Oral bisphosphonates are commonly used to improve bone density in patients who suffer from a variety of pathologies. However, they have also been known to cause bisphosphonate-related osteonecrosis of the jaws (BRONJ). The aim of this clinical case presentation is to (1) determine whether the currently recommended length of time that oral bisphosphonates should be discontinued, before performing dental implant surgery, is sufficient to prevent BRONJ and (2) to describe an alternative treatment for BRONJ. A 65-year-old female patient developed BRONJ after receiving mandibular dental implants 5 months after discontinuing alendronic acid (Fosamax). The BRONJ was treated by surgical osteotomy and plasma rich in growth factors (PRGF), and the patient was followed up with biweekly examinations, which included 0.2% chlorhexidine mouthwashes and removal of any remaining necrotic bone. The dental implants were loaded 41 weeks after surgery and followed up with periapical radiographs and implant stability quotient measurements at 3, 6, 12, and 24 months postloading. Although the Association of Oral and Maxillofacial Surgeons protocols for suspension of presurgical oral bisphosphonates were followed, this patient still developed BRONJ after implant surgery. While a multitude of treatments have been described in the literature, there is not enough scientific evidence to support any one treatment. Based on this clinical case, it can be concluded that the potential adverse effects of oral bisphosphonates on the jaws could be greater than expected and that treatment with PRGF produces promising results, although more long-term studies are necessary to confirm these findings.

Bisphosphonates are a group of pyrophosphate analogues that have been shown to reduce vertebral fractures and those of the peripheral skeleton. They have a carbon atom to which 2 phosphorus atoms are attached, which allows them to fix efficiently and quickly to the hydroxyapatite crystals that are found on the bone mineral surface.15  The indications for bisphosphonates have increased in recent years. They can be classified according to their chemical composition, with their bioavailability depending on the mode of administration.6 

Nowadays, they are used in pathologies involving increased bone resorption, including hypercalcemia of tumor origin, bone metastasis, osteoporosis type I, and Paget's disease. Moreover, they can also be used in osteogenesis imperfecta, hypertrophic osteopathy, systemic mastocytosis, fibrous dysplasia, and sternocostoclavicular hypertosis.13,6 

The main complication associated with bisphosphonate intake in the field of oral surgery is the appearance of osteonecrosis of the jaws.7  However, it was only in 2003 that the phenomenon of osteonecrosis of the jaws associated with bisphosphonates was first described in the literature.7  In 2007, the American Association of Oral and Maxillofacial Surgeons (AAOMS) established a clear definition of the process, denominating the entity as bisphosphonate-related osteonecrosis of the jaws (BRONJ).8,9  As a consequence of the growing number of cases of osteonecrosis and antiresorptive and antiangiogenic therapies, the AAOMS has since changed the name BRONJ to medication-related osteonecrosis of the jaw (MRONJ).10,11 

Because of the increasing number of patients receiving bisphosphonates, clinicians' concerns regarding MRONJ as an oral surgery–related complication have led to the description of several treatment protocols, although no clear standard has been defined.10,11 

This clinical case description has 2 objectives: (1) to offer an alternative treatment for osteonecrosis of the jaws associated with bisphosphonates (MRONJ) and (2) to assess the need to increase the length of time for which bisphosphonates should –be avoided prior to treatment.

Medical history

In July 2014, a 65-year-old white woman was referred to the dental office for rehabilitation of the lower left mandibular first and second molars (Nos. 18 and 19) and upper left maxillary first premolar and first molars with dental implants (Nos. 12 and 14). The patient's medical history included osteoporosis type I, hypertension, and primary epilepsy, respectively, treated with the following drugs: alendronic acid (10 mg 1-0-0), nifedipine (10 mg 1-0-0), and valproate (900 mg). The patient had been taking alendronic acid (10 mg 1-0-0) since January 2013, a 20-month period prior to the consultation. The patient had excellent oral hygiene with no unhealthy habits and had no other significant medical conditions reported.

The patient's dental history included composite resin and silver amalgam restorations, completed 20 years ago, and the extraction of the lower left mandibular first and second molars (Nos. 18 and 19) and upper left maxillary first premolar and first molars (Nos. 12 and 14) 5 years ago. To carry out a complete analysis of the clinical case, a radiologic study was performed, which included periapical radiographs, an orthopantomography, and a computerized axial tomography. This was followed by a clinical analysis using photographs and study models assembled in a semi-adjustable articulator (Figure 1). No pathology associated with the dentition was found during the radiologic and clinical analyses.

Figure 1

Radiographic and photographic presurgical analysis.

Figure 1

Radiographic and photographic presurgical analysis.

Although the patient had been taking oral bisphosphonates for less than a 3-year period, her physician advised her to temporarily discontinue the medication at least 3 months prior to the surgery. The patient stopped taking the medication in September 2014, and the surgery was performed 5 months later in February 2015.9  Twelve months after restoring the dental implants and completing treatment, the patient restarted the oral bisphosphonate treatment with authorization from her physician.

Surgery for placement of dental implants Nos. 12, 14, 18, and 19

Before the surgery, the patient was informed of the possible risks and complications of the implant treatment and signed an informed consent form.

The patient was instructed to rinse her mouth using mouthwash containing 0.2% chlorhexidine (Oraldine Perio, Johnson and Johnson, Madrid, Spain) for 1 minute prior to surgery. This was followed by a crestal incision with an intrasulcular extension to the adjacent tooth without discharge, and subsequently, a mucoperiosteal flap was raised. With the help of a surgical splint from the diagnostic wax up, Implant-Guide Biomet 3i (West Palm Beach, Fla), to place dental implants in type II bones, was used, leaving a distance of more than 3 mm between the implant of the first lower left molar (Biomet 3i NT510, with stability of 40 Ncm) and the second lower left molar implant (Biomet 3i NT510, with stability of 35 Ncm).12  The same surgical protocol was employed in type III–IV bones to dental implants of the first upper left premolar (Biomet 3i INT411.5, with stability of 35 Ncm) and the first upper left molar (Biomet 3i INT510, with stability of 35 Ncm), leaving a distance of more than 1.5 mm to adjacent teeth.

All dental implants were placed juxtacrestal and sutured with a synthetic nonabsorbable polyamide suture, Supramid 4/013 (Figure 2). The patient received amoxicillin/clavulanic acid 875/125 mg as a prophylactic antibiotic on the day before surgery and 6 days after the surgery and ibuprofen 600 mg 1 hour before the surgery and for 2 days after the surgery, 3 times a day.

Figure 2

Dental implant placement surgery (Nos. 20 and 21).

Figure 2

Dental implant placement surgery (Nos. 20 and 21).

The patient arrived to the clinic with an emergency episode 6 days after surgery, experiencing discomfort in the lower surgical area without any complications and excellent healing in the maxilla. After the clinical evaluation, an open flap exploratory surgery was carried out. Bone exposure was observed; therefore, the antibiotic treatment was continued for 4 more days, and the edges of the flap were sutured together. At the 15th day postsurgery follow-up visit, the patient presented symptoms suggestive of osteonecrosis without suppuration in the interimplant lingual area; therefore, the following treatment was prescribed: chlorhexidine 0.2% (Oraldine Perio, Johnson and Johnson) mouthwash 3 times per day combined with topical application of chlorhexidine gel (Oraldine Perio, Johnson and Johnson). At the fourth week postsurgery control, a bony lingual exposure of 7 mm in length and 3 mm in width was present with no other symptoms. A periapical control radiography was performed, antibiotic treatment with amoxicillin/clavulanic acid 875/125 mg was prescribed for 7 days, and the chlorhexidine protocol was continued (Figure 3). A blood test was performed to determine, among other parameters, the blood level of carboxyl terminal telomere of type I collagen (CTX). At the eighth week postsurgery control, the lesion presented with the same clinical signs. The wound was disinfected with gauze, impregnated with 0.2% chlorhexidine, and the antibiotic treatment was continued. The blood test showed CTX values of 0.150 pg/mL, which were within the appropriate parameters.14 

Figure 3

Radiographic and clinical analysis 4 weeks after surgery.

Figure 3

Radiographic and clinical analysis 4 weeks after surgery.

Osteotomy surgery and Plasma Rich in Growth Factors

After periodic reviews at the 9th and 10th weeks postsurgery, it was decided to interrupt the antibiotic treatment and continue with 0.2% chlorhexidine mouthwash. Twelve weeks after surgery, necrotic bone osteotomy surgery was performed using a tungsten drill and handpiece. plasma rich in growth factors (PRGF) activated with calcium chloride was then applied in the surgical area and stabilized with suture type Surgicryl 5/0 (Figure 4).15,16 

Figure 4

Osteotomy surgery + plasma rich in growth factors.

Figure 4

Osteotomy surgery + plasma rich in growth factors.

The patient was recalled 15 weeks after initial surgery and 3 weeks after necrotic bone removal to remove the suture. At the 18th, 28th, 32nd, and 38th week follow-up visits, the patient presented with lingual soft-tissue dehiscence and a 3-mm exposure of necrotic bone that gradually decreased until it disappeared completely on week 38 (Figure 5). During the follow-up visits, the remaining necrotic bone was removed using a 7/8 Gracey curette, and the wound was disinfected with 0.2% chlorhexidine. Forty weeks after initial surgery, a periapical radiograph was performed that showed bone loss distal to implant No. 19 up to the third thread and mesial loss at implant No. 18 up to the second thread. Prior to loading the implants, the implant stability quotient (ISQ) was measured using the Osstell system (Gothenburg, Sweden) to evaluate the stability of the dental implants (Nos. 12, 14, 18, and 19). The ISQ was determined on 2 occasions on the fourth week after the second surgery, with values between 67 and 70 obtained for all dental implants.

Figure 5

Radiographic and clinical analysis 29 weeks after surgery.

Figure 5

Radiographic and clinical analysis 29 weeks after surgery.

Throughout this long period of time, the maxillary dental implants showed no complications, with excellent healing and no bone loss.

Therefore, definitive impressions were taken to start the prosthodontics rehabilitation of the maxilla and mandible. The semiprecious metal milled metal structure was tested to verify the passive adjustment and the design of all crowns. After the color determination and final ceramics manufacturing, the rehabilitation was fixed to 25 Ncm with a hexagonal head screw, as indicated by the implant manufacturer.17  Finally, the occlusion was adjusted with respect to its antagonist following the appropriate procedures18  (Figure 6).

Figure 6

Analysis with Osstell and loading of dental implants.

Figure 6

Analysis with Osstell and loading of dental implants.

Once the definitive prosthesis was placed in the mouth, the torque was checked again after 15 days, and clinical reviews were carried out at the 3, 6, 12, and 24 months postload. Periapical radiographs were also taken to evaluate the bone remodeling at each appointment. Peri-implant bone stability was observed in all reviews, and ISQ values were between 66 and 69 (Figure 7).

Figure 7

Dental implants after 2 years of follow-up.

Figure 7

Dental implants after 2 years of follow-up.

Oral bisphosphonates are used as a treatment option in many entities that cause an increase in bone resorption. However, there have been several reported cases of the presence of osteonecrosis of the jaw associated with oral surgery following the use of bisphosphonates.13,6  For this reason, the AAOMS established the term BRONJ, meaning any persistent bone exposure or intra- or extraoral fistula in the maxillofacial region for more than 8 weeks, in a patient under current or previous treatment with antiresorptive or antiangiogenic drugs and without any history of radiotherapy or bone metastasis in the jaws. BRONJ can be divided into 3 grades: grade 0, no exposure of any necrotic bone but nonspecific clinical symptoms; grade 1, exposure of necrotic bone, asymptomatic and without signs of acute infection; grade 2, exposure of necrotic bone associated with pain and signs of infection; and grade 3, exposure of necrotic bone associated with pain, signs of infection, cutaneous fistula, and clinical or radiographic evidence of bone sequestration or another complication.

To reduce the prevalence of this type of complication, the AAOMS established a protocol of action when performing any oral surgery, depending on the time that the patient has been taking oral bisphosphonates: less than 3 years: if they do not present any risk factor, they can undergo any surgical intervention without the need to stop the pharmacologic treatment, and more than 3 years: in 2014, the AAOMS recommended suspending the drug 2 months before and 2 months after surgery, providing that the systemic conditions allow this.10,11 

Starck and Epcker19  were the first to report the possible association between implant therapy and the development of osteonecrosis of the maxilla in patients treated with bisphosphonates. The risk of suffering BRONJ is considered to decrease when the bisphosphonates are administered orally; however, the prevalence of BRONJ increases if bisphosphonates are used for long periods.2023  However, there are articles reporting that BRONJ can develop after periods of less than 3 years with the placement of dental implants.24  To the authors' knowledge, there are no studies with described cases of BRONJ after less than 3 years of treatment with bisphosphonates and with suspension of the drugs 5 months before implant surgery, as is the clinical case described in this article.

Although following the AAOMS recommendations decreases the risk of BRONJ, its occurrence is still a possibility. If this happens, there are many possible treatments: medical treatment, minimally invasive surgery, medical treatment + minimally invasive surgery, medical treatment + minimally invasive surgery + major surgery, laser light therapy, growth factors (PRGF or bone morphogenetic protein–2), ozone treatment, hyperbaric oxygen therapy, teriparatide, and major surgery. However, there is no clear scientific evidence establishing which treatment to use depending on the size of the lesion, location, type of bisphosphonate (oral or intravenous), other associated pathologies, or periodontitis.2527 

In the clinical case presented herein, the complication was solved with a combination of treatments: medical treatment, surgical resection, and the use of PRGF. Medical treatment was carried out by antibiotic and chlorhexidine therapy. We considered the short-term use of chlorhexidine necessary in this study for its antiseptic effects, despite the fact that previous studies demonstrated that it has an inhibitory effect on the proliferation and migration of fibroblasts and osteoblasts.28  Another possible intervention is surgical resection of the necrotic bone with primary closure, which has been used in several studies with promising results.15,16  However, there are no randomized clinical trials comparing all of the different techniques.

The action potential of oral bisphosphonates on the maxilla may be much more aggressive than previously thought, given the clinical case described herein in which osteonecrosis developed in the jaw after the placement of dental implants following the use of oral bisphosphonates (alendronic acid) for 20 months and suspension of the drugs for 5 months prior to implant treatment. On the other hand, necrotic bone resection therapy, which maintained the perilesional soft tissue without raising a flap and was associated with autologous growth factors and antibiotic medical treatment and topical antiseptic (chlorhexidine), led to good results in our case. Randomized clinical trials are needed to establish a clear protocol of action to prevent and treat this type of complication of oral or implant surgery.

Abbreviations

    Abbreviations
     
  • AAOMS

    American Association of Oral and Maxillofacial Surgeons

  •  
  • BRONJ

    bisphosphonate-related osteonecrosis of the jaws

  •  
  • CTX

    carboxyl terminal telomere of type I collagen

  •  
  • ISQ

    Implant Stability Quotient

  •  
  • MRONJ

    medication-related osteonecrosis of the jaw

  •  
  • PRGF

    Plasma Rich in Growth Factors

We would like to thank John Lindberg, DMD candidate, University of Pennsylvania, for assistance in proofreading the manuscript.

1
Ellemann
K,
Sjogren
P,
Banning
AM,
Jensen
TS,
Smith
T,
Geertsen
P.
Trial of intravenous lidocaine on painful neuropathy in cancer patients
.
Clin J Pain
.
1989
;
5
:
291
294
.
2
Heaney
RP,
Yates
AJ,
Santora
AC
II.
Bisphosphonate effects and the bone remodeling transient
.
J Bone Miner Res
.
1997
;
12
:
1143
1151
.
3
Allen
MR,
Burr
DB.
The pathogenesis of bisphosphonate-related osteonecrosis of the jaw: so many hypotheses, so few data
.
J Oral Maxillofac Surg
.
2009
;
67
(
5 suppl
):
61
70
.
4
Rogers
MJ.
From molds and macrophages to mevalonate: a decade of progress in understanding the molecular mode of action of bisphosphonates
.
Calcif Tissue Int
.
2004
;
75
:
451
461
.
5
Vannucchi
AM,
Ficarra
G,
Antonioli
E,
Bosi
A.
Osteonecrosis of the jaw associated with zoledronate therapy in a patient with multiple myeloma
.
Br J Haematol
.
2005
;
128
:
738
.
6
Malden
N,
Beltes
C,
Lopes
V.
Dental extractions and bisphosphonates: the assessment, consent and management, a proposed algorithm
.
Br Dent J
.
2009
;
206
:
93
98
.
7
Marx
RE.
Pamidronate (Aredia) and zoledronate (Zometa) induced avascular necrosis of the jaws: a growing epidemic
.
J Oral Maxillofac Surg
.
2003
;
61
:
1115
1117
.
8
Colella
G,
Campisi
G,
Fusco
V.
American Association of Oral and Maxillofacial Surgeons position paper: bisphosphonate-related osteonecrosis of the jaws—2009 update: the need to refine the BRONJ definition
.
J Oral Maxillofac Surg
.
2009
;
67
:
2698
2699
.
9
Rupel
K,
Ottaviani
G,
Gobbo
M,
et al.
A systematic review of therapeutical approaches in bisphosphonates-related osteonecrosis of the jaw (BRONJ)
.
Oral Oncol
.
2014
;
50
:
1049
1057
.
10
Ruggiero
SL,
Dodson
TB,
Fantasia
J,
et al.
American Association of Oral and Maxillofacial Surgeons position paper on medication-related osteonecrosis of the jaw—2014 update
.
J Oral Maxillofac Surg
.
2014
;
72
:
1938
1956
.
11
Khan
AA,
Morrison
A,
Hanley
DA,
et al.
Diagnosis and management of osteonecrosis of the jaw: a systematic review and international consensus
.
J Bone Miner Res
.
2015
;
30
:
3
23
.
12
Tarnow
DP,
Cho
SC,
Wallace
SS.
The effect of inter-implant distance on the height of inter-implant bone crest
.
J Periodontol
.
2000
;
71
:
546
549
.
13
De Stavola
L,
Tunkel
J.
The role played by a suspended external-internal suture in reducing marginal flap tension after bone reconstruction: a clinical prospective cohort study in the maxilla
.
Int J Oral Maxillofac Implants
.
2014
;
29
:
921
926
.
14
Hutcheson
A,
Cheng
A,
Kunchar
R,
Stein
B,
Sambrook
P,
Goss
A. A
C-terminal crosslinking telopeptide test-based protocol for patients on oral bisphosphonates requiring extraction: a prospective single-center controlled study
.
J Oral Maxillofac Surg
.
2014
;
72
:
1456
1462
.
15
Mozzati
M,
Arata
V,
Gallesio
G.
Tooth extraction in patients on zoledronic acid therapy
.
Oral Oncol
.
2012
;
48
:
817
821
.
16
Del Fabbro
M,
Gallesio
G,
Mozzati
M.
Autologous platelet concentrates for bisphosphonate-related osteonecrosis of the jaw treatment and prevention: a systematic review of the literature
.
Eur J Cancer
.
2015
;
51
:
62
74
.
17
Moreira
AH,
Rodrigues
NF,
Pinho
AC,
Fonseca
JC,
Vilaca
JL.
Accuracy comparison of implant impression techniques: a systematic review
.
Clin Implant Dent Relat Res
.
2015
;
17
(
suppl 2
):
e751
e764
.
18
Yuan
JC,
Sukotjo
C.
Occlusion for implant-supported fixed dental prostheses in partially edentulous patients: a literature review and current concepts
.
J Periodontal Implant Sci
.
2013
;
43
:
51
57
.
19
Starck
WJ,
Epker
BN.
Failure of osseointegrated dental implants after diphosphonate therapy for osteoporosis: a case report
.
Int J Oral Maxillofac Implants
.
1995
;
10
:
74
78
.
20
Marx
RE,
Cillo
JE
Jr,
Ulloa
JJ.
Oral bisphosphonate-induced osteonecrosis: risk factors, prediction of risk using serum CTX testing, prevention, and treatment
.
J Oral Maxillofac Surg
.
2007
;
65
:
2397
2410
.
21
Grbic
JT,
Landesberg
R,
Lin
SQ,
et al.
Reduced incidence with zoledronic acid once yearly pivotal fracture trial research: incidence of osteonecrosis of the jaw in women with postmenopausal osteoporosis in the health outcomes and reduced incidence with zoledronic acid once yearly pivotal fracture trial
.
J Am Dent Assoc
.
2008
;
139
:
32
40
.
22
Ruggiero
SL,
Dodson
TB,
Assael
LA,
et al.
American Association of Oral and Maxillofacial Surgeons position paper on bisphosphonate-related osteonecrosis of the jaw—2009 update
.
Aust Endod J
.
2009
;
35
:
119
130
.
23
Fleisher
KE,
Welch
G,
Kottal
S,
Craig
RG,
Saxena
D,
Glickman
RS.
Predicting risk for bisphosphonate-related osteonecrosis of the jaws: CTX versus radiographic markers
.
Oral Surg Oral Med Oral Pathol Oral Radiol Endod
.
2010
;
110
:
509
516
.
24
Holzinger
D,
Seemann
R,
Matoni
N,
Ewers
R,
Millesi
W,
Wutzl
A.
Effect of dental implants on bisphosphonate-related osteonecrosis of the jaws
.
J Oral Maxillofac Surg
.
2014
;
72
:
1937.e1931
1937.e1938
.
25
Fernandez Ayora
A,
Herion
F,
Rompen
E,
Reginster
JY,
Magremanne
M,
Lambert
F.
Dramatic osteonecrosis of the jaw associated with oral bisphosphonates, periodontitis, and dental implant removal
.
J Clin Periodontol
.
2015
;
42
:
190
195
.
26
Fliefel
R,
Troltzsch
M,
Kuhnisch
J,
Ehrenfeld
M,
Otto
S.
Treatment strategies and outcomes of bisphosphonate-related osteonecrosis of the jaw (BRONJ) with characterization of patients: a systematic review
.
Int J Oral Maxillofac Surg
.
2015
;
44
:
568
585
.
27
Napenas
JJ,
Kujan
O,
Arduino
PG,
et al.
World Workshop on Oral Medicine VI: controversies regarding dental management of medically complex patients: assessment of current recommendations
.
Oral Surg Oral Med Oral Pathol Oral Radiol
.
2015
;
120
:
207
226
.
28
Liu
JX,
Werner
J,
Kirsch
T,
Zuckerman
JD,
Virk
MS.
Cytotoxicity evaluation of chlorhexidine gluconate on human fibroblasts, myoblasts, and osteoblasts
.
J Bone Jt Infect
.
2018
;
3
:
165
172
.