Pharmacological treatment of osteoporosis

Prof. Juraj PAYER, M.D, PhD.5th Department of Internal Medicine

Medical Faculty Comenius University BratislavaSlovakia

Slovak Society for Osteoporosis and Metabolic Bone Diseases

3rd I. O. A. Prague, 30. APRIL – 1. MAY 2010

Principles of the Care for a Patient with Osteoporosis

General principleselimination of known risk factors of osteoporosisreduction of risk of fall (various barriers, bad

sight, drugs ...)modification of eating habits and physical activity

Supporting therapy

physical therapy, physiotherapy, analgetics, myorelaxants

Specific therapy

Rovenský J., Payer J. (Edt.), The Dictionary of Rheumatology. Springer Verlag 2009

Antiporotic agents

Improvement of bone turnover

Increase both cortical and trabecular bone mass (bone mineral density) and improve bone quality

Decrease fracture risk

Antiporotic agents should prevent fractures through effects on bone strength

Mode of Action

Bone resorption Bone formation

Calcium & Vitamin D ⇩ ⇩

HRT ⇩ ⇩

Tibolone ⇩ ⇩

SERMs ⇩ ⇩

Bisphosphonates ⇩ ⇩Calcitonin ⇩ ⇩

rhPTH (TPTD) ⇧ ⇧

Strontium ranelate ⇩ ⇧

Denosumab ⇩ ⇩

Effective Treatment Is Based on Efficacy, Safety/Tolerability and

AdherenceEffective Treatment

Efficacy Safety/Tolerability+ Adherence+

The capacity for beneficial change, or therapeutic effect of a given intervention

Defined as freedom from undesirable side-effects/adverse events, and decrease in susceptibility to the effects of a medication resulting from continued administration

Reflects a combination of behaviours determining the extent to which patients take medications as prescribed

Payer J, et al. Biomed Pharmacother 2007;61:191-193.

Adherence Encompasses Both Persistence and

Compliance

Payer J, et al. Biomed Pharmacother 2007;61:191-193.

Adherence

Persistence Compliance+

Reflects a combination of behaviours determining the extent to which patients

take medications as prescribed

The length of time from beginning to completion or discontinuation of therapy

The consistency and accuracy with which a prescribed regimen is followed

Short-time vs long-time treatment

of osteoporosis and bone density

0,5

0,6

0,7

0,8

0,9

1

1,1

45 50 55 60 65

Age (years)

Bone

Min

eral

Age (year)

Bone

Min

eral

Short-time treatment

Long-time treatment

Osteoporosis Therapies and Patient Adherence

Less than 50% of patients persist with their osteoporosis therapy for more than 1 year

Siris E.S. et al. Am. J. Med. 2009; 122: S3-S13

Patients initiating therapy

Patients continuing therapy

Adherence

Side effects

Safety concerns

Health problems

Lack of results

Lack of motivation

Cost

Inconvenient dosing

Withdrawn by others

0,0

0,2

0,4

0,6

0,8

1,0

1,2

1,4

>90% 80 to 90% 50 to <80% <50%

Poor Adherence is Associated with Increased Fracture Risk

Huybrechts KF, et al. Bone. 2006;38:922-928.

11.09

1.18 1.21

Incr

ease

d Ri

sk o

f Fra

ctur

e

Fracture Risk by Adherence Level

Data from 38,000 women in a managed care database

p < 0.0001

p = 0.0002

p = 0.12

high low

low high

Adherence Level

Good adherence leads to reduced fracture

risk and reduced risk of hospitalisation

Goettsch WG, et al. J Bone Miner Res 2005;20(Suppl. 1):S278 (Abstract SU388)

20–30% reduction in risk of hospitalisation for fracture

20–30% reduction in risk of hospitalisation for fracture

30% reduction in risk for fracture

30% reduction in risk for fracture

Patients persistent with bisphosphonates

for 1 year

Patients persistent with bisphosphonates

for 1 year+

Note:greatest protective effect (30%) against hospitalisation for fracture was seen in patients persistent >1year

Reduction of mortality by osteoporosis treatment

Effective osteoporosis treatments (bisphosphonates, strontium ranelate, denosumab) that prevent vertebral and nonvertebral fractures reduce mortality by approximately 10% in older, frailer individuals with osteoporosi who are at high risk of fractures.

A 10% RR reduction would correspond to an absolute mortality benefit ranging from 0.4–7 deaths prevented per 1000 patient-years of treatment

Bolland MJ et al. J Clin Endocrinol Metab 2010; 95: 1174-1181

Bolland, M. J. et al. J Clin Endocrinol Metab 2010;95:1174-1181

The effect of treatment of osteoporosis on mortality in 10 studies included in the secondary

analysis, grouped by individual agents

Compliance and fracture rate

≥ 90% compliance led to significantly lower risk of fracture versus < 30% compliance

20% increase in the risk of fracture in individuals with an MPR of 50-89% compared with those with an MPR ≥ 90%

The relationship between compliance and fracture rate has consistently been shown to be non-linear

Compliance and persistence with osteoporosis therapies are suboptimal with a clear impact on fracture rates

Siris et al. Am J Med 2009; 122: S3-S13MPR – the length of time the medication was avialable to the patient, based on refill patterns – used to measure compliance

14

HORMONE REPLACEMENT THERAPY

HORMONE REPLACEMENT THERAPY

Effect of estradiol on bone

WHI Study – EPTWomen´s Health Initiative Randomized Controlled

Trial

16 608 postmenopausal women (50 - 79 y.) 0,625 mg conjug. estrogen + MPA 2,5 mg 5,6 y; STOPPED by NIH - In July 2002

Study Type: Interventional Study Design: Prevention, Randomized, Placebo Control

JAMA, 288, 2002

WHI Study- ET-Alone

10 739 postmenopausal women ( 50 – 79y.) after hysterectomy

0,625 mg conjugated estrogen 6,8 years; STOPPED by NIH – february 2004

Study Type: Interventional Study Design: Prevention, Randomized, Placebo Control

Cauley JA, et al. JAMA 2004

WHI Results: Reduction in Fracture Risk With E+P and E-Alone

Cauley JA, et al. JAMA. 2003;290:1729-38; Women’s Health Initiative Steering Committee. JAMA. 2004;291:1701-12.

Hazard Ratio (± 95% CI)

1 20.3 0.5 0.7 1.5

Hip

Vertebral

Lower Arm/Wrist

All Fractures

WHI: Relative risk or benefit

Outcome E + P E alone

RR Nominal 95% CI

RR Nominal 95% CI

Coronary Heart Disease 1.24 1.00-1.54 0.91 0.75-1.12

Strokes 1.31 1.02-1.68 1.39 1.10-1.77

Venous thromboembolism 2.11 1.58-2.82 1.33 0.99-1.79

Breast cancer 1.24 1.02-1.50 0.77 0.59-1.01

Dementia 0.61 0.42-0.87 1.08 0.75-1.55

Colorectal cancer 0.67 0.47-0.96 0.61 0.41-0.91

Hip fractures 2.05 1.21-3.48 1.49 0.83-2.66

JAMA 2004; 291: 1701-12JAMA 2004; 291: 2947-58

Hormon Replacement Therapy

HRT is approved by FDA for the prevention of osteoporosis, relief of vasomotor symptoms and vulvovaginal atrophy associated with menopause.

Because of the risks (MI, stroke, pulmonary embolism, deep vein phlebitis) HRT should be used in the lowest effective doses fort the shortest duration to meet treatment goals.

HRT is indicated during menopause to avoid complications of climacteric syndrome such as fractures, cardiovaskular risks and neurological signs

HRT is indicated for the prevention and not for treatment.

Because of the risks associated with long-term use, HRT should be used for prevention of OP only in women who are unable to use other medicines that are authorised for this purpose.

Clinician´s Guide to Prevention and Treatment od Osteoporosis. NOF 2008. EMEA 2007

22

BISPHOSPHONATESBISPHOSPHONATES

Bisphosphonate structures

Drake M. T. et.al. Mayo Clin Proc. 2008;83:1032-1045

Molecular Mechanisms of Action of Nitrogen-Containing Bisphosphonates

Mevalonate

Geranylpyrophosphate + IPP

Farnesyl diphosphate (FPP)

Geranylgeranyl diphosphate (GGPP)

HMG-CoA

FPP synthase

Ras S

Rho S

NBPs inhibits FPP synthase, thus blocking the prenylation of small signaling proteins required for cell function and survival

X

Kavanagh et al. PNAS, 2006; Rondeau et al. Chem Med Chem. 2006; Kavanagh et al. JBC. 2006.

GGPP synthase

Bisphosphonates

Alendronate Alendronate 10 mg daily Alendronate 70 mg 1x a week

Risedronate Risedronate 5 mg once a day Risedronate 35 mg once a week Risedronate 75 mg 2x monthly

Ibandronate Ibandronate tbl. 150 mg p.o. 1x a month Ibandronate inj. 3 mg i.v. 1x in 3 months

Zolendronate Zolendronate inj. 5 mg i.v. 1x a year

Study name Drug/Dosage Treatment EffectsOTS Phase III3-years, N=994

ALE 5 or 10 mg/day for 3y 20mg/day for 2y

Vertebral fractures: RR 0.52 (95%CI 0.28-0.95)Nonvertebral fractures: RR 0.79 (95%CI 0.52-1.22

FIT I3 years, N=2027

ALE 5 mg/day (raised to 10 mg/day after 2 years)

Vertebral fractures: RR 0.53 (95%CI 0.41-0.68), p<0.001Clinical fractures: RH 0.72 (95%CI 0.58-0.90)Nonvertebral fractures: RH 0.80 (95%CI 0.63-1.01)

FIT II4 years, N=4432

ALE 5 mg/day (raised to 10 mg/day after 2 years)

Vertebral fractures: RR 0.56 (95%CI 0.39-0.80) p=0.002Clinical fractures: RH 0.86 (95%CI 0.73-1.01) p=0.07Nonvertebral fractures: RH 0.88 (95%CI 0.74-1.04) p=0.13

VERT-NA3 years, N=2458

RIS 5 mg/day Vertebral fractures: RR 0.59 (95%CI 0.43-0.82) p=0.003Nonvertebral fractures: RR 0.6 (95%CI 0.39-0.94) p=0.02

VERT-MN3 years, N=1226

RIS 5 mg/day Vertebral fractures: RR 0.51 (95%CI 0.36-0.73) p<0.001Nonvertebral fractures: RR 0.67 (95%CI 0.44-1.04) p=0.06

HIP3 years, N=9331

RIS 5 mg/day Hip fractures: RR 0.7 (95%CI 0.6-0.9) p=0.02Nonvertebral fractures: RR 0.8 (95%CI 0.7-1.0) p=0.03

BONE3 years, N=2929

IBAN 2.5 mg/day

Vertebral fractures: daily RR 52 (95%CI 29-68) p<0.002

HORIZON3 years, N=7736

ZOL 5 mg infusion/year Vertebral fractures: RR 0.30 (95%CI 0.24-0.38) p<0.001Clinical fractures: RH 0.67 (95%CI 0.58-0.77) p<0.001Nonvertebral fractures: RH 0.75 (95%CI 0.64-0.87) p<0.001

HORIZON3 years, N=2127

ZOL 5 mg infusion/day Vertebral fractures: RR 0.54 (95%CI 0.32-0.92) p=0.02Clinical fractures: RH 0.65 (95%CI 0.50-0.84) p=0.001Nonvertebral fractures: RH 0.73 (95%CI 0.55-0.98) p=0.03

Pazianas et al. Reviews on Recent Clinical Trial, 2009; 4: 122-130RR – Relative Risk, RH – Relative Hazard

Alendronate 10 mg dailyAlendronate 70 mg 1x a week

BISPHOSPHONATES

Alendronate for the primary and secondary prevention of osteoporotic fractures in

postmenopausal women - Meta-analysis

Wells GA et all. Cochrane Database of Systematic Reviews, Issue 1, 2009

1203 citations

85 potentially relevant article

11 relevant article

Alendronate for the secondary prevention of osteoporotic fractures in postmenopausal women - Meta-analysis

Wells GA et al. Cochrane Database of Systematic Reviews, Issue 1, 2009

Risedronate 5 mg once a dayRisedronate 35 mg once a week(Risedronate 75 mg twice monthly)

BISPHOSPHONATES

VERT trialThe Vertebral Efficacy with Risedronate Therapy

randomized, double-blind 3-year study conducted at multiple centres in North America, Europe, and Australia

2 arms The multinational arm (MN) ... 80 centres ... 1226 patients The North American arm ....... 110 centres ... 2458 patients

women who were at least 5 years postmenopausal with two or more radiographically identified vertebral fractures or one vertebral fracture and low lumbar BMD, defined as a T-score of less than or equal to 22.0.

treatment: risedronate sodium, 2.5 mg/d; risedronate sodium, 5 mg/d; or placebo

Reginster, J.Y., Ost.Int., 2000 Harris,S a spol.,JAMA,1999

VERT trial – MN / NA

risedronate reduced the incidence of vertebral fracture after 1 year of treatment by 61% / 65%

risedronate reduced the incidence of vertebral fracture after 3 years of treatment by 49% / 41%

NNT per year = 14 / 25

Reginster, J.Y., Ost.Int., 2000 Harris,S a spol.,JAMA,1999

0,0

1,0

2,0

0 3 6* 9* 12*

Čas (mesiace)

Paci

entk

y (%

) Control group Risedronate

Roux, CH a spol, Curr Med Res Opin, 20, 2004, 433-439Harrington, JT a spol, Calcif Tissue Int, 74, 2004, 129-135

6 months – RR 0,08 9 months – RR 0,16 12 months – RR 0,31

• Pooled data from studies:– VERT-MN;– VERT-NA, – BMD-MN, – BMD-NA

Time (months)

Patie

nts

(%)

Rapid effect of risedronate:reduction of clinical vertebral fractures already after 6 month of treatment

Months

59% p = 0.002

NNT=22

0

2

4

6

8

10

6 12 18 24 30 36

% o

f pati

ents

Control Risedronate 5mg

*

**

*

*

* **

**

*

* p <0.05Harrington JT et al, Calcif Tissue Int 2004; 74:129-135

Rapid effect of risedronate:reduction of clinical nonvertebral fractures already after 6 month of treatment

Long-time effect of risedronate nad the risk of new vertebral fractures – after 7 years of treatment

0

2

4

6

8

10

12

14

Placebo Ris 5mg Placebo Ris 5mg Ris 5mg Ris 5mg

year 0-3 year 4-5 year 6-7

After 5. year change to RIS

Sorensen, et al, ISCD abstract, 2/03 annual meeting.

*

Yearly incidence of new vertebral fractures in years 0-3, 4-5 a 6-7

VERT-MN: vertebral fractures on X-ray

*p=0.007, McNemar Test

Inci

denc

ia za

rok

(%)

HIP study Risedronate in the therapy of postmenopausal osteoporosis

3-year randomised, double-blind, placebo-controlled study

9331 postmenopausal women

2 arms: 5445 women (aged 70-79) with low BMD in the area of proximal femur (T score

-3) and at least 1 fracture risk factor 3886 women (over 80) with at east 1 fracture risk factor regardless of BMD

McClung,M.R. et al., N.Engl.J.Med.,544, 2001

The HIP – results

of relative risk of femur neck fracture in 30% of relative risk of femur neck fracture in the first group in 40%, and in case of former

vertebral fractures, in 60% Risedronate reduces the risk of clinical vertebral fractures already after 6 months of

the therapy

McClung,M.R. et al.N.Engl.J.Med.,344, 2001

Roux, CH et al, Curr Med Res Opin, 20, 2004

0,0

1,0

2,0

0 3 6* 9* 12*

Time (months)

Patien

ts (%

)

Control group Risedronate

Wells GA et all. Cochrane Database of Systematic Reviews, Issue 1, 2009 Summary of Findings for Secondary Prevention

Risedronate for the secondary prevention of osteoporotic fractures in postmenopausal women - Meta-analysis

REAL

Silverman SL, Watts NB, Delmas PD,Lange JL, Lindsay R

OP Int 2007 18: 25-34Presented at XXVIII. Annual Meeting of the American Association for Bone and

Mineral Research, Philadelphia ; 15 -19 September 2006

Efficiency of bisphosphonates on nonvertebral and lumbal fractures in the first year of the therapy: cohort study with

risedronate and alendronate

REAL - Input CharacteristicsInput factors affecting the risk of fractures

Silverman SL, Watts NB, Delmas PD Lange JL, Lindsay R: Osteoporosis Int (2007) 18:25-34

Characteristics Risedronate AlendronateGroup size (n) 12.215 21.615

Age (years) at the start of the study (average)* 74.8 74.6

Medication – 6 month anamnesis

Current number of drugs (average)* 4.0 3.6

Gastrointestinal drugs (%)* 26.2 20.1

Estrogens (%) 17.2 16.5

Glucocorticosteroids (%)* 10.3 8.5

Personal – 6 months anamnesis

Hospitalization (%) 8.2 8.2

Check-ups (average)* 5.6 5.1

Diagnosis of rheumatoid arthritis (%)* 2.7 2.3* p<0.05 among the groups

Cumulative incidence of nonvertebral fractures

(lumbus, wrist, arm, clavicula, pelvis, leg)

0.0

0.5

1.0

1.5

2.0

2.3 alendronate

risedronate

↓18%* in 12th month

% o

f p

ati

en

ts w

ith

no

nv

ert

eb

ral

fra

ctu

re

*Adjusted Relative Rate Reduction, p = 0.03, 95% CI: 9% - 32%Delmas PD et al. J Bone Miner Res 2006;21(Suppl 1):S180

month 12month 6

Cumulative incidence of hip fractures

Start month 6 month 12

% o

f p

ati

en

ts w

ith

lu

mb

al

fra

ctu

re

0.00

0.10

0.20

0.30

0.40

0.50

0.58

alendronate

risedronate

↓43% * In 12th month

Delmas PD et al. J Bone Miner Res 2006;21(Suppl 1):S180

*Adjusted Relative Rate Reduction, p = 0.01, 95% CI: 13% - 63%

Ibandronate tbl. 150 mg p.o. 1x a month

Ibandronate inj. 3 mg i.v. 1x in 3 months

BISPHOSPHONATES

Reduction of Vertebral

Fracture Risk In

cid

ence

of

fra

ctu

res

(%) 10

8

6

4

2

0

ITT population after 3 years NS = non-significant (p=0.2785 between the groups for incidence of fractures )Chesnut CH, et al. J Bone Miner Res 2004;19:1241–9 BONE štúdia

NS

62% RRR(95% CI: 41–75)

p=0.0001

50% RRR(95% CI: 26–66)

p=0.0006

n=975 n=977 n=977

Placebo Ibandronate Ibandronate 20mg 2,5mg daily >2 months

without therapy

Reduction in Risk of Non-Vertebral Fractures in Subgroups with

Higher Risk

Placebo Ibandronate*

Inci

denc

e of

non

-ver

tebr

al fr

actu

res

(%)

Inci

denc

e of

non

-ver

tebr

al fr

actu

res

(%)

20

15

10

5

0

69% reduction in

risk of fractures‡1

Placebo Ibandronate†

20

15

10

5

0

60% reductionin risk of fractures§2

1Chesnut CH, et al. J Bone Miner Res 2004;19:1241–9- the BONE Trial*Patients with baseline BMD T-score of femur neck <–3.0; ‡p=0.0122Bauss F, Schimmer R. Ther Clin Risk Manage 2006;2:3–18†BMD lumbar spine (T-score <–2.5) and anamnesis of clinical fracture in the last 5 years; §p=0.037

Zolendronate inj. 5 mg i.v. 1x a year

BISPHOSPHONATES

Values above columns are 3-year cumulative numbers of attacks based on Kaplan-Meier assumptions. *P = .0024; †P < .0001; ‡P = .0002; reduction of relative risk as compared to placebo § Fracture of hip joint was not excluded from analysis of other fractures than vertebral fractures. Black DM, et al. N Engl J Med. 2007;356:1809-1822.

41%*(17%, 58%)

77%†

(63%, 86%)

25%‡

(13%, 36%)

Clinically evidentvertebral fracture

Fracture of hip joint

Other fracture than vertebral fracture§

1.4%(52/3875) 0.5%

(19/3875)

2.5%(88/3861)

2.6%(84/3861)

8.0%(292/3875)

10.7%(388/3861)

Cu

mu

lati

ve in

cid

ence

(%

) o

f n

ew

clin

ical

ly e

vid

ent

frac

ture

s w

ith

in 3

yea

rs

0

10

5

15

Zolendronate and Risk of Clinical Fractures

(femur, vertebrae, other fractures)

ZOL 5 mg Placebo

0

2

4

6

8

10

12

14

16

Infusion once a year

Pyrexy

Myalgy

Flu-like syndromeHeadache Arthralgy

1 2 3 1 2 3 1 2 3 1 2 3 1 2 3

Pre

vale

nce

(%

)

15%

2%

1%1% 2%

1%

2%

1%2%

1%

8%

7%6% 5%

Crossed datas for placebo

1%

Black DM, et al. N Engl J Med. 2007;356:1809-1822.

HORIZON Pivotal Fracture Trial (PFT)

Safety and tolerance

Adverse effects of long-term bisphosphonate use

BISPHOSPHONATES

Complications of long-term bisphosphonates use

Osteonecrosis of the jaw Subtrochanteric and diaphyseal fractures Negative effects on bone strenght , bone turnover and

bone quality (and then microdamages) Esophagitis, esophageal cancer (?) Atrial fibrillation (?)

Rovensky J, Payer J (eds). Dictionary of rheumatology 2009; Miller PD. Osteoporosis 2008; Abrahamsen B, Eiken P, Eastell R. J Bone Miner Res 2009; Singh AP. N Engl J Med 2009

51

SELECTIVE ESTROGEN RECEPTOR MODULATOR

Raloxifene HCl 60 mg/day oraly

Raloxifene

Agonist Antagonist

Selective Estrogen Receptor Modulators II. generation

Effect on serious vertebral fractures

Siris E. ,et al., Osteoporos Int (2002)13:907 –913

0,0

2,0

4,0

6,0

8,0

10,0

12,0

14,0

16,0

placebo RLX 60mg

37%

With vertebral fracture

0,0

0,5

1,0

1,5

2,0

2,5

placebo RLX 60g

% o

f wom

en

with

new

fra

ctu

re

61%

Without vertebral fracture

RR 0.39(95% CI = 0.17, 0.69)

RR 0.63(95% CI = 0.49, 0.83)

RUTH MORE CORE

Incid

en

ce

pe

r 1

00

0 w

om

an

-yrs

0

1

2

3

4

5

6PlaceboRaloxifene

71%

56%

44%

Reductions in Invasive Breast Cancer

55

STRONTIUM RANELATE

2g pulvis daily p.o.

Replication

Preosteoblast Preosteoclast

Bone formation

Osteoblasts

Apoptosis

Bone resorption

Osteoclast

Activity Synthesis of

bone matrix

Diferrentiation

CaSR +?

CaSR

OPG

RANK RANKL

Diferrentiation

Strontium Ranelate and Osteoporosis

Strontium reduces the risk of vertebral fracture (SOTI)

First year 0-3 years

Pat

ien

ts (

%)

placebo

Strontium 2 g/day

0

5

10

15

20

25

30

35

- 41%*

- 49%*

RR=0.51, 95%CI [0.36 ; 0.74] * p<0.001 RR=0.59, 95%CI [0.48 ; 0.73] * p<0.001

Meunier P J et al. N Engl J Med. 2004; 350:459-468.

Strontium ranelate reduces non-vertebral fracture risk

(TROPOS)

1. Reginster JY, Seeman E, De Vernejoul MC, et al. J Clin Endocrinol Metab 2005; 90(5): 2816-2822.2. Reginster JY, Hoszowski K, Roces Varela A et al. Bone 2003; 32(5): S94.

Placebo% p

atie

nts

with

OP-

rela

ted

maj

or

non-

verte

bral

frac

ture

s ov

er 3

yea

rs

n=2537Strontium ranelate

n=2555

19%*

95% Cl 0.66-0.98

* p=0.031

0

2

6

10

12

8

4

59

CALCITONIN

Daily – nasal spray 200 I.U/kg

Calcitonin

Skeletal effects of calcitonin decreases the rate of bone resorption binds to specific receptors on osteoblasts and decreases the activity of those

cells bone formation may be augmented by calcitonin through increased osteoblastic

activity

Calcitonin – nasal spray is used: In Europe since 1987 In USA since 1995

0

5

10

15

20

25

30

35placebo200 IU

New vertebral fractures

*

**

* P < .05 vs placebo.

1. year 2. year 3. year 4. year 5. year

% o

f pat

ient

s

36%

62

PARATHORMONE AND TERIPARATIDE

once-daily subcutaneous

once-daily continuous

RANKL OPG

osteoclast

bone resorption

serum Ca++

osteoblast apoptosis

boneliningcells

­ cbfa1 ­ BMP­ PPAR­ Wnt­ IGF 1,2­ amphiregulin

osteoblast number/function

bone formation

bone mass/strength

RANKL OPG

PTH

1 10

20

30

Ser Val Ser Glu Ile Gln Leu Met His AsnLeu

GlyLysHisLeuAsnSerMetGluArgValGlu

Trp

LeuArg Lys Lys Leu Gln Asp Val His Asn Phe

50

40

6070

80

-COOH

H2N-

Human Parathyroid Hormone

1-34 and 1-84

TPTD1-34 PTH

*P <0.001 vs. placeboRR = relative risk vs. placebo

Teriparatide and risk of vertebral

fractures

Neer et al. N Engl J Med 2001

New Vertebral Fractures

% o

f w

om

en

with

>1

ve

rte

bra

l fra

ctu

re

0

2

4

6

8

10

12

14

16

Placebo(64 / 448)

TPTD20(22 / 444)

TPTD40(19 / 434)

RR 65%* RR 69%*

% o

f wom

en

with

>1

vert

ebra

l fra

ctur

e

Multiple New Fractures

% o

f wom

en w

ith>1

ver

tebr

al fr

actu

re

0

1

2

3

4

5

Placebo(22 / 448)

TPTD20(5 / 444)

TPTD40(3 / 434)

RR 77%*

RR 86%*

Placebo(22 / 448)

TPTD20(5 / 444)

TPTD40(3 / 434)

Risk of new fractures (primary endpoint)

Risk of multiple vertebral fractures

Fracture Prevention TrialRisk of nonvertebral osteoporotic

fractures

Neer et al. N Engl J Med 2001

* P = 0.02 vs. placebo † P = 0.01 vs. placebo

RR = relative risk vs. placebo

Nonvertebral Fragility Fractures%

of w

om

en

wh

o h

ad

> 1

fra

gili

ty fra

ctu

re

0

1

2

3

4

5

6

Placebo(30 / 544)

TPTD20(14 / 541)

TPTD40(14 / 552)%

of w

omen

with

>1

oste

opor

otic

fract

ure

RR 53%* RR 54%†

Monitoring of treatment

Measurement of bone mass by DXA Biochemical markers of bone turnover Clinical examination

Economic impact

In Europe, total direct costs of osteoporosis were estimated in 2000 at 31.7 billion

In 2002 report, estimated direct costs of treating work-place osteporotic fractures in the US, Canada an Europe were

US $ 48 billion per year

Indirect costs (lost productivity) in the work-place, due to osteporotic fractures, in the US alone, was estimated:

between US $ 4.5 billion and US $ 6.4 billion per year

Kanis JA, Johnell O, on behalf of the Committee of Scientific Advisor of the International Osteoporosis Foundation. Requirements for DXA for the management of osteoporosis in Europe. Osteoporos Int 2005; 16:229-238

Cost of fractures in Europe

Strom 2007

Country Hip fracture Vertebral fracture

Belgium 16 823 3 721

Denmark 22 283 1 163

France 9-24 000 3 383

Italy 17 478 3 866

Germany 17 399 5-6 000

Norway 24 059 932

Spain 6 922 1 531

Sweden 9 – 25 000 3 626

UK 17 – 22 000 2 – 3 000

Slovakia 14 221 - - -

Main aspects for treatment

Individual profil of the patient

EBM datas

Aditive benefits

Safety and tolerance

Price

Better life expectancy of patients with OP

Fracture reduction

Thank you for attention

Juraj Payer