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Kendler DL, Bessette L, Hill CD, Gold DT, Horne R, Varon SF, Borenstein J,
Wang H, Man HS, Wagman RB, Siddhanti S, Macarios D, Bone HG.
Preference and satisfaction with a 6-month subcutaneous injection versus a
weekly tablet for treatment of low bone mass.
Osteoporos Int. 2009 Aug 6.
2009年８月１３日 8:30-8:55
８階医局
埼玉医科大学総合医療センター内分泌・糖尿病内科
Department of Endocrinology and Diabetes,
Saitama Medical Center, Saitama Medical University
松田昌文
Matsuda, Masafumi
65歳以上の高齢女性における
2型糖尿病と骨折の関連
1.82
臀部骨折
臀部骨折
1.14
(95%CI:0.42-3.08)
(95%CI:1.24-2.69)
上腕骨近位
骨折
足骨折
1.94
(95%CI:1.24-3.02)
上腕骨近位
骨折
2.38
(95%CI:0.97-5.81)
2.68
足骨折
1.09
(95%CI:1.18-6.06)
(95%CI:0.64-1.84)
0 1 2 3
1 3 5 7
相対危険度
相対危険度
非糖尿病群
で優位
インスリン未使用
糖尿病群で優位
非糖尿病群
で優位
インスリン使用
糖尿病群で優位
対象と方法： 65才以上の女性9,704名が参加したコホート研究であるSOF( the Study of Osteoporosis Fractures )
を解析することによって得られた。
Ann V. Schwartz et al.:J.Clin.End.Met.,86,32-38,2001. より作図
TZDの骨折リスクについて
ADOPT
（5年）
骨折※
PROactive
（3年）
PERISCOPE
（1年半）
Rosi
SU薬
Pio
ﾌﾟﾗｾﾎﾞ
9.3%
3.5%
5.1%
2.5%
（女）
（女）
（女）
（女）
3.0%
4.0%
3.4%
1.7%
2.1%
（男2女6）
（男）
（男）
（男）
（男）
Pio
PRACTICAL
（1年半）
ｸﾞﾘﾒﾋﾟﾘﾄﾞ
Pio
0%
0.3%（女）
0.1%（男）
※骨折は有害事象として報告された数を集計したもの。CHICAGOでは骨折のデータなし。
2007年11月、アクトス使用上の注意改訂（医薬情報 34巻27号）
「外国の臨床試験で、女性において骨折の発現頻度上昇が認められている」
★アクトスは海外の報告を受け、使用上の注意を改訂（2007.11月）
★ただし、日本人で骨折リスクが上昇したという成績はない
PROBE study（国内成績）においては
骨折発現率は対照群と差なし
項目
ピオグリタゾン投与群
（293例）
従来治療群
（294例）
286（97.6）
285 （96.9）
46（15.7）
2（ 0.7）
6（2.0)
38（12.9）
0
8（2.7）
84（28.7）
9（3.1）
18（6.1）
15（ 5.1）
0
18（ 6.1）
9/184（4.9）
9/109（8.3）
13/212（6.1）
5/81（6.2）
7/181（3.9）
11/113（9.7）
9/204（4.4）
9/90（10.0）
有害事象発現例数
低血糖症
主
な
有
害
事
象
心不全
虚血性心疾患
浮腫関連事象
体重増加
骨折関連事象
骨折関連事象の性別･年齢別内訳
性
年齢
男
女
～64歳
65歳以上
2型糖尿病患者587例を従来治療群（294例）とピオグリタゾン群（293例）の2群に無作為に割り付け、例数（%）
PROBE法にて大血管イベント予防および長期の糖代謝への影響を平均2.8年間検討した。
加来浩平（川崎医科大）：第51回日本糖尿病学会年次学術集会（2008.5 東京）
The receptor
activator of
nuclear factor
kappa B ligand
(RANKL)
signaling
pathway is a
key mediator
of bone
remodeling
and so
represents an
attractive
target for the
development
of novel
osteoporosis
drugs.
Wittrant Y, Théoleyre S, Chipoy C, Padrines M, Blanchard F, Heymann D, Rédini F. RANKL/RANK/OPG:new
therapeutic targets in bone tumors and associated osteolysis. Biochimica Biophysica Acta Rev on Cancer,
2004, 1704: 49-57. Copyright © 2004 Elsevier B.V.
Denosumab (formerly
known as AMG 162,
proposed trade name
Prolia is a fully-human
monoclonal antibody
which is being studied
in the treatment of
osteoporosis,
treatment-induced bone
loss, bone metastases,
rheumatoid arthritis,
multiple myeloma and
giant cell tumor of bone.
Denosumab is designed to target RANKL (RANK ligand), a protein that
acts as the primary signal to promote bone removal. In many bone loss
conditions, RANKL overwhelms the body's natural defense against bone
destruction. Denosumab therefore mimicks the endogenous effects of
osteoprotegerin.
The antibody is being developed by the company Amgen.
P436FR. EFFECTS OF DENOSUMAB IN POSTMENOPAUSAL WOMEN TRANSITIONING FROM
ALENDRONATE THERAPY IN COMPARISON WITH CONTINUED ALENDRONATE
Kendler DL1, Benhamou CL2, Brown JP3, Lillestol M4, Roux C5, Man HS6, Siddhanti S6, San Martin J6,
Bone HG7; 1Clinical Research Center, Vancouver, BC, Canada, 2Centre Hospitalier, Orleans, France,
3CHUQ, Laval University, Quebec City, QC, Canada, 4Internal Medicine Associates, Fargo, ND, USA,
5Hopital Cochin, Paris, France, 6Amgen Inc., Thousand Oaks, CA, USA, 7Michigan Bone and Mineral
Clinic, Detroit, MI, USA
Previous studies showed the RANKL inhibitor denosumab increased BMD and decreased bone turnover
in postmenopausal women with low BMD. Many patients with osteoporosis are currently treated with
bisphosphonates but may want or need to switch therapy in their lifetime. Thus it is important to
understand the safety and efficacy of transitioning patients from bisphosphonates to denosumab. In this
phase 3, double-blind, double-dummy study, postmenopausal women ≥55 years old with a lumbar spine or
total hip T-score of ≤−2.0 and ≥−4.0 who had received alendronate therapy equivalent to 70 mg/week for ≥6
months were eligible. After enrollment, all subjects received open-label branded alendronate 70 mg once
weekly for 1 month, then were randomized to continue receiving alendronate or to receive subcutaneous
denosumab 60 mg Q6 M. All subjects received daily supplements of calcium and vitamin D. The primary
endpoint was percent change in total hip BMD at 12 months. 504 subjects (253 denosumab; 251
alendronate) with a mean age of 67.6 years and mean lumbar spine T-score of -2.63 were enrolled. The
median length of prior bisphosphonate therapy was 36 months. Denosumab significantly increased total
hip BMD by 1.90% at 12 months compared with a 1.05% increase in subjects continuing on alendronate
(p<0.0001). Significantly greater BMD gains with denosumab compared with alendronate were also
achieved at 12 months at the lumbar spine (3.03% vs 1.85%), femoral neck (1.40% vs 0.41%), trochanter
(2.95% vs 1.90%), and 1/3 radius (0.87% vs 0.15%) (p<0.0125 for all). Median serum CTX levels remained
near baseline in the alendronate group and were significantly decreased vs alendronate (p<0.0001) at all
time points in the denosumab group. Subject incidence of adverse events (AEs) (197 denosumab; 196
alendronate) and serious AEs (15 denosumab; 16 alendronate) was balanced between the two groups. No
AEs of hypocalcemia were reported. In these subjects previously treated with alendronate, denosumab
produced greater increases in BMD at all measured skeletal sites as well as a greater reduction of CTX
than did continued alendronate, with a similar safety profile in both groups. These results may reflect the
different mechanisms of inhibiting bone turnover between the two drugs.
Osteoporos Int 9(Suppl 2):S385–S386, 2008
Comparison of the Effect of Denosumab and Alendronate on Bone Mineral Density and
Biochemical Markers of Bone Turnover in Postmenopausal Women With Low Bone Mass: A
Randomized, Blinded, Phase 3 Trial
Denosumab is a fully human monoclonal antibody that inhibits bone resorption by
neutralizing RANKL, a key mediator of osteoclast formation, function, and survival. This
phase 3, multi-center, double-blind study compared the efficacy and safety of denosumab
with alendronate in postmenopausal women with low bone mass. One thousand one
hundred eighty-nine postmenopausal women with a T score ≤ -2.0 at the lumbar spine or
total hip were randomized 1:1 to receive subcutaneous denosumab injections (60 mg every
6 months [Q6M]) plus oral placebo weekly (n=594) or oral alendronate weekly (70 mg) plus
subcutaneous placebo injections Q6M (n=595). Changes in BMD were assessed at the total
hip, femoral neck, trochanter, lumbar spine, and 1/3 radius at 6 and 12 months, and in bone
turnover markers at months 1, 3, 6, 9, and 12. Safety was evaluated by monitoring adverse
events and laboratory values. At the total hip, denosumab significantly increased BMD
compared with alendronate at month 12 (3.5% versus 2.6%; p<0.0001) Furthermore,
significantly greater increases in BMD were observed with denosumab treatment at all
measured skeletal sites (12-month treatment difference: 0.6% femoral neck; 1.0% trochanter;
1.1% lumbar spine; 0.6% 1/3 radius; p≤0.0002 all sites). Denosumab treatment led to
significantly greater reduction of bone turnover markers compared with alendronate therapy.
Adverse events and laboratory values were similar for denosumab- and alendronate-treated
subjects. Denosumab demonstrated significantly larger gains in BMD and greater reduction
in bone turnover markers compared with alendronate. The overall safety profile was similar
for both treatments.
Journal of Bone and Mineral Research, Published online
September 3, 2008:10.1359/jbmr.080910
Prohealth Clinical Research, University of British Columbia, Vancouver, Canada Le
Centre Hospitalier Universitaire de Québec, Pavillon CHUL, Quebec City, QC,
Canada RTI Health Solutions, RTI International,, USA Center for Aging, Duke
University Medical Center, Durham, NC, USA Centre for Behavioral Medicine, The
School of Pharmacy, University of London, London, UK Amgen Inc., One Amgen
Center Drive, Thousand Oaks, CA, USA Cambridge, UK South San Francisco, CA,
USA Stanford University School of Medicine, Stanford, CA, USA Michigan Bone and
Mineral Clinic, P.C., Detroit, MI, USA
BACKGROUND
The PSQ compares patient
preference and satisfaction
between a 6-month
subcutaneous injection and a
weekly oral tablet for treatment
of bone loss.
METHODS
Postmenopausal women with low bone mass
who enrolled in two separate randomized
phase 3 double-blind, double-dummy studies
received a 6-month subcutaneous
denosumab injection (60 mg) plus a weekly
oral placebo or a weekly alendronate tablet
(70 mg) plus a 6-month subcutaneous
placebo injection. After 12 months, patients
completed the PSQ to rate their preference,
satisfaction, and degree of bother with each
regimen.
the Determining Efficacy: Comparison
of Initiating Denosumab versus
AlEndronate (DECIDE) trial
the Study of Transitioning from
AleNdronate to Denosumab (STAND)
trial
Fig. 2 Patient-reported preference (a) and satisfaction with
frequency of treatment administration (b). The values shown are
combined data from the DECIDE and STAND trials.*P<0.0001 for 6month injection versus weekly tablet
RESULTS
Most enrolled patients (1,583 out of
1,693; 93.5%) answered ≥1 item of the
PSQ. Significantly more patients
preferred and were more satisfied with
the 6-month injection versus the weekly
tablet (P<0.001). More patients reported
no bother with the 6-month injection
(90%) than the weekly tablet (62%).
CONCLUSIONS
Patients preferred, were more satisfied, and
less bothered with a 6-month injection
regimen for osteoporosis.
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