Transcript 11/30 ******

The incidence of BRONJ in
TAIWAN population
0516
大有進度報告
Incidence
• Incidence is a measure of the risk of
developing some new condition within a
specified period of time.
• Cumulative incidence is the number of new
cases within a specified time period divided by
the size of the population initially at risk.
– Wikipedia
Oral BRONJ Incidence
• Oral bisphosphonates
– 0.7 cases per 100,000 person-years’ exposure
• The total number of reported cases of possible BON in people taking
alendronate is approximately 170 worldwide, according to Merck &Co.
• The total U.S. prescriptions for Fosamax between May 2003 and April 2004
were 22 million.
– 170/22000000 = 0.77 / 100,000
– C. Arsever, oral communication, March 2006
– 28 cases (95% CI 14 to 53) per 100,000 person-years
• The cumulative exposure was 32,678 person-years of treatment.
• They identified 9 cases of ONJ diagnosed in 2006 to 2008 with ONJ severity
stages 1-2.
– 9/32678= 27.5/100,000
– Lo, J. C, J Oral Maxillofac Surg , 2010
Material and Method
• A random sample of 100,000 people selected from
22 million people registered with the NHI in Taiwan
(1/220 total population) were followed prospectively
from 2006 for 3 years.(LHID2005)
• The definition of BRONJ made by AAOMS at 2009
was followed to screen the sampled population.
• All analyses were conducted using Statistical
Analysis Systems statistical software, version
9.2.2 (SAS Institute, Cary, NC).
Definition of BRONJ
• Patients may be considered to have
BRONJ if all of the following three
characteristics are present:
1. Current or previous treatment with a
bisphosphonate;
2. Exposed bone in the maxillofacial
region that has persisted for more than
eight weeks; and
3. No history of radiation therapy to the
jaws.
-AAOMS,2009
BPs
>8 weeks
No RT
Figure 1 . Study design
BPs: Bisphosphonates,
ONJ: osteonecrosis of the jaw,
ORN: osteoradionecrosis,
BRONJ: bisphposphonate –related osteonecrosis of the jaw
25.68 million enrollees in the TAIWAN NHI
Randomly sampled
1,000,000 people
(Longitudinal Health Insurance Database
2005, LHID2005)
Total dead :5669
Total ONJ :131
Observe from
2006 to 2008
958,136 subjects have been obtained form
LHID2005 since 2006 to 2008.
953,527 No BPs exposure
4,609 BPs exposure
4,603 no ONJ
6 ONJ
953,402 no ONJ
125 suspected ONJ
1 suspect ORN
4,604 no ONJ
5 suspected
BRONJ
215 dead
0 dead
5450 dead
4 dead
Study end points
• Endpoints:
– 1:BRONJ (in_date, status=1)
– 2:Dead (tran_code :4 or 9 ,status=0)
– 3:Upper limit of database
(20081231,status=0,censor)
Table 1. Characteristics of the 5 patients
with bisphosphonate-related osteonecrosis
of jaw.
Gender
Age
Bisphosphonate
Route
DRUG
_FRE
Disease
Exposure
(days)
Operation
Admission diagnosis
Sequestrectomy of
facial bone
Inflammatory conditions of jaw
M
84
ALENDRONATE
70MG
Oral
QW
OP
53
F
64
ZOLEDRONIC
ACID
IV
QD
BT
150
Open reduction of
fracture with internal
fixation, humerus
Inflammatory conditions of jaw
Personal history of malignant neoplasm of breast
Secondary malignant neoplasm of bone and bone marrow
F
69
ALENDRONATE
70MG
Oral
QW
OP
236
Partial
mandibulectomy
Cellulitis and abscess of oral soft tissues
F
82
ALENDRONATE
70MG
Oral
QW
OP
1004
Sequestrectomy of
facial bone
Inflammatory conditions of jaw
Cellulitis and abscess of oral soft tissues
Sequestrectomy of
facial bone
Inflammatory conditions of jaw
Unspecified osteomyelitis, other specified sites
Non-healing surgical wound
Multiple myeloma, without mention of remission
Pathologic fracture of vertebrae
M
67
DISODIUM
CLODRONATE
IV
TID
MM
1076
(IV =intravenous ; QW = per week; QD = per day; TID = three times per day; OP =
osteoporosis; BT = breast tumor; MM = multiple myeloma; M = male; F = female)
Osteonecrosis
Table 2
Characteristic
Yes
No
%
No. of
Patients
%
No. of
Patients
P values
Gender
(0.300)
Male
2
40.0
1003
21.8
Female
3
60.0
3601
78.2
Age, Years
?
Median
69
74
Range
64-82
6-100
Diseases
{0.001*}
Multiple myeloma
1
20.0
60
1.3
(0.064)
Breast cancer
1
20.0
181
3.9
(0.183)
Other cancers
0
0
299
6.5
(0.621)
Osteoporosis
3
60.0
2602
56.5
(0.715)
Other diseases
0
0
1462
31.8
(0.148)
Subtotal, diseases
5
100.0
4604
100.0
Route of bisphosphonate
(0.108)
Oral
3
60.9
4066
88.3
IV
2
40.0
538
11.7
Dental exposure for tooth extraction within 90 days
(0.0000196)
Extraction
3
60.0
124
2.7
No extraction
2
40.0
4480
97.3
[]: Continous test
(): Fisher’s test
{}: Pearson 卡方
Table 3. The relevant variables of age, gender,
deliveray routs of BPS and tooth extraction in the
development of RONJ as included in the Multivarite
analysis (Cox’s regression).
Definition of groups
(group 1 vs group 2)
Age
Hazard ratio
(group 2 relative to group 1)
95% Confidence interval
P-value
Continous
1.052
0.942-1.175
0.369
Gender
Male vs Female
1.327
0.175-10.048
0.784
Routes
IV vs Oral
10.261
1.087-96.856
0.042
Extract vs non-Extract
61.484
9.839-384.214
0.0000105
Extraction
Definition of groups
(group 1 vs group 2)
Hazard ratio
(group 2 relative to group 1)
95% Confidence interval
P-value
<median vs ≥median
1.225
0.164-9.164
0.844
Gender
Male vs Female
1.535
0.217-10.831
0.667
Routes
IV vs Oral
6.779
0.794-57.912
0.080
Extract vs non-Extract
59.053
9.425-370.011
0.0000132
Age
Extraction
Cumulative indicence (100,000 personyear) of BRONJin populations with or
with bisphosphonate.
Cumulative Incidence of BRONJ
Without bisphosphonates (BPs)
With bisphosphonates
Oral
IV
4.38
63.17
42.01
258.19
Effect of varied factors on the
accumulative incidences
P3a
Zb
P value
0.000046
-7.584766
<0.00002*
0.000045
-4.670724
<0.00002*
0.000045
-9.892482
<0.00002*
0.000612
2.112296
0.045*
BPs vs Control
BPs by Oral vs Control
BPs by IV vs Control
BPs by Oral vs by IV
a:
P3 = (P1*N1 + P2*N2)/(N1 + N2)
b: Z = (P1-P2)/SQRT(P3 * (1-P3) * (1/N1 + 1/N2) )
*: Significant difference at p < .05
Cumulative hazards for oral and IV delivery routes and
for tooth extraction and non-extraction.
整體比較
Log Rank (Mantel-Cox)
卡方統計量
自由度
顯著性
Oral vs IV
5.337
1
.021
tooth extraction vs non-extraction
63.597
1
1.5E-150
Kaplan-Meier survival functions of BRONJ according
to the incidence tooth extraction (Extraction within 90
days) (BRONJ in Extraction Blue = oral, Green = IV )
整體比較a
卡方統計量
Log Rank (Mantel-Cox)
6.929
自由度
顯著性
1
GROUPs 不同水準的存活分配等式檢定。 a. 為 0:no extract 1: extract 進行調整。
.008
THANKS FOR
YOUR ATTENTION!
Problems
• 無法確定住院資料手術部位
– 使用新定義 (先從牙科住院開始抓)
• 無法確定之前有無服藥
– 將資料庫範圍向前延伸到2001年(BPs藥物剛核准時)
• 同一個人 可能有多筆門診資料與多筆住院資
料，當刪除重複值時僅隨機挑選，沒有控制選
取對象(可能誤留或誤刪)
– 先不刪除重複值將服藥天數排序，抓最長的那一筆
TIME:
2001-2008
Total population
(N=1000000)
People
6595人
Total population
People
(N=1000000)
taking
BPs
Admitted
Total population
People
In
(N=1000000)
taking Dental
Department
BPs
N=18
(Oral = 12; IV =6)
Drug prescribed Before Admission
N=10
(Oral = 7; IV =3)
Drug prescribed
Admission Before Admission
Radiation
N=8
(Oral = 7; IV =1)
Devided by delivery route
Oral
N= 7
IV
N=1
Result 1
Osteoporosis
Cancer
Other disease
Total
F
M
F
M
F
M
Oral BPs
7/1843
0/383
1/39
0/9
4/941
1/266
13/3481
IV BPs
0/6
0/1
2/243
2/180
0/13
0/9
4/452
The prevalence of ONJ among the three year database in
oral bisphosphonates was a frequency of 240 per 100,000
person-years of oral bisphosphonate treatment.
The prevalence of ONJ among the three year database IV
bisphosphonates was a frequency of 566 per 100,000
person-years of iv bisphosphonate treatment.