The Tawanese Osteoporosis Association

103

2013 ASBMR /

/

/

O

03-3281200#8957

03-3187510

E m a i l toaservice@gmail.com

www.toa1997.org.tw

2013 ASBMR /

/

/

1 /

/

X (DXA) /

/

-Capture the Fracture /

2014 (APBMR) /

1

3

4

4

10

15

121

111

28

28

50

84

94

98

62

1

714

IOF Regionals - 5th

Asia-Pacific Osteoporosis Meeting in Taipei

2014APBMR

1

2

5 24 POST

ASBMR

2

3

review

BRONJ

Capture the

fracture

ASBMR 2014 2nd APBMR

IGF-1

3

4

2013 ASBMR

ASBMR

(Baltimore) webcast

Wnt

1. LRP 5/6 Wnt co-receptor frizzled LRP

Wnt ligand

2. Wnt 19 Wnt 1Wnt 3 Wnt 1

osteogenesis inperfecta Wnt16

5

3. R-spondingWnt

DKK (

4 ) sclerostin ( 1 )

4. sclerostin osteosarcoma

leukemia

(OA) sclerostin OA

5. ER

Wnt

6. serotonin

-blocker SSRI

serotonin

6

7. Anti-myostatin ? aged mice

1.

2. Denosumab

Denosumab

remodeling (mechanical stimulations) bone

formation periosteum endosteum

modeling process subcortical porosity

subcortical porosity

remodeling

7

porosity modeling

formation subcortical porosity

3. Denosumab teriparatide

RANKL

bone formation

4. zolendronic acid

Zest study

Zolendronic acid

5. Sclerostin Amgen romosozumab

210 mg

5% hip 3%

sclerostin Wnt/beta-catenin RANKL

sclerostin

8

6. sclerostin

DXA QCT (HRQCT)

finite element analysis (FEA) stiffness

QCT (vBMD)

romosozumab DXA

teriparatide

7. HRQCT FEA

microindentation test (MIT) invasive

9

()

10

1960

2009 30

6.7

11

1. Forteo)

12

18000

2. bisphosphonate)

3. prolia) RANKL

13

4. Evista)SERM

5. Protos)

14

15

1 1,2

1

2

(1)

2003

(BONJ

bisphosphonate-associated osteonecrosis of the jaw) (2)

(:

zolendronic acid, 4mg)

(: ) (3-5)

16

(6, 7)

0.028% 4.3% (8) 150

2007

(AAOMS The American Association of Oral and

Maxillofacial Surgeons)

(9)

17

(population level)

(referral

bias) Sedghizadeh

(10)

4.3%

2007

(ICD-9th CM codes)

2007 (ICD-9th CM

codes: 733.45)Solomon

2010

(8)

18

AAOMS (11,

12) ()

Lo

(8, 11)

Kaiser Permanente of Northern California

13,946

AAOMS

0.07%-0.10%

(13-15)

(14, 16)

2012Tennis

19

(HealthCore Integrated Research Database)

(14)

(adjusted rate ratio,

0.61; 95 % CI, 0.084.9)

AAOMS

(active control)

2014

(6, 7)

(7)

50 alendronate raloxifene

20

raloxifene

6,485 alendronate 1,869 raloxifene

alendronate

(adjusted hazard ratio, 7.42; 95%CI, 1.02-54.09) 12

alendronate 0.55%

clinical outcome

(:

)

(referral bias)

lost-follow up

(raloxifene )

21

hazard ratio (adjusted hazard ratio, 7.42;

95%CI, 1.02-54.09) (unmeasured

confounders)

2003-2007 50

(alendronate, raloxifene calcitonin) raloxifene

calcitonin

(8)

8

8

(: penicillin, cephalosporin, clindamycin, fluoroquinolone)

50

0.07-0.08% alendronate

(raloxifene/calcitonin)

22

(propensity score matching) (HR,

0.86; 95 % CI, 0.441.69)

on-treatment scenario

()

(misclassification bias)

23

( USFDA EMA)

USFDA denosumab

(Prolia)

(17)

2020

24

0.07%-0.55%

(patient registry)

1. Silverman SL, Landesberg R. Osteonecrosis of the jaw and the role of bisphosphonates: a

critical review. [Review] [60 refs]. American Journal of Medicine. 2009;122(2

Suppl):S33-45.

2. Marx RE. Pamidronate (Aredia) and zoledronate (Zometa) induced avascular necrosis of the

jaws: a growing epidemic. J Oral Maxillofac Surg. 2003;61(9):1115-7.

3. Woo SB, Hellstein JW, Kalmar JR. Systematic review: bisphosphonates and osteonecrosis of

the jaws (vol 144, pg 753, 2006). Annals of Internal Medicine. 2006;145(3):235-.

4. Ruggiero SL, Mehrotra B, Rosenberg TJ, Engroff SL. Osteonecrosis of the jaws associated

with the use of bisphosphonates: A review of 63 cases. Journal of Oral and Maxillofacial

Surgery. 2004;62(5):527-34.

5. Marx RE, Sawatari Y, Fortin M, Broumand V. Bisphosphonate-induced exposed bone

(osteonecrosis/osteopetrosis) of the jaws: Risk factors, recognition, prevention, and treatment.

Journal of Oral and Maxillofacial Surgery. 2005;63(11):1567-75.

6. Lin TC, Yang CY, Yang YHK, Lin SJ. Incidence and risk of osteonecrosis of the jaw among

the Taiwan osteoporosis population. Osteoporosis International. 2014;25(5):1503-11.

7. Chiu WY, Chien JY, Yang WS, Juang JM, Lee JJ, Tsai KS. The risk of osteonecrosis of the

jaws in Taiwanese osteoporotic patients treated with oral alendronate or raloxifene. J Clin

Endocrinol Metab. 2014:jc20134119.

25

8. Solomon DH, Mercer E, Woo SB, Avorn J, Schneeweiss S, Treister N. Defining the

epidemiology of bisphosphonate-associated osteonecrosis of the jaw: prior work and current

challenges. Osteoporos Int. 2013;24(1):237-44.

9. Advisory Task Force on Bisphosphonate-Related Ostenonecrosis of the Jaws AAoO,

Maxillofacial S. American Association of Oral and Maxillofacial Surgeons position paper on

bisphosphonate-related osteonecrosis of the jaws. Journal of Oral & Maxillofacial Surgery.

2007;65(3):369-76.

10. Sedghizadeh PP, Stanley K, Caligiuri M, Hofkes S, Lowry B, Shuler CF. Oral

bisphosphonate use and the prevalence of osteonecrosis of the jaw An institutional inquiry.

Journal of the American Dental Association. 2009;140(1):61-6.

11. Lo JC, O'Ryan FS, Gordon NP, Yang J, Hui RL, Martin D, et al. Prevalence of osteonecrosis

of the jaw in patients with oral bisphosphonate exposure. J Oral Maxillofac Surg.

2010;68(2):243-53.

12. Hong JW, Nam W, Cha IH, Chung SW, Choi HS, Kim KM, et al. Oral

bisphosphonate-related osteonecrosis of the jaw: the first report in Asia. Osteoporos Int.

2010;21(5):847-53.

13. Wilkinson GS, Kuo YF, Freeman JL, Goodwin JS. Intravenous bisphosphonate therapy and

inflammatory conditions or surgery of the jaw: a population-based analysis.[see comment].

Journal of the National Cancer Institute. 2007;99(13):1016-24.

14. Tennis P, Rothman KJ, Bohn RL, Tan H, Zavras A, Laskarides C, et al. Incidence of

osteonecrosis of the jaw among users of bisphosphonates with selected cancers or

osteoporosis. Pharmacoepidemiology & Drug Safety. 2012;21(8):810-7.

15. Zavras AI, Zhu S. Bisphosphonates are associated with increased risk for jaw surgery in

medical claims data: is it osteonecrosis?[see comment]. Journal of Oral & Maxillofacial

Surgery. 2006;64(6):917-23.

26

16. Pazianas M, Blumentals WA, Miller PD. Lack of association between oral bisphosphonates

and osteonecrosis using jaw surgery as a surrogate marker. Osteoporosis International.

2008;19(6):773-9.

17. Xue F, Ma H, Stehman-Breen C, Haller C, Katz L, Wagman RB, et al. Design and methods

of a postmarketing pharmacoepidemiology study assessing long-term safety of Prolia

(denosumab) for the treatment of postmenopausal osteoporosis. Pharmacoepidemiology &

Drug Safety. 2013;22(10):1107-14.

27

28

1

1 (IGF-1)

.?

IGF-1

IGF-1

IGF-1 (insulin-like growth factor 1)

SM

29

somatomedins

IGF-1 IGF-2

1957 Salmon Daughaday (growth hormone,

GH )

35s GH

GH

[1]

1963 Froesh

NSILAS

(non-suppressible insulin-like activity)[2]

1972PiersonTemin

(multiplication-stimulating activity)

30

[3, 4]

1978 Rinderknech Humbel NSILA()

proinsulin

(IGF)

IGF

[5-8]

IGFs (IGF-IGF-)

IGF- 70

7649Da IGF- 67

7471Da 0.1%SDS 62%IGF-1

49%IGF-2

47%IGFs

IGF IGF-

IGF- (-6 ) (Mannose-6-phosphate

receptorM6PR

(Insulin receptor, Ir) 22

31

IGF (Insulin, Ins) IGF

Ir Ins > IGF-> IGF- IGF-IGF-

> IGF- > Ins IGF-IGF- > IGF- Ins

IGF-1

90%IGF-1

IGF-1 HGH

HGH HGH

IGF-1 20 HGH

IGF-1

IGF-1

IGFs

(Binding Proteins, BPs)

8 IGFBP12345678

50%

IGF

IGFBP3 80% IGF

IGFBP3 150kDa (

32

IGF )IGFBP2,5,6 IGF-

IGFBP134 IGF- IGF-IGFBP

IGF IGF IGF

IGF IGF/IGFBP

IGF (1)

IGF

(2)IGF IGFBP

(3) IGFBP

IGF

33

IGF- IGF-

IGFs

34

IGF- IGF-IGF-

GH DNA

IGF- IGF-

IGFs

Kniss

IGFs

IGFs

IGF- mRNA IGF- mRNA

IGF-I mRNA

IGF-mRNA

35

IGF-

IGF- 15

IGF- IGFBP1

IGF-IGF-

IGF- IGF-

40% IGF- 8%

10%IGFBP1

IGF-

IGF-

131

19 40 IGF- IGF-

IGFs

[9-13]

IGF- IGF-

10.5

30%IGF- IGF-

IGF-R IGF-R

45%

36

IGF IGF

[14, 15]

Daughaday 1988 IGF- IGF-

(1) IGF-BP3(2) GH

GH IGF-IGF- GH IGF-I

IGF- IGF-

IGF- GH

IGF- GH

IGF--GH

GH IGF-IGF- GH IGF

IGF- GH

GH

IGF- GH

IGF- IGF-

IGF-

37

IGF- mRAN IGF-

GH IGF-

IGF-[16]

Backeljauw, P. F. and L. E. Underwood [16] IGFs

GH Laron's GH

Laron's GH GH IGF-

GH IGF- GH

GH GH

GH GH Laron's

IGF- 2 10cm/

GH

GH IGF-

GH IGF-1

IGF-1

38

IGF-1 IGF-1 IGF-1

12 IGF-1

IGF-1

GH IGF-1

GH IGF-1 IGF-1

IGF-1

Environmental cues Brain

LiverTargettissues

Pit.

Growth hormone

Insuline

Nutrition/Food

IGFBPs

IGF-1

IGF-1/IGFBPs

Growth

-

+

+

+

+

+/-

Environmental cues Brain

LiverTargettissues

Pit.

Growth hormone

Insuline

Nutrition/Food

IGFBPs

IGF-1

IGF-1/IGFBPs

Growth

-

+

+

+

+

+/-

Insulin

Environmental cuesEnvironmental cues Brain

LiverTargettissues

Pit.

Growth hormone

Insuline

Nutrition/Food

IGFBPs

IGF-1

IGF-1/IGFBPs

Growth

-

+

+

+

+

+/-

Environmental cues Brain

LiverTargettissues

Pit.

Growth hormone

Insuline

Nutrition/Food

IGFBPs

IGF-1

IGF-1/IGFBPs

Growth

-

+

+

+

+

+/-

Insulin

Environmental cues

39

IGF-1

IGF-1

1. IGF-1

II

[17]

2. IGF-1

3. IGF-1

4. IGF-1

IGF-1

II

40

5. IGF-1

6. IGF-1

7. IGF-1

IGF-1

IGF-1

IGF-1

1. IGF-1

2. IGF-1

II

II IGF-1

45

3. IGF-1

41

IGF-1

IGF-1

1. IGF-1

, IGF-1

IGF-1

IGF-1 NIH1991

Because these hormones are digested in the gastro-

intestinal tract and are not absorbed intact into the bloodstream,

they are not believed to have biological significance when

ingested, at least after the newborn period.

2. IGF-1 10%

80% 46%

IGF-1

IGF-1

IGF-1

42

250ml/

IGF-1

10%

IGF-1

IGF1

IGF1

IGF1 IGF

[18,19]

IGF-1 ?

1994 FDA rBGH

1520

IGF1

IFG1

43

IGF-1

IGF-1

IGF-1 IGF-1

IGF-1

IGF-1

IGF-1

IGF1

IGF1 5%% IGF1

IGF1

IGF1

[18, 19]

IGF-1 ?

44

IGF-1

[20]

(1)

(2)

(3)

(4)

(5)

(6)

IGF-1

IGF-1 [21]

IGF-1 IGF-1

(1)

(2)

(3)

(4)

(5) LDL(-)

(6) HDL(-)

(7)

(8)

45

(9)

(10)

(11)

(12)

(13)

(14)

(15)

(16) ()

IGF-1

(1)

(2)

(3)

(4)

(5)

(6)

(7)

(8)

(9)

IGF-1?

IGF-1 level

[22- 24] IGF-1

46

modulation of IGF-1 deposition in the bone matrix

could potentially be a therapeutic approach to delay or prevent

osteoporosis.

1. Salmon, W.D., Jr. and W.H. Daughaday, A hormonally controlled serum factor which

stimulates sulfate incorporation by cartilage in vitro. J Lab Clin Med, 1957. 49(6): p. 825-36.

47

2. Froesch, E.R., et al., Antibody-Suppressible and Nonsuppressible Insulin-Like Activities in

Human Serum and Their Physiologic Significance. An Insulin Assay with Adipose Tissue of

Increased Precision and Specificity. J Clin Invest, 1963. 42: p. 1816-34.

3. Daughaday, W.H., et al., Somatomedin: proposed designation for sulphation factor. Nature,

1972. 235(5333): p. 107.

4. Pierson, R.W., Jr. and H.M. Temin, The partial purification from calf serum of a fraction with

multiplication-stimulating activity for chicken fibroblasts in cell culture and with

non-suppressible insulin-like activity. J Cell Physiol, 1972. 79(3): p. 319-30.

5. Blundell, T.L., et al., Insulin-like growth factor: a model for tertiary structure accounting for

immunoreactivity and receptor binding. Proc Natl Acad Sci U S A, 1978. 75(1): p. 180-4.

6. Rinderknecht, E. and R.E. Humbel, Primary structure of human insulin-like growth factor II.

FEBS Lett, 1978. 89(2): p. 283-6.

7. Rinderknecht, E. and R.E. Humbel, The amino acid sequence of human insulin-like growth

factor I and its structural homology with proinsulin. J Biol Chem, 1978. 253(8): p. 2769-76.

8. Zapf, J., et al., Nonsuppressible insulin-like activity (NSILA) from human serum: recent

accomplishments and their physiologic implications. Metabolism, 1978. 27(12): p. 1803-28.

9. Spencer, J.A., et al., Third trimester fetal growth and umbilical venous blood concentrations

of IGF-1, IGFBP-1, and growth hormone at term. Arch Dis Child Fetal Neonatal Ed, 1995.

73(2): p. F87-90.

10. Wang, H.S., J.D. Lee, and Y.K. Soong, Effects of labor on serum levels of insulin and

insulin-like growth factor-binding proteins at the time of delivery. Acta Obstet Gynecol

Scand, 1995. 74(3): p. 186-93.

11. Larsen, T., et al., Growth hormone, insulin-like growth factor I and its binding proteins 1 and

3 in last trimester intrauterine growth retardation with increased pulsatility index in the

umbilical artery. Clin Endocrinol (Oxf), 1996. 45(3): p. 315-9.

48

12. Ostlund, E., M. Tally, and G. Fried, Transforming growth factor-beta1 in fetal serum

correlates with insulin-like growth factor-I and fetal growth. Obstet Gynecol, 2002. 100(3): p.

567-73.

13. Verhaeghe, J., et al., Regulation of insulin-like growth factor-I and insulin-like growth factor

binding protein-1 concentrations in preterm fetuses. Am J Obstet Gynecol, 2003. 188(2): p.

485-91.

14. Baker, J., et al., Role of insulin-like growth factors in embryonic and postnatal growth. Cell,

1993. 75(1): p. 73-82.

15. Liu, J.P., et al., Mice carrying null mutations of the genes encoding insulin-like growth factor

I (Igf-1) and type 1 IGF receptor (Igf1r). Cell, 1993. 75(1): p. 59-72.

16. Backeljauw, P.F. and L.E. Underwood, Prolonged treatment with recombinant insulin-like

growth factor-I in children with growth hormone insensitivity syndrome--a clinical research

center study. GHIS Collaborative Group. J Clin Endocrinol Metab, 1996. 81(9): p. 3312-7.

17. Aydin, F., et al., IGF-1 Increases with Hyperbaric Oxygen Therapy and Promotes Wound

Healing in Diabetic Foot Ulcers. J Diabetes Res, 2013. 2013: p. 567834.

18. Key, T.J., Diet, insulin-like growth factor-1 and cancer risk. Proc Nutr Soc, 2011: p. 1-4.

19. Genkinger, J.M., et al., Consumption of dairy and meat in relation to breast cancer risk in the

Black Women's Health Study. Cancer Causes Control, 2013. 24(4): p. 675-84.

20. Sax, A.T., et al., The insulin-like growth factor axis: A biological mechanism linking physical

activity to colorectal cancer survival. Cancer Epidemiol, 2014. 38(4): p. 455-9.

21. Kochanska-Dziurowicz, A.A., et al., The effect of maximal physical exercise on relationships

between the growth hormone (GH) and insulin growth factor 1 (IGF-1) and transcriptional

activity of CYP1A2 in young ice hockey players. J Sports Med Phys Fitness, 2014.

22. Paccou, J., J. Dewailly, and B. Cortet, Reduced levels of serum IGF-1 is related to the

presence of osteoporotic fractures in male idiopathic osteoporosis. Joint Bone Spine, 2012.

79(1): p. 78-82.

49

23. Ohlsson, C., et al., Older men with low serum IGF-1 have an increased risk of incident

fractures: the MrOS Sweden study. J Bone Miner Res, 2011. 26(4): p. 865-72.

24. Carney, E.F., Bone: modulation of IGF-1 might prevent osteoporosis. Nat Rev Rheumatol,

2012. 8(8): p. 440.

50

Calcitonin

Alendronate, Ibandronate, Zoledronate(PTH

1-34) Selective estrogen receptor modulator (SERM) (Raloxi-

fen)(Bazedoxifene) (Strontium Ranelate) RANKL antibody

(Denosumab)

osteoblastogenesis osteoclastogenesis

osteoblast osteoclast

osteoclast osteoclast

demineralization cysteine protease type

1 collagen matrix Cathepsin K

(collagen type I) 90%

Cathepsin K cysteine protease Cathepsin K

51

matrix degradation bone losscathepsin K L-006235

Cathepsin K inhibitor

odanacatib (MK-0822)balicatib (AAE581) relacatib (SB-462795)

balicatib relacatib cathepsin

Balicatib Phase II

relacalib ()

MSD odanacatib Phase 2

2010 5 JBMR 2 Phase 2

odanacatib 25 mg spine, total hip

BMD resorption marker JBMR

online first 3 odanacatib 50 mg 2

spine, total hip BMD resorption marker2012

11 JBMR 5 Phase 2 50mg

3 5 50mg5

spine BMD 11.9% femoral neck BMD 9.8%

25 mg 50mg BMD

50mg 3 10 mg

52

50mg BMD bone marker

CTX 53bone specific ALP 15PINP 7.2%

TRAP5b 57 osteoclast type I collagen

bone formation 50mg

odanacatib

UTI

2 QCT spine trabecular hip

vBMD femoral neck cortical bone mineral content cortical

volume L1 Placebo 14.3

hip Placebo 5.610

hip

QCT odanacatib proximal femur cortical,

subcortical trabecular vBMD BMC radius tibia

QCT highresolution peripheral (HRp)QCT odanacatib

radius tibia trabecular vBMD, cortical vBMD, cortical

53

thickness,cortical area(HRp)QCT odanacatib

radius tibia strength (failure load) distal radius

odanacatib trabecular thickness, bone volume/total volume (BV/TV)

proximal radiusodanacatib cortical porosity distal tibia

odanacatib trabecular number, separation BV/TV

2007

16000 2012 7

odanacatib

ONO-5334 Phase II

(OCEAN study) 50mg 2 100mg

300mg2 lumbar spine, femoral neck total hip

BMD 300mg serum urine CTX

alendronate Resorption marker TRAP5b odanacatib

Formation marker bALP PINP 6

baselineformation and resorption marker

alendronate

54

osteoclast v3integrin

v3integrin bone loss2005 JCEM

v3integrin antagonist (L-000845704) 200mg bid

spine, total hipfemoral neck total body BMD bone

formation resorption marker headache, dermatitis,pruritus,

rash urticaria

Src tyrosine kinase inhibitors Src tyrosine kinase

ruffled border Saracatinib

(AZD0530) Src tyrosine kinase inhibitors 2010 JBMR

60 to 250 mg Phase I 250mg

sCTX 88%uNTX/Cr 67

maker sCTX 75uNTX/Cr 60

Formation marker

Glucagon-like peptide 2 (GLP-2) intestinal endocrine cells

bone resorption bone

formationphase II 2009 bone

0.4 mg, 1.6 mg 3.2 mg GLP-2 resorption

marker CTX formation marker osteocalcin 3.2 mg

55

trochanter total hip BMD spine BMD

activin Aactivin A antagonist

ACE-011 (sotarcept) phase I study 2009 JBMR

single subcutaneous doses (from 0.01 to 3.0 mg/kg) and intravenous

doses (from 0.03 to 0.1 mg/kg) bone ALP CTX and

TRACP-5b

osteoblastogenesisWnt- -catenin signaling

Wnt- -catenin signaling bone

formation Sclerostin Dkk-1 Wnt- -catenin signaling

monoclonal sclerostin antibody (Romosozu-

mab(AMG 785) Blosozumab) Wnt- -catenin signaling

bone formation

monoclonal Dkk-1 antibody (BHQ880) multiple myeloma

Phase II trial

Ronacaleret ca sensor receptor antagonist

PTH Phase II 200, 300, 400mg

56

ronacaleret trabecular bone vBMD 400mg

vBMD alendronate teriparatide

1/3 cortical BMD placebo

spine

BMD hip BMD

Nitroglycerin 2010

JAMA double-blindRCTNitroglycerin ointment (15 mg/d)

spine, hip, femoral neck BMD6.7%, 6.2%, 7%

radius tibia trabecular vBMD cortical thickness

increased bone-specific ALP 34.8% urine

N-telopeptide 54.0% placebo

PTHestrogen receptor

modulator PTH(131), US 2009/0010940 Al

45g spine, total hipfemoral neck BMD

Forteo 20g BMD

Phase III trial

2013 bone PK profiles Cmax

57

5 mg24 spine BMD 2.2%

formation marker osteocalcin 23% resorption marker CTx-1

PTH-related protein 136 (PTHrP[136]) (BA058,formerly

BIM44058)Phase II trial ClinicalTrial.gov

(NCT00542425) 80g spine, total hip

BMD Forteo 20g Phase III trial

(NCT01343004)

Delayed-release risedronate bisphosphonate pH

sensitive enteric coating

Phase II

delayed-release risedronate 35mg

BMD 5 mg risedronate formation

resorption marker

Ligand lasofoxifene PEARL study 2010 NEJM

3 Phase III trial lasofoxifene 0.25 and 0.5 mg

estrogen receptor breast cancer

58

lasofoxifene 0.5 mg

Lasofoxifene 0.5mg breast cancer 79%

ER-positive invasive breast cancer 83%

Lilly arzoxifene Generations trial 2009 JCEM

2 Phase III trial (FOUNDATION study) arzoxifene 20

mg spine, total hip BMD bone formation

resorption marker2010 JBMR 3

Phase III trial arzoxifene 20 mg

invasive breast cancer

breast cancer tamoxifen

Phase III

Osteologix Strontium malonate

40 Servier Protos 27 Phase

II trial0.751 2 g) strontium malonate resorption marker

BMD

59

2010 JCEM

PTH1-34 40g 30

spine, total hip BMD Forteo 20g bone

formation resorption markerplacebo2010 J Clin Pharm

0.8mg calcitonin calcitonin

resorption marker

50ml 200ml calcitonin

calcitonin trial (ORACAL) Phase III 2012 JBMR

calcitonin spine BMD calcitonin placebo

trochanteric and total proximal femur BMDresorption markers

80%

10%

1. Bone. 2013;53: 160166.

2. N Engl J Med 2010;362:686-96.

3. JAMA. 2011;305(8):800-807

60

4. J Bone Miner Res. 2012; 27(2): 255262.

5. J Bone Miner Res. 2012; 27(11):2251-8.

6. J Clin Endocrinol Metab. 2013;98(2):571-80.

7. J Bone Miner Res. 2014; 29(8):1786-94.

8. J Bone Miner Res. 2014 Jun 4. doi: 10.1002/jbmr.2292.

9. Bone 67 (2014) 104108

10. J Bone Miner Res. 2014; 29(2):458-66.

11. Osteoporos Int. 2013; 24(1):301-10.

12. J Bone Miner Res. 2010; 25: 463-71.

13. Bone 45 (2009) 833842

14. J Bone Miner Res 2009;24:744752.

15. J Natl Cancer Inst.102(22)(2010): 17061715.

61

62

X (DXA)

9

[1-5]

20%[6-7] 50

[8][9]

50

20%

40-50 2050

[2]

(1)(low

bone mass) (2) (microarchitectural

deterioration of bone tissue)

[10] X

63

(DXA) DXA

DXA [11]

DXA (bone mineral density, BMD)

DXA /(osteopenia/ low bone mass)

()

(High-resolution peripheral

quantitative computed tomography, HRpQCT)

(Flat-panel volume CT)(Magnetic resonance imaging,

MRI)

64

X

2D 3D

DXA DXA

X DXA

X

(finite element analysis of X-ray images, FEXI)

2D [12-14]

(densitometric evaluation) DXA

[15]

DXA2D

2DDXA

(trabecular bone score, TBS)

(TBS) 2D

3D ( Fourier

conversion, fractal analysis, run-length analysis) 3D

65

3D

(Trabecular Bone Score, TBS)?

2D

DXA

(variogram)

2D 3D

2D -

(log-log transform)

()

66

2D

2D

TBS

DXA

(

)

DXA

(

)

L1-L4

TBS 1.35TBS 1.2-1.35

67

TBS

68

model index, SMI)

DXA 3D

Silva

(HRpQCT)

(trabecular stiffness)

Silva 115

(QCT)

QCT

HRpQCT

69

45-85 L1-L4 14.5%

(65 8.5%)[18] Simonelli

46-90 L1-L4

16% 65

-0.004 -0.006[19] 29,407

[20]

(Precision)

BMD TBS

BMD 1.1% 1.35% TBS 1.9%

1.5% [21] OPUS TBS 1.44%BMD

1.18% [22]Popp TBS 1.12%BMD

0.9% [23]TBS 1.12-1.9%BMD

0.9-1.35%

70

[24-29]

(BMD) T

(TBS)

[30, 31]

TBS 1.8-3.81

1.71 1.3-2.46

(Odds ratios) 95%Y

71

() TBS 1.45-1.54

1.46 1.34-1.62

OPUS(the Osteoporosis and Ultrasound Study)[22]

(Odds ratios) 95%Y

72

(antiresorptive

therapy)

Teriparatide

(

)X *Antiresorptives: Bisphosphonates(86%),

Raloxifene(10%) Calcitonin(4%)

73

[39][40,41]

[42][43][44]

[45][46][47]

(Vertebral osteoarthritis)

Dufour [18]

(r=0.503, p

74

FRAX

( fracture risk assessment tool,

FRAX) 10

FRAX

[48,49]

(p

75

15-35kg/m2

GE Lunar Hologic

DXA

DXA

DXA

DXA

DXA (

2013 ISCD )

76

(histomorphometry) HRqQCT

[50,51] GE-Lunar DXA

TBS

TBS

BMI 15 35kg/m2

CT

DXA

77

DXA

TBS iNsight

medimaps group

1. Barbara C Silva,1 William D Leslie,2 Heinrich Resch, et al. Trabecular bone score: a

noninvasive analytical method based upon the DXA image. J Bone Miner Res. 2014 Mar;

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with osteoporotic fractures. Osteoporos Int. 2006 Dec;17(12):172633.

78

3. Kanis J. on behalf of the World Health Organization Scientific Group. Assessment of

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Group Technical Report; 2007.

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management of osteoporosis in postmenopausal women. Osteoporos Int. 2013

Jan;24(1):2357.

5. Oden A, McCloskey EV, Johansson H, Kanis JA. Assessing the impact of osteoporosis on

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7. Hannan EL, Magaziner J, Wang JJ, et al. Mortality,locomotion 6 months after

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using anteroposterior dualenergy Xray absorptiometry acquisition, and 3dimensional

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Clin Densitom. 2011 JulSep;14(3):30212.

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80

21. Hans D, Goertzen AL, Krieg MA, Leslie WD. Bone microarchitecture assessed by TBS

predicts osteoporotic fractures independent of bone density: the Manitoba study. J Bone

Miner Res. 2011 Nov;26(11): 27629.

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density for prediction of osteoporotic fractures in postmenopausal women: the OPUS study.

Bone. 2013 Nov;57(1): 2326.

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Mar;28(3):44954.

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spine BMDmatched, casecontrol study. J Clin Densitom. 2009 AprJun;12(2):1706.

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27. Del Rio LM, Winzenrieth R, Cormier C, Di Gregorio S. Is bone microarchitecture status of

the lumbar spine assessed by TBS related to femoral neck fracture? A Spanish casecontrol

study. Osteoporos Int. 2013 Mar;24(3):9918.

28. Krueger D, Fidler E, Libber J, et al. Spine trabecular bone score subsequent to bone mineral

density improves fracture discrimination in women. J Clin Densitom. 2013 Jun 14. [Epub

ahead of print].

81

29. Lamy O, Krieg MA, Stoll D, et al. The OsteoLaus Cohort Study: bone mineral density,

microarchitecture score and vertebral fracture assessment extracted from a single DXA

device in combination with clinical risk factors improve significantly the identification of

women at high risk of fracture. Osteologie. 2012;21:7782.

30. Leib E, AubryRozier B, Winzenrieth R, Hans D. Vertebral microarchitecture and fragility

fracture in men: a TBS study. J Bone Miner Res. 2012;27(Suppl 1):S435 (abstract).

31. Lorenc R, HorstSikorska W. TBS as a predictor of vertebral fracture in Polish men.

ASBMR 2012. J Bone Miner Res. 2012;27(Suppl 1):S487 (abstract).

32. Boutroy S, Hans D, SornayRendu E, et al. Trabecular bone score improves fracture risk

prediction in non osteoporotic women: the OFELY study. Osteoporos Int. 2013

Jan;24(1):7785.

33. Iki M, Tamaki J, Kadowaki E, et al. Trabecular bone score (TBS) predicts vertebral

fractures in Japanese women over 10 years independently of bone density and prevalent

vertebral deformity: the Japanese populationbased osteoporosis (JPOS) cohort study. J

Bone Miner Res. 2014 Feb;29(2):399407.

34. Krieg MA, AubryRozier B, Hans D, Leslie WD. Effects of antiresorptive agents on

trabecular bone score (TBS) in older women. Osteoporos Int. 2013 Mar;24(3):10738.

35. Kalder M, Hans D, Kyvernitakis I, et al. Effects of exemestane and tamoxifen treatment on

bone texture analysis assessed by TBS in comparison with bone mineral density assessed by

DXA in women with breast cancer. J Clin Densitom. 2013 Apr 5. [Epub ahead of print].

36. Hans D, Krieg M, Lamy O, Felsenberg D. Beneficial effects of strontium ranelate compared

to alendronate on trabecular bone score in post menopausal osteoporotic women. A 2year

study. Osteoporos Int. 2012;23(Suppl 2):S265S7 (abstract).

37. Gnther B, Popp A, Stoll D, et al. Beneficial effect of PTH on spine BMD and

microarchitecture (TBS) parameters in postmenopausal women with osteoporosis. A 2year

study. Osteoporos Int. 2012;23(Suppl 2): S332S3 (abstract).

82

38. McClung M, Lippuner K, Brandi M, et al. Denosumab significantly improved trabecular

bone score (TBS), an index of trabecular microarchitecture, in postmenopausal women with

osteoporosis. J Bone Miner Res. 2012;27(Suppl 1):S589 (abstract).

39. Kanis JA, Johansson H, Oden A, et al. A metaanalysis of prior corticosteroid use and

fracture risk. J Bone Miner Res. 2004 Jun;19(6): 8939.

40. de Liefde II, van der Klift M, de Laet CE, et al. Bone mineral density and fracture risk in

type2 diabetes mellitus: the Rotterdam Study. Osteoporos Int. 2005 Dec;16(12):171320.

41. Strotmeyer ES, Cauley JA, Schwartz AV, et al. Nontraumatic fracture risk with diabetes

mellitus and impaired fasting glucose in older white and black adults: the health, aging, and

body composition study. Arch Intern Med. 2005 Jul 25;165(14):16127.

42. Leslie WD, AubryRozier B, Lamy O, Hans D. TBS (trabecular bone score) and diabetes

related fracture risk. J Clin Endocrinol Metab. 2013 Feb;98(2):6029.

43. Breban S, Briot K, Kolta S, et al. Identification of rheumatoid arthritis patients with

vertebral fractures using bone mineral density and trabecular bone score. J Clin Densitom.

2012 JulSep;15(3):2606.

44. Romagnoli E, Cipriani C, Nofroni I, et al. Trabecular bone score (TBS): an indirect measure

of bone microarchitecture in postmenopausal patients with primary hyperparathyroidism.

Bone. 2013 Mar;53(1): 1549.

45. EllerVainicher C, Morelli V, Ulivieri FM, et al. Bone quality, as measured by trabecular

bone score in patients with adrenal incidentalomas with and without subclinical

hypercortisolism. J Bone Miner Res. 2012 Oct;27(10):222330.

46. Colson F, Picard A, Rabier B, Piperno M, Vignon E. Trabecular bone microarchitecture

alteration in glucocorticoids treated women in clinical routine? A TBS evaluation. J Bone

Miner Res. 2009;24(Suppl 1): Abstract.

47. Leib E, Stoll D, Winzenrieth R, Hans D. Lumbar spine microarchitecture impairment

evaluation in chronic kidney disease: a TBS study. J Clin Densitom. 2013;16(Suppl):266

(abstract).

83

48. Leslie W, Kanis J, Lamy O, et al. Adjustment of FRAX probability according to lumbar

spine trabecular bone score (TBS): The Manitoba BMD Cohort. J Clin Densitom.

2013;16(Suppl):2678 (abstract).

49. Lamy O, Krieg M, Stoll D, et al. What is the performance in vertebral fracture

discrimination by bone mineral density (BMD), microarchitecture estimation (TBS), and

FRAX in standalone, combined or adjusted approaches: the OsteoLaus Study. Presented at:

ECTS 2013; May 1821, 2013; Lisbon, Portugal.

50. Aaron JE, Makins NB, Sagreiya K. The microanatomy of trabecular bone loss in normal

aging men and women. Clin Orthop Relat Res. 1987 Feb (215):26071.

51. Khosla S, Riggs BL, Atkinson EJ, et al. Effects of sex and age on bone microstructure at the

ultradistal radius: a populationbased noninvasive in vivo assessment. J Bone Miner Res.

2006 Jan;21(1):12431.

84

2013

(IOF 2013 The Asia-Pacific regional audit)()

160 95

74%

392

(Capture the fracture)

85

ISCD

86

FDA

SERM

SERM

87

(BRONJ) 0.01%~0.04%

FDA 18

88

0.09%~0.34%

X

AAOMS BRONJ 1.

2. 3.

BRONJ

AAOMS

89

Atypical Fractures of the

Femoral Shaft(AFFs)

AFFs

AFFs AFFs

2011 NEJM

AFFs 5/10000 /

2014

50%

90

50%

50%

aspirinMajor

bleeding 6%

0.01%

Aspirin 6%

0.01%

( Drug holiday) 3

91

1. --

2.

3-5

(Anabolic agent)

3.

2012 NEJM

1.

2. ( BMD

) 3-5

3. (BMD

T-score

92

ISCD Dr. E.Michael Leweiki

1

(T-score >-2.0) 3-5

10

2

3

6

1-2 ()

( BMD < -2.5)

93

94

-Capture the Fracture

50

(1-4)

50%

320 200

.(International Osteoporosis Foundation)

95

2012 (Capture the Fracture)

.

50 60

70

(5,6)

.

(7) 30-50%.

.

96

:

.

Capture the Fracture

1. Strom O, Borgstrom F, Kanis JA, Compston J, Cooper C, McCloskey EV et al (2011)

Osteoporosis: burden, health care provision and opportunities in the EU: a report prepared

in collaboration with the International Osteoporosis Foundation(IOF) and the European

Federation of Pharmaceutical Industry Associations (EFPIA). Arch Osteoporos 6:59-155

2. van Staa TP, Dennison EM, Leufkens HG, Cooper C(2001) Epidemiology of fractures in

England and Wales. Bone 29:517-522

3. U.S. Department of Health and Human Service (2004) Bone health and osteoporosis: a

report of the Surgeon General. U.S. Department of Health and Human Services, Office of

the Surgeon General, Rockville, MD

4. Kanis JA, McCloskey EV, Johansson H, Cooper C, Rizzoli R, Reginster JY, on behalf of

the Scientific Advisory Board of the European Society for Clinical and Economic Aspects

of Osteoporosis and Osteoarthritis (ESCEO) and Committee of Scientific Advisors of the

97

International Osteoporosis Foundation (IOF)(2013) European guidance for the diagnosis

and management of osteoporosis in postmenopausal women. Osteoporos Int 24:23-57

5. Klotzbuecher CM, Ross PD, Landsman PB, Abbott TA, 3rd, Berger M, Patients with prior

fractures have and increased risk of futhre fractures: a summary of the literature and

statistical synthesis. J Bone Miner Res. Apr 2000;15(4)721-739

6. Kanis JA, Johnell O, De Laet C, et al. A meta-analysis of previous fracture and subsequent

fracture risk. Bone. Aug 2004;35(2)375-382

7. Carnney A, Guyatt G, Griffith L, et al. Meta-analyses of therapies for postmenopausal

osteoporosis. IX: Summary of meta-analyses of therapies for postmenopausal osteoporosis.

Endocro Rev. Aug 2002;23(4):570-578

98

2014 (APBMR)

(TOPTEAM)

2014 5 30

(Asia-Pacific Bone & Mineral Research, APBMR)

(Korean Society for Bone and Mineral Research, KSBMR)

Catholic University of Korea, St. Mary's

Lecture Hall Seoul Palace Hotel

05300601

track

250-300 APBMR

99

Plenary lecture Gary S Stein

"Architecturally dynamic epigenetic landscape of skeletal biology and

pathology " State of Art lecture John Kanis "FRAX and

intervention threshold for osteoporosis" meet the professor

workshop Symposium

Sarcopenia and Bone

Calcium supplement and CVD in Asia

Epidemiology of Osteoporosis in Asia

Osteoblast and regeneration

Emerging therapies in osteoporosis

Bone maintenance and remodeling

Drug holidays in bisphosphonate therapy

Genetics of skeletal disorders

Bone resorption and metabolic bone disease

Prevention of secondary fracture (FLS)

0530

Epidemiological Implication of ISCD/IOF

FRAX Consensus of Official Position in Asia-Pacific Region

100

FRAX threshold

4.0%-20.0% 1.6% to 3.0%

Drug holidayEgo Seeman

Ego drug holiday

drug holiday?Ego ridiculous

concept dosage adjustment bone maker

Kanis FRAX

cost-benefit

FRAX

teriparatideraloxifene strontium ranelate

FRAX clodronatebazedoxifene

denosumab FRAX

Natalie A Sims IL-6

(osteocyte, osteoclast, osteoblast)

fracture liaison service (FLS)

101

Hiroshi Hagino ( )(

) Joon Kiong Lee (,)

( Ha Yong-Chan)

Hiroshi Hagino Joon Kiong

Lee IOF FLS

102

() St. Mary's Lecture Hall,

Catholic University, Seoul 2016

APBMR faculty

( Ha Yong-Chan)(

) APBMR faculty

faculty

2016 7

ASBMR

103

faculty

(Ho-Yeon Chung)()

faculty

Ha

Yong-Chan()Joog Kiong Lee ()Qing

Jiang ()Timothy C.Y. Kwok()Toshi Yoneda

()Ho Yeon Chung ()Toshio Matsumoto()Yong

Taik Lim (KSBMR )Tuan V. Nguyen(

)Yong-Ki Min(KSBMR )

104

Faculty of Asia-Pacific Bone & Mineral Research (APBMR)

No Nationality Name Affiliation

1 Australia Ming Hao Zheng

Centre for Orthopaedic Research, School of Surgery, University of Western

Australia

2 Korea Ho-Yeon Chung

Department of Endocrinology and Metabolism, Kyung Hee University

School of Medicine

3 Korea Zang Hee Lee

Department of Cell and Developmental Biology Seoul National University

School of Dentistry

4 Japan Toshio Matsumoto

Department of Medicine and Bioregulatory Sciences

University of Tokushima Graduate School of Medical Sciences

5 Japan Toshi Yoneda

Division of Hematology and Oncology, Indiana University School of Medi-

cine

6 Japan Seiji Fukumoto

Division of Nephrology and Endocrinology, Department of Medicine, Uni-

versity of Tokyo Hospital

7 Hong Kong Timothy Kwok

Department of Medicine and Therapeutics, Prince of Wales Hospital, The

Chinese University of Hong Kong

8 Vietnam Lan T Ho-Phrm Department of Internal Medicine Pham Ngoc Thach University of Medicine

9 Malaysia Joon Kiong Lee

ANOC Neuroscience & Orthopaedic Centre, Assunta Hospital, Petaling Ja-

ya, Hospital Pantai Kuala Lumpur

10 China Jiang Qing

Department of Orthopaedics, Drum Tower Hospital, Nanjing University

Medical School

11 India Ambrish Mithal

Division of Endocrinology and Diabetes, Medanta the Medicity, Gurgaon,

Haryana, India

12 Thailand Khunying Kobchitt

Limpaphayom

Department of Obstetrics & Gynaecology, Faculty of Medicine,

Chulalongkorn University

13 Singapore Lau Tang Ching

Division of Rheumatology, Department of Medicine, National University

Health System

105

KSBMR

"Increased Risk of Fracture and Postfracture Adverse Events in

Patients With Diabetes: Two Nationwide Population-Based Retrospective

Cohort Studies" 2000-2003 32471

1:2 2000-2008

1.66( 95%CI 1.60-1.72) 2004-2010

17002 '

1.34(96%CI 1.06-1.71) 1.42(95%CI 1.23-1.64)

1.27( 95%CI 1.02-1.60) Diabetes Care May 7

online

106

() Lim

Yong-Taik

()

Deog-Yoon Kim (Department of Nuclear Medi-

cine, Kyung Hee University) Chan Soo Shin

(Department of Internal medicine, Seoul National University

) ISCD AP Panelist

Chan Soo Shin

107

IOF Calcium, vitamin D

and antiepileptic drugs calcium CVD

( Ha Yong-Chan)()

8:00

"Go home! Why don't you go home? Have a good

sleep and see you tomorrow meeting."

second run

108

Joon Kiong Lee ()

Shin

four knights of osteoporotic prevention

109

110

111

()

PINP as a biological response marker during teriparatide treatment

for osteoporosis

J. H. Krege, N. E. Lane, J. M. Harris, P. D. Miller

Osteoporosis International (Epub ahead print): DOI

10.1007/s00198-014-2646-0

teriparatide (BMD)

BMD

IOF

[1]

BMD

teriparatide

112

(bone formation) (osteocalcin)

(bone-specific alkaline phosphatase, bone ALP)procollagen

type 1 N propeptide (P1NP) procollagen type 1 C propeptide (P1CP)

P1NP (osteoblast)

P1NP

teriparatide

P1NP P1NP

P1NP

teriparatide P1NP

10 mcg/L ()

teriparatide P1NP

10 mcg/L P1NP

()

113

P1NP BMD

antiresorptive

P1NP BMD [2]

P1NP a BMD b

Teriparatide 95% 94%

3% 20%

P1NP 1-3 10 mcg/L BMD 12 3% P1NP teriparatide

114

1. International Osteoporosis Foundation. The adherence gap: why osteoporosis patients dont

continue with treatment.

http://www.iofbonehealth.org/sites/default/files/PDFs/adherence_gap_report_2005.pdf.

2. Tsujimoto M, Chen P, Miyauchi A, Sowa H, Krege JH (2011) PINP as an aid for monitoring

patients treatedwith teriparatide. Bone 48(4):798803

115

()

Vitamin D status in non-supplemented postmenopausal Taiwanese

women with osteoporosis and fragility fracture

Jawl-Shan Hwang, Keh-Sung Tsai, Yuh-Min Cheng, Wen-Jer Chen,

Shih-Te Tu, Ko-Hsiu Lu, Sheng-Mou Hou, Shu-Hua Yang, Henrich

Cheng, Hung Jen Lai, Sharon Lei and Jung-Fu Chen

BMC Musculoskeletal Disorders 2014, 15:257

D D (deficiency)

fragility fracture D (inadequacy)

low-trauma

D [ D 25 (OH) D 30

ng/mL]

116

199 8 194

113 58.2% 81 41.8%

25 (OH) D 21.1 9.3

ng/mL D 86.6%

D

117

118

()

Long-term fracture rates seen with continued ibandronate treatment:

pooled analysis of DIVA and MOBILE long-term extension stud-

ies.

Miller PD, Recker RR, Harris S, Silverman S, Felsenberg D,

Reginster J, Day BM, Barr C, Masanauskaite D.

Osteoporos Int. 2014 Jan;25(1):349-57.

ibandronate

ibandronate 5

2-3

ibandronate

ACE10.8

ibandronate 2 MOBILE

ibandronate 2 DIVA

119

3 LTEs ibandronate

5

ibandronate 150 N=176 2

ibandronate 2 N=253 3

ibandronate 3 N=263 3

N=1,924/ ibandronate

Kaplan-Meier

log-rank test

120

ibandronate

ACE10.8

P = 0.005 5 ibandronate

ibandronate 5

121

20140531

~~

122

20140717

123

20140719

124

20140812 expert meeting

Advisory Board

Osteoporosis in Patient with Breast Cancer