Avances Farmacoteraputicos en Osteoporosis- ANCYM 2006 Dr.

Enrique Snchez Delgado

Internista-Farmaclogo Clnico Director de Educacin Mdica del HMVP Miembro del Comit Ejecutivo de ISIM (SIMI) Miembro Fundador de ANCYM

Principales Avances:

1.- Ranelato de Estroncio (Protelos) 2.- Denosumab (Mo Ab anti RANKL) 3.- Folato + B 12

Development results of a new antiosteoporotic treatment: Strontium ranelate

31/03/03

Strontium ranelate

- OOC

CH 2

CN

Sr++
- OOC

* S N *

CH2

COO-

Sr++
C H2
CO O -

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Strontium ranelate decreases bone resorption in ovariectomized rats

Histomorphometry Tibial metaphysis Ovariectomized rats
26 24

- 24 %
* *

Oc.S/BS (%)

22 20 18 16 14 12 10

SHAM OVX

77 154 Strontium ranelate (mg/kg/d) 31/03/03

0.05 vs OVX; P 0.05 vs SHAM

From Marie P et al. JBMR.1993;8:607-615.

Mean SEM * P

Strontium ranelate increases collagen synthesis by preosteoblasts and osteoblasts

Osteoblasts Preosteoblasts
Non Collagen Synthesis (10-3 dpm/well)

30
Collagen synthesis (10-3 dpm/well)

60 50 40 30 20 10

*
25 20 15 10 5 0 0 10-5M 10-4M 10-3M

* *

10-5M 10-4M 10-3M Strontium ranelate

Strontium ranelate
Canalis E et al. Bone.1996;18:517-523.

MeanSEM, * P<0.05 vs control

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Preclinical results: Summary

Pharmacological studies in animal models indicate that Strontium ranelate:  increases bone formation and decreases bone resorption  preserves the mean degree of mineralization  increases bone strength at the vertebra and midshaft femur

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Pharmacokinetic data

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Strontium ranelate: dose-related bone effects in postmenopausal osteoporotic women

STrontium RAnelate for Treatment of OSteoporosis (STRATOS)
Multicenter, randomized, double-blind, placebo-controlled 2-year trial Prof PJ Meunier

Meunier PJ et al. J Clin Endocrinol Metab. 2002;87:2060-2066.

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Strontium ranelate 2 g/day increases lumbar BMD

+ 7.3% per year (mean)
Change in lumbar BMD (%) 15
* Annual slopes (%)
means + SD

10

* *

Placebo 500 mg/day 1 g/day 2 g/day

0.5 + 2.8 2.9 + 3.3 * 4.5 + 4.3 * 7.3 + 4.9 *

* *

* P<0.001 vs placebo

2 g/day 1 g/day

0 M0 M12 M24 Months

500 mg/day Placebo

Meunier PJ et al. J Clin Endocrinol Metab. 2002;87(5):2060-2066.

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Strontium ranelate 2 g/day reduces the risk of vertebral fractures during the second year
Patients (%) 50 40 30

- 44%

Strontium ranelate 2g Placebo

20

10

First year

Second year

* P < 0.01, vs placebo

Meunier PJ et al. J Clin Endocrinol Metab. 2002;87(5):2060-2066.

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STRATOS study: Conclusion

The STRATOS study shows that Strontium ranelate 2 g/day induces: a significant (+7.3%/year) increase in lumbar BMD

a significant decrease in the number of patients with new vertebral fractures during the second year (-44%) Strontium ranelate is well tolerated at the bone tissue level
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STRONTIUM RANELATE: New efficient antiosteoporotic treatment for vertebral and nonvertebral osteoporosis in postmenopausal women

Spinal Osteoporosis Therapeutic Intervention (SOTI)

Prof PJ Meunier

TReatment Of Peripheral OSteoporosis (TROPOS)

Prof JY Reginster

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PRIMARY END POINT: INCIDENCE OVER 3 YEARS OF PATIENTS WITH NEW VERTEBRAL FRACTURE

Strontium ranelate reduces the vertebral fracture risk as early as the first year and over the years
Patients (%)
40 35 30

RR=0.59 95% CI [0.48; 0.73] * P<0.001

NNT=9

25 20 15 10 5 0

RR=0.51 95% CI [0.36 ; 0.74] * P<0.001

- 41%
* Strontium ranelate 2g

- 49%
*

Placebo

0-1 year
Meunier PJ et al. Osteoporos Int. 2002;13(suppl3):S34(P66).

0-3 years
Incidence of patients with NVF: Kaplan-Meier; RR: Cox model

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CLINICAL VERTEBRAL FRACTURE RISK REDUCTION Strontium ranelate reduces the clinical vertebral fracture risk as early as the first year and over the years
RR = 0.62 95% CI [0.44; 0.83] **P < 0.001 RR = 0.48 95% CI [0.29 ; 0.80] * P = 0.003

Patients (%)

20 15 10 5 0

- 38%
** Strontium ranelate 2g Placebo

- 52%
*

0-1 year

0-3 years

Reginster JY et al. Arthritis and Rheumatism. 2002;46(suppl9):S584(1571).

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SOTI - BONE MINERAL DENSITY Relative change from baseline LUMBAR L2-L4
16 12

FEMORAL NECK
*
12 8

* * * * *

8 4 0 -4 0 6

+ 14.4%

4 0 -4

+ 8.3%

12

18

24

30

36

12

18

24

30

36
Months

SR 2 g At M36 At M36 Placebo E (SE) = 8.3 (0.41) 95% CI [7.50 ; 9.10] E (SE) = 14.4 (0.58) 95% CI [13.27 ; 15.53] P<0.001

P<0.001 mean (SEM) Meunier PJ et al. Osteoporos Int. 2002;13(6):520-522(O45). * P<0.001 Hierarchical step-down procedure
Meunier PJ et al. Data on file.

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SOTI - bALP and S-CTX: TIME-POINT DIFFERENCES (SR-placebo) IN ABSOLUTE CHANGES FROM BASELINE
Estimate change (E)
1.4 1.2 1 0.8 0.6 0.4 0.2
0 -200

*** * *

***

**
bALP (ng/mL)

S-CTX (pmol/L)
-400 -600 -800

***
0 3

***
6

***
12

*
24

**
Months

36 31/03/03

E= Estimate change of difference Strontium ranelate minus placebo, covariance analysis, baseline adjusted *** P<0.001; ** P<0.01; * P<0.05 Meunier PJ et al. Osteoporos Int. 2002.13:520-522(O45). Meunier PJ et al. Data on file.

New nonvertebral fractures

Patients (%) 15

ITT population

- 16%
10

Placebo

Strontium ranelate 2g

0 Months

12

18

24

30

36

Kaplan-Meer, adjusted Cox Model

RR (relative risk) = 0.84, 95% CI [0.71;1.00], P=0.05

SR: n=233 patients with fracture Placebo: n=276 patients with fracture 31/03/03
Reginster JY et al. Osteoporos Int. 2002;13(suppl3):S14(O14). Reginster JY et al. Data on file.

Hip fractures
Per-protocol
Patients (%)

- 41%
Placebo

0 0 6 12 18 24

Strontium ranelate 2g
30 36

Months 42

Kaplan-Meer, Cox model

RR (relative risk) = 0.59, 95% CI [0.37;0.95], P=0.025

SR: n=24 patients with fracture Placebo: n=61 patients with fracture
Reginster JY et al. Osteoporos Int. 2002;13(suppl3):S14(O14). Reginster JY et al. Data on file.

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TROPOS - BONE MINERAL DENSITY Relative change from baseline

FEMORAL NECK
Mean % change
8 6 4 2 0 -2 -4 0 6 12 18 24 30 36 16

LUMBAR L2-L4
Mean % change * * * * Mean % change
8

* * * * * *

12

* *

+14.74%

+ 8.21%

4 0 -4 0 6 12 18 24 30

Month

Month

36

At M36 E(SE)=8.21 (0.26), 95% CI [7.70; 8.73] P<0.001

Reginster JY et al. Data on file.

SR 2 g Placebo mean (SEM)

At M36 E(SE)=14.74 (0.35), 95% CI [14.06; 15.42] P<0.001

* P<0.001 Hierarchical step-down procedure

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SOTI and TROPOS studies: Conclusion

Strontium ranelate, provides osteoporotic postmenopausal women with an early and sustained antifracture efficacy Strontium ranelate, 2 g once daily, significantly: reduces vertebral fracture risk as early as the first year and over a 3-year period reduces nonvertebral fracture risk reduces hip fracture risk Strontium ranelate: has an excellent tolerability profile has an innovative mode of action, simultaneously increasing bone formation and decreasing bone resorption

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Meunier PJ, NEJM 2004 (Jan 29), 350:459 Ranelato de Estroncio reduce el riesgo de fracturas vertebrales en mujeres con osteoporosis postmenopusica. 1649 mujeres, promedio 69 aos 2 g de R de estroncio oral v. placebo por 3 a. Anablico y antiresortivo. Activa el Receptor Sensitivo del Calcio. Se absorbe como el Calcio. De base Calcio + Vit. D Las Fx vertebrales sintomticas: RRR 41 %, ARR, 6.1%, NNT, 17. Fx vertebrales no sintomticas (Rx): RRR 37%, ARR 11.9%, NNT 9. Regla 3-30 de MBE + !!! Estudios Comparables: Alendronato NNT 14-18, Risedronato NNT 9-20. BMD aumenta 14.4% (ajustada + 6.8%). Mejora en parmetros bioqumicos, como la F. alcalina especfica. Estudios iniciales con Alendronato + 1-4% en 3 a. Ref. AMB 5/2004

BMJ 2001;323:1100 ( 10 November ) Making evidence easy for general practitioners: Rule 3-30 12 November 2001. Enrique Snchez-Delgado.

After analyzing hundreds of trials, I recognized a pattern, which I tested and confirmed to simplify the evaluation of the evidence. I called this pattern: THE 3-30 RULE OF EVIDENCE BASED MEDICINE.[2]. Basically it means that the trials that are clinically significant and/or cost- effective fulfill at least two of the following characteristics: a Relative Risk Reduction of 30% or more (not less than 20%), an Absolute Risk Reduction of 3% or more (not less than 2%), and a Number Needed to Treat or NNT of 30 or less (not more than 50), that is, for every 30 patients that we treat, we save a life or avoid one clinical event. For the Risk Factors, the most important ones increase the Relative Risk (RRI) at least 30%, mostly having a Relative Risk of 3.0 or more. This simple rule rapidly identifies the Randomized Clinical Trials (R.C.T.) that could have practical clinical applications. The following is a partial list of very successful and well known R.C.T. that clearly fulfill THE 3-30 RULE OF EVIDENCE BASED MEDICINE: ISIS-2, RALES, 4S, LIPID, CARE, WOSCOPS, AFCAPS/TexCAPS, CURE and ASSENT-3, among many others. Prof. Enrique Snchez-Delgado, M.D. Member of the Executive Committee of the International Society of Internal Medicine (ISIM), and of the Nicaraguan Association of Internal Medicine (ANMI). 1.- A C Freeman and K Sweeney. Why general practitioners do not implement evidence: qualitative study. BMJ 2001; 323: 1100 (10 November). 2.- E Snchez-Delgado. Evidence Based Medicine: Rule 3-30. Presented at the XXXII National Medical Congress of the Nicaraguan Medical Association. Managua 08 September 2001.

The Effects of Strontium Ranelate on Bone Remodeling and Bone Safety Assessed by Histomorphometry in Patients with Postmenopausal Osteoporosis convencin anual de la ASBMR 2005 en Nashville (USA). M. E. Arlot et al, J Bone Miner Res. 2005;20(suppl1):S22-23

Bone biopsy in 49 treated and 87 placebo Fem.

The positive effects of SR on bone formation were confirmed by a significant higher osteoblastic surfaces (Ob.S/BS) in treated as compared to untreated (+38%; p=0.047) and by a significant greater Mineral Apposition Rate (MAR) in cancellous and cortical bone (+8%; p=0.008, +11%; p=0.033, respectively). All these findings indicate the stimulating effects of strontium ranelate on the osteoblastic population and MAR and a moderate decrease in bone resorption. They are in agreement with the increase of biochemical markers of formation and the decrease of those of resorption shown in clinical studies

ACKNOWLEDGEMENTS
AUSTRALIA Prof TJ. MARTIN Dr J. GRAHAM Prof KW. NG Dr J. PRINS Dr R. PRINCE Prof E. SEEMAN Prof J. WARK FRANCE Prof PJ. MEUNIER Dr JP. AQUINO Prof C. BENHAMOU Prof F. BLOTMAN Dr O. BONIDAN Prof P. BOURGEOIS Prof J. DEHAIS Dr P. FARDELLONE Prof A. KAHAN Prof JL. KUNTZ Prof C. MARCELLI Prof A. PROST Prof MC. de VERNEJOUL Prof B. VELLAS Prof G. WERYHA GERMANY Dr EM. LEMMEL Dr D. FELSENBERG Prof J. HENSEN Prof HP. KRUSE Prof SCHMIDT Dr J. SEMLER Prof G. STUCKI ITALY Prof S. ORTOLANI Prof S. ADAMI Prof G. BIANCHI Dr ML. BRANDI Prof D. CUCINOTTA Prof C. FIORE Prof C. GENNARI Prof G. ISAIA Prof G. LUISETTO Prof R. PASSARIELLO Prof M. PASSERI Prof G. ROVETTA Prof L. TESSARI BELGIUM Prof JY. REGINSTER Prof JP. DEVOGELAER Prof JM. KAUFMAN Dr F. RAEMAN Dr M. WALRAVENS DENMARK Dr S. PORS-NIELSEN Prof H. BECK-NIELSEN Dr P. CHARLES Dr OH. SRENSEN

U.K Dr T. SPECTOR Dr M. CLEMENTS Dr DV. DOYLE Dr P. RYAN Dr IG. SMITH Dr R. SMITH

SPAIN Dr JB. CANNATA Prof DIAZ-CURIEL / Prof RAPADO Dr TORRIJOS Dr JM. PADRINO Dr A. ROCESVARELA POLAND Prof J. BADURSKI Dr K. HOSZOWSKI Prof RS. LORENC Dr A. SAWICKI GREECE Dr C. PHENEKOS

HUNGARY Dr A. BALOGH Prof R. de CHATEL Prof Z. TULASSAY

SWITZERLAND Prof JP. BONJOUR / Prof R. RIZZOLI

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Michael R. McClung et al.NEJM. Volume 354:821-831 February 23, 2006 Denosumab in Postmenopausal Women with Low Bone Mineral Density

Receptor activator of nuclear factor-B ligand (RANKL) is essential for osteoclast functions. human monoclonal antibody denosumab (anti-RANKL), antiresorptive
Denosumab, s.c., either every three months (at a dose of 6, 14, or 30 mg) or every six months (at a dose of 14, 60, 100, or 210 mg)

Denosumab treatment for 12 months resulted in an increase in bone mineral density at the lumbar spine of 3.0 to 6.7 percent (as compared with an increase of 4.6 percent with alendronate and a loss of 0.8 percent with placebo), at the total hip of 1.9 to 3.6 percent (as compared with an increase of 2.1 percent with alendronate and a loss of 0.6 percent with placebo) The 30-mg and 60-mg doses of denosumab administered at intervals of every three or six months, respectively, appear to be most appropriate for further clinical trials, on the basis of the present report. McClung et al.

Sato y et al.JAMA. 2005 Mar 2;293(9):1121-2. Effect of folate and mecobalamin on hip fractures in patients with stroke: a randomized controlled trial. Hyperhomocysteinemia is a risk factor for both ischemic stroke and osteoporotic fractures in elderly men and women A double-blind, randomized controlled study of 628 consecutive patients aged 65 years or older with residual hemiplegia at least 1 year daily oral treatment with 5 mg of folate and 1500 microg of mecobalamin, or double placebo RRR, 80%...ARR, 7.1%...NNT, 14..!!! Regla 3-30 + !!

Hip fractures: