Osteoporosi e CTIBL: Quali novità

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1 TERAPIE MEDICHE DELL OSSO:UPDATE Osteoporosi e CTIBL: Quali novità Francesco Bertoldo Dipartimento di Medicina Universita di Verona

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4 (Mean age 62.5) T-score < -2.5 T-score > -1 T-score < -1 > Servitja S et al,the Breast 2012

5 Elevato turnover osseo nei pazienti con carcinoma ELEVATO TURNOVER OSSEO (menopausa + terapia ormonale adiuvante + metastasi) CTIBL FRAGILITÀ PROGRESSIONE OSSEA SRE Nuova metastasi Perdita ossea Homing delle cellule tumorali Crescita della metastasi ossea CTX NTX P1NP SDF-1 TGF b PDGF IGF-1 OP CTX NTX P1NP SDF-1 TGF b PDGF OP CTX NTX P1NP SDF-1 TGF b PDGF OP Scheletro non metastatico Nicchia preneoplastica Metastasi ossea Bertoldo F

6 The Bone Health concept in Cancer Patients Hormonal Adiuvant Therapy Chemotherapy Age Low vitamin D levels High Bone Turnover Bone Fragility Bone Loss/Bone Quality Fragility Fracture SRE Fracture Radiotherapy Spinal Compression Orth. Surg. Pain Bone Metastasis

7 CANCER TREATMENT INDUCED BONE LOSS Rate of BMD Loss Normal men Late menop. women 0.5% 1% Early menop women Aromatase Inhibitor Bone Marrow transpl 2 % 2.6% 3.3% Androgen deprivation 4.6% AI + GNrh agonist 7.0% Ovarian failure due chemiother % Lumbar spine BMD (% /year Bone Loss)

8 High Bone Turnover SLOW REVERSIBLE Loss of Bone Mass RAPID IRREVERSIBLE Qualitative / Microarchitectural Damage Bone Fragility Fracture Boivin G et al. Connect Tissue Res. 2002;43:

9 High prevalence of vertebral fractures in women with breast cancer starting aromatase inhibitor therapy 497 women 63 y.o 19.1 % non vertebral Fx 19.7% > 1 vertebral Fx ETA < 60 aa aa >70 aa % > 1 VFX Bouvard B et al; Annals of Oncology, 2012

10 Page 10 AC Lassemiante et al. Endocrine 2014

11 CATEGORIE AD ALTO RISCHIO DI CTIBL / FX BC premenopausa dopo Kemio o K+ GnrH + TAM ( anche dopo la sospensione della terapia adiuvante) BC pre- o postmenopausa alla sospensione TAM BC postmenopausa con switch TAM- AI BC postmenopausa in AI giovani ( < 65 aa) PC men Page 11 Bertoldo F

12 TRATTAMENTO BPs ( denosumab) Linee Guida AIOM 2013 ALGORITMO DECISIONALE NELLA CTIBL Presenza di frattura da fragilità Grado di evidenza II Raccomandazione B SI TERAPIA CON BP o DNB (Secondo le indicazioni della nota 79) NO ETA < 60 aa 60-75aa > 75aa T-score < -2 DEXA T-score < fattore di rischio DEXA T-score <- 1 T-score < fattore di rischio

13 Coleman R et al.

14 ALGORITMO DECISIONALE NELLA CTIBL Linee Guida AIOM 2013 Presenza di frattura da fragilità SI NO TERAPIA CON BP o DNB indicazioni (Secondo le della nota 79) ETA < 60 aa 60-75aa > 75aa DEXA DEXA T-score < -2 T-score < fattore di rischio T-score <- 1 T-score < fattore di rischio TRATTAMENTO BPs ( denosumab)

15 CTIBL IN PROSTATE CANCER- SPECIFIC GUIDELINES GUIDELINES Therapeutic Threshold Treatment EAU 2013 DEXA T-score <-2.5 DNB 60 mg/6 mo. ZOL 4 mg /6 mo. NCCN 2013 FRAX HIP > 3% FRAX major FX >20% AL 70 mg / week ZOL 5 mg /Year DNB 60mg/6 mo.

16 QUALI EVIDENZE PER PREVENZIONE/ TRATTAMENTO DELLA CTIBL? Le attuali linee guida indicano l utilizzo dei bisfosfonati (BP) e DNB Tutti gli studi in BC con BPs e DNB hanno come end-point la prevenzione della perdita di BMD Vi è un unico studio (PC) con end-point la riduzione del rischio di frattura (DNB) Non è definita la posologia del BPs da utilizzare (quella utilizzata per la PMO? Maggiore?) Non vi sono BPs registrati con indicazione CTIBL. E registrato ( ma non rimborsabile ) denosumab (PROLIA 60mg/6 mesi) in PC in ADT

17 % from baseline Effects of Antiresorptive therapy on BMD in BC Women treated with AI % 6.5% Risedronate 35mg/w Ibandronate 150 mg/mo Zoledronate 4 mg 6 mo Denosumab 60 mg/6 mo 4 3% 3.5% 4% 3 2.1% 2 1.% Ellis JCO 2008 Spine Hip Eidtman Ann Oncol 2010 Lester Clin Can Res 2008 Van Poznak JCO 2010

18 J Clin Oncol 2008

19 Lester JE Clin Canc Res 2008

20 Zoledronic acid (zoledronate) for postmenopausal women with early breast cancer receiving adjuvant letrozole (ZO-FAST study): final 60-month results Coleman R et al Annals of Oncology 24: , 2013

21 Denosumab 60 mg/ 6 mo. in PMO Women with BC and AI BMD Mean Percent Change From Baseline (± 95% CI) Primary Endpoint: Percentage change from baseline in lumbar spine BMD vs Placebo Placebo (n = 122) P < versus Placebo Months 5.5% Difference at Month 12 Denosumab (n = 123) 7.6% Difference at Month Ellis GK et al. J Clin Oncol. 2008;26: Reprinted with permission American Society of Clinical Oncology. All rights reserved.

22 BMD Mean Percent Change From Baseline (± 95% CI) Denosumab 60 mg/ 6 mo. Effect on BMD at Cortical Bone Sites Total Hip and Distal 1/3 Radius BMD Mean Percent Change From Baseline (± 95% CI) Total Hip (Proximal Femur) Placebo (N = 122) Denosumab (N = 123) Months 4.7% Difference at Month Distal 1/3 Radius Placebo (N = 106) Denosumab (N =115) Months 6.1% Difference at Month 24 P < versus Placebo Ellis GK et al. J Clin Oncol. 2008;26:

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24 ZOL (Horizon) ALN (FIT1) IBA (BONE) ALN (FIT1) RAL (MORE) StrRan(TROPOS) ZOL (Horizon) % RRR ALN (FIT1) RAL (MORE) IBA (BONE) StrRan(TROPOS) ZOL (Horizon) StrRan(TROPOS) RAL (MORE) IBA (BONE) RRR of fractures in ad hoc pivotal trials 0 Vertebral Non-Vertebral Hip RIS (VERT) Denosumab RIS (VERT) Denosumab RIS (VERT) Denosumab NICE, modif

25 Persistenza d effetto di singola infusione di acido zoledronico 5 mg/5anni Grey et al. Bone 2012

26 > 70% hip fracture reduction

27 % from baseline Bone target agents: effects on BMD in Men with ADT Induced Bone Loss 7 Risedronate 35mg % 4.2% 4% 4.6% 5.3% 4.1% 4.8%. Alendronate 70 mg) Zoledronate 4 mg once y Zoledronate 4mg/ 3 mo DNB 60 mg/6 mo ) 3 2.4% 3.2% 2 1 2% 2% 1.1% 1.1% 0 Spine Ishizako K 2007 Smith NEJM 2009 Michaelson MD 2007; Satoh T 2009 Hip Smith MR 2003; Campbell 2010 Bhoopalam 2009

28 Greenspan S J Clin Oncol 2008

29 RANDOMIZATION Follow-up End of study Prevention of Cancer Treatment Induced Bone Loss (CTIBL) HALT-PC ( ): Denosumab in ADT-Treated Prostate Cancer Key elegibility Criteria Prostate cancer subjects on ADT Subjects 70 years of age or < 70 with T-score < -1.0 No previous IV and limited oral BP use Planned N = 1226 Denosumab 60 mg SC, Day 1 of Months 6, 12, 18, Placebo 60 mg SC, Day 1 of Months 6, 12, 18, Study Month Screen/Randomize Treatment Follow-up/EOS Primary Endpoint: Percentage Change in Lumbar Spine BMD at Month 24 Secondary Objectives: Efficacy of denosumab compared with placebo on: Fractures and BMD at nonvertebral sites Smith M et al. N Engl J Med, 361:745-55, Enrico Cortesi

30 Baseline Characteristics (cont d) Characteristic Placebo (n = 734) SC Denosumab (n = 734) Subjects with T-score < 2.5 at any site a, n (%) 111 (15.1) 105 (14.3) Lumbar spine BMD T-score Median (range) 0.6 ( ) 0.5 ( ) Mean ±SD 0.4 ± ± 1.8 Total hip BMD T-score Median (range) 1.0 ( ) 0.9 ( ) Mean ±SD 0.9 ± ± 1.0 Femoral neck BMD T-score Median (range) 1.5 ( ) 1.5 ( ) Mean ±SD 1.4 ± ± 0.9 a Any site = lumbar spine, total hip, or femoral neck. Smith MR, Egerdie B, Toriz NH, et al. N Engl J Med. 2009;361: Copyright 2009 Massachusetts Medical Society. All rights reserved.

31 Primary/Secondary End Point: BMD Lumbar Spine Total Hip 10 8 Placebo (n = 734) Denosumab (n = 734) 10 8 Placebo (n = 734) Denosumab (n = 734) % difference at 24 mo a % difference at 24 mo P.001 at all measured sites a Primary end point Study Month Smith MR, Egerdie B, Toriz NH, et al. N Engl J Med. 2009;361: Copyright 2009 Massachusetts Medical Society. All rights reserved Study Month

32 Incidence of New Vertebral Fracture Secondary End Point: New Vertebral Fractures Placebo (n = 673) SC Denosumab (n = 679) Month RR 0.15 P =.004 RR 0.31 P =.004 RR 0.38 P = Subject Incidence RR = relative risk. Nb patients 1. 9 % 0. 3 % 3. 3 % 1. 0 % 3. 9 % 1. 5 % Smith MR, Egerdie B, Toriz NH, et al. N Engl J Med. 2009;361: Copyright 2009 Massachusetts Medical Society. All rights reserved.

33 Primary/Secondary End Point: BMD Lumbar Spine Total Hip 10 8 Placebo (n = 734) Denosumab (n = 734) 10 8 Placebo (n = 734) Denosumab (n = 734) % difference at 24 mo a % difference at 24 mo P.001 at all measured sites a Primary end point Study Month Smith MR, Egerdie B, Toriz NH, et al. N Engl J Med. 2009;361: Copyright 2009 Massachusetts Medical Society. All rights reserved Study Month

34 TOREMIFENE REDUCES FRACTURE RISK IN MEN RECEIVING ANDROGEN DEPRIVATION THERAPY FOR PROSTATE CANCER Smith MR, J Urol 2010

35 Incidence new fracture (%) TOREMIFENE REDUCES FRACTURE RISK IN MEN RECEIVING ANDROGEN DEPRIVATION THERAPY FOR PROSTATE CANCER 10_ 9 _ 8 _ 7 _ 2 years RRR 38% (CI ) P _ 5 _ RRR 50% (CI ) P< _ New vertebral fx all fractures Smith MR, J Urol 2010

36 The Bone Health concept in Cancer Patients Goserelin Chemotherapy Aromatase inhibitors Menopause Age Low vitamin D levels High Bone Turnover Homing Cancer cell Premetastatic niche Bone Loss Fragility Fracture SRE Fracture Radiotherapy Spinal Compression Orth. Surg. Pain Bone Metastasis

37 CONCLUSIONI LA normalizzazione del turnover ( entro range anni/premenopausale) permette la prevenzione della perdita di massa ossea, la prevenzione delle fratture ( probabilmente l effetto adiuvante (DSF e OS) Questo si puo realizzare con amino BP e denosumab ( indicazioni, rimborsabilità) alle dosi utilizzate per l OP.Postmenop.