[1] Ruggiero SL, Dodson TB, Fantasia J, Goodday R, Aghaloo T, Mehrotra B, O’Ryan F;
American Association of Oral and Maxillofacial Surgeons (2014) American
Association of Oral and Maxillofacial Surgeons position paper on medication-related
osteonecrosis of the jaw--2014 update. J Oral Maxillofac Surg 72:1938–1956.
[2] Otto S, Pautke C, Van den Wyngaert T, Niepel D, Schiødt M (2018) Medication-related
osteonecrosis of the jaw: Prevention, diagnosis and management in patients with cancer
and bone metastases. Cancer Treat Rev 69:177-187.
10
[3] Berenson JR, Rajdev L, Broder M (2006) Treatment strategies for skeletal
complications of cancer. Cancer Biol Ther 5:1074-1077.
11
[4] Fizazi K, Carducci M, Smith M, Damião R, Brown J, Karsh L, Milecki P, Shore N,
12
Rader M, Wang H, Jiang Q, Tadros S, Dansey R, Goessl C (2011) Denosumab versus
13
zoledronic acid for treatment of bone metastases in men with castration-resistant
14
prostate cancer: a randomised, double-blind study. Lancet 377:813-822.
15
16
17
18
[5] Marx RE (2003) Pamidronate (Aredia) and zoledronate (Zometa) induced avascular
necrosis of the jaws: a growing epidemic. J Oral Maxillofac Surg 61:1115–1117.
[6] Migliorati CA. Bisphosphonates and oral cavity avascular bone necrosis. J Clin Oncol.
2003;21(22):4253-4.
19
[7] Yoshimura H, Ohba S, Yoshida H, Saito K, Inui K, Yasui R, Ichikawa D, Aiki M,
20
Kobayashi J, Matsuda S, Imamura Y, Sano K (2017) Denosumab-related osteonecrosis
21
of the jaw in a patient with bone metastases of prostate cancer: A case report and
22
literature review. Oncol Lett 14:127-136.
23
[8] Mavrokokki T, Cheng A, Stein B, Goss A (2007) Nature and frequency of
24
bisphosphonate-associated osteonecrosis of the jaws in Australia. J Oral Maxillofac
25
Surg 65:415–423
26
27
[9] Kunchur R, Need A, Hughes T, Goss A (2009) Clinical investigation of C-terminal
cross-linking
telopeptide
test
in
prevention
and
management
of
18
bisphosphonate-associated osteonecrosis of the jaws. J Oral Maxillofac Surg 67:1167.
[10] Hasegawa T, Kawakita A, Ueda N, Funahara R, Tachibana A, Kobayashi M, Kondou E,
Takeda D, Kojima Y, Sato S, Yanamoto S, Komatsubara H, Umeda M, Kirita T, Kurita
H, Shibuya Y, Komori T; Japanese Study Group of Cooperative Dentistry with Medicine
(JCDM) (2017) A multicenter retrospective study of the risk factors associated with
medication-related osteonecrosis of the jaw after tooth extraction in patients receiving
oral bisphosphonate therapy: can primary wound closure and a drug holiday really
prevent MRONJ? Osteoporos Int 28:2465-2473.
[11] Hoff AO, Toth BB, Altundag K, Johnson MM, Warneke CL, Hu M, Nooka A, Sayegh
10
G, Guarneri V, Desrouleaux K, Cui J, Adamus A, Gagel RF, Hortobagyi GN (2008)
11
Frequency and risk factors associated with osteonecrosis of the jaw in cancer patients
12
treated with intravenous bisphosphonates. J Bone Miner Res 23:826–836.
13
[12] Hasegawa T, Hayashida S, Kondo E, Takeda Y, Miyamoto H, Kawaoka Y, Ueda N,
14
Iwata E, Nakahara H, Kobayashi M, Soutome S, Yamada SI, Tojyo I, Kojima Y, Umeda
15
M, Fujita S, Kurita H, Shibuya Y, Kirita T, Komori T; Japanese Study Group of
16
Co-operative Dentistry with Medicine (JCDM) (2019) Medication-related osteonecrosis
17
of the jaw after tooth extraction in cancer patients: a multicenter retrospective study.
18
Osteoporos Int 30(1):231-239.
19
[13] Brown JP, Fortier M, Frame H, Lalonde A, Papaioannou A, Senikas V, Yuen CK;
20
Osteoporosis Guidelines Committee (2006) Canadian Consensus Conference on
21
osteoporosis, 2006 update. J Obstet Gynaecol Can 28(2 Suppl 1):S95-112.
22
[14] Lipton A, Steger GG, Figueroa J, Alvarado C, Solal-Celigny P, Body JJ, de Boer R,
23
Berardi R, Gascon P, Tonkin KS, Coleman RE, Paterson AH, Gao GM, Kinsey AC,
24
Peterson MC, Jun S (2008) Extended efficacy and safety of denosumab in breast
25
cancer patients with bone metastases not receiving prior bisphosphonate therapy. Clin
26
Cancer Res 14(20):6690-6.
27
[15] Anastasilakis AD, Toulis KA, Polyzos SA, Anastasilakis CD, Makras P (2012)
19
Long-term treatment of osteoporosis: safety and efficacy appraisal of denosumab. Ther
Clin Risk Manag 8:295-306.
[16] Amgen, Inc. Prolia (denosumab) prescribing information. 2010 updated 2014.
[17] Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, Carbone PP
(1982) Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am
J Clin Oncol 5(6):649-655.
[18] Fizazi K, Lipton A, Mariette X, Body JJ, Rahim Y, Gralow JR, Gao G, Wu L, Sohn W,
Jun S (2009) Randomized phase II trial of denosumab in patients with bone metastases
from prostate cancer, breast cancer, or other neoplasms after intravenous
10
bisphosphonates. J Clin Oncol 27(10):1564-71.
11
[19] Lipton A, Steger GG, Figueroa J, Alvarado C, Solal-Celigny P, Body JJ, de Boer R,
12
Berardi R, Gascon P, Tonkin KS, Coleman R, Paterson AH, Peterson MC, Fan M,
13
Kinsey A, Jun S (2007) Randomized active-controlled phase II study of denosumab
14
efficacy and safety in patients with breast cancer-related bone metastases. J Clin Oncol
15
25(28):4431-7.
16
[20] Smith MR, Egerdie B, Hernández Toriz N, Feldman R, Tammela TL, Saad F, Heracek
17
J, Szwedowski M, Ke C, Kupic A, Leder BZ, Goessl C; Denosumab HALT Prostate
18
Cancer Study Group (2009) Denosumab in men receiving androgen-deprivation therapy
19
for prostate cancer. N Engl J Med 361(8):745-55.
20
[21] Smith MR, Saad F, Coleman R, Shore N, Fizazi K, Tombal B, Miller K, Sieber P,
21
Karsh L, Damião R, Tammela TL, Egerdie B, Van Poppel H, Chin J, Morote J,
22
Gómez-Veiga F, Borkowski T, Ye Z, Kupic A, Dansey R, Goessl C (2012) Denosumab
23
and bone-metastasis-free survival in men with castration-resistant prostate cancer:
24
results of a phase 3, randomised, placebo-controlled trial. Lancet 379(9810):39-46.
25
[22] Okuma S, Matsuda Y, Nariai Y, Karino M, Suzuki R, Kanno T (2020) A
26
Retrospective Observational Study of Risk Factors for Denosumab-Related
27
Osteonecrosis of the Jaw in Patients with Bone Metastases from Solid Cancers. Cancers
20
(Basel) 12(5):1209.
[23] Limones A, Sáez-Alcaide LM, Díaz-Parreño SA, Helm A, Bornstein MM,
Molinero-Mourelle P (2020) Medication-related osteonecrosis of the jaws (MRONJ) in
cancer patients treated with denosumab VS. zoledronic acid: A systematic review and
meta-analysis. Med Oral Patol Oral Cir Bucal 25(3):e326-e336.
[24] Ueda N, Nakashima C, Aoki K, Shimotsuji H, Nakaue K, Yoshioka H, Kurokawa S,
Imai Y, Kirita T (2020) Does inflammatory dental disease affect the development of
medication-related osteonecrosis of the jaw in patients using high-dose bone-modifying
agents? Clin Oral Investig [Online ahead of print].
10
[25] Matsumoto A, Sasaki M, Schmelzeisen R, Oyama Y, Mori Y, Voss PJ (2017) Primary
11
wound closure after tooth extraction for prevention of medication-related osteonecrosis
12
of the jaw in patients under denosumab. Clin Oral Investig 21(1):127-134.
13
[26] Saad F, Brown JE, Van Poznak C, Ibrahim T, Stemmer SM, Stopeck AT, Diel IJ,
14
Takahashi S, Shore N, Henry DH, Barrios CH, Facon T, Senecal F, Fizazi K, Zhou L,
15
Daniels A, Carrière P, Dansey R (2012) Incidence, risk factors, and outcomes of
16
osteonecrosis of the jaw: integrated analysis from three blinded active-controlled phase
17
III trials in cancer patients with bone metastases. Ann Oncol 23:1341-1347.
18
[27] Yamazaki T, Yamori M, Ishizaki T, Asai K, Goto K, Takahashi K, Nakayama T, Bessho
19
K (2012) Increased incidence of osteonecrosis of the jaw after tooth extraction in
20
patients treated with bisphosphonates: a cohort study. Int J Oral Maxillofac Surg
21
41:1397-1403.
22
[28] Soutome S, Hayashida S, Funahara M, Sakamoto Y, Kojima Y, Yanamoto S, Umeda M
23
(2018) Factors affecting development of medication-related osteonecrosis of the jaw in
24
cancer patients receiving high-dose bisphosphonate or denosumab therapy: Is tooth
25
extraction a risk factor? PLoS One 13(7):e0201343.
26
[29] Schwartz S, Joseph C, Iera D, Vu DD (2008) Bisphosphonates, osteonecrosis,
27
osteogenesis imperfecta and dental extractions: a case series. J Can Dent Assoc
21
74(6):537-42.
[30] Chahine C, Cheung MS, Head TW, Schwartz S, Glorieux FH, Rauch F (2008) Tooth
extraction socket healing in pediatric patients treated with intravenous pamidronate. J
Pediatr 153(5):719-20.
[31] Guilbeau, J.M. (2002) Delayed wound healing with sirolimus after liver transplant.
Ann Pharmacother. 2002 Sep;36(9):1391-5.
[32] Cavalli RC, Tambara Filho R, Gomes Rde P, Veronez DA, Slongo J, Fraga Rd (2014)
Analysis of the histology of the scar bladder and biochemical parameters of rats with a
solitary kidney undergoing immunosuppression with tacrolimus. Acta Cir Bras
10
29(8):508-14.
11
[33] Weinstein RS (2012) Glucocorticoid-induced osteonecrosis. Endocrine 41(2):183-90.
12
[34] Weinstein RS (2012) Glucocorticoid-induced osteoporosis and osteonecrosis.
13
Endocrinol Metab Clin North Am 41(3):595-611.
14
[35] Takano-Murakami R, Tokunaga K, Kondo N, Ito T, Kitahara H, Ito M, Endo N (2009)
15
Glucocorticoid inhibits bone regeneration after osteonecrosis of the femoral head in
16
aged female rats. Tohoku J Exp Med 217(1):51-8.
17
[36] Aljohani S, Gaudin R, Weiser J, Tröltzsch M, Ehrenfeld M, Kaeppler G, Smeets R,
18
Otto S (2018) Osteonecrosis of the jaw in patients treated with denosumab: A
19
multicenter case series. J Craniomaxillofac Surg 46(9):1515-1525.
20
21
[37] Wong LS, Tay KK, Cheing YL (2015) Osteonecrosis of mandible: a rare complication
of long-term steroid use. J Oral Maxillofac Surg Med Pathol 27:255-257.
22
[38] Hoefert S, Yuan A, Munz A, Grimm M, Elayouti A, Reinert S (2017) Clinical course
23
and therapeutic outcomes of operatively and non-operatively managed patients with
24
denosumab-related osteonecrosis of the jaw (DRONJ). J Craniomaxillofac Surg
25
45(4):570-578.
26
[39] Bone HG, Bolognese MA, Yuen CK, Kendler DL, Miller PD, Yang YC, Grazette L,
27
San Martin J, Gallagher JC (2011) Effects of denosumab treatment and discontinuation
22
on BMD and bone turnover markers in postmenopausal women with low bone mass. J
Clin Endocrinol Metab 96(4):972-80.
[40] Miller PD, Bolognese MA, Lewiecki EM, McClung MR, Ding B, Austin M, Liu Y,
San Martin J; Amg Bone Loss Study Group (2008) Effect of denosumab on BMD and
turnover in postmenopausal women with low bone mass after long-term continued,
discontinued, and restarting of therapy: a randomized blinded phase 2 clinical trial.
Bone 43(2):222-9.
[41] Malan J, Ettinger K, Naumann E, Beirne OR (2012) The relationship of denosumab
pharmacology and osteonecrosis of the jaws. Oral Surg Oral Med Oral Pathol Oral
10
11
12
Radiol 114(6):671-6.
[42] Taylor KH, Middlefell LS, Mizen KD (2010) Osteonecrosis of the jaws induced by
anti-RANK ligand therapy. Br J Oral Maxillofac Surg 48(3):221-3.
13
[43] Hayashida S, Yanamoto S, Fujita S, Hasegawa T, Komori T, Kojima Y, Miyamoto H,
14
Shibuya Y, Ueda N, Kirita T, Nakahara H, Shinohara M, Kondo E, Kurita H, Umeda
15
M (2020) Drug holiday clinical relevance verification for antiresorptive agents in
16
medication-related osteonecrosis cases of the jaw. J Bone Miner Metab 38(1):126-134.
17
18
19
20
[44] McClung MR (2016) Cancel the denosumab holiday. Osteoporos Int 27(5):1677-82.
23
TABLE AND FIGURE CAPTIONS
Tab.1 Characteristics of patients according to whether or not denosumab-related
osteonecrosis of the jaw was present
Tab. 2 Characteristics of extracted teeth according to whether or not denosumab-related
osteonecrosis of the jaw was present
10
Tab. 3 Results of multivariate logistic regression analysis of risk factors for
denosumab-related osteonecrosis of the jaw
11
12
Fig. 1 Cumulative incidence rate of denosumab-related osteonecrosis of the jaw in patients
13
with cancer on denosumab therapy.
14
15
Fig. 2 Receiver-operating characteristic curve for duration of administration of denosumab
16
as an indicator of possible denosumab-related osteonecrosis of the jaw.
17
18
ACKNOWLEDGEMENTS
19
We thank Editage (https://www.editage.jp/) for editing a draft of this manuscript.
20
21
Table 1. Characteristics of patients according to whether or not denosumab-related osteonecrosis of the jaw was present
Variable
DRONJ
P-value
Present
Absent
n (%)
n (%)
25 (34.7)
47 (65.3)
Stage 0
1 (4.0)
Stage 1
10 (40.0)
Stage 2
11 (44.0)
Stage 3
3 (12.0)
Male
10 (40.0)
21 (43.1)
Female
15 (60.0)
26 (56.9)
44–82
41–85
66.3 ± 11.3
64.60 ± 12.2
0.534 **
0 or 1
23 (92.0)
44 (93.6)
1.000 *
2 or 3
2 (8.0)
3 (6.4)
Yes
3 (12.0)
9 (19.1)
No
18 (72.0)
33 (70.2)
Unknown
4 (16.0)
5 (10.6)
5–51
1–85
Mean ± SD
22.4 ± 13.5
13.7 ± 15.3
< 0.001**
≥ 18 months
16 (66.7)
10 (27.8)
< 0.001*
< 18 months
9 (33.3)
37 (72.2)
Yes
2 (8.0)
3 (6.4)
No
23 (92.0)
44 (93.6)
Yes
4 (16.0)
8 (17.0)
No
21 (84.0)
39 (83.0)
Patients, n
Sex
0.805 *
Age
Range (years)
Mean ± SD
Performance status
Smoking history
0.735*
Duration of oncologic doses of denosumab
Range (months)
Comorbidity or drug-induced risk factors
Diabetes mellitus
1.000*
Corticosteroid therapy
Additional chemotherapy
1.000*
Yes
17 (72.3)
34 (70.8)
0.787*
No
8 (27.7)
13 (28.2)
Breast cancer
8 (32.0)
12 (25.5)
Prostate cancer
2 (8.0)
12 (25.5)
Multiple myeloma
1 (4.0)
4 (8.5)
Lung cancer
2 (8.0)
6 (12.8)
Other
1 (4.0)
4 (8.5)
11 (44.0)
9 (19.1)
1–283
2–272
66.0 ± 61.7
58.9 ± 63.5
0.367**
Yes
18 (46.2)
54 (55.7)
0.347*
No
21 (53.8)
43 (44.3)
Yes
16 (64.0)
25 (56.9)
No
9 (36.0)
22 (43.1)
Yes
3 (12.0)
10 (21.3)
No
22 (88.0)
37 (78.7)
Yes
4 (16.0)
2 (4.6)
No
21 (84.0)
45 (95.7)
Maxillary
10 (40.0)
23 (48.9)
Mandibular
14 (56.0)
21 (44.7)
1 (4.0)
3 (6.4)
2 (8.0)
5 (10.6)
22 (88.0)
37 (78.7)
1 (4.0)
5 (10.6)
Adequate alveolar bone volume
19 (76.0)
31 (66.0)
Bone loss
6 (24.0)
16 (44.0)
24 (96.0)
29 (61.7)
Type of cancer
Unknown
0.171***
Interval between tooth extraction and last denosumab injection
Range (days)
Mean ± SD
Drug holiday before tooth extraction
Reason for tooth extraction
Periapical periodontitis
0.457*
P4 periodontitis
0.521*
Pericoronitis
0.173*
Jawbone
Maxillary and mandibular
0.881***
Site of tooth extraction
Anterior region
Molar region
Anterior and molar region
0.562***
Bone volume around tooth
0.432*
Pre-existing inflammation
Yes
0.002*
No
1 (4.0)
18 (38.3)
Yes
24 (61.5)
51 (52.6)
No
15 (38.5)
46 (47.4)
Single
11 (44.0)
20 (42.6)
Multiple
14 (56.0)
27 (57.4)
Yes
11 (44.0)
11 (23.4)
No
14 (56.0)
36 (76.6)
Yes
5 (20.0)
6 (12.8)
No
20 (80.0)
41 (87.2)
Open
12 (48.0)
15 (31.9)
Closed with suture
12 (48.0)
28 (59.6)
1 (4.0)
4 (8.5)
Preoperative antibiotics administration
0.446*
Number of teeth extracted
1.000*
Additional surgical procedure
Bone removal
0.106*
Root amputation
0.497*
Wound status after extraction
Completely closed with relaxation incision or removal
0.736***
of bone edge
*Fisher’s exact test, **Mann-Whitney U test, ***chi-squared test. DRONJ, denosumab-related osteonecrosis of the jaw; SD,
standard deviation
Table 2. Characteristics of extracted teeth according to whether or not denosumab-related osteonecrosis of the jaw was
present
Variable
DRONJ
P-value
Present
Absent
n (%)
n (%)
39 (28.7)
97 (71.3)
Male
16 (41.0)
47 (48.5)
Female
23 (59.0)
50 (51.5)
44–82
41–85
66.6 ± 10.0
66.0 ± 13.0
0.860**
0 or 1
36 (92/3)
87 (89.7)
0.355*
2 or 3
3 (7.7)
10 (10.3)
5–51
1–85
Mean ± SD
23.4 ± 13.1
15.7 ± 14.0
< 0.001**
≥18 months
26 (66.7)
27 (27.8)
< 0.001*
<18 months
13 (33.3)
70 (72.2)
Yes
2 (5.1)
16 (6.2)
No
37 (94.9)
91 (93.8)
Yes
9 (23.1)
13 (13.4)
No
30 (76.9)
84 (86.6)
Yes
27 (69.2)
63 (64.9)
No
12 (30.8)
34 (35.1)
Breast cancer
13 (33.3)
32 (33.0)
Prostate cancer
6 (15.4)
34 (35.1)
Multiple myeloma
1 (2.6)
6 (6.2)
Lung cancer
3 (7.7)
9 (9.3)
Teeth, n
Sex
0.454*
Age
Range (years)
Mean ± SD
Performance status
Duration of oncologic doses of denosumab
Range (months)
Comorbidity or drug-induced risk factors
Diabetes mellitus
1.000*
Corticosteroid therapy
0.200*
Additional chemotherapy
0.692*
Type of cancer
0.386***
Other
3 (7.7)
4 (4.1)
13 (33.3)
12 (12.4)
1–283
2–272
61.5 ± 53.1
84.6 ± 77.3
0.376**
Yes
18 (46.2)
54 (55.7)
0.347*
No
21 (53.8)
43 (44.3)
24 (61.5)
37 (38.1)
Periapical periodontitis + radicular cyst
1 (2.6)
1 (1.0)
P4 periodontitis
7 (18.0)
33 (34.0)
C4 caries
1 (2.6)
17 (17.5)
Pericoronitis
4 (10.3)
3 (3.1)
Root fracture
1 (2.6)
6 (6.2)
Other
1 (2.6)
0 (0)
Yes
25 (64.1)
38 (39.2)
No
14 (35.9)
59 (60.8)
Yes
7 (18.0)
33 (34.0)
No
32 (82.0)
64 (66.0)
Yes
4 (10.3)
3 (3.1)
No
35 (89.7)
94 (96.9)
Maxillary
16 (41.0)
54 (55.7)
Mandibular
23 (59.0)
43 (44.3)
Anterior region
8 (20.5)
25 (25.8)
Molar region
31 (79.5)
72 (74.2)
Adequate alveolar bone volume
26 (66.7)
49 (50.5)
Bone loss
13 (33.3)
48 (49.5)
Yes
38 (97.4)
65 (67.0)
No
1 (2.6)
32 (33.0)
Unknown
Duration between tooth extraction and last denosumab injection
Range (days)
Mean ± SD
Drug holiday before tooth extraction
Reason of tooth extraction
Periapical periodontitis
0.009***
Periapical periodontitis
0.014*
P4 periodontitis
0.095*
Pericoronitis
0.104*
Jawbone
0.134*
Site of tooth extraction
0.659*
Bone volume around tooth
0.127*
Pre-existing inflammation
< 0.001*
Preoperative administration of antibiotics
Yes
24 (61.5)
51 (52.6)
No
15 (38.5)
46 (47.4)
Single
15 (38.5)
33 (34.0)
Multiple
24 (61.5)
64 (66.0)
Yes
17 (43.6)
30 (30.9)
No
22 (56.4)
67 (69.1)
Yes
8 (20.5)
8 (8.2)
No
31 (79.5)
89 (91.8)
Open
17 (43.6)
33 (34.0)
Closed with suture
20 (51.3)
51 (52.6)
2 (5.1)
13 (13.4)
0.446*
Number of teeth extracted
0.693*
Additional surgical procedure
Bone removal
0.169*
Root amputation
0.073*
Wound status after extraction
Completely closed with relaxation incision or removal
0.297***
of bone edge
*Fisher’s exact test, **Mann-Whitney U test, ***chi-squared test. DRONJ, denosumab-related osteonecrosis of the jaw; SD,
standard deviation
Table 3. Results of multivariate logistic regression analysis of risk factors for denosumab-related osteonecrosis of the
jaw
95% CI
Variable
P-value
Odds ratio
Lower
Upper
0.001
243.77
11.03
5390.17
< 0.001
73.50
7.45
724.71
Periapical periodontitis
0.001
14.13
3.06
65.29
Longer duration of high-dose denosumab therapy
0.016
4.69
1.34
16.49
Female sex
0.037
1.04
1.00
1.09
Pre-existing inflammation
Steroid therapy
CI, confidence interval
...
論文の公開元へ
