Treatment of Major Rheumatic Diseases

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Treatment of Major Rheumatic Diseases

• Dr Tanya Potter
• Consultant Rheumatologist

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Aims

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

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

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Osteoarthritis

• most common
• 75 people gt 70 radiographic OA F M 2.51

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Osteoarthritis

• Joint space narrowing
• Osteophytes
• Subchondral sclerosis
• Bone cysts

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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 one button clothes?
• Can make own meals everyday?
• Gives good reliable data

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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
• Muscle strengthening important -esp. quads muscle
• PT OT important
• Use devices for joint protection (canes, walkers
  etc)

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Drugs

• Mild to moderate
• Paracetamol
• Topical agents non steroidals, rubefacients
• Moderate to severe
• As above, plus
• NSAIDs
• combination analgesics (paracet opiods) /
  Opiods/ Tramadol

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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
• Caution with chronic liver dz (hepatotoxicity, gt
  2 gm)
• Thrombocytopaenia, neutropaenia rare

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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

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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)

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NSAIDS

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

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NSAID risk

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

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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

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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
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42
58
81
without symptoms
with symptoms
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prostoglandins
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NSAIDs Inhibit cox enzymes
Asthma
blocked
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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

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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

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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

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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

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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

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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

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CAUTIONS

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

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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.

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SIDE EFFECTS

• GI ND, 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)

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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
• lt 6 discontinue
• Severe toxicity 2.1/100 pt years
• NNT 42 to prevent 1 serious GI event

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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.

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prostoglandins
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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

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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)

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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?

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NSAIDs - past strategies

• Enteric Coating
• Pro-drugs hepatic metabolism
• Gastro-protective agentsPPIs, misoprostol, H2
  blockade

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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

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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

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Visco-supplementation

• OA, where physio, weight loss, simple analgesia
  /- NSAIDs insufficient
• IA steroids not helpful /not lasting
• Awaiting/ unfit for surgery

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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

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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

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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

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Gout

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

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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

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• 2-17 of population are hyperuricaemic
• The higher the uric acid the higher the chance of
  gout
• Self reported adult prevalence of 8/1000
• 2-7M1F
• Increase in blacks may reflect increased rates of
  hypertension

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Figure 4 Simplified diagram of uric acid
production and excretion
2/3
1/3
2/3
1/3
Roddy E et al. (2007) The changing epidemiology
of gout Nat Clin Pract Rheumatol 3 443449
doi10.1038/ncprheum0556
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Epidemiology

• Middle aged men
• Dietary purine consumption
• Alcohol
• DrugsLow dose aspirin, diuretics
• Inherited metabolic abnormalities

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Clinical features

• Gouty Tophi on pinnae
• Olecranon bursitis
• Gouty tophi on hands
• Gouty nephropathy
• stones
• Large joint oligoarthritis
• 1st metatarsophalangeal
• joint arthritispodagra

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erosions with a punched out appearance
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Management

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

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Aspirate joint

• Differential diagnosis monoarthritis?

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Management of Acute Gout (1)

• Goal is to rapidly resolve pain and inflammation
• High doses of NSAID used
• Naproxen. 500mg bd until the attack has passed
• Indomethacin, diclofenac, etoricoxib also used

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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.

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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

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Side effects colchicine

• GI
• Haemorrhagic gastroenteritis
• Myoneuropathy on prolonged course

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Acute gout treatment cont.

• NSAIDs- take early
• Upper limit of usual therapeutic dose
• Selective and non selective
• Glucocorticoids
• Intra-articular
• Oral pred
• IM pred

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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

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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

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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

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Management of Chronic GoutAllopurinol

• 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

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Management of chronic goutAllopurinol Dose

• Initial 100mg OD ( Preferably after food)
• Then adjusted accordingly to plasma/urinary uric
  acid levels
• Mild 100-200mg daily
• Moderately severe 300-600mg daily
• Severe 700-900mg daily

Dosesgt 300mg should be given in divided doses
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Management of Chronic GoutAllopurinol 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

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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

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Management of Chronic gout (5)Sulfinpyrazone

• A uricosuric drug increases the excretion of
  uric acid
• Used instead of allopurinol, or in conjunction.
• Dose 100-200mg 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

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Also address

• Obesity
• Triglycerides
• Alcohol
• Hypertension
• Thiazide therapy- consider alternative

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Questions?
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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

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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)

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• 5-10 very aggressive disease
• 60 moderate
• 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

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DMARDS What are they?

• Disease -modifying antirheumatic drugs, (used in
  other chronic inflammatory diseases as well)
• 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

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Current Treatment

• Early Aggressive
• Sulphasalazine, Methotrexate, Cyclosporin,
  Leflunomide, (IM Gold)
• Single or combination Rx

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RA/ PsA

• Others (D-penicillamine, azathioprine,
  hydroxychloroquine)
• More aggressive (cyclophosphamide, mycophenolate)
• Any/ all may be ineffective /or toxic

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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

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• 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

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• 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

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• dose methotrexate is usually given orally but
  can be given im or subcut (intrathecally- only in
  oncology)
• 7.5mg once WEEKLY
• max 25mg/week.

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• Pre-tx assessment
• FBC, UE'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
• UE's 6-12 monthly (more frequently if there is
  any reason to suspect deteriorating renal
  function).

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• Action to be taken (i.e. discuss with
  rheumatologist) if
• WBC lt4.0x109/l, neutrophilslt2.0x109
• Plateletslt150x109 /l
• gt2-fold rise in AST, ALT (from upper limit of
  reference range)
• Unexplained fall in albumin
• Rash or oral ulceration
• New or increasing dyspnoea or cough
• MCVgt105fl (investigate and if B12 or folate low
  start appropriate supplementation)
• Significant deterioration in renal function
• Abnormal bruising or sore throat

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• 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.

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Sulphasalazine (EN)

• 1st or 2nd choice in UK mild to moderate
• not teratogenic or strong immunosupressant
• Up to three months to take effect
• GI SE, 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

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Corticosteriods

• start early to tide over or adjunct e.g. to MTX
• Prednisolone
• Modest dose (7.5-10 mg/day) decrease
• Long term dose should not exceed 10 mg/day
• Treat acute flares IA IM or IV
• SE
• Wt gain, Cushings, bruising, osteoporosis,
  infection risk
• Discontinuation may be difficult

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Gold therapy

• Establishedgt 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

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Hydroxcloroquine (Plaquinal)

• Least toxic, no blood tests
• 6 month response mild RA/ skin or joint lupus
• decreases antigen processing by macrophages
  dendritic cells
• ocular toxicity (rare- high cumulative dose)
• retinal deposits
• (useful in SLE)

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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

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Leflunomide

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

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Mycophenolate Mofetil

• Reversible inhibitor inosine monophosphate
  dehydrogenase
• inhibition lymphocyte proliferation/ antibody
  formation/ adhesion molecule expression
• Improved safety cf. other immunosupressants
• SLE nephritisrefractory to cyclophosphamide
• Scleroderma.
• (RA)

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Biological therapy Anti-TNFs

• anticytokine therapy
• specifically target TNF-alpha, which is an
  important mediator of rheumatoid inflammation
• uses RA, psoriatic arthritis and ankylosing
  spondylitis
• 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

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Pre-administration

• Disease Activity Score (DAS) of joint count on
  two occasions (one month apart) before treatment
• Pre-tx bloods (FBC, UE, LFT, ANA and DNA
  binding), 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

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Adalimumab, Infliximab Etanercept

• monoclonal antibody against TNF-alpha or fusion
  protein 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

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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.

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References

• www.rheumatology.org.uk
• BNF
• various pharmacology books and websites..

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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

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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

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Questions?
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OSTEOPOROSIS

• Common, preventable, potentially disabling
• Worth treating to prevent further , improve
  quality of life
• Primary Care

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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.

D1202
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Age Related Changes in Bone Mass1
Bone Mass
1. Compston JE. Clinical Endocrinology 1990 33
653-682.
D1202
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• Osteopaenia T score lt-1-lt2.5
• Osteoporosis T score lt-2.5
• T score means comparing the pts density to a 25
  year old female.

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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

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Identifying those at risk

• drugs
• Current or planned long term oral corticosteroid
  use (gt7.5mg prednisolone / day for gt 3/12
• Anticonvulsants
• heparin

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Management 1. Patient Education

• Lifestyle Changes
  Diet
  Weight
  bearing exercise
  Habits smoking excess alcohol
• Falls Prevention
  home assessment
  hip
  protectors
  

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NICE guidance 1

• Primary prevention
• Complex
• gt70 with a risk factor for fracture or an
  indicator for fracture and t score lt-2.5

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NICE 2

• Secondary prevention ie at least 1 fracture Ca
  vit D
• gt75yrs bisphosphonate
• 65-74 DEXAlt and if lt2.5 then bisphos
• lt65 treat if T score lt -3, or -2.5 plus a risk
  factor

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NICE 3

• Prevention of steroid induced OP
• Lifestyle advice
• Ca vit d
• lt65 yrs DEXA, bisphosphonate if osteopaenic
• gt65 bisphosphonate

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Osteoporosis Pharmacology
Bisphosphonates
Calcitonin
Osteoporosis
Vitamin D
Raloxifene Teriparatide
Calcium salts
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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 400-800mg/ day
• Adcal D3 forte, calcichew D3 Forte

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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

• Side effects Vascular calcification,
  nephrocalcinosis, soft-tissue calcification

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Bisphosphonates Pharmacology

• Alendronate and residronate orally, pamidronate,
  ibandronate and zoledronate IV

• Mechanism of action inhibit osteoclastic
  activity. Specifically reduce 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

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Raloxifene (Evista)

• Selective oestrogen receptor modulator (SERM)
  treatment / for prevention of postmenopausal
  osteoporosis
• Demonstrates oestrogen agonist activity on bone
  partially on cholesterol metabolism, but
  oestrogen antagonism in uterine and breast
  tissues.
• ? Benefits in stroke and breast cancer reduction

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Strontium ranelate (Protelos)

• granules for oral suspension
• treatment of postmenopausal osteoporosis
• As good as bisphosponates well tolerated (even
  in very elderly)
• Increases bone formation decr bone resorption
• Absorption affected by food milk/derivatives.
• Suspension should ideally be given at bedtime, at
  least two hours after any food drink
• cost per month comparable with branded
  bisphosphonates raloxifene.

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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 osteoporosis, pagets disease of
  bone, malignancy-associated hypercalcaemia

• Adverse effects allergic reaction (flushing,
  redness or tingling of face), nausea, increased
  urinary frequency

• Dose for postmenopausal osteoporosis 200 units
  (1 spray) intranasally

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teriparatide rDNA (Foresteo)

• 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
  271.88
• Raloxifene 60mg daily
  21.74
• Fosamax once weekly 70mg 23.12
• stimulates new bone formation

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Teriperatide cont

• animal studies increased incidence osteosarcoma
• Can use for secondary prevention if gt65 and
  bisphosphates not helpful and T score lt-4

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Denosumab

• Fully human monoclonab 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

119
So

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

120

• Questions?