停經後骨質疏鬆症與骨折 蔡克嵩 Nov. 8, 2009

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)

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)

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

# 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

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���