Practical Management of Osteoporosis Dr Sanjeev Patel BM DM

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Practical Management of Osteoporosis

• Dr Sanjeev Patel BM DM FRCP
• Consultant Senior Lecturer in Rheumatology
• Epsom St Helier University Hospitals
• St Georges, Unversity of London

2
Overview

• Bone
• Osteoporosis epidemiology
• Mechanisms of fractures
• Skeletal
• Non-skeletal risk factors
• Absolute fracture risk
• Secondary prevention of fractures
• Review of drug therapies
• Cases

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Changes in bone resulting in osteoporosis
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(No Transcript)
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Principal sites of osteoporotic fractures
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Projected number of osteoporotic hip fractures
worldwide
Total number ofhip fractures1990 1.66
million 2050 6.26 million
742
378
Estimated no of hip fractures (1000s)
Adapted from Cooper C et al, Osteoporosis Int,
19922285-289
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Morbidity associated with osteoporotic fractures
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Fracture risk assessment

• History
• Previous fracture
• Family history
• Steroid therapy
• Skeletal risk factors
• Variables that determine bone strength
• Nonskeletal risk factors
• Fall risk

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Pathogenesis of osteoporotic fractures
Neuromuscular function Environmental hazards Time
spent at risk
Risk of fall Force of impact Strength of
bone
Type of fall Protective responses Energy
absorption
Risk of fracture
Bone mineral density Geometry of bone Quality of
bone
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Pathogenesis of osteoporotic fractures
Neuromuscular function Environmental hazards Time
spent at risk
Risk of fall Force of impact Strength of
bone
Type of fall Protective responses Energy
absorption
Risk of fracture
Bone mineral density Geometry of bone Quality of
bone
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Falls and osteoporotic fractures
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Type of fall is important
MOVIE
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Modifiable fall-related risk factors
Eyesight
Crude RR risk of hip fracture
EPIDOS (Dargent-Molina Lancet 1996)

• Fall risk and BMD
• Study of 150 women (mean age 78 yrs) at SGH
• Improvement in VA with pinhole
• 28 in one eye
• 11 in both eyes Durward et al Lancet 1999

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Modifiable fall-related risk factors
Eyesight - cataracts
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Modifiable fall-related risk factors
Eyesight - cataracts
306 women
Surgery
Expedited 4 weeks
Routine 12 months
Harwood et al B J Opth 2005
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Modifiable fall-related risk factors
Eyesight - cataracts
During 12 months follow-up Falling - reduced
by 34 in operated group (rate ratio 0.66 95
CI 0.45 to 0.96 p 0.03) Fractures - 3
in operated group vs 8 in controls (p0.04)
Harwood et al B J Opth 2005
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Physical activity and fall reductionsThai Chi
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Environmental measures and falls reductions
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Reducing risk of falling and fractures

• Patient specific measures
• Multiple risk factor intervention

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Pathogenesis of osteoporotic fractures
Neuromuscular function Environmental hazards Time
spent at risk
Risk of fall Force of impact Strength of
bone
Type of fall Protective responses Energy
absorption
Risk of fracture
Bone mineral density Geometry of bone Quality of
bone
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Variables determining bone strength

• Bone density
• Bone turnover
• Bone quality
• Bone architecture
• Bone mineralisation
• Bone cell apoptosis
• Bone size
• Bone geometry

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Variables determining bone strength

• Bone density
• Bone turnover
• Bone quality
• Bone architecture
• Bone mineralisation
• Bone cell apoptosis
• Bone size
• Bone geometry

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Changes in bone density with age
Attainment of peak bone density
Maintenance of bone density
Oestrogen related bone loss Age related bone loss
Bone density
0 20 50 65 100
Age (years)
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Bone density measurement
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Variables determining bone strength

• Bone density
• Bone turnover
• Bone quality
• Bone architecture
• Bone mineralisation
• Bone cell apoptosis
• Bone size
• Bone geometry

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Variables determining bone strength

• Bone density
• Bone turnover
• Bone quality
• Bone architecture
• Bone mineralisation
• Bone cell apoptosis
• Bone size
• Bone geometry

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Variables determining bone strength

• Bone density
• Bone turnover
• Bone quality
• Bone architecture
• Bone mineralisation
• Bone cell apoptosis
• Bone size
• Bone geometry

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Variables determining bone strength

• Bone density
• Bone turnover
• Bone quality
• Bone architecture
• Bone mineralisation
• Bone cell apoptosis
• Bone size
• Bone geometry

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Variables determining bone strength

• Bone density
• Bone turnover
• Bone quality
• Bone architecture
• Bone mineralisation
• Bone cell apoptosis
• Bone size
• Bone geometry

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Variables determining bone strength

• Bone density
• Bone turnover
• Bone quality
• Bone architecture
• Bone mineralisation
• Bone cell apoptosis
• Bone size
• Bone geometry

Women Men
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Variables determining bone strength

• Bone density
• Bone turnover
• Bone quality
• Bone architecture
• Bone mineralisation
• Bone cell apoptosis
• Bone size
• Bone geometry

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Bone strength

• Bone density best surrogate
• We can measure
• Predictive of
• Precise
• Reproducible

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Bone density cholesterol as predictors of
clinical events
KANIS JA Osteoporoses, Blackwell Science (1994)
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Fracture risk assessment

• Current
• T scores
• often in isolation of clinical risk factors
• Relative risk important
• Future
• T-scores with clinical risk factors
• Absolute fracture risk
• Develop cost-effectiveness threshold

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Absolute fracture risk

• Strong analogy with cardiovascular diseases
• Risk of event increases with
• increasing number of risk factors
• If a clinical event has occurred already (e.g
  MI, stroke, fracture)

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CVS events compared to fractures

• CVS events
• Age
• Raised cholesterol
• Raised blood pressure
• Diabetes
• Smoking
• FH
• Previous MI / stroke

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CVS events compared to fractures

• CVS events
• Age
• Raised cholesterol
• Raised blood pressure
• Diabetes
• Smoking
• FH
• Previous MI / stroke

• Osteoporotic fractures
• Age
• Low bone density
• Secondary causes of low bone density e.g.
  steroids
• FH
• Increased fall risk
• Previous fracture

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Joint British Societies Coronary Risk Prediction
Chart
Age Gender Diabetes Blood pressure Cholesterol
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NZ Cardiovascular absolute risk tables
New Zealand
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From T-scores to absolute fracture risk
Simonski et al Canadian Assoc Radiol Journal
200556178-188
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Absolute fracture risk

• Combination of BMD (T score)
• Clinical risk factors
• Use a 10 year period
• Define the 10 year absolute fracture risk
  threshold that will be cost effective
• Work is ongoing

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Secondary prevention
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Secondary prevention of cardiovascular diseases

• Secondary prevention means
• Treating a patient with a new diagnosis of high
  cholesterol or hypertension
• Treating hypercholesterolaemia or hypertension in
  a patient with diabetes
• Treating hypercholesterolaemia or hypertension in
  patient with a recent MI

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Secondary prevention of cardiovascular diseases

• As a GP
• I systematically practice secondary prevention
  of CVS disease
• I usually practice secondary prevention of CVS
  disease
• I occasionally consider secondary prevention of
  CVS disease
• I rarely consider secondary prevention of CVS
  disease

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Secondary prevention of osteoporotic fracture

• Secondary prevention of osteoporosis means
• Treating a patient with a low bone density on a
  DXA scan (T score lt -2.5)
• Treating patients who are on steroids
• Treating low bone density in a patient with a
  recent low trauma fracture

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Secondary prevention of osteoporotic fracture

• As a GP
• I systematically practice secondary prevention
  of osteoporosis
• I usually practice secondary prevention of
  osteoporosis
• I occasionally consider secondary prevention of
  osteoporosis
• I rarely consider secondary prevention of
  osteoporosis

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Secondary prevention of osteoporotic fracture

• Re-fracture rates can be halved
• Relative risk reduction is independent of
  absolute fracture risk
• How do we find fracture patients ?

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UK Osteoporosis Falls GuidelinesJanuary 2005
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Fracture-osteoporosis epidemiology
UK population 60.5 million
Curr Med Res Opin 2005214475-482 Brankin E et
al
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Secondary prevention of osteoporosis

• Best done by a systematic hospital based service
  (e.g. fracture liaison service)
• Secondary care identifying patients and GPs
  treating has limited impact
• Empowering the patient may help

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Secondary prevention after Colles fractures
empowering the patient
Patel et al Rheumatology 200443387389
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Assessment of a patient with an osteoporotic
fracture

• Fracture
• Spontaneous
• Following a fall from the upright position
• Investigate
• Exclude secondary causes of osteoporosis
• Assess severity of osteoporosis
• Assess fall risk
• Treatment
• (Guided by absolute fracture risk)
• Increase bone strength
• Reduce risk of falling

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Improving bone strength

• Physical activity
• Main role is to reduce falls
• Drug therapy

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Bone active drugs

• Anti-resorptive drugs
• Oestrogen
• SERMs (raloxifene)
• Bisphosphonates
• Anabolic drugs
• Teriparatide
• Dual Acting Bone Active (DABA)
• Strontium ranelate

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Bone active drugs

• Anti-resorptive drugs
• Oestrogen
• SERMs (raloxifene)
• Bisphosphonates
• Anabolic drugs
• Teriparatide
• Dual Acting Bone Active (DABA)
• Strontium ranelate

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Hormone Replacement Therapy

• Oestrogens / Progestogens
• More data available about long-term benefits and
  risk

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Prescribing HRT-general points

• Short - term use of HRT for menopausal symptoms
  is reasonable
• For long term use women should be counselled
  about benefits versus risk
• Treatment decisions should be individualised and
  reviewed regularly

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HRT and osteoporosis

• Newly diagnosed women
• Reserve for women with menopausal symptoms
• Use only for 3 to 5 years
• Women on HRT known to have osteoporosis
• Use non-HRT drugs particularly following
  prolonged use
• Women on HRT not known to have osteoporosis
• Measure bone density and treat accordingly

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Action of oestrogen and SERMs
Oestrogen Tamoxifen Raloxifene Bone ? ? ? ?
? ? CVS ? ? ? ? ? ? Symptoms ? x x Bre
ast x ? ? ? ? Uterus x x ? ?
60
25
RR 0.70 (95 CI 0.56, 0.86)
20
30
15
of Women with Incident Vertebral Fracture
10
RR 0.50 (95 CI 0.29, 0.71)
5
50
0
Without Prevalent Vertebral Fractures
With Prevalent Vertebral Fractures
10.Ettinger B et al. JAMA 1999 282637-45.
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Raloxifene - summary

• Reduces risk of vertebral fractures
• No effect on non-vertebral fractures
• No increased risk of breast cancer
• CVS events ?
• Easy to take
• Does not alleviate menopausal symptoms
• Can increase risk of VTE

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Bone active drugs

• Anti-resorptive drugs
• Oestrogen
• SERMs (raloxifene)
• Bisphosphonates
• Anabolic drugs
• Teriparatide
• Dual Acting Bone Active (DABA)
• Strontium ranelate

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Bisphosphonates

• Oral weekly
• Alendronate (Fosamax)
• Risedronate (Actonel)
• Monthly oral
• Ibandronate (Bonviva)
• Intravenous
• Ibandronate (3 monthly)

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Alendronate and vertebral fractures
Reduction 47, p lt 0.001
Reduction 44, p 0.001
Vertebral Fractures Fracture Status at baseline
Black DM, et al. Lancet. 1996 3481535-1541.
Cummings SR, et al. JAMA. 1998 2802077-2082.
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Risedronate and hip fractures
6
60
CI(20, 80) p0.003 NNT 28
5
4
Percent () of Patients
3
Control
2
1
Risedronate
0
0
12
24
36
Months
Patients with established PMO aged 70-79 yrs
McClung et al. NEJM 2001 344(5) 333-340.
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Ibandronate

• Newest licensed bisphosphonate
• Good data for vertebral fracture reduction
• Intermittent therapy
• Oral monthly 150mg dose
• Intravenous 3 monthly 3 mg dose

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Ibandronate Compliance may be better than weekly
bisphosphonate
Time-to-failure-to-persist data for the ITT
population were used to estimate the probability
of persistence at each time-point
Int J Clin Practice 200660896-905 Cooper A et
al
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Bisphosphonates - summary

• Etidronate (Didronel) superseded
• Alendronate and risedronate
• effective at the spine and hip (and other
  indications)
• Alendronate is now generic

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Bisphosphonates summary contd

• Intermittent dosage now the trend
• Oral monthly ibandronate 150 mg
• Intravenous bisphosphonates
• Ibandronate available
• Zoledronate in future

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Bone active drugs

• Anti-resorptive drugs
• Oestrogen
• SERMs (raloxifene)
• Bisphosphonates
• Anabolic drugs
• Teriparatide
• Dual Acting Bone Active (DABA)
• Strontium ranelate

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Human parathyroid hormone 1-34 and 1-84
Source
Review
Reviewer Memo
Slide Modified on 2/19/2002 114219 AM SL25
Rev 217
Memo
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Effects on Lumbar Spine BMD
Slide Modified on 10/03/2001 15406 PM
Rev 215
Change from Baseline ? SE
PTH 40


16
16
PTH 40

12
12

ALN 10
8
8

4
ALN 10
4
0
0
14
0
3
6
12
Endpoint (14 mo median drug exposure)
Months
Plt0.001 PTH40 vs. ALN10
Body JJ, et al.,J Clin Endocrinol Metab
874528-4535, 2002
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Effect of teriparatide on the risk of moderate
and severe new vertebral fractures
Source
Review
P lt0.001 vs. Placebo
RR 0.22 (95 CI, 0.11 to 0.45)
RR 0.10 (95 CI, 0.04 to 0.27)
0
Reviewer Memo
20
40
Risk Reduction
of Women
60
78
90
80
42
9
4
100
Placebo (n448)
TPTD20 (n444)
TPTD40 (n434)
No. of women who had gt 1 moderate or severe
fracture
Neer R et al., N Engl J Med 2001 3441434-41
Slide Modified on 2/19/2002 114209 AM SL8
Rev 217
Memo
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Teriparatide - Summary

• Reserved for women with severe osteoporosis with
  multiple vertebral fractures
• Unresponsive or intolerant of treatment
• Daily subcutaneous injection
• Course of treatment 3000 / year

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Bone active drugs

• Anti-resorptive drugs
• Oestrogen
• SERMs (raloxifene)
• Bisphosphonates
• Anabolic drugs
• Teriparatide
• Dual Acting Bone Active (DABA)
• Strontium ranelate

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Strontium ranelate

• Mechanims of action not fully understood
• Unique effect
• Inhibits bone resorption
• Stimulates bone formation ?

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Strontium

• Alklaine earth element
• Similar to calcium
• Absorbed from gut
• Incorporated into bone
• Eliminated by the kidneys
• After 3 years treatment bone will contain one
  strontium atom for every 100 calcium atoms
• In animal studies a ratio of 110
  strontiumcalcium did not affect crystal formation

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SOTI study - Vert fracture reduction

• RR reduction
• 0.51 (95 CI 0.36 to 0.75) plt0.001 at 12
  months
• 0.59 (95 CI 0.48 to 0.73) plt0.001 at 36 months

Meunier et al NEJM 2004350459-468
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TROPOS study - non vertebral fractures

• Designed to see if strontium ranelate reduces
  non-vertebral fractures
• 5091 women with OP

Reginster et al JCEM 2005350459-468
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Strontium ranelate - summary

• Reduces vert and non-vert fractures
• Older women included
• Has to be administered fasting
• No upper GI side effects
• Diarrhoea main side effect
• Apparent increases in bone density
• Relatively new

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Summary of drugs

• Bisphosphonates are the mainstay
• Weekly and a new monthly preparation
• New intravenous preparation in future
• Strontium
• SERMs Useful options
• Teriparatide
• Calcium and vitamin D for all patients

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NICE guidance (HTA 87)

• Recognised that osteoporosis is important
• Focus only on postmenopausal women
• Secondary prevention guidance
• Clarifies role of DXA scanning and other risk
  factors
• Local implementation group

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NICE secondary prevention of postmenopausal
osteoporotic fractures (HTA 87)
Strontium ranelate
84
Cases

• Late postmenopausal women gt 75 years
• Early postmenopausal women 50 to 70 years
• With fractures
• Without fractures
• Young adults lt 50 years

85
Cases

• Late postmenopausal women gt 75 years
• Early postmenopausal women 50 to 75 years
• With fractures
• Without fractures
• Young adults lt 50 years

86
Late postmenopausal osteoporosis

• Mrs EF 79 year old woman
• Referred to Bone Clinic
• Previous Colles fracture history of falls
• Back pain for years
• PMH / DH / FH unremarkable

87
Late postmenopausal osteoporosis

• Mrs EF 79 year old woman
• Examination
• Kyphosis two vertebral fractures
• Fall related risk factors present
• poor eyesight
• inability to stand without help
• multiple drugs
• DXA scan - osteoporosis at total hip

88
Late PMO gt 75 years
Bone density
Fall risk
0 20 50 65 100
Age (years)
89
Late postmenopausal osteoporosis

• Treatment
• Improving bone strength
• Bisphosphonates
• Strontium ranelate (second line)
• Calcium vitamin D (for all)
• Reducing risk of falling
• Modifiable fall-related risk factors
• Eyesight
• Reduce impact on skeleton (hip protectors)

90
The MRC RECORD StudyCalcium vitamin D
supplementation for secondary prevention of
fractures
A multicentre UK trial of secondary fracture
prevention with daily oral vitamin D 800 i.u.
and/or calcium carbonate 2.5g
No effect on fall rates or fracture
91
Reducing the impact of falling

• Hip protectors
• Concerns about efficacy when applied to a
  population

• 85 women at high risk of fracture
• 32 (38) agreed to wearing

Patel et al Rheumatology 2003
92
Late postmenopausal osteoporosis

• Summary
• Multiple mechanisms of fracture
• Bone strength can be improved with drugs
• Falls can be reduced (evolving evidence)
• Role of calcium Vitamin D (monotherapy) ?
• Role of hip protectors ?

93
Cases

• Late postmenopausal women gt 75 years
• Early postmenopausal women 50 to 75 years
• With fracture
• Without fracture
• Young adults lt 50 years

94
Early PMO with fracture

• Mrs CD 65 year old woman
• Recent acute back pain with height loss
• GP noted kyphosis
• Normal examination and blood tests
• X-ray vertebral fractures
• DXA scan showed low bone density

95
Early PMO with fracture 50 to 75 years
Bone density
0 20 50 65 100
Age (years)
96
Early PMO with fracture
Osteoporosis with fracture
Good data for all licensed drugs
97
Early postmenopausal osteoporosis

• Mrs CD 65 year old woman
• Recent acute back pain with height loss
• GP noted kyphosis
• Normal examination and blood tests
• X-ray vertebral fractures
• DXA scan showed low bone density
• Diagnosis Postmenopausal osteoporosis with
  vertebral fractures
• Action Drug treatment (Bisphosphonates)

98
Early PMO with fracture (severe)
Severe osteoporosis with multiple fractures

• ? Role for anabolics
• Teriparatide

99
Severe PMO with multiple fractures

• Mrs JR 62 yrs old
• 6 month h/o back pain
• Previous acute episodes in past
• Chiropractic treatment no help
• Further acute bout of pain
• X-rays showed multiple vertebral fractures
• GORD
• Upper GI symptoms with bisphosphonates

100
Severe osteoporosis with multiple fractures

• DXA Hologic scanner St Anthonys
• Absolute T score Z score
• (gm/cm2)
• LS 0.566 - 4.7 - 3.0
• TH 0.857 - 0.7 0.4

101
Severe osteoporosis with multiple fractures

• Severe spinal osteoporosis with multiple
  vertebral fractures
• Future fracture risk is high
• Anti-resorptives standard treatment
• Use of anabolics ?

102
Severe osteoporosis with multiple fractures

• Managed in Rheumatology Clinic at St Anthonys
• Treated with teriparatide (self-funding)
• 12 increase in BMD at spine over one year

103
Early PMO with fracture

• Common
• Tends to cause vertebral fractures and distal
  radius fractures
• Usually associated with back pain and height loss
  with kyphosis but can be silent
• Immediate treatment is necessary because
  vertebral fractures predict further vertebral
  fractures
• Tailor treatment to patient
• All modalities suitable mainly bisphosphonates

104
Cases

• Late postmenopausal women gt 75 years
• Early postmenopausal women 50 to 75 years
• With fracture
• Without fracture
• Young adults lt 50 years

105
Early PMO without fracture
Post menopausal osteoporosis
Osteoporosis without fracture PRIMARY prevention
106
Early PMO without fracture

• Limited data for efficacy long-term
  side-effects
• Previously major role of HRT but now role for
  raloxifene

Post menopausal osteoporosis
Osteoporosis without fracture NICE primary
Prevention guidelines
107
Early PMO without fracture
Bone density
0 20 50 65 100
Age (years)
108
From T-scores to absolute fracture risk
Simonski et al Canadian Assoc Radiol Journal
200556178-188
109
Early PMO without fracture

• Do BMD if strong clinical risk factors
• Estimate absolute fracture risk
• Monitor or HRT / raloxifene / bisphosphonates
• NICE primary prevention guidance awaited

Bone density
0 20 50 65 100
Age (years)
110
Cases

• Late postmenopausal women gt 75 years
• Early postmenopausal women 50 to 75 years
• With fracture
• Without fracture
• Young adults lt 50 years

111
Young adult - low peak bone density

• Miss AB - 28 year old
• Back pain with X-ray suggesting ? Osteoporosis
• Normal history including normal periods
• DXA scan showed low bone density
• Investigations for secondary causes normal
• Diagnosis Low peak bone density
• Action Monitor and no need for drugs until
  menopause

112
Young adult
Bone density
0 20 50 65 100
Age (years)
113
Young adult - low peak bone density

• Usually asymptomatic without fractures
• Vast majority have no underlying secondary
  disease
• Absolute fracture risk usually not high enough
  for drug therapy
• May need specialist opinion if previous fracture
• Monitor rather than treat with drugs which have
  only been used in older people

114
NICE, osteoporosis and falls

• Guidelines issued
• Clinical Guidelines on falls
• Secondary prevention of fracture
• Guidelines awaited
• Primary prevention
• Clinical assessment and management

115
NICE and HTAs

• NICE HTA 87
• Secondary prevention of osteoporotic fractures
• Other usage continues unchanged
• eg primary prevention, men, steroids etc

116
Clinical Cost effectiveness
Cost Clinical effectiveness
Cost / QALY NNT
117
Clinical Cost effectiveness
Secondary prevention
Cost Clinical effectiveness
Cost / QALY NNT
NICE HTA 87
118
Clinical Cost effectiveness
Primary prevention HTA awaited
Cost Clinical effectiveness
Cost / QALY NNT
119
NICE secondary prevention of osteoporotic
fractures
Flow diagram provided by Eli Lilly
120
Osteoporosis drug treatment
lt -2.5 S.D. Fragility Fracture
-1.5 to -2.5 S.D.
lt -2.5 S.D.
Prevention PMO
Secondary Prevention
Primary prevention PMO
HRT?
SERMs
Bisphosphonates
Strontium
PTH
adjunctive Ca Vit-D3 supplementation
age
50 to 60 yrs
60 to 75 yrs
55 to 75 yrs
7-15
121
Summary

• Assessment and treatment is poor even for
  secondary prevention
• Strong evidence base for drug therapy
• Management approach varies according to patient
• Late postmenopausal women
• Early postmenopausal women
• Young women with low peak BMD
• Multiple interventions may be needed