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Table 2 Included literature

From: Dental implants in patients treated with antiresorptive medication – a systematic literature review

Implant

Author Year Reference

Study type

Patients

Primary disease in BP patients (n)

BP BP-Th (years min- max)

BP-ONJ cases due to implants

Implants (n)

Implant insertion in all patients (patients [n]) Point of time

Comment

before BP therapy

during BP therapy

after BP therapy

 Al-Sabbagh 2015 [24]

RS CS

203 patients with 515 implants; 20 out of those patients with osteoporosis and oral BP

Osteoporosis 20

Oral BP > 3

0

46

n.s.

n.s.

n.s.

All patients with implant therapy from 08/2000 until 05/2004 were contacted and data was collected by interview (in person/per telephone). 203 patients with 515 implants; in 20 patients (46 implants) with osteoporosis and oral BP no ONJ occurred no implant was lost. There is no data regarding the implant success in the patients without osteoporosis.

 Nisi 2015 [20]

RS CS

90 patients with established ONJ some of them with implants

Malignoma 90

Z n.s.

9

n.s.

n.s.

n.s.

n.s.

All patients with BP-ONJ from 01/2004 until 12/2015 were retrospectively analyzed. 78% had an additional radiation. It is not clear if the head and neck region was affected and if the implant patients were affected. The study describes the cumulative BP dose, smoking, steroid intake and the maxillary location as risk factors for an increases BP-ONJ stage.

 Holzinger 2014 [9]

RS CS

13 patients with established ONJ due to dental implants

Osteoporosis 5

breast cancer 3

lung cancer 1

Langerhans cell

histiocytosis 1

Z A P I-

0.5 – 9

0 – 15.6

13

47

3

7

3

All patients with BP-ONJ from 04/2004 – 07/2012 were analyzed. Among those were 13 patients (47 implants) with implants as a trigger. 30 implants had to be removed.

It takes longer for BP-ONJ development if implants are placed during or after BP treatment compared to implants being inserted before BP treatment.

 Lopez-Cedrun 2013 [10]

RS CS

9 Patients with established ONJ due to dental implants

Osteoporosis Polymyalgia rheumatica

A I R

0.5 - 10

9

57

-

9

-

Retrospective multicenter study analyzing all patients with BP-ONJ due to dental implants from 01/2009 – 06/2012.

The authors state that the ONJ was more common in the mandible (8/9) and more often in the premolar and molar region.

28 implants maxilla → 1 BP-ONJ

29 implants mandible →8 BP-ONJ

 Tam 2013 [16]

RS CS

6 patients with established BP-ONJ due to dental implants

Osteoporosis 4 breast cancer 1 multiple myeloma 1

A Z

1.5-6

6

 

-

6

-

All patients with BP-ONJ due to dental implants from 2009 – 2011 were analyzed; 3 patients with BP-ONJ in the posterior maxilla 3 patients with BP-ONJ in the mandible (2 distal, 1 anterior)

 Kwon 2014 [17]

RS CS

19 patients with established BP-ONJ due to dental implants

Osteoporosis 18 multiple myeloma 1

A I P R Z 1 - 5

19

n.s.

3

16

-

All patients with BP-ONJ due to dental implants from 06/2008 – 12/2011 were analyzed. 8 patients with BP-ONJ in the maxilla, 9 patients with BP-ONJ in the mandible, 2 patients with BP-ONJ in mandible and maxilla

 Jacobsen 2013 [18]

RS CS

14 patients with established BP-ONJ due to dental implants

Osteoporosis 5

Breast cancer 5

multiple myeloma 2

prostate cancer 1

lung cancer 1

A I P Z

Average BP duration

3.2 osteoporosis; 4.2 malignant disease

14

n.s.

n.s.

n.s.

n.s.

The authors state that implants placed posterior are of higher risk than implants in the anterior region.

4 patients had implants in the posterior maxilla, 5 in the posterior mandible and 3 in the anterior mandible.

In one patient implants were removed and new implants were inserted at the same site with continuing problems.

In one patient a sinus lift was performed

 Famili 2011 [25]

RS CS

211 female patients with 592 dental implants, out of those 120 older than 50 y with 347 implants out of those 22 with BP and 75 implants

Osteoporosis 21 osteoarthritis 1

A I

<1 - > 5

0

75

n.s.

At least 20

n.s.

All female patients with implant therapy from 01/2008 – 06/2010 were analyzed. Among those 22 with oral BP therapy.

One implant did not heal and was successfully replaced

 Kwon 2011 [21]

RS CCS but not focused on dental implants

→ RS CS

Biochemical bone markers were evaluated in 23 osteoporosis patients with established BP-ONJ

Osteoporosis

A

2.5 - 5

2

n.s.

n.s.

n.s.

n.s.

It is not clear, when and how the 23 BP-ONJ patients were recruited. 61 BP control patients.

2 patients developed BP-ONJ due to implants

CTX was evaluated at the time of ONJ diagnosis and not at the time point of any possible BP-ONJ triggering intervention.

 Koka 2010 [22]

RS CS

370 patients over 50 years old with 818 implants. 233 patients could not be reached so that the phone interview was conducted with remaining 137 patients: 55 BP patients and 82 non-BP patients

Osteoporosis

A & n.s.

<3 - > 5

0

121

-

55

-

All patients from 11/2006 – 05/2009 that had not denied access to data for research purposes. None of the BP patients had a drug holiday. 121 implants were inserted, one did not survive.

The patients were not examined only a phone interview was conducted.

The control group consisted of 82 non-BP users with 166 implants (163 survived, 2 losses in 1 patient). 233 patients could not be reached by phone and were excluded.

 Lazarovici 2010 [19]

RS CS

27 patients with established ONJ due to dental implants

Osteoporosis 11

multiple myeloma 7

breast cancer 7

prostate cancer 2

A P Z

average BP duration

A 5.7

Z 1.4

P 4.2

27

n.s.

2

25

-

All patients from 04/2003 – 01/2009 with BP-ONJ and dental implants. 15 patients had implants in the posterior mandible, 5 in the anterior mandible, 4 in the posterior maxilla, 3 in the anterior maxilla

 Goss 2010 [26]

RS CS

Questionnaire to 46 dentists placing either > 50 implants/y or treat BP-ONJ in South Australia

Osteoporosis in the 7 patients with implant loss

A R in the 7 patients with implant loss

7

≥9

4

3

-

46 dentists placed approximately 28,000 implants in 16,000 patients. There is no number given how many patients received BP. 7 implants were lost in patients with BP

 Lo 2009 [27]

RS CS questionnaire

Questionnaire to 13,496 patients with oral BP therapy, 8,572 answered, 2,159 reported dental symptoms, 1005 were examined, 9 BP-ONJ

n.s.

A I R

≥1

1

n.s.

n.s.

n.s.

n.s.

13,946 questionnaires were sent, 5,374 did not participate, 9 ONJ were identified and 1 was associated with an implant loss and a tooth extraction. The bisphosphonates had been administered before implant insertion

 Bell 2008 [28]

RS CS

42 patients with BP therapy and oral bone grafting or implant placement

n.s.

A R I

0

100 or 101 both numbers are given in the paper

-

42

-

All patients from ??/1990 - ??/???? (paper published in 2008) with BP treatment prior to implant therapy were analyzed. 5 implants failed, no patient with more the 1 implant loss, all implants successfully replaced.

30 patients received an additional bone augmentation (socket graft, sinus lift, closed sinus lift, guided tissue regeneration, or tunnel graft).

 Grant 2008 [29]

RS CS

Questionnaire to all 1,319 female patients over 40 y and with implants,

458 patients responded,

115 out of those had oral BP,

72 patients came to a follow-up

n.s.

A I R

Mean 3.2

0

456 in the 115 patients

26

out of the 115

89

out of the 115

-

All 1,319 patients over 40 y of age with implant therapy between 01/1998 – 12/2006 were contacted.

 Fugazotto

2007

[30]

RS CS

61 patients out of two private practices with oral BP

n.s.

A R

Mean 3.3

0

169

-

61

-

All 61 patients with oral bisphosphonates with implant therapy between 01/2005 – 12/2005 were analyzed. 43 immediate implants

1 Pat had exposed bone at a different location that was treated by debridement. At the next control there was granulated soft tissue.

 Jeffcoat 2006 [31]

PS

50 patients with 210 implants

25 patients with oral BP 102 implants

25 patients without BP 108 implants

Osteoporosis 25

A R

1 - 4

0

102

-

102

-

Longitudinal single-blind controlled study

Two-stage osseointegrated implants in all patients,

no BP-ONJ

 Marx 2005 [23]

RS CS

119 patients with BP-ONJ

n.s. for the patients with implants

n.s. for the patients with implants,

in 1 case Z & P

4

n.s.

n.s.

n.s.

n.s.

RS with 119 ONJ patients, 4 due to dental implants

Denture

Author Year Reference

Study type

Patients

Primary Disease in BP-ONJ

BP/Denosumab

BP-ONJ Cases

Comment

 Nibbe 2015 [15]

RS

424 patients with oral/IV BP or denosumab.

128 patients with IV BP or denosumab - further investigation of this group

68 patients with dentures

n.s. in all cases

Oral/IV BP

Denosumab

16

424 patients with oral or IV BP were analyzed, 21 BP-ONJ, only IV BP patients for further analysis

34 removable dentures → 11 BP-ONJ

34 fixed partial denture → 5 BP-ONJ

60 patients without denture → 5 BP-ONJ

ONJ only in patients with IV BP or denosumab

 Hasegawa 2012 [43]

RS

Questionnaire was sent to 248 medical institutions regarding BP-ONJ

250 patients

99 with dentures

151 without dentures

n.s.

Oral/IV BP

99

151 osteonecrosis patients without denture had a longer osteonecrosis free time.

Most ONJ in the mandible with a focus on the premolar and molar region

154 patients with IV BP, 102 with oral BP, 7 both

 Jabbour 2012 [35]

RS

14 patients with BP-ONJ

4 due to dentures

Osteoporosis 2

kidney cancer 1

breast cancer 1

A P

4

RS analyzing the reason for osteonecroses

 Vahtsevanos 2009 [39]

RS

1,621 patients with IV BP

n.s.

n.s. for the denture patients

24

24 out of 80 BP-ONJ patients denture as triggering factor diseases and BP for the patients with dentures n.s. I P Z were used as BP in the BP-ONJ patients.

 Kos 2010 [36]

RS

34 patients with BP-ONJ

n.s.

n.s. for denture patients

3

34 patients with osteonecrosis. A I P R Z were used as BP it is not clear what the patients with the dentures received and which primary disease was present.

BP-therapy for all patients 0.3 – 8 y

 Carmagnola 2008 [34]

RS

39 oncologic patients with BP

Multiple myeloma 2

breast cancer 3

prostate cancer 1

kidney cancer 1

P Z

7

7 out of 20 BP-ONJ patients had an osteonecrosis due to denture pressure sores

BP given for 1.1 – 6.8 y

 Walter 2008 [40]

CSS

43 patients with prostate cancer out of those 21 patients with denture out of those 6 with ONJ

Prostate cancer

Z

1

1 denture induced ONJ

 Kyrigidis 2008 [38]

CCS

20 breast cancer patients 40 matched controls

Breast Cancer

Z

8

20 patients with breast cancer and osteonecrosis, 8 with dentures use of dentures associated with BP-ONJ

 Kumar 2008 [37]

RS CS

13 patients with BP-ONJ

Osteoporosis 4

breast cancer 1

multiple myeloma 1

A Z

6

6 out of 13 patients denture as the trigger factor

 Yarom 2007 [42]

RS CS

11 patients with BP-ONJ

Osteoporosis

A

2

2 out of 11 BP-ONJ triggered by denture Alendorante was given for 2 and 6 y

2 patients (1 osteoporosis, 1 rheumtoid arthritis) had an implant related BP-ONJ in the posterior mandible, BP was given for 5 and 7 years

 Walter 2007 [41]

RS CS

163 patients with an osteonecrosis, 17 BP-ONJ

Multiple Myeloma

P

1

1 BP-ONJ due to a denture pressure sore in the mandible

P was given for 5 y

 Bamias 2005 [33]

PS

252 patients with BP

17 with BP-ONJ

Multiple Myeloma

n.s.

2

2 BP-ONJ due to a denture pressure sore

I P Z for all 252 patients

Quality of life

Author Year Reference

Patients

Comment

 DeBaz 2015 [44]

524 patients asked to fill out the survey

237 completed survey

3 groups:

64 dental implant supported prosthesis

47 non-implant supported fixed restoration

60 non-implant supported removable restoration

66 no restoration of missing teeth

The quality of life assessment:

occupational score

health score

emotional score

sexual score

The patients dental implant supported prosthesis had the overall best score regarding quality of life compard to the other groups

In total 134 patients reported oral BP, 51 IV BP, 10 patients denosumab

In the implant group 35 patients received oral BP, 12 IV BP, 3 denosumab

no ONJ

Persisting alveolar socket

Author Year Reference

Study type

Patients

Comment

 Hutchinson 2010 [46]

CSS

10 patients with stage 0 BP-ONJ

Consistent findings of regional or diffuse osteosclerosis, density confluence of cortical and cancellous bone, prominence of the inferior alveolar nerve canal, thickened sclerotic lamina dura, periradicular radiolucencies, cortical disruption, and persisting alveolar sockets.

 Grötz 2006 [45]

RS CS

42 patients with BP-ONJ

Consistent findings of persisting alveolar sockets.

Hand search

Author Year Reference

Study type

Patients

Comment

 Grötz 2012 [1]

Guideline

German guidelines on bisphosphonate-associated osteonecrosis of the jaws (BP-ONJ) and other medication-related necroses of the jaw

 Grötz [52]

 

Description on many important aspects on implant surgery in bisphosphonate patients or patients with other resorptive medications.

 Grötz 2013 [53]

Review

The authors state the necessity for an individual risk assessment. The evaluation of dentures vs. implants. It is suggested to not place immediate implants in patients with antiresorptive therapy, atraumatic surgery with perioperative antibiotics, the necessity of a recall and the avoidance of bone augmentations

 Grötz 2010 [54]

Review

The authors provide an algorithm how to proceed with patients receiving BP seeking implant therapy.

The authors state the necessity for an individual risk assessment and avoidance of bone augmentations

 Krimmel 2014 [55]

RS

50 patients with BP-ONJ

DMFT of all patients 20.5 ± 4.2

disease free interval for patients with DMFT < 20: 39.7 ± 1.1 months

disease free interval for patients with DMFT > 20: 14.4 ± 2.8 months

The DMFT had no influence on the overall healing rate of BP-ONJ

 Tsao 2013 [56]

CCS

63 patients

22 BP-ONJ patients

41 matched controls

Caries similar between groups

Periodontal disease associated with BP-ONJ (pocket depth, IgG serum titer against Porphyromonas gingivalis, IL 1ß level in gingival cervical fluid)

 Thumbigere-Math 2013 [57]

CCS

73 patients

25 BP-ONJ patients

48 matched controls

BP infusions BP-ONJ 38.4 and control 18.8

BP-ONJ vs control:

missing teeth: 7.8 vs 3.1

clinical attachment level: 2.18 vs 1.56

radiogic bone loss at teeth > 50%: 20% vs. 6%

 Martin 2010 [58]

CSS

8,752 patients with oral BP returned dental survey (62% response rate)

589 patients with dental implants

16 patients with 26 implant failures

8 patients with failure of 12 implants in the maxilla

9 had failure with 14 implants in the mandible

 Shabestari 2009 [59]

RS

21 female osteoporotic women with oral BP and 46 implants

No BP-ONJ, no signs of peri-implantitis

 Zahid 2011 [60]

RS

362 patients with implants

26 BP patients with 51 implants

3 implants failed

Patients with BP had more thread exposure

 Memon 2012 [61]

RS

200 patients

BP: 100 women with 153 implants

control: 100 women with 132 implants

Success equal for both groups 93.5 (BP) vs. 95.5 (control)

crestal bone change from implant insertion to stage two surgery: no difference between the groups

 Yip 2012 [62]

CCS

337 patients

114 patients with implant failure

223 patients without implant failure

% of patients using BP

Implant failure group: 9.65%

no implant failure: 4.04

 Walter 2014 [3]

RS

504 patients with osteonecrosis

227 with BP-ONJ

7 out of 227 patients with BP-ONJ implant as trigger factor

 Lopez-Jornet 2011 [63]

Animal study

120 rats with pamidronate treatment and molar extraction

60 with penicillin

60 without penicillin

Osteonecrosis rate

Penicillin group: 18 → 34.6 %

no penicillin group: 5 → 9.61%

 Montefusco 2008 [51]

RS

178 patients with multiple myeloma und BP treatment

75 patients with dental procedures

32 with antibiotics

43 without antibiotics

ONJ rate

with antibiotics: 0

without antibiotics: 8

Antibiotic prophylaxis can reduce the incidence of BP-ONJ

 Kyrgidis 2012 [50]

PS

Group 1: BP-ONJ breast cancer 21

Group 2: breast cancer 21

Group 3: oral cancer 22

Quality of life assessment before surgery

Group 1 is affected in many factors such as pain, swallowing, senses, social eating, social contacts

 Boquete-Catro 2015 [32]

Review

Analysis of patients with denosumab associated ONJ

No implant related ONJ reported

  1. A: Alendronate; CCS: Case control study, CS: Case series; CSS: Cross sectional study; D: Denosumab; I: Ibandronate; LSBCD: Longitudinal single-blind controlled study; n.s.: Not specified; P: Pamidronate; PS: Prospective Study; R: Risedronate; RS: Retrospective study, Z: Zoledronate