Management of

Medication-Related
O s t e o n e c ros i s o f t h e J a w
William Bradford Williams, DMD, MD, Felice O’Ryan, DDS*

KEYWORDS
 MRONJ  Bisphosphonate  Denosumab  Oral surgery  Maxillofacial surgery  BRONJ

KEY POINTS
 Treatment of medication-related osteonecrosis of the jaw (MRONJ) should be based on the pa-
tient’s symptoms, comorbidities, and goals.
 Collaboration with members of the patient’s dental and medical team is encouraged.
 Effective medical management of MRONJ includes topical and oral antimicrobials, pentoxifylline,
and vitamin E.
 Plain films are inadequate for surgical planning.
 Successful surgery is predicated on primary wound closure and complete excision of necrotic
bone.

INTRODUCTION without a cure (palliation). The American Associa-

tion of Oral and Maxillofacial Surgery 2014 Position
Medication-related osteonecrosis of the jaw Paper on Medication-Related Osteonecrosis of the
(MRONJ) was first reported in 2003 and primarily Jaws states that the “Treatment objectives for pa-
involved patients receiving intravenous bisphosph- tients with an established diagnosis of MRONJ
onates for treatment of skeletal-related malig- are to eliminate pain, control infection of the soft
nancies.1 Soon thereafter, similar cases involving and hard tissue, and minimize the progression or
oral bisphosphonates and denosumab began ap- occurrence of bone necrosis.”3 Additionally, we
pearing. Although the mechanism of action of feel that helping patients to understand the chro-
these drugs may differ, both involve osteoclast nicity and potential progression of the disease is
inhibition and disruption of normal bone turnover essential to a satisfactory outcome.
and healing.2 The aim of this review is to share our treatment
There is no consensus regarding the clinical approach to patients with MRONJ once the diag-
management of patients with MRONJ. Among the nosis has been made. Fundamentally, treatment
reasons for this are an incomplete understanding can be divided into medical and surgical therapies,
of the etiopathogenesis of the disease and the dif- although a combination is often used. For pur-
ficulty in defining successful treatment. Successful poses of clarity, when referring to disease stage
treatment may be that which results in a cure, with in this review we employ the staging system as
oralmaxsurgery.theclinics.com

complete mucosal coverage and elimination of dis- described in the 2014 American Association of
ease, or that which improves the quality of life Oral and Maxillofacial Surgery position paper.3

Division Maxillofacial Surgery, Oakland Medical Center, Kaiser Permanente, 3600 Broadway Kaiser, Oakland,
CA 94611, USA
* Corresponding author.
E-mail address: Felice.O’[email protected]

Oral Maxillofacial Surg Clin N Am 27 (2015) 517–525

http://dx.doi.org/10.1016/j.coms.2015.06.007
1042-3699/15/$ – see front matter Ó 2015 Elsevier Inc. All rights reserved.
518 Williams & O’Ryan

MEDICAL MANAGEMENT routinely recommend chlorhexidine in addition to

other medical and surgical therapies.
In our practice, treatment of MRONJ with medical
therapy alone is most commonly employed for pa- Oral antimicrobials
tients with less severe disease, those who decline Antimicrobials are a mainstay in the management
surgery, or those whose comorbidities preclude of MRONJ.3,7,9,10 Antimicrobial therapy is based
them from surgery. Medical therapies currently in on clinical observation and scientific literature sug-
use include topical, oral and intravenous antimi- gesting that pathogenic bacteria may contribute to
crobials, other medications and hyperbaric oxy- MRONJ. The precise organism(s) responsible
gen (HBO). remain to be identified but it seems that most in-
fections are polymicrobial.3,11,12 Systemic antibi-
Antimicrobials otics may decrease bacterial counts in the oral
Topical antimicrobials cavity, including pathogenic organisms. Selection
Chlorhexidine gluconate 0.12% is a topical bacte- of specific antibiotics should be based on patient
ricidal and bacteriostatic agent4–6 that has been tolerance, compliance, and prior antibiotic expo-
shown to be effective in treatment of patients with sure. One should also consider therapies targeted
MRONJ.3,7 Although the pathogenesis of MRONJ against common colonizers of MRONJ lesions,
remains unclear, there is evidence that the oral including Actinobacteria, Firmicutes, Fusobacte-
flora, and more specifically biofilms, contribute to ria, and Bacteroidetes.13–15 Members of these
the disease process.8 The use of chlorhexidine is phyla include aerobic and anaerobic organisms
thus rationalized by its ability to decrease total commonly susceptible to penicillin; therefore,
bacterial counts, including potentially pathologic penicillin remains our first antibiotic choice. Our
organisms. Advantages of chlorhexidine include most common penicillin alternates are clinda-
low cost, ease of use, availability, patient accep- mycin, fluoroquinolones, and/or metronidazole
tance, and efficacy. Disadvantages include patient (Fig. 2). Although there are no data to clarify the
intolerance, lack of compliance associated with most appropriate duration of antibiotic therapy
long-term use, dental staining, and opportunistic for MRONJ, we generally prescribe a 2-week
infection, as well as alterations in taste. In our prac- course for patients with persistent stage 1 disease
tice, we commonly recommend chlorhexidine for and up to a 4- to 6-week course for more severe
management of stage 1 disease as a singular ther- cases.
apy (Fig. 1). For more advanced stages, we Intravenous antimicrobials
Intravenous antimicrobials may be of benefit in pa-
tients with pathogenic organisms resistant to oral
agents and may provide greater tissue penetration
in certain cases. However, there have been no
satisfactory trials demonstrating greater efficacy
of intravenous agents compared with oral medica-
tions in management of MRONJ.16,17 When all
available oral agents have been exhausted and
no less invasive option exists, it is our practice to
employ long-term (6 weeks) intravenous antimi-
crobials. In the future, it is conceivable that antimi-
crobial therapy may be more effective in MRONJ
treatment when combined with developing deliv-
ery mechanisms most capable of penetrating
biofilms.

Other Medications
Fig. 1. Stage 1 medication-related osteonecrosis of the Pentoxifylline and vitamin E
jaw of the right alveolar ridge, which was asympto-
The combination of pentoxifylline and vitamin E
matic but noted on routine dental examination after
has been used successfully in the treatment of
dental extractions. There was no exposed bone in the
extraction sites. The patient had a 12-year history of jaw osteoradionecrosis and MRONJ; however,
oral bisphosphonate exposure for treatment of osteo- the specific mechanism of action in MRONJ
porosis and no other comorbidities. Treatment included remains unclear.18–22 Pentoxifylline (Trental), a
chlorhexidine oral rinses and routine oral hygiene prac- xanthine derivative with an excellent safety profile,
tices. Resolution of the lesion was seen at 3 months. is used primarily for the treatment of intermittent
 Management of Medication-Related Osteonecrosis 519

Fig. 2. (A) Stage 2 medication-related osteonecrosis of the jaw (MRONJ) in the right mandible of a 77-year-old
man with multiple myeloma and a 12-month history of pamidronate exposure. His comorbidities included dia-
betes mellitus, end-stage renal disease, and gout. He presented with several areas of painful exposed bone in
the right mandibular alveolus that developed after wearing a poorly fitting partial denture. (B) CT demonstrates
bony sclerosis in the area but no bony sequestra. Treatment consisted of oral antibiotic therapy (clindamycin
because the patient was allergic to penicillin) and chlorhexidine rinses. The patient died with stage 2 MRONJ
several months after diagnosis.

claudication and other symptoms of peripheral osteoporosis. The drug is composed of 34 amino
vascular disease. It has been shown to decrease acids of the N-terminal chain of parathyroid hormone
inflammation and reduce blood viscosity by and retains the anabolic effects of endogenous
increasing erythrocyte deformability.23 Vitamin E parathyroid hormone, including promotion of bone
decreases tissue inflammation and fibrosis, and remodeling. Its use in MRONJ treatment began
is a scavenger of free radicals capable of cellular when osteoporotic patients with bisphosphonate-
injury.19 Alpha tocopherol is the most active form associated MRONJ had their osteoporosis therapy
of vitamin E in humans, and is widely available, changed to teriparatide and resolution of their oral
well-tolerated, and readily absorbed. Numerous lesions was noted.25 There is also a case report of
reports supporting the role of both inflammation intravenous bisphosphonate-related MRONJ re-
and decreased vascularity as contributors to solving after teriparatide administration.26 Teripara-
MRONJ make the use of this relatively well- tide is thought to stimulate effectively osteoblast
tolerated drug combination a rational choice.3 function and proliferation, increase osseous cell
The duration of treatment has not been clarified, signaling (including Wnt), and activate osteoclasts.27
but borrowing from the osteoradionecrosis litera- At the time of this publication, there are several
ture benefits may plateau after 2 to 3 years of case reports but few well-controlled studies to
use.22,24 Our group typically offers this therapy to demonstrate the efficacy of this medica-
any patient regardless of disease stage. The rec- tion.10,25,26,28 The safety, side effects, dosing,
ommended dose of pentoxifylline is 400 mg sus- and duration of therapy for the management of
tained release twice daily and 1000 IU vitamin E MRONJ are not known. Currently, we have not
daily. Reasons for termination of therapy include used this agent in our practice for treatment of
patient intolerance, disease resolution, or after MRONJ and it is important to note that teriparatide
36 months. However, because treatment duration is contraindicated in patients with metastatic bone
remains empiric continued administration should disease or osteosarcoma. Certainly, promising re-
be determined by the patient, treating physician, sults have been observed with this therapy and,
and medical team. In addition, we routinely main- given the limited options available for treatment
tain these medications perioperatively in those of MRONJ, its use should be considered and stud-
who require surgical treatment of the MRONJ. ied further.

Hyperbaric Oxygen Therapy

Teriparatide
Teriparatide (Forteo) is a subcutaneously adminis- HBO therapy has been used for management of
tered drug used primarily in the treatment of osteoradionecrosis of the jaw for many years
520 Williams & O’Ryan

and more recently has been applied to treatment alveolus, with the goal of maintaining an intact
of MRONJ.3,10,29 Those advocating HBO for inferior border of the mandible. Segmental resec-
treatment of MRONJ argue that HBO provides tion, on the other hand, refers to en bloc removal
greater oxygen to tissues with impaired vascular- of involved bone, including the inferior border of
ization. Additionally, HBO reverses impaired the mandible, with a resulting continuity defect.
leukocyte function and also supplies reactive ox- Success rates vary widely in response to local
ygen and nitrogen species. All of these effects debridement/marginal resection ranging from
theoretically contribute to improved wound heal- 15% to 100%.10 Higher success rates have
ing and bone turnover. HBO is seldom used as been found when debridement was combined
a singular treatment modality, but is more with multilayer primary soft tissue closure and fail-
commonly used as a surgical adjunct. Freiberger ure to achieve adequate soft tissue closure has
and colleagues29,30 demonstrated slightly greater been thought to affect surgical outcomes
healing in patients who received HBO after surgi- adversely.31–33 Success of debridement or mar-
cal debridement (52%) compared with those who ginal resection may also be limited by the difficulty
underwent only surgical debridement (33%), but in differentiating healthy from diseased bone.
this difference was not statistically significant Inadequate removal of affected bone has been
(P 5 .203). In summary, the clinical utility of found to increase MRONJ recurrence.34,35
HBO for management of MRONJ remains unclear Because the extent of the osteonecrosis is often
and for this reason we rarely use it for our pa- greater than what is seen clinically, preoperative
tients. HBO therapy is a controversial, costly, imaging with CT or cone beam CT, bone scintig-
and time-intensive treatment whose efficacy de- raphy, and/or MRI can also aid in determining
serves further study. the type and extent of surgery and assist in identi-
fying bony margins.36–38
SURGICAL MANAGEMENT Intraoperative fluorescence-guided debride-
ment has been suggested to assist in differen-
Our focus in the surgical treatment of MRONJ is tiating necrotic from viable bone.39–43
directed toward stage-specific therapeutic op- Tetracycline is used as a bone label for this pur-
tions. Patients with stage 0 and stage 1 disease pose because it is incorporated into sites of
generally do not warrant surgical intervention, bone remodeling and thus will only be seen in
but benefit from medical management, as outlined viable bone. The technique involves preoperative
elsewhere in this article. In our practice, surgical administration of doxycycline (100 mg twice a day
treatment is offered when disease progresses to 10 days before surgery). A fluorescent light
the point where symptoms are not controlled source is applied to the affected region during
with medical therapies. Regardless of disease debridement and areas of necrotic bone are
stage any overtly mobile necrotic bony sequestra seen to fluoresce as a pale bluish-white color
should always be removed. whereas viable bone appears brightly fluores-
A wide spectrum of disease is often seen with cent.41 Autofluorescence (using the fluorescent
stage 2 MRONJ, ranging from focal minimally lamp without preoperative administration of doxy-
symptomatic exposed bone to severely painful cycline) has also been reported to aid with the
widespread bone necrosis. It is thus difficult to identification of viable bone.43
recommend a single surgical treatment approach During surgical debridement, extraction of any
in these patients. Rather, the decision regarding involved teeth is also indicated. It is better to
operative intervention depends on the patient’s debride diseased tissue adequately, including
medical status, comorbidities, pain level, their removing adjacent potentially involved teeth,
treatment goals, and the extent of disease. Those than it is to leave the area inadequately treated
with mild stage 2 disease who have minimal pain to preserve teeth. Any sharp bony spicules should
and localized bone exposure may not require sur- be removed and extraction sockets and bony mar-
gical intervention and may remain stable with gins should be free of sharp edges to aid in
medical management. A number of surgical treat- achieving tension-free primary closure.
ment modalities, all with varying success rates, All resected hard and soft tissue should be sent
have been described for patients with symptom- for histopathologic examination as well as culture
atic stage 2 MRONJ. and sensitivities to allow directed postoperative
Debridement and marginal and segmental antibiotic therapy. Bedogni and colleagues34
resection are terms commonly seen in the litera- noted that recurrent MRONJ was seen in those
ture describing surgical treatment of MRONJ. cases where bony margins showed chronic osteo-
Debridement and marginal resection both refer myelitis indicating inadequate removal of diseased
to removal of necrotic bone, primarily in the tissue.
 Management of Medication-Related Osteonecrosis 521

Adjunctive treatments, including autologous Low-level laser therapy, purported to stimulate

platelet-rich plasma and low-level laser therapy, bone healing by increasing vascularity and osteo-
have been used in conjunction with surgical blastic differentiation, has been used in conjunction
debridement to improve postoperative heal- with surgical debridement of osteonecrosis.46,47
ing.10,44,45 The data are inconclusive as to the However, rates of healing after surgical debride-
added value of these modalities. A systematic re- ment with and without low-level laser therapy are
view of the literature on autologous platelet con- comparable and further research is needed to
centrates concluded that, although the evidence determine the value of low-level laser
was weak, the addition of platelet concentrates therapy.10,48–50
improved healing outcomes after surgical debride- In summary, in cases of stage 2 MRONJ when
ment of osteonecrosis.44 debridement and marginal resection is determined

Fig. 3. (A) Stage 3 medication-related osteonecrosis of the jaw (MRONJ) in the left mandible 1 year after extrac-
tion of left mandibular second molar tooth in a 57-year-old woman with metastatic breast cancer and a 3-year
history of zolendronate exposure. (B) Axial CT demonstrating the bony sequestrum (arrow) and extensive scle-
rosis of the left hemi-mandible. The patient had received oral and intravenous antibiotics with no improvement
and presented with severe (10/10) pain not responsive to any type of narcotic therapy. (C) Bone scintigraphy with
Tc99 demonstrates involvement of the left hemimandible. We elected to resect the left hemimandible transorally.
(D) Intraoperative view of left hemimandible with bone sequestrum visible along the lingual aspect of the alve-
olar ridge. A custom bent osteosynthesis plate was placed. (E) Frontal view of patient 7 years postoperatively
without recurrent MRONJ. (F) Intraoral view 7 years postoperatively. (G) Posteroanterior 3-dimensional (3D) im-
age of the patient at 7 years status post left hemimandibulectomy with osteosynthesis reconstruction. (H) Lateral
3D image of patient 7 years status post left hemimandibulectomy with osteosynthesis reconstruction.
522 Williams & O’Ryan

to be the indicated, treatment the following princi- 6. Restraint from wearing any oral prosthetic de-
ples should be applied: vices until complete mucosal healing is seen.
1. Appropriate preoperative imaging to assess the Patients with stage 3 MRONJ who present with
extent of disease, extensive maxillofacial involvement may benefit
2. Removal of all necrotic bone and any involved from wide local debridement or segmental resec-
teeth to achieve disease-free bony margins, tion of necrotic bone. We reserve this treatment
3. Removal of any sharp bony edges and for those with severe symptomatic disease when
spicules, other modalities have failed. Segmental resection
4. Achievement of a layered tension-free primary for treatment of stage 3 osteonecrosis of the jaw
wound closure whenever possible, has shown generally favorable outcomes with up
5. Culture-directed postoperative antibiotic ther- to a 90% success rate.10,34,51,52 As with stage 2
apy until mucosal healing is seen, and disease, evidence of osteomyelitis at one of the

Fig. 4. (A) 74-year-old woman with right periorbital cellulitis and stage 3 maxillary medication-related osteonec-
rosis of the jaw (MRONJ). Her history was significant for multiple myeloma and 4 years of intravenous bisphosph-
onate therapy. Two years before admission, she had undergone extraction of the right maxillary second molar
tooth, which failed to heal. She had been off and on oral antibiotic therapy since that time. (B) Intraoral view
of exposed necrotic bone in the right maxilla. (C) Axial and (D) coronal CT demonstrating extensive MRONJ of
the right hemimaxilla, right inferior turbinate, and orbital floor. (E) Right maxillary stage 3 MRONJ showing
extent of necrosis. (F) Fragments of necrotic right maxilla, dentoalveolar bone, and associated dentition. (G) Fron-
tal view 5 years postoperatively. She has had no recurrence of MRONJ. (H) Intraoral view without and (I) with
prosthesis 5 years postoperatively.
 Management of Medication-Related Osteonecrosis 523

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