndications: Osteoporosis, CRF, osteomalacia, hypoparathyroidismSE: Vascular calcification, nephrocalcinosis, soft-tissue calcification
120Bisphosphonates Pharmacology Alendronate and residronate orally, pamidronate, ibandronate and zoledronate IVMechanism of action: inhibit osteoclastic mediated bone resorption (mimics pyrophosphate). Reduces the resorption and formation of hydroxyapatite crystals.Indications: postmenopausal osteoporosis, paget’s disease of bone, malignancy-associated hypercalcaemiaAdverse effects: bone pain, osteomalacia (etidronate), oesophagitis, nausea, diarrhea70mg alendronate once a week with ca and vit d
121Strontium ranelate (Protelos) oral suspensionpostmenopausal osteoporosisAs good as bisphosponates & well tolerated (even in very elderly)Increases bone formation & decreased bone resorptionAbsorption affected by food & milk/derivatives.Suspension given at bedtime, at least two hours after any food or drinkcost per month comparable with branded bisphosphonates & raloxifene.
122CalcitoninSynthesised and secreted by parafoliicular C cells of thyroid glandMechanism of action: decreases osteoclastic bone resorption and calcium and phosphate resorption from kidney.Indications: painful osteoporotic fracture osteoporosis, paget’s disease of bone, malignancy-associated hypercalcaemiaAdverse effects: allergic reaction (flushing, redness or tingling of face), nausea, increased urinary frequency
123teriparatide rDNA (Forsteo) Synthetic parathyroid hormone; 5X greater BMD in lumbar spine than alendronate after 6/12BUT daily injections with 20mg Forteo for 18/12Teriparatide 20mcg daily - 1 prefilled pen = £750Strontium £25.60/monthalendronate once weekly 70mg £1.44/ monthstimulates new bone formation
124Teriperatide cont animal studies increased incidence osteosarcoma Can use for secondary prevention if >65 and bisphosphates not helpful and T score <-4
125Denosumab Fully human monoclonal antibody to RANK ligand RANK is expressed by pre-osteoclasts, and induces their conversion into mature osteoclastsThere for inhibits clasts, reducing bone resorptionSub cut every 6 monthsCost similar to branded bisphosphonates
126Alendronate can commonly cause Lower GI DisturbanceUpper GI disturbanceLFT DysfunctionMyalgiaof120
127So Plenty of hope with new treatments BUT Also plenty of a) COST & b) scope for causing harm