80
80
60
60
40
40
20
20
1850
1900
1950
2000
1-5 56% 5
26%
. .
.
(
)
40-44
1.3
5.7
65-6不
22.1
26.7
Premenopause
~5%
~15%
15-25 yrs
25-35 yrs
Benefits of Endogenous E2
Perimenopause
35-45 yrs
45-55 yrs
Primary Benefits of HT
Mikkola TS, et al. Ann Med. 2004;36:402-13.
Postmenopause
55-65 yrs
65 yrs
No Benefits of HT
/ 1000
Nachtigall et al, 1979
1.2
--
0
Hammond et al, 1979
0.5
6.5
0
Gambrell, 1987
2.5
3.9
0.5
Persson et al., 1989
1.4
1.8
0.9
子宮內膜癌的人數 每十萬名婦女罹患
：Gordon et al.
雌激素缺乏
正常
雌激素對泌尿道的影響 雌激素可增加尿道壓力 而不容易漏尿
雌激素缺乏會減少尿道壓力 而容易漏尿
雌激素
雌激素
黏膜密合
漏尿
子宮脫垂
2
1
30 噁
)
2 50%
70%
95%
青壯年25-31人 44歲
老年65歲以上 82人
15%
青壯年25-44歲
39%
中年45-64歲
46%
老年65歲以上
中年45-64歲 95人
84年 年
42.81
24.37
85年 年
47.28
28.35
86年 年
53.42
33.06
87年 年
55.26
34.91
88年 年
65.92
40.86
89年 年
67.53
42.65
90年 年
65.84
46.22
乳癌的危險因子 Hormonal Factors: Hormone Level & Stimulation Duration 6. 0 高乳房
5
高血清 雌二醇 者
相對危險性
密度者
4 3 2 1
RR 2.73.5
RR 2.8 (1.9 -3.5)
RR 2.0
RR 2.0
RR 1.6
RR 1.4 (1.2 6)
RR 1.2 1.5
RR 1.2 1.4
RR: 1
RR 0.3 3
7 6 5
高骨質 密度者
4 第一 胎生 育 晚於 30歲 歲
停經後 肥胖 大於20 大於 公斤
3 55歲後 歲後 晚發性 停經者
腰臀 比率 BMI
12歲以前 歲以前 雌激 初經來潮 雌激素 素黃 療法 體素 療法
2
35歲以前 歲以前 卵巢全切 除
Santen R.J., 2003; William’s Textbook of Endocrinology, 10th edition
1
相對危險性
6
RR 5.0 (1.8 -5.0)
7
35 1%~2% , 3~10% ,
正常骨質
骨質疏鬆
Spinal vertebrae
Normal
Osteoporosis
Peripheral bone
脊椎骨骨折圖
骨質密度比較 正常骨質
被壓垮的脊椎骨 骨折
骨質疏鬆 髖部骨折圖
股骨頸骨折
正常髖關節 大小轉子間骨折
ďźšChristiansen C et al. Lancet 1981:1:459
ďźšLindsay R., Clin Obstet Gynecol 1987;30:847
, 噁
)
噁HRT .Bisphosphonate Calcitonin) 噁Calcium,VITD,Fluoride,protos.polia) 噁Calcium,VIT
1 shot 60mg every 6 months Subcutaneously Prolia Package with attached reminder card
Prolia Package with top-web blister pack
RANKL: Receptor Activator for Nuclear Factor κ B Ligand OPG: Osteoprotegerin
RANK Ligand RANK
Osteoclast precursors RANK
RANK
OPG
Differentiated Osteoclast
Bone Resorption and Formation are Balanced in Premenopausal Women
Oestrogen
RANK Ligand
OPG binds to RANK Ligand
OPG
Vitamin D
Oestrogen limits the expression of RANK Ligand
Osteoblasts
IL-11
Osteoblasts
IL-6 IL-1
PTHrP
TNF-α α
PGE2
PTH
Activated Osteoclast
Glucocorticoids
OPG: osteoprotegerin Boyle WJ, et al. Nature 2003;423:337-342. Kostenuik PJ, et al. Curr Pharm Des 2001;7:613-635.
X Normal
No BMD Change
OPG absent
Decreased BMD
OPG excess
Increased BMD
Bolon B, et al. Arthritis Rheum. 2002; 46: 3121-3135. Reprinted with permission of Wiley-Liss, Inc., a subsidiary of John Wiley & Sons, Inc.
RANKL
OPG
=
Normal estrogen levels in healthy premenopausal women
RANKL Postmenopausal patient, low estrogen levels
Healthy bone
OPG
= Increased bone loss leading to osteoporosis
ProliaÂŽ rapidly decreases active osteoclasts within hours of administration as measured by bone turnover markers, and increases BMD from as early as month 1 of treatment (P < 0.05)1 Serum denosumab
Lumbar Spine BMD
Serum concentration of denosumab ng/ml
- 20 6000
4000
-
-0 - -40
-
- -60 2000
0
-
- -80
0
2
4 6 Time (Month)
8
10
-0 12
-5 -4 -3 -2 -1 -0
Lumbar Spine BMD Percentage Change from Baseline (%)
-
Seum CTX Change (%) From Baseline Mean Âą SE
8000
Serum CTX
McClung MR, et al. N Engl J Med. 2006;354:821-31 ; Vasikarin SD. Crit Rev Clin Lab Sci .2008;45:221-258
Crude Incidence (%)
RR = 68% P < 0.0001
RR = 71% P < 0.0001
RR = 61% P < 0.0001
Intent-to-treat, last observation carried forward analysis GSK Data on file.
68% reduced risk of new vertebral fractures
Cumulative Incidence (%)
Placebo
8
†
20%
6.5%*
6 4 2 0 0
6
12
3,906
18
24
30
3,264
3,121
20% reduced risk of nonvertebral fractures
36
Month
Number of patients at risk
Placebo, n
8.0%
Denosumab 60 mg Q6M
3,750
3,578
3,410
3,009
Denosuma 3,902 3,759 3,594 3,453 3,337 3,228 3,130 † Nonvertebral fractures were reduced by 20% (95% CI: 0.67, 0.95) b, n *P = 0.01 Cummings SR, et al. N Engl J Med. 2009;361:756-765. Copyright © 2009 Massachusetts Medical Society. All rights reserved.
Cumulative Incidence (%)
Placebo Denosumab 60 mg Q6M
1.2
1.2%
†
40%
0.8
0.7%*
0.4
24
30
40% reduced risk of hip 36 fractures
3,430
3,311
3,221
3,397
3,311
0.0 0
6
12
3,799
3,672
Number of patients at risk
Placebo, n
3,906
18 Month 3,538
Denosuma 3,902 3,796 3,676 3,566 3,477 † Hip fractures were reduced by 40% (95% b, n
CI: 0.37, 0.97)
*P = 0.04 Cummings SR, et al. N Engl J Med. 2009;361:756-765. Copyright © 2009 Massachusetts Medical Society. All rights reserved.
CFU-GM
Pre-fusion osteoclast
Osteoclast formation inhibited
RANKL RANK OPG RANKL inhibitor
Osteoclast function and survival inhibited
Hormones Growth factors Cytokines
Osteoblasts
Bone formation
Bone resorption inhibited
CFU-GM=colony forming unit granulocytemacrophage; M-CSF=macrophage colony stimulating factor. Boyle WJ, et al. Nature 2003;423:337-342.
BP = bisphosphonates High affinity for hydroxyapatite (HAP) crystals
RANK L
BP
RANK BP BP
OPG Denosumab
BP
Denosumab blocks RANK Ligand
X Denosumab blocks osteoclast formation, formation function and survival
BP BP
BP BP
Bone
BPs bind to bone mineral at sites of bone resorption
BP BP BP BP BP BP
Bone
BP
BP BP
BP BP BP
BP BP
Bone
BPs cause loss of resorptive function but ‘disabled’ osteoclasts may persist
JAMA, Feb. 18, 2009-Vol 301,No.7
Bisphosphonates Reduce Bone Turnover and Allow Increased Mineralization of Existing Bone
Reproduced with permission from Seeman E. Advances in Osteoporotic Fracture Management 2002 and Fyhrie DP. Bone 1994
Bone Remodeling is Accelerated in Osteoporosis
Building up the bone capital: PROTOS generates new bone Menopause
Bone mass
PROTOS
As early as possible Right from 50
ild ne u b bo e R ew n
Maintain Anti-resorptive
0
10
20
30
40
50
60
70
80 Age
From: Compston JE. Clin Endocrinol. 1990;33:653-682
3
1. 2.
3.
噁4
)
4. 5. 6.
Window Plunger
Needle guard Needle cover
Where should you give the injection? The best places to inject are the top of the thighs and the abdomen
1
2
3
4
5
6