Australian Dental Journal

The official journal of the Australian Dental Association

Australian Dental Journal 2014; 59: 9–19 doi: 10.1111/adj.12140

The use of bisphosphonates in children: review of the literature and guidelines for dental management RN Bhatt,* SA Hibbert,*† CF Munns‡ *Department of Orthodontics and Paediatric Dentistry, Westmead Centre for Oral Health, Westmead, New South Wales. †Department of Dentistry, Children’s Hospital Westmead, Westmead, New South Wales. ‡Department of Endocrinology and Diabetes, Children’s Hospital Westmead, Westmead, New South Wales, and Discipline of Paediatrics and Child Health, Sydney Medical School, The University of Sydney, Sydney, New South Wales.

ABSTRACT Bisphosphonates are inhibitors of osteoclastic bone resorption with therapeutic benefit in a variety of bone disorders in both adults and children. While these agents have been routinely used in adults for the past three decades, their more recent introduction into paediatric medicine means there is a paucity of data on long-term safety and effects on dental development. There is uncertainty regarding the dental management of children treated with bisphosphonates, particularly when invasive dental procedures, such as extractions and oral surgical procedures, are required. There are limited data with which to make recommendations about the dental management of patients treated with bisphosphonates, and there are no published recommendations that specifically address paediatric patients. This paper aims to outline paediatric uses and adverse effects of bisphosphonates and present recommendations on the dental management of children receiving bisphosphonates. Keywords: Bisphosphonate, BRONJ, child, dental, guideline. Abbreviations and acronyms: AVN = avascular necrosis; BRONJ = bisphosphonate-related osteonecrosis of the jaw; CRMO = chronic recurrent multifocal osteomyelitis; N-Bisphosphonate = nitrogen-containing bisphosphonate; OI = osteogenesis imperfecta. (Accepted for publication 26 June 2013.)

INTRODUCTION Bisphosphonates are a group of agents that are widely used in adults for pathologic conditions of bone such as osteoporosis, Paget’s disease of bone, multiple myeloma and cancer-related conditions such as skeletal metastases and hypercalcaemia of malignancy.1 The fundamental biologic action of all bisphosphonates is to inhibit osteoclastic bone resorption. In clinical terms, the overall effect of these agents is an increase in bone mass, improvement in bone strength and reduction in the risk of pathologic fracture. Over the last decade, paediatric indications for bisphosphonates have emerged, and these agents are being increasingly used in children and adolescents, most commonly for the management of osteogenesis imperfecta. Generally, these agents are well tolerated, though there are some adverse effects. Of particular interest to the dental profession is bisphosphonate-related osteonecrosis of the jaw, or BRONJ. This is a rare condition involving necrosis of a section of the jaw, and is primarily observed in oncology patients treated with high dose intravenous bisphosphonates.2,3 To © 2014 Australian Dental Association

date, there have been no cases reported in children. However, the half-life, due to skeletal retention, of bisphosphonates is long, with evidence of urinary excretion up to eight years following cessation of treatment in children.4 Thus, it is not known whether BRONJ could be encountered following invasive dental procedures long after bisphosphonate treatment has ceased. Also of interest is whether the use of these agents in the growing child may influence development of the dentition. Resorption of primary teeth roots is required for their exfoliation, and resorption of bone is critical to tooth eruption. The potential effect that bisphosphonates may have on these processes is currently unknown. While various consensus guidelines and recommendations pertaining to the dental management of patients treated with bisphosphonates have been published,3,5–11 none of these specifically address paediatric patients. This has led to protocols intended for adults being implemented in paediatric patients. The reason for bisphosphonate treatment, the dosing regimen, the route of administration and the local 9

RN Bhatt et al. anatomy and vasculature of the jaws differ significantly between paediatric and adult patients, making implementation of adult guidelines in children unscientific and possibly unsound. Despite the fact that there have been no reported cases of BRONJ in children or adolescents, there is a great deal of uncertainty regarding the management of such patients. The purpose of this article is to outline the indications for bisphosphonates and discuss potential dental effects of these agents in the paediatric patient. Given the lack of guidelines addressing paediatric patients treated with these agents, we also aim to present guidelines that have been developed by a Working Party at the Children’s Hospital at Westmead, Sydney, Australia, for the dental management of children undergoing bisphosphonate treatment. BISPHOSPHONATES IN CHILDREN The systematic use of bisphosphonates in children has been limited to the past 15 years. The successful and potential uses of bisphosphonates in children are more diverse than in adults and include:12 (1) Primary structural defects in type I collagen and other structural bone proteins (e.g. osteogenesis imperfecta). (2) Fibrous dysplasia of bone (e.g. McCune-Albright syndrome). (3) Bone abnormalities resulting from systemic disease or the effects of systemic treatment (e.g. steroid treatment of chronic disease or immobilization). (4) Bone matrix abnormalities (e.g. osteoporosis pseudoglioma syndrome). (5) Conditions with a primary defect in bone mineralization (e.g. idiopathic juvenile osteoporosis). (6) Malignancy associated hypercalcaemia. (7) Focal orthopaedic disorders (e.g. traumatic avascular necrosis of the femoral head). The majority of data on the clinical use and mechanism of action in children comes from studies of intravenous (IV) pamidronate therapy in moderate to severe osteogenesis imperfecta (OI).13 In children and adolescents with OI, pamidronate therapy has been associated with improvements in muscle force, vertebral bone mass and size, bone pain, fracture rate and growth.13,14 Similar clinical and densitometric results have been demonstrated in children with osteoporosis associated with various chronic illness including glucocorticoid induced osteoporosis, cystic fibrosis, cerebral palsy, Duchenne muscular dystrophy, spina bifida and Gaucher disease.15–21 IV bisphosphonates have been found to reduce bone pain in fibrous dysplasia and chronic recurrent multifocal osteomyelitis (CRMO);22,23 and to help prevent collapse of bone in children with avas10

cular necrosis (AVN) of bone (slipped capital femoral epiphysis and Perthes disease).24,25 Hypercalcaemia secondary to disorders such as malignancy, William syndrome and subcutaneous fat necrosis have been treated successfully with 1 to 2 doses of intravenous bisphosphonate;26–28 and they have also proven beneficial in delayed bone healing.29 The bisphosphonate treatment regimen and duration of treatment is variable and dependent on the diagnosis and response to therapy. Pamidronate tends to be administered at a dose of 9 mg/kg/year, given at intervals of between 1 to 4 monthly.21 The zoledronic acid dose tends to be 0.1 mg/kg/year, at intervals of between 3 to 12 monthly.21 In OI and secondary osteoporosis, most children would be treated for at least two years, with many requiring ongoing therapy. The duration of treatment for fibrous dysplasia and CRMO varies with response to pain, but most children would receive treatment for at least 12 months.22,23 AVN is treated for 12 months24,25 whereas children with delayed bone healing often require only two doses. The safety of bisphosphonate therapy continues to be of concern to clinicians.30 The most commonly reported adverse effects associated with bisphosphonate use in children are an acute-phase reaction (flu-like symptoms, typically occurring with the first infusion only), gastrointestinal irritation and chemical oesophagitis (for oral agents), muscle/bone pain and short-term electrolyte abnormalities.13,31–36 Intravenous bisphosphonates lower serum calcium concentrations, this is most marked following the first infusion cycle.13,37 In vitamin D replete individuals receiving the recommended calcium intake, the hypocalcaemia is self remitting.13 Transient uveitis also occurs in approximately 1% of children who receive pamidronate.13 Given that these agents suppress bone turnover, the potential for detrimental effects on skeletal growth in the growing patient are of interest. While diminished longitudinal growth has been observed following administration of high-dose bisphosphonates in growing animals;38,39 no adverse effects on growth have been detected in children treated for moderate to severe OI,13,40,41 osteoporosis42 or traumatic AVN,24 with several studies actually reporting a trend for increased height in children treated with intravenous bisphosphonates compared to pre-treatment values and historical controls.33,40,43 Because bisphosphonates persist in mineralized bone for many years, concern has also been expressed that bisphosphonates administered to females before conception could be released from the maternal skeleton during the pregnancy and affect the foetus.30,44 For this reason, bisphosphonates are contraindicated during pregnancy and all females of reproductive age © 2014 Australian Dental Association

Dental guidelines for bisphosphonates in children should have a negative pregnancy test before each treatment cycle or before commencing oral bisphosphonates. Further systematic follow-up of pregnancy outcome in this cohort is required and females should be counselled about the uncertainty surrounding this aspect of bisphosphonate therapy. Bisphosphonates have been proven to be welltolerated and safe in the doses used in clinical trials in children in the short term;32,33,36,45 however, little is currently known of the long-term consequences in these patients.41 Therefore, it is prudent for all children treated with these agents to be routinely monitored for unexpected late complications. Bisphosphonate-related osteonecrosis of the jaw First reported in 2003,46 bisphosphonate-related osteonecrosis of the jaw (BRONJ) has been defined as a condition of exposed bone in the mandible or maxilla that persists for more than eight weeks in a patient who has taken or currently is taking a bisphosphonate and who has no history of radiation therapy to the jaw.47 The pathogenesis of BRONJ remains poorly understood.6 Bisphosphonate-induced alteration of bone metabolism in conjunction with surgical insult or prosthetic trauma appear to be key factors in the pathological presentation.48 Other factors thought to play a part include soft tissue toxicity, the presence of infection, and drugs or pathologies which suppress bone or soft tissue healing or the immune response.1 Oral flora may also play a key role in its pathogenesis.49 The reader is referred to comprehensive reviews for further information pertaining to the mechanism of action of bisphosphonates,1 and the prevention, management and implicated risk factors for BRONJ,1–3,50 as relates to adult patients. DENTAL CONSIDERATIONS FOR BISPHOSPHONATES IN CHILDREN There are two main potential dental complications for children receiving these agents: the possibility of BRONJ, and the effect that inhibition of resorption may have on the development of the dentition and the occlusion. Potential effects on orthodontic tooth movement is also of interest. BRONJ in children To date, there have been no reported cases of BRONJ in children or adolescents.51–54 Malmgren et al. examined 64 patients with OI who had received monthly pamidronate infusions for a minimum of six months.51 Thirty-eight oral surgical procedures (including extractions and dentoalveolar surgical procedures) had been performed in 22 of these patients. © 2014 Australian Dental Association

Brown et al. examined 42 paediatric patients currently undergoing bisphosphonate treatment.53 Patients were examined clinically and radiographically for signs of BRONJ. Eleven of these patients had invasive dental treatment during bisphosphonate therapy. No signs or symptoms suggestive of BRONJ were determined at review in both studies. In a study by Chahine et al., 278 patients who had received at least one cycle of intravenous pamidronate in childhood were contacted.52 Of these, 113 had undergone dental extraction during or after pamidronate treatment. It was determined from patient/parent recall that none of these patients had a history suggestive of BRONJ. In a chart review of 15 patients with OI in whom 60 dental extractions and been performed,54 no complications were recorded. In this sample, most patients had undergone extractions during or after a period of bisphosphonate treatment; one patient was not treated with bisphosphonates at all, and it was not known whether another patient had received this treatment or not. The children in this sample received bisphosphonate treatment at the same centre (Shriners Hospital for Children in Montreal) as those in the previously-mentioned study;52 hence they probably form part of the sample of children reported above. At our treatment centre at the Children’s Hospital at Westmead (CHW), Australia, children treated with intravenous bisphosphonates are being prospectively followed to dental maturity. As part of the baseline survey of the oral health of these children, 99 children were clinically and radiographically examined.55 Nineteen of these had undergone oral surgical procedures (including 50 dental extractions), during or after a period of intravenous bisphosphonate treatment. As with previous studies, no complications were identified. Tooth eruption and exfoliation Bone resorption is critical to tooth eruption. For permanent teeth, eruption requires resorption of both the roots of the deciduous predecessors, as well as bone coronal to the developing tooth. Given the action of bisphosphonates on inhibition of bone resorption, the potential for these agents to delay tooth eruption is of interest. In the rat model, delayed tooth eruption has been found following administration of bisphosphonates to newborn rats.56–58 In two of these studies, enamel defects and areas of ankylosis between the alveolar bone and the developing hard dental tissues were also found.57,58 These findings have been attributed to bisphosphonate-induced arrest of bone remodelling and altered osteoclastic activities. Clinical evidence to support these results is currently limited. Kamoun-Goldrat and colleagues59 investigated the effect of N-bisphosphonates on tooth 11

RN Bhatt et al. eruption and dental age in 33 children with OI, finding a dose dependent delay in the mean age of tooth eruption of 1.6 years, and a mean difference in dental age between the bisphosphonate and control group of 1.5 years. Malmgren and colleagues have found similar results investigating delayed eruption in bisphosphonate-treated children with OI (written communication).60 In our baseline study at the Children’s Hospital at Westmead, Australia,55 infra-occlusion of primary teeth, which could be the result of delayed exfoliation and/or ankylosis, was identified in 27% of patients assessed. A trend towards a delayed dental age compared to chronological age was also observed along with delayed eruption of permanent teeth in 12.5% of subjects in whom this could be assessed. Until followup study is completed, the implications of these findings are unclear. Orthodontic implications The impact of bisphosphonates on orthodontic tooth movement is of interest as osteoblastic and osteoclastic activity is necessary for orthodontic tooth movement to occur, and bisphosphonates inhibit osteoclastic activity and may also decrease the microcirculation. A systematic review by Iglesias-Linares et al.61 investigated the possible effects of bisphosphonates on orthodontic therapy. The 13 articles included displayed significant heterogeneity and were all animal or in vitro studies. Therefore, the authors accepted the difficulty in extrapolating the results to the clinical setting, and it should be remembered that the possible dose and duration of bisphosphonates that could impact upon tooth movement, has not been quantified in humans. Nevertheless, they concluded that a longer period of orthodontic treatment would be expected, due to a significant decrease in orthodontic tooth movement. They went on to discuss potential beneficial effects of bisphosphonates for reduced root resorption, anchorage procedures and reduction of relapse, but recognized the need for human studies. A further review by Ghoneima et al,62 came to similar conclusions. An additional concern is that increased alveolar bone turnover as a result of orthodontic treatment may increase the uptake of bisphosphonates locally in the jaw, potentially increasing the risk of developing BRONJ in the future.62 The current literature relating to the orthodontic considerations of bisphosphonate therapy relates to the treatment of adults. Zahrowski suggests that orthodontic treatment should be avoided in patients receiving IV bisphosphonates,63 and similar concerns have been expressed by Graham.64 However, these papers refer to adults, not children, and the differ12

ences in therapy between adults and children, as highlighted in this paper, should be remembered. While a retrospective study of orthodontic outcomes in women over 50 has reported longer treatment times and increased odds of poor space closure and root parallelism,65 there have been no studies to date demonstrating that the benefits of orthodontic treatment should be withheld in children treated with bisphosphonates. In the absence of a clear understanding of difficulties that may be encountered, it is advisable that patients/parents are warned of the potential for increased treatment time and failure to achieve optimal tooth movement. Potential risks should be discussed and informed consent obtained prior to commencing orthodontic treatment. Depending on the risk category of the patient (based on dose, route and duration of bisphosphonate treatment), compromises in the treatment plans such as avoiding or minimizing elective surgery including extractions and miniscrew placement (temporary anchorage devices), may be advisable.63,64 Where invasive procedures are deemed necessary, the clinician should advise the medical specialist of planned treatment and should consider referral to an oral and maxillofacial surgeon with experience and knowledge in the management of patients at risk for BRONJ. Informed consent must be obtained from the parent or legal guardian outlining the potential for BRONJ, the potential for increased treatment time, and possible compromises in the treatment plan and outcome. DEVELOPMENT OF GUIDELINES The lack of any guidelines for dental management that specifically address paediatric patients treated with these agents has led to protocols intended for adults, such as prophylactic antibiotic regimens, being implemented in children. Based on data from adult experience, the key features required to initiate BRONJ appear to be trauma to the jaws (dental extraction or dentoalveolar surgery) and a history of prolonged exposure to high dose N-bisphosphonates. The risk appears to be far greater in the presence of dental or periodontal infection or inflammation (e.g. periodontal disease, periapical abscess and so forth), and in cases where there is concomitant corticosteroid or chemotherapeutic treatment. There are several key differences comparing bisphosphonate treatment of adults and children (Table 1), with clear differences in risk between these groups. The increasing use of these agents in children and the variation in prophylactic regimens being practised calls for some specific guidelines for the dental management of children on intravenous bisphosphonates. © 2014 Australian Dental Association

Dental guidelines for bisphosphonates in children Table 1. Key differences between bisphosphonate usage in children and adults Feature Drug factors

Medical factors

Social factors for BRONJ Dental factors

Route of administration Dose received

Duration of treatment Reason for treatment with intravenous agents Smoking and increased alcohol consumption Periodontitis Tooth extractions

Oral surgical indications Microbial burden at surgical site Incidence of BRONJ

Children

Adults

Predominantly IV due to difficulties with administration and compliance in the young child Varies considerably with treatment regimen and indication. Common dosage of pamidronate for a child with OI may be up to 9 mg/kg/year (maximum of 60 mg/dose) and zoledronic acid 0.1 mg/kg/year (maximum of 4 mg/yr) Long term, and may be life-long for children with significant primary or secondary osteoporosis Mainly musculoskeletal conditions, in children who are otherwise well.

IV is usually reserved for management of skeletal complications of malignancy Varies considerably with treatment regimen and indication. Common dosage of zoledronic acid for a 70 kg adult treated for osteoporosis would be 4 mg/yr

These would rarely be potential risk factors in young children While gingivitis is common in children, periodontitis is rare Primary teeth have smaller roots, in varying stages of resorption. Permanent teeth are commonly extracted in children for orthodontic purposes; such teeth are generally free of infection Usually for anomalies; most common examples include removal of supernumerary teeth, ankylosed primary molars, and exposure of impacted canines Surgical site is generally non-infected for management of anomalies and orthodontic extractions No cases to date

Generally limited duration for IV agents and oral agents with trend towards ‘drug holidays’ Intravenous BP in adults are generally reserved for oncology patients who may have a range of medical co-morbidities related to their background condition These represent more common risk factors in adult patients Common in adults. Incidence increases with increasing age. Permanent teeth have longer roots (greater bony exposure following extraction) and are most commonly removed because of infection Invasive dentoalveolar surgery is frequently indicated because of infection e.g. removal of grossly carious or periodontally-involved teeth Surgical site is usually heavily infected/ microbial-laden Low incidence, mainly in older oncology patients treated with high dose IV Nbisphosphonates

IV = intravenous; BP = bisphosphonate; BRONJ = bisphosphonate-related osteonecrosis of the jaw; N-bisphosphonates = nitrogen-containing bisphosphonates.

The following recommendations were developed based on an evaluation of existing literature and guidelines, assessment of the relevance of these to the paediatric population, and the expert opinions of a Working Party at the Children’s Hospital at Westmead comprised of specialists in the fields of bone and mineral medicine, oral medicine, infectious diseases and paediatric dentistry. GUIDELINES FOR DENTAL MANAGEMENT OF CHILDREN ON INTRAVENOUS BISPHOSPHONATES The recommendations below have been divided into some general preventive recommendations for bisphosphonate-treated children, followed by specific recommendations for instances when the need to carry out invasive oral surgical procedures arises. These recommendations are summarized in Fig. 1. General principles for prevention of BRONJ in children Prevention is clearly the best approach to this complication.5 For all children treated with these agents, the primary focus must be avoiding the need for invasive © 2014 Australian Dental Association

dental procedures and emergency dental treatment once bisphosphonate treatment has commenced. Therefore, the goals for these children should be: (1) Comprehensive dental assessment, and elimination of dental disease or foci of oral infection, prior to commencement of bisphosphonates. (2) Patient education for maintenance of optimal dental health. (3) Postponement of bisphosphonate therapy until dental health is optimized, or at least until any surgical sites have healed.66 The following basic principles should be observed for all children treated with bisphosphonates: (1) All patients should be referred to a dentist for dental examination prior to commencing bisphosphonate treatment. For children on longterm/indefinite bisphosphonate treatment, high quality specialist dental care, with involvement of a paediatric dental specialist, is recommended. (2) Comprehensive clinical and radiographic examination should be undertaken to identify teeth with a poor or questionable prognosis. Panoramic radiographs are advised for an overview of the entire jaw and to allow assessment and identification of pathology or anomalies that may 13

RN Bhatt et al. Dental treatment required?

Yes

- OH education and dietary counselling - Refer to paediatric dentist if long–term BP treatment - Periodic review

No

Has BP treatment commenced?

Yes

Consult treating physician to delay commencement of BP therapy until 3 weeks after completion of invasive treatment

No

Invasive procedures (tooth extraction, oral surgery)

Restorative treatment

Routine management

Duration of BP therapy

Long-term

Short-term

Immediate treatment required?

No

- Alert physician of future invasive treatment needs - Refer to oral surgeon/paediatric dentist - Periodic review until appropriate time for intervention

Immediate treatment required?

Yes

No

- Refer to oral surgeon/paediatric dentist - Relief of pain - Liaise with physician - Conduct invasive treatment 3 weeks prior to the next infusion - Consider need for Ab cover (table 2)

- Defer elective treatment as long as possible after BP cessation - Alert physician of future invasive treatment needs - Refer to oral surgeon/paediatric dentist - Periodic review

Fig. 1 Dental management decision pathway for children receiving bisphosphonates. BP = bisphosphonate; OH = oral hygiene; Ab = antibiotic.

necessitate invasive dental treatment at the present time, or at some stage in the future. (3) Preventive advice must be given to patients and their carers encompassing oral hygiene instruction, dietary counselling, and attendance for regular dental review. (4) Attempts should be made to complete all necessary invasive dental procedures prior to commencement of intravenous bisphosphonates.6 Three weeks would be considered ideal to allow adequate time for healing.7 Consideration should be given to extracting all teeth of questionable prognosis if bisphosphonate treatment has not yet started. (5) In the event of a true dental emergency, invasive dental treatment need not be withheld. Recommendations for oral surgical procedures in children on bisphosphonates Common oral surgery indications in children include extraction of carious teeth of poor prognosis, extraction of teeth for orthodontic purposes, and anomalies 14

or pathology that may be identified on radiographic examination, such as supernumerary teeth, ectopic canines, and impacted third permanent molars. The primary considerations for children receiving bisphosphonates in need of surgical procedures are: (1) Whether bisphosphonate treatment has already commenced? (2) Whether bisphosphonate treatment will be shortterm or long-term therapy? (3) Whether dental treatment is immediately required, or can be deferred? (Fig.1) Invasive treatment should ideally be completed prior to starting bisphosphonate treatment. Unless associated with acute pathology, elective procedures such as the surgical management of anomalies, as listed above, should be deferred for as long as practically possible after cessation of bisphosphonate treatment. For those receiving short-term treatment, elective procedures should ideally be deferred for a minimum of two years post-cessation of therapy. Following the cessation of bisphosphonate treatment, the growing child increases bone turnover by 30% within two years, whereas those at final height increase bone © 2014 Australian Dental Association

Dental guidelines for bisphosphonates in children turnover by only 10%.67 As such, it would appear reasonable to recommend older children (above age 14) be off bisphosphonate therapy for longer periods before their risk status is reduced. Children receiving indefinite or long-term therapy, e.g. children with OI, should be referred to a paediatric dentist or oral and maxillofacial surgeon to carefully evaluate the need to perform elective procedures and determine the ideal time for surgery. In children where bisphosphonate infusions have already commenced, teeth of poor prognosis should be removed as late in the infusion cycle as possible, allowing a minimum of three weeks before the next infusion, to allow for soft tissue healing. These schedules must be co-ordinated with the child’s physician. Recommendations for a ‘drug holiday’ of 3 to 6 months, or a period of bisphosphonate cessation, have been made in several guidelines for adults treated with IV bisphosphonates requiring invasive dental procedures.3,6,7 Though there is no clear evidence to support this recommendation, reports that a drug holiday may be useful have emerged.66,68 As children turnover bone more rapidly than adults, a threemonth cessation period may be considered adequate. The majority of children with OI tend to be treated with 3–6 monthly bisphosphonate infusions.41 Therefore, the most practical approach in these children would be to carry out invasive procedures towards the end of the infusion cycle, whilst allowing at least three weeks for soft tissue healing prior to the next infusion. This protocol would thereby normally allow a natural three-month cessation period prior to the required dental procedures. If this timing cannot be achieved the clinician should liaise with the child’s physician to establish if their next scheduled infusion can be deferred. Completion of non-urgent treatment in patients on oral bisphosphonates a sextant at a time has been advised in adult guidelines, allowing two months between sextants to assess for the development of BRONJ before treating the next sextant;9 this approach is not practical or appropriate for paediatric patients who commonly require a general anaesthetic for extensive dental treatment. Recommendations to consider antibiotic prophylaxis prior to dental extractions in bisphosphonate-treated patients have been published in existing guidelines for adult patients.8,11,69,70 In contrast, other working parties9,10 do not advise it due to lack of evidence of any benefit in their use. The practice of prophylactic antibiotics for dental procedures is controversial, and is based on the rationale that dental extractions or oral surgery allows translocation of oral flora to bisphosphonate-modified bone that has an impaired ability to heal and which may also be hypovascular.49 The combined position paper of the Australian and © 2014 Australian Dental Association

New Zealand Bone and Mineral Society, Osteoporosis Australia, Medical Oncology Group of Australia and the Australian Dental Association,8 recommends a single pre-operative dose of 2 g amoxicillin for nonallergic patients in a high risk category undergoing extractions. These authors acknowledge a lack of evidence basis for this recommendation. For this reason, our recommendation is that antibiotics should be used only in those children considered to be at the highest risk (Table 2). It should be recognized that the children who fall into this category, e.g. those requiring complex surgical procedures, or with significant infection, invariably are given peri-operative antibiotics, regardless of bisphosphonate usage. Where deemed necessary, we have followed the recommendations above, with addition of an alternative antibiotic for allergic patients (Table 3); based on the American Heart Association Infective Endocarditis (IE) guidelines for prophylactic antibiotics in children,71 and the antibiotic prophylaxis recommendations of the Therapeutic Guidelines (Oral and Dental) of Australia.70 Taking the above into account the following protocol for invasive dental procedures in children was developed by the Working Party: (1) The timing of the procedure should be as long as possible from the last infusion, leaving a healing period of three weeks prior to the next infusion to allow for closure of surgical wounds. That is, the dental procedure should be planned for three weeks prior to the next scheduled infusion. (2) Use 0.12% chlorhexidine gluconate mouthrinse twice a day for 5 days before the procedure to minimize inflammation and reduce the microbial burden at the surgical site; followed by twice daily rinse for 5 days after the procedure or until primary healing has occurred.69 (3) Conservative surgical technique.9 (4) Suturing of extraction sockets to approximate the gingival tissues as much as possible. Primary closure is not considered necessary if it would necessitate raising a mucoperiosteal flap. (5) Periodic review of surgical sites up to 12 months postoperatively. If healing appears to be delayed, Table 2. Risk factors when considering children at highest risk Factor Invasiveness of surgery Bacterial contamination at surgical site Duration of bisphosphonate therapy

Comment Surgical or traumatic procedures Associated soft tissue abscess or sinus, radiographic evidence of periapical pathology indicating significant bacterial contamination of the surrounding alveolar bone Receiving infusions for 2 or more years, and having the last infusion within the past 2 years for children under 14 years, or the past 5 years for children over 14. 15

RN Bhatt et al. Table 3. Recommended protocol for peri-operative antibiotic prophylaxis for patients deemed to be high risk Situation

Agent

Dose

Timing

IV

Ampicillin

50 mg/kg (maximum dose 2 g)

Oral Allergic to penicillin – IV

Amoxicillin Clindamycin

50 mg/kg (maximum dose 2 g) 15 mg/kg (maximum dose 600 mg)

Allergic to penicillin – Oral and able to swallow capsules/tablets* Allergic to penicillin – Oral but unable to swallow capsules/tablets*

Clindamycin

10 mg/kg (maximum dose 450 mg)

Immediately prior to procedure or at general anaesthetic induction 1 hour prior to procedure Immediately prior to procedure or at general anaesthetic induction 1 hour prior to procedure

Consult infectious disease specialist

Consult infectious disease specialist

Consult infectious disease specialist

*As an oral agent, clindamycin is only available in Australia in capsule form. IV = intravenous.

consideration should be given to referral to an oral and maxillofacial surgeon or an oral medicine specialist. (6) Where an ‘elective drug holiday’ has been taken bisphosphonate therapy should not be recommenced until the surgical sites have healed (14– 21 days).6,7 (7) Prophylactic antibiotics should only be considered for those children deemed to be at highest risk for BRONJ (Table 2). Recommendations for prevention of BRONJ for other (non-surgical) procedures As with guidelines for adult patients,9 no specific recommendations are made for restorative dentistry, prosthodontics, routine intra-canal endodontics or routine periodontal therapy; except to say that prevention of dental disease is of paramount importance in these patients. At this time there is no evidence to suggest that orthodontic treatment should be withheld from children on long-term bisphosphonate therapy. DISCUSSION Bisphosphonates have been shown to be of benefit in children and are therefore being used increasingly in this population. As the use of these agents in children is relatively recent compared with adults, there is little data on potential adverse effects in the long term. To date, there have been no reported cases of BRONJ in children or adolescents. Existing studies investigating the occurrence of BRONJ in bisphosphonate-treated children are all retrospective with relatively small sample sizes.51–54 However, these studies are still of value in demonstrating that no cases of BRONJ have been reported in children and adolescents despite the use of variable doses of intravenous bisphosphonates in a number of patients at more than one treatment centre; and despite the fact that many of these children had undergone invasive dental procedures during or after bisphosphonate treatment. Malmgren et al. remark that children across the world are now being 16

treated with this mode of therapy with no reports of BRONJ so far.51 They conclude that ‘the risk of ONJ in these patients must be considered so low that the patients with indications for treatment should be treated and get the chance to experience the welldocumented beneficial effect for children with severe OI’.51 However, the authors also comment that despite individual treatment doses received by these children being far less (roughly half) than that which is given to adults with malignancy, the overall duration of therapy in these children and the relative cumulative doses received by them are likely to exceed the corresponding doses given to adults who have developed BRONJ.51 Therefore, the risk for these patients developing BRONJ in childhood, or subsequently in adulthood, cannot be assumed to be negligible. As BRONJ is a relatively recent clinical entity, there is a paucity of high-quality data from clinical trials, and existing guidelines and recommendations (for adults) are essentially based on anecdotal evidence and collective multidisciplinary expert opinion.6 The authors of the present paper acknowledge that while there is a definite need for guidelines for paediatric patients, there is currently no evidence upon which to base these guidelines. Furthermore, since there are no paediatric cases of BRONJ in the published literature, it is possible that we may never have enough data to support evidence-based guidelines. Existing guidelines are fairly consistent in advising comprehensive oral assessment and ensuring patients are dentally fit prior to commencing bisphosphonates, particularly for IV bisphosphonates.72 Comprehensive examination and instigation of rigorous preventive measures should be considered standard practice for all children treated with these agents, particularly in light of the unknown potential for long-term complications. For children with OI receiving long-term or indefinite bisphosphonate treatment, provision of high quality specialist dental care is essential. As such, referral to a paediatric dental specialist is advised, along with regular general dental review to detect dental disease early and reinforce oral hygiene instruction. © 2014 Australian Dental Association

Dental guidelines for bisphosphonates in children Existing guidelines regarding BRONJ have also highlighted the importance of close collaboration between health care professionals.3 This is especially true for paediatric patients on long-term treatment. Medical practitioners should emphasize to patients the need to maintain good oral health and arrange for dental assessment prior to commencing bisphosphonate treatment. Communication of the indication for, and the likely duration of bisphosphonate treatment to the dental clinician is important. Dental practitioners should also maintain close professional ties with medical colleagues to inform and plan for any invasive dental procedures required. As adolescents are transitioned from paediatric to adult care, it is essential that the new dental practitioner is fully informed of the child’s history of bisphosphonate therapy. Prospective studies are clearly needed to follow these children to dental maturity for data on the effect on tooth eruption and malocclusion; and into adulthood to generate incidence data of any pathology such as BRONJ. This will enable a greater understanding of potential risks, and will allow recommendations regarding dental management of children treated with these agents to be refined and supplemented where necessary. It is also envisaged that as more information on the pathogenesis and risk factors for BRONJ in adults come to light, our understanding of the relative risks in the paediatric population will also be enhanced. CONCLUSIONS Bisphosphonates are being increasingly used in paediatric medicine, primarily for OI. In the absence of a detailed understanding of potential complications in this population, prevention of dental disease is of paramount importance to minimize the need for interventional care. Our recommendations are intended to provide guidance in concert with practitioners’ own clinical judgement for each individual case. Ultimate treatment decisions should follow consideration of the clinical circumstances for each case, discussion of options available and expected outcomes with the parents or carers and informed consent. Where uncertainty arises, practitioners should liaise with the appropriate medical specialists, or consider referral to a tertiary hospital facility where such children are usually managed. Finally, open communication between dental clinicians and medical physicians should always be maintained for holistic multidisciplinary care of these vulnerable children.

following members of the Working Party who contributed to the development of these guidelines: Associate Professor Craig Munns (Staff Specialist, Endocrinology and Diabetes, CHW); Professor Alison Kesson (Infectious Disease and Immunology Specialist, CHW); Dr Sally Hibbert (Consultant Paediatric Dentist, CHW); Dr Mark Schifter (Consultant in Oral Medicine, Westmead Centre for Oral Health); Associate Professor Richard Widmer (Consultant Paediatric Dentist Specialist, CHW) and Dr Reena Bhatt (Paediatric Dental Specialist, Westmead Centre for Oral Health). This paper formed part of research that was supported by an Australian Dental Research Foundation Grant Application (No. 89/2009).

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ACKNOWLEDGEMENTS The authors would like to acknowledge Dr Neeta Prabhu for reviewing the original manuscript and the © 2014 Australian Dental Association

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Address for correspondence: Dr Reena Bhatt Department of Orthodontics and Paediatric Dentistry Westmead Centre for Oral Health Darcy Road Westmead NSW 2145 Email: [email protected]

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