Prof. Juraj PAYER, M.D, PhD.
5th Department of Internal Medicine
Medical Faculty Comenius University Bratislava
Slovakia
S...
General principles
elimination of known risk factors of osteoporosis
reduction of risk of fall (various barriers, bad si...
Improvement of bone turnover
Increase both cortical and trabecular bone mass (bone
mineral density) and improve bone quali...
Bone resorption Bone formation
Calcium & Vitamin D ⇩ ⇩
HRT ⇩ ⇩
Tibolone ⇩ ⇩
SERMs ⇩ ⇩
Bisphosphonates ⇩ ⇩
Calcitonin ⇩ ⇩
r...
Effective Treatment
Efficacy Safety/Tolerability+ Adherence+
The capacity for
beneficial change,
or therapeutic
effect of ...
Payer J, et al. Biomed Pharmacother 2007;61:191-193.
Adherence
Persistence Compliance+
Reflects a combination of behaviour...
0,5
0,6
0,7
0,8
0,9
1
1,1
45 50 55 60 65
Age (years) Age (year)
Short-time treatment Long-time treatment
Less than 50% of patients persist with their
osteoporosis therapy for more than 1 year
Siris E.S. et al. Am. J. Med. 2009;...
0,0
0,2
0,4
0,6
0,8
1,0
1,2
1,4
>90% 80 to 90% 50 to <80% <50%
Huybrechts KF, et al. Bone. 2006;38:922-928.
1
1.09
1.18 1....
Goettsch WG, et al. J Bone Miner Res 2005;20(Suppl. 1):S278 (Abstract SU388)
20–30% reduction in risk
of hospitalisation f...
 Effective osteoporosis treatments (bisphosphonates,
strontium ranelate, denosumab) that prevent vertebral
and nonvertebr...
Bolland, M. J. et al. J Clin Endocrinol Metab 2010;95:1174-1181
The effect of treatment of osteoporosis on mortality in 10...
 ≥ 90% compliance led to significantly lower risk of fracture
versus < 30% compliance
 20% increase in the risk of fract...
14
 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...
 10 739 postmenopausal women ( 50 – 79y.)
after hysterectomy
 0,625 mg conjugated estrogen
 6,8 years; STOPPED by NIH –...
Cauley JA, et al. JAMA. 2003;290:1729-38; Women’s Health Initiative Steering Committee. JAMA. 2004;291:1701-12.
Hazard Rat...
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 1.3...
 HRT is approved by FDA for the
prevention of osteoporosis,
relief of vasomotor symptoms
and vulvovaginal atrophy
associa...
22
Drake M. T. et.al. Mayo Clin Proc. 2008;83:1032-1045
Mevalonate
Geranylpyrophosphate + IPP
Farnesyl diphosphate (FPP)
Geranylgeranyl diphosphate (GGPP)
HMG-CoA
FPP
synthase
Ra...
 Alendronate
 Alendronate 10 mg daily
 Alendronate 70 mg 1x a week
 Risedronate
 Risedronate 5 mg once a day
 Risedr...
Study name Drug/Dosage Treatment Effects
OTS Phase III
3-years, N=994
ALE 5 or 10 mg/day for 3y
20mg/day for 2y
Vertebral ...
Alendronate 10 mg daily
Alendronate 70 mg 1x a week
Wells GA et all. Cochrane
Database of Systematic Reviews, Issue 1, 2009
1203
citations
85 potentially
relevant article
11 ...
Wells GA et al. Cochrane Database of Systematic Reviews, Issue 1, 2009
Risedronate 5 mg once a day
Risedronate 35 mg once a week
(Risedronate 75 mg twice monthly)
 randomized, double-blind 3-year study conducted at multiple centres in North
America, Europe, and Australia
 2 arms
 T...
 risedronate reduced the incidence of vertebral fracture after
1 year of treatment by 61% / 65%
 risedronate reduced the...
0,0
1,0
2,0
0 3 6* 9* 12*
Čas (mesiace)
Pacientky(%)
Control group Risedronate
Roux, CH a spol, Curr Med Res Opin, 20, 200...
Months
59%
p = 0.002
NNT=22
0
2
4
6
8
10
6 12 18 24 30 36
%ofpatients
Control Risedronate 5mg
*
*
*
*
*
* *
*
*
*
*
* p <0...
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
...
 3-year randomised, double-blind, placebo-controlled study
 9331 postmenopausal women
 2 arms:
 5445 women (aged 70-79...
  of relative risk of femur neck fracture in 30%
  of relative risk of femur neck fracture in the first group in 40%, ...
Wells GA et all. Cochrane
Database of Systematic Reviews, Issue 1, 2009Summary of Findings for Secondary Prevention
Silverman SL, Watts NB, Delmas PD,
Lange JL, Lindsay R
OP Int 2007 18: 25-34
Presented at XXVIII. Annual Meeting of the Am...
Silverman SL, Watts NB, Delmas PD Lange JL, Lindsay R: Osteoporosis Int (2007) 18:25-34
Characteristics Risedronate Alendr...
0.0
0.5
1.0
1.5
2.0
2.3 alendronate
risedronate
↓18%*
in 12th
month
%ofpatientswithnonvertebralfracture
*Adjusted Relative...
Start month 6 month 12
%ofpatientswithlumbalfracture
0.00
0.10
0.20
0.30
0.40
0.50
0.58
alendronate
risedronate
↓43% *
In ...
Ibandronate tbl.
150 mg p.o. 1x a month
Ibandronate inj.
3 mg i.v. 1x in 3 months
Incidenceoffractures(%)
10
8
6
4
2
0
ITT population after 3 years
NS = non-significant (p=0.2785 between the groups for in...
Placebo Ibandronate*
Incidenceofnon-vertebralfractures(%)
Incidenceofnon-vertebralfractures(%)
20
15
10
5
0
69% reduction ...
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; ‡...
0
2
4
6
8
10
12
14
16
Infusion once a year
Pyrexy
Myalgy
Flu-like syndrome
Headache Arthralgy
1 2 3 1 2 3 1 2 3 1 2 3 1 2 ...
Adverse effects
of long-term bisphosphonate use
BISPHOSPHONATES
 Osteonecrosis of the jaw
 Subtrochanteric and diaphyseal fractures
 Negative effects on bone strenght , bone turnover ...
51
Raloxifene HCl 60 mg/day oraly
Raloxifene
Agonist Antagonist
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 verte...
RUTH MORE CORE
Incidenceper1000woman-yrs
0
1
2
3
4
5
6
Placebo
Raloxifene
71%
56%
44%
55
2g pulvis daily p.o.
 Replication
Preosteoblast Preosteoclast
 Bone formation
Osteoblasts
 Apoptosis
 Bone resorption
Osteoclast
 Activity...
First year 0-3 years
Patients(%)
placebo
Strontium 2 g/day
0
5
10
15
20
25
30
35
- 41%*
- 49%*
RR=0.51, 95%CI [0.36 ; 0.74...
1. Reginster JY, Seeman E, De Vernejoul MC, et al. J Clin Endocrinol Metab 2005; 90(5): 2816-2822.
2. Reginster JY, Hoszow...
59
Daily – nasal spray 200 I.U/kg
 Skeletal effects of calcitonin
 decreases the rate of bone resorption
 binds to specific receptors on osteoblasts and ...
0
5
10
15
20
25
30
35
placebo
200 IU
*
*
*
* P < .05 vs placebo.
1. year 2. year 3. year 4. year 5. year
%ofpatients
36%
62
once-daily subcutaneous
once-daily continuous
 RANKL
 OPG
 osteoclast
 bone resorption
 serum Ca++
 osteoblast
apoptosis
bone
lining
cells
...
1 10
20
30
Ser Val Ser Glu Ile Gln Leu Met His Asn
Leu
Gly
LysHisLeuAsnSerMetGluArgValGlu
Trp
Leu
Arg Lys Lys Leu Gln Asp ...
*P <0.001 vs. placebo
RR = relative risk vs. placebo
Neer et al. N Engl J Med 2001
New Vertebral Fractures
%ofwomenwith
>1...
Neer et al. N Engl J Med 2001
* P = 0.02 vs. placebo
† P = 0.01 vs. placebo
RR = relative risk vs. placebo
Nonvertebral Fr...
 Measurement of bone mass by DXA
 Biochemical markers of bone turnover
 Clinical examination
In Europe, total direct costs of osteoporosis were estimated in
2000 at 31.7 billion
In 2002 report, estimated direct cost...
Strom 2007
Country Hip fracture Vertebral fracture
Belgium 16 823 3 721
Denmark 22 283 1 163
France 9-24 000 3 383
Italy 1...
Individual profil of the patient
EBM datas
Aditive benefits
Safety and tolerance
Price
Better life expectancy of patients ...
Thank you for attention
Juraj Payer
Payer - Liečba osteoporózy
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Payer - Liečba osteoporózy

  1. 1. Prof. Juraj PAYER, M.D, PhD. 5th Department of Internal Medicine Medical Faculty Comenius University Bratislava Slovakia Slovak Society for Osteoporosis and Metabolic Bone Diseases 3rd I. O. A. Prague, 30. APRIL – 1. MAY 2010
  2. 2. General principles elimination of known risk factors of osteoporosis reduction 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
  3. 3. 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
  4. 4. Bone resorption Bone formation Calcium & Vitamin D ⇩ ⇩ HRT ⇩ ⇩ Tibolone ⇩ ⇩ SERMs ⇩ ⇩ Bisphosphonates ⇩ ⇩ Calcitonin ⇩ ⇩ rhPTH (TPTD) ⇧ ⇧ Strontium ranelate ⇩ ⇧ Denosumab ⇩ ⇩
  5. 5. Effective 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.
  6. 6. 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
  7. 7. 0,5 0,6 0,7 0,8 0,9 1 1,1 45 50 55 60 65 Age (years) Age (year) Short-time treatment Long-time treatment
  8. 8. 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
  9. 9. 0,0 0,2 0,4 0,6 0,8 1,0 1,2 1,4 >90% 80 to 90% 50 to <80% <50% Huybrechts KF, et al. Bone. 2006;38:922-928. 1 1.09 1.18 1.21 IncreasedRiskofFracture 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
  10. 10. Goettsch WG, et al. J Bone Miner Res 2005;20(Suppl. 1):S278 (Abstract SU388) 20–30% reduction in risk of hospitalisation for fracture 30% reduction in risk for fracture Patients persistent with bisphosphonates for 1 year + Note: greatest protective effect (30%) against hospitalisation for fracture was seen in patients persistent >1year
  11. 11.  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
  12. 12. 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
  13. 13.  ≥ 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-S13 MPR – the length of time the medication was avialable to the patient, based on refill patterns – used to measure compliance
  14. 14. 14
  15. 15.  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
  16. 16.  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
  17. 17. 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
  18. 18. 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: 1701-12 JAMA 2004; 291: 2947-58
  19. 19.  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
  20. 20. 22
  21. 21. Drake M. T. et.al. Mayo Clin Proc. 2008;83:1032-1045
  22. 22. 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
  23. 23.  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
  24. 24. Study name Drug/Dosage Treatment Effects OTS Phase III 3-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 I 3 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<0.001 Clinical fractures: RH 0.72 (95%CI 0.58-0.90) Nonvertebral fractures: RH 0.80 (95%CI 0.63-1.01) FIT II 4 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=0.002 Clinical fractures: RH 0.86 (95%CI 0.73-1.01) p=0.07 Nonvertebral fractures: RH 0.88 (95%CI 0.74-1.04) p=0.13 VERT-NA 3 years, N=2458 RIS 5 mg/day Vertebral fractures: RR 0.59 (95%CI 0.43-0.82) p=0.003 Nonvertebral fractures: RR 0.6 (95%CI 0.39-0.94) p=0.02 VERT-MN 3 years, N=1226 RIS 5 mg/day Vertebral fractures: RR 0.51 (95%CI 0.36-0.73) p<0.001 Nonvertebral fractures: RR 0.67 (95%CI 0.44-1.04) p=0.06 HIP 3 years, N=9331 RIS 5 mg/day Hip fractures: RR 0.7 (95%CI 0.6-0.9) p=0.02 Nonvertebral fractures: RR 0.8 (95%CI 0.7-1.0) p=0.03 BONE 3 years, N=2929 IBAN 2.5 mg/day Vertebral fractures: daily RR 52 (95%CI 29-68) p<0.002 HORIZON 3 years, N=7736 ZOL 5 mg infusion/year Vertebral fractures: RR 0.30 (95%CI 0.24-0.38) p<0.001 Clinical fractures: RH 0.67 (95%CI 0.58-0.77) p<0.001 Nonvertebral fractures: RH 0.75 (95%CI 0.64-0.87) p<0.001 HORIZON 3 years, N=2127 ZOL 5 mg infusion/day Vertebral fractures: RR 0.54 (95%CI 0.32-0.92) p=0.02 Clinical fractures: RH 0.65 (95%CI 0.50-0.84) p=0.001 Nonvertebral 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
  25. 25. Alendronate 10 mg daily Alendronate 70 mg 1x a week
  26. 26. Wells GA et all. Cochrane Database of Systematic Reviews, Issue 1, 2009 1203 citations 85 potentially relevant article 11 relevant article
  27. 27. Wells GA et al. Cochrane Database of Systematic Reviews, Issue 1, 2009
  28. 28. Risedronate 5 mg once a day Risedronate 35 mg once a week (Risedronate 75 mg twice monthly)
  29. 29.  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  womenwho were at least 5 years postmenopausal with two or more radiographically identified vertebral fractures or one vertebral fracture andlow lumbar BMD, defined as a T-score of less than or equal to22.0.  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
  30. 30.  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
  31. 31. 0,0 1,0 2,0 0 3 6* 9* 12* Čas (mesiace) Pacientky(%) Control group Risedronate Roux, CH a spol, Curr Med Res Opin, 20, 2004, 433-439 Harrington, 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)
  32. 32. Months 59% p = 0.002 NNT=22 0 2 4 6 8 10 6 12 18 24 30 36 %ofpatients Control Risedronate 5mg * * * * * * * * * * * * p <0.05 Harrington JT et al, Calcif Tissue Int 2004; 74:129-135
  33. 33. 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 Incidenciazarok(%)
  34. 34.  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
  35. 35.   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) Patients(%) Control group Risedronate
  36. 36. Wells GA et all. Cochrane Database of Systematic Reviews, Issue 1, 2009Summary of Findings for Secondary Prevention
  37. 37. Silverman SL, Watts NB, Delmas PD, Lange JL, Lindsay R OP Int 2007 18: 25-34 Presented 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
  38. 38. Silverman SL, Watts NB, Delmas PD Lange JL, Lindsay R: Osteoporosis Int (2007) 18:25-34 Characteristics Risedronate Alendronate Group 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
  39. 39. 0.0 0.5 1.0 1.5 2.0 2.3 alendronate risedronate ↓18%* in 12th month %ofpatientswithnonvertebralfracture *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
  40. 40. Start month 6 month 12 %ofpatientswithlumbalfracture 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%
  41. 41. Ibandronate tbl. 150 mg p.o. 1x a month Ibandronate inj. 3 mg i.v. 1x in 3 months
  42. 42. Incidenceoffractures(%) 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
  43. 43. Placebo Ibandronate* Incidenceofnon-vertebralfractures(%) Incidenceofnon-vertebralfractures(%) 20 15 10 5 0 69% reduction in risk of fractures‡1 Placebo Ibandronate† 20 15 10 5 0 60% reduction in 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=0.012 2Bauss 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
  44. 44. Zolendronate inj. 5 mg i.v. 1x a year BISPHOSPHONATES
  45. 45. 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 evident vertebral 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) Cumulativeincidence(%)ofnew clinicallyevidentfractureswithin3years 0 10 5 15 ZOL 5 mgPlacebo
  46. 46. 0 2 4 6 8 10 12 14 16 Infusion once a year Pyrexy Myalgy Flu-like syndrome Headache Arthralgy 1 2 3 1 2 3 1 2 3 1 2 3 1 2 3 Prevalence(%) 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.
  47. 47. Adverse effects of long-term bisphosphonate use BISPHOSPHONATES
  48. 48.  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
  49. 49. 51 Raloxifene HCl 60 mg/day oraly
  50. 50. Raloxifene Agonist Antagonist
  51. 51. 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 %ofwomenwithnewfracture 61% Without vertebral fracture RR 0.39 (95% CI = 0.17, 0.69) RR 0.63 (95% CI = 0.49, 0.83)
  52. 52. RUTH MORE CORE Incidenceper1000woman-yrs 0 1 2 3 4 5 6 Placebo Raloxifene 71% 56% 44%
  53. 53. 55 2g pulvis daily p.o.
  54. 54.  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
  55. 55. First year 0-3 years Patients(%) 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.
  56. 56. 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 %patientswithOP-relatedmajor non-vertebralfracturesover3years n=2537 Strontium ranelate n=2555 19%* 95% Cl 0.66-0.98 * p=0.031 0 2 6 10 12 8 4
  57. 57. 59 Daily – nasal spray 200 I.U/kg
  58. 58.  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
  59. 59. 0 5 10 15 20 25 30 35 placebo 200 IU * * * * P < .05 vs placebo. 1. year 2. year 3. year 4. year 5. year %ofpatients 36%
  60. 60. 62 once-daily subcutaneous
  61. 61. once-daily continuous  RANKL  OPG  osteoclast  bone resorption  serum Ca++  osteoblast apoptosis bone lining cells cbfa1 BMP PPAR Wnt IGF 1,2 amphiregulin  osteoblast number/function  bone formation  bone mass/strength  RANKL  OPG
  62. 62. 1 10 20 30 Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly LysHisLeuAsnSerMetGluArgValGlu Trp Leu Arg Lys Lys Leu Gln Asp Val His Asn Phe 50 40 6070 80 -COOH H2N- TPTD 1-34 PTH
  63. 63. *P <0.001 vs. placebo RR = relative risk vs. placebo Neer et al. N Engl J Med 2001 New Vertebral Fractures %ofwomenwith >1vertebralfracture 0 2 4 6 8 10 12 14 16 Placebo (64 / 448) TPTD20 (22 / 444) TPTD40 (19 / 434) RR  65%* RR  69%* %ofwomen with>1vertebralfracture Multiple New Fractures %ofwomenwith >1vertebralfracture 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
  64. 64. 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 %ofwomenwhohad >1fragilityfracture 0 1 2 3 4 5 6 Placebo (30 / 544) TPTD20 (14 / 541) TPTD40 (14 / 552) %ofwomenwith>1osteoporoticfracture RR  53%* RR  54%†
  65. 65.  Measurement of bone mass by DXA  Biochemical markers of bone turnover  Clinical examination
  66. 66. 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
  67. 67. 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 - - -
  68. 68. Individual profil of the patient EBM datas Aditive benefits Safety and tolerance Price Better life expectancy of patients with OP Fracture reduction
  69. 69. Thank you for attention Juraj Payer

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