1. Journal Club 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 2011 年 5 月 12 日 8:30-8:55 ８階 医局 Turner MR, Camacho X, Fischer HD, Austin PC, Anderson GM, Rochon PA, Lipscombe LL. Levothyroxine dose and risk of fractures in older adults: nested case- control study. BMJ. 2011 Apr 28;342:d2238.

2. 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。 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。

3. ［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）

4. BMJ 2011;342:d2238

5. Objective To quantify the effect of levothyroxine dose on risk of fractures in older adults.

6. 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.

7. 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。 Case-Control Studies Nested in Closed Cohorts http://dr-urashima.jp/pdf/eki-200406-8.pdf 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、 case-control study ではあたかも cohort study の如く study population が明確。 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。

8. 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 case- control 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

9. 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.

10. 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). Cases, controls, and matching

11. Fracture

12. 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. §Include non-SSRI or SNRI antidepressants and antiparkinsonian drugs.

18. 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. 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. 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.

19. 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

20. 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 0.044- 0.093 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.

21. 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.

22. 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。

26. Matsuda Index (FPG X FPI)X(G X I) 10,000 ISI(comp)= 120 G= ∫ g(t)dt 0 120 1 I= ∫ i(t)dt 0 120 1 0 mean Matsuda M, DeFronzo RA.: Diabetes Care 22(9):1462-70, 1999. Usually we have OGTTs with 120 minutes. And the initial validation was done from the data up to 120 min.

27. MCR (metabolic clearance rate) Dose of glucose AUC of PG conc. (non- steady state) = Glucose Dose PG 0 ~180min mean MCR After glucose administration

28. Insulin Sensitivity during OGTT MCR of glucose Average Insulin conc. Dose of glucose PG × Insulin = can be estimated by After glucose administration

29. Induction of Composite Index ISI(comp) Inverse of Geometric Mean