Petra Rugani*, Astrid Truschnegg, Stephan Acham, Barbara Kirnbauer and Norbert Jakse
Department of Oral Surgery and Radiology, Medical University of Graz, Austria
Received date: August 01, 2013; Accepted date: August 28, 2013; Published date: August 30, 2013
Citation: Rugani P, Truschnegg A, Acham S, Kirnbauer B, Jakse N (2013) Use of Photodynamic Therapy in Treatment of Bisphosphonate-related Osteonecrosis of the Jaws: Literature Review and Case Series. J Anal Bioanal Tech S1:006. doi: 10.4172/2155-9872.S1-006
Copyright: © 2013 Rugani P, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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Introduction: Even though surgical intervention is the preferred option in treatment of Bisphosphonate-related Osteonecrosis of the Jaws (BRONJ) the application of low-level-laser therapy (LLLT) has been described either as part of conservative protocols or as adjuvant measure in surgical regimes. So far there are no reports concerning adjuvant photodynamic laser application in this indication in the literature.
Case series: We present the integration of Photodynamic Therapy (PDT) in a stage related treatment concept and report 10/12 cases in which PDT application was beneficial for achieving mucosal healing of BRONJ lesions.
Discussion and conclusion: In treatment of bisphosphonate-related osteonecrosis conservative therapeutic measures like the application of low-level-laser therapy and photodynamic therapy help to manage symptoms or may even promote mucosal healing. They are particularly helpful if surgical procedures are not indicated. Photodynamic therapy additionally provides antimicrobial effects and can therefore be used if complications in postoperative healing occur.
Bisphosphonate; Osteonecrosis; Photodynamic therapy
Bisphosphonates are important agents for the treatment of skeletalrelated events in cancer therapy, as well as for the treatment of multiple myeloma and osteoporosis. Bisphosphonate-related osteonecrosis of the jaws (BRONJ) is a serious side-effect of bisphosphonate therapy. Its cardinal symptom is exposure of jawbone that does not heal within eight weeks. This condition significantly compromises the patient’s quality of life. It affects mainly patients suffering from solid tumors like breast, prostate, bronchial and renal cell carcinoma or multiple myeloma who receive high-potency compounds in a high dosage intravenously , but has also been described in patients with osteoporosis .
Conservative regimes aim at enhancing the patient’s quality of life by controlling BRONJ symptoms and preventing progression of disease [3-5]. The main therapeutic measures are systemic medical therapy (antibiotics, anti-inflammatory therapy), local disinfectant rinsing (e.g. 3% hydrogen peroxide, 0.1-0.2% Chlorhexidindigluconate)  and low-level laser therapy (LLLT) [6-8].
In recent publications the superiority of surgical regimes for treating this condition was demonstrated [6,9,10]. Surgical treatment consists of the surgical removal of necrotic parts of the jawbone and, in most cases, safe and permanent mucosal coverage of former BRONJ sites. Nevertheless, adjuvant conservative therapeutic measures, such as disinfectant rinsing and medical therapy still help to manage subjective BRONJ symptoms like pain, swelling and purulent drainage, reduce the bacterial colonization prior to surgery and manage postoperative complications like local infections and dehiscences. This is particularly important if surgical therapy cannot be performed due to the patient’s poor general health or patient’s wish.
In 2006, Vescovi et al.  introduced the application of LLLT. Several case reports dealing with this issue have been published [7,8,12-14] but controlled trials assessing the effectiveness of LLLT are rare and often not conclusive [9,10,13,15-20] (Table 1).
|Authors||Indication||LLLT + settings||Treatment||Outcome|
|Da Guarda et al. ||1 pat. PC||GaAlAs diode; 860 nm; 70 mW; SS 4 mm2. Fl: 4.2 J/cm2; 5x – 10d||STL EP:MH||1 case healed|
|Vescovi et al. ||BM: Stage 1 (18), 2(48) and 3(3) MM: Stage 1(12), 2(44) and 3(3)||Nd:YAG; 1.25 W; 15 Hz; fd320 μm; dist: 2 mm; 5x 1min, 1/w, 2 mo||MT vs. MTL EP:MH||18.2% vs. 21.4 %|
|STL + LLLT as described above or Er:YAG – Laser supported ST||ST vs. STL vs. Er:YAG-ST; EP: MH||53.8% vs. 70.6% vs. 90.3%;|
|Vescovi et al. ||128 pat.; MM(52), BM(53), OP(23); Stage 1 (17), 2 (92), 3 (19); 101 treated sites||Nd:YAG 1064 nm; 1.25 W; 15 Hz; DC: 0.15%; fd320 μm; dist: 2 mm; 5x1 min (PD 268.81 W/cm2, Fl:14.37 J/cm2)||MT vs. MTL; EP: CI||25% vs. 66%|
|ST vs.STL; EP: CI||53%vs 89%|
|Vescovi et al. ||151 pat.; 139 treated sites; MM (56); BM (65); OP (30)||Nd:YAG 1064 nm, 1.25 W; 15 Hz; fd: 320 μm; 1/w, 2 mo||MT vs. MTL EP: MH||7.85% (5/28) vs. 28.125% (9/32)|
|Nd:YAG laser; 1064 nm; 1.25 W; 15 Hz; fd: 320 μm; 1/w, 2 mo;||ST vs. STL EP: MH||64.7% (11/17) vs. 72.72% (24/33) sign.|
|Martins et al. ||22 pat.; BC (13); PC (4); LC (1); MM (2)||InGaAlP diode laser; 660 nm; 40 mW, SS 0.042 cm2, Fl: 6 J/cm2; 6 s; PD: 0.24 J/point; 1/d.||MT (3) vs. ST (5) vs. PRP + LLLT+ suturing (14)||1/3 (33.3%) vs. 3/5 (60%) vs. 12/14 (85.7%)|
|Luomanen et al. ||1 pat., MM||Nd: YAG 1,064 nm; 1.25 W; 15 Hz; fd: 320 μm; dist: 1-2 mm; 1 min; 9x in 6 mo; 5x/session, PD:1.555 W/cm2; Fl/min 167.94 J/cm2||LLLT||MH(9 w)|
|Atalay ||20 pat.; BC (11); PC (1); MM(7); NEUR (1); stage 1 + 2, MT ineffective||Nd:YAG; 1 min, dist: 4 cm; R24 950 μm fiber handpiece; 0.25 W, 10 Hz; 2.5 J. Fl: 6.25 J/cm2.||ST vs. Er:YAG -STL||4/10 vs. 7/10, signif.|
|Romeo et al. ||12 pat.; MM (4); BM (7); OP (1); 7 pat with BRONJ||Double diode, 650 nm + 904-910 nm; SS=8mm; Fl: 0.053J/cm2; 5x15min, 1/3d, 2w; dist: 1mm||LLLT EP: CI||Sign. pain reduction 6/7|
|Manfredi et al. ||25 pat.; OP; Stage 1 (4), 2 (19), 3 (2)||Nd:YAG; 1064 nm, dist: 2 mm; 5×1 min; PD 268.57 W/cm2; 1.25 W; 15 Hz; fd: 320 nm; 1x/w, 2 mo;||MT vs. MTL EP: MH (6mo)||3/5 (40%) vs. MTL: 4/7 (57%)|
|Pat. not responsive to 3 AB cycles||Er:YAG laser (2940 nm) ST, LLLT as described above; 1/w, 1 mo;||ST vs. STL EP: MH (6 mo)||4/4 vs. 6/6|
|Rugani et al. ||5 Pat.; BRONJ stage 2; 2 Pat. dehiscences BC + MM,||ErCrYSGG-ST; PDT: diode laser; 75 mW; 680 nm, 90s, dist: 2 mm; PS: methylene blue||MH after 12 mo||2/2 MH|
|Vescovi et al. ||91 pat.; 55 BRONJ sites MM (27), BM (18), OP(10), Stage 1(8), 2(41), 3(6)||Nd:YAG; 1,064 nm; 1.25 W; 15 Hz; fd 320 μm; dist 2 mm; 1 min; 5x; PD: 268.57 W/cm2; Fl: 2.0175 J/cm2||MT vs. MTL 3 Mo EP: MH||0/13 vs. 7/17 (41%) (P= 0.033)|
|Er:YAG laser supported surgery Nd:YAG laser-irridation as above||ST+ vs. Er:YAG – STL;EP: MH||6/13 (46%) vs. 10/12 (83.3%)|
|Scoletta et al. ||20 pat.; BC (6), MM (6), OP (5), PC (3); Stage 1 (2), 2 (16), 3 (2/20)||Pulsed diode(GaAs); 904 nm; 50 kHz, Fl: 28.4 J/cm2; dc40%; SS 0.8 cm; 5 min: 59 J - 60 kHz + 10 min 120 J - 40 kHz 10x in 20 d||LLLT; BRONJ symptoms EP: CI||sign: pain, clinical size, edema, pus, fistulas|
|Vescovi et al. ||19 pat.; 20 sites; MM (9), BM (8), OP (2); 5 treated sites MT or MTL||Nd:YAG; 1064 nm; 1.25 W, 15 Hz, fd 320 μm; dist 1-2 mm; 1 min; PD 1555: W/cm2, Fl/min 167.94 J/cm2); 5x/session; twice;||Mucosal healing Follow-up at least 4 (to 9 months)||Medical 1/3 vs. (33.3%) vs. Medical + LLLT 2/2 (100%)|
|15 sites ST after ineffective MT||Nd:YAG as above; twice; (2 pat. some mo later)||ST vs. STL EP: MH (4 mo)||4/8 (50%) vs. 6/7 (85.7%)|
|Miglorati et al. ||1 pat. PC, stage 0||diode laser 815 nm; 1.0 W; fd 400 μm; pockets 5 x + fistulas 3x 15s, after 4w CO2-Laser||EP: CI||Progress Stage 1|
|Merigo et al. ||BM (14), MM (12), OP (3)||Nd:YAG, settings not specified||MT vs. ST vs. LLLT||Partial success, not specified|
|Vescovi et al. ||26 pat., MM (9), BM (14), OP (3)||Nd:YAG; 125 W, 15Hz, 60 s, 5 x; fd 320 μm||6 MT + 6 ST vs. 6 MTL + 6 STL EP: MH||4/12 (33.3%) vs. 9/14 (64.3%)|
pat: Patient; BM: Bone metastasis; PC: Prostate cancer; BC: Breast cancer; LC: Lung cancer; MM: Multiple Myeloma; NEUR: Neuroendocrine tumor; AB: Antibiotics; fd: fibre diameter; dist: distance; PD: Power Density; Fl: Fluence; DC: duty cycle; SS: Spot size; PS: Photo sensitizer; iv. Intravenous; BP: Bisphosphonate; vs.: versus; MT: Medical therapy; MTL: Medical therapy and LLLT; LPM: Long pulse mode; ST: Surgical therapy; STL: Surgical therapy and LLLT; d: day(s); w week(s); mo: month(s); EP: Endpoint; MH: Mucosal healing; CI: Clinical improvement
Table 1: Published reports on use of low-level-laser therapy (LLLT), preferred endpoint: Mucosal healing.
Basically, the effect of lasers in the mW range is classified in two categories: Biostimulation (corresponding with LLLT) and photodynamic therapy (PDT). In biostimulation (LLLT) the laser acts directly on the tissue and aims to support tissue healing. In PDT the laser acts on a chemical medium (photosensitizer), which subsequently induces cell (e.g. bacteria) and tissue damage as a chemical effect.
From a clinical point of view LLLT has in general become a wellaccepted adjuvant medical tool for enhancing wound-healing processes, although the exact biochemical mechanisms are not quite clear so far. Numerous clinical studies report about laser-induced stimulation especially of soft tissue healing, in particular to promote healing of ulcers and postoperative wound dehiscences [21,22]. A meta-analysis of the literature revealed a highly significant positive effect on wound healing in general and a significant shortening of healing time .
More recently the potency of LLLT on hard tissue regeneration has become a focus of scientific interest. Numerous clinical and experimental studies indicate enhancement of bone regeneration by laser irradiation [24-32]. Dörtbutak et al.  demonstrated significantly stimulated in vitro bone matrix formation in osteoblast cultures by low energy laser irradiation. In vitro laser irradiation of osteoblast cultures evidently enhances both cellular proliferation and cellular differentiation, which results in an increase of the number of more differentiated osteoblastic cells and finally an increase in bone matrix formation . An in vitro study of Stein et al.  confirms evidence that low energy laser irradiation promotes proliferation and maturation of human osteoblasts. Biochemically the stimulating effect of LLLT is explained by an increase of ATP synthesis in irradiated cells .
Consisting of the additional application of photosensitizers, photodynamic therapy (PDT) was introduced in particular to treat cancer and several studies have shown its antimicrobial properties [35-38]. A study of the effects of PDT on osteoblast growth showed that whether PDT results in biostimulation of osteoblastic cell cultures or a cytotoxic effect may depend only on the applied dose . PDT is so far clinically established in the adjuvant local treatment of infected wounds and ulcers [40-42]. Furthermore periodontitis and peri-implantitis could be potential indications for the application of PDT [36,43-45]. BRONJ could be another possible indication.
The following section describes a potential role of photodynamic therapy in a stage-related treatment concept (Table 2) and demonstrates its beneficial application in a case series of 12 patients.
|Stage 0||Antiseptic mouth rinses; medical therapy (antibiotic, antimycotic, antiphlogistic, analgetic); LLLT (altered neurosensory function); PDT (fistulas; HelboMinilaser 2075 F dent [HELBO Photodynamic Systems, Austria], 75 mW, 680 nm; photosensitizer: methylene-blue;)|
|Stage 1||Intital CoTr for max. 8 weeks; LRST; impaired healing: Disinfectant rinsing, PDT|
|Stage 2||Preoperatively: CoTr, PDT; LRST; impaired healing: Disinfectant rinsing, PDT|
|Stage 3||Radical surgery; impaired healing: Disinfectant rinsing, PDT|
Staging: AAOMS classification 
LRST: limited-resective surgical therapy; CoTr: conservative treatment;
Table 2: BRONJ Treatment concept .
In case of evident BRONJ the choice of treatment options relies on staging according to AAOMS staging system (Table 2) . Photodynamic therapy is additionally applied for symptomatic treatment in stage 0, preoperatively to reduce the bacterial burden and, in cases of healing deficiencies, after surgical intervention in stages 1, 2 and 3.
Furthermore PDT is the adjuvant conservative treatment of choice for palliative therapy of compromised patients or if patients refuse surgery to control symptoms and avoid progression of disease.
We describe the benefit of photodynamic therapy in five cases of BRONJ stage 0 and seven cases of BRONJ stage 2.
Five women with breast cancer who participated in a study to assess BRONJ after adjuvant administration of zoledronate in a lowdose protocol (7 infusions over three years, totaling 28 mg) displayed fistulas and further clinical and radiological symptoms corresponding to stage 0 (Figure 1 and Table 1) . According to our standardized protocol fistulas were rinsed with antiseptic fluids and photodynamic therapy was applied twice a week for the first two weeks. We used a diode laser emitting 680 nm visible red light at 2 mm distance for 90 seconds (Helbo Mini laser 2075 F dent [HELBO Photodynamic Systems, Austria], 75 mW) and methylene blue (methylthioninium chloride 50 mg/5 ml, Monico, Italy) as photosensitizer (Power density: 1.25 W/cm2; fluence: 112.5 J/cm2; total energy: 6.75 J). The methylene blue was applied topically on the surface of all affected tissue and no incubation time was awaited. After two weeks all five fistulas healed and correlating clinical symptoms vanished.
In seven of 27 surgically treated patients with BRONJ stage 2, mucosal closure did not remain stable postoperatively. They developed dehiscences to various extents (Figure 2). As a consequence photodynamic therapy, as described above was started immediately. Five of seven lesions are healed by secondary granulation (75%). In two cases the lesion did not heal. One patient was scheduled for another, more invasive surgical intervention indicated by the appearance of a further sequester. In the second patient, suffering from breast cancer, general health worsened significantly and therefore conservative maintenance therapy was applied (Table 3).
|Patients with early BRONJ and bone exposure via fistulas|
|D.M.||f||60||27.05.10||BC||Zol||Stage 0 region 36||Desinfectant rinsing, LLLT||Mucosal healing|
|S.R.||f||57||23.02.10||BC||Zo||Stage 0 region 44-45||Desinfectant rinsing, LLLT||Mucosal healing|
|Sc.E.||f||48||25.03.10||BC||Zo||Stage 0 (pus) region 37, 27||Desinfectant rinsing, LLLT||Mucosal healing|
|St.E.||f||51||10.05.10||BC||Zo||Stage 0 region 46||Desinfectant rinsing, LLLT||Mucosal healing|
|vH.W.||f||54||23.02.10||BC||Zo||Stage 0 (pus) region 47||Desinfectant rinsing, LLLT||Mucosal healing|
|Patients with impaired healing after BRONJ surgery|
|B.T.||f||69||17.08.10||OP||Al||Stage 2, 35-38,||Er:YAG Surgery 18.10.10; Dehiscence 10 days after surgery → LLLT||Mucosal healing|
|C.E.||f||65||31.05.11||BC||Zo||Stage 2, 35-38 lingually||Er:YAG Surgery 18.07.11 Dehiscence 38 PDprogredient||No success|
|D.A.||f||86||26.06.07||MM||Zo||Stage 2, region 44-45||ErCrYSGG Surgery 13.01.09; Postoperative dehiscence → LLLT||Mucosal healing|
|H.W.||m||69||22.11.10||PC||Zo||Stage 3, region 45||Er:YAG surgery 07.03.11 Fistula||No success|
|K.M.||f||74||05.10.10||BC||Zo||Stage (0) 2, 46-47||Er:YAG Surgery 23.05.11; Dehiscence 10 days after surgery → LLLT||Mucosal healing|
|S.E.||f||68||30.07.10||BC||Zo||Stage 2, region 16-17||Er:YAG Surgery 17.1.11; Dehiscence 10 days after surgery → LLLT||Mucosal healing - 1 month|
|S.W.||f||66||03.08.10||BC||Zo→Ib||Stage (0) 2, region 13||Er:YAG Surgery 28.02.11; Dehiscence 10 days after surgery → LLLT||Mucosal healing|
Pat: Patient; S: Sex; m: male; f: female; PD: Primary disease; BC: Breast cancer; BrC: Bronchial Carcinoma; MM: Multiple Myeloma; PC: Prostate cancer; OP: Osteoporosis; BP: Bisphosphonate; Zo: Zoledronate; Ib: Ibandronate; Al: Alendronate; CMT: conservative maintenance therapy; Tooth numbering: World Dental Federation notation
Table 3: Patients-Use of Photodynamic Therapy in BRONJ treatment.
The illustrated cases demonstrate that photodynamic therapy can be an effective adjuvant tool for treating BRONJ in the very early stages or for managing healing impairment in surgically treated BRONJ sites.
Application of LLLT in cases of BRONJ has been described in numerous studies, but to our knowledge the issue of photodynamic therapy is not reported in the literature so far (Table 1). LLLT was introduced by Vescovi et al.  in 2006 who used Nd:YAG laser biostimulation in addition to medical or surgical therapy and were, albeit not conclusively able to demonstrate a better healing tendency. Shortly thereafter the group confirmed this statement with the publication of a controlled study of 20 BRONJ sites in 19 patients. These were treated with medical therapy alone, medical therapy and LLLT, surgery or surgery and LLLT. Patients received laser stimulation only twice and healing improved from 33.3% to 100% and from 50% to 85.7% respectively. In a further report in 2010 that compared 13 medically treated BRONJ sites to 17 sites where LLLT was additionally applied improvement was significant . In this study Vescovi et al. also took the next step of using Er:YAG radiation for minimal invasive bony ablation, which is also known to have bactericidal  and detoxification effects  and to promote better healing , and which may also bebio-stimulant . This observation has also been reported by other authors . Atalay et al.  used this regime in patients with malignant diseases and Manfredi et al.  in patients with osteoporosis and BRONJ. And recently Vescovi et al. [9,10] published two further reports dealing with this issue. All of them reported better healing if medical or surgical therapy was supplemented with LLLT. Romeo et al.  used LLLT to treat patients experiencing pain in necrotic areas and reached significant pain reduction in 6 of 7 patients. Luomanen and Alaluusua  treated one multiple myeloma patient with Nd:YAG LLLT only and accomplished mucosal closure. Notably this was not done until a bony sequester protruded by itself. Surgical removal may have been beneficial to achieve this result earlier. Martins et al.  combined the use of LLLT with platelet-rich plasma and primary wound closure and reached better results than with medical or surgical therapy, although group sizes were not comparable. Recently da Guarda et al.  reported a case of successful BRONJ treatment with the GaAIAs diode laser in combination with bone curettage.
Summarizing the literature we conclude that the use of LLLT seems to be beneficial for treatment of BRONJ, although to date there are no larger-scale studies that demonstrate significant improvement. We combined the low-level laser beam with the use of a photosensitizer as defined by photodynamic therapy.
PDT is primarily used in the treatment of cancer and due to its antimicrobial properties it is also indicated in bacterial and fungal infections. Further indications may be psoriasis, actinic keratosis, rheumatoid arthritis and age-related macular degeneration .
It has been hypothesized that the presence of microflora is a triggering or promoting factor of BRONJ. Biopsies and cultures sampled from BRONJ lesions noted the presence of species such as Fusobacterium, Eikenella, Bacillus, Actinomyces, Staphylococcus and Streptococcus [3,54-56]. The majority of microbes in affected patients seem to be facultative anaerobes. These organisms are predisposed to survive in oxygen-depleted areas of necrotic bone that lack adequate blood supply, as typical in BRONJ .
The antimicrobial activity of photosensitizers is mediated by singlet oxygen. The high chemical reactivity of molecular oxygen results in a direct effect on extracellular molecules. Thus, the polysaccharides present in the extracellular matrix of a bacterial biofilm are also sensitive to photodamage. This is a significant advantage. Breaking down biofilms may inhibit plasmid exchange involved in the transfer of antibiotic resistance and interrupt colonization .
Even though surgery is our first treatment option to deal with BRONJ we are applying photodynamic therapy for several purposes. Prior to surgery we treat the symptoms that come along with infection of the BRONJ site. Pain, swelling and purulent discharge can be well managed and the bio-stimulative effect of the laser beam is appropriate if neurosensory dysfunction is already evident. This is particularly helpful in patients with advanced primary disease or suffering from other severe sicknesses resulting in a general poor health condition where a surgical treatment is not indicated.
At very early BRONJ stages photodynamic therapy might be even sufficient to promote secondary granulation and the formation of mucosal coverage and consequently surgery is not even necessary. This was also demonstrated with the application of LLLT as reported by Scoletta et al.  who showed that the presence of fistulas significantly decreased after four weeks. Controlled studies opposing LLLT and PDT using exactly the same laser parameters are needed to evaluate if the additional use of a photosensitizer is beneficial.
Applying photodynamic therapy immediately after surgical intervention may increase success rates as complications linked to impaired healing of the wound can be effectively handled. Nevertheless, we are aware of a possible bias that may arise from the fact that those patients are recalled much more often to get irradiated, which may also affect possible relapse factors such as poor oral hygiene or pressure marks. A controlled study evaluating the effects of PDT after BRONJ surgery should therefore contain the same recall interval for both groups and leave patients and doctors blindfold.
Photodynamic therapy can be a supportive tool in BRONJ treatment. It may be used as an adjuvant before or after BRONJ surgery or as the primary treatment option in cases of very early BRONJ or if surgery is not indicated.
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