Introduction
Bisphosphonates are very effective to treat benign and malignant conditions involving intense osteoclast bone resorption, for instance osteoporosis, Paget’s disease, and multi- ple myeloma.1,2 Bisphosphonates are pyrophosphate analog compounds, and are potent osteoclast-mediated bone resorption inhibitors, therefore suppressing bone remode- ling.1,3 When administered, bisphosphonates are rapidly driven towards the bones, due to high affinity for hydroxyapatite, and are accumulated through time.1 Nitrogen- containing bisphosphonates are the most potent, and are intravenously administered;
the ones that do not have nitrogen are less potent, and are orally administered.2,4,5 One of the most common and serious side effects of this medication is bisphosphonate- related osteonecrosis of the jaws (BRONJ).
Spec Care Dentist 36(1): 43-47, 2016
*Corresponding author e-mail: fabianohegg@gmail.com
1Researcher, Laboratory of Biocorrosion and Biodegradation, National Institute of Technology, Rio de Janeiro, Brazil; 2Master Degree Student, Postgraduate Program in Pathology, Medical School, Fluminense Federal University, Rio de Janeiro, Brazil; 3Associate Professor, Postgraduate Program in Pathology, Medical School, Fluminense Federal University, Rio de Janeiro, Brazil; 4Associate Professor, Postgraduate Program in Pathology, Medical School, Fluminense Federal University, Rio de Janeiro, Brazil; 5Associate Professor, Postgraduate Program in Dentistry, Facult of Dentistry, Estácio de Sá University, Rio de Janeiro, Brazil; 6Associate Professor of Oral Pathology, Facult of Dentistry, Fluminense Federal University, Nova Friburgo, Brazil; 7Professor, Postgraduate Program in Pathology, Medical School, Fluminense Federal University, Rio de Janeiro, Brazil.
Fabiano Luiz Heggendorn, DDS, MSc, PhD;1* Taiana Campos Leite, DDS, MSc;2 Karin Soares Gonçalves Cunha, DDS, MSc, PhD;3 Arley Silva Junior, DDS, MSc, PhD;4 Lucio Souza Gonçalves, DDS, MSc, PhD;5 Karla Bianca Fernandes Fontes da Costa, DDS, MSc, PhD;6 Eliane Pedra Dias, MDS, MSc, PhD7
Bisphosphonate-related osteonecrosis of the jaws: Report of a case using
conservative protocol
BRONJ is an uncommon condition characterized by the exposure of necrotic bone for more than 8 weeks in patients who have used or are using oral or intra- venous bisphosphonates and that have not been subjected to radiotherapy.4,6 This condition has increasing attention since its first reports in 2003.3,7 Most patients present BRONJ lesions after invasive dental treatments, especially dental extractions, although spontaneous
bone exposure has been reported.8,9 There are also reports of BRONJ related to trauma to the mucosa, implants, and endodontic treatment.10–13 The most common clinical features are pain, bone exposure, soft tissue swelling, infection, dental mobility, and purulent discharge.3 The exact pathogenicity of BRONJ remains unclear, however, some theories have been proposed in order to explain it. One of them says that BRONJ would
A B S T R A C T
Bisphosphonates have been the first- line treatment option for osteometabolic diseases, such as osteoporosis, hyper- calcaemia in malignant bone diseases, and in bone metastasis. It is possible to observe a growing number of cases of osteonecrosis of the jaws in patients using this medication, called bisphos- phonate-related osteonecrosis of the jaws. The purpose of this study was to report a conservative treatment for bis- phosphonate-related osteonecrosis of the jaws—Stage 2, using antibacterial solution and low-level laser therapy. At the end of the treatment, the patient pre- sented improvement of the lesion with the healing of the mucosa. The literature still lacks successful definite protocols, thus the present case may contribute with another option for conservative management for bisphosphonate-related osteonecrosis of the jaws. More research is necessary in order to develop a good protocol management for bisphosphonate-related osteonecro- sis of the jaws.
KEY WORDS: bisphosphonates, osteonecrosis, low-level laser therapy, iodides and hydrogen peroxide
be induced by an excessive suppression of bone remodeling, due to the accumu- lation of the medication in the bones, leading to the inhibition of osteoclastic function.3,14,15 Another one states that BRONJ could be a response to an infec- tion.16,17 Bisphosphonates act on modulation of immune response of dif- ferent cell types, which could make it easier for a reaction toward specific bio- film pathogens, such as Actinomyces species, which are found on most BRONJ cases.16,17 A third explanation for BRONJ is that it could be a similar result of ischemia, caused by the antiangiogenic effect of bisphosphonates.18 The final possible cause is based on the fact that the localized bisphosphonate accumula- tion and its toxicity could, combined with other antineoplastic medications, lead to damages in the mucosa, which would in turn lead to bone exposure and osteonecrosis.19,20 Therefore, the manage- ment for BRONJ is very complicated, and the well-succeeded treatment includes elimination of infection, controlling symptoms, and stopping progression of the lesion, even if there is still bone exposure.6
The American Association of Oral and Maxillofacial Surgeons (AAOMS) has established management strategies toward BRONJ.5,6 The patients are first classified in stages, according to the grav- ity of their condition, and for each one
there is a specific conduct, displayed on Table 1. According to them, the priority is to prevent the disease, and whenever treatment is initiated, it must be as con- servative as possible.6
The BRONJ management is still unclear, and there is no gold-standard treatment, although suggested protocols have been accepted.18,21 It is not always possible to reach mucosal closure, and in these cases, the infection control is con- sidered effective.2,21 In this context, low-level laser therapy (LLLT) has been used for treatment of BRONJ.22–25
The aim of this paper was to report a case of BRONJ in a patient with history of bisphosphonate therapy, successfully treated with a conservative protocol using LLLT and topical iodide-hydrogen peroxide solution, revising the main aspects of this condition.
Case repor t
A 54-year-old white female patient came to the Stomatology clinic of the Antônio Pedro Fluminense Federal University Hospital, reporting a mandibular lesion with a 7-month progression, which appeared after the introduction of a new lower partial prosthesis. During anamne- sis, a diagnosis of multiple myeloma was reported, and the patient was under zolendronate (Zometa) treatment for 2 years and 10 months. General and
extraoral physical exams did not demon- strate any other alteration. Intraoral exam showed an area of painful necrotic bone exposure on the lingual surface of the left posterior mandible, with ery- thema of the surrounding tissue, without purulent discharge, measuring 1.3 cm × 0.5 cm. Panoramic and periapical radio- graphs were requested (Figure 1A).
Based on the clinical information as well as the physical and radiographic exams the diagnosis was BRONJ, Stage 2.
A conservative treatment was initi- ated, using 0.2% topical chlorhexidine digluconate gel through silicon guard, twice a day, and the patient was advised to interrupt prosthesis use. After 64 days of weekly consultations, there was a dis- crete enlargement of the exposed bone area, which at that moment measured 2.0 cm × 0.5 cm. Due to this evolution, another topical treatment was weekly added at the Stomatology clinic, which comprised of direct irrigation of a 1:1 solution containing 1% potassium iodate and 10% hydrogen peroxide. A daily 0.12% chlorhexidine digluconate solu- tion mouthwash was also recommended.
Between the second and third irrigation appointment, the patient reported a spontaneous fragment bone sequestrum.
Intraoral exam revealed a significant decrease in the bone exposure size area.
However, two small exposure areas were still present, one at the original lesion’s Table 1. BRONJ stages and their respective management according to the American Association of Oral and Maxillofacial Surgeons.2
Stages Management
Risk category: absence of bone exposure in patients treated with oral or intravenous bisphosphonates
Nothing to do; patient advice only
Stage 0: absence of apparent osteonecrosis and presence of unspecific clinical signs and symptoms
Systemic management with antibiotics and/or analgesics
Stage 1: presence of exposed necrotic bone in asymptomatic patient and absence of infection
Mouthwash with oral antibiotics; monthly clinical follow-up; patient advice and review of indications for bisphosphonate administration
Stage 2: presence of exposed necrotic bone and infection, with pain and erythema on affected area, with or without purulent discharge
Mouthwash with oral antibiotics; pain management; use of systemic antibiotics and analgesics; superficial debridement to relieve soft tissue pain
Stage 3: presence of exposed necrotic bone and infection, in addition to one or more of the following: osteonecrosis extending beyond the alveolar bone, resulting in pathological fracture, extraoral fistulae, oroantral or oronasal communication, or osteolisis extending toward the inferior mandibular border or the sinus floor
Mouthwash with oral antibiotics; pain management; use of systemic antibiotics and analgesics; surgical debridement or resection for long-term relief of pain and infection
Figure 2. Clinical aspect 7 months after the first LLLT session showing complete remission of the lesion with only slight erythema.
mesial site, and another on its lower distal edge, depicting small bone spicu- lae, without signs of infection. A central area compatible with granulation tissue was also observed. Panoramic and peria- pical radiographic exams showed an approximately 5.0 cm osteolysis area on the left posterior part of the mandible.
During the third irrigation session, a sig- nificant improvement of the exposed bone area was observed (Figures 1B and C). The patient was asymptomatic, except for a mild discomfort regarding to the bone spiculae with a cutting edge, which was carefully removed with a
#15-scalpel blade.
Thirty-five days after the beginning of the irrigation treatment, the lesion remained with two small bone exposure areas, located at the same sites as described earlier, and the adjacent mucosa was still red, with a significant and evident bone loss. The irrigations were interrupted, and the chlorhexidine mouth rinses were maintained. An LLLT protocol was then initiated (Flash Lase III, DMC, Brazil). Five weekly sessions
were performed, during which punctual applications were carried out, with a 4.0 J dose of infrared light (790 to 830 nm), with 140 J/cm2 density, and 100 mW potency with 40 seconds per point.
At the end of the 58th day after LLLT began (Figure 1D), an important reduc- tion of bone-exposed areas were observed, with partial reepithelization of the mucosa on the central area of the lesion. Another LLLT was planned, twice a month; however, the patient only returned after 5 months, due to a bone marrow transplant. Physical exam at that moment revealed total remission of the lesion, without bone exposure, and with complete reepithelization of the mucosa, which showed only mild erythema (Figure 2). The patient remains under periodic follow-up, and shows no signs of BRONJ exposure.
Discussion
Considering the possible etiologies, pre- vention is definitely the best approach towards BRONJ. Therefore, whenever
possible, before the bisphosphonate intake, it is important to resolve all con- ditions that require bone remodeling, or that present risk of breaking mucosa.18,26 Periodontal pockets must be eliminated, all necessary dental extractions must be performed, as well as restorative and endodontic treatments.4,18 When the patient is already using bisphosphonates, whether or not BRONJ is established, nonsurgical urgent treatments must be carried out with caution.18
Our patient presented bone exposure in the mandibular posterior lingual region. Such finding is compatible with the literature reports, which refer to BRONJ prevalence in the milohyoid line area, representing a trauma-prone site, covered by extremely thin mucosa.8
BRONJ is very difficult to resolve, and to date there is no treatment that warrants absolute success. Early diagno- sis for BRONJ is one of the most
important determinants for better disease control.27 Gegler et al.28 reported two cases of BRONJ in which necrotic areas were still present, even after antibiotic therapy and the use of chlorhexidine mouthwash. Carvalho et al.27 treated case of BRONJ in a multiple myeloma patient with a history of zolendronate use with many antibiotic cycles, and there was only spontaneous sequestrum of a bone fragment, without remission of neither the bone lesion, nor the mucosal ulcer.
Furthermore, Merigo et al.29 reported only “partial success” in the use of surgi- cal and antibiotic therapies, in addition Figure 1. (A) Initial clinical aspect of BRONJ with necrotic bone exposure and erythematous sur-
rounding mucosa. (B) Panoramic radiograph showing osteolysis area (arrows). (C) Periapical radiograph showing osteolysis area (arrows). (D) Clinical aspect after 54 days of LLLT showing partial reepithelization of the lesion.
to mouthwashes and Nd:YAG laser in 29 BRONJ patients.
Due to the lack of valid protocols for BRONJ treatment, laser therapy has therefore been recommended for control of this condition. However, the reports using lasers with this purpose vary according to dosimetry, to the form of application, and to the type of laser. In the present report, immediately after spontaneous sequestrum of bone, we chose the use of laser therapy using infrared light as an alternative, with the purpose of stimulating biomodulation of bone and mucosa. Romeo et al.17
reported two similar cases with the use of infrared laser in continuous scanning mode (0.053 J/cm2 fluence during 15 minutes; five sessions for 2 weeks), in a patient who presented complete repair of the lesion after spontaneous bone seques- trum, as well as five other patients, who showed partial healing of mucosa and partial relief of pain.
To date, there are only a few studies reporting the use of LLLT to treat BRONJ, thus more research is needed in order to elucidate a definitive protocol.
Vescovi et al.25 and Luomanen and Alaluusua23 performed five consecutive weekly applications, with 1,064 nm Nd:YAG pulsed laser, with 1.25 W potency, frequency of 15 Hz for 1 minute, in 28 patients, with good long- term results. Da Guarda et al.22
performed punctual laser therapy using 860 nm GaAlAs laser, with 70 mW potency and 4.2 J per point, for 1.5 minutes each, with a 48-hour inter- val, for a total of 10 days, also attaining success. Romeo et al.17 evaluated pain management following LLLT, and con- cluded that 100% of the patients had significant pain reduction. Manfredi et al.30 reported partial remission of BRONJ in patients treated with antibiot- ics in association with laser therapy.
LLLT irradiation generates a series of cellular effects, stimulating cell prolifera- tion, tissue repair, angiogenesis, pain relief, and other anti-inflammatory actions.9 Many studies have shown bone repair, fibroblast, and osteoblast biostim- ulation, and optimization of calcium transportation following of LLLT.31–33 It
is therefore an excellent alternative for BRONJ management.
A conservative management before LLLT seems to be another option to deal with BRONJ. In our case, we chose a top- ical therapy, with the association of chlorhexidine digluconate, 1% potassium iodide, 10% hydrogen peroxide, and LLLT. The patient demonstrated a good recovery with resolution of the signs and symptoms of BRONJ. Hydrogen peroxide releases oxygen when in contact with the tissue, causing an antimicrobial effect.
This mechanism promotes antisepsis of wounds and aids in the removal of debris, and the reactions involved may be catalyzed by adding iodide.34 Potassium iodide speeds the hydrogen peroxide decomposition, leading to a much faster release of oxygen.34 This association was shown to be productive in the elimina- tion of microorganisms, as well as in the mechanical removal of debris and necrotic rests.34
The use of 2% sodium iodide and 3%
hydrogen peroxide irrigation was more effective than other treatments in cases of osteorradionecrosis and osteorradiomye- litis.35,36 The use of this combination of solutions in infected rat alveoli was also reported.34
Studies using iodide and hydrogen peroxide solution are scarce. A search in the PUBMED database for “BRONJ,”
“iodide,” and “hydrogen peroxide” in association, and without “BRONJ” did not present any results in 2014/10/08, demonstrating the need for future inves- tigations of this solution, especially regarding clinical trials.
Conclusion
Since the first clinical reports of BRONJ, the knowledge about the disease has increased, however the exact pathogenesis is not clear. It is important to point out that despite the reported cure for some cases in the literature, treatment is very difficult, and there are still no well-established treatment proto- cols. Professionals should understand that prevention is the key to BRONJ management. Health care professionals must be aware of BRONJ, avoiding
predisposing factors and whenever possi- ble, should perform all dental procedures before the beginning of bisphosphonate intake. The therapeutic protocol pre- sented in this report using direct
irrigation of a 1:1 solution containing 1%
potassium iodide and 10% hydrogen per- oxide for microbiological control with subsequent LLLT application was suc- cessful, resulting in complete remission of the clinical picture. However, future clinical studies evaluating the effects of the association between the solution and LLLT for BRONJ are required.
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