Transcript nested case-control study. BMJ. 2011 Apr 28

Journal Club
Turner MR, Camacho X, Fischer HD, Austin PC, Anderson GM,
Rochon PA, Lipscombe LL.
Levothyroxine dose and risk of fractures in older adults: nested casecontrol study.
BMJ. 2011 Apr 28;342:d2238.
2011年5月12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
チラーヂンS 錠の長期処方自粛および分割調剤について、医療関係者
の皆様にご協力賜りますよう、お願い申し上げます。
いわき工場から出荷した弊社製品につきまし
ては、放射線の影響について問題はないと考
えております。
［供給に関する取り組み］
１、製造委託会社による生産
２、海外製品（レボチロキシンナトリウム）の緊急輸入
３、いわき工場の操業再開
あすか製薬は4月8日より、ドイツにあるサンドの関連会社から輸入したレボチロキシンの出荷を開始
した。国内製造で安定供給されるまで輸入される製品の薬価は1錠9.6円で、保険の取り扱いはサン
ドが日本で販売するレボチロキシンNa錠50μg「サンド」と同じ。
① 3か月処方といった長期処方を避け、原則1か月以内の期間の処方とする
② 状況によっては、さらに短い処方により、譲り合う
③ 神経発達上どうしてもレボチロキシンが必要な新生児・乳児および妊婦への処方を優
先する（これらの処方は合わせても全処方量の1％未満と推測されます）
BMJ 2011;342:d2238
Objective
To quantify the effect of levothyroxine dose on
risk of fractures in older adults.
Design Nested case-control study.
Setting Population based health databases, Ontario,
Canada.
Participants Adults aged 70 or more prescribed
levothyroxine between 1 April 2002 and 31 March 2007
and followed for fractures until 31 March 2008. Cases were
cohort members admitted to hospital for any fracture,
matched with up to five controls from within the cohort who
had not yet had a fracture.
Main outcome measure Primary outcome was fracture
(wrist or forearm, shoulder or upper arm, thoracic spine,
lumbar spine and pelvis, hip or femur, or lower leg or
ankle) in relation to levothyroxine use (current, recent past,
remote). Risk among current users was compared
between those prescribed high, medium, and low
cumulative levothyroxine doses in the year before fracture.
Case-Control Studies Nested in Closed Cohorts
コホート内症例対照研究（nested case control study）：追跡中のコホート内に発生した患
者を症例とし，対照が症例と同じコホートから選択されるが，その選択が症例の発症後に行
われる症例対照研究。対照群と症例群の生存時間のバランスがとれるなど，多くの交絡因
子が除去される。
Nested case control study とは、非常によく調査された集団(closed cohort)からcases と
control が発生した場合に行なうことができる。通常のcase control study ではstudy
population が不明確であったり、case とcontrol で異なっていることさえあるが、casecontrol study ではあたかもcohort study の如くstudy population が明確。
Nested case control study とするには、ある集団で経過観察中にoutcomeを持った(case)
全てとcontrol 全てを把握している場合に行なうことがでる。現実問題として、もともとcohort
study を行なっていたのだけれども、可能性のあるconfounder をフォローできていなかった
ために、closed cohort の中からcontrol を選んでcase control study を行う。データはインタ
ビューやカルテによって収集される。またconfounder でなくexposure を再検討する場合に
も有効。これは最初の目的とは異なった目的が新たに発生した場合などに便利。
http://dr-urashima.jp/pdf/eki-200406-8.pdf
Case-Control Studies Nested in Closed Cohorts
In a nested case-control study, cases of a disease that occur in a defined cohort are
identified and, for each, a specified number of matched controls is selected from
among those in the cohort who have not developed the disease by the time of
disease occurrence in the case. For many research questions, the nested casecontrol design potentially offers impressive reductions in costs and efforts of data
collection and analysis compared with the full cohort approach, with relatively minor
loss in statistical efficiency (see restricted randomization). The nested case-control
design is particularly advantageous for studies of biologic precursors of disease. To
advance its prevention research agenda, NIH might be encouraged to maintain a
registry of new and existing cohorts, with an inventory of data collected for each; to
foster the development of specimen banks; and to serve as a clearinghouse for
information about optimal storage conditions for various types of specimens.
Compared with case-control studies, nested case-control studies can reduce 'recall
bias' and temporal ambiguity, and compared with cohort studies can reduce cost and
save time.
The drawback of nested case-control studies is non-diseased persons from whom the
controls are selected may not be fully representative of the original cohort, due to
death or failure to follow-up cases.
http://en.wikipedia.org/wiki/Nested_case-control_study
The Ontario drug benefit database records all publicly funded drugs dispensed to
Ontarians aged 65 or older.
The national ambulatory care reporting system database details visits to emergency
departments
The Canadian Institute for Health Information discharge abstract database provides
information on hospital admissions
Independent comparisons have validated the discharge abstract database against
hospital medical records, determining accuracy of the database for procedures,
diagnoses for primary admission, and major complications
（have been used extensively for data on fractures）
The Ontario health insurance plan database identifies claims for physician services,
and the registered persons database provides information on demographics and
death.
Diabetes status was obtained from the Ontario diabetes database and history of
thyroid cancer from the Ontario cancer registry.
Cases, controls, and matching
We defined a case as any cohort member who had at least
one relevant fracture during follow-up, with the date of
admission to hospital for the first fracture serving as the index
date.
For each case we selected up to five potential controls from
the cohort who were still at risk for an event on the index date.
Controls were assigned the same index date as their
respective case.
Participants could serve as a control more than once and
were later eligible to become a case.
We matched controls to cases on age (within one year), sex,
and duration in cohort (follow-up 30 days either way).
Fracture
SSRI=selective serotonin reuptake inhibitors; SNRI=serotonin noradrenaline (norepinephrine) reuptake inhibitors.
*Unless otherwise listed, medical comorbidities and drugs were scored as yes or no; numbers of yes responses are listed.
†Include nitrates, calcitonin, oestrogen, and selective oestrogen receptor modulators.
‡Include heparins, anticonvulsants, thiazolidinediones, aromatase inhibitors, and androgen deprivation treatments.
Higher doses of levothyroxine are more likely to be associated with iatrogenic
hyperthyroidism, which can decrease bone quality and bone mineral density, leading
to a higher risk of fracture. Excess thyroid hormone can also increase the risk of
arrhythmias and muscle weakness in older people, which can contribute to a greater
risk of falls.
Although we were not able to measure thyroid function in our study, we attempted to
assess whether recent dose changes, as a measure of recent thyroid monitoring,
had an effect on fracture risk. We found a slight increase in fracture risk associated
with a decrease in dose and a small protective effect associated with an increase.
The mechanism behind these effects is not clear. A recent decrease in dose may
reflect previous hyperthyroidism, which may predispose to fractures, and an increase
in dose may reflect previous hypothyroidism, which may have been protective for
bone and reduce the risk of fractures. The small magnitude of this effect limits its
clinical significance.
To minimise the risk of fracture further work is necessary to determine whether bone
can be affected by “euthyroid” doses of levothyroxine and whether treatment targets
need to be adjusted in older people whose true “normal” thyroid stimulating hormone
levels may be higher than thought.
WHAT IS ALREADY KNOWN ON THIS TOPIC
Excess levothyroxine and subclinical
hyperthyroidismare associated with lower bone density
as well as other risk factors for falls and fractures
WHAT THIS STUDY ADDS
Before this study the effect of levothyroxine dose on
fracture outcomes was not known, particularly in the at
risk population of older people (≥70 years) In this
population, higher doses of levothyroxine treatment
were associated with a twofold to threefold increased
risk of fracture compared with lower doses
Results Of 213 511 prevalent levothyroxine users
identified, 22 236 (10.4%) experienced a fracture over a
mean 3.8 years of follow-up, 18 108 (88%) of whom
were women. Compared with remote levothyroxine use,
current use was associated with a significantly higher
risk of fracture (adjusted odds ratio 1.88, 95%
confidence interval 1.71 to 2.05), despite adjustment for
numerous risk factors. Among current users, high and
medium cumulative doses (>0.093 mg/day and 0.0440.093 mg/ day) were associated with a significantly
increased risk of fracture compared with low cumulative
doses (<0.044 mg/day): 3.45 (3.27 to 3.65) and 2.62
(2.50 to 2.76), respectively.
Conclusion Among adults aged 70 or
more, current levothyroxine treatment was
associated with a significantly increased
risk of fracture, with a strong dose
response relation. Ongoing monitoring of
levothyroxine dose is important to avoid
overtreatment in this population.
Message/Comments
カナダでは臨床データが詳しく蓄積されている。
その蓄積データのコホートを用いて多くのデー
タ解析がされているようである。
チラーヂンSの補充はしすぎないようにというこ
とのようである。
一応議論されているが、甲状腺機能検査がない
のが気になる。
Matsuda Index
10,000
ISI(comp)=
(FPG X FPI)X(G X I)
G=
I=
120 ∫
120
1
120
1
120 ∫
0
0
g(t) dt
mean
i(t) dt
0
120
Usually we have OGTTs with 120 minutes. And the initial validation was done from the data up to 120 min.
Matsuda M, DeFronzo RA.: Diabetes Care 22(9):1462-70, 1999.
After glucose administration
MCR (metabolic clearance rate)
Dose of glucose
=
AUC of PG conc.
(non- steady state)
PG
Glucose Dose
mean
MCR
0
~180min
After glucose administration
Insulin Sensitivity during OGTT
can be estimated by
MCR of glucose
Average Insulin conc.
=
Dose of glucose
PG × Insulin
Induction of Composite Index
ISI(comp)
Inverse of Geometric Mean