201408 會訊9 3
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The Tawanese Osteoporosis Association
103
2013 ASBMR /
/
/
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O
03-3281200#8957
03-3187510
E m a i l [email protected]
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
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1
714
IOF Regionals - 5th
Asia-Pacific Osteoporosis Meeting in Taipei
2014APBMR
1
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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
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9
()
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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.
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27
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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;
29(3):518-30.
2. Johnell O, Kanis JA. An estimate of the worldwide prevalence and disability associated
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
osteoporosis at the primary health care level [Internet]. Sheffield, UK: WHO Scientific
Group Technical Report; 2007.
4. Kanis JA, McCloskey EV, Johansson H, et al. European guidance for the diagnosis and
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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79
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the proximal femur in a longitudinal study of hip fracture. J Bone Miner Res. 2013
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using anteroposterior dualenergy Xray absorptiometry acquisition, and 3dimensional
parameters of bone microarchitecture: an experimental study on human cadaver vertebrae. J
Clin Densitom. 2011 JulSep;14(3):30212.
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normative, agespecific reference curve for lumbar spine trabecular bone score (TBS) in
French women. Osteoporos Int. 2013 Nov;24(11):283746.
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curve at lumbar spine in US Caucasian women derived from DXA. J Clin Densitom.
2013;16(Suppl):272 (abstract).
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trabecular bone score. J Clin Densitom. 2013 Feb 26;16(3):3749.
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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.
23. Popp AW, Guler S, Lamy O, et al. Effects of zoledronate versus placebo on spine bone
mineral density and microarchitecture assessed by the trabecular bone score in
postmenopausal women with osteoporosis: a threeyear study. J Bone Miner Res. 2013
Mar;28(3):44954.
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score to complement bone mineral density in the diagnosis of osteoporosis: a preliminary
spine BMDmatched, casecontrol study. J Clin Densitom. 2009 AprJun;12(2):1706.
25. Winzenrieth R, Dufour R, Pothuaud L, Hans D. A retrospective casecontrol study assessing
the role of trabecular bone score in postmenopausal Caucasian women with osteopenia:
analyzing the odds of vertebral fracture. Calcif Tissue Int. 2010 Feb;86(2):1049.
26. Rabier B, Heraud A, GrandLenoir C, Winzenrieth R, Hans D. A multicentre, retrospective
casecontrol study assessing the role of trabecular bone score (TBS) in menopausal
Caucasian women with low areal bone mineral density (BMDa): analysing the odds of
vertebral fracture. Bone. 2010 Jan;46(1):17681.
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].
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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).
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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
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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