停經後骨質疏鬆症與骨折蔡克嵩. Nov. 8, 2009

Transcription

1 停經後骨質疏鬆症與骨折蔡克嵩 Nov. 8, 2009

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3 Two types of age related osteoporosis in women Type I, early postmenopausal Estrogen deficiency, spine fracture Type II, elderly, bone cells dysfunction, renal and nutritional deficiency, spine and hip fracture Riggs et al. 1983

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5 Bone turnover markers change in opposite directions in the two genders Tsai KS et al. CTI 1996 males females

6 The higher the turnover rate, the lower the BMD, regardless of age and BW Tsai KS et al. CTI 1996

7 Mecahanisms of age related bone loss in both genders 140% 140% 135% Female R 130% Female F 125% 100 % Relative activity Male R 90% Male F 85% Age (yrs)

8 骨質疏鬆症防治工作之內容 Reduce any fracture risk Identify the high risk subjects Treat the bone: timing, duration and complications Socioeconomic considerations 最終目標在於減少骨折

9 Prevalence of Vertebral Compression Deformity in Taiwan (morphometric criteria used : < 3 SD) > elderlies with prevelent vert. fx. In percent ~ 9 Age (years) Tsai KS et al. CTI 1996

10 Incidence of Hip Fracture in Taiwan (10 5 ) y y y y y y y 85+ Beijing female Beijing male US female US male HK female HK male Taiwan1996 female Taiwan1996 male Taiwan1997 female Taiwan1997 male Taiwan1998 female Taiwan1998 male Taiwan1999 female Taiwan1999 male Taiwan2000 female Taiwan2000 male

11 骨質疏鬆症防治工作之內容 Reduce any fracture risk Identify the high risk subjects Treat the bone: timing, duration and complications Socioeconomic considerations 最終目標在於減少骨折

12 DXA vs Ultrasound? 1. DXA 2. Ultrasound

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14 台大醫院 vert comp fx 病人之 BMD,1990 JFMA

15 NORA: Fracture Rate vs Number of Fractures by T-Score Fracture Rate per 1000 Person-Years >1.0 BMD Distribution Fracture Rate # Fractures 0.5 to to to to 3.0 < to to to to to 3.5 Adapted from Siris ES, et al. JAMA. 2001;286: BMD T-scores Number of Fractures

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17 每個因素提高約兩倍骨折風險

18 治療骨密數值還是骨折?

19 歐洲各國的骨折風險不一樣 ( 應各自考量 )

20 以骨折風險決定是否治療

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22 骨質疏鬆症防治工作之內容 Reduce any fracture risk Identify the high risk subjects Treat the bone: timing, duration and complications Socioeconomic considerations 最終目標在於減少骨折

23 Antiresorptive Agents Increase BMD by Decreasing Remodeling Space and Prolonging Mineral Acquisition High Turnover Older, relatively highly Mineralized bone Antiresorptive Agent Low Turnover Remodeling space Adapted from David Dempster, Ph.D. New relatively under-mineralized bone

24 Hormonal treatment of postmenopausal osteoporosis Estrogens with or without progestin, lessons from WHI SERM: raloxifene and others Tibolone: effective but not recommended as a first line drug

25 Classes of bisphosphonates Simple non-n BPs Cl HO P CH 3 HO O O P OH OH OH Etidronate Cl Cl O O P P HO OH OH OH OH Clodronate OH OH O P P S O Tiludronate 1 Thurlimann B. Recent Results Cancer Res 1999;149: Fleisch H. Endocr Rev 1998;19: OH Alkyl-amino BPs H 2 N H 2 N O HO P O OH OH OH P OH Pamidronate CH 3 CH 3 N HO O O HO P HO P O P OH O OH Alendronate OH OH OH OH P OH Ibandronate Heterocyclic N BPs N N N O HO HO P O O = P P = O Risedronate OH OH OH OH OH P OH OH OH Zoledronic acid

26 Molecular mechanism of action of nitrogen-containing bisphosphonates Statins HMG-CoA X Mevalonate N-BPs inhibit FPP synthase, thus blocking the prenylation of small signalling proteins essential for cell function and survival Geranyl diphosphate FPP synthase Farnesyl diphosphate (FPP) Cholesterol X Geranylgeranyl diphosphate (GGPP) Ras Rac Rho Rab S S S S

27 Bisphosphonates are internalised by osteoclasts during bone resorption Top view Intracellular BP Resorption pit Side view Bisphosphonate (bone surface) Osteoclast membrane Cytoskeleton Courtesy of Dr Fraser Coxon, University of Aberdeen

28 Giant Osteoclast Formation and Long-Term Oral Bisphosphonate Therapy Normal Multinucleated Osteoclast Tightly Adherent to Bone from a Patient Receiving Placebo N Engl J Med 2009;360: An osteoclast from a patient who received 5 mg of alendronate per day for 3 years.

29 Bisphosphonates have different binding affinities for bone mineral Octacalcium phosphate Hydroxyapatite Adsorption affinity constant (K L L/mol x 10 6 ) Adsorption affinity constant (K L/mol x 10 6 ) L Zoledronic acid Alendronate Ibandronate Etidronate Risedronate Clodronate Alendronate Zoledronic acid Etidronate Risedronate Ibandronate Clodronate Nancollas GH, et al. Bone In press

30 Bisphosphonate: osteoporosis vaccine? Once daly: all, ritual. Once weekly: alendronate,risedronate Once monthly: ibandronate(p.o.) Once quarterly: ibadronate (i.v.) Once annually: zolendronic acid (i.v.) Once in life time:???

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32 Daily ibandronate reduces vertebral 10 fracture risk at 3 years Fracture incidence (%) % RRR (95% CI p= vs placebo) 0 Placebo Ibandronate prescribing information is available on request RRR = relative risk reduction; intent-to-treat (ITT) at 3 years Relative risk = 0.38 (95% CI: ) Chesnut CH, et al. J Bone Miner Res 2004;19: n=975 n=977 Ibandronate (2.5mg daily) 32

33 Monthly oral ibandronate significantly Mean change from baseline at 2 years (%) increases proximal femur BMD 2.5mg daily (n=292) * 150mg monthly (n=289) * * 0 Total hip Femoral neck Trochanter *p<0.05 vs 2.5mg daily PP population Reginster JY, et al. Ann Rheum Dis 2006;65:654 61

34 Zoledronic Acid Reduced 3-Year Risk of Morphometric Vertebral Fractures (Stratum I) by 70% % Patients With New Vertebral Fractures % (106/2853) 60%* (43%, 72%) 1.5% (42/2822) Placebo 7.7% (220/2853) ZOL 5 mg 71%* (62%, 78%) 2.2% (63/2822) 10.9% (310/2853) 70%* (62%, 76%) 3.3% (92/2822) Years *P <.0001, relative risk reduction vs placebo (95% confidence interval) Adapted from Black DM, et al. N Engl J Med. 2007;356:

35 Zoledronic Acid Reduced Cumulative 3-Year Risk of Hip Fractures (Strata I + II) by 41% Cumulative Incidence (%) Placebo (n = 3861) ZOL 5 mg (n = 3875) P = %* (17%, 58%) Time to First Hip Fracture (months) *Relative risk reduction vs placebo (95% confidence interval) Adapted from Black DM, et al. N Engl J Med. 2007;356:

36 Total hip BMD increases with bisphosphonates Mean change from baseline at 2 years (%) Ibandronate monthly (150mg) 1 Not comparative studies 1 Reginster JY, et al. Ann Rheum Dis 2006;65: Rizzoli R, et al. J Bone Miner Res 2002;17: Harris ST, et al. Curr Med Res Opin 2004;20: Alendronate weekly (70mg) 2 0 Risedronate weekly (35mg) 3

37 ACE 10.8 mg ACE 5.5 mg

38 A Compliance of >50% Is Required For Probability of Fracture Any Treatment Benefit No benefit A B C Refill Compliance (MPR) Over 24-Month Period A = a refill compliance level equivalent to taking one dose in every two; B = equivalent to missing one weekly dose a month; C = equivalent to missing 1 month out of 12 months. Siris ES, et al. Mayo Clin Proc. 2006;81:

39 健保給付規定 Product Bonviva 3mg/3ml injection quarterly Fosamax 70mg tablet weekly Aclasta 5mg/100Ml Solution for infusion Generic name ibandronic acid alendronate sodium zoledronic acid Brand Roche MSD Novartis Indication 用於治療停經後婦女之骨質疏鬆症 (BMD T- SCORE< -2.5 SD) 以減少脊椎骨折 停經婦女骨質酥鬆症之治療, 男性骨質疏鬆症之治療 Reimbursed criteria 1. 停經後婦女因骨質疏鬆症 (BMD TSCORE< SD) 引起之脊椎壓迫性骨折 ( 需於病歷詳細記載 ) 1. 停經後婦女或男性因骨質疏鬆症引起之脊椎壓迫性骨折或髖骨骨折病患 ( 需於病歷詳細記載 ) 1. 變形性骨炎 (Paget s disease) 或停經後婦女因骨質疏鬆症 (BMD T- SCORE< -2.5 SD) 引起之脊椎壓迫性骨折或髖骨骨折 ( 需於病歷詳細記載 ) 2. 血清肌酸酐 (serum creatinine) 小於或等於 2.3mg/dl 的患者 2. 血清肌酸酐 (serum creatinine) 小於或等於 1.6mg/dl 的患者 2. 血清肌酸酐 (serum creatinine) 小於或等於 1.6mg/dl 的患者 3. 本藥品不得併用 calcitonin raloxifene 及活性維生素 D3 等藥物 3. 本藥品不得併用 calcitonin raloxifene 及活性維生素 D3 等藥物 3. 本品不得併用其他骨質疏鬆症治療藥

40 Adversive Effects of Bisphophonates GI upset ONJ Acute renal failure Bone-Joint-Muscular pain Acute phase reaction/first dose effect (plateaus with monthly dose) Uveitis Atrial fibrillation Over-suppression bone syndrome Atypical subtrochanteric fracture Esophageal adenocarcinoma in preceeding Barret s esophagitis.??effects on bone fracture healing/excessive callus

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43 Acute Phase Reaction and Nitrogen- Containing Bisphosphonates PBMC HMG Co-A N-BPs Mevalonate Isopentenyl-PP R ( ) T Cell Flu-like Fever, myalgia Lymph CRP IL-6 Transient Farnesyl-PP Geranylgeranyl-PP N-BPs = nitrogen-containing bisphosphonates. Modified from Thompson K, Rogers MJ. J Bone Miner Res. 2004;19: Activation, Proliferation IFN-, TNF- IL-6

44 Clinical Presentation and Working Diagnosis of ONJ 1 cm Clinical features of suspected ONJ Exposed bone in maxillofacial area that occurs in association with dental surgery or occurs spontaneously, with no evidence of healing a Working diagnosis of ONJ No evidence of healing after 6 weeks of appropriate evaluation and dental care No evidence of metastatic disease in the jaw or osteoradionecrosis ONJ, osteonecrosis of the jaw. Weitzman R, et al. Crit Rev Oncol Hematol. 2007;62(2): a Refer for appropriate dental evaluation and care as soon as possible.

45 Risk Factors for ONJ Periodontal disease Dento-alveolar surgery Oral trauma Corticosteroid therapy Immuno-compromised state (ie, diagnosis of cancer, receiving chemotherapy) Single nucleotide polymorphisms Other possible risk factors Ruggiero, et al. J Oncol Pract. 2006;2(1):7-14; Khosla S, et al. J Bone Miner Res. 2007;22(10): ; Ailawadhi S, et al. Presented at: ASH 50th Annual Meeting and Exposition; December 6-9, 2008; San Francisco, CA. Abstract 2786.

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47 ONJ has been increasingly suspected to be a potential complication of bisphosphonate therapy in recent years. Thus, the ASBMR leadership appointed a multidisciplinary task force to address key questions related to case definition, epidemiology, risk factors, diagnostic imaging, clinical management, and future areas for research related to the disorder. This report summarizes the findings and recommendations of the task force.introduction: The increasing recognition that use of bisphosphonates may be associated with osteonecrosis of the jaw (ONJ) led the leadership of the American Society for Bone and Mineral Research (ASBMR) to appoint a task force to address a number of key questions related to this disorder. MATERIALS AND METHODS: A multidisciplinary expert group reviewed all pertinent published data on bisphosphonate-associated ONJ. Food and Drug Administration drug adverse event reports were also reviewed. RESULTS AND CONCLUSIONS: A case definition was developed so that subsequent studies could report on the same condition. The task force defined ONJ as the presence of exposed bone in the maxillofacial region that did not heal within 8 wk after identification by a health care provider. Based on review of both published and unpublished data, the risk of ONJ associated with oral bisphosphonate therapy for osteoporosis seems to be low, estimated between 1 in 10,000 and <1 in 100,000 patienttreatment years. However, the task force recognized that information on incidence of ONJ is rapidly evolving and that the true incidence may be higher. The risk of ONJ in patients with cancer treated with high doses of intravenous bisphosphonates is clearly higher, in the range of 1-10 per 100 patients (depending on duration of therapy). In the future, improved diagnostic imaging modalities, such as optical coherence tomography or MRI combined with contrast agents and the manipulation of image planes, may identify patients at preclinical or early stages of the disease. Management is largely supportive. A research agenda aimed at filling the considerable gaps in knowledge regarding this disorder was also outlined. PMID: [PubMed - indexed for MEDLINE]

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49 Adverse Effects of Bisphophonates GI upset ONJ Acute renal failure Bone-Joint-Muscular pain Acute phase reaction/first dose effect (plateaus with monthly dose) Uveitis Atrial fibrillation Over-suppression bone syndrome Atypical subtrochanteric fracture??effects on bone fracture healing/excessive callus Esophageal adenocarcinoma in preceeding Barret s esophagitis.

50 How Long?(FLEX)

51 Importance of Connectivity: reversing Osteoporosis Osteoporosis Osteoblast Healthy Human Iliac Crest Biopsy Osteoporotic Human Iliac Crest Biopsy

52 Teriparatide concentration (pmol/l) Teriparatide 20 µg Pharmacokinetics Fracture Prevention trial Upper Limit of Normal Endogenous PTH(1-84) Time (Hours)

53 Teriparatide Efficacy: Nonvertebral fractures The longer the duration of treatment with TPTD, the greater the decrease in risk for nonvertebral fractures (monthly by 9.1%) Fractured as a percent of patients at risk 1.8 Placebo, n = TPTD, n = Pohl, et al. Arthritis Rheum 2003;48(Suppl 9):S Months on therapy RR = 0.47 (95%CI, 0.25; 0.86)

54 Effect of Teriparatide on Skeletal Architecture Patient treated with teriparatide 20µg Data from Jiang, J Bone Min Res 2003;18(11): Baseline Follow-up Jiang UCSF Female, age 65 Duration of therapy: 637 days (approx 21 months) BMD Change: Lumbar Spine: +7.4% (group mean = 9.7 ± 7.4%) Total Hip: +5.2% (group mean = 2.6 ± 4.9%) 2005

55 PTH: Mechanism Of Action Dempster et al. 2003

56 Effect of Teriparatide on Structural Indices Quantitative analysis-significant changes Baseline Post treatment Trabecular bone volume P=0.001 Structure model index P=0.025 Connectivity density P=0.034 Cortical thickness P=0.012 Jiang et al. J Bone Miner Res 2003;18(11):

57 PTH (teriparatide) Effect on Cortical Bone Improves geometry (Increases diameter) Increases thickness

58 Effects of Teriparatide on Cortical Bone in the Distal Radius Assessed by Peripheral Quantitative Tomography (pqct) Comparison after 18 months of therapy pqct Periosteal Circumference (mean ± SD) pqct Polar Moment of Inertia (mean ± SD) Periosteal Circumference (mm) * Placebo TPTD20 TPTD40 Polar Moment of Inertia (mm 4 ) * * Placebo TPTD20 TPTD40 * P<0.005; P<0.001 * P<0.001 n=101 Zanchetta et al. J Bone Miner Res 2003; 18(3):

59 BMD increased by 10% after 18 m of Forteo, then, +/- Fosamax for 2 years in Men

60 After 1.5 yrs of PTH, Fosamax makes difference

61 Net gain after a total period of 4 years : Do not leave patients alone after PTH treatment

62 Effect of Anti-osteoporotic traitements on Bone Metabolism Bone Formation Bone resorption Bisphosphonates SERMs Calcitonins Teriparatide Strontium Ranelate

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64 Dual Effects of Strontium Ranelate in vitro Bone formation Bone resorption Pre-osteoblast Pre-osteoclasts CaSR Replication OPG RANKL RANK Differentiation Osteoblasts Differentiation Bone Matrix Synthesis Activity Osteoclasts CaSR Apoptosis

65 Clinical confirmation of uncoupling Bone alkaline phosphatase C cross-linking telopeptide of type I collagen * Meunier et al. SOTI. N Engl J Med. 2004

66 TROPOS study - Bone Mineral Density Relative change from baseline Mean change (%) Femoral neck * * * * * % * Mean change (%) Lumbar L2-L4 * * * * * % * Month At M36 E(SE)=8.21 (0.26), 95% CI [7.70; 8.73] P<0.001 Mean (SEM) -4 strontium ranelate 2 g/day Month placebo At M36 E(SE)=14.74 (0.35), 95% CI [14.06; 15.42] P<0.001 Mean (SEM). * P<0.001 Hierarchical step-down procedure

67 Strontium ranelate reduce the risk of Vertebral Fracture in SOTI study 41% 49% * Meunier et al. SOTI. N Engl J Med. 2004

68 Incidence of patients with hip fractures (PP) Patients (%) 4-41% RR = % CI [0.37;0.95] P= placebo 0 strontium ranelate 2 g/day Months Number of patients with hip fracture: strontium ranelate: n=24, placebo: n=61 Kaplan-Meïer, Cox model

69 Potential target for new medication SDRM, SARM, calcimimetics, calcilytics, NFkB aby etc.

70 有太多病人未經診斷, 未曾接受治療 醫師們應參與國人骨質疏鬆症之防治 骨鬆症之診斷, 骨折風險評估及葯物與非葯物治療, 已有完整成熟之成套指引 請各位醫師多加入中華民國骨鬆症學會, 多執行骨鬆症防治醫療業務, 並試著取得由該學會發給的 骨質疏鬆症專家醫師證書 ( 必要條件為 該會會員 連續兩年參加年會, 並參加兩次共 8 小時講習課程, 通過考試, 並持有效之國際臨床骨密學會 (ISCD) 證書 )