Paget ’ s disease of bone , biphosphonates 1 and jaw osteonecrosis : a case report

Objective: Paget’s disease of bone is characterized by a focal increase in bone 
resorption and accelerated bone formation leading to a weaker and disorganised bone. Bisphosphonates (BPs) have been the treatment of choice of Paget’s disease since the 1990s. Medication related osteonecrosis of the jaw (MRONJ) is a rare event in non oncologic patients. We describe a rare case of  Paget’s disease 
involving the maxilla with osteonecrosis in a context of bisphosphonate treatment. 
  
Case report: an 87-year-old woman presented with 4 episodes of bone necrosis in 15 years. In this case report there is a clear chronologic association between the occurrence of MRONJ and the administration of iv BP for Paget’s disease. 
Maxillofacial involvement of Paget’s disease occurs in less than 15% of cases. There is a lack of information in the literature about the association of MRONJ and Paget’s disease. Even if osteonecrosis of the jaw could be a consequence of the 
disease, in this case, it is more in relation to the BP treatment. 
  
Conclusions: Although MRONJ might be considered a rare condition in Paget’s disease, patients prior to starting antiresorptive therapy and in particular iv BPs should have a complete dental examination and panoramic X-Ray. 
  
Nemesis relevance: side effect of bisphosphonate treatment 
 


Introduction
Paget's disease of bone (PD) is characterized by a focal increase in bone resorption and accelerated bone formation leading to a weaker and disorganised bone.It can affect one or more site throughout the skeleton [1].
Described in 1876 by Sir James Paget, this "osteitis deformans" is the second most common metabolic bone disease after osteoporosis.
The disease affects preferentially a male population after 55 y.The incidence is higher in Western Europe, Australia and in America, affecting 2-7% of the Caucasian population [2,3].
The maxillofacial type occurs in less than 15% of patients, and the maxilla is more commonly affected than the mandible by a 2:1 ratio [4].
Treatment of PD tends to relieve bone pain and restore normal turnover.
Bisphosphonates (BPs) have been the treatment of choice since the 1990s, either in the form of oral BPs (alendronate, risedronate…) or IV BPs (pamidronate, zoledronate).The frequency and dose of BPs treatment is determined by patient response [1].

Medication related osteonecrosis of jaws (MRONJ) was first described in 2003
under the name of bisphosphonate related osteonecrosis of the jaw [5,6].The vast majority of cases occur in patients with advanced malignancies and skeletal metastases who have received frequent, high cumulative doses of antiresorptive therapy (IV BPs or denosumab).Less than 5% of MRONJ occurs in non-cancer patients (osteoporosis, Paget's disease, fibrous dysplasia, rheumatoid arthritis…), which received lower and less frequent doses of oral, iv BPs or denosumab and presented with less comorbidity [3,7].
We report a case of Paget's disease of the skull and maxilla in a patient who received multiple courses of IV BPs and presented with 4 episodes of maxillary bone necrosis.

Case report
An 87-year-old non-smoking Caucasian woman was referred to the outpatient maxillofacial department in 2009 for maxillary bone pain that had evolved over the previous 3 months.She was diagnosed with Paget's disease affecting the skull and maxilla in 1965 (Figure 1).after her last injection of alendronate, she presented with pain in the nasal spine region.On oral examination, bone exposure was detected in the left maxillary.A panoramic X-Ray (Figure 2), axial CT scan (Figure 3), coronal CT scan (Figure 4) and 3D CT scan (Figure 5) confirmed the presence of a left maxillary sequestrum.
Spontaneous expulsion of the sequestrum (2x1 cm) 10 weeks after the symptoms began revealed a normal underlying mucosa (Figure 6).Monostotic PD of bone usually does not provoke significant elevation of serum alkaline phosphatase.
Aetiology of PD is unclear but genetic and viral components are suggested.
Mutations in the sequestome SQSTM1/p62 gene were identified in 46% of familial inclusions in the osteoclast nuclei, like paramyxovirus or syncitial respiratory virus has led to a viral hypothesis [1][2][3].
PD is considered to be a primary disorder of the osteoclast.The pathology is characterized by increased osteoclast bone resorption, followed by inadequate bone formation, leading to a disorganized bone with reduced mechanical strength [1].
Symptomatic PD is the main indication for treatment (pain, nerve compression…) [1].
Treatment aims at the suppression of osteoclast activity and is achieved with bisphosphonates.
The optimal regimen of BPs remains controversial.Oral formulations may be limited by complicated dosing regimens and poor gastrointestinal absorption.
Currently, zoledronic acid is administrated as a single 5 mg infusion and normalizes alkaline phosphatase in the majority of patients [9,10].Denosumab had been used less frequently in patients refractory or intolerant to BPs [11].
Medication related osteonecrosis of the jaw is defined as an exposed bone or bone that can be probed through an intraoral or extraoral fistula in the maxillofacial region that has persisted for longer than 8 weeks in a patient with current or previous treatment with antiresorptive or antiangiogenic agents, in the absence of radiation therapy to the jaws or obvious metastatic disease to the jaws [12].
The exact mechanism of MRONJ remains unclear.Alteration of bone turnover, hypovascularisation and infection seem to play a role.The majority of MRONJ are in relation with tooth extraction.
The real incidence of MRONJ is still unknown and varies between 1,2% and 12,8% in cancer patients.In a report of Mavrokokki [13], the overall incidence of MRONJ is 1 in 930 with 1 in 87 for cancer patient, 1 in 2260 for osteoporotic patients and 1 in 56 for Paget's disease.For other authors the overall maximum frequency of extraction-related MRONJ is 1 in 125, with 1 in 11 for bone metastasis, 1 in 296 for osteoporosis, and 1 in 7,4 for PD [14,15].
Limited data are available about the risk of MRONJ in patients affected by non neoplastic diseases.
Only a few cases of MRONJ in PD patients have been reported in the literature.In a review in 2010, Filleul et al [16] analysed 2408 patients with MRONJ including 0,7% of patients with PD.
More recently, a systematic review from McGowan et al [17] identified 4106 patients with MRONJ.Twenty-four patients presented with non malignant systematic diseases other than osteoporosis (0,5%) including 5 PD.
Even sequestration can be an exceptional but normal complication in PD, treatment with BPs may be the trigger factor of the osteonecrosis.In our patient, the first episode of bone necrosis appeared after oral surgery and repeated doses of iv BP.

Fig. 1
Fig. 1 Plain X-Ray demonstrating typical cotton wool aspect and bone enlargement in the maxillary and cranial vault.
Pathological examination found necrotic lamellar bone and bacteria colonies.The patient's serum alkaline phosphatase level, calcium and phosphate were within normal limits at that time.A new obturator prosthesis was made.The patient received a final course of IV alendronate in July 2009 and presented with a new episode of bone exposure and infection in March 2010 for which she received multiple course of antibiotics until resolution.

Fig. 2 Fig. 3 Fig. 4 Fig. 5 Fig. 6
Fig. 2 Panoramic X-Ray, showing the same sequestrum and periostal reaction in the remaining maxillary bone.We can see the typical condensation of maxillary pagetic bone.Mandibular aspect seems to be normal.
Ray.If therapy can be delayed, oral infection should be treated, restorative care, dental extraction for non salvage teeth should be carried on.Use of soft liners on denture also seems prudent.Once BPs treatment is started, regular oral examination and preventive approach are important for early diagnosis and treatment if necessary.Patients should be informed about the risk of developing MRONJ in association with oral surgery and invasive dental procedures, even if dental implant placement.The poor quality of bone in PD renders it susceptible to infection.In these at risk patients, the only "intervention" with a proven decreased risk of MRONJ is prevention, as it is the case with radiotherapy.This is the first description of a patient diagnosed with a maxillary localisation of Paget's disease of bone presenting 4 episodes of MRONJ in 15 years, each bone exposure following a course of iv BPs.
 Funding sources statement: authors received no funding for this case report  Competing interests: all authors declare no competing interest  Ethical approval: not applicable  Informed consent: not applicable