停經後骨質疏鬆症與骨折 - fma.org.t”¡克嵩.pdf · 骨質疏鬆症 (bmd t- score< -2.5...
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停經後骨質疏鬆症與骨折 蔡克嵩 Nov. 8, 2009
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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
-
Bone turnover markers change in opposite directions in the two genders
males femalesTsai KS et al. CTI 1996
-
The higher the turnover rate, the lower the BMD, regardless of age and BW
Tsai KS et al. CTI 1996
-
Mecahanisms of age related bone loss in both genders
100 %
Relative activity
50 85
Female R 130%
Female F 125%
Male R 90%Male F 85%
140%
135%
140%
Age (yrs)
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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
0
5
10
15
20
25
30
40-44 45-49 50-54 55-59 60-64 65-69 70-74 75-79 80~
Prevalence of Vertebral Compression Deformity in Taiwan
(morphometric criteria used : < –3 SD)
>330000 elderlies with prevelent vert. fx. In 2009
Age (years)
perc
ent
Tsai KS et al. CTI 1996
-
0
500
1000
1500
2000
2500
3000
50-54 y 55-59 y 60-64 y 65-69 y 70-74 y 75-79 y 80-84 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
Incidence of Hip Fracture in Taiwan (105)
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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
-
DXA vs Ultrasound?
1. DXA
2. Ultrasound
-
台大醫院vert comp fx病人之 BMD,1990 JFMA
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# Fractures
NORA: Fracture Rate vs Number of Fractures by T-Score
BMD T-scores
Frac
ture
Rat
e pe
r 100
0 Pe
rson
-Yea
rsN
umber of Fractures
>1.01.0 to 0.5
0.5 to 0.00.0 to –0.5
–0.5 to –1.0–1.0 to –1.5
–1.5 to –2.0–2.0 to –2.5
–2.5 to –3.0–3.0 to –3.5
< –3.5
Adapted from Siris ES, et al. JAMA. 2001;286:2815-22.
Fracture RateBMD Distribution
0
10
20
30
40
50
60
0
50
100
150
200
250
300
350
400
450
-
每個因素提高約兩倍骨折風險
-
治療骨密數值還是骨折?
-
歐洲各國的骨折風險不一樣 (應各自考量)
-
以骨折風險決定是否治療
-
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
-
Antiresorptive Agents Increase BMD by Decreasing Remodeling Space and
Prolonging Mineral Acquisition
Remodeling space
Antiresorptive Agent
High Turnover
Low Turnover
New relatively under-mineralized boneAdapted from David Dempster, Ph.D.
Older, relatively highlyMineralized bone
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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
-
Classes of bisphosphonates
1Thurlimann B. Recent Results Cancer Res 1999;149:1–113 2Fleisch H. Endocr Rev 1998;19:80–100
Etidronate
HO
HO OHOH
OH
O
O
P
PCH3
OH
OH
OH
OHO
OP
P
Cl
Cl
HOOH
OH
OHO
O P
PSCl
Clodronate
Tiludronate
‘Simple’ non-N BPs
Ibandronate
Pamidronate
HO
O
OP
POHOH
OH
OHH2N
OHOH
OHO
ON P
P
OH
HO
CH3
CH3
H2NHO
HO
OHOH
OH
O
OP
P
Alendronate
Alkyl-amino BPs
Zoledronic acid
NN
O
O
P
P
HO OH
OHOH
OH
Risedronate
HON O
O=
=
P
P
OHOH
OHOH
Heterocyclic N BPs
-
Molecular mechanism of action of nitrogen-containing bisphosphonates
Mevalonate
Geranyl diphosphate
Farnesyl diphosphate (FPP)
Geranylgeranyl diphosphate (GGPP)
HMG-CoA
FPP synthase
Cholesterol
Statins XN-BPs inhibit FPP synthase, thus blocking the prenylation of small signalling proteins essential for cell function and survival
XRas S
S
S
SRho
Rab
Rac
-
Courtesy of Dr Fraser Coxon, University of Aberdeen
Side view
Top view
Resorption pitIntracellular BP
Bisphosphonates are internalised by osteoclasts during bone resorption
Bisphosphonate (bone surface)Osteoclast membraneCytoskeleton
-
Normal Multinucleated Osteoclast TightlyAdherent to Bone from a Patient Receiving Placebo
An osteoclast from a patient who received 5 mg of alendronate per day for 3 years.
N Engl J Med 2009;360:53-62.
Giant Osteoclast Formation and Long-Term Oral Bisphosphonate Therapy
-
Hydroxyapatite
Ads
orpt
ion
affin
ity
cons
tant
(KL
L/m
ol x
106
)
Octacalcium phosphate
Clod
rona
te
16
12
8
4
0
Nancollas GH, et al. Bone 2005. In press
Bisphosphonates have different binding affinities for bone mineral
Adsorption affinity
constant (KL L/m
ol x 106)
4
3
2
1
0
Etidr
onate
Rise
dron
ate
Iband
rona
te
Alen
dron
ate
Zoled
ronic
acid
Clod
rona
teEt
idron
ate
Rise
dron
ateIba
ndro
nate
Alen
dron
ate
Zoled
ronic
acid
-
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: ???
-
32
Daily ibandronate reduces vertebral fracture risk at 3 years
Ibandronate prescribing information is available on requestRRR = relative risk reduction; intent-to-treat (ITT) at 3 years Relative risk = 0.38 (95% CI: 0.25–0.57)Chesnut CH, et al. J Bone Miner Res 2004;19:1241–9
Frac
ture
inci
denc
e (%
)
10
8
6
4
2
0Placebo Ibandronate
(2.5mg daily)
62% RRR (95% CI 41–75 p=0.0001 vs
placebo)
n=975 n=977
-
Monthly oral ibandronate significantly increases proximal femur BMD
7
6
5
4
3
2
1
0Total hip Femoral neck Trochanter
Mea
n ch
ange
from
bas
elin
eat
2 y
ears
(%)
2.5mg daily (n=292) 150mg monthly (n=289)
*p
-
% P
ati
en
ts W
ith
New
Vert
eb
ral Fra
ctu
res
60%* (43%, 72%)
71%* (62%, 78%)
00
1010
0–1 0–2 0–3
Years
55
1515
1.5% (42/2822)
3.7% (106/2853) 2.2%
(63/2822)
7.7% (220/2853)
3.3% (92/2822)
10.9% (310/2853)
70%* (62%, 76%)
*P < .0001, relative risk reduction vs placebo (95% confidence interval) Adapted from Black DM, et al. N Engl J Med. 2007;356:1809-1822.
Zoledronic Acid Reduced 3-Year Risk of Morphometric Vertebral Fractures (Stratum I) by
70%ZOL 5 mg Placebo
-
*Relative risk reduction vs placebo (95% confidence interval)Adapted from Black DM, et al. N Engl J Med. 2007;356:1809-1822.
P = .0024
1
2
3
0
Placebo (n = 3861) ZOL 5 mg (n = 3875)
Time to First Hip Fracture (months)0 3 6 9 12 15 18 21 24 27 30 33 36
41%* (17%, 58%)
Zoledronic Acid Reduced Cumulative 3-Year Risk of Hip Fractures (Strata I + II) by 41%
Cu
mu
lati
ve I
nci
den
ce (
%)
-
4.54
3.53
2.52
1.51
0.50
4.54
3.53
2.52
1.51
0.50
Total hip BMD increases with bisphosphonates
Mea
n ch
ange
from
bas
elin
eat
2 y
ears
(%)
Not comparative studies1Reginster JY, et al. Ann Rheum Dis 2006;65:654–612Rizzoli R, et al. J Bone Miner Res 2002;17:1988–963Harris ST, et al. Curr Med Res Opin 2004;20:757–64
Ibandronate monthly (150mg)1
4.54
3.53
2.52
1.51
0.50 Alendronate
weekly (70mg)2Risedronate
weekly (35mg)3
3.84.1
3.0
-
ACE 10.8 mg
ACE 5.5 mg
-
A Compliance of >50% Is Required For Any Treatment Benefit
Refill Compliance (MPR) Over 24-Month Period
Prob
abili
ty o
f Fra
ctur
e
Siris ES, et al. Mayo Clin Proc. 2006;81:1013-1022
0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 10.0700.0750.0800.0850.0900.0950.1000.1050.1100.1150.120
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.
A B C
No benefit
51
-
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
Reimbursedcriteria
1. 停經後婦女因骨質疏
鬆症(BMD TSCORE< - 2.5 SD)引起之脊椎壓迫
性骨折 (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
3. 本藥品不得併用
calcitonin、 raloxifene 及活性維生素D3等藥物
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)
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
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
1.6mg/dl 的患者
3. 本品不得併用其他骨質
疏鬆症治療藥
-
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
-
N-BPs = nitrogen-containing bisphosphonates. Modified from Thompson K, Rogers MJ. J Bone Miner Res. 2004;19:278-288.
Acute Phase Reaction and Nitrogen- Containing Bisphosphonates
HMG Co-A
Mevalonate
Farnesyl-PP
Geranylgeranyl-PP
Isopentenyl-PP
R
() T Cell
Activation, Proliferation
IFN-, TNF-
IL-6
PBMCPBMC
N-BPs
Flu-likeFever, myalgia
CRPIL-6
Transient
Lymph
-
Clinical Presentation and Working Diagnosis of ONJ
Clinical features of suspected ONJ• Exposed bone in maxillofacial area
that occurs in association with dental surgery or occurs spontaneously, with no evidence of healinga
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
a Refer for appropriate dental evaluation and care as soon as possible.
ONJ, osteonecrosis of the jaw.
Weitzman R, et al. Crit Rev Oncol Hematol. 2007;62(2):148- 152.
1 cm
-
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 factorsRuggiero, et al. J Oncol Pract. 2006;2(1):7-14; Khosla S, et al. J Bone Miner Res. 2007;22(10):1479-1491; Ailawadhi S, et al. Presented at: ASH 50th Annual Meeting and Exposition; December 6-9, 2008; San Francisco, CA. Abstract 2786.
-
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
-
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.
-
How Long?(FLEX)
-
Healthy HumanIliac Crest Biopsy
Osteoporotic HumanIliac Crest Biopsy
Importance of Connectivity:reversing Osteoporosis
Osteoporosis
Osteoblast
-
Teriparatide 20 µg Pharmacokinetics Fracture Prevention trial
Terip
arat
ide
conc
entr
atio
n (p
mol
/L)
Upper Limit of NormalEndogenous PTH(1-84)
0 243 9 18 2115120
10
20
30
40
50
60
70
Time (Hours)6
-
Pohl, et al. Arthritis Rheum 2003;48(Suppl 9):S234
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%)
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%)
Months on therapy0-6 6-12 12-18 18+
Frac
ture
d as
a p
erce
nt o
f pa
tient
s at
risk
0.0
0.2
0.4
0.6
0.8
1.0
1.2
1.4
1.6
1.8 Placebo, n =544TPTD, n = 541
RR = 0.47 (95%CI, 0.25; 0.86)
-
Patient treated with teriparatide 20µg
Female, age 65Duration 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%)
Effect of Teriparatide on Skeletal Architecture
Baseline Follow-up Jiang UCSF
2005Data from Jiang, J Bone Min Res 2003;18(11):1932-1941
-
PTH: Mechanism Of Action
Dempster et al. 2003
-
Effect of Teriparatide on Structural Indices Quantitative analysis-Significant changes
Trabecular bone volume
Structure model index
Connectivity density
Cortical thickness
P=0.025
P=0.034
P=0.001
P=0.012
Jiang et al. J Bone Miner Res 2003;18(11):1932-1941
Baseline
2005
Post treatment
-
Increasesthickness
Improves geometry (Increases diameter)
PTH (teriparatide) – Effect on Cortical Bone
-
Zanchetta et al. J Bone Miner Res 2003; 18(3):539-543
Comparison after 18 months of therapy
n=101
pQCT Periosteal Circumference(mean ±
SD)
37
38
39
40
41
42
Placebo TPTD20 TPTD40
Perio
stea
lCirc
umfe
renc
e(m
m)
†
*
* P
-
BMD increased by 10% after 18 m of Forteo, then, +/- Fosamax for 2
years in Men
-
After 1.5 yrs of PTH, Fosamax makes difference
-
Net gain after a total period of 4 years : Do not leave patients alone after PTH
treatment
-
Teriparatide
SERMs
Bisphosphonates
Strontium Ranelate
Calcitonins
Bone Formation
Bone resorption
Effect of Anti-osteoporotic traitementson Bone Metabolism
-
Replication
Pre-osteoblast Pre-osteoclasts
Bone formation
Osteoblasts
Apoptosis
Bone resorption
Osteoclasts
Activity
Bone Matrix Synthesis
OPG
RANK RANKL
Dual Dual EffectsEffects of Strontium of Strontium RanelateRanelate in vitroin vitro
Differentiation
CaSR
CaSR
Differentiation
-
Clinical confirmation of uncoupling
• ↑Bone alkaline phosphatase• ↓C cross-linking telopeptide of type I collagen
* Meunier et al. SOTI. N Engl J Med. 2004
-
-4
-2
0
2
4
6
8
0 6 12 18 24 30 36
At M36E(SE)=8.21 (0.26), 95% CI [7.70; 8.73]
P
-
Strontium ranelate reduce the risk of Vertebral Fracture in SOTI study
49%
41%
* Meunier et al. SOTI. N Engl J Med. 2004
-
Incidence of patients with hip fractures(PP)
Kaplan-Meïer, Cox model
0 6 12 18 24 30 36 42
- 41%
placebo
4
2
0
strontium ranelate 2 g/day
Patients (%)
Months
Number of patients with hip fracture:
RR = 0.59 95% CI [0.37;0.95] P=0.025
strontium ranelate: n=24, placebo: n=61
-
Potential target for new medicationSDRM, SARM, calcimimetics, calcilytics, NFkB aby etc.
-
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)。
停經後骨質疏鬆症與骨折�蔡克嵩�Nov. 8, 2009投影片編號 2Two types of age related osteoporosis in women投影片編號 4Bone turnover markers change in opposite directions in the two genders The higher the turnover rate, the lower the BMD, regardless of age and BWMecahanisms of age related bone loss in both genders骨質疏鬆症防治工作之內容投影片編號 9投影片編號 10骨質疏鬆症防治工作之內容DXA vs Ultrasound?投影片編號 13台大醫院vert comp fx病人之BMD,1990 JFMANORA: Fracture Rate vs Number �of Fractures by T-Score投影片編號 16每個因素提高約兩倍骨折風險治療骨密數值還是骨折?歐洲各國的骨折風險不一樣� (應各自考量)以骨折風險決定是否治療投影片編號 21骨質疏鬆症防治工作之內容投影片編號 23Hormonal treatment of postmenopausal osteoporosisClasses of bisphosphonates投影片編號 26Bisphosphonates are internalised by osteoclasts during bone resorption投影片編號 28Bisphosphonates have different �binding affinities for bone mineralBisphosphonate: osteoporosis vaccine?投影片編號 31Daily ibandronate reduces vertebral fracture risk at 3 yearsMonthly oral ibandronate significantly increases proximal femur BMDZoledronic Acid Reduced 3-Year Risk of Morphometric Vertebral Fractures (Stratum I) by 70%Zoledronic Acid Reduced Cumulative 3-Year Risk of Hip Fractures (Strata I + II) by 41%Total hip BMD increases with bisphosphonates投影片編號 37A Compliance of >50% Is Required For Any Treatment Benefit健保給付規定Adversive Effects of Bisphophonates投影片編號 41投影片編號 42Acute Phase Reaction and Nitrogen-Containing BisphosphonatesClinical Presentation and �Working Diagnosis of ONJRisk Factors for ONJ投影片編號 46投影片編號 47投影片編號 48Adverse Effects of BisphophonatesHow Long?(FLEX)投影片編號 52Teriparatide 20 µg Pharmacokinetics�Fracture Prevention trial投影片編號 57Effect of Teriparatide on�Skeletal ArchitecturePTH: Mechanism Of ActionEffect of Teriparatide on Structural Indices�Quantitative analysis-Significant changes投影片編號 62Effects of Teriparatide on Cortical Bone in the Distal Radius Assessed by Peripheral Quantitative Tomography (pQCT)BMD increased by 10% after 18 m of Forteo, then, +/- Fosamax for 2 years in MenAfter 1.5 yrs of PTH, Fosamax makes differenceNet gain after a total period of 4 years :�Do not leave patients alone after PTH treatment投影片編號 70投影片編號 71投影片編號 72Clinical confirmation of uncoupling投影片編號 74Strontium ranelate reduce the risk of �Vertebral Fracture in SOTI study投影片編號 76投影片編號 77���
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