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Management of bisphosphonate preparation-treated children in the field of pediatric dentistry

Since most of the reports of BRONJ onset are adults, in order to clarify the current situation of BRONJ onset in children, it is necessary to search for articles and report on the current status and actual conditions of surgical treatment of children with BP preparations who are being followed up in our clinic. In previous reports both inside and outside Japan, there was no mention of jaw bone necrosis during tooth extraction or surgery in children who were receiving or had a history of BP administration. There were 15 children with a history of BP administration who manage the oral cavity in our clinic. No unpleasant events in the extraction of deciduous teeth were confirmed in medical records. It is necessary to intervene early on oral management of pediatric BP-administered children, especially BP-and steroid-administered children, obtain plaque control to keep the oral cavity cleaner, respond early to infectious diseases, and manage to prevent inflammation from spreading to the jawbone. When surgical treatment is unavoidable, it is important to consider reducing the invasion as much as possible and to cooperate with the medical department such as administration of antibiotics to prevent infection.


Introduction
In the field of pediatric dentistry, the frequency of encountering children who have received bisphosphonate (BP) preparations is not high in clinical practice. Surgical treatment, such as tooth extraction, is required in some children, but impaired tooth eruption accounts for the greater portion [1]. Desiring spontaneous replacement if possible, we have confirmed a position paper, and managed individual conditions in consultation with attending pediatricians if necessary.
BP potently inhibits bone resorption by suppressing osteoclasts. It is routinely used in cancer patients with bone metastasis or osteoporosis patients. the sockets of BP-treated patients [2]. Thereafter, many patients with BRONJ were also reported in Japan [1,[3][4][5]. BRONJ induces serious symptoms, such as infectious exposure of the jaw, severe persistent pain, gingival swelling, and purulent discharge. It was reported that cutaneous fistula formation or jaw fracture occurred with the exacerbation of infection even when BRONJ was asymptomatic in the absence of pain [6]. Since the first report was published, the accumulation/analysis of many patients have deepened the understanding of BRONJ, contributing to preventive strategies. As a new drug, denosumab, was used. This drug is a human IgG2 monoclonal antibody preparation against RANKL, which suppresses bone resorption by osteoclasts like BP. But it was expected that osteonecrosis of the jaw (ONJ) would not occur because of its short half-life, no deposition or residue on bone, and no induction of apoptosis in osteoclasts [7].
Contrary to this expectation, ONJ (DRONJ, denosumab-related ONJ) developed at a similar rate [8]; Although the mechanism of action is different, both are drugs that suppress bone resorption by osteoclasts and are involved in the onset of clinically similar ONJ, so BRONJ and DRONJ has been comprehensively termed the name antiresorptive agent-related ONJ (ARONJ). In addition, the American Association of Oral and Maxillofacial Surgery (AAOMS) has proposed the name medication-related ONJ (MRONJ) because the delivery rate of BRONJ and DRONJ increases due to the administration of drugs used in combination with anticancer drugs in cancer treatment [9].
In Japan, the incidences of BRONJ after the use of injection and an oral preparation were estimated to be 1-2% and 0.01-0.02%, respectively. Tooth extraction increases the risk of BRONJ, being the most important risk factor [4]. A study reported that the incidence of ONJ in cancer patients was higher than in patients with osteoporosis [8].
In the jaw, infection-prone environmental factors are present in comparison with other bones: the presence of the gap between the epithelium and teeth, which may be an oral source of infection, a direct approach to the jaw through the root canal, presence of oral bacteria as a source of infection, and inflammation of the jaw mediated by infectious diseases, such as caries and periodontal disease. These factors may be involved in the onset of BRONJ [10].
Most case reports on BRONJ involve adults, especially elderly patients. To clarify the current status of BRONJ in children, we report the actual status of surgical treatment in BP-preparation-treated children during follow-up in our department, and review the literature.

Presentations and articles in Japan and other countries
We searched for articles with keywords, such as BP, children, and osteonecrosis of the jaw using the Central Medical Journal (Japanese) and PubMed, but few reports and reviews were identified. Initially, as a domestic report, there was a case report presented as a poster at a meeting held by the Japanese Society of Pediatric Dentistry in 2009 [11]. An 8-year-and-6-month-old boy with systemic juvenile idiopathic arthritis had received a steroid over a long period. As a BP preparation, Alendronate had been administered for 10 months before tooth extraction. At the time of treatment, an antimicrobial drug was prophylactically administered in cooperation with the Department of Pediatrics, and a primary tooth remaining in the late phase was extracted. After treatment, there were no abnormal findings. The authors suggested that the risk of BRONJ is low in young patients, but concluded that it was necessary to manage BP-treated patients in cooperation with the Department of Pediatrics or Department of Internal Medicine while maintaining a favorable oral hygiene state. One case report was found internationally. In this report, a 6 years 6 months year child, who was receiving bisphosphonate therapy for osteogenesis imperfecta, had numerous teeth restored and multiple primary molar extractions in the operation room under general anesthesia. The patient received prophylactic antibiotics intraoperatively, so demonstrated no clinical signs of BPassociated osteonecrosis when seen at follow-up [12]. The authors concluded that consent for extraction should include the risk of bone necrosis and careful post-operative observation to monitor would healing for receiving multiple extraction on the child with BPtreated osteogenesis imperfecta.
As many children with osteogenesis imperfecta are treated with BP preparations, a survey involving 26 children was conducted in 2014, and the results of analysis based on chart information on 67 primary teeth extracted due to exchange-phase disturbance in 13 children were reported [13]. The authors suggested that there are no problems regarding exchange-phase primary tooth extraction even in BP-treated children, because such tooth extraction was not problematic.
Internationally, in 2008, Schwartz et al. [14], Malmgren et al. [15], and Maines et al. [16] investigated the relationship between BP administration and tooth extraction/surgical treatment in children with osteogenesis imperfecta, and reported that there was no ONJ. Brown et al. [17] and Chahine et al. [18] reported tooth extraction or surgical treatment in BP-treated children with osteogenesis imperfecta or those with other diseases, respectively, and indicated that there were no abnormal findings, such as osteonecrosis of the jaw. Furthermore, Chriostou et al. [19] indicated that adulthood BRONJ had been reported in detail, whereas there had been no similar case in children. In addition, they reviewed the background of BP, indication of prescriptions for children, adverse reactions, especially BRONJ, and a protocol available for dental management guidance. As there was no public recommendation with respect to oral management for BP-treated children, Bhatt et al. proposed recommendations for dental management in BP-treated children [20]: a dental management decision pathway and risk-factor-based preoperative administration to high-risk children.
Thus, no study has reported osteonecrosis of the jaw related to tooth extraction or surgical treatment in children receiving BP or those who had received it.

Current/actual status of surgical treatment in BP-treated children during follow-up in our clinic
There were 15 BP-treated children in whom our department was responsible for oral management (Table 1). One-third of these (case10-15 in Table 1) had osteogenesis imperfecta, followed by Langerhans cell histiocytosis (case 1-3 in Table 1). Two children (case 6, 8 in Table 1) had received long-term steroid therapy. Eight children had experienced tooth extraction; exchange-phase primary teeth were extracted in most children. In 2 of these (case 7, 8 in Table 1), tooth extraction was performed during BP administration. There was no description of uncomfortable events related to primary tooth extraction in any medical records. As our department was responsible for oral management, there was no tooth requiring tooth extraction in the presence of inflammation. Furthermore, primary teeth with advanced root resorption were extracted in many children, and most children were followed-up in the Department of Pediatrics in our hospital; therefore, the risk of ONJ may have been low because of cooperation with the Department of Pediatrics.

A patient with a poor long-term outcome
Of the children presented in Table 1, one in whom delayed healing after cystectomy involving a tooth. (case 8 in Table 1).
The patient is a girl with the initial consultation at the age of 14 years and 3 months.
Her chief complaint was caries treatment. The medical history is described below. The diagnosis of sarcoidosis was made at the age of 10 months. Since then, steroid and immunosuppressive therapies had been continued.
Later, she was diagnosed with Cushing's syndrome related to long-term steroid therapy.
In particular, steroid-induced osteoporosis was observed, but withdrawal from steroids was impossible due to cardiac sarcoidosis, and oral administration was continued.
Steroid-induced osteoporosis led to compression fracture of the 3rd lumbar vertebra at 11 years of age. To achieve bone mass recovery, the use of a BP (Alendronate) preparation was started, and this treatment is being continued.
As the physical examination, it was found that lower left first molar was dentin caries, upper left second primary molar prolonged retention, upper left second premolar was malposition/impaction, and lower right second and third molar tooth was containing cyst (Fig. 1).
Treatment and course was CR repair of lower left first molar, the extraction of upper left second primary molar (at 14 years and 4 months of age), lower right second and third molar fenestration at the tooth-containing cyst site (at 14 years and 6 months of age), lower right third molar tooth extraction (at 15 years and 5 months of age), and lower right second molar tooth extraction (at 16 years and 2 months of age) Figs. 2 and 3.
After that, tooth-extracted sockets were covered with granulation tissue. Although the gingival orifice was reduced, bone recovery was not achieved. At 21 years of age, It subsided at 22 years and 9 months of age through frequent lavage and gauze exchanges.
Childhood osteoporosis is classified into two types: primary and secondary osteoporosis, as described for adults. Primary osteoporosis involves genetic diseases, such as osteogenesis imperfecta. Secondary osteoporosis is related to various diseases or drug administration, such as steroid administration. Risk factors include malnutrition, a reduction in physical activity, chronic inflammation, and endocrine dysfunction. If childhood secondary osteoporosis is mild, it may be spontaneously reduced in the process of skeletal development by overcoming risk factors. However, this girl had received a steroid and BP preparation over a long period based on the general condition. Due to her general condition, steroid and BP medications could not be temporarily discontinued for oral surgical procedures. Patients taking steroids are considered to be susceptible to infection because they show considerable delayed wound healing and immunosuppression. Furthermore, her age at the time of cyst treatment was 14-15 years. Childhood bone-mass acquisition reaches a peak in puberty, but decreases with aging [21]. In this girl, the development of osteoporosis was consistent with such timing, and this may have led to delayed healing after lower third molar and second molar extraction treatment. We expected to reduce the size of the cyst and eruption of the second molar by performing fenestration in cooperation with our oral surgery department, however unfortunately it was necessary to remove both cyst and teeth, which would eventually take a long time to heal [22]. It is thought that the healing was delayed due to long-term use of steroid. In patients requiring long-term steroid therapy for a systemic disease and receiving BP therapy over a long period to reduce osteoporosis, such as the above patient, jaw/surgical treatment should be avoided if possible. If necessary, treatment and subsequent continuous management until healing must be performed in cooperation with the Department of Pediatrics or Department of Internal Medicine.

Pathogenesis of BRONJ
For fracture prevention/treatment in patients with bone diseases characterized by bone fragility, such as osteoporosis, BP preparations, which are highly useful, are used. However, osteonecrosis of the jaw, as an adverse reaction, in adults has been reported, although the number of patients is small. To clarify the pathogenesis of BRONJ, animal experiments have been conducted.
Fujita et al. examined the pathogenesis of steroid-induced osteoporosis of the growth-period jaw and BP treatment using rats [23]. Steroid-induced osteoporosis may occur through inhibition of bone formation related to the steroid-associated suppression of osteoblast proliferation/differentiation, enhancement of apoptosis, and functional disorder [24]. They prepared a steroid-induced osteoporosis model by administering a steroid to growth-period rats, and indicated that a reduction in the cortical bone quality rather than the cavernous bone in the mandible was an important factor for a reduction in the bone strength, and that the pathogenesis of osteoporosis of the mandible differed from that of the long bones. After BP is absorbed in the digestive tract, it is deposited in the bone resorption cavity within a few hours, and ingested by osteoclasts through phagocytosis. Subsequently, apoptosis is induced through enzyme inhibition. The above model was treated with risedronate. Although there was no recovery from delayed growth of the fibula, recovery from delayed mandibular growth, especially mandibular length recovery, was confirmed. An improvement in the bone strength, which had reduced in the two bones, was achieved. There are several hypotheses on the pathogenesis of BRONJ, [25][26][27][28] but, as a factor for the jaw-specific disease that is frequent in adults, a study reported that high-concentration BP enhanced oral bacterial growth [29], and some studies indicated that histological findings of osteonecrosis of the jaw included inflammation in all cases [30,31].  These studies suggest the involvement of the oral flora, such as periodontal disease bacteria.
Kikuiri et al. prepared a mouse model using immunocompromised mice from the viewpoint that steroid-therapyrelated immunosuppression plays an important role in the onset of BRONJ, and reported the pathogenesis of BRONJ [32]. BP and steroid administration to immunocompromised mice (beige nu/nu Xid (III)) did not lead to closure of the epithelium of a tooth-extracted socket, facilitating examination of necrotic bone exposure. Pathologically, the infiltration of inflammatory cells and extensive loss of osteocytes were observed. As immune-response-related effects were eliminated due to mouse characteristics, they investigated changes in the status of the tooth-extracted socket using T cells, compared the size of an open wound with that after the infusion of T-cell groups (complete T-cell population (PanT), Treg cells alone, and PanT or Treg cell-removed population), and found that the presence or absence of Treg cells was closely involved in the presence or absence of medication-related osteonecrosis of the jaw (MRONJ). Concerning the pathogenesis of BRONJ, it is suggested that the immune responses of Th cells to Treg-cell hypofunction persist through surgical invasion related to tooth extraction in the bone tissue in which the kinetic balance is suppressed through the actions of BP, enlarging the extent of jaw injury and contributing to the onset of BRONJ [33].
Thus, ONJ models have been prepared by extracting teeth after BP or RANKL inhibitor administration using animals [28,31,34,35]. The condition/pathogenesis of BRONJ or ARONJ may be clarified by utilizing these, and research for new drug development may be promoted.

Conclusion
We reviewed the current status based on the contents of a presentation regarding BRONJ in children at the 28th symposium of the Japanese Society of Pediatric Oral Maxillofacial Surgery.
As many adults with BRONJ or ARONJ have been reported, close attention should be paid when performing surgical treatment, such as tooth extraction, in BP-treated children. However, fortunately, no study has reported childhood BRONJ or ARONJ. In a position paper, it was also stated that there has been no report on BRONJ or DRONJ development in BP-treated children with osteogenesis imperfecta [1]. It has not yet been clarified whether children using absorption inhibitors such as BP and denosumab are at risk of developing ONJ after surgical procedures such as tooth extraction. It is stated that it may be involved in the susceptibility to BRONJ when becoming an adult using BP continuously for a long period of time from childhood because of reduction of bone turnover over years [36]. In addition, it was stated that the onset of BRONJ is triggered by infection, and that infection prevention can be sufficiently prevented before dental treatment to reduce the occurrence of BRONJ [1]. Therefore, if it is necessary to use BP for long term, it seems that plaque control in the oral cavity on a daily basis from childhood.
It is expected that the pathogenic mechanism of BRONJ will be clarified by further case analysis and studies using model animals, and that a treatment method for osteoporosis that does not develop BRONJ will be developed. It has also been suggested that the immune system and oral bacteria are involved in the onset of BRONJ. Children are growing day by day and are changing systemically, locally in the oral cavity, morphologically and functionally. Comprehensive analysis of the bacterial flora in the oral cavity of children has revealed that it changes with growth [37]. From these facts, the age-related involvement in the onset of BRONJ may also be clarified.
It is important to keep the balance between immune-response activation and suppression for maintaining cell/tissue homeostasis [38]. However, previous long-term steroid therapy may affect this balance in some cases. In children treated with steroids for a long period, the influence on susceptibility to infection or bone remodeling, which depends on the general condition, must be considered more carefully than in children treated with BP alone.
With respect to oral management in BP-treated children, early intervention should be performed, and plaque control is necessary to keep the oral cavity clean. Concerning infection, early management may be necessary to prevent inflammation affecting the jaw. When surgical treatment is required, considerations must be paid so that procedures are minimally invasive, and cooperation with the Department of Pediatrics, such as antibiotic administration for infection control, may be important.

Role of funding source
There is no funding for this review.