Experimental and clinical studies of different ways to improve the outcome of implants placed in bone of deficient quantity and quality

Introduction

During the 1970s it was demonstrated that osseointegration presents with a reliable mode of anchorage for oral implants. Osseointegrated implants, in contrast to other devices, anchored mainly in soft tissue, have indeed been documented with reliable clinical success rates over time periods of more than 5 years (^{Adell et al., 1990} ; ^{Albrektsson et al., 1988} ; ^{Buser et al., 1997} ; ^{Arvidsson et al., 1998}). However, the majority of positive long-term reports on oral implants relates to implantation sites of generally good bone structure, such as the anterior mandible. It has been known for long that the situation is different in regions with a poor bone quantity and quality, such as many maxillas (^{Brånemark et al., 1977} ; ^{Adell et al., 1981}). This has lead to the launching of several implant designs and surfaces with claimed superior results in these compromised bone regions, lamentably without any proper documentation verifying these claims. When long-term clinical results of so introduced oral implants have been scrutinized, the outcome has not been very positive and surely less good than what could be expected with the original, threaded titanium implants (^{Albrektsson, 1993} ; ^{Albrektsson, 1998}).

^{Albrektsson et al. (1981)} presented 6 different factors thought important for osseointegration. These factors included hardware parameters such as implant material, design and surface, and clinical factors such as status of the host bed, the surgical technique and the loading conditions (^{fig. 1a} and ^1b). Theoretically, the optimization of anyone of these factors may result in improved clinical results. What was presented in Brånemark's pioneering research (^{Brånemark et al., 1977}) was empirical evidence that when particular c.p. titanium implants were inserted and loaded in a two stage procedure, good clinical results ensued. One may, therefore, speculate that deliberate changes in implant hardware parameters or clinical conditions may present with improved treatment results or simplify the used and so far recommended clinical techniques. One example of the latter is the one stage insertion of mandibular implants that under certain conditions may even allow loading the very same day as the implants have been placed (^{Brånemark et al., 1999}), an approach that was not recommended when the original clinical material was presented.

However, changes in a well established clinical protocol need to be implemented with caution, so that presented innovations do not lead to poorer results than those registered before. In the present review, we will separately go through the three main possibilities to achieve improved clinical results of implants placed in compromised bone, namely changing the implant hardware, reinforcing the host bed and altering the surgical technique. The aim of this review is focused on the many different approaches that have been suggested for the improvement of implant results in compromised bone.

Since there are hundreds of papers published under each one of several subheadings on this topic, we have for space reasons decided to limit the references to a few experimental papers per subheading and instead concentrate this review on clinical findings, if available.

Definition of poor bone quantity and quality

^{Atwood and Coy (1971)} have observed that the average reduction of residual bone height in the mandible was about 0,4 mm annually which is four times more rapidly than maxillary annual bone loss. The residual bone loss is dependent on anatomic, metabolic and mechanical reasons. If there are disturbances in the normal bone remodelling due to e.g. hormonal dysbalance, osteoporosis or mode of force application, a resultant acceleration of the resorption of the alveolar ridge may ensue, resulting in poor bone quantity.

There is no consensus on what is represented by the term bone quality, but factors such as bone mineral density, cortical thickness and trabecular density have been suggested as important (^{Horner and Devlin, 1998a} and ^b). ^{Lekholm and Zarb (1985)} have presented a classification system where bone quality 1 stands for predominantly cortical bone, whereas the other extreme bone quality 4 stands for cancellous very soft bone. Whereas patient bone quantity is best described by radiographical techniques, it is more difficult to establish the bone quality solely by using radiographical techniques. Many clinicians simply try to estimate the softness of the bone when doing surgery, a clearly subjective approach. Modern ways of trying to establish the bone quality include quantitative computerized tomography, bone mineral density measurements, ultrasound attenuation, magnetic resonance imaging, evaluation of bone biopsies and measuring the true cutting resistance (^{Friberg, 1999}).

Deficient bone as used in this paper means a combination of poor bone quantity and quality.

Change of implant hardware to improve outcome of implants in deficient bone

The observation that direct bone anchorage is preferable to a soft tissue interface has led to the speculation that increasing the amount of bone attachment or otherwise accelerating the early bone response is advantageous and, indeed, this hypothesis has inspired a lot of experimental research on oral implants. The three hardware parameters have been particularly interesting for many implant manufacturers and it has been a common claim that specific hardware characteristics would result in a stronger bone response and, hence, a specific type of implant then has been tooted as particularly recommendable. The bases for such assumptions have in the great majority of cases been limited to either in vitro studies or short term animal findings. Needless to say it is important to strive for implants leading to improved clinical results, but it is sad to learn that experimental data of an unknown significance for the clinic in many cases have been allowed to replace controlled clinical studies in motivating the use of new, alledgedly improved, types of implants. When, at last, often many years after their original clinical introduction, some clinical studies have been presented as supportive of the previous experimentally based claims of improved function, the quality of those reports have commonly been lamentably poor and really not indicative of any clinical superiority of the novel implant. The risks with this uncritical attitude are obvious. What is regarded as a clinical improvement may, in reality, represent a step in the opposite direction.

Experimental and clinical evidence of using alternative implant materials

Titanium alloys, zirconium, tantalum and niobium

C.p. titanium was chosen as implant material because of its good biocompatibility which is mainly due to the adherent oxide layer that covers all titanium implants (^{Albrektsson et al., 1981}). However, in the 1960s, when c.p. titanium was preferred to other potential implant materials, there were no experimental models available that permitted a comparative study of the hard tissue reactions to c.p. titanium on the one hand and metals such as titanium alloys, zirconium, tantalum and niobium on the other.

The referred metals have some similarities to c.p. titanium and e.g. titanium-6aluminum-4vanadium alloy has the additional potential advantage of being stronger than c.p. titanium. However, the titanium-6aluminum-4vanadium alloy has since been tested in animal experiments and found to have a significantly weaker bone response than seen to control c.p. titanium implants (^{Han et al., 1998} ; ^{Johansson et al., 1998}). The reason for this impaired bone response may be aluminum or vanadium leakage from the titanium alloy (^{Johansson et al., 1992} ; ^{Ektessabi et al., 1996}). Titanium-6aluminum-4vanadium alloy has been used in at least a couple of oral implant designs such as the Screw-Vent^® and the Endopore^®. Screw-Vent implants have been documented with slightly negative clinical results (de ^{Bruyn et al., 1999}) whilst the Endopore^® implant has been reported with a 5-year mandibular success (CSR) of 93,4 % (^{Deporter et al., 1999}). The precise clinical implications of these reports are uncertain, since no controlled studies comparing c.p. titanium and titanium-6aluminum-4vanadium implants have been published to the knowledge of the present authors. However, the outcome of the studies is not very impressive.

Other metals such as zirconium, tantalum and niobium have been experimentally tested and found to present similar results as reported from c.p. titanium (^{Gottsauner-Wolf et al., 1987} ; ^{Johansson et al., 1990}, ¹⁹⁹¹ and ¹⁹⁹⁴). However, there is no long-term clinical evidence available and, at least in the case of niobium, one may wonder if this metal has the adequate strength to funtion as an oral implant.

Calcium phosphate-coatings

Calcium phosphate-coatings (or hydroxyapatite, HA) were clinically launched by the mid-1980s, based solely on some short term experimental data (^{fig. 2}). ^{Gottlander (1994)} has summarized the knowledge from in vitro and short term in vivo animal studies that generally have verified a more rapid bone response to HA-coated implants, hence suggesting some promise for clinical usage in compromised bone.

However, when the clinical literature on HA-coated implants recently was evaluated by one of the present authors (^{Albrektsson, 1998}), the hypothesis that an improved clinical outcome of calcium phosphate-coated implants in compromised bone could not be verified. Despite numerous claims of superior clinical results with HA-coated implants, it was found that the actual outcome was proven positive only over the short term follow-up, whereas long-term followed-up clinical studies generally showed less good results of HA-coated implants than would be expected with non-coated ones. In fact, some studies verified that the outcome of calcium phosphate-coated implants in compromised bone showed clearly poorer results than originally hypothesized (^{Albrektsson, 1998}).

Experimental and clinical evidence of using alternative implant designs

Cylindrical designs

Cylindrical implant designs, generally with a plasma-sprayed titanium surface, were introduced during the 1980s accompanied by verbal claims that this design/surface combination was ideal and presented similar good results whether the implants were inserted in good mandibles or whether in maxillas of deficient bone quality (^{Kirsch and Ackermann, 1989}). Such designs were demonstrated to show a good bone to implant anchorage, at least over short term in animals. However, the clinical results were not as positive as originally hypothesized, mainly because the cylindrical implant designs did not result in steady state bone conditions (^{Flemmig and Höltje, 1989} ; ^{Quirynen et al., 1992}). Particularly poor clinical results have been reported over 5-10 years of observations (^{Dietrich et al., 1993} ; ^{Haas et al., 1996}) and, at the level of our current knowledge, there seems to be no indication for implant cylinders in routine clinical praxis and they certainly do not show acceptable results in areas of deficient bone.

Porous-coated designs

Porous coating is a form of surface enlargement commonly used in orthopaedic reconstruction. It has been hypothesized that this design is a preferable one and useful for deficient bone areas (^{Deporter et al., 1996}). Currently, there is one commercially available porous-coated oral implant design : the Endopore^®. This implant system belongs to the few that have been carefully documented and this is particularly interesting since the Endopore^® implant combines a special cylindrical design and titanium-6aluminum-4vanadium alloy which truly makes it a unique type of implant.

Double threaded designs

The Nobel Biocare^® Mark IV implant represents a double threaded implant design particularly developed for use in bone of poor quality. The initial mean peak insertion torque as well as resonance frequency values (^{Meredith et al., 1996}) have been demonstrated as significantly greater for this implant in comparison with different look alike implants, but with single threads. This does suggest some promise for the double threaded design implant, but as yet there is no published clinical follow up study verifying greater success rates of this implant compared to controls in soft bone.

Experimental and clinical evidence of using alternative implant surfaces

Increasing surface energy

Based on in vitro findings of a greater tissue attachment to surfaces of a high surface energy (^{Baier et al., 1984}), commercial companies started introducing plasma cleaning machines that result in increased surface energy. It was claimed that such high surface energy implants would show better results in deficient bone. However, an animal study (^{Carlsson et al., 1989}) failed to verify any potential advantages in bone response to plasma cleaned implants compared to ordinarily sterilized controls. One hypothesis to explain why the increased surface energy did not result in an enhanced bone response was that once the implant was removed from the plasma cleaning container and placed in the oral cavity, it lost its high energy state because of contamination. Plasma cleaning represents a possible way of sterilizing implants, but there is no clinical evidence of this treatment being possible for increasing implant success rates in deficient bone.

Intermediate surface roughness

^{Wennerberg (1996)} has presented a series of experimental studies documenting a stronger bone response to implants of an intermediate surface roughness ; i.e. an Sa of about 1,5 µm (^{fig. 3}). Typical turned implants are of a roughness of about 0,5-0,8 µm Sa (^{fig. 4}) whereas plasma-sprayed devices generally have a roughness of 2-3 µm Sa. The results of experimental work such as that by ^{Wennerberg (1996)} has too rapidly been implemented as a clinical reality. The fact is that however promising experimental studies, in the absence of clinical documentation, it must be regarded as unknown whether it is possible to generalize these animal findings to any clinical reality, let alone the situation with compromized bone. At present, short term clinical papers by ^{Sullivan et al. (1997)}, ^{Lazarra et al. (1998)} and ^{Åstrand et al. (1999)}, and the longer followed-up study by ^{Lindhe et al. (1997)} do not verify the hypothesis that intermediately roughened implants are clinically preferable. In addition, long term side effects of roughened implants may include tissue corrosion and increased incidence of peri-implantitis which, at the present time, further motivate a conservative attitude towards generalizing the experimental findings to the clinical reality.

Fluoride treatment of implant surfaces

Recently published experimental data by ^{Ellingsen (1995)} indicate that fluoride treated implants demonstrate a significantly stronger bone response than control implants that have not been treated with fluoride. These observations suggest some promise, but to the knowledge of the present authors there is as yet no clinical documentation of the potential benefits of fluoride treatment of titanium implants.

Alkaline treatment of implant surfaces

Titanium implants that received alkali-and heat treatment to 600 °C showed significantly stronger bone attachments than did non treated controls (^{Kim et al., 1996} ; ^{Yan et al., 1997} ; ^{Nishiguchi et al., 1999}). ^{Skripitz and Aspenberg (1998)} found evidence of strong tensile detachment loads of so treated titanium implants, indicative of a chemical bonding. These are interesting experimental data that however so far have not been tested in the clinical reality.

Increasing oxide thickness

There are various ways (e.g. heating, chemical treatment, anodising) to increase the thickness of the oxide layer of titanium implants. ^{Brien et al. (1998)} found evidence of that thickened oxide layers gave rise to a similar enhanced bone response as that seen to hydroxyapatite in comparison to non-treated titanium. ^{Larsson et al. (1994)} investigated the experimental outcome of titanium implants where the oxide layer had been reinforced to a thickness of up to about 200 nm. This represents a relatively small increase in oxide thickness and there were generally no significant differences observed in the bone response between this reinforced implant and the untreated control. However, it was observed that the parts of the implant that were localized in the marrow space indeed demonstrated a higher degree of bony contact than did the control. ^{Sul et al. (1999)} (^{fig. 5a} and ^5b) in a rabbit study confirmed that there were no or only minor differences between the bone response to 200 nm thick oxidised implants and to controls, but when the oxide thickness was 600 nm or more there was a significantly stronger bone response to the oxidised implant. It must be observed that increasing the oxide layer on a titanium implant is connected to other surface changes such as a different implant roughness at the nanometer level of resolution. The precise reason for the stronger bone response to oxide-reinforced implants is therefore unknown. These referred studies are quite interesting, but it must be observed that there is a lack of clinical studies confirming the potential advantages by using oxide-reinforced titanium implants.

Reinforcement of the host bed to improve outcome of implants in deficient bone

Under this heading we will mainly discuss potential ways of reinforcing a host bed with poor bone quantity and quality for general reasons, but not commenting on bone beds suffering from specific types of disease or maltreatment such as various metabolic bone disorders or irradiation where specific treatments or clinical routines exist.

Furthermore, bone beds of a poor bone quantity and quality may have to be reinforced with some type of bone graft. Autologous bone is then preferable compared to various types of foreign materials (^{Albrektsson, 1979}). In compromised jaw bone, a bone graft must be regarded as one alternative to improve the situation, making it possible to insert oral implants. The outcome of oral implants in grafted bone is likely to be less good than that in normal bone. Since bone grafting in itself raises many other questions best discussed in a full, separate review, they will because of space reasons not be discussed in further detail in the present paper.

Systemic treatment : hyperbaric oxygen

^{Nilsson et al. (1987)} investigated the amount of bone formed in bone harvest chamber implants when animals were placed in diver's chambers which result in increasing levels of pO₂. ^{Nilsson et al. (1987)} were able to describe a positive bone response in this normal, non-irradiated tissue in comparison to controls that were placed in the chambers but without increasing the pressure. The thought mechanism for this hyperbaric oxygen action is that even in non-irradiated cases, the lack of tissue oxygen is a major reason for slow bone healing. However, to the knowledge of the present authors there are no supportive clinical studies that have tried to evaluate the actions of hyperbaric oxygen in deficient, non-irradiated bone. In irradiated bone, on the other hand, there is clinical evidence of significantly fewer extraoral implant failures with hyperbaric oxygen treatment than without (^{Granström et al., 1999}).

Local treatment

Electrical stimulation

Various types of electrical signals have, since the original findings by ^{Yasuda (1954)}, been suggested as ideal ways of treating deficient bone. Even if the main indications for electrical signals have been fractures or non-unions, their role in the improvement of implant incorporation has been emphasized as well (^{Otter et al., 1998}). ^{Buch (1985)} was indeeed able to demonstrate that certain types of electrical signals did improve the bone response to experimental implants, hence such signals may prove important in deficient bone areas. However, the step from experimental studies to the clinical reality is substantial in that what is found being effective electric signals in animals must be recalculated substantially to be valid for man. So far, the present authors are not aware of any published evidence of the efficacy of clinical signals that has been proven in the case of implants and deficient bone.

Mechanical intervention

^{Lundgren et al. (1995)} performed an experimental study where they drilled in rabbit, maxillary bone to provoke a healing response. At 8 weeks they found a significant increase in trabecular bone density on the treated side, but the study was limited to short term follow-up. To the knowledge of the present authors, there is no controlled clinical tests of the effects of implant incorporation in bone formed after such mechanical intervention.

Distraction osteogenesis

The technique of distraction osteogenesis, described in orthopaedics by ^{Ilizarov (1989)}, has been combined with oral implants in several recent studies (^{Block et al., 1998} ; ^{Urbani et al., 1999}). ^{Oda et al. (1999)} used this technique in one study and were able to report a ridge augmentation of 5 mm in 6 days. However, some bone resorption and loss of implants were reported too.

Membrane reinforcement

Various types of membranes will according to the priciples of guided tissue regeneration (GTR) result in increasing amounts of bone in the region underneath the membranes. However, there is evidence that although the bone mass may increase (^{Pal et al., 1998}), the quality of the regenerated bone does not always improve the healing situation and the bone does not seem to get in close contact with the implant (^{Becker et al., 1994}). In clinical analyses of GTR-formed new bone in dehiscences and fenestration defects, the positive outcome of the treatment was questioned (^{Becker et al., 1999}).

Drugs

Supplementation of growth factors

Various types of growth factors have been regarded as promising agents for the reinforcement of deficient bone areas (^{Zellin, 1998}). In a recently published experimental study, ^{Cochran et al. (1999)} found a stronger bone response around canine oral implants treated with BMP-2 compared to non-treated controls. The follow-up times in this study were 4 and 12 weeks. Although growth factors have been the focus of many experiments and the fact that numerous commercial companies advocate their use, there is a dearth of information concerning the success in clinical usage of growth factors in deficient bone areas.

Administration of calcium, vitamine D and œstrogen

This triple treatment has been found effective for female, osteoporotic patients. ^{Jacobs et al. (1996)} reported of increase in mandibular bone mass after treatment. The present authors are unaware of any controlled clinical studies with triple treatment and oral implants.

Administration of biphosphonates

Alendronate, a synthetic biphosphonate, has been reported to reduce the number of osteoclasts, thereby resulting in an increase of bone mineral density (^{McClung et al., 1998}). The present authors are unaware of any studies documenting a positive outcome of biphosphonates in conjunction with implant therapy.

Altering of the surgical technique to improve outcome of implants placed in deficient bone

If the literature on implants placed in bone of a poor quantity and quality is scrutinized, there are only two publications with long-term clinical results of above 90 % success. Both these publications utilized the same type of threaded, c.p. titanium implant. ^{Bahat (1993)} and ^{Friberg (1999)} presented a clinical material of respectively 732 and 523 Brånemark^® type implants. The out-come of some 200 implants placed in grade 4 bone was found to show a failure rate, over 3-7 years, of between 4 and 7 % in the two studies. It is interesting to observe that such good results were achieved with a turned, minimally roughened titanium implant. ^{Friberg (1999)} has stated his opinion for the reason for the good clinical results : The surgeons had drilled smaller holes than usually recommended in the deficient bone. Theoretically, this simple action may have helped to create an improved initial stability in the bone, hence the excellent results.

Concluding remarks

This review has had the aim to summarize experimental and clinical knowledge of the ideal implant or treatment to use in bone of poor quantity and quality. One striking conclusion of the referred literature is that although numerous types of changes in the implant hardware have resulted in a reinforced bone response at short terms of follow-up in animals, there is yet very little supportive evidence of this leading to improved clinical results.

The various stimuli discussed under the hardware and host bed headings have one thing in common : they build on the hypothesis that since a direct bone anchorage is preferable to a soft tissue attachment of a foreign material, the more bone that is established in the interface the better it is. From a clinical standpoint, this assumption may not necessarily be correct. It is possible that we need a certain minimal level of bone attachment for appropriate clinical function, but this does not imply that more bone present with an improved clinical result. In fact, there is some evidence that experimental findings of more bone is not at all coupled to improved clinical results. One piece of such evidence is represented by the HA experience, when the finding of more bone in short term animal studies in fact is coupled to less good clinical results compared to non-coated titanium designs. Another indication pointing in the same direction is the study by ^{Ivanoff (1999)} where the authors found significantly stronger bone reactions to a 5 mm wide implant when placed in animals. However, when the same wide implant was tried in a clinical series, the outcome was only in the 80 % range of success.

It is noteworthy that the only documented positive, long-term results of implants placed in bone of a poor quantity and quality, two studies by ^{Bahat (1993)} and ^{Friberg (1999)}, used a well documented threaded titanium screw implant without manipulating its surface or the bony bed. These positive results were seen after a minor change in the surgical routine. One cannot help thinking that while there is a general trend of introducing a great number of novel types of implants, the major increase in success rates may follow changes in the software rather than the hardware.

Demande de tirés à part :

Tomas ALBREKTSSON, Department of Biomaterials/Handicap Research, Institute for Surgical Sciences, University of Göteborg - SWEDEN.

BIBLIOGRAPHIE

• ADELL R, LEKHOLM U, ROCKLER B, BRÅNEMARK PI. A 15-year study of osseointegrated implants in the treatment of the edentulous jaw. Int J Oral Surg 1981;10:387-416.
• ADELL R, ERIKSSON B, LEKHOLM U, BRÅNEMARK PI, JEMT T. A long-term follow-up study of osseointegrated implants in the treatment of totally edentulous jaws. Int J Oral Maxillofac Implants 1990;5:347-359.
• ALBREKTSSON T. Healing of bone grafts. In vivo studies of tissue reactions at autografting of bone in the rabbit tibia [PhD Thesis]. Göteborg : Department of Anatomy, Göteborg University, 1979:1-89.
• ALBREKTSSON T. On long-term maintenance of the osseointegrated response. Aust Prosthodont J 1993;7(suppl):15-24.
• ALBREKTSSON T. Hydroxyapatite-coated implants : a case against their use. J Oral Maxillofac Surg 1998;56:1312-1326.
• ALBREKTSSON T, BRÅNEMARK PI, HANSSON HA, LINDSTRÖM J. Osseointegrated titanium implants. Acta Orthop Scand 1981;52:155-170.
• ALBREKTSSON T, DAHL E, ENBOM L, ENGEVALL S, ENQUIST B, ERIKSSON RA et al. Osseointegrated oral implants. A Swedish multicenter study of 8 139 consecutively inserted Nobelpharma implants. J Periodontol 1988;59:287-296.
• ARVIDSSON K, BYSTEDT H, FRYKHOLM A, VON KONOW L, LOTHIGIUS E. Five-year prospective follow-up report of the Astra Tech Dental Implant System in the treatment of edentulous mandibles. Clin Oral Implant Res 1998;9:225-234.
• ÅSTRAND P, ENGQUIST B, DAHLGREN S, ENGQUIST E, FELDMANN H, GRÖNDAHL K. Astra Tech and Brånemark system implants : a prospective 5-year comparative study. Results after one year. Clin Implant Dent Rel Res 1999;1:17-26.
• ATWOOD DA, COY WA. Clinical, cephalometric and denistometric study of reduction of residual ridges. J Prosthet Dent 1971;26:280-295.
• BAHAT O. Treatment planning and placement of implants in the posterior maxillae : report of 731 consecutive Nobelpharma implants. Int J Oral Maxillofac Implants 1993;8:151-161.
• BAIER RE, MEYER AE, NATIELLA JR, CARTER JM. Surface properties determine bioadhesive outcomes;methods and results. J Biomed Mater Res 1984;18:337-335.
• BECKER W, LEKHOLM U, DAHLIN C, BECKER B, DONATH K. The effect of clinical loading on bone regeneration by GTAM barriers : a study in dogs. Int J Oral Maxillofac Implants 1994;9:305-313.
• BECKER W, DAHLIN C, LEKHOLM U, BERGSTRÖM C, VAN STEENBERGHE D, HIGUCHI K et al. Five-year evaluation of implants placed at extraction and with dehiscences and fenestration defects augmented with ePTFE membranes : results from a prospective multicenter study. Clin Implant Dent Rel Res 1999;1:27-32.
• BLOCK MS, ALMERICO B, CRAWFORD C, GARDINER D, CHANG A. Bone response to functioning implants in dog mandibular alveolar ridges augmented with distraction osteogenesis. Int J Oral Maxillofac Implants 1998;13:342-351.
• BRIEN M, SCHLIEPHAKE H, BECKER J, REICHART PA. Histomorphometrische tierexperimentelle Studie von Implantatoberflächen (Duraplant^®). Z Zahnärtztl Implantol 1998;14:208-212.
• DE BRUYN H, COLLAERT B, LINDÉN U, JOHANSSON C, ALBREKTSSON T. Clinical outcome of Screw-Vent implants. A 7-year prospective follow-up study. Clin Oral Impl Res 1999;10:139-148.
• BRÅNEMARK PI, HANSSON BO, ADELL R, BREINE U, LINDSTRÖM J, HALLÉN O et al. Osseointegrated implants in the treatment of the edentulous jaw. Experience from a 10-year period. Scand J Plast Reconstr Surg 1977;11(suppl 16):1-132.
• BRÅNEMARK PI, ENGSTRAND P, ÖHRNELL LO, GRÖNDAHL K, NILSSON P, HAGBERG K et al. Brånemark Novum : a new treatment concept for rehabilitation of the edentulous mandible. Preliminary results from a prospective clinical follow up study. Clin Implant Dent Rel Res 1999;1:2-16.
• BUCH F. On electrical stimulation of bone tissue [PhD thesis]. Göteborg : Department of Biomaterials/Handicap Research, University of Göteborg, 1985.
• BUSER D, MERICKSE-STERN R, BERNARD JP, BEHNEKE A, BEHNEKE N, HIRT HP et al. Long-term evaluation of non-submerged ITI implants. Part I. 8-year life table analysis of a prospective multicenter study with 2 359 implants. Clin Oral Impl Res 1997;8:161-172.
• CARLSSON LV, ALBREKTSSON T, BERMAN C. Bone response to plasma-cleaned titanium implants. Int J Oral Maxillofac Implants 1989; 4: 199-204.
• COCHRAN DL, SCHENK R, BUSER D, MOZNEY JM, JONES AA. Recombinant human bone morphogenetic protein-2 stimulation of bone formation around endosseous dental implants. J Periodontol 1999;70:139-150.
• DEPORTER DA, WATSON PA, PILLIAR RM, PHARAOH M, SMITH DC, CHIPMAN M et al. A prospective clinical study in humans of an endosseous dental implant partially covered with a powder-sintered porous coating : 3-4 year results. Int J Oral Maxillofac Implants 1996;11:87-96.
• DEPORTER D, WATSON P, PHARAOH M, LEVY D, TODESCAN R. Five to six-year results of a prospective clinical trial using the Endopore^® dental implant and a mandibular overdenture. Clin Oral Implant Res 1999;10:95-102.
• DIETRICH U, LIPPOLD R, DIRMEIER T, BEHNEKE N, WAGNER W. Statistische Ergebnisse zur Implantat prognose am Beispiel von 2017 IMZ-Implantaten underschiedlicher Indikation der letzten 13 Jahren. Z Zahnärztl Implantol 1993;9:9-18.
• EKTESSABI AM, OTSUKA T, TSUBOI Y, MOUHYI J, ALBREKTSSON T, SENNERBY L et al. Ion release from titanium dental implants. In : Ueda M., ed. Proceedings of the Third International Congress on Tissue Integration in Oral and Maxillofacial Reconstruction. Tokyo : Quintessence Co, 1996:13-16.
• ELLINGSEN JE. Pre-treatment of titanium implants with fluoride improves their retention in bone. J Mater Sci Mater Med 1995;6:749-753.
• FLEMMIG TF, HÖLTJE WG. Periimplantäre Mukosa und Knochen bei Titanimplantaten. Z Zahnärztl implantol 1989;5:185-190.
• FRIBERG B. On peroperative bone density measurements and implant stability [PhD thesis]. Göteborg : Department of Biomaterials/Handicap Research, University of Göteborg, 1999.
• GOTTLANDER M. On hard tissue reactions to hydroxyapatite-coated titanium [PhD thesis]. Göteborg : Department of Biomaterials/Handicap Research, University of Göteborg, 1994.
• GOTTSAUNER-WOLF G, DALLANT P, PFLÜGER G, PLENK H Jr, GRUNDSCHOBER F, SCHIDER S. Histomorphometrical and roentgenological evaluations of bone reactions to cementless niobium femoral stems in dogs. Adv Biomaterials 1987;6:753-758.
• GRANSTRÖM G, TJELLSTRÖM A, BRÅNEMARK PI. Osseointegrated implants in irradiated bone : a case-controlled study using adjunctive hyperbaric oxygen therapy. J Oral Maxillofac Surg 1999;57:493-499.
• HAAS R, MENSDORFF-POUILLY N, MAILATH G, WATZEK G. Survival of 1 920 IMZ implants followed for up to 100 months. Int J Oral Maxillofac Implants 1996;11:581-588.
• HAN CH, JOHANSSON CB, WENNERBERG A, ALBREKTSSON T. Quantitative and qualitative investigations of surface enlarged titanium and titanium alloy implants. Clin Oral Impl Res 1998;9:1-10.
• HORNER K, DEVLIN H. The relationships between two indices of mandibular bone mineral quality and bone mineral density measured by dual energy X-ray absorptiometry. Dentomaxillofac Radiol 1998a; 27:17-21.
• HORNER K, DEVLIN H. The relationship between mandibular bone mineral density and panoramic radiographic measurements. J Dent 1998b; 26:337-343.
• ILIZAROV GA. The tension-stress effect on the genesis and growth of tissues. Part II. The influence of the rate and frequency distraction. Clin Orthop 1989;239:263-285.
• IVANOFF CJ. On surgical and implant related factors influencing integration and function of titanium implants [PhD thesis]. Göteborg : Department of Biomaterials/Handicap Research, University of Göteborg, 1999.
• JACOBS R, GHYSELEN J, KONINCKX P, VAN STEENBERGHE D. Long-term bone mass evaluation of mandible and lumbar spine in a group of women receiving hormone replacement therapy. Eur J Oral Sci 1996;104:10-16.
• JOHANSSON C, HANSSON HA, ALBREKTSSON T. Qualitative interfacial study between bone and tantalum, niobium or commercially pure titanium. Biomaterials 1990;11:277-280.
• JOHANSSON C, ALBREKTSSON T. A removal torque and histomorphometric study of commercially pure niobium and titanium implants in rabbit bone. Clin Oral Implant Res 1991;2:24-29.
• JOHANSSON C, ALBREKTSSON T, THOMSEN P, SENNERBY L, LODDING A, ODELIUS H. Tissue reactions to titanium-6aluminum-4vanadium alloy. Eur J Exp Musculoskeletal Res 1992;1:161-169.
• JOHANSSON C, WENNERBERG A, ALBREKTSSON T. A quantitative comparison of screw shaped commercially pure titanium and zirconium implants in rabbit tibia. J Mater Sci Mater Med 1994;5:340-344.
• JOHANSSON C, HAN CH, WENNERBERG A, ALBREKTSSON T. A quantitative comparison of machined commercially pure titanium and titanium-aluminum-vanadium implants in rabbit bone. Int J Oral Maxillofac Implants 1998;13:315-321.
• KIM HM, MIYAJI F, KOKUBO T, NAKAMURA T. Preparation of bioactive Ti and its alloys via simple chemical surface treatment. J Biomed Mater Res 1996;32:409-417.
• KIRSCH A, ACKERMANN KL. The IMZ osseointegrated implant system. Dent Clin North Am 1989;33:733-791.
• LARSSON C, THOMSEN P, LAUSMAA J, RODAHL M, KASEMO B, ERICSON LE. Bone response to surface modified titanium implants : studies on electropolished implants with different oxide thicknesses and morphology. Biomaterials 1994;15:1062-1074.
• LAZARRA RJ, PORTER SS, TESTORI T, GALANTE J, ZETTERQVIST L. A prospective multicenter study evaluating loading of osseotite implants two months after placement : one year results. J Esthet Dentistry 1998;10:280-289.
• LEKHOLM U, ZARB GA. Patient selection and preparation. In : Brånemark PI, Zarb GA, Albrektsson T, eds. Tissue integrated prostheses. Chicago : Quintessence Publ Co, 1985:199-209.
• LINDHE J. Prospective clinical trials on implant therapy in the partially edentulous dentition using the Astratech dental implant system. In : 13 th European Conference for Biomaterials. Transactions of Workshops, Götebor : Thomson P, 1997:9.
• LUNDGREN D, LUNDGREN AK, SENNERBY L. The effect of mechanical intervention on jaw bone density. An experimental study in the rabbit. Clin Oral Impl Res 1995;6:54-59.
• MCCLUNG M, CLEMMESEN B, DAIFOTIS A, GILCHRIST NL, EISMAN J, WEINSTEIN RS et al. Alendronate prevents postmenopausal bone loss in women without osteoporosis. A double-blind, randomized, controlled trial. Ann Intern Med 1998;128:253-261.
• MEREDITH N, RASMUSSEN L, SENNERBY L, ALLEYNE D. Mapping implant stability by resonance frequency analysis. Med Sci Res 1996;24:191-193.
• NILSSON LP, GRANSTRÖM G, ALBREKTSSON T. The effect of hyperbaric oxygen treatment of bone regeneration. An experimental study in the rabbit using the bone harvest chamber (BHC). Int J Oral Maxillofac Implants 1987;3:43-48.
• NISHIGUCHI S, NAKAMURA T, KOBAYASHI M, KIM HM, MIYAJI, KOKUBO T. The effect of heat treatment on bone-bonding ability of alkali-treated titanium. Biomaterials 1999;20:491-500.
• ODA T, SAWAKI Y, UEDA M. Alveolar ridge augmentation by distraction osteogenesis using titanium implants : an experimental study. Int J Oral Maxillofac Surg 1999;28:151-156.
• OTTER MW, MCLEOD KJ, RUBIN CT. Effects of electromagnetic fields in experimental fracture repair. Clin Orthopaed Related Res 1998;355S:S90-S104.
• PAL GL, STEVENSON A, KLINEBERG IJ, PEARSON M, ALBREKTSSON T, JOHANSSON C. A volumetric study of guided bone regeneration around titanium implants in the New Zealand white rabbit. Aust Dent J 1998;43:73-80.
• QUIRYNEN M, NAERT I, VAN STEENBERGHE D, DUCHATEAU L, DARIUS P. Periodontal aspects of Brånemark and IMZ implants supporting overdentures. A comparative study. In : Laney W, Tolman D, eds. Tissue integration in oral, orthopaedic and maxillofacial reconstruction. Chicago : Quintessence, 1992:80-93.
• SKRIPITZ R, ASPENBERG P. Tensile bond between bone and titanium : a reappraisal of osseointegration. Acta Orthop Scand 1998;69:315-319.
• SUL YT, JOHANSSON C, ALBREKTSSON T. Bone response to anodised titanium implants. Soumis pour publication, 1999.
• SULLIVAN DY, SHERWOOD RL, MAI TN. Preliminary results of a multicenter study evaluating a chemically enhanced surface for machined commercially pure titanium implants. J Prosth Dentistry 1997;78:379-386.
• URBANI G, LOMBARDO G, SANTI E, CONCOLO U. Distraction osteogenesis to achieve mandibular vertical bone regeneration : a case report. Int J Periodont Rest Dent 1999;19:321-331.
• WENNERBERG A. On surface roughness and implant incorporation [PhD thesis]. Göteborg : Department of Biomaterials/Handicap Research, University of Göteborg, 1996.
• YAN WQ, NAKAMURA T, KOBAYASHI M, KIM HM, MIYAJI F, KOKUBO T. Bonding of chemically treated titanium implants to bone. J Biomed Mater Res 1997:37;267-275.
• YASUDA I. On the piezoelectric activity of bone. J Jap Orthop Surg 1954;28:267-275.
• ZELLIN G. Growth factors and bone regeneration. Implications of barrier membranes. Swedish Dent J 1998;129(suppl):1-65.