Medical Treatment for Osteoporosis ~From today to tomorrow. Presented by 劉明村

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1 Medical Treatment for Osteoporosis ~From today to tomorrow Presented by 劉明村

2 Miacalcic Qualitative Effects of Salmon Calcitonin Therapy (QUEST)

3 NIH Definition of Osteoporosis Osteoporosis is defined as a skeletal disorder characterized by compromised bone strength predisposing a person to an increased risk of fracture. Bone strength primarily reflects the integration of bone density and bone quality. Normal bone Osteoporosis NIH Consensus Development Panel on Osteoporosis. JAMA 285 (2001):

4 Bone quantity vs bone quality: Evolution of the paradox Treatment Fluoride 1 Raloxifene 2 Salmon calcitonin 3 Risedronate 4 Alendronate 5 Strontium-ranelate 6 BMD: Bone mineral density Decrease in vertebral fracture risk (%) Increase in vertebral BMD (%) Riggs BL et al. N Engl J Med. 1990;322: Ettinger B et al. JAMA. 1999;282: Chesnut C III et al. Am J Med. 2000;109: Harris ST et al. JAMA. 1999;282: Black DM et al. Lancet. 1996;348: Meunier P et al. N Engl J Med. 2004;350;459-68

5 The importance of architectural integrity Normal bone 10% decrease in BMD due to loss in trabecular thickness equals 20% reduction in bone strength 10% decrease in BMD due to loss in trabecular number equals 70% reduction in bone strength Silva MJ. Gibson LJ. Bone. 1997:21;191 9 Parfitt AM. Am J Med. 1991; 91 (Suppl5B):42S-46S.

6 Conclusion Thus, based on BMD alone, antiresorptive agents that induce a greater increase in BMD cannot be assumed to be more efficacious in reducing fracture risk than those producing a lower BMD increase. Riggs BL, Melton LJ III. J Bone Miner Res 2002;17:11 4

7 Study design 2-year, double-blind, randomized, placebo-controlled study Miacalcic 200 IU NS vs placebo NS All patients received calcium 500 mg daily 91 postmenopausal women At least 5 years post menopause 1 5 vertebral fractures at baseline

8 Change vs placebo (%) Bone turnover serum CTx Difference to placebo in serum CTx in the QUEST Study (*p < 0.05) 0 QUEST study 1 2 years * serum CTx Chesnut CH III et al. J Bone Miner Res. 2005; in press 2. Srivastava A et al. Calcif Tissue Int. 2004;75:477-81

9 Median change vs placebo (%) BMD data from QUEST and PROOF Difference to placebo in BMD at the lumbar spine in the QUEST and PROOF studies at 2 years QUEST study / 2 years PROOF study / 2 years 1. Chesnut CH III et al. J Bone Miner Res in press 2. The Proof study. Data on file

10 3D visualization from high-resolution MRI 36-year-old male (BV/TV = 0.28) 69-year-old male (BV/TV = 0.14) Beuf O, Ghosh S, Newitt DC et al. Arthritis Rheum 2002;46:385 93

11 Bone microarchitecture MRI of the radius Only trabecular structures were evaluated Region 1 Region 2 Region 3 Region 4 Region 1 is 7 mm from the distal endplate Regions 1 4 are each 2.5 mm thick (corresponding to 5 MRI slices)

12 Mean % change Radius MRI: Trabecular bone volume Mean percentage change in apparent trabecular bone volume (BV/TV) from baseline to 24 months 6 4 * p = 0.03 p = Miacalcic Placebo *** Region 1 Region 2 Region 3 Region 4 *** Change from baseline within group: *p < 0.05; ***p < 0.005

13 Mean % change Radius MRI: Trabecular number Mean percentage change in apparent trabecular number from baseline to 24 months 6 4 p = 0.05 p = 0.01 p = ** Miacalcic Placebo *** *** Region 1 Region 2 Region 3 Region 4 Change from baseline within group: **p < 0.01; ***p < 0.005

14 Mean % change Radius MRI: Trabecular spacing Mean percentage change in apparent trabecular spacing from baseline to 24 months Miacalcic Placebo p = 0.01 p = ** ** * Region 1 Region 2 Region 3 Region 4 Change from baseline within group: *p < 0.05; **p < 0.01

15 Bone quality: Microarchitecture MRI of the hip (trabecular bone) Four regions of the hip were analysed: Femoral Neck Ward s triangle Upper trochanter Lower trochanter

16 Mean change from baseline (%) Hip MRI Mean percentage change in T2*, from baseline to 24 months *** * *** Miacalcic Placebo p = *** -4-6 Femoral neck Ward s triangle Upper trochanter Lower trochanter Change from baseline within group: *p < 0.05; ***p < 0.005

17 Conclusions Treatment with Miacalcic 200 IU NS for 2 years demonstrated Improvements (vs. placebo) in bone quality (i.e. BV/TV, trabecular number and spacing) in the forearm (radius), as measured by MRI Improvements in bone quality (vs. placebo), expressed by T2 ( decreased % relative to placebo) at the hip (femoral neck, Ward s triangle, upper and lower trochanters), statistically significant at the lower trochanter BMD increase of 0.8% (ns) at the lumbar spine vs. placebo 26% decrease in bone resorption (p < 0.05), as evaluated by serum CTx No differences in the bone formation marker (serum BSAP) compared to placebo

18 Miacalcic 產品特色 對於治療骨折急性期伴隨骨痛的骨質疏鬆症患者 Miacalcic ( 密鈣息 ) 是 : 第一線的快速有效止痛且安全的鼻噴劑藥物, 它提供增加 β-endorphine 濃度, 達到止痛的效果, 減少臥床情況 Miacalcic 長期使用可減少骨質流失 ; 增加骨密度與骨品質 (PROOF and QUEST); 預防再次骨折, 增加生活品質

19 健保局給付規範 處方 Miacalcic 之建議 抑鈣激素製劑 (Salmon calcitonin nasal spray, injection) 限惡性疾病之高血鈣症或變形性骨炎 (Paget s disease) 或停經後骨質疏鬆症引起之骨折 請先了解在處方 Miacalcic 前, 是否已完成下列事項 : 1. 是否病人已完成骨鬆檢查 (DXA<-2.5) ( 需提及為骨質疏鬆症 ) 2. 是否詳述病人年齡及性別 ( 需說明停經多久 ) 3. 是否有骨折 ( 需附骨折部位之 X 光片 ) 4. 不得併用 Fosamax, Actonel, Evista, Vitamine D3 5. 是否詳述症狀 - 疼痛嚴重性, 疼痛多久及部位, 活動能力 6. 請說明病人已經用過同藥理之常用藥品無效, 並舉出藥品名稱 藥品代碼藥品名稱價格劑型 B MIACALCIC AMPOULES 100I.U./ML 注射劑 B MIACALCIC INJECTION 50 MRC-U/ML (50IU /ML) 注射劑 B MIACALCIC NASAL SPRAY 200I.U. 2.8KIU/BOT 14PUFF 1,976.0 鼻用氣化噴霧

20 Zoledronic Acid: Annual Bone Health management for Osteoporosis ~ From Cancer treatment to Paget s Disease and PMO treatment ~

21 Molecular Structure of Zoledronic Acid Zoledronic acid is a potent nitrogen containing bisphosphonate Core bisphosphonate moiety (red arrows) R 2 side chain: imidazole ring (blue arrows) N N O HO P O OH P C OH OH OH Green JR, et al. J Bone Miner Res. 1994;9:

22 = Proposed Mechanism of Local Recycling of Zoledronic Acid in Bone Zoledronic acid has high affinity for bone mineral leading to: N N HO O P P = O OH OH OH OH ZOL has long duration of action Avid uptake BP Low desorption BP High re-attachment through recycling BP BP BP High-affinity BPs may diffuse less well in bone and remain nearer accessible surfaces G Russell (2005).

23 IC 50 (mm) K L (L/mol x 10 6 ) Zoledronic Acid: Key Pharmacological Characteristics High binding affinity for bone in vitro Maximizes attachment Minimizes detachment Potent FPP synthase inhibition in vitro Maximizes antiresorptive potential Minimizes total amount of drug required Allows single administration of total annual dose 1. Nancollas GH, et al. Bone. 2006, in press. 2. Dunford JE, et al. J Pharmacol Exp Ther. 2001;296: Binding to Hydroxyapatite CLO ETD RIS IBA ALN ZOL rhfpp synthase ALN IBA RIS ZOL

24 Pharmacological Properties of Zoledronic Acid Achieves prolonged suppression of bone resorption No deleterious effect on bone quality Increases bone mineral density Reduces bone turnover Does not impair mineralization Has favourable effects on structural & mechanical properties of bone IV administration does not blunt bone anabolic response to PTH

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26 Zoledronic Acid Demonstrated Broad Efficacy in Women With Postmenopausal Osteoporosis In women with postmenopausal osteoporosis, once yearly infusion of ZOL 5 mg over 3 years significantly reduces 1 : Vertebral fractures (morphometric 70%, clinical 77%) 1 Hip fractures (41%) 1 Non-vertebral fractures (25%) 1 Days of disability due to fracture or back pain 2 Height loss 1 Significantly superior to placebo in increasing or preserving BMD 1 Markers of bone formation and resorption were reduced and maintained within premenopausal reference range over 36 months 1 Generally well tolerated 1 Fracture efficacy coupled with high adherence suggests potential role for ZOL 5 mg as treatment for osteoporosis 1 1. Black DM, et al. N Engl J Med. 2007;356: Black DM, et al. Presented at: ASBMR 28th Annual Meeting; September 15-19, 2006; Philadelphia, Pa. Abstract (n=7,736)

27 The HORIZON Recurrent Fracture Trial *Lyles KW, et al. N Engl J Med. 2007; :1-11.

28 Recurrent Fracture Trial Study Conclusions Zoledronic acid*: significantly reduced risk of overall clinical fracture by 35% and multiple clinical fractures by 33% significantly reduced mortality risk by 28% significantly reduced risk of clinical vertebral and non-vertebral fractures by 46% and 27%, respectively had a 30% lower risk in hip fractures compared to placebo (NS) significantly increased/preserved total hip and femoral neck BMD at all time points showed comparable incidence of AEs and SAEs to placebo demonstrated no evidence of long-term effect on renal function demonstrated a 20% reduction in risk of atrial fibrillation/atrial flutter SAEs (n=12, 1.1%) relative to the placebo (n=15, 1.4%) No adverse effects on fx. healing or ONJ risk *Lyles KW, et al. N Engl J Med. 2007; :1-11. (n=2,127; men and women)

29 Zoledronic Acid will Improve Patient Compliance as Once-Yearly IV Therapy is Preferred More convenient More satisfying Once-Yearly IV Both Are Equal Once-Weekly Pill More willing to take long term Overall preference N = % of Patients Data from Lindsay R, et al. Poster presented at ECCEO6; March 15-18, 2006; Vienna, Austria.

30 Thanks for your attention! Aclasta is coming soon