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S. Stübinger et al. (eds.)Lasers in Oral and Maxillofacial Surgerydoi.org/10.1007/978-3-030-29604-9_14
14. Laser Treatment of MEDICATION-Related Osteonecrosis of the Jaws
MRONJ is a multifactorial disease, and it is therefore difficult to realize an aetiological therapy.
MRONJ management is controversial: there are no evidence-based guidelines in the literature, in particular with regard to surgical procedures possibly associated with good results during a long-term follow-up.
The literature recommends a conservative treatment as initial therapy for pain control and elimination of acute inflammatory signs before any surgical option, for all stages of disease.
Laser applications at low intensity (low-level laser therapy—LLLT) have been reported in the literature for the treatment of MRONJ. Biostimulant effects of laser improve reparative process, increase inorganic matrix of bone and osteoblast mitotic index and stimulate lymphatic and blood capillary growth. It has been reported that LLLT has anti-inflammatory actions and it can help to control pain as well. LLLT also holds biostimulatory properties with favourable actions on bacterial control and wound healing. The review of the literature confirmed the superiority of the LLLT association with antibiotic therapy in comparison to other noninvasive approach to MRONJ management.
In our experience, more than 60% of MRONJ patients treated with laser biostimulation and antibiotic therapy (2 g of amoxicillin and 1 g of metronidazole a day for 2 weeks) have had improvement of their symptomatology, and 35% have had complete mucosal healing during 6 months of follow-up.
This therapy is easy to administer and useful also for aged and compromised patients, and it is not associated with any known side effect.
A soft surgical approach performed with laser, in patients unresponsive to antibiotic therapy or LLLT, represents a good solution: it is rapid and poorly invasive and can be performed under local anaesthesia in day-surgery regimen. The erbium-doped yttrium aluminium garnet (Er:YAG) laser has emerged as a possible alternative to conventional methods of bone ablation as the main components of bone have a high absorption of laser light at the wavelength of 2.94 μm. The histological findings of bone treated with erbium laser highlighted vital lamellar bone at the lased margins without microscopic evidence of inflammation or osteoclastic activity. Some recent researches reported that Er:YAG laser irradiation stimulates the secretion of platelet-derived growth factor in osteotomy sites and has bactericidal effect against Actinomyces and anaerobes. Results confirm that the laser surgery represents the best therapeutic option for minimally invasive treatment of the early stages of the disease also in immunocompromised patients.
The association of the Er:YAG laser and autofluorescence examination seems to be highly useful in removing additional minimal necrotic bone after osteoplasty. It is possible to use laser evaporation in areas in which absence of fluorescence or hypofluorescence has been revealed. Moreover, the previously cited biological advantages of Er:YAG surgery combined with the biomodulation of the soft and hard tissues induced by LLLT seem to integrate a valid approach for MRONJ treatment.
MEDICATION-related osteonecrosis of the jaw (MRONJ)Low-level laser therapy (LLLT)Laser jaw bone surgeryErbium laserDiode laserNd:YAG laser
Robert Marx described in 2003 an unusual condition related to bisphosphonate therapy in cancer patients: diffuse or localized area of necrotic jaw bone .
In 2014, the American Association of Oral and Maxillofacial Surgeon (AAOMS) published an update of the 2009 Position Paper on Bisphosphonate-Related Osteonecrosis of the Jaws .
The term “MEDICATION-related osteonecrosis of the jaw (MRONJ)” has recently replaced the previous “bisphosphonate-related osteonecrosis of the jaw (BRONJ)”. Such as a decision was taken to include in the definition the growing number of osteonecrosis cases involving the maxilla and mandible associated with drugs different than bisphosphonates (BP), such as antiresorptive (denosumab) and antiangiogenic (bevacizumab, sunitinib) medications [3–5]. Patients may be diagnosed with MRONJ if all of the following characteristics are present: (1) current or previous treatment with antiresorptive or antiangiogenic agents; (2) exposed bone or bone that can be probed through an intraoral or extraoral fistula (e) in the maxillofacial region that has persisted for more than 8 weeks; and (3) no history of radiation therapy or obvious metastatic disease to the jaws.
The prevalence of MRONJ in patients under BP therapy (BPT) for osteopenia, osteoporosis and Paget’s disease is significantly lower (from 0.1% to 0.21%) than prevalence in those treated intravenously for multiple myeloma and bone metastases (from 0.7% to 6.7%) .
Many hypotheses concerning the pathophysiology of MRONJ have been put forward, but none could explain all of the peculiar features of this disease.
Many factors such as anatomic site and high concentration and release of bisphosphonates (BPs) in the jaw bone, bone remodelling suppression, inhibition of the vascularization, soft tissue toxicity, bacterial infection, local trauma and genetic predisposition are involved.
Denosumab , a monoclonal antibody that is used in the treatment of osteoporosis and bone metastasis, has been shown to have an equal or higher capacity to suppress bone turnover than bisphosphonates. It acts by inhibiting osteoclast activity, reducing bone resorption and increasing bone density. Its highly specific mechanism of action is the inhibition of receptor activator of nuclear factor-kappa B ligand (RANKL).
Local factors associated with ONJ appearance in patients receiving BPs or denosumab are dental extractions (or other surgical procedure in the jawbone), periodontal diseases and poor oral hygiene and trauma induced by dental removable prostheses [7–9].
Prevention of ONJ related to BPs or denosumab is still debated, although a combined approach seems to be beneficial: preventive measures for the elimination or reduction of the risk factors, including periodic clinical screening.
MRONJ is a multifactorial disease, and it is therefore difficult to realize an aetiological therapy.
MRONJ management is controversial: there are no evidence-based guidelines in the literature, in particular with regard to surgical procedures possibly associated with good results during a long-term follow-up. The first purposes of treatment should be the reduction of pain and infection and the interruption of the progression of disease. Within such a context, the literature supports a noninvasive approach especially for asymptomatic stages of MRONJ. Temporary suspension of BPs offers no short-term benefit, whilst long-term discontinuation (if feasible with patient systemic conditions) may be beneficial in stabilizing sites of ONJ and reducing clinical symptoms .
Patients with exposed bone are usually treated with systemic antibiotics (penicillin or clindamycin along with metronidazole), oral rinses (chlorhexidine gluconate or hydrogen peroxide) or antimycotic agents (nystatin, ketoconazole or fluconazole).
The main problem of local or systemic antibacterial therapy is the nonpersistent clinical result (abscess disappearance, pain, swelling improvement) which is usually followed by a recurrence after an mean time of 3 weeks. Such an approach has as main problem the usual advanced age of patients and their usual administration with chemotherapy, leading to poor health conditions, which make them not able to bear the side effects of a prolonged (and sometimes permanent) antibiotic schedule. The second issue is the possible evolution of the disease and the unpredictable shifting from stage I to advanced stages of MRONJ .
14.2 Conservative Management of MRONJ
Ozone therapy (OT) and hyperbaric oxygen therapy (HBO) may stimulate cell proliferation and soft tissue healing, thus reducing pain.
Laser applications at low intensity (low-level laser therapy—LLLT) have been reported in the literature for the treatment of MRONJ. Biostimulant effects of laser improve reparative process, increase inorganic matrix of bone and osteoblast mitotic index and stimulate lymphatic and blood capillaries growth. HBO, OT and LLLT are usually recommended in addition to medical or surgical therapy: frequently, the positive clinical result is associated with an improvement of results obtained with conventional treatments, supplemented by alternative therapies [14–16].
14.2.1 Low-Level Laser Therapy (LLLT) and MRONJ Treatment
The mechanism of action underlying the biological effect of laser therapy has been widely investigated by researchers, but it remains controversial.
Laser applications at low intensity (low-level laser therapy—LLLT) produce some changes in cellular metabolism: the light is absorbed by primary photoacceptors, and this event triggers a pathway on the existing cell regulation mechanism. The wide range of applications of low-power laser effects and the possibility of using different wavelengths for irradiation depend on the fact that the primary photoacceptors of monochromatic visible light are the respiratory chain components [17, 18]. A secondary reaction consists in the transduction of the signal outside the mitochondria leading to enhancement of cell differentiation and/or proliferation, which represent the ultimate effects of light irradiation. The modulation of macromolecular synthesis has been suggested as part of the secondary reaction at the tissue level, related to the laser irradiation .
The effects of LLLT with different wavelengths on the trophism of skin and mucosa and stimulation of blood capillaries have been reported by several authors, and these observations could, to some extent, give support for a possible usefulness of laser biostimulation in the prevention and treatment of MRONJ.
LLLT represents an effective option largely reported in the literature for the management of chemotherapy- and/or radiotherapy-induced oral mucositis and, during the last 12 years, for MRONJ management.
It has been reported that LLLT has anti-inflammatory actions and it can help to control pain as well. LLLT also holds biostimulatory properties with favourable actions on bacterial control and wound healing .
In in vitro studies, a stimulatory effect of many wavelengths (diode or Nd:YAG laser) on the cell viability and proliferation of human osteoblast-like cell culture exposed to BPs was reported [21–23].
Osteocalcin seems to have several functions in bone metabolism: it has an important role in the process of bone remodelling affecting both osteoblast and osteoclast activities, and it is also a regulator of bone mineralization. In vivo studies in animal models show that laser irradiation after tooth extraction can promote osteoblast differentiation. In the same studies, it has been also demonstrated a higher expression of bone markers osteopontin (OPN) and osteocalcin (OCN), 8 days after surgical interventions .
Clinical studies performed in cancer and non-cancer patients under BPT reported an important reduction of pain, oedema, size of bone exposure, pus, fistulas and halitosis with significant improvement of quality of life .
In our experience, more than 60% of MRONJ patients treated with laser biostimulation and antibiotic therapy (2 g of amoxicillin and 1 g of metronidazole a day for 2 weeks) have had improvement of their symptomatology, and 35% have had complete mucosal healing during 6 months of follow-up [26, 27]. On the contrary, percentage of improvement after systemic antibiotic therapy and local antibacterial rinses (without the laser applications) can be estimated between 20% and 30%.
LLLT was delivered through an Nd:YAG laser (1064 nm) with power of 1.25 W, frequency of 15 Hz and a fibre diameter 320 μm. The laser source was used at a distance of 1–2 mm from tissues for 1 min (PD 1555 W/cm2, total fluence 167.94 J/cm2) for five consecutive applications. Laser energy was widely applied by scanning the affected area. Each patient underwent five laser irradiation sessions (one during the first week of medical treatment and the other every 7 days after the first).
The review of the literature confirmed the superiority of the LLLT association with antibiotic therapy in comparison to other noninvasive approach [28, 29]. This therapy is easy to administer and useful also for aged and compromised patients, and it is not associated with any known side effect.
14.3 Surgical Management of MRONJ
Surgery may be avoided if permanent mucosal repair appears after the conservative management; however, such an occurrence seems to be limited to very few cases. Surgical approach seems unavoidable in most of the cases of MRONJ, where complete healing or permanence of symptoms has not been obtained irrespectively by the stage of the disease.
The rate of remission reported in the literature is higher for MRONJ in non-cancer patients (osteoporosis) and those with multiple myeloma than for MRONJ in those with solid tumours and slightly higher for early stages than for late stages of disease [30–32]. Discontinuation of BPs or denosumab therapy can favour the surgical outcome, most probably for the reduction of the action of the drugs in the soft tissues.
Surgical debridement or resection in combination with antibiotic therapy may offer long-term palliation with resolution of acute infection and pain. Mobile segments of bony sequestrum and necrotic tissue should be removed extending surgery until unaffected bone . In diffuse MRONJ, the resection of mandible and vascularized reconstruction with free fibula flaps have been proposed in the literature. In case of large and complex surgical interventions, a careful evaluation of the general conditions of each patient, including situation and evolution of disease, age, performance status and life expectancy, is advisable .
14.3.1 Laser Surgery of MRONJ
A soft surgical approach performed with laser, in patients unresponsive to antibiotic therapy or LLLT, represents a good solution: it is rapid and poorly invasive and can be performed under local anaesthesia in day-surgery regimen. Over the last decades, in several experimental and clinical studies, it has been reported the benefit of laser osteotomy in oral-maxillofacial surgery with efficient ablation rates and rare or absent carbonization phenomenon.
The erbium-doped yttrium aluminium garnet (Er:YAG) laser has emerged as a possible alternative to conventional methods of bone ablation as the main components of bone have a high absorption of laser light at the wavelength of 2.94 μm. The wavelength-dependent absorption coefficient for water is at its maximum peak at 2.94 μm. The Er:YAG laser theoretically has an absorption coefficient of water that is 10 being 15,000–20,000 times higher than the CO2 and the Nd:YAG lasers, respectively. Air and water spray reduces overheating of both hard and soft tissues, but also it cleans the site of irradiation, increases ablation rate and efficiency and facilitates the ablation process. Water and air spray advantages include the prevention of tissue dessication and the excess of heat accumulation in tissues due to desiccation of bone surfaces, the improvement of bone ablation for photoacoustic effect and the improvement of surgical activity for increase of visibility due to smear layer elimination in aerosol .
Bone temperature during Er:YAG laser osteotomy has a mean increase of 3.3 °C. The mean biological advantage of erbium laser in comparison to other surgical devices is the bone and mucosal healing improvement. After Er:YAG laser ablation, red blood cell aggregate was noted over the treated bone surface. At 6 and 24 h and 3, 7 and 14 days, initial events of bone and soft tissue healing appear to progress earlier in comparison to CO2 laser or traditional tungsten burr. Osteotomy sites after Er:YAG laser ablation exhibited more prominent inflammatory cell infiltration, revascularization and proliferation of fibroblasts and osteoblasts, indicating active osteoid tissue formation. The irregular surface structure after Er:YAG laser ablation, with no smear or char layers, provided a favourable surface for cell attachment and thus accelerated bone healing and formation . The application of Er:YAG laser in the bone surface promotes the production of PGE2 and COX2 from fibroblasts of human gingiva promoting the early phases of wound healing .
Studies on bone damages induced through different cutting systems reported that all sections obtained with Er:YAG laser were better than those obtained with piezosurgery, high-speed drills and low-speed drills. Er:YAG laser showed poor peripheral carbonization with a regular incision without residual bone smear layer . The histological findings of bone graft harvested from the mandibular ramus using an erbium laser highlighted vital lamellar bone at the lased margins without microscopic evidence of inflammation or osteoclastic activity [39–41]. Some recent researches reported that Er:YAG laser irradiation stimulates the secretion of platelet-derived growth factor in osteotomy sites .
The bactericidal effect of Er:YAG laser against periodontopathogens forms such as Actinomyces and anaerobes is well reported in the literature. The efficacy of erbium laser, in comparison to other wavelength, is described also for periodontopathogen bacteria, Candida spp., in biofilm models [43, 44].
Er:YAG laser could be used also for oral mucosa incision without thermal damage to the surrounding and underlying tissues inducing less pain and better healing than traditional scalpel.
Taking into account the possible MRONJ pathogenesis, the aim of intervention should be the elimination of the maximum of necrotic bone and the covering of the surgical field with a vascularized soft tissue.
In our experience, all surgical interventions were performed under local anaesthesia. Prophylactic antibiotics (amoxicillin and clavulanic acid 2 g a day—metronidazole 1 g a day) were administered starting 4 days before surgery and were continued postoperatively for 2 weeks. The surgical procedure begun with a detachment of an envelope flap through a linear mucoperiosteal cut around bone exposure, without lateral incisions to contain risk of reduction of vascularization. The inflamed margins of the mucosa were eliminated for at least 2 mm to obtain a better quality tissue to cover bone surgical area.
Laser can be used for conservative surgery through a vaporization of necrotic bone, until healthy bone is reached. The erbium laser penetrates only very slightly (0.1 mm), being therefore very safe and allowing a precise, minimally invasive treatment. The minimally invasive technique of evaporation allows us to obtain a regularity of the sectioned bone surfaces, and it can be used to create micro-perforations at the base for stimulating vascularization. The additional advantages of laser surgery are the bactericidal and biostimulatory action of the laser beam with a better postoperative recovery [45–49].
Bone spicule and defects can be eliminated to obtain a smooth surface to avoid local traumatisms and to facilitate soft tissue healing over the surgical site. The surgical sites were abundantly rinsed with iodopovidone solution.
Intraoral closure was achieved by a tension-free mucosal flap sitting passively over the bone with a 4–0 silk suture. The sutures were removed from 10 to 14 days after surgical intervention (Figs. 14.6, 14.7, 14.8, 14.9, 14.10, 14.11, 14.12, 14.13, 14.14, 14.15, 14.16 and 14.17).