Differentiating Pharmacological Therapies for Osteoporosis Socrates E Papapoulos Department of Endocrinology & Metabolic Diseases Leiden University Medical Center The Netherlands Competing interests: consulting/speaking fees from: Amgen, GSK, Lilly, Merck, Novartis,Pfeizer, Roche, Warner Chilcott
Osteoporosis A systemic skeletal disease characterised by low bone mass and microarchitectural deterioration of bone tissue, with a consequent increase in bone fragility and susceptibility to fracture Consensus Development Conference, 1993 Horizontal Disconnections Dempster 2000
Osteoporotic Fractures Clavicle, scapula, sternum Humerus Ribs Pelvis Distal forearm Femur Tibia, fibula WHO Scientific Technical Report 2007
Clinical Significance of Osteoporotic Fractures Fractures are: frequent associated with increased morbidity and deterioration of the quality of life increase the risk of new fractures associated with increased mortality
Fracture Prevention General measures vitamin D, calcium Non-pharmacological interventions frequency or impact of falls Pharmacological interventions
Pharmacological Agents for the Treatment of Osteoporosis Inhibitors of bone turnover Bisphosphonates, Calcitonin, Denosumab Oestrogens, SERMs, Tibolone Stimulators of bone formation Parathyroid Hormone Uncertain action Strontium Ranelate.
Principles of Evidence-Based Medicine First principle Some evidence is stronger than other There is a hierarchy of evidence Use evidence as high in hierarchy as possible Second principle Evidence alone is never enough Should be combined with clinical judgment and patient values (Guyatt et al 1999)
EBM Antifracture Efficacy of Pharmacological Interventions VERTEBRAL Fx NON-VFx HIP Fx ALN, ETID, IBN, RIS, ZOL Dmab PTH SR ALN, IBN, RIS, ZOL Dmab PTH 1-34 SR ALN, RIS ZOL Dmab RCTs -Meta-analysis
Long-Term Effects Several drugs have proven benefits in the treatment of postmenopausal osteoporosis, Due to the chronic, progressive nature of the disease, therapies are likely to be prescribed for >5 10 years Thus, it is important to explore the efficacy of long-term treatment: Sustained effect (BMD, bone turnover, fracture risk) Reversibility of effect upon discontinuation
Fracture Incidence % FLEX: Incidence of Fractures by Treatment Group 25 20 ALN/PLB (n = 437) ALN/ALN (n = 662) RR = 1.0 CI (0.8, 1.3) 15 10 RR = 0.9 CI (0.6, 1.2) 5 RR = 0.45 CI (0.2, 0.8) RR = 1.0 CI (0.5, 2.1) 0 5% 2% 11% 10% 19% 19% Clinical Vertebral Vertebral Morphometric Nonvertebral 3% 3% Hip Black DM et al. JAMA. 2006
% Patients Continuous ZOL Treatment Resulted in Significantly Fewer New Morphometric VFx 15 PBO ZOL Core Study (Yr 0-3) Z3P3 Z6 P3Z3 10.9% (310/2853) RH 70% 10 6.2% (30/486) RH 52% 5 3.3% (92/2822) 3.0% (14/469) 2.9% (17/585) 0 Core study 1 Extension study Morphometric Vertebral Fractures P3Z3 group included only to maintain core study blind. Patients not included in the pre-planned primary or secondary efficacy analysis. Caution should be used in interpreting the findings as approx. 500 P3Z3 patients completed the study prior to end of Year 3; P3Z3 not comparable to other arms Black et al JBMR 2012
Serum CTX-I (ng/ml) Serum PINP (μg/l) Serum CTX-I and P1NP Values Over Time Alendronate Denosumab sctx I P1NP 0.9 DECIDE 1 STAND 2 70 DECIDE 1 STAND 2 0.8 60 0.7 0.6 0.5 50 40 0.4 0.3 0.2 0.1 0 BL 1 3 6 9 12 BL 1 3 6 9 12 Study Month 30 20 10 0 BL 1 3 6 9 12 BL 1 3 6 9 12 Study Month Dotted line is lower limit of the premenopausal reference range (The University of Sheffield Bone Marker Laboratory). Values are medians; error bars represent the interquartile range; P 0.01 1. Brown JP, et al. J Bone Miner Res 2009;24:153;. 2. Kendler DL, et al. J Bone Miner Res. 2010;25:72.
Effect of 6 Years of Continuous Denosumab Treatment on Total Hip BMD Phase 2 Extension Study Denosumab Discontinued denosumab Alendronate Discontinued alendronate Parent Study Placebo Extension Study 6.1% vs baseline 6 18 Adapted from: Miller PD et al. J. Clin Endocrinol Metab. 2011 Feb;96(2):394-402.
FREEDOM Extension Study Design International, multicenter, open-label, single-arm study FREEDOM EXTENSION R A N D O M I S A T I O N R A N D O M I Z A T I O N Year 0 1 2 3 4 5 6 7 8 9 10 Year Denosumab 60 mg SC Q6M (N = 3902) Placebo SC Q6M (N = 3906) Denosumab 60 mg SC Q6M (N = 2343) Calcium and Vitamin D Denosumab 60 mg SC Q6M (N = 2207) 0 1 2 3 4 5 6 7 Long-term Denosumab Cross-over Denosumab Key Inclusion Criteria Must have completed the FREEDOM study (received denosumab or placebo) Not receiving any other osteoporosis medications Adapted from : Cummings S et al. N Engl J Med 2009;361:756-65. ; Papapoulos S, et al. JBMR 2012; 27(3): 694-701.
Percent Change From FREEDOM Baseline Percent Change in BMD at the Lumbar Spine and Total Hip 18 16 14 12 10 8 6 4 2 0 2 Placebo Lumbar Spine FREEDOM EXTENSION 10 FREEDOM EXTENSION 15.2% 2 0 0 1 2 3 4 5 6 Study Year Cross-over Denosumab 8 4 2 Total Hip 6 10.1% 9.4% 5.7% Long-term Denosumab 0 1 2 3 4 5 6 Study Year 7.5% 4.8% LS means and 95% confidence intervals. P < 0.05 vs FREEDOM baseline; P < 0.0001 vs FREEDOM baseline and Extension baseline. Yellow numbers on the graphs represent the percent change in BMD while on denosumab treatment.
Yearly Incidence of Nonvertebral Fracture (%)s Yearly Incidence of Nonvertebral Fractures Through 6 Years: Long-term Group 3.5 3.0 2.5 2.0 3.1% 2.6% Placebo Denosumab FREEDOM EXTENSION 2.9% 2.5% 2.2% 2.1% 1.5 1.4% 1.2% 1.3% 1.0 0.5 0.0 n N 116 98 3906 3902 103 75 3688 3682 83 73 3454 3487 32 26 24 2343 2243 2066 1 2 3 4 5 Years of Treatment Exposure 6
Incidence of Hip Fractures Over 6 years According to Age Papapoulos S et al ASBMR 2012
Conclusions Antiosteoporotic treatments are generally efficacious and well tolerated They have a favourable risk/benefit ratio, particularly these which reduce the incidence of hip fractures Knowledge of the efficacy, mechanism of action and risk profile of every treatment prescibed is essential for proper patient care