Osteoporosis Who to teat and with what

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Osteoporosis Who to teat and with what? Dr
Neil Gittoes Senior Lecturer
Endocrinology, University of Birmingham, UK
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Key facts about osteoporosis

• The clinical relevance of OP is fracture
• Age is the best predictor of fracture risk
• BMD/DXA is not the be all and end all in fracture
  assessment
• Previous fracture increases risk of subsequent
  fracture 2-5 fold
• Drugs can reduce fracture risk by gt60 in high
  risk patients
• Think how a DXA result will change management

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Osteoporosis is not a problem if you dont
fracture
Fractures
Bone fragility
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Osteoporosis the age factor

• T score is number of SDs above or below young
  adult mean BMD

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Ageing population osteoporosis is the norm
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10 year risk age and risk of with low BMD
Kanis et al, 2001
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Ageing society osteoporosis a growing problem

• Hip fracture
• 24 first year mortality
• 50 unable to walk without aid
• 33 totally dependent

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Combined effect of BMD and prior
Ross et al, 1991
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What are the current challenges in treatment of
osteoporosis?

• Which patients to treat?
• Where do the new drugs fit?
• How do we get patients to take drugs long term?
• Treatment guidelines
• What is new with calcium and vitamin D?
• How long to treat for?
• How do we determine if drugs are working?
• Depo provera
• Availability of effective drugs is the least
  concern!

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Case finding strategy for prevention -high risk
groups

• Low trauma fracture (wrist, L-spine, hip, rib,
  upper humerus) lt75
• Prednisolone for gt3 months if lt65 years
• First degree relative with history hip fracture
  before age 70 years
• First degree relative with osteoporosis (Tlt-2.5)
  
• Premature (lt45) menopause not on HRT
  (iatrogenic/spontaneous)
• Radiological evidence of osteopenia
• Prolonged amenorrhoea (gt6/12) not
  pregnancy/contraception
• Male hypogonadism without testosterone
  replacement
• Anorexia nervosa (BMI lt 19kg/m²)
•        
• OTHER INDICATIONS FOR BONE MINERAL DENSITY
  (Secondary care?)
• Thyrotoxicosis Primary hyperparathyroidism
  
• Cushings syndrome Organ transplantation
• Malabsorption Chronic liver disease

Send these patients for BMD measurement
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Predictors of fracture risk bone density
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patients with vertebral fractures
30
25
20
15
10
5
0
-5
-4
-3
-2
-1
0
Tscore
SD Standard deviation Watts, 2001
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Facts about local DXA service

• GP direct access
• Under utilised
• Capacity for further 1000 scans per year
• Short wait time
• 50 per scan
• Budget in place
• Responds to urgent requests
• Clinical reporting/access to outpatient clinics
• Excellent quality service

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Available therapies to reduce fracture risk

• Highly effective in high risk groups
• Fractures, older, low BMD (Tlt-2.5)
• 60 anti-fracture efficacy
• Sustained effect (10 yrs)
• Safe
• Rapid onset of anti-fracture effect
• 6-12 months
• Multiple treatment options
• Bisphosphonates, raloxifene, teriparatide,
  strontium ranelate, Ca/D

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Which drug for which patient?
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Strontium ranelate - proposed mode of action
In vitro
.
Marie et al, 2001
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Strontium ranelate
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GI tolerability strontium ranelate

• Diarrhoea higher vs placebo with strontium
  ranelate
• 6.1 vs 3.6 p0.02
• effect resolved after first 3 months
• Constipation slightly lower vs placebo with
  strontium ranelate
• 5.3 vs 7.1 plt0.05

Meunier et al, 2004
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Other observations

• Overall annual incidence of VTE in strontium
  studies
• 0.7 (0.9 in Sr group / 0.6 in placebo group)
• OR 1.42 (Cl 1.021.98, p0.036)
• No biological plausible explanation
• Caution advised on SPC rather than
  contraindication

Protelos Summary of Product Characteristics. Date
of preparation September 2004.
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Key points - strontium ranelate

• Significant reduction in
• Vertebral fractures (clinical and radiographic)
• Non-vertebral fractures
• Hip fractures in a high risk elderly population
• Anti-fracture efficacy demonstrated in over 80s
• Side effects (diarrhoea) mild and transient
• Positioning
• First line alternative to bisphosphonate
• Particularly in elderly
• Concerns regarding upper GI complications
• Women with intolerance/inadequate response to
  other Rx

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Combination bisphosphonate vitamin D

• Fosavance ALN 70 mg 2800 iU D
• BPs dont work in setting of vit D deficiency
• Vitamin D deficiency is common
• Adherence/compliance big problem

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Vitamin D inadequacy worldwide
81
90
N1285
80
63
70
59
59
52
51
60
50
Prevalence ()
40
30
20
10
0
LatinAmerica
Asia
All
Australia
Europe
Middle East
Regions
Vitamin D inadequacy defined as serum 25(OH)D lt30
ng/ml 1285 community-dwelling women with
osteoporosis from 18 countries to evaluate serum
25(OH)D distribution. Lim S-K et al, 2005
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Vitamin D action
UVB
Sun
ProD3 ? PreD3 ? Vitamin D3
Skin
DietVitamin D3 Vitamin D2
25(OH)D
Kidney
Increase calcium and phosphorus absorption
1,25(OH)2D
Maintain serum calcium and phosphorus
Metabolic functions
Bone health
Neuromuscular functions
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Consequences of vitamin D insufficiency
Calcium absorption
Parathyroidhormone
Appropriateneuromuscularfunction
Bone mineraldensity
Risk of fracture
Falls
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Probable reasons for prevalence of vitamin D
inadequacy

• Lack of sunlight exposure (with age)
• Vitamin D is not common in the diet
• Ability to synthesize vitamin D in the skin
  decreases with age
• Lack of compliance taking daily supplements
• Growing use of sun screens
• All clinical trials have had supplemental Ca/D
• 500mg Ca 400iU vitamin D
• Evidence based practice

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Fosavance

• Supersedes Fosamax/ALN
• Deals with potential vitamin D deficiency
• One weekly tablet
• Adherence/compliance
• Pricing
• Ca/D supplementations
• Some may need further vitamin D (calcium?)
  supplementation

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Bisphosphonates
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Ibandronate vertebral fracture incidence over 3
years
10 8 6 4 2 0
62 fracture risk reduction
9.6
Incidence new vertebralfractures at year 3 ()
4.7
Placebo 2.5 mg daily ibandronate
p0.0001 vs placebo
Chesnut et al, 2004
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MOBILE study monthly non inferiorityLumbar
spine BMD
Year 2
Year 1
7 6 5 4 3 2 1 0
6.6
5.0
4.9
3.9
Mean change from baseline ()
2.5mg 150mg
2.5mg 150mg daily monthly
daily monthly
p0.002 vs daily ibandronate (2.5mg) plt0.001
vs daily ibandronate (2.5mg)
Delmas et al, 2005
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MOBILE study non inferiorityHip BMD
2.5mg daily 150mg monthly

7 6 5 4 3 2 1 0
6.2
4.2
4.0
3.1
Mean change from baseline ()
2.5
1.9
Total hip
Femoral neck Trochanter
plt0.05 vs daily ibandronate (2.5mg)
Delmas et al 2005
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MOBILE study Adverse events
Lewiecki et al, 2004
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Conclusions - monthly ibandronate

• Prevents vertebral fractures
• No conclusive supporting evidence that prevents
  non-spine and hip fractures
• Is well tolerated
• Offers potential for improved compliance
• Does well in persistence studies
• Is supported by a patient support programme

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NICE tell us how to manage patients with
fragility fracturesSecondary prevention of
osteoporotic fractures NICE technology
appraisal 87, January 2005
So how do we use these drugs?
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NICE HTA 87 some background

• Low trauma/fragility fracture
• as result of fall from standing height or less
• Fractures other than skull are included
• Minority of vertebral present clinically
• Coincidental vertebral on XR
• Clinical diagnosis of OP if no history of
  significant trauma
• Consider underlying conditions predisposing to
• Check T in men

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Secondary prevention of osteoporosis(after
fracture) - NICE
Treat (BP)
Treat (BP)
Treat (BP)
Low BMI, unRx menop, FH hip , GC, infl, immob
T-score
Age
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Limitations of NICE guidelines

• Deals with populations rather than individuals
• Treat patients with no evidence base
• Made all BPs equal
• Concept of treatment failure is difficult
• Did not deal with men
• Strontium ranelate to follow
• Primary prevention to follow

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• What do I do with a
• 53 year old F with recent Colles ?
• DXA
• Dependent on T-score treat with BP Ca/D
• 77 year old F with recent ankle?
• Empirical treatment with BP Ca/D
• 75 year old M with 2 T-spine wedge on XR?
• Consider secondary causes (measure T, etc)
• T replacement if appropriate
• Empirical treatment with ALN

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A fracture liaison service for S Bham?
Clinical , age gt50
Fracture clinic
Orthopaedic wards
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Age stratified approach to managing osteoporosis
IBN
HRT
PTH
Strontium
SERM
Weekly BP
Ca/D
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