Transcript Drugs Used in Treatment of Major Rheumatic Diseases. (therapeutic

Treatment of Major Rheumatic
Diseases
Dr Tanya Potter
Consultant Rheumatologist
Aims
• 1 To pass your exam
• 2 Encourage safe prescribing (and
remember that have an exam in this
also)
• Rheumatoid arthritis (RA) or osteoarthritis
(OA) most common types seen in clinics
(& exams)
• Dramatically improved treatments in past
20 yrs
Osteoarthritis
• most common
• 75% people > 70
radiographic OA
F: M 2.5:1
Osteoarthritis
•
•
•
•
Joint space narrowing
Osteophytes
Subchondral sclerosis
Bone cysts
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
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)
Drugs
• Mild to moderate
– Paracetamol;
– Topical agents: non steroidals, rubefacients
• Moderate to severe
– As above, plus
– NSAIDs
– combination analgesics (paracet +opiods) /
Opiods/ Tramadol
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
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
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)
NSAIDS
• 25 million NSAID prescriptions/ yr in UK
• Non selective
–
–
–
–
–
Aspirin
Ibuprofen
Naproxen
Indomethacin
Piroxicam
• Selective cox 2 inhibiters
–
–
–
–
Celecoxib
Etoricoxib
Meloxicam
etodolac
NSAID risk
• How many GI bleed admissions annually
in the uk?
• What percentage are likely to due to
NSAIDs?
• How many deaths annually?
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
GI event may be devoid of warning symptoms
Many patients asymptomatic prior to serious NSAIDassociated GI event (bleeding, perforation)
n = 141
n = 1,921
19%
58%
42%
without symptoms
81%
with symptoms
prostoglandins
NSAIDs:
Inhibit cox enzymes
Asthma
blocked
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
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
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
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
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 coprescription with warfarin
• Cons:
– More expensive compared to traditional NSAID’s
– Results not as good as endoscopic drug studies suggest
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
CAUTIONS
• Elderly
• Pregnancy- miscarriage, early closure of
ductus arteriosus
• Breast feeding
• Coagulation defects
• Renal, cardiac (heart failure/ hypertension/
IHD) or hepatic impairment
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.
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)
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
Cardiovascular toxicity
• Increased cardiovascular risk of selective
NSAIDs is a problem
• unopposed pro-thrombotic effects of COX1-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.
prostoglandins
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
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)
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?
NSAIDs - past strategies
• Enteric Coating
• Pro-drugs; hepatic metabolism
• Gastro-protective agents:PPIs,
misoprostol, H2 blockade
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
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
Visco-supplementation
• OA, where physio, weight loss, simple
analgesia +/- NSAIDs insufficient
• & IA steroids not helpful /not lasting
• Awaiting/ unfit for surgery
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
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
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
Approximately how many upper GI admissions are
attributable to NSAID use in the UK per annum?
1.
2.
3.
4.
3000
6000
12000
24000
25%
25%
25%
25%
0
of
120
1
2
3
4
Gout
• Joint inflammation caused by uric acid crystal
deposits in the joint space
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
• 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
Figure 4 Simplified diagram of uric acid production and excretion
1/3
2/3
1/3
Roddy E et al. (2007) The changing epidemiology of gout
Nat Clin Pract Rheumatol 3: 443–449 doi:10.1038/ncprheum0556
2/3
Epidemiology
•Middle aged men
•Dietary purine consumption
•Alcohol
•Drugs:Low dose aspirin, diuretics
•Inherited metabolic abnormalities
Clinical features
• Gouty Tophi on pinnae
• Olecranon bursitis
• Gouty tophi on hands
• Gouty nephropathy&
stones
• Large joint oligoarthritis
• 1st metatarsophalangeal
joint arthritis‘podagra’
Management
• Prevent occurrence!
• Diagnose
• Treat acute flare
• Reduce risk of further flare
• Reduce associated morbidity secondary to HBP,
hypercholesterolaemia
Aspirate joint
• Differential diagnosis monoarthritis?
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
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.
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
Side effects colchicine
• GI
• Haemorrhagic gastroenteritis
• neuropathy on prolonged course
Acute gout treatment cont.
• Glucocorticoids
– Intra-articular
– Oral pred
– IM pred
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
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
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
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
Management of chronic gout
Allopurinol Dose
• Initial 100mg OD ( Preferably after food)
• Then adjusted accordingly to plasma/urinary uric acid
levels:
• Mild: 100-200mg daily
• Moderately severe: 300-600mg dailyDoses> 300mg
should be given in
• Severe: 700-900mg daily
divided doses
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
febuxostat
• Inhibits xanthine oxidase
• Used if allopurinol not tolerated
• More expensive!
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
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
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
Also address…
•
•
•
•
•
Obesity
Triglycerides
Alcohol
Hypertension
Thiazide therapy- consider alternative
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
33%
33%
33%
0
of
120
1
2
3
Questions?
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
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)
• 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
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
Current Treatment
– Early & Aggressive
• Sulphasalazine, Methotrexate,
hydroxychloroquine, Cyclosporin,
Leflunomide, (IM Gold)
• Single or combination Rx (NICE)
RA/ PsA
• Others -D-penicillamine, azathioprine
• More aggressive (cyclophosphamide,
mycophenolate)
• Any/ all may be ineffective + /or toxic
• Difficult to predict who will benefit
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
• 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), breastfeeding
• 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
• 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
• 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.
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).
•
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
• 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.
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
Corticosteriods
• start early to tide over or adjunct e.g. to MTX
• Prednisolone
– Modest dose (7.5-10 mg/day) & decrease
– Long term < 10 mg/day
– Treat acute flares IA, IM or IV
• SE: ?
• start early to tide over or adjunct e.g. to MTX
• Prednisolone
– Modest dose (7.5-10 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
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
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
Leflunomide
• pyrimidine antagonist
• comparable efficacy to SZP
• probably comparable toxicity
 may be tolerated/ effective where other drugs
not suitable
 after methotrexate, before CyA
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)
Biologic therapies
• Evolving group of drugs which more
dramatically act as immunomodulaters
• All increase infection risk
• List is growing quickly
• Cost impact huge
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
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
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
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 Bcell.
Newer biologics
• Tocilizumab- anti IL6
• Abatacept- inhibits costimulation T cells
Methotrexate acts as a
1. Purine antagonist
2. Pyramidine
antagonist
3. HMG CoA
Reductase
inhibitor
4. Xanthine Oxidase
Inhibitor
25%
25%
25%
25%
0
of
120
1
2
3
4
References
• www.rheumatology.org.uk
• BNF
• various pharmacology books and
websites..
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
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
Questions?
OSTEOPOROSIS
• Common, preventable, potentially
disabling
• Worth treating to prevent further #, &
improve quality of life
• Primary Care
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
Age Related Changes in Bone Mass1
Attainment of Peak
Bone Mass
Consolidation
Bone
Mass
Age Related Bone Loss
Menopause
Men
Fracture
threshold
Women
0
10
20
30
40
50
60
Age (years)
1. Compston JE. Clinical Endocrinology 1990; 33: 653-682.
D1202
• Osteopaenia: T score <-1-<2.5
• Osteoporosis ; T score <-2.5
• T score means comparing the pts density
to a 25 year old female.
Risk Factors?
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
Identifying those at risk
• drugs
– Current or planned medium or long term oral
corticosteroid use
– Anticonvulsants
– heparin
Management 1. Patient Education
• Lifestyle Changes:
Diet
Weight bearing exercise
Habits: smoking & excess alcohol
• Falls Prevention
home assessment
hip protectors
NICE guidance 1
• Primary prevention
• Complex
• >70 with a risk factor for fracture or an
indicator for fracture and t score <-2.5
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
NICE 3
• Prevention of steroid induced OP:
• Lifestyle advice
• Ca & vit d
• <65 yrs DEXA, bisphosphonate if
osteopaenic
• >65
bisphosphonate
Osteoporosis
Pharmacology
Bisphosphonates
Calcitonin
Osteoporosis
Raloxifene &
Teriparatide
Vitamin D
Calcium salts
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
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, softtissue calcification
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
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.
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, malignancyassociated hypercalcaemia
• Adverse effects: allergic reaction (flushing, redness or
tingling of face), nausea, increased urinary frequency
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
Teriperatide cont
• animal studies increased incidence
osteosarcoma
• Can use for secondary prevention if
>65 and bisphosphates not helpful
and T score <-4
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
Alendronate can commonly cause
1. Lower GI
Disturbance
2. Upper GI
disturbance
3. LFT Dysfunction
4. Myalgia
25%
25%
25%
25%
0
of
120
1
2
3
4
So
• Plenty of hope with new treatments
• BUT
• Also plenty of
• a) COST &
• b) scope for causing harm
• Questions?