Abstract
This pilot study evaluates the clinical stability of bisphosphonate-coated dental implants placed using a two-stage surgical procedure in five patients. Each patient received seven regular Brånemark implants, one of which was coated with bisphosphonate in a fibrinogen matrix. The coated implant was inserted where the bone was expected to have the least favourable quality. The level of the marginal bone around each implant was measured by intraoral periapical radiographs and implant stability was recorded using resonance frequency measurements. Frequency values (ISQ) were obtained peroperatively before flap closure and after 6 months at abutment connection. At abutment connection the bisphosphonate-coated implants were removed en bloc in two patients for histological examination. An animal experiment had previously confirmed that gamma-sterilization did not reduce bioactivity of the bisphosphonate coating. In each patient, the bisphosphonate-coated implant showed the largest improvement in ISQ level of all implants. Their values at the start tended to be lower, and the absolute value at 6 months did not differ. No complications occurred with the coated implants. Histology showed no abnormalities. Improvement in ISQ values was an expected effect of the bisphosphonate coating, but could be due to the choice of insertion site. This finding warrants a randomized, blinded study.
In the last decade, most dental implant manufacturers have focused on implant surfaces to improve bone-to-implant contact . Common methods of treating titanium dental implant surfaces are blasting, acid etching and chemical modification . Bisphosphonates are antiresorptive drugs that act specifically on osteoclasts, thereby maintaining bone density and strength . Bisphosphonates are used in many clinical settings, including prevention and treatment of primary and secondary osteoporosis, Paget’s disease of bone, hypercalcemia, multiple myeloma and osteolysis associated with bone metastases of malignant tumors.
Several animal studies have been published concerning improvement in mechanical fixation of screw-shaped implants by coating the surface with bisphosphonates . These implants were inserted in the tibia. The effect of systemic administration of alendronate on implant osseointegration in the hip was investigated after total hip replacement. The results indicate that alendronate increases the amount of peri-implant bone . Bisphosphonate (alendronate)-coated dental implants in dog mandibles have shown increased bone density and bone formation . An overview of the literature on bisphosphonates and implants was recently published .
Bisphosphonates can be linked to metal surfaces via a fibrinogen layer attached to the surface. Implants treated in this way obtained stronger fixation in a tibial rat model and the strength of the fixation increased more than that of the controls during prolonged follow-up . The purpose of this study was to evaluate the clinical stability of similarly bisphosphonate-coated dental implants placed using a two-stage surgical procedure in five patients.
Materials and methods
This study was approved by the regional ethics committee. Five consecutive edentulous patients (one woman and four men, mean age 66 years) were included. They were referred for rehabilitation of the masticatory function in the upper jaw using a fixed bridge supported by titanium fixtures. The patients were examined preoperatively by CT scan to determine bone volume, and classified according C awood & H owell . Exclusion criteria were: systemic or immunologic disease, alcoholism, uncontrolled diabetes and smoking. Local exclusion criteria were: previous tumour, trauma and surgery. Patients classified as Cawood and Howell class IV–VI maxilla-bone were excluded.
Brånemark MK III Ti Unite, 3.75 mm in diameter, were used. The coated implants were 10 mm long. The other implants varied between 11.5 and 13 mm. The coating procedure was performed exactly as described by T engvall et al. . Briefly, a crosslinked layer of fibrinogen was covalently bound to the metal, and then small amounts of pamidronate and ibandronate were bound and adsorbed to the fibrinogen. The amount of bisphosphonate on similarly treated surfaces has been measured to be less than a microgram per cm , and about 60% of similarly bound radiolabelled alendronate was released after 8 h in vitro . Each screw had a fibrinogen carrier with two bisphosphonates. After preparation and sterile packaging, the screws were sterilized with gamma radiation (25 kGy; ARTIM, Praha, Czech Republic).
Radiographic intraoral films (Kodak Insight Super Poly-soft) were obtained in a standardized manner peroperatively, after 8 weeks, and at abutment connection after 6 months, using a long cone technique. The level of bone around the fixture (mesially and distally) was estimated by measuring from a reference point on the implant to the first implant–bone contact.
The implants were evaluated with a resonance frequency analyser, ‘Ostell’ (Integration Diagnostics, Sävedalen, Sweden). This was carried out peroperatively at insertion and at abutment connection after 6 months. The implant stability quotient (ISQ) was recorded. A change in the ISQ value is considered to reflect a change in implant stability . Measurements were repeated three times for each implant with the transducer oriented perpendicular to the long axis of the implants. The mean of these measurements was recorded.
In each patient, six ordinary implants (Brånemark System, Mk III Ti Unit) were inserted according to routine surgical principles . These implants were placed in position 13–23 according to the available bone height and ridge width, and were considered sufficient for the clinical needs. The bisphosphonate implant was placed in the premolar or molar region, at a minimum distance of 5–6 mm distal to the last regular implant ( Figs 1 and 2 ).
At abutment connection, two of the bisphosphonate-coated implants were removed en bloc with an osteotome, fixed in formaldehyde and prepared for undemineralized histology using the Exact™ system. The remaining coated implants were left in the maxilla for possible future follow-up.
Statistical analysis
This study is a descriptive investigation, initiated to see if there were complications or other problems. The authors also tested the hypothesis that mechanical fixation would be better for the bisphosphonate-coated implants. The most important variable for this would be the increase in resonance frequency (ISQ) . The authors ranked the implants within each patient according to increase in ISQ, and calculated the probability for the outcome to be a random event. This was not planned a priori, and should be regarded as descriptive, rather than rejection of a primary null hypothesis.
Statistical analysis
This study is a descriptive investigation, initiated to see if there were complications or other problems. The authors also tested the hypothesis that mechanical fixation would be better for the bisphosphonate-coated implants. The most important variable for this would be the increase in resonance frequency (ISQ) . The authors ranked the implants within each patient according to increase in ISQ, and calculated the probability for the outcome to be a random event. This was not planned a priori, and should be regarded as descriptive, rather than rejection of a primary null hypothesis.
Animal experiments
Although previous animal experiments showed the bioactivity of the bisphosphonate coating led to improved fixation, these implants had not been sterilized . Before the human study, the effects of gamma irradiation were studied in an experiment on 50 male Sprague–Dawley rats (weight 416 g, SD 22), to see if sterilization had any negative influence on mechanical fixation. Each rat received a stainless steel screw in the proximal tibia as previously described . The screws had been coated as described above for the clinical implants, and in previous animal studies . Of 50 screws, 40 were sent for gamma-sterilization with 0 (null), 5, 15 or 25 kGy, and 10 screws were coated with fibrinogen only, without bisphosphonates. There were 10 screws with each treatment (no coating, unsterilized coating and three different radiation doses). The screws were inserted in random order in the 50 rats. After 4 weeks, implant fixation was evaluated by pull-out test as previously described . The entire experiment was performed with blinding for specimen treatment until data lock. Results were analysed by Anova and Bonferroni-Dunn post hoc test.
Results
During the 6-month observation period, one untreated implant failed to integrate and the resonance frequency had fallen. No complications were seen with the coated implants.
105 radiographs (210 implant sites) were taken. Marginal bone loss at the bisphosphonate-coated implant was seen in three patients. Two of these showed 1 mm bone loss on both the mesial and distal sides, and one showed 1 mm loss only on one side. For control implants, one patient showed 1 mm bone loss on one side of one implant, and one patient showed 1 mm bone loss on one side of each of three implants. No significant differences were found for this variable.
The ISQ values for all implants ranged from 47 to 82, with a mean for all implants of 62 at insertion and 64 at abutment connection. ISQ values for bisphosphonate-coated implants ranged from 51 to 76, with a mean of 58 at insertion and 69 at abutment connection. Comparing the seven implants in each patient, the bisphosphonate-coated implants always had the largest increase in ISQ value, although in one patient there was a tie ( Fig. 3 , Table 1 ). The probability for this occurring randomly is (1/7) 5 = 1/16,807 (i.e. <0.0001); removing the patient with a tie, it is still less than 0.001
| Patient | Implant 1 | Implant 2 | Implant 3 | Implant 4 | Implant 5 | Implant 6 | BC Implant 7 | |
|---|---|---|---|---|---|---|---|---|
| 1 | Insertion | 64 | 63 | 52 | 49 | 82 | 81 | 67 |
| Abutment | 60 | 50 | 60 | 58 | 67 | 69 | 70 | |
| 2 | Insertion | 47 | 63 | 65 | 69 | 70 | 59 | 55 |
| Abutment | 60 | 69 | 66 | 75 | 72 | 64 | 68 | |
| 3 | Insertion | 64 | 61 | 67 | 60 | 66 | 63 | 59 |
| Abutment | – | 58 | 59 | 60 | 70 | 56 | 68 | |
| 4 | Insertion | 60 | 66 | 63 | 76 | 63 | 64 | 51 |
| Abutment | 55 | 68 | 63 | 71 | 68 | 74 | 64 | |
| 5 | Insertion | 63 | 52 | 56 | 61 | 70 | 52 | 58 |
| Abutment | 64 | 55 | 57 | 61 | 70 | 55 | 76 | |
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