Renata Caudarella. Fondazione Ettore Sansavini per la Ricerca Scientifica (Health Science Foundation ) - GVM Care & Research

Transcription

1 Renata Caudarella Fondazione Ettore Sansavini per la Ricerca Scientifica (Health Science Foundation ) - GVM Care & Research

2 Introduc/on During the past two decades, many randomized controlled trials (RCTs) have inves=gated the use of drug treatment to reduce fracture risk in women with postmenopausal osteoporosis, who are at high risk of fractures. The results of these RCTs guide therapy for postmenopausal osteoporosis and, to a lesser degree of evidence, for glucocor=coid- induced osteoporosis (GIOP).

3 Treatment of osteoporosis The goal of osteoporosis treatment is the preven=on of bone fractures by stopping bone loss and by increasing bone density and strength. Although early detec=on and =mely treatment of osteoporosis can substan=ally decrease the risk of future fracture, none of the available treatments for osteoporosis are complete cures. In other words, it is difficult to completely rebuild bone that has been weakened by osteoporosis. Therefore, preven=on of osteoporosis is as important as treatment.

4 Osteoporosis treatment and preven=on measures are: Life style changes including quikng cigarele smoking, curtailing alcohol intake, exercising regularly, and consuming a balanced diet with adequate calcium and vitamin D; Medica=ons that stop bone loss and increase bone strength, such as : alendronate, risedronate, raloxifene, ibandronate, ranelate, calcitonin; Medica=ons that increase bone forma=on such as teripara=de (Forteo).

5 Established treatments for osteoporosis Rachner TD. et al. Lancet 2011; 9:

6 Calcium & Vitamin D u Pa=ents receiving an=resorp=ve (or anabolic) therapy for documented osteoporosis should receive supplementa=on unless calcium intake and vitamin D status are known to be op=mal u Low intakes of calcium may cause secondary hyperparathyroidism, while high intakes carry a risk of side effects u A total intake from diet and supplements of about 1000 mg/d probably is sufficient and safe

7 The 25(OH)D level needed to maintain a favorable BPs response is 33 ng/ml Pa=ents with a mean 25(OH)D 33 ng/ml had a ~4.5- fold greater odds of a favorable response (P<0.0001). 25(OH)D level was significantly associated with response a 1 ng/ml decrease in 25(OH)D was associated with ~5% decrease in odds of responding (odds ra=o=0.95; 95% CI, ; P=0.0006). Carmel SA, et al. 2012

8 A new classifica?on of bisphosphonates based on mechanism of ac?on. Non- nitrogen- containing bisphosphonates (N- BPs) act by incorpora?on into ATP, whereas alkyl- amino BPs act by interfering with farnesyl pyrophosphate synthase (FPPS). The heterocyclic N- BPs also inhibit the FPPS enzyme and in addi?on stabilize conforma?onal changes that magnify their inhibitory potency Russell R.G.G. et al. Osteoporos Int (2008) 19:

9 Mechanism of ac/on of bisphosphonates on osteoclasts Russell R.G.G. et al. Osteoporos Int (2008) 19:

10 Risk reduc=ons for vertebral fractures a?er 3- year treatment with BPs in clinical trials RR: 0.51 (95% CI: 0.26, 0.63) RR: 0.53 (95% CI: 0.41, 0.68) RR: 0.50 (95% CI: 0.34, 0.78) Pa=ents (%) - 47% - 49% - 50% Boonen S Bone 2007

11 Risk reduc=ons for nonvertebral fractures a?er 3- year treatment with BPs in clinical trials RR: 0.80 (95% CI: 0.63, 1.01) Pa=ents (%) - 20% RR: 0.61 (95% CI: 0.39, 0.94) - 39% NS Boonen S Bone 2007

12 Hip Fracture: Alendronate 3 Placebo Alendronate 5/10mg % incidence % p=0.047 RR=0.49 [CI ] 0 Placebo N=1005 Alendronato N=1022 Black et al. Lancet 1996

13 Hip Fracture: Risedronate Women 70 to 79 years old Women > 80 years old Pa=ents with Hip fractures (%) - 41% p= % n.s. Risedronate Placebo Risedronate Placebo McClung MR et al. New Engl J Med 2001

14 Zoledronic Acid Reduced Cumula=ve 3- Year Risk of Clinical Fractures (Hip, Clinical Vertebral, Non- vertebral) Cumulative Incidence (%) of New Clinical Fractures Over 3 Years %* (17%, 58%) 2.5% (88/3861) Hip Fracture 1.4% Placebo 77% (63%, 86%) 2.6% (84/3861) ZOL 5 mg (52/3875) 0.5% (19/3875) Clinical Vertebral Fracture 10.7% (388/3861) 25% (13%, 36%) 8.0% (292/3875) Non-vertebral Fracture Values above bars are 3-year cumulative event rates based on Kaplan-Meier estimates. *P = ; P < ; P = ; relative risk reduction vs placebo Hip fracture was not excluded from analysis of non-vertebral fracture. Black DM, et al. N Engl J Med. 2007;356:

15 Black DM. et al. NEJM 2012 In the 21st century, osteoporosis, a disease once considered an inevitable consequence of aging, is both diagnosable and treatable. Large, randomized, controlled trials have shown that bisphosphonate therapy for 3 to 4 years is effec=ve in reducing the risk of both non vertebral and vertebral fractures in osteoporo=c women.

16 How long should treatment continue? It remains unclear whether an=- fracture efficacy is sustained beyond 3-5 years. Stopping treatment is followed by increased remodelling, bone loss and further structural damage. There is disagreement whether short periods of 1-2 years off therapy are appropriate aqer every 3-5 years of treatment.

17 Risk to benefit ra?o of BPs BMD increase over 10 yrs Fracture risk reduc=on: probably no further beneficial effect aqer 5-7 yrs Persis=ng an=fracture efficacy, at least for 1-2 yrs aqer discon=nua=on Increased risk of subtrochanteric fractures aqer 5 yrs Possible increased risk of other =me- dependent AEs

18 Bisphosphonates for Osteoporosis Where Do We Go from Here? All labeling for bisphosphonates that are currently approved for treatment of osteoporosis contains an Important Limita=on of Use statement: The op=mal dura=on of use has not been determined. All pa=ents on bisphosphonate therapy should have the need for con=nued therapy re- evaluated on a periodic basis. To op=mize the efficacy of bisphosphonates in reducing fracture risk, decisions to con=nue, treatment must be based on individual assessment of risks and benefits and on pa=ent preference. Whitaker M. et al. New England J Medicine May 2012

19 Published long-term studies of bisphosphonates for osteoporosis Eriksen EF et al. Bone 2013

20 Black DM et al. JAMA 2006 BMD change in FLEX par=cipants

21 Black DM et al. JAMA 2006 Biochemical Markers of Bone Turnover in FLEX Par=cipants

22 Recommenda=ons for Drug Holiday from Bisphosphonates McClang M et al. Am J Med 2013

23 Recent Safety Topics about BPs G.I. side effects Osteonecrosis of the jaw A=picasl diaphysial femoral fracture (Subtrochanteric Fractures) Renal toxicity Atrial Fibrilla=on Transient influenza- like symptoms

24 Denosumab Binds RANK Ligand and Inhibits Osteoclast Forma=on, Func=on, and Survival CFU- GM Hormones Growth Factors Cytokines Prefusion Osteoclast RANKL RANK OPG Denosumab Osteoclast Forma=on, Func=on, and Survival Inhibited Osteoblasts Bone Forma=on Bone Resorp=on Inhibited The above depic=on is currently believed to be the mechanism of ac=on of denosumab; this product is inves=ga=onal. Adapted from: Boyle WJ, et al. Nature. 2003;423: Amgen Inc. All rights reserved. Do not copy or distribute.

25 The Effect of Denosumab on Fracture Risks at 36 Months Phase 3: The FREEDOM Trial RR = 68% P < RR = 20% P = 0.01 Placebo Denosumab RR = 40% P = 0.04 RR = risk reduc=on Cummings SR et al. N Engl J Med 2009

26 Bone turnover markers change in the FREEDOM study Eastell R et al. J Bone Miner Res 2011

27 Percentage change from FREEDOM baseline in BMD at the lumbar spine (A), total hip (B), femoral neck (C), and 1/3 radius (D). Bone HG et al J Clin Endocrinol Metab 98: 4483

28 Cummings SR et al. N Engl J Med 2009 Studio FREEDOM: Even= Avversi

29 Human Parathyroid Hormone H 2 N and Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Glu Val 20 Arg Glu Met Ser Asn Leu His Lys Gly Trp Leu Arg Lys Lys Leu Gln Asp Val His Asn Phe COOH Proc Natl Acad Sci USA 1974;71:

30 PTH - Intermittent PTH - Anabolic effect Stimulates bone formation in both trabecualr and cortical bone - Continuous PTH - Catabolic effect - Stimulates cortical bone resorption - Decreases cortical thickness

31 CHANGE FROM BASE LINE IN BONE MINERAL DENSITY AND TOTAL- BODY BONE MINERAL Neer RM. et al. N Engl J Med, 2001;344:

32 Fracture Preven=on Trial EffeLo di Teripara=de sul rischio di nuove fralure vertebrali % di donne con >1 fralura vertebrale RR 65%* 0 Placebo (64 / 448) TPTD20 (22 / 444) Adapted from Neer et al. N Engl J Med 2001 *P <0.001 vs. placebo RR = rischio relativo vs. placebo

33 Fracture Preven=on Trial EffeLo di Teripara=de sul rischio di fralure non- vertebrali da fragilità 6 % di donne con >1 fralura da fragilità RR 53%* * P = 0.02 vs. placebo 0 Placebo (30 / 544) TPTD20 (14 / 541) Adapted from Neer et al. N Engl J Med 2001

34 Teripara=de Reduces the Risk of Non- Vertebral Low Trauma Fractures Fracture Preven=on Trial (=me to first fracture) Women * (%) Placebo (n=544) RRR=53% ARR=2.9% Teripara=de 20 μg/d (n=541) Months Since Randomiza=on p 0.05 Neer, et al. N Engl J Med 2001;344: * Percent of women who had one or more non- vertebral low trauma fractures during the study

35 Cumula=ve propor=on of women who had 1 non- spine low trauma fracture during follow- up period 0.16 Probability of fracture Placebo TPTD20 TPTD40 (n=1262) 13.5% 8.5% 7.3% RRR=48% Fracture Preven=on Trial Follow- up Study Months since randomization Prince et al., J Bone Miner Res 2005;20: Log rank P- value = 0.009

36 In postmenopausal women with osteoporosis, increased dura=on of teripara=de versus placebo treatment was associated with a progressive decrease in the rates of nonvertebral fragility fractures and back pain. Compared with placebo, the rela=ve hazard for nonvertebral fragility fractures decreased by 7.3% for each addi=onal month of TPTD20 [hazard ra=o=0.927, 95% CI (0.876 to 0.982), p=0.009] and by 7.6% for each addi=onal month of TPTD40 [hazard ra=o=0.924, 95% CI (0.871 to 0.981), p=0.009]. Clinical vertebral fractures appeared to increase over =me in the placebo group and occurred primarily in the first =me interval in the teripara=de treatment groups. Conclusions :These findings suggest increased nonvertebral fracture protec/on

37 Effects of intravenous zoledronic acid plus subcutaneous teripara=de and of subcutaneous denosumab plus subcutaneous teriparatide in postmenopausal osteoporosis

38 Daily and Cyclic TPTD in Women Receiving Alendronate Cosman F et al. NEJM 2005 Lumbar spine Hip bone

39 Teripara=de and denosumab, alone or combined, in women with post- menopausal osteoporosis: the DATA study randomised trial Tsai JN et al. Lancet 2013

40 Teripara=de and denosumab, alone or combined, in women with post- menopausal osteoporosis: the DATA study randomised trial Tsai JN et al. Lancet 2013

41 It was found that combining an=resorp=ve agents with exercise had addi=ve effects on improving lumbar spinebone mass gains in adults with low bone mass. To verify the addi=ve effects further, more RCTs with longer dura=on and larger sample sizes are needed

42 BMD and biochemical parameters at baseline and at 12 months following treatment with iv zoledronate and denosumab: mean (SD) Mosali P. et al. Calcif Tissue Int (2014) 94:

43 Meta- analysis (EX combined an=resorp=ve agent plus exercise, Control an=resorp=ve agent alone) Mosali P. et al. Calcif Tissue Int (2014) 94: