Thiazolidinediones類藥物與骨折風險有關


  October 6, 2009 — 根據發表在9月號PLoS醫學期刊的一項英國資料庫研究結果,使用Thiazolidinediones類藥物,在校正年齡後,已經證實與骨折風險有關。
  
  來自英國倫敦衛生與熱帶醫學倫敦學院的lan J. Douglas博士及其同事們表示,臨床研究的結果已經證實,使用Thiazolidinediones類抗糖尿病藥物rosiglitazone及pioglitazone與骨折風險增加有關,但是這些研究的統計力量有限。這些研究看到的骨折風險增加顯然僅侷限於女性,且主要牽涉到手臂、手腕、手或是腳:目前並不能完全解釋這些風險的型態。我們的目的在於進一步研究使用Thiazolidinediones類藥物是否與骨折風險有關。
  
  研究使用來自英國一般執業研究資料庫不記名的臨床照護數據,包括來自400個一般執業場所,超過6百萬病患的臨床紀錄,研究者們確認出1,819位40歲以上曾經發生骨折,且至少有一次使用Thiazolidinediones類藥物處方。在這項自身控制、病例群研究中,相較於未使用Thiazolidinediones類藥物患者,使用Thiazolidinediones類藥物病患發生骨折的機率;研究結果校正發生骨折時的年齡,以年為單位。
  
  以任何部位骨折而言,使用任何Thiazolidinediones類藥物,在暴露藥物與未暴露藥物時,病患自身比例比值為1.43(95%信賴區間[CI]為1.25-1.62)。暴露於rosiglitazone或是pioglitazone,男性與女性的病患自身比例比值是相仿的。使用Thiazolidinediones類藥物增加的風險在許多骨折部位是顯而易見的,包括髖骨、脊椎、手臂、足與手腕。增加暴露Thiazolidinediones類藥物的時間,進一步增加了骨折的風險。暴露超過4年以上,比例比值為2.00(95% CI為1.48-2.70)。
  
  研究作者們寫到,發生過骨折的病患,相較於沒有暴露在Thiazolidinediones類藥物時,使用這些藥物的那一段時間風險增加(不論是rosiglitazone還是pioglitazone)。在男性與女性以及許多部位所觀察到的風險是上升的。這項風險也隨著使用時間增加。
  
  這項研究的限制包括潛在的誤差來源、觀察性研究設計、以及缺乏隨機分派。除此之外,在決定於一般執業研究資料庫所記錄的診斷是新的狀況,還是只是過去診斷的重複紀錄有先天的困難。
  
  研究作者們的結論是,我們已經證實,接受Thiazolidinediones類藥物相關的骨折風險增加。這些發現應該被列入到有關於使用Thiazolidinediones類藥物可能風險與好處的相關爭議。
  
  威爾康信託贊助這項研究。部分研究作者表示與葛蘭素史克以及/或是歐洲藥物署藥物安全監視工作小組有許多資金上的往來。
  

Thiazolidinediones Linked to Bone Fracture Risk

By Laurie Barclay, MD
Medscape Medical News

October 6, 2009 — Use of thiazolidinediones has been linked to bone fracture risk, after adjustment for age, according to the results of a UK database study reported in the September issue of PLoS Medicine.

"The results of clinical trials have suggested that the thiazolidinedione antidiabetic agents rosiglitazone and pioglitazone are associated with an increased risk of fractures, but such studies had limited power," write Ian J. Douglas, BSc, MSc, PhD, from the London School of Hygiene and Tropical Medicine, London, United Kingdom, and colleagues. "The increased risk in these trials appeared to be limited to women and mainly involved fractures of the arm, wrist, hand, or foot: risk patterns that could not be readily explained. Our objective was to further investigate the risk of fracture associated with thiazolidinedione use."

Using anonymized primary care data from the computerized UK General Practice Research Database containing clinical records from more than 6 million patients seen at 400 general practices, the investigators identified 1819 individuals at least 40 years old who had a recorded bone fracture and who had been prescribed a thiazolidinedione at least once. In this self-controlled case-series study, within-person rate ratios were determined by comparing the rate of bone fracture in the identified population when these patients were taking a thiazolidinedione drug vs bone fracture rate when they were not taking a thiazolidinedione drug. Results were adjusted for age at the date of fracture, in single-year bands.

For fracture at any site, within-person rate ratio was 1.43 (95% confidence interval [CI], 1.25 - 1.62) comparing exposed vs unexposed periods among patients prescribed any thiazolidinedione. Within-person rate ratio was similar in men and women and with exposure to either rosiglitazone or pioglitazone. The increased risk with thiazolidinedione use was apparent at a range of fracture sites, including the hip, spine, arm, foot, and wrist. Fracture risk was further increased with increasing duration of thiazolidinedione exposure. For 4 years of exposure or longer, rate ratio was 2.00 (95% CI, 1.48 - 2.70).

"Within individuals who experience a fracture, fracture risk is increased during periods of exposure to thiazolidinediones (both rosiglitazone and pioglitazone) compared with unexposed periods," the study authors write. "The increased risk is observed in both men and women and at a range of fracture sites. The risk also increases with longer duration of use."

Limitations of this study include potential sources of bias, observational design, and lack of randomization. In addition, there are inherent difficulties in determining whether a recorded diagnosis in the General Practice Research Database is a new condition or a repeated record of a previous diagnosis.

"We have demonstrated an increased risk of fractures associated with thiazolidinedione treatment," the study authors conclude. "These findings should be taken into consideration in the wider debate surrounding the possible risks and benefits of treatment with thiazolidinediones."

The Wellcome Trust funded this study. Some of the study authors have disclosed various financial relationships with GlaxoSmithKline and/or the Pharmacovigilance Working Party at the European Medicines Agency.

PLoS Med. 2009;6:e1000154.

    
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