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Bisphosphonate related osteonecrosis of the jaw (BRONJ) can occur in patients affected by malignancy associated hypercalcemia, bone metastases of solid tumors or multiple myeloma intaking amino-bisphosphonates or other bone resorption inhibitors. BRONJ occurs initially with alveolar bone radiographic alterations, with peripheral facial neurological symptoms and thereafter with bone exposition and necrosis.Drug related ONJ were also reported in oncologic patients intaking angiogenesis inhibitors or monoclonal antibodies that inhibit bone resorption (e.g. Denosumab).In the present case report, Denosumab has been administered to treat bone lesions related to invasive ductal breast cancer.Before starting therapy with Denosumab, in order to restore oral and periodontal health, dental extractions were performed without any modifications to surgical protocols and waiting the complete healing of extraction sites (6 weeks).Even if ministerial recommendations were followed, even if we waited the biologic healing and even if denosumab therapy started without symptoms, BRONJ occurred in this patient.The mistake made in the management of the present case is that we did not carefully evaluated early radiological signs (alveolar crest thickening, bone sclerosis, persistent alveolar post-extraction socket, periodontal space widening, formation of bone sequestrum) that could bring the clinician to the diagnostic suspect of BRONJ before the onset of clinical signs (fistula, and bone exposure).Identifying early radiological signs could bring the clinician to an early diagnosis and consequently a better prognosis.
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Are ministerial recommendations sufficient to avoid bisphosphonate related osteonecrosis of the jaw? A case report
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                                                                                                          Case report


Are ministerial recommendations sufficient to avoid
bisphosphonate related osteonecrosis of the jaw?
A case report

A. Massaria1                                                 Introduction
M.V. Bartolucci1
R. Baldi1                                                    Bisphosphonate related osteonecrosis of the jaw (BRONJ)
M. Messi1                                                    is an adverse effect characterized by a progressive bone
                                                             necrosis of the jaws in patients intaking bisphosphonates
                                                             or resorption inhibitors without previous exposition to radia-
1
    U.O.C. (Complex Operative Unit) Oral Surgery & Odon-     tion therapy. Table 1 reports diagnostic criteria for BRONJ.
    tostomatology A.V.2 Ancona (Provincial Administration)   The reason of the exclusive occurrence of BRONJ in the
    - A.S.U.R. Marche (Regional Healthcare Agency) -Italy    jaws is unknown.
                                                             To this regard some hypotheses were proposed:
                                                             • the bone turnover is physiologically faster in the jaws;
Corresponding author:                                        • the lower jaw has a terminal vascularization
M. Messi                                                     • presence of a thin mucoperiosteal layer that protects
                                                                  the underlying bone tissue;
                                                             • oral biofilm
Abstract                                                     • dento-alveolar interface that predispose to bone expo-
Bisphosphonate related osteonecrosis of the jaw                   sition in case of oral surgery.
(BRONJ) can occur in patients affected by malignan-
cy associated hypercalcemia, bone metastases of              Table 1. BRONJ Diagnostic criteria.
solid tumors or multiple myeloma intaking amino-bi-
                                                              Diagnostic Criteria
sphosphonates or other bone resorption inhibitors.
BRONJ occurs initially with alveolar bone radio-              Current or previous therapy with:
graphic alterations, with peripheral facial neurolog-         • Bisphosphonates
ical symptoms and thereafter with bone exposition             • Denosumab
                                                              • Antgiogenesis inhibitors
and necrosis                                                  • Clinical or radiological diagnosis of progressive
Drug related ONJ were also reported in oncologic                bone destruction or bone necrosis
patients intaking angiogenesis inhibitors or mono-
                                                              Exclusion Criteria
clonal antibodies that inhibit bone resorption (e.g.
Denosumab).                                                   • Previous or simultaeous radiation theraphy head
In the present case report, Denosumab has been ad-              and neck region
ministered to treat bone lesions related to invasive          Doubt Criteria
ductal breast cancer.
Before starting therapy with Denosumab, in order to           • Primary bone neoplasm primitiva and/or bone jaw
restore oral and periodontal health, dental extrac-             metastasis
tions were performed without any modifications to
surgical protocols and waiting the complete healing          The literature Medication-related ONJ as (1-8) :
of extraction sites (6 weeks).                               1) BRONJ
Even if ministerial recommendations were followed,           2) NON BRONJ: ONJ related non-bisphosphonates drugs.
even if we waited the biologic healing and even if           Two groups of resorption inhibitor drugs are described:
denosumab therapy started without symptoms,                  bisphosphonates and denosumab. Bisphosphonates bind
BRONJ occurred in this patient.                              to the hydroxyapatite crystals of bone and include amin-
The mistake made in the management of the pres-              obisphosphonates and non-aminobisphosphonates. Am-
ent case is that we did not carefully evaluated early        inobisphosphonates were mainly associated to BRONJ
radiological signs (alveolar crest thickening, bone          (56). These drugs are prescribed to treat bone metastases
sclerosis, persistent alveolar post-extraction socket,       secondary to solid neoplasms o multiple myeloma and os-
periodontal space widening, formation of bone se-            teo-metabolic deseases.
questrum) that could bring the clinician to the diag-        Aminobisphosphonates are also prescribed to prevent
nostic suspect of BRONJ before the onset of clinical         drug induced osteoporosis after hormonal therapy for
signs (fistula, and bone exposure).                          breast or prostate cancer (61-63).
Identifying early radiological signs could bring the         Denosumab is monoclonal antibody that temporary inhib-
clinician to an early diagnosis and consequently a           its osteoclasts recruitment and activation with a conse-
better prognosis.                                            quent bone turnover reduction.

Annali di Stomatologia 2021; XII (1-4): 6-11                                                                                  6
    Are ministerial recommendations sufficient to avoid bisphosphonate related osteonecrosis of the jaw? A case report

    First cases of denosumab related ONJ were described in           patients with a suspect of ONJ. The CT provides detailed
    2010 (26-99-100-132-13).                                         information about the number and the nature of osteolytic
    Three studies compared ONJ prevalence between deno-              osteosclerotic lesions (188-192). The CT permits to inves-
    sumab and zoledronic acid treatment in patients with bone        tigate cortical and spongious bone and to discern between
    metastases secondary to solid tumors (26-99-100). These          healthy and pathologic bone giving information about the
    studies showed that ONJ prevalence after the intake of           extension of pathologic process (193-186-192-198-199-
    these drugs is similar (1-2%) (27-70-24-135-134). The            200). Table 3 reports the radiological criteria for the diag-
    Italian society of Maxillo-Facial Surgery (SICMF) and the        nosis of medication-related ONJ.
    Italian society of oral medicine and pathology (SIPMO) no-
    ticed the need of defining the medication-related ONJ on
                                                                     Table 3. radiological criteria for the diagnosis of medica-
    the basis of clinical and radiological criteria different from
                                                                     tion-related ONJ.
    the only observation of exposed necrotic bone (39-173).
    Even if necrotic bone exposition remains the main indica-        Medication-related ONJ non-specific signs
    tor of ONJ, the clinician should identify other clinical and      OPM
    instrumental signs that can place the suspect of ONJ also
    without bone exposition (175-178) These signs are report-         Early signs
                                                                      Increased thickness of alveolar crest
    ed in table 2. SICMF e SIPMO stated that X-rays exams
                                                                      Lamina dura sclerosis
    are fundamentals to a diagnostic confirm of medication-re-
                                                                      Post-extractive site presistance.
    lated ONJ (mainly without bone exposition).
                                                                      Sequestrum
    Without x-rays imaging and only following classifications         Widening of periodontal space
    based on clinical signs, there are 25% of false negative
    with negative consequences on prognosis and on world              Late signs
    health care cost (40).                                            Pathologic fracture
                                                                      Increased thickness of alveolar nerve canal
    Table 2. Clinical criteria for the diagnosis of medica-           Widespread osteosclerosis
    tion-related ONJ.                                                 Radiopacity maxillary sinus
                                                                      Periostal reaction
     Symptoms and clinical signs
                                                                      CT
     •   Halitosis
     •   Dental abscess                                               Early signs
                                                                      Cortical Erosion
     •   Mandibular asymmetry
                                                                      Increased thickness of alveolar crest and lamina dura
     •   Pain originated form teeth or bone                           Increased thickness of spongious bone
     •   NECROTIC BONE EXPOSITION                                     Focal midollar osteonecrosis
     •   Mucous Fistola                                               Post-extractive site presistance.
     •   Extra-oral Fistula                                           Sequestrum
     •   Hyperemic mucosae                                            Widening of periodontal space
     •   Absence of complete healing of extraction sites
     •   Dental mobility                                              Late signs
     •   Abnormal mandibular range of motion                          Oro-antral, oro-nasal and muco-cutaneous fistula
     •   Labial Paresthesia/disesthesia                               Pathologic fracture
                                                                      Increased thickness of alveolar nerve canal
     •   Exudate emission from the nose
                                                                      Osteolysis extended to maxillary sinus.
     •   Purulent secretion                                           Widespread osteosclerosis
     •   Bone fragments spontaneous Sequestrum                        Zygomatic and hard palate osteosclerosis
     •   Trisma                                                       Periostal reaction
     •   Soft tissues tumefaction                                     Sinusitis


    The ONJ suspect should induce the clinician to perform a         Nowadays the preventive approach represents the more
    complete anamnesis with first and second line x-rays in-         effective strategy in the management of patients that will
    vestigations.                                                    intake ONJ-related drugs (4-10).
    Orthopantomography (OPM) and endoral x-rays are the              The aim of primary prevention is the control of risk factors
    first line investigations (190-191), while the computed          in order to reduce the chance to develop infections and
    tomography (CT) represents the second lie investigation          inflammatory events that do not respond to conservative
    (192-193). First line investigations are useful in order to      therapy, while secondary prevention is based on the ear-
    identify bone sequestrum and osteolytic areas. These in-         ly diagnosis throughout clinical and radiological signs and
    vestigations permit to evaluate some osteonecrosis sub-          associated symptoms identification
    clinical signs such as periodontal space widening, lamina        Following current ministerial recommendations (19) the
    dura sclerosis and alteration of spongious bone, but do not      patients that are candidates to therapy with ONJ-related
    permit to discern between generic osteolytic lesions and         drugs must undergo a dental examination and to treatment
    bone metastases.                                                 of oral pathologies before starting drug therapy.
    With the OPM it is possible to identify an osteolytic lesion     If dental surgical therapies are indicated to solve oral
    only when there is a bone mineral loss over 30-40% (192-         pathologies (e.g. dental extractions), the onset of the
    194). However, the OPM is very useful as first approach in       ONJ-related drugs therapy should be 4-6 weeks after the

7                                                                                        Annali di Stomatologia 2021; XII (1-4): 6-11
A. Massaria et al.

surgical procedures or however not before the complete          07.01.2019 Complete healing of the tissues. Absence of
epithelialization of extraction site.                           symptoms. The therapy with Denosumab started.
In the clinical case the we will present despite all the min-
isterial recommendations have been followed, some mis-          14.06.2019 Dental evaluation: absence of acute or
takes brought to a bad management of the patients with          chronic inflammation. Further x-rays investigations were
consequent late diagnosis.                                      not prescribed.
The aim of the present case report is to underline that
following the ministerial recommendation should be not          10.10.2019 The patient refers pain during chewing in the
sufficient in order to avoid the ONJ risk. Furthermore the      4th quadrant. The clinician decided to modify the low-
present work aims at the importance of early radiologi-         er removable prostheses in order to eliminate areas of
cal signs that should bring the clinician to the suspect of     pressure.
ONJ before the onset of clinical signs in order to have
                                                                15.11.2019 After an initial improvement, the symptoms
an early diagnosis and a consequent better prognosis.
                                                                get worse and a new OPM was prescribed.

Case report
                                                                The OPM is significant concerning early ONJ signs. In
A female aged 70 affected by bone metastases second-            this case these signs were misinterpreted by the dentist
ary to ductal invasive breast cancer was waiting to start       and the radiologist and were confused with root residu-
the therapy with resorption inhibitor drugs (DENOSUM-           als in the 43-44 area. In 41-42 area a late healing was
AB) and undergone a dental clinical evaluation that un-         detected (the extractions were performed 1 year before).
derlined the need of some dental extractions (1.2-2.2-          Endoral x-rays were performed in order to confirm the ra-
3.2-3.3-4.2-4.3).                                               diological suspect (presence of root residuals) but these
26.11.2018: dental extractions were performed following         investigations show the presence of a bone thickening
appropriate surgical protocols (29-79-89) and prescrib-         caused by the denosumab therapy.
ing antibiotic therapy (Amoxicillin 1gr 3 times a day start-    Therefore, we decided to further modify the lower pros-
ed 3 days before the surgery and stopped 1 week after           thesis in order to remove pressure areas.
the surgery) (29-79-82-84-85-88-90). Dental extractions         Actually, the OPM and the endoral x-rays show evident
were performed after a rinse with a 0.2% chlorhexidine          signs of ONJ: post-extractive socket persistence after
mouthwash without alcohol for 1 minute. After the local         more than 1 year from the extraction; widespread os-
anesthesia, the extractions of teeth were performed with        teosclerosis and spongious thickening in the extraction
the minimum intrusiveness for the bone after removing           areas; bone sequestrum in 44-45 areas.
granulation tissue. The wounds were sutured in order to         The progressive bone thickening is more clear if this
obtain a healing by primary intention.                          area of osteosclerosis is compared to the bone density
                                                                of adjacent or contralateral areas (187-203).
03.12.2018 After one week the sutures were removed and          These radiological signs were ignored or misinterpret-
the post-surgical control was planned after one month           ed as late healing caused by resorption inhibitors drugs.




OPM 16.11.2018

Annali di Stomatologia 2021; XII (1-4): 6-11                                                                                8
    Are ministerial recommendations sufficient to avoid bisphosphonate related osteonecrosis of the jaw? A case report




    OPM 15.11.2019                                                                              OPM 15.11.2019 (detail)

    This contributed to a delayed diagnosis and to a conse-         Conclusion
    quent worst prognosis.
    28.11.2019 After about 2 months the patient come back           In this case the pain referred by the patient was underes-
    for a dental control because of persistent pain. The clin-      timated and misinterpreted. Furthermore, since all steps
    ical examination showed the presence of a fistula in the        of the management protocols were followed, the early
    43-44 area. Therefore we decided with the oncologist to         radiological signs were not recognized.
    suspend the therapy with Denosumab and to refer the             The results of the present clinical experience aim to un-
    patient to the maxilla-facial section in order to treat a       derline that detecting early signs of medication-related
    possible medication-related ONJ.                                ONJ could be difficult. Furthermore, we would like to




    OPM 14-04-2020




    ENDORAL x-rays: FISTULA

9                                                                                      Annali di Stomatologia 2021; XII (1-4): 6-11
A. Massaria et al.

highlight that this pathology can occur even if all ministe-                  Bisphosphonate-Related Osteonecrosis of the Jaw? J Oral
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11                                                                                              Annali di Stomatologia 2021; XII (1-4): 6-11
