Elsevier

Bone

Volume 50, Issue 5, May 2012, Pages 1148-1151
Bone

Original Full Length Article
A bisphosphonate-coating improves the fixation of metal implants in human bone. A randomized trial of dental implants

https://doi.org/10.1016/j.bone.2012.02.001Get rights and content

Abstract

Many surgical procedures use metal implants in bone. The clinical results depend on the strength of the bone holding these implants. Our objective was to show that a drug released from the implant surface can improve parameters reflecting the quality or amount of this bone. Sixteen patients received paired dental titanium implants in the maxilla, in a randomized, double-blinded fashion. One implant in each pair was coated with a thin fibrinogen layer containing 2 bisphosphonates. The other implant was untreated. Fixation was evaluated by measurement of resonance frequency (implant stability quotient; ISQ) serving as a proxy for stiffness of the implant-bone construct. Increase in ISQ at 6 months of follow-up was the primary variable. None of the patients had any complications. The resonance frequency increased 6.9 ISQ units more for the coated implants (p = 0.0001; Cohen's d = 1.3). The average difference in increase in ISQ, and the effect size, suggested a clinically relevant improvement. X-ray showed less bone resorption at the margin of the implant both at 2 months (p = 0.012) and at 6 months (p = 0.012). In conclusion, a thin, bisphosphonate-eluting fibrinogen coating might improve the fixation of metal implants in human bone. This might lead to new possibilities for orthopedic surgery in osteoporotic bone and for dental implants.

Graphical abstract

Highlights

► Dental implants coated with bisphosphonates showed higher resonance frequency. ► Resonance frequency reflects stiffness of the bone-implant construct. ► Randomized double-blinded trial with internal controls. ► First clinical study to show improved implant fixation in bone by coating with a drug.

Introduction

Insertion of metal implants in bone is one of the most common of all surgical procedures. It is part of fracture treatment, joint replacement, and dental surgery. The success of these operations is dependent of the fixation of the implants, which, in turn, depends on the strength of the bone that holds them. If the bone quality is poor, surgical procedures are modified to provide sufficient mechanical fixation by adding more screws or larger devices, or by protecting the implant from mechanical loading for a considerable postoperative time for “osseointegration”. Thus, if the quality of the bone holding the implant could be improved locally, surgical procedures would become simpler and rehabilitation would become faster.

It has been suggested that implants that release growth factors or other drugs that stimulate bone formation would improve implant fixation. This has proven to be successful in animal experiments using a BMP, [1] but so far it has not been shown in the clinic. Also, implants releasing bisphosphonates—a class of drugs that reduce bone resorption—have improved implant fixation in animal experiments [2]. The response to the trauma of implant insertion in cancellous bone involves both bone formation and resorption. These are not entirely coupled, and by reducing resorption, the net amount of bone around the implant will increase. In animal experiments, this leads to fast formation of a shell of new woven bone surrounding the implant, which becomes slowly remodeled into lamellar bone [3]. The shell can become several millimeters thick [4]. Thus, the implant will be held by stronger bone.

To our knowledge, implants releasing a drug for improvement of fixation have so far not been tested against controls in humans. Such testing requires a method to measure the quality of fixation, which to our knowledge is available only for dental implants, by measurement of mechanical resonance frequency. The method, its validation and clinical use have been comprehensively reviewed [5]. High-frequency vibrations are applied to the implant, and the frequency at which it will vibrate in resonance is recorded. The resonance vibrations include the bone surrounding the implant, and the stiffer the construct (including the bone), the higher the frequency. Low values predict implant failure, and a change in the value is considered to reflect a change in implant stability [5].

Here we report a randomized clinical trial of a drug-releasing implant that was designed for better fixation in bone. We used dental implants, resonance frequency, and a bisphosphonate coating that has been evaluated in a series of animal experiments [2], [3], [6], [7]. The hypothesis was that the coating increases the resonance frequency, reflecting improved fixation.

Sixteen patients in need of at least 2 dental implants in the upper jaw at sites with similar bone quality (mean age 65 years, 11 women) received one bisphosphonate-coated implant and one ordinary implant. Each patient thus provided his/her own control. All other treatment and follow-up procedures were carried out according to clinical routines. The patients were examined preoperatively by CT-scan to ensure a sufficient maxillary bone volume and shape (in practice a bucco-ligual distance more than 6 mm). Exclusion criteria were: systemic or immunologic disease, drug abuse, uncontrolled diabetes, smoking, previous tumor, trauma or surgery in the maxillary region, or a maxillary bone classified as Cawood and Howell classes IV–VI [8]. The patients were recruited between September 2008 and November 2010.

The surgery was performed by the first author at the department of maxillo-facial surgery of Linköping University Hospital. The implants were Brånemark Mk III Ti Unite, 3.75 mm diameter. The coated and control implants were both 11.5 mm long and visually indistinguishable. Most patients received more than the 2 implants under study; these varied in size between 11.5 and 13 mm. The surgeon chose 2 implantation sites that he considered to be as similar as possible, and named them A and B. A nurse outside the room, who was not otherwise involved in the treatment or in the study, opened a non-transparent randomization envelope. She then delivered either a coated or a control implant for insertion at site A, and the other for site B, depending on the instructions in the envelope. Randomization was performed by the last author by shuffling 16 sealed envelopes in 3 blocks with one crossover between each block, and then marking them with consecutive numbers. After delivering the implants, the nurse placed a paper with the patient's personal identity number and name in the envelope and sealed it again. The envelopes were then stored by the monitor until data lock and unblinding. Thus, the trial was performed double-blind, with exception of the otherwise uninvolved nurse. Implant position is given in Table 1.

After insertion, a resonance frequency analyzer (Osstell Mentor; Integration Diagnostics, Gothenburg, Sweden) was used to measure the implant stability quotient (ISQ) with the transducer oriented perpendicular to the long axis of the implant. The mean of 3 measurements was recorded for each implant.

The implants were then covered with gingiva and left to osseointegrate. After 6 months, the implants were exposed, their resonance frequency was measured, and transgingival abutments for connection with the dental bridge were applied. A few weeks later, the bridge was connected and the patients could start using their new teeth.

Radiographic intraoral films (Insight Super Poly-soft; Kodak, Rochester, NY) were obtained preoperatively and after 2 and 6 months, using a long cone technique. The level of the bone contour at the fixture (marginal bone level) mesially and distally was estimated by the first author by measuring from a reference point on the implant to the first implant-bone contact (Fig. 1). Change in bone level over time was expressed as the mean of the changes at the two sides of the implant in 0.25 mm increments. All radiographic measurements were repeated by an independent, blinded observer.

The number of patients was predetermined by a power analysis based on a pilot study [9]. All patients signed an informed consent document. The study was registered at clinicaltrials.gov (NCT00767169), was approved by the Regional Ethical Board of Linköping, followed the Helsinki declaration of 1983, and was monitored by Linköping Academic Research Center, which reviewed all procedures during the study and checked data before data lock and unblinding. The second and third authors—with possible bias due to economic interests—had no contact with the patients or the data between enrollment of the first patient and data lock.

The coating procedure was performed as described by Tengvall et al. [2]. Briefly, a cross-linked layer of fibrinogen was covalently bound to the metal, and then small amounts of pamidronate and ibandronate were bound and adsorbed to the fibrinogen matrix.

In detail, the procedure was as follows: The screws were placed in a chamber with 0.2 ml 3-aminopropyltriethoxysilane, H2N(CH2)3Si(OC2H5)3 (APTES; from ABCR, Germany), and baked at 60 °C at 6 mbar pressure for 10 min, after which the temperature was increased to 150 °C for 1 h. The surfaces were rinsed for 2 min in xylene (99%; Merck) in an ultrasonic bath, rinsed in xylene, and stored in xylene until use—no longer than 1 h. The APTES-coated screws were blown dry with flowing nitrogen and incubated 30 min in freshly prepared 6% glutardialdehyde, HOC(CH2)3CHO, (GA), in 0.2 M Tris buffer, pH 9, at room temperature. The surfaces were extensively rinsed and stored in Tris buffer, pH 9. The fibrinogen matrix was prepared as follows. The APTES and glutardialdehyde-coated screws were incubated for 30 min in 1 mg/ml protein (human plasminogen-free fibrinogen; Haemochrom Diagnostica, Sweden) dissolved in phosphate-buffered saline (PBS) at pH 7.4. The surfaces were extensively rinsed in PBS and incubated for 30 min in a PBS solution at pH 5.5, containing 0.2 M ethyl-dimethyl-aminopropylcarbodiimide (EDC; Sigma) and 0.05 M N-hydroxy-succinimide (NHS, Sigma). Then a new 1 mg/ml protein solution was prepared in PBS buffer, pH 5.5. The surfaces were incubated for 30 min, rinsed in PBS, and again incubated in the EDC/NHS solution. This procedure was repeated 10 times and resulted in an approximately 23-nm thick cross-linked fibrinogen matrix. Two N-bisphosphonates were bound to the fibrinogen-coated surfaces. Pamidronate disodium (Aredia®, 1 mg/ml in distilled water; Novartis, Sweden) was first immobilized in the fibrinogen multilayer using the EDC/NHS coupling technique, and finally ibandronate (Bondronate®, 50 μg/ml in distilled water; Roche, Switzerland) was spontaneously adsorbed during overnight incubation on top of pamidronate-fibrinogen.

The amount of bisphosphonate, approximately 60% pamidronate and 40% ibandronate, on similarly treated surfaces has been measured to be less than a microgram per cm2. About 60% of similarly bound radiolabeled alendronate was released after 8 h in vitro.

After preparation and sterile packaging, the screws were sterilized by gamma irradiation (25 kGy; ARTIM, Prague, Czech Republic).

Evaluation was based on internal controls. The hypothesis was that bisphosphonate-coated implants would show better fixation. The predetermined primary-effects variable was the increase in ISQ value from insertion to 6 months. This and the absolute ISQ values at 6 months were analyzed by paired t-test. Marginal bone levels on radiographs were analyzed with Wilcoxon's test for paired data.

Section snippets

Results

There was no loss to follow-up. There were no surgical complications, and the treatment was clinically successful in all patients. However, 2 control implants had ISQ values less than 57 at 6 months, suggesting insufficient or questionable fixation.

The bisphosphonate-coated implants showed a larger increase in ISQ value from baseline to 6 months than did the controls (a difference in increase of 6.9 units between experiment and control implants; 95% confidence interval: 4.1–9.8; p = 0.0001) (Table 2

Discussion

These results represent clinical proof of the principle of improving implant fixation by use of a drug coating. This is different from improvements in implant surface material or texture, which can increase the contact area between implant and bone but probably has less influence on the amount or quality of bone at some distance from the surface. Modifications of dental implants, leading to increased surface energy, have shown a larger increase in ISQ from insertion to 12 weeks than controls in

Conclusion

A thin, bisphosphonate-eluting fibrinogen coating can improve the fixation of metal implants in human bone. This might lead to new possibilities for orthopedic surgery in osteoporotic bone and for dental implants.

Acknowledgments

The study was funded by the Swedish Research Council (VR 2009–6725).

PA and PT have a patent on the coating procedure, and have shares in a company (Addbio AB) trying to commercialize the principle. PA also has received consulting reimbursement and grants from Eli Lilly & Co and from Amgen. JA recruited all patients, performed all surgery and all measurements. PT developed and supervised the coating procedure. PA initiated the study, wrote the protocol together with JA and wrote the first

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