探討影響雙磷酸鹽類藥物相關顎骨壞死 發生的風險因子及治療的預後因子

Factors affecting the occurrence and treatment outcomes of bisphosphonate-related osteonecrosis of the jaw (BRONJ)

張玲瑜(Ling-Yu Chang)

指導教授 ： 李正喆

國立臺灣大學/牙醫專業學院/臨床牙醫學研究所/碩士(2011年)

https://doi.org/10.6342/NTU.2011.10480

摘要

目的： 雙磷酸鹽類藥物會抑制骨吸收，臨床上時常用來治療癌症骨轉移及骨質疏鬆症，近年來出現越來越多與此藥物相關的併發症案例：雙磷酸鹽類藥物相關顎骨壞死，嚴重影響病人的生活品質，本篇研究的目的在於探討與此相關的風險因子與預後因子，並驗證相關血清骨代謝生化指標是否可以作為雙磷酸鹽類藥物相關顎骨壞死發生及預後的預測工具。
病人與方法： 本研究自2003年至2011年收入157例在台大醫院口腔顎面外科確診為雙磷酸鹽類藥物相關顎骨壞死的病人，記錄系統性特徵、藥物資訊、可能的引發事件、臨床症狀、局部因子、治療方法及血清骨生化指標。接著以單變數、多變數分析方法及病例對照研究，找出可能影響發生雙磷酸鹽類藥物相關顎骨壞死的風險因子及預後因子。
結果： 157位病人中，有45位使用雙磷酸鹽類藥物治療癌症骨轉移，112位用來治療骨質疏鬆症，癌症組病人平均發生雙磷酸鹽類藥物相關顎骨壞死的時間較短（29.1個月，範圍6至84個月），骨鬆組病人為44.6個月（範圍6至180個月）。在發生雙磷酸鹽類藥物相關顎骨壞死癌症組病例對照研究中，經單變數分析，影響發生風險的因素有：多發性骨髓瘤（p=0.024）、使用雙磷酸鹽類藥物的時間長短（p=0.006）、合併使用類固醇（p=0.0011），以及進行牙科手術（p=0.012）；經多變數分析，影響發生風險的因素有：使用雙磷酸鹽類藥物的時間長短（p=0.03）。在發生雙磷酸鹽類藥物相關顎骨壞死骨鬆組病例對照研究中，經單變數分析，影響發生風險的因素有：年齡（p=0.028）、使用BP藥物超過36個月（p＜0.001）；經多變數分析，影響發生風險的因素有：使用雙磷酸鹽類藥物超過36個月（p=0.004）。符合評估治療預後的107位病人中，有78位（72.9%）達到完全痊癒，平均治療天數為238.4天（範圍30至1506天）；經單變數分析發現，女性（p=0.017）、使用雙磷酸鹽類藥物治療骨鬆（p＜0.001）、使用福善美®（p＜0.001）、未合併使用化療藥物（p=0.0013）、病灶數目較少（p=0.036）等因素會使預後較佳；病灶位於上顎區（p=0.018）、前牙區（p=0.0014），及自發性病灶（p=0.029）對於雙磷酸鹽類藥物相關顎骨壞死治療反應較迅速。血清骨生化指標對發生的風險與治療的預後，並沒有準確的預測價值。
結論： 本篇研究呈現台灣目前數量最大的病例系列，並找出影響雙磷酸鹽類藥物相關顎骨壞死發生與預後的風險因子，未來希望能針對這些風險因子及早介入預防，希望能減少雙磷酸鹽類藥物相關顎骨壞死之發生率，並縮短治療之病程。

關鍵字

雙磷酸鹽類藥物 ； 顎骨壞死 ； 病例對照研究 ； 風險因子 ； 預後因子 ； 血清骨生化指標

並列摘要

Purpose: Bisphosphonates (BPs) are bone-remodeling inhibitors that are commonly used to manage cancer bone metastases and osteoporosis. Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a devastating side effect of BPs use. The purpose of this study was to identify factors that influence the occurrence and treatment outcomes of BRONJ, in addition, to determine whether related serum bone markers could be predictor for BRONJ.
Patients and Methods: This study evaluates 157 BRONJ cases diagnosed between 2003 and 2011 in Oral and Maxillofacial surgery department, National Taiwan University Hospital. Data on demographics, drugs use, possible trigger events, clinical symptoms, local factors, treatment methods, and serum bone markers are recorded. We use univariate analysis, multivariate analysis and a case-control study design to estimate possible risk factors and prognostic factors.
Results: Of the 157 patients, 45 receive BP therapy for cancer and 112 for osteoporosis. The mean interval to development of BRONJ is shorter in the patients with cancer (29.1 months, range between 6 and 84 months) than patients with osteoporosis (44.6 months, range between 6 and 180 months). In BRONJ cancer case-control study, by univariate analysis, factors that increased the risk of BRONJ occurrence were multiple myeloma (p=0.024), duration of BPs use (p=0.006), combined steroid use (p=0.0011), dentoalveolar surgery (p=0.012). By multivariate analysis, the risk factor was duration of BPs ues (p=0.03). In BRONJ osteoporosis case-control study, by univariate analysis, factors that increased the risk of BRONJ occurrence were age (p=0.028), and BP therapy exceeded 36 months (p＜0.001). By multivariate analysis, the risk factor was BP therapy exceeded 36 months (p=0.004). Of the 107 patients treated, 78 (72.9%) reach complete healing with a mean follow-up of 238.4 days (range between 30 and 1506 days). By univariate analysis, female (p=0.017), BP therapy for osteoporosis (p＜0.001), alendronate （Fosamax®） use (p＜0.001), no chemotherapy(p=0.0013), and fewer lesions (0.036) all seem to have better prognosis. Lesions located in maxilla (p=0.018) and anterior sextant (p=0.0014) and spontaneous lesions (p=0.029) respond faster to BRONJ treatment. However, serum bone markers are of little value to predict the occurrence and prognosis.
Conclusion: We present the largest case series in Taiwan and identify the factors affecting the occurrence and treatment outcomes of BRONJ. Towards the factors, we hope for early intervention, reducing the incidence of BRONJ, and shortening the duration of treatment.

並列關鍵字

Bisphosphonates ； Osteonecrosis of the jaw ； Case-control study ； Risk factor ； Prognostic factor ； Serum bone marker

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