Medication-related osteonecrosis of the jaw (MRONJ) is a serious complication in patients
receiving antiresorptive therapies, such as Bisphosphonates and Denosumab. It is defined by
the presence of exposed bone or a fistula that probes bone in the jaws for a period greater
than 8 weeks in patient with a history of current or past antiresorptive or antiangiogenic
treatment, and in the absence of prior radiotherapy or maxillary bone metastases. Depending
on the severity of the disease 4 stages are described.
On the other hand, although the presence of alterations in the levels of certain biomarkers
in saliva has been documented in patients with MRONJ compared to healthy patients, its
applicability in clinical practice is still unknown.
Until recently, the status quo favored the adoption of a conservative strategy (non-surgical)
for the initial management of patients with stage I and II. However, in recent years, this
paradigm has been challenged by multiple authors who report better and more predictable
outcomes with surgical treatment.
Based on the hypothesis that patients with MRONJ stage I and II subjected to initial surgical
treatment have better results than those undergoing conservative (non-surgical) treatment, te
research group has designed a unicentric, quasi-experimental clinical trial where the
clinical and radiological outcome at the third month of 2 groups of patients with stages I
and II MRONJ undergoing non-surgical treatment (Group 1 / control) versus initial surgical
treatment (Group 2 / intervention) will be compared.
Also, the investigators hypothesize that the patients with complete resolution of the disease
will also normalize salivary biomarkers levels unlike those with stable or progressive
disease, meaning there is a correlation between clinical and biochemical response.
Accordingly, the levels of specific salivary biomarkers at baseline and at the third month
will be determined and compared with the clinical outcome.
After enrollment patients will be instructed and offered both treatment strategies, and
assigned to the corresponding group according to their choice. Patients in group 1
(non-surgical) will receive traditional conservative treatment while patients undergoing
surgical treatment will receive the same guidelines of conservative treatment plus surgery
according to a specific surgical protocol.
- Type of study: unicentric quasi-experimental clinical trial
2.1. Patients with MRONJ stage I and II subjected to initial surgical treatment have
better results than those undergoing conservative (non-surgical) treatment.
2.2. There is a correlation between clinical and biochemical outcome and the detection
in saliva of certain biomarkers such as Amino Terminal Crosslinked Telopeptides of Type
1 Collagen (NTX), Matrix metallopeptidase 9 (MMP-9), Interleukin 1a (IL-1a), Interleukin
1b (IL-1b), Interleukin 6 (IL-6), Interleukin 17 (IL-17) and Interleukin 36 (IL-36)
may be useful to monitor treatment response.
3. Main Objectives:
3.1. To compare the clinical and radiological outcome after 3 months of conservative
treatment versus initial surgical treatment in patients with MRONJ stage I and II.
3.2. To determine the levels of salivary biomarkers at the beginning and after 3 months
of treatment while correlating them with the clinical outcome.
4. Secondary Aims
- To determine if there is a relationship between the initial surface of exposed bone
and the outcome.
- To determine if clinical and radiological concordance in the outcome at the third
month for each group.
- To determine the rate of postoperative complications in the surgical group.
- To determine if there is a relationship between the number of surgical
interventions and the outcome.
- To determine the percentage of patients undergoing conservative treatment which
eventually end up requiring surgical treatment due to disease progression.
- To determine the elapsed time until complete healing for both groups.
- To determine the variables associated with a higher cure rate.
- To determine the variables associated with increased risk of disease progression or
recurrence. 5. MATERIAL AND METHODS 5.1. Sample Size Accepting an alpha risk of 0.05 and a beta risk of
0.2 in a bilateral contrast, 21 patients per group are required to detect a cure rate of
30% and 70% in the conservative and surgical treatment group, respectively. Adding 10%
to cover possible experimental losses, the sample increases to 23 per group.
5.2. Main Variables
- MRONJ Stage (1. Stage 1; 2. Stage 2).
- Type of treatment (GROUP 1/Control: Conservative Treatment, GROUP 2: Surgical
- Clinical outcome at the third month
- Radiological outcome at the third month
- Levels of biomarkers in saliva at baseline and at the third month (NTX, MMP-9, IL-1a,
IL-1b, IL-6, IL-17 and IL-36). In the case scientific evidence of other relevant
markers appears during the course of the study they may be included in the study.
5.3. Secondary Variables 5.3.1. Both groups
- Age (years)
- Sex (1.Man; 2.Mother)
- Diabetes (1. Yes; 2. No)
- Medication associated with the disease (1. Oral bisphosphonates, 2. Intravenous
Bisphosphonates, 3. Denosumab, 4: Antiangiogenic).
- Underlying disease for antiresorptive therapy (1. Osteoporosis, 2. Cancer)
- Duration of treatment with medication associated with the disease.
- Factor that triggers the disease (1. Tooth Extraction; 2. Use of removable prosthesis;
3. Unclear cause)
- Suspension of medication associated with the development of MRONJ (1. Yes, 2. No)
- Concomitant treatment with corticosteroids (1. Yes, 2. No)
- Concomitant treatment with antiangiogenic drugs (1. Yes, 2. No)
- Visual Analogue Scale (VAS) pain in the inclusion visit, and in all follow-up visits.
- Exposed bone surface (1. mild: <0,5cm2; 2. Moderate: 0,5-2cm2; Severe:> 2cm2) or number
of intraoral fistulas otherwise.
- Dimension of greater diameter of radiolucent area or sequestrum in the CT or Cone
Beam-CT scan (cm)
- Time elapsed until complete healing.
5.3.2. Group 1 (Conservative medical treatment)
- Need for surgical treatment due to disease progression
- Time elapsed until surgical rescue treatment due to disease progression.
5.3.3. Group 2 (Surgical treatment)
- Postoperative complications.
- Number of interventions.
5.4. Inclusion Visit
- Patients will be informed about the different aspects of the study and will be given the
information sheet to read carefully. Informed consent document will be given to read and
- A thorough medical history will be collected including data about their socio-family
environment, psychiatric illnesses and addictions.
- Complete and careful physical examination of the head and neck area will be carried out,
including the measurement of the area of exposed bone in cm2 or, otherwise, the number
of fistulas. Based on the clinical findings, stage 1 or 2 will be assigned according to
the AAOMS guidelines.
- Once verified that the patient meets the inclusion criteria, patients will be assigned
to the corresponding group according to their chosen treatment strategy.
- Radiological assessment will be carried out with Orthopantomography and CT-scan/Cone
Beam-CT in all patients.
- Both groups will receive the same standard conservative treatment according to our
protocol, meaning group 1 (non-surgical) will serve as control group.
- For patients enrolled in the surgical group, routine preoperative exams will be
requested and surgical intervention will be scheduled within a maximum period of 3 weeks
from the inclusion visit following a rigorous and standardized surgical protocol.
5.4.1 STANDARD PROTOCOL FOR CONSERVATIVE TREATMENT (applicable to both groups)
- Soft diet.
- Suspension of the use of prostheses or intraoral devices.
- Oral hygiene guidelines.
- Topical antiseptics: in the form of mouthrinses with 0.12% chlorhexidine after every
meal and clorhexidine gel over the exposed bone or fistula.
- Systemic antibiotics: for patients in stage 2 in which active acute infection is
detected with Amoxicillin/Clavulanic Acid 875/125 mg every 8 hours for 2 weeks. Those
allergic to penicillin will receive clindamycin 300 mg every 8 hours for 2 weeks or
Levofloxacin 500 mg / day for 2 weeks. Systemic antibiotics treatment can be prolonged
indefinitely until infection and symptoms are controlled.
5.4.2. SPECIFIC PROTOCOL FOR SURGICAL TREATMENT
- Wide mucoperiosteal flaps and complete surgical excision of necrotic bone together with
a mucosa margin of at least 2 mm.
- Removal of dental pieces included in the diseased area and regularization of bony
margins avoiding leaving sharp edges or spicules.
- Secure a two layered waterproof closure without tension (simple or with local flaps).
- Samples will be sent for Pathological and microbiological analysis.
- Stitches removal after two weeks
- Postoperative systemic antibiotic following the mentioned protocol until stitches
5.4.3. SALIVA COLLECTION PROTOCOL
- Patients must avoid rinsing and ingestion of solids or liquids for at least 1 hour prior
- The collection will take place between 8 and 10 am.
- Five minutes after an oral rinse with distilled water, 5 ml of unstimulated full saliva
from the lower lip will be collected.
- The samples will be processed within the first hour of collection of the sample by
centrifuging at 2,600 x g for 15 minutes at 4 C. The supernatant will be collected and
stored at -80 C until the biomarkers are analyzed.
5.4.4. SUCCESSIVE VISITS
- Controls will be carried out 2 weeks after the inclusion visit and then monthly until
the third month when the outcomes will be determined and the second sample of saliva
will be collected. Long term follow-up will continue every three to six months depending
on patient characteristics and desires.
- At each visit, the following information will be recorded: symptoms with VAS for pain;
physical examination of head and neck; presence of exposed bone and surface in cm2 or
number of fistulas otherwise. If complete mucosal healing is found, the time elapsed
since the start of treatment will be recorded.
- Patients in GROUP 1, may develop disease progression refractory to conservative
management. In that case, the second saliva sample will be collected before the third
month and previous to surgical treatment.
- Patients of GROUP 2 with persistent disease, recurrence or significant worsening will
undergo revision surgery if accepted.
- Radiological follow-up will be carried out with orthopantomography and CT scan/Cone
Beam-CT at the third month.
5.4.5. STATISTICAL ANALYSIS Normality tests and graphs will be used to determine if the
variables follow a normal distribution. Variables with normal distribution are expressed as
mean standard deviation and those without normal distribution are expressed as median and
interquartile range. To evaluate the differences between groups, the student's t test or the
Mann-Whitney U test will be used for quantitative variables; and the chi-square test or
Fisher's exact test for qualitative variables.
The correlations will be examined by the Spearman or Pearson rank correlation. Paired or
related sample tests will be used to assess intragroup differences. A value of p <0.05 will
be considered an indicator of a significant difference.