J Oral Pathol Med
doi: 10.1111/jop.12419
BRIEF REPORT
Modified protocol including topical minocycline in orabase
to manage medication-related osteonecrosis of the jaw
cases
Jumana A. Karasneh1, Kamal Al-Eryani1, Glenn T. Clark1, Parish P. Sedghizadeh2
1
Department of Oral Medicine and Orofacial Pain, Division of Diagnostic Sciences, University of Southern California, Los Angeles, CA,
USA; 2Centre for Biolms, University of Southern California, Los Angeles, CA, USA
OBJECTIVE: Management of medication-related osteone-
crosis of the jaw (MRONJ) with active infection can be a
serious challenge for clinicians. Based on Association of
Oral and Maxillofacial Surgeons (AAOMS) recommenda-
tions, we have tested a modified treatment protocol
using topical minocycline.
STUDY DESIGN: Five patients diagnosed with stage II or
III MRONJ lesions were willing to consent to our proto-
col. In addition to conventional treatment as suggested
by the AAOMS, such as, surgical debridement, chlorhex-
idine irrigation, and systemic antibiotics, we applied 10%
minocycline to the lesions once a week for sustained local
antibiotic delivery.
RESULTS: All five patients reported pain relief after the
first minocycline application. Complete healing occurred
in three patients; case three healed completely after the
third application, one case continues to improve toward
resolution and one withdraws due to other non-relevant
medical problem.
CONCLUSIONS: In this study, we are reporting favor-
able results using a modified protocol with topical
minocycline to treat MRONJ lesions.
J Oral Pathol Med (2016)
Keywords: biofilm; bisphosphonate; minocycline; medication-
related osteonecrosis of the jaw
Introduction
Medication-related osteonecrosis of the jaw (MRONJ) is
dened by the American Association of Oral and Maxillo-
facial Surgeons (AAOMS) as exposed bone or bone that can
Correspondence: Jumana Karasneh, Department of Oral Medicine and Oral
Surgery, Jordan University of Science and Technology, PO Box: 3030,
Irbid 22110, Jordan. Tel: +962-799515777, Fax: +962-2-7095115,
E-mail: jumana2003@yahoo.com
Accepted for publication December 14, 2015
2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
wileyonlinelibrary.com/journal/jop
be probed through an intraoral or extraoral stula(e) in the
maxillofacial region that has persisted for more than
8 weeks in a patient with current or previous treatment
with antiresorptive or anti-angiogenic agents and no history
of radiation therapy to the jaws or obvious metastatic
disease to the jaws (1). A protocol to manage MRONJ cases
is supported by the AAOMS, which aims to control
infection by systemic antibiotics during the acute phase,
conservative initial debridement, control pain if present, and
maintenance of a favorable environment in the mouth using
antibacterial oral rinses (1).
Systemic antibiotics are commonly used for MRONJ
treatment, but limitations include systemic toxicity and poor
penetration into ischemic and necrotic bone tissue typical of
MRONJ lesions (2, 3). Topical application of antibiotics
addresses these disadvantages by maintaining a high local
antibiotic concentration for an extended duration without
systemic toxicity (4, 5).
Minocycline is a broad spectrum antibiotic, which has
several biological actions beyond its antimicrobial activity,
including inhibiting tissue collagenases and anti-inamma-
tory activities (68). Topical minocycline has the unique
ability to bind bone and root surfaces and demonstrate slow
release from these reservoirs (9), which makes it useful to
sustain a therapeutic level in bony lesions. Furthermore,
minocycline causes a signicant stimulation of osteoblasts,
which has the potential to increase bone matrix (10).
Therefore, the purpose of this study was to assess the
effect of topical minocycline application in MRONJ lesions
in a series of complicated cases and to evaluate the
feasibility of including this procedure in an MRONJ
treatment protocol.
Materials and methods
Five patients were willing to consent to our modied
protocol for managing MRONJ lesions in accordance
with the Declaration of Helsinki. These patients were
being managed by us as part of an ongoing natural
history study with appropriate approval by the institu-
tional review board at University of Southern California
 Modified protocol for MRONJ management
Karasneh et al.

2
(USC IRB#HS-09-00307). MRONJ diagnosis was con-
rmed based on the AAOMS criteria (1) and was classied
as stage II or III (Table 1). None of the patients had a
history of head and neck radiation or had concomitant
steroids with antiresorptive therapy. All patients received
antiresorptive medications to manage osteoporosis and none
had the medication for bone metastases.
Initially, all patients followed the standard treatment
protocol, which included bone debridement, removal of
bone sequestrum, 7 days of postoperative antibiotics (875/
125 mg Augmentin BID), chlorhexidine rinses QID using a
12-cc monoject syringe (Vista Dental Products, Racine, WI,
USA), and analgesics as needed. As those cases did not
respond to the standard protocol, the modied protocol was
adopted. Figure 1 Topical minocycline compounding and use. (A) The upper left
syringe contains 100 mg minocycline powder and the upper right syringe
A 10% topical minocycline was prepared by mixing contains 1 gm of Orabase measured in the scale, and the two syringes
100 mg minocycline HCl capsule with 1 g Orabase paste connected by female/female connector. 10% minocycline paste is com-
(ConvaTec, Flintshire, UK); mixing was performed using pounded by mixing the powder and Orabase forward and backward from
two 5-cc syringes connected by a female/female luer-lock one tube to another until the mixture is completely homogenous. (B)
connector (Cadence Inc., Staunton, VA, USA) (Fig. 1). Applying the compounded topical minocycline into the bony defect.
Patients were seen on weekly bases; each visit, the bony
lesion was explored using excavator and any loose bony for the lesion. All patients in this study were followed for a
fragments were removed. Irrigation was performed initially minimum of 10 weeks.
with normal saline then with chlorhexidine. The bony
defect was dried by sterile gauze and topical minocycline
was applied using the Q-tip. Sterile gauze was applied Results
over the minocycline paste and the patient was asked not All MRONJ patients were females from 76 to 91 years in
to eat or drink for 2 h and not to do any rinses for that age (mean age  SD = 84.8  6.5 years). All were ini-
day. tially symptomatic with pain ranging from 4 to 7 in VAS
Weekly follow-ups continued until complete epithelial- ranging from 0 to 10. One patient complained of numbness
ization of the lesion, and then, patients were seen every of the lower lip (case 2), which represented the most severe
other week for 1 month and on a monthly basis for case. All patients were diabetic, hypertensive and had
3 months. At the end of this period, a radiograph was taken osteoporosis; none of them were able to perform oral

Table 1 History and clinical data for cases

Medication Lesion duration

Case Age Race Medication duration (year) Site Stage (month) Prior management
1 88 Asian Boniva 20072011 7 R/mandible II/III 15 Debridement, systemic antibiotics
Forteo 20112013
Prolia 20112013
2 89 Asian Alendronate 70 mg/w 10 L/mandible III 12 Amoxicillin and Chlorhexidine rinses
3 76 Asian Alendronate 70 mg/w 3 L/mandible II 24 Surgical Debridement, Amoxicillin
20092012
4 91 Hispanic Alendronate 70 mg/w 3 Tooth #3 III 24 Systemic antibiotics
2012Current date
5 80 Asian Alendronate 10 mg/d 6 Tooth #2 III 24 Systemic antibiotics and
20082014 Stopped Alendronate

Table 2 Management details of patients

Total # of minocycline Needed surgical Time needed for healing

Case applications Daily home care intervention during treatment Healing after minocycline Follow-Up
1 5 times Not adequate Extraction tooth # 32 Completed 2 months 3 months
2 15 times Not adequate Extraction tooth # 20 95% Not completed Not completed
3 3 times Not adequate None Completed 1 month 15 months
4 7 times Not adequate Sequestrectomy Completed 5 months 1 month
5 3 times Not adequate Stopped Follow-Up For medical condition

J Oral Pathol Med


irrigation due to their fragile condition and lack of assistance
with home care.
All patients reported pain relief after the rst minocycline
application. Complete healing occurred in three patients
(Table 2); case three healed completely after the 3rd
application given within 1 month and continued to show
improvement with bone regeneration at the 15-month
follow-up visit. Two minocycline applications were needed
to complete the healing after extraction of tooth #32 for case
one. Pus disappeared from the lesion in the 2nd case only
after extraction of tooth #20. Ninety-ve percent epithelial-
ization was achieved after a second minocycline application,
but 5 mm of exposed bone persisted even after a 6th
minocycline application, with no symptoms or any signs of
infection. Complete healing for the 4th case was achieved
2 weeks after surgical removal of a second bony sequestrum
(2 9 2 cm).
Discussion
This study represented a modied protocol to manage
patients with MRONJ lesions using minocycline com-
pounded in Orabase. We report favorable results when
using topical minocycline in terms of controlling pain,
infection, and less dependence on home care. Osteoporosis
patients receiving antiresorptive agents are mainly post-
menopausal females who have been using these medications
for several years. In most instances, those patients suffer
from other medical problems and conditions, which exclude
aggressive surgical treatment or long-term systemic therapy
from treatment options. Cases presented in this study are
typical cases of MRONJ wherein patients have several
independent risk factors for disease development and
conditions which may contribute to poor wound healing
or infection; the only difference is the lack of home care
which made us think of an alternative way to manage
patients without the need for close home care.
Mixing minocycline in Orabase maintains the compound
at high concentration within a well-conned area for a
prolonged period. The 10% concentration offered a high
Modified protocol for MRONJ management
Karasneh et al.
3
antibiotic concentration at the area and did not induce any
adverse reactions when used on a weekly basis. Higher
concentrations were tried preliminarily up to 50% which
resulted in tissue irritation and inammation.
In conclusion, we presented a modication in MRONJ
treatment protocols by using topical minocycline com-
pounded in Orabase. Validation of topical minocycline
efcacy for treatment of MRONJ requires large, well-
controlled prospective clinical studies.
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J Oral Pathol Med