Current state of orthodontic patients under Bisphosphonate therapy

Background Bisphosphonates are a common medication for the prevention and therapy of osteoporosis, but are also applied for tumor diseases. They affect bone metabolism, and therefore also orthodontic treatments, but how it does has yet not been definitively clarified. Therefore, the aim of this research was to evaluate and demonstrate the reported effects and the current state of scientific research regarding orthodontic treatment and bisphosphonate medication exclusively in humans. Material and methods A systematic research of the literature for selected keywords in the Medline database (Pubmed) as well as a manual search was conducted. The following search terms were used: ‘Bisphosphonate’ in combination with: orthodontic, orthodontic treatment, tooth movement. Findings To date, only nine reported patients (case reports/series) and one original article (retrospective cohort study) regarding orthodontic treatment under bisphosphonate medication in humans have been published. Decelerated tooth movement with increased side effects (especially in high-risk patients) and longer treatment duration was reported in some articles. Patients with initial spacing or extraction cases had a higher risk of incomplete space closure and poor root parallelism. Conclusions Orthodontic tooth movement under bisphosphonate medication is possible, especially in low-risk patients (low dose and short period of intake). But the treatment is still not predictable, especially in high-risk patients. Therefore, the altered bone metabolism and higher extent of side effects should be considered in treatment planning, especially in extraction cases or high-risk patients. Regardless, longer treatment duration, decelerated tooth movement, and more side effects, e.g., incomplete space closure and poor root parallelism, should be expected, especially in extraction cases or space closure.


Introduction
Bisphosphonates (BPs) are used in patients with metabolic bone diseases such as osteoporosis and in patients with malignomas and metastases to the bone. They have an inhibiting effect on osteoclastic activity and therefore decrease the bone resorption. The half-life can be more than 10 years [1]. One side effect is a bisphosphonate associated osteonecrosis of the jaws (BP-ONJ) [2][3][4][5][6][7][8]. The risk of BP-ONJ seems to depend on the type of BP, dose, duration and application form (intravenous or oral). Patients with IV BP and malignant disease are at a higher risk compared to patients with oral BP and benign diseases [2][3][4][5][6][7][8].
To date, the altered bone metabolism and the following consequences to orthodontic therapy and, possibly, revised indications have not been clarified. Only statements regarding dentosurgical therapies have been published by the field societies [5][6][7]. Concerning orthodontic aspects, there are no guiding principles.
Therefore, the aim of this study was to analyze the literature reporting on the combination of orthodontic treatment and BP medication exclusively in humans.

Material and methods
A systematic research in PubMed was performed covering publications from Jan 2000-Jan 2013. In conjunction with this, a manual search of national professional orthodontic journals published in German but not listed in PubMed was conducted. In addition, the citations in identified articles were analyzed as well. Inclusion criteria were reports on humans, BP treatment, and orthodontic treatment. Exclusion criteria were reports on animals, and a lack of BP and/or orthodontic treatment. The following search terms were used: 'Bisphosphonate' in combination with: orthodontic, orthodontic treatment, tooth movement.
The original article presented a retrospective cohort study with women <50 years-of-age [15]. The study was approved by the institutional review board at the University of Washington in Seattle. Orthodontists from the USA were invited to perform case reviews of their patients regarding women <50 years-of-age. The sample comprised 113 female patients, divided into two groups, one with (n = 20; 19 with oral BP, 1 with IV BP) and one without (n = 93) BP treatment. BP patients that were treated orthodontically with extractions and space closing had to be treated significantly longer, and they had a higher risk of incomplete space closure and poor root parallelism at the end of treatment. No BP-ONJ was described. Both groups had an alignment of the incisors of less than 1 mm discrepancy.
The following is a summary of the nine reported patients on BP with orthodontic treatment (  [13]. 3. A 60-year-old low-risk female patient (oral alendronate for 18 months) with osteoporosis had a severe right posterior open bite which was scheduled to be closed orthodontically. Before starting the treatment, a mild sclerosis was observed at tooth 47. Two years later sclerotic bone occurred around the treated teeth with a widened PDL. BP was stopped after 3.5 years in total. The radiographic signs were enhanced and tooth movement was decelerated so that orthodontic treatment was discontinued after 4.5 years. No apical root resorption occurred [14]. 4. A 50-year-old low-risk female patient underwent space closing after periodontal treatment and extraction of tooth 34. Alendronate intake due to osteoporosis was not known by the orthodontist. BP treatment was stopped after 12 months because of esophagitis (common side effect of BP). In 19 months of treatment, only crown-tipping occurred instead of bodily movement, and tooth movement was slowed down. Hypermineralized areas were found at the extraction site. Even 13 months after stopping BP and completion of further orthodontic treatment, extensive mobility and widened PDL were observed [14]. 5. A 74-year-old low-risk female patient with 36 months of oral alendronate use (for osteoporosis) and severe bone loss because of periodontal disease had tooth 31 extracted with orthodontic space closure. BP treatment was stopped 3 months prior to orthodontic treatment, which took 14 months. On initial radiographs mild sclerosis around the mandibular molars and obscured anterior PDL gaps were diagnosed. The final radiographs showed mild sclerotic and PDL spaces, mild apical root resorption of mandibular incisor, and no increased mobility. Space closure and alignment were considered successful [14]. 6. A 68-year-old low-risk female patient taking oral ibandronate for osteoporosis had an augmentation of the right sinus with autologous particulated bone from the anterior mandible. For skeletal anchorage a rigid fixation plate was inserted at the os zygomaticum. After 6 months of healing, teeth 13, 14, and 15 were distalized using the bone anchor, and all teeth were aligned (duration: 26 weeks). After distalization, all teeth were orthodontically aligned and dental implants inserted in the posterior right maxilla. The overall duration of orthodontic treatment was not specified, and no complications related to the BP medication were observed [9]. 7. "Bloodless tooth extraction" after orthodontic extrusion was performed in a 70-year-old low-risk  female patient with long-term oral BP therapy for osteoporosis. The first and second right mandibular molars were hemisected. The distal roots were orthodontically extruded for several weeks and afterwards extracted [10]. 8. An alveolar bone grafting was performed on a 15-year-old high-risk female patient with polyostotic fibrous dysplasia as well as a surgically-treated cleft lip and palate. BP treatment started at the age of 13 with 4 times IV pamidronate. Teeth 12 and 22 were missing, with an anterior crowding in the mandible and an anterior cross bite. It took 6 months after the graft surgery, until an obvious bone bridge at the recipient site became visible and orthodontic treatment was begun (sign of decreased healing potential of bone). Therefore, the orthodontic treatment was performed over a longer time and less aggressive. After 3.5 years of orthodontic treatment, the patient had a sufficient occlusion [11]. 9. Dental implants were inserted in the lateral segments of a 66-year-old low-risk female patient and used as skeletal anchorage during orthodontic treatment. Upper and lower front teeth were in-and retruded (duration: 13 months). BP medication for osteoporosis (alendronate oral) by her general practitioner was begun without knowledge of the dental facility and stopped after 7 months because of recurrent colitis (common side effect). After treatment, the patient had enlarged PDL, sclerotic bone areas, apical root resorptions of the upper frontal teeth, and increased mobility of the mandibular incisors [12].

Discussion
The number of adult and elderly patients requiring orthodontic treatment is increasing, leading to new challenges for the provider: fundamental differences in anatomical and physiological conditions, altered periodontal situations, and different medical histories with different medications, all of which have a considerable influence on orthodontic planning and treatment [16]. In addition to the anamnesis, good communication between the dentist/ orthodontist and the general practitioner is necessary. Two of the nine reported patients were medicated with a BP without orthodontist's knowledge [12,14]. The medical history must be investigated far into the past due to the long half-life of several medications [13,14]. Drug holidays are controversially discussed: the long half-life of BPs in the bone (10-12 years) [1,14] versus the effects of the BPs on the soft tissue including the vascular system [17].
Known risk factors for BP-ONJ development include the specific characteristics of the BP taken (type, dose, duration of use, and administration route) as well as further medications such as steroids taken in parallel [2][3][4][5][6][7]. In the analyzed articles BP-ONJ only occurred in one highrisk patient suffering from multiple myeloma who was treated with IV zoledronate and chemotherapy [13].
The analyzed cases show that the high-risk patient had the most severe side effects, but that even low-risk patients have some. The cohort study reported that low-risk BPpatients with extractions or initial spacing had higher odds of incomplete space closure, poor root parallelism and longer treatment duration [15]. The case reports/ series with extractions reported on compromised root paralleling and crown-tipping instead of bodily movement [13,14].
Radiographic signs such as sclerosis of the alveolar bone and widened PDL were found [12][13][14]. Apical root resorptions in the anterior region were described in two of the nine patients [12,14], while none were described in three cases [13,14] and were not specified in four other cases [9][10][11]14].
Regarding the common use of BP for osteoporosis in postmenopausal women, an untreated control group of rats was compared with a group of ovariectomized rats and a group of ovariectomized rats with zolendronate treatment [24]. The ovariectomized/zoledronate group showed similar results as the control group. The ovariectomized group had the highest amount of root resorptions and tooth movement [24].

Conclusion
Due to the increasing number of older patients requiring orthodontic treatment, the number of patients with a medical history including BP treatment is increasing. Regarding the half-life of BPs, an intensive examination of the medical history before treatment should be obligatory. Due to the missing scientific evidence, orthodontic tooth movement in patients exposed to BPs is still unpredictable, and risk stratification should be performed. The altered bone metabolism and higher extent of side effects should be considered in treatment planning, especially in extraction cases or high-risk patients. Also, longer treatment duration, decelerated tooth movement and, in patients with initial spacing or extraction cases, incomplete space closure and poor root parallelism should be expected.