Title: Treatment of Major Rheumatic Diseases
1Treatment of Major Rheumatic Diseases
- Dr Tanya Potter
- Consultant Rheumatologist
2Aims
- 1 To pass your exam
- 2 Encourage safe prescribing (and you will
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
4Osteoarthritis
- most common
- 75 people gt 70 radiographic OA F M 2.51
5Osteoarthritis
- Joint space narrowing
- Osteophytes
- Subchondral sclerosis
- Bone cysts
6Management
- 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
7OA - 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)
8Drugs
- Mild to moderate
- Paracetamol
- Topical agents non steroidals, rubefacients
- Moderate to severe
- As above, plus
- NSAIDs
- combination analgesics (paracet opiods) /
Opiods/ Tramadol
9Paracetamol
- 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
10Tramadol
- 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
11Strong 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)
12NSAIDS
- 25 million NSAID prescriptions/ yr in UK
- Non selective
- Aspirin
- Ibuprofen
- Naproxen
- Indomethacin
- Piroxicam
- Selective cox 2 inhibiters
- Celecoxib
- Etoricoxib
- Meloxicam
- etodolac
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 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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16GI 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
42
58
81
without symptoms
with symptoms
17prostoglandins
18NSAIDs Inhibit cox enzymes
Asthma
blocked
19Action
- 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
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 function - COX-2 is produced when joints are inflamed or
injured
21Action
- 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
22Older 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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24COX-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
25Indications
- 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
26CAUTIONS
- Elderly
- Pregnancy- miscarriage, early closure of ductus
arteriosus - Breast feeding
- Coagulation defects
- Renal, cardiac (heart failure/ hypertension/ IHD)
or hepatic impairment
27Contraindications
- 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.
28SIDE 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)
29GI
- 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
30Cardiovascular 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.
31prostoglandins
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 trials - Up to 42 higher risk of MI with selective
- 0.6/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 doses
- In high risk pts, give with PPI
- Which one?
35NSAIDs - past strategies
- Enteric Coating
- Pro-drugs hepatic metabolism
- Gastro-protective agentsPPIs, misoprostol, H2
blockade
36OA- 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
37Visco-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
38Visco-supplementation
- OA, where physio, weight loss, simple analgesia
/- NSAIDs insufficient - IA steroids not helpful /not lasting
- Awaiting/ unfit for surgery
39Capcaisin 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
40What are the alternatives?
- Cod liver oil other fishy oils
- Evening primrose oil
- Borage or Starflower oil
- Change in balance of cell membrane fatty acids
41Alternatives?
- 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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43Gout
- Joint inflammation caused by uric acid crystal
deposits in the joint space -
44Gout
- Primary
- Over production (10)
- Under secretion (90)
- Enzyme mutations
- Predominantly secondary
- Overproduction (mutations, heavy exercise,
obesity) - Under excretion severe renal diseases, drugs,
alcohol, HBP
45- 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
46Figure 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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48Epidemiology
- Middle aged men
- Dietary purine consumption
- Alcohol
- DrugsLow dose aspirin, diuretics
- Inherited metabolic abnormalities
49Clinical features
- Gouty Tophi on pinnae
- Olecranon bursitis
- Gouty tophi on hands
- Gouty nephropathy
- stones
- Large joint oligoarthritis
- 1st metatarsophalangeal
- joint arthritispodagra
50erosions with a punched out appearance
51Management
- Prevent occurrence
- Diagnose
- Treat acute flare
- Reduce risk of further flare
- Reduce associated morbidity secondary to HBP,
hypercholesterolaemia
52Aspirate joint
- Differential diagnosis monoarthritis?
53Management 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
54Management 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.
55Treatment
- 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
56Side effects colchicine
- GI
- Haemorrhagic gastroenteritis
- Myoneuropathy on prolonged course
57Acute gout treatment cont.
- NSAIDs- take early
- Upper limit of usual therapeutic dose
- Selective and non selective
- Glucocorticoids
- Intra-articular
- Oral pred
- IM pred
58Management 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
59Management 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
60Choice 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
61Management 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
62Management 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
63Management 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
64Uricosurics
- 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
65Management 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
66Also address
- Obesity
- Triglycerides
- Alcohol
- Hypertension
- Thiazide therapy- consider alternative
67Questions?
68RA ( 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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70Management
- 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)
71- 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
72DMARDS 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
73Current Treatment
- Early Aggressive
- Sulphasalazine, Methotrexate, Cyclosporin,
Leflunomide, (IM Gold) - Single or combination Rx
74RA/ PsA
- Others (D-penicillamine, azathioprine,
hydroxychloroquine) - More aggressive (cyclophosphamide, mycophenolate)
- Any/ all may be ineffective /or toxic
75Methotrexate
- 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
76- 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
77- 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
78- dose methotrexate is usually given orally but
can be given im or subcut (intrathecally- only in
oncology) - 7.5mg once WEEKLY
- max 25mg/week.
79- 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).
80- 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
81- 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.
82Sulphasalazine (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
83Corticosteriods
- 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
84Gold 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
85Hydroxcloroquine (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)
86Cyclosporin 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
87Leflunomide
- pyrimidine antagonist
- comparable efficacy to SZP
- probably comparable toxicity
- may be tolerated/ effective where other drugs
not suitable - after methotrexate, before CyA
88Mycophenolate 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)
89Biological 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
90Pre-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
91Adalimumab, 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
92Biological 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.
93References
- www.rheumatology.org.uk
- BNF
- various pharmacology books and websites..
94Psoriatic 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
95Ankylosing 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
96Questions?
97OSTEOPOROSIS
- Common, preventable, potentially disabling
- Worth treating to prevent further , improve
quality of life - Primary Care
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99Socioeconomic 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
100Age Related Changes in Bone Mass1
Bone Mass
1. Compston JE. Clinical Endocrinology 1990 33
653-682.
D1202
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102- 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.
103Identifying 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
104Identifying those at risk
- drugs
- Current or planned long term oral corticosteroid
use (gt7.5mg prednisolone / day for gt 3/12 - Anticonvulsants
- heparin
105Management 1. Patient Education
- Lifestyle Changes
Diet
Weight
bearing exercise
Habits smoking excess alcohol - Falls Prevention
home assessment
hip
protectors
106NICE guidance 1
- Primary prevention
- Complex
- gt70 with a risk factor for fracture or an
indicator for fracture and t score lt-2.5
107NICE 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
108NICE 3
- Prevention of steroid induced OP
- Lifestyle advice
- Ca vit d
- lt65 yrs DEXA, bisphosphonate if osteopaenic
- gt65 bisphosphonate
109Osteoporosis Pharmacology
Bisphosphonates
Calcitonin
Osteoporosis
Vitamin D
Raloxifene Teriparatide
Calcium salts
110Calcium
- 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
111Vit 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
112 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
113Raloxifene (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
114Strontium 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.
115Calcitonin
- 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
116teriparatide 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
117Teriperatide cont
- animal studies increased incidence osteosarcoma
- Can use for secondary prevention if gt65 and
bisphosphates not helpful and T score lt-4
118Denosumab
- 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
119So
- Plenty of hope with new treatments
- BUT
- Also plenty of
- a) COST
- b) scope for causing harm
120