Transcript
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
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