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 colchicineGI
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 www.rheumatology.org.uk 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?