Lasers Med Sci (2012) 27:251–255 DOI 10.1007/s10103-011-0929-7
BRIEF REPORT
Treatment of bisphosphonate-induced osteonecrosis of the jaws with Nd:YAG laser biostimulation Marita Luomanen & Satu Alaluusua
Received: 28 April 2010 / Accepted: 18 April 2011 / Published online: 20 May 2011 # Springer-Verlag London Ltd 2011
Introduction Bisphosphonates are pharmaceuticals that are increasingly used in the treatment and management of bone disorders like osteoporosis, metabolic bone disease, and bone metastases associated with cancer and multiple myeloma. However, in recent years innumerous cases of necrosis of the jawbone have been documented in patients treated with bisphosphonates and consequently bisphosphonate-induced osteonecrosis of the jaws (ONJ-BP) has been described as a complication secondary to bisphosphonate therapy [1–4]. The risk for bone necrosis has proven to be considerably higher in those cases where bisphosphonates have been given intravenously than per os [3]. Osteonecrosis in patients medicated with bisphosphonates may establish in the maxilla, mandible, or both. Mandibular involvement is, however, more common. The exposed avascular necrotic bone becomes generally infected and the condition can be very painful for the patient, making eating and speaking difficult. If the necrosis is extensive and near the mandibular nerve, paresthesia of
M. Luomanen (*) Institute of Biomedicine/Anatomy, University of Helsinki, PO Box 63, Haartmaninkatu 8, 00014 Helsinki, Finland e-mail:
[email protected] S. Alaluusua Institute of Dentistry/Department of Pediatric and Preventive Dentistry, University of Helsinki, PO Box 41, 00014 Helsinki, Finland S. Alaluusua Department of Oral and Maxillofacial Diseases, Helsinki University Central Hospital, PO Box 263, 00029 Helsinki, Finland
the lower lip may occur. Swelling of the jaw, loose teeth, sinusitis, oral or cutaneous fistulae, and fracture of the mandible are symptoms frequently connected with ONJ-BP. The symptoms adversely affect the quality of life and produce significant morbidity in the patients suffering from this condition [3]. Treatment strategies of ONJ-BP have so far been controversial since medical and surgical methods of curing have not clearly been effective [5]. Patients with exposed bone are mainly treated with systemic antibiotics, antimycotics and/or oral antimicrobial rinses. Patients in whom the symptoms in spite of medication persist are subjected to surgical procedures. However, little efficacy has been shown for the surgical removal of bone since it frequently results in additional areas of exposed necrotic bone [2, 6, 7]. Interestingly, recent results on a surgical approach with Er:YAG laser and on biostimulation of the ONJ-BP–affected jaws with Nd:YAG laser have been promising [4, 8, 9]. Several studies both in vitro and in vivo have shown that both low-energy and high-intensity lasers are capable of stimulating the regeneration of cells in healing wounds. Low-energy laser light has been suggested to be absorbed by the cellular molecules and its photostimulatory effect seems to result in an increase in the production of mitochondrial enzymes, porphyrins, flavins, and cytochromes [10, 11]. On the other hand, high-intensity infrared laser wavelengths have proven to be capable of stimulating the proliferation of blood and lymphatic vessels in healing wounds [12, 13]. Moreover, high-intensive laser irradiation has been shown to elevate the activity of osteoblast-like cells stimulate bone formation and to increase the mineralization of the healing bone verified by Raman spectroscopy [14–16]. Additionally, Nd:YAG laser irradiation has proven to have an antimicrobial effect [17].
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In the present report, we describe our experience of treating a patient suffering from ONJ-BP with high-intensity pulsed infrared Nd:YAG laser biostimulation.
Case report A 59-year-old woman was diagnosed with osteoporosis 4 years prior to the diagnosis of multiple myeloma. Because of the osteoporosis, the patient had received alendronate sodium (10 mg/d or 70 mg/week) irregularly already for 4 years before the diagnosis of multiple myeloma. From the start of the myeloma therapy she received zoledronic acid 4 mg i.v. once a month for 6 months, and after that, disodium clodronate 1,600 mg/day. The treatment was continued until the diagnosis of osteonecrosis of the lower jaw was clear. The therapy for multiple myeloma started with dexamethasone (Dex), which was administered in a pulse dose fashion (40 mg/day) given on days 1–4, 9–12, and 17–20 of a 28-day cycle. The patient altogether received seven cycles. Dex was supplemented with thalidomide (100 mg/d) during the last three cycles. The patient proceeded to autologous stem cell transplantation (SCT) after the thalidomide/Dex therapy. The stem cells were collected with growth factor in combination with cyclophosphamide. Because of a poor response of the disease, the patient received additional therapy with bortezomib/Dex (20 mg/day). After three cycles and a high dose of melphalan given at 200 mg/m2, the patient underwent SCT. After the SCT, no signs of relapse were seen. Taken together, the patient received a massive bisphosphonate and corticosteroid medication as the treatment included Fig. 1 a Mandibular fistula indicated by an arrow in the apical region of dd 36–37. b A fistula in the apical region of dd 46–47 (white arrows) and a red area in the mucosa (black arrows) are seen in the right lingual surface of the mandible. c Panoramic radiograph showing no bone lesions in the mandible. d Periapical x-ray with no bone involvement in the apical region of dd 46–47
Lasers Med Sci (2012) 27:251–255
bisphosphonates for approximately 5 years with six infusions of zoledronic acid and Dex therapy for 9 months with 7 monthly high-dosage cycles. On clinical examination of the oral cavity, fistulas were diagnosed on the lingual surfaces of the alveolar mucosa in the apical region between dd. 36–37 and 46–47 (Fig. 1a, b). A separate oval dark red area of the size of 2 × 3 mm was also noted in the lingual mucosa distally from d. 47 (see Fig. 1b). Eight weeks prior to the examination the patient had already been to a dentist for a regular dental check-up. At the checkup, a small afta-like lesion was present at the lingual side of dd 46–47. One week thereafter, the patient experienced pain in the region. She had used analgetics and within 2 days the pain had disappeared. The “afta-like” lesion was a fistula, which was persistent and did not heal within 8 weeks’ time from the first recognition. A panoramic radiograph (Fig. 1c) and periapical x-rays were taken of the mandibular molars (Fig. 1d). The patient had no history of any dental infections or extractions of teeth in the molar areas in question. A 1,064-nm wavelength Nd: YAG laser (Fotona, Ljubljana, Slovenia) was used according to the manufacturer’s instructions at 1.25-W power and 15-Hz frequency for biostimulation and for antibacterial treatment of the jaw bone and the mucosa. A 320-μm-diameter laser fiber was moved in defocus in circular movements at a distance of 1–2 mm from the mucosa for 1 min by scanning an area of the mandible with a 5-mm margin surrounding the fistulas and including the dark red area in the mucosa. The laser exposures were repeated five times at each session with a 5-s interval between each exposure. The theoretical power density of the laser with the used parameters was 1,555 W/cm2 and the theoretical fluence/min 167.94 J/cm2.
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Laser therapy was given at nine separate sessions at 1 to 6-week intervals within a total treatment time of 6 months. The interval between the first laser sessions was 1–2 weeks, and was thereafter extended to 4 and 6 weeks. After the third laser session at 7 weeks, approximately 3 × 3 × 2 mm pieces of bone were seen to protrude through the fistulas in the mucosa at both the left and right lingual sides of the lower jaw (the left side is shown in Fig. 2a). The pieces of bone were pulled out with the help of tweezers. At the time of the fifth laser session 9 weeks after the first laser treatment, complete closure of the fistulas with reepithelialization of the mucosa could be observed (Fig. 2b). Laser treatment was thereafter still continued at four successive sessions until a total treatment time of 6 months was reached. At the last laser session, shallow grooves could be observed in the bone beneath the mucosa at the sites of the previous sequesters. No recurrence of the fistulas or any other alterations could be observed in the mandible on follow-up at 12 months. At the time of the fourth laser session, the patient received antibiotic treatment (doxycycline 150 mg/day for 10 days) for a lower respiratory infection. The patient did not have any other medication during and after laser treatment except vitamin D and calcium supplementation.
Discussion The management of ONJ-BP has in spite of the recommended treatment strategies so far remained controversial and it is considered to be a chronic disease with a poor healing prognosis. The risk of developing ONJ-BP has been reported to be related to time, drug, dose, and route of administration. The drug zoledronic acid has proven to be even more potent in causing the ONJ-BP than the other bisphosphonates [3]. The i.v. route of administration results in a significantly greater risk for this disease but oral use of bisphosphonates, when lasting over 3 years, also increases the risk for developing ONJ-BP [3]. The present patient had been diagnosed with both osteoporosis and multiple myeloma. Fig. 2 a A small piece of bone (arrow) extruding through the lingual mucosa of the mandibula at the apical region of dd 36–37. b Intraoral vision of the healed mucosa at the site of dd 36–37. Re-epithelialization has occurred but a reddish area (arrow) is still discerned at the site of the former fistula
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She was medicated with bisphosphonates, zolendronic acid, and alendronate sodium both i.v. and orally for a time period significantly longer than 3 years. Furthermore, the patient had been simultaneously treated with massive doses of corticosteroids, which is considered to additionally elevate the risk of developing ONJ-BP [3]. As the diagnosed fistulas did not heal within 8 weeks, we could set the diagnosis of ONJ-BP at stage 1 [3]. The radiographical alterations of ONJ-BP may appear as an irregular sclerotic area with a cotton-wool-like appearance. Here, in spite of the clearly visible clinical signs of ONJ-BP, no specific radiographic alterations could be diagnosed either in the panoramic or the periapical x-rays taken (see Fig. 1c, d). It seems that the radiographic diagnosis of ONJ-BP can be in many cases uncertain and the diagnostic criteria of ONJ-BP from x-rays unclear [4]. Therefore, the possible benefit of the multi-dimensional x-ray techniques in the early diagnosis of ONJ-BP should be thoroughly clarified in the near future. Patients receiving i.v. bisphosphonates and subjected to dentoalveolar surgery or with a history of periodontal or dental inflammation have been found to be at least seven times more likely to develop ONJ-BP [3]. Consequently, all surgery involving osseous injury is considered to be a local risk factor for developing ONJ-BP and such interventions should be avoided in patients under bisphosphonate medication. Good oral hygiene and preventive dental care have been emphasized to be of great importance in preventing inflammatory dental disease. Therefore, thorough oral examination with removal of all unsalvageable teeth, completion of all invasive dental procedures and periodontal treatment have been recommended as preventive management strategies for patients treated with bisphosphonates [3]. In the present case, inflammatory factors could not be found to play any role in creating the osteonecrosis, as the oral hygiene of the patient was found to be good and there was no previous history of dental infections in the affected area. Bisphosphonates have been reported to inhibit the osteoblast bone remodeling function by preventing the development of osteoblasts from bone marrow [18].
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Moreover, bisphosphonates have been described to inhibit endothelial proliferation and thus cause an avascular necrosis of the jaw bone [19]. Although the biostimulatory and antimicrobial effect of several laser wavelengths have been described in a number of studies [4, 12, 15, 20–23] also in the presence of dexamethasone [16], there still remain controversies of such variables, such as the type of laser, output power, frequency of pulse, fluence, time of application, and distance from tissue surface. Ninomiya et al. [24] have shown that the acoustic waves created by the high-intensity pulsed Nd:YAG laser, in addition to its photochemical effect, are capable of inducing bone formation. The average fluence used in their study was approximately 60 J/cm2. It seems reasonable that the higher fluence of 168 J/cm2 used in this study could be capable of reaching the periost and the underlying bone. The repeated pulses could create a transient energy wave enhancing the healing bone and stimulating the proliferation of blood and lymphatic vessels as well. However, the mechanism by which lasers affect the bone still needs further clarification. Scoletta et al. [25] have described the use of pulsed lowlevel laser biostimulation in multiple myeloma patients suffering from ONJ-BP. The results of their study show a statistically significant reduction for reported pre- and post-operative pain, clinical size, edema, and presence of pus and fistulas when laser biostimulation is used. In the present case, after the third laser treatment session, small pieces of necrotic bone extruded from the fistulas followed by complete re-epithelialization. After finishing the laser treatment, the patient has been symptomfree of ONJ-BP at a follow-up time of 12 months. As spontaneous healing in the unprovoked ONJ cases like the one here is very rare [25, 26], we would like to propose that the intensive laser pulses together with the quick intervention with the laser were decisive in leading to the favorable result and laser therapy could be the possible mode of treatment to improve the management of ONJ-BP. Although the present results are not conclusive, they are well in line with other similar studies suggesting laser biostimulation for patients suffering of ONJ-BP. Complete renewal of the bony skeleton is a slow process, and can take up to 10 years. Therefore, a complete or even a partial resolution of the clinical symptoms of ONJ-BP can be considered a success. In the present case, the favorable result was achieved with rapid invention with laser therapy for nine successive times within a time period of 6 months. It seems that we managed so far to prevent the extension and development of new areas of bone necrosis. However, additional long-term studies of laser biostimulation in similar cases are needed.
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