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Treatment of Major Rheumatic Diseases

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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 can’t use NSAIDs (gu / du/ renal/ warfarin) Doesn’t 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 Upper GI complications
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 This slide summarises the overall incidence of emergency upper GI admissions in the UK, & shows that about 18% are attributable to NSAIDs.1 The authors concluded that “NSAID use is associated with significant morbidity & mortality each year in the UK”. Reference 1. Blower AL et al. Aliment Pharmacol Ther 1997;11:


16 GI event may be devoid of warning symptoms
Many patients asymptomatic prior to serious NSAID-associated GI event (bleeding, perforation) n = 141 n = 1,921 19% 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. References 1. Armstrong CP, Blower AL. Gut 1987;28: 2. Singh G et al. Arch Intern Med 1996;156: without symptoms with symptoms

17 prostoglandins

18 NSAIDs: Inhibit cox enzymes Asthma blocked

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 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 selective Paracetamol – acts partly by reducing cytoplasmic peroxidase

22 Older nonselective NSAID’s (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 NSAID’s longer lasting drug – longer relief do not thin the blood therefore can consider co-prescription with warfarin Cons: More expensive compared to traditional NSAID’s 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 NNT 42 to prevent 1 serious GI event
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, H2 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?
3000 6000 12000 24000 of 120


44 Gout Joint inflammation caused by uric acid crystal deposits in the joint space A syndrome of synovitis in response to uric

45 Gout Primary Predominantly secondary 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 8/1000 2-7M:1F Increase in blacks may reflect increased rates of hypertension

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


49 Epidemiology Middle aged men Dietary purine consumption Alcohol
Drugs:Low dose aspirin, diuretics Inherited metabolic abnormalities Called the rich man’s disease because urate is a by product of purine metabolism, purines being found in meat and seafood more expensive foods Inherited metabolic abnormalities….. leading to the over-production or under-excretion of uric acid.

50 Clinical features Gouty Tophi on pinnae Olecranon bursitis
Gouty tophi on hands Gouty nephropathy& stones Large joint oligoarthritis 1st metatarsophalangeal joint arthritis‘podagra’ Classic gout – monoarthritis of the first MTP Attacks are agonising and last 7-10 days. Precipitated by trauma, exercise alcohol excess or starvation.


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 Colchicine 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.

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. See BMJ article ‘colchichine in acute gout’ by Morris et al

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 (doesn’t 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: 1st 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 NSAID—which 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 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 attack When symptoms lessen When symptoms have subsided 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, Crohn’s 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
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 WBC <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<2.0x10^9 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) 1st 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 patient’s 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 Purine antagonist Pyramidine antagonist
HMG CoA Reductase inhibitor Xanthine Oxidase Inhibitor 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 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

107 Age Related Changes in Bone Mass1
Age (years) Attainment of Peak Bone Mass Consolidation Age Related Bone Loss Men Women Menopause Fracture threshold Bone Mass This 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


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 65-74 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 >65 bisphosphonate

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

118 Calcium Indications: Osteoporosis, ↓Ca2+, ↑ PO4
Contraindications: Conditions associated with ↑Ca2+ 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, paget’s 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, paget’s 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
Lower GI Disturbance Upper GI disturbance LFT Dysfunction Myalgia 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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