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. Key facts about osteoporosis. The clinical relevance of OP is fracture Age is the best predictor of fracture risk

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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 >60% in high risk patients

  • Think how a DXA result will change management


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Osteoporosis

Falls

Fracture

Falls risk

Force of fall

Osteoporosis is not a problem if you don’t 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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Projected number of hip fractures (000) world wide

Number

Year

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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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 - osteoporosis?high risk groups

  • Low trauma fracture (wrist, L-spine, hip, rib, upper humerus) <75

  • Prednisolone for >3 months if <65 years

  • First degree relative with history hip fracture before age 70 years

  • First degree relative with osteoporosis (T<-2.5)

  • Premature (<45) menopause not on HRT (iatrogenic/spontaneous)

  • Radiological evidence of osteopenia

  • Prolonged amenorrhoea (>6/12) not pregnancy/contraception

  • Male hypogonadism without testosterone replacement

  • Anorexia nervosa (BMI < 19kg/m²)

  • OTHER INDICATIONS FOR BONE MINERAL DENSITY (Secondary care?)

  • Thyrotoxicosis ·Primary hyperparathyroidism

  • Cushing’s syndrome · Organ transplantation

  • Malabsorption · Chronic liver disease

Send these patients for BMD measurement


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2 x osteoporosis?

–1SD

Predictors of fracture risk – bone density

35

% patientswith vertebral fractures

30

25

20

15

10

5

0

-5

-4

-3

-2

-1

0

T–score

SD – Standard deviation

Watts, 2001


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Facts about local DXA service osteoporosis?

  • 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 osteoporosis?

  • Highly effective in high risk groups

    • Fractures, older, low BMD (T<-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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FORMATION osteoporosis?

RESORPTION

Sr

+

Pre-OB

Pre-OC

REPLICATION

Sr -

DIFFERENTIATION

OB

OB

OB

Sr -

OC

+ BONE FORMING ACTIVITY

BONE RESORBING

ACTIVITY

Bone

Strontium ranelate - proposed mode of action

In vitro

.

Marie et al, 2001


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Strontium ranelate osteoporosis?


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GI tolerability strontium ranelate osteoporosis?

  • Diarrhoea higher vs placebo with strontium ranelate

    • 6.1% vs 3.6% p=0.02

    • effect resolved after first 3 months

  • Constipation slightly lower vs placebo with strontium ranelate

    • 5.3% vs 7.1% p<0.05

Meunier et al, 2004


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Other observations osteoporosis?

  • Overall annual incidence of VTE in strontium studies

    • 0.7% (0.9% in Sr group / 0.6% in placebo group)

    • OR 1.42 (Cl [1.02;1.98], p=0.036)

    • 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 osteoporosis?

  • 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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Proportion with hip # > 60 years (n = 553) with vitamin D osteoporosis?

inadequacy, according to six different thresholds

Gallacher et al, 2005

Combination bisphosphonate + vitamin D

  • Fosavance – ALN 70 mg + 2800 iU D

  • BPs don’t work in setting of vit D deficiency

  • Vitamin D deficiency is common

  • Adherence/compliance big problem


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Vitamin D inadequacy worldwide osteoporosis?

81%

90

N=1285

80

63%

70

59%

59%

52%

51%

60

50

Prevalence (%)

40

30

20

10

0

All

Australia

LatinAmerica

Asia

Middle

East

Europe

Regions

Vitamin D inadequacy defined as serum 25(OH)D <30 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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Liver osteoporosis?

Intestine

Bone formation

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 osteoporosis?

Calcium absorption

Parathyroidhormone

Bone mineraldensity

Appropriateneuromuscularfunction

Risk of fracture

Falls


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Probable reasons for prevalence of vitamin D inadequacy osteoporosis?

  • 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 osteoporosis?

  • 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 osteoporosis?


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Ibandronate vertebral fracture incidence over 3 years osteoporosis?

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

†p=0.0001 vs placebo

Chesnut et al, 2004


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MOBILE study – monthly non inferiority osteoporosis?Lumbar 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

*p=0.002 vs daily ibandronate (2.5mg)

†p<0.001 vs daily ibandronate (2.5mg)

Delmas et al, 2005


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MOBILE study – non inferiority osteoporosis?Hip 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

*p<0.05 vs daily ibandronate (2.5mg)

Delmas et al 2005


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MOBILE study – Adverse events osteoporosis?

Lewiecki et al, 2004


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Conclusions - monthly ibandronate osteoporosis?

  • 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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So how do we use these drugs? osteoporosis?

NICE tell us how to manage patients with fragility fracturesSecondary prevention of osteoporotic fractures – NICE technology appraisal 87, January 2005


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NICE – HTA 87 – some background osteoporosis?

  • 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 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 osteoporosis?

  • 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 osteoporosis?

    • 53 year old F with recent Colle’s #?

      • 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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Assess osteoporosis?

suitability

Assess

suitability

Consider

long term BP if OP

Consider

long term BP if OP

1 stop DXA

1 g Ca +

800U vit D

1 g Ca +

800U vit D

OP – antiresorptive

+ Ca/D

Non-OP

Lifestyle advice

A fracture liaison service for S Bham?

Clinical #, age >50

Fracture clinic

Orthopaedic wards


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40 osteoporosis?

30

20

10

Vertebrae

Annual incidence per 1000 women

Hip

Wrist

50 60 70 80

Age (Years)

Age stratified approach to managing osteoporosis

IBN

HRT

PTH

Strontium

SERM

Weekly BP

Ca/D


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