There is controversy regarding whether locally delivered alendronate enhances osseointegration. The aim of this systematic review was to assess the role of local alendronate delivery (topical, or as a coating on implant surfaces) in the osseointegration of implants. The focused question was, “Does the local delivery of alendronate affect osseointegration around implants?”. To address this question, indexed databases were searched, without time or language restriction, up to and including January 2017. Various combinations of the following key words were used: “alendronate”, “bisphosphonates”, “osseointegration”, and “topical administration”. letters to the editor, historic reviews, commentaries, case series, and case reports were excluded. In total, 18 experimental studies were included: alendronate-coated implants were used in 13 of these studies and local delivery in five studies. The results of 11 of the studies showed that alendronate coating increased new bone formation, the bone volume fraction, or bone-to-implant contact (BIC) and biomechanical properties. Results from two studies in which alendronate was administered topically indicated impaired BIC and/or biomechanical fixation around implants. On experimental grounds, local alendronate delivery seems to promote osseointegration. From a clinical perspective, the results in animal models support phase 1 studies in healthy humans (without co-morbidities other than edentulism).
Dental implants are a predictable and successful treatment strategy for the replacement of missing teeth in partially and totally edentulous patients . Local factors that may influence the overall success and survival of implants include primary stability at the time of implant placement, the formation of a direct bone to implant contact (BIC) , and the quantity and/or quality of the residual bone . Substantial efforts have been made to accelerate healing around implants. In this regard, adjunct therapies such as the placement of osteogenic coatings on implant surfaces have been proposed in an attempt to enhance BIC and new bone formation (NBF) around implant surfaces. Modifications in implant surface chemistry have also been reported to enhance the proliferation and differentiation of osteoprogenitor cells and to increase alkaline phosphatase (ALP) activity and the expression of osteogenic genes (which helps to enhance BIC and promote osseointegration) . Such implant surface modifications have been shown to improve osseointegration in systemically healthy as well as immunosuppressed patients, such as those with osteoporosis or poorly controlled diabetes mellitus .
Alendronate, which belongs to the bisphosphonate class of drugs, is an anti-catabolic agent that inhibits bone resorption and is therefore widely used for the treatment of skeletal disorders such as osteoporosis, bone metastases, and Paget’s disease . It has been suggested that alendronate influences the three phases of bone remodeling, which are microinjury, osteoclastogenesis, and osteogenesis, thereby stimulating NBF by enhancing the proliferation and differentiation of osteoblasts and inhibiting osteoclast function . In addition to the bone antiresorptive effect, in vitro studies have shown that the administration of alendronate modulates osteoprotegerin (OPG) production by fibroblasts , and decreases phosphatase activity and the expression of osteoclast markers .
According to Hazzaa et al., the systemic administration of alendronate significantly improves osseointegration around titanium implants placed in animals with induced osteoporosis . A recent systematic review also concluded that systemic bisphosphonate supplementation promotes implant osseointegration in animals with induced osteoporotic conditions . However, in a clinical scenario, the potential risk of bisphosphonates related to osteonecrosis of the jaw cannot be disregarded . Other complications related to the systemic administration of alendronate such as nausea, epigastric pain, vomiting, and dyspepsia, could be avoided by local alendronate release directly from the implant to the surrounding bone .
Conflicting results have been reported regarding whether local alendronate delivery (topical, or as a coating on implant surfaces) enhances osseointegration and NBF around implants . Therefore, the aim of this systematic review was to assess the role of local alendronate delivery (topical, or as a coating on implant surfaces) in the osseointegration of implants.
Materials and methods
Based on the PRISMA guidelines (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) , a specific question was constructed according to the PICO principle (participants, interventions, control, outcomes). The focused question was, “Does the local delivery of alendronate affect osseointegration around implants?” Participants (P) had to have undergone implant treatment. The intervention of interest (I) was the effect of local delivery of alendronate on osseointegration. The control intervention (C) was implant placement without adjunctive local alendronate administration. Outcome measures (O) included BIC, NBF, bone volume/tissue volume (BV/TV), and/or biomechanical fixation around implants with and without alendronate local delivery.
The eligibility criteria were as follows: (1) original studies, (2) randomized controlled trials, (3) prospective and retrospective studies, (4) cohort studies, (5) experimental studies (animal models), (6) studies with a control group, (7) intervention: effect of local alendronate (topical or coating) on osseointegration. Letters to the editor, historic reviews, commentaries, in vitro studies, case series, case reports, and studies where alendronate was delivered systemically were excluded. Articles available online in electronic form ahead of print were considered eligible for inclusion.
Literature search protocol
In order to identify studies relevant to the focused question, an electronic search without time or language restriction was conducted in January 2017 in the PubMed (National Library of Medicine, Washington, DC, USA), Google Scholar, Scopus, Embase, MEDLINE (OVID), and Web of Knowledge databases. The following medical subject headings (MeSH) were used: (1) alendronate, (2) bisphosphonates, (3) osseointegration, (4) topical administration, and the combinations 1 or 2 and 3; 1 or 2 and 4; and 1, 2, and 3 or 4. Other relevant non-MeSH words were used in the search process to identify articles discussing osseointegration parameters and/or alendronate administration. These included: “local delivery”, “local administration”, “coating”, “coated”, “bone-to-implant contact”, and “new bone formation”.
Titles and abstracts of studies identified using the protocol described above were screened by two authors (SVK and VRM) and checked for agreement to exclude irrelevant articles and duplicates. The full texts of studies judged by title and abstract to be relevant were read and evaluated independently for the stated eligibility criteria. Reference lists of potentially relevant original and review articles were hand-searched to identify studies that had remained unidentified in the previous step. Once again, the articles were checked for disagreement via discussion among the authors. Kappa scores (Cohen’s kappa coefficient) were used to determine the level of agreement between the two reviewers (κ = 0.90) . Data were extracted using standardized evaluation forms. Authors of the studies included were contacted via e-mail in the case of missing data or for additional information regarding their studies if required. Fig. 1 summarizes the literature search strategy according to the PRISMA guidelines.
A quality assessment of the studies that were included was performed in an attempt to increase the strength of the systematic review. The studies that were included underwent a quality assessment with the Critical Appraisal Skills Program (CASP) cohort study checklist . The CASP tool uses a systematic approach based on 12 specific criteria, which are (1) study issue is clearly focused (effect of local alendronate delivery on osseointegration); (2) cohort is recruited in an acceptable way; (3) exposure (alendronate delivery) is accurately measured; (4) outcome (osseointegration and/or NBF around implants) is accurately measured; (5) confounding factors are addressed; (6) follow-up is long and complete; (7) results are clear; (8) results are precise; (9) results are credible; (10) results can be applied to the local population; (11) results fit with available evidence; and (12) there are important clinical implications. Each criterion was given a response of either ‘yes’, ‘no’, or ‘cannot tell’. Each study could have a maximum score of 12. CASP scores were used to grade the methodological quality of each study assessed in the present systematic review.
A meta-analysis was performed for four studies in which the effect of local alendronate on BIC was assessed . The heterogeneity in the treatment difference between control and treatment groups across the studies was assessed using the Q statistic. The random-effects meta-analysis model was used to combine the results from the different studies . The data analysis was conducted using OpenMetaAnalyst version 6 software (Center for Evidence Synthesis, Brown School of Public Health, Providence, RI, USA).
Three hundred and sixty-five potential articles were initially identified. In the first step, 303 publications, which were either duplicates or did not answer the focused question, were excluded. In the next step, 44 further articles were excluded ( Supplementary Material ). In total, 18 studies were included and processed for data extraction .
General characteristics of the studies included
All studies were prospective and performed in animals. Three studies were performed in male rats , three in male rabbits , and one in female rabbits ; the sex of the rabbits was unclear in one study . Two studies were performed in sheep and the sex was not reported . Four studies were performed in female dogs , two in male dogs , and two in female and male dogs . In all studies, alendronate was delivered locally. Alendronate-coated implants were used in 13 studies , and intra-cavity injections of alendronate were administered in four studies . A morselized allograft soaked in alendronate solution was used in one study . The follow-up period in all studies ranged between 2 and 24 weeks.
Topical delivery of alendronate
An alendronate solution (2 mg alendronate per 1 ml saline) was injected into the bone cavity 60 s prior to implant placement in three studies . Sodium alendronate gel (10 mg/g) was injected into the surgical alveolus before implant placement in one study . Jakobsen et al. investigated the effects of morselized allograft soaked with 5 ml alendronate solution packed in a 2.5-mm gap around titanium implants placed in the humerus in a canine model .
Implants with alendronate-coated surfaces
In 13 studies, alendronate was incorporated as a coating on the implant surfaces, with a concentration ranging between 0.02 mg and 1 mg ( Table 1 ) . The alendronate was incorporated into hydroxyapatite-coated implants in five studies and into calcium phosphate (CaP)-coated implants in two studies .
|Authors (Study design)||Study subjects (Mean age)||Study groups||Bisphosphonate doses and concentrations||Follow-up, weeks||Analysis methods||Outcomes|
|Implants with an alendronate-coated surface|
|Bobyn et al.||10 male and female dogs (NA)||Group 1: uncoated Ti||ALE: 0.2 mg||12||Micro-CT||Groups 2 and 3 presented significantly higher NBF compared to group 1|
|(Experimental)||Group 2: ALE 0.2 mg||ALE: 1 mg||Histology|
|Group 3: ALE 1 mg||BEM|
|Ferguson et al.||Sheep
|Group 1: uncoated Ti||Group 5: ALE 10 μg/cm 2||2, 4, and 8||Removal torque||Groups 1, 3, 5, and 6 presented significantly higher removal torque compared to groups 2 and 4|
|(Experimental)||Group 2: uncoated Zr||Micro-CT||Outcomes in BV/TV were comparable among the groups|
|Group 3: Ti + CaP|
|Group 4: Ti + CaP + APC|
|Group 5: Ti + ALE|
|Group 6: Ti + collagen + CS|
|Garbuz et al.||18 female rabbits||Group 1: uncoated Ta||Group 3: ALE 10 −4 M||4||Fluorescence||Group 3 presented higher NBF, gap filling, and bone ingrowth compared to groups 1 and 2|
|(Experimental)||(NA)||Group 2: Ta + CaP||HIST|
|Group 3: Ta + CaP + ALE||BEM–FM|
|Harmankaya et al.||32 male rats
|Group 1: mesoporous TiO 2||Group 2: ALE 0.8 mg/ml||4||Removal torque||Group 2 presented significantly higher BA compared to groups 1, 2 and 3|
|(Experimental)||Group 2: mesoporous TiO 2 + ALE||Histology||No significant difference in BIC among the groups|
|Group 3: mesoporous TiO 2 + RLX||HIST||Group 2 presented increased removal torque compared to groups 1 and 4|
|Group 4: hydrophobic mesoporous TiO 2||qPCR|
|Karlsson et al.||Male rats||Group 1: mesoporous TiO 2 + ALE||Group 1: ALE 0.8 mg/ml, 170 ng per implant||4||Micro-Raman spectroscopy||Group 1 presented higher BMD and NBF compared to group 2|
|(Experimental)||(NA)||Group 2: mesoporous TiO 2||BEM–SEM|
|Kim et al.||12 rabbits||Group 1: uncoated Ti||Groups 2 and 4: ALE 10 −6 M||8||Micro-CT||Group 4 presented higher BA and NBF compared with groups 1, 2, and 3|
|(Experimental)||(3 months old)||Group 2: Ti + ALE||Histology|
|Group 3: Ti + UV|
|Group 4: Ti + UV + ALE|
|Langhoff et al.||15 sheep||Group 1: uncoated Ti||Group 5: ALE 10 μg/cm 2||2, 4, and 8||Fluorescence||No significant difference in BIC among the groups|
|(Experimental)||(24–36 months old)||Group 2: Ti + CaP coated||Radiographs|
|Group 3: Ti + CaP + APC||Histology|
|Group 4: Ti + collagen + CS|
|Group 5: Ti + ALE|
|Group 6: uncoated Zr|
|Linderback et al.||40 male rats||Group 1: uncoated SS||Group 4: ALE 0.1 mg/ml||4||Pull-out test||Group 4 presented significantly higher strength of fixation compared to groups 1, 2, and 3|
|(Experimental)||(NA)||Group 2: SS + TiO 2 + CaP|
|Group 3: SS + TiO 2 + CaP + systemic ALE|
|Group 4: SS + TiO 2 + CaP + local ALE|
|Meraw et al.
|6 male dogs
|Group 1: HA + ALE||Group 1: ALE 0.1 mmol||4||Fluorescence||Group 3 presented higher BIC compared to groups 1, 2, and 4|
|Group 2: uncoated Ti + ALE||Group 2: ALE 2.8 μg||HIST||Group 2 presented higher BIC compared to group 4|
|Group 3: HA||Histology||Groups 1 and 2 presented significantly higher NBF compared to groups 3 and 4|
|Group 4: uncoated Ti|
|Meraw et al.||6 male dogs||Group 1: HA + ALE||Group 1: ALE 0.1 mmol||4||Histology||Group 2 presented significantly higher BA compared to groups 1, 3, and 4|
|(Experimental)||(NA)||Group 2: uncoated Ti + ALE||Group 2: ALE 2.8 μg||HIST|
|Group 3: HA|
|Group 4: uncoated Ti|
|Niu et al.||36 male rabbits||Group 1: HA + IPP||Group 2: ALE 100 μg||12 and 24||HIST||Group 2 presented significantly higher BIC, NBF, BMD, and implant stability compared to groups 1 and 3 after 24 weeks|
|(Experimental)||(NA)||Group 2: HA + IPP + ALE||Group 3: RIS 50 μg||Push-out test||Groups 2 and 3 presented significantly higher BV/TV compared to group 1|
|Group 3: HA + IPP + RIS||ELISA|
|Niu et al.||30 male rabbits||Group 1: HA||Group 3: 100 μg ALE||12||HIST||Group 3 presented higher BV/TV, MAR, BIC, NBF, and implant stability compared to groups 1 and 2|
|(Experimental)||(NA)||Group 2: HA + IPP||Histology|
|Group 3: HA + IPP + ALE||Micro-CT|
|Pura et al.||8 male dogs and six female dogs||Group 1: uncoated Ti||ALE||12||Histology||Groups 4 and 5 presented higher bone ingrowth compared to groups 1, 2 and 3|
|(Experimental)||(3–9 years old)||Group 2: HA||Group 3: 0.02 mg/cm 2||BEM–SEM||Group 4 presented higher bone apposition compared to groups 1, 2, 3, and 5|
|Group 3: HA + ALE 0.02||Group 4: 0.06 mg/cm 2|
|Group 4: HA + ALE 0.06||Group 5: 0.18 mg/cm 2|
|Group 5: HA + ALE 0.18|
|Topical delivery of bisphosphonates|
|Guimaraes et al.||10 male rabbits||Group 1: uncoated Ti||Group 2: 1 ml ALE gel (10 mg/g), intra-cavity injection||4||Removal torque||Group 2 presented significantly lower removal torque values, BIC, and NBF compared to group 1|
|(Experimental)||(NA)||Group 2: uncoated Ti + ALE gel||Histology|
|Jakobsen et al.||10 female dogs||Group 1: cancellous allograft soaked with saline||Group 2: 5 ml ALE solution (2 mg ALE × 1 ml saline); soaked morselized allograft||4 and 12||HIST||Group 2 presented significantly decreased biomechanical fixation, BIC, and NBF compared to group 1|
|(Experimental)||(NA)||Group 2: cancellous allograft soaked with ALE||Push-out test|
|Jakobsen et al.||10 female dogs||Group 1: saline||Group 2: 5 ml ALE solution (2 mg ALE × 1 ml saline); intra-cavity injection (60 s)||12||Bacterial culture||Group 2 presented significantly higher biomechanical fixation, BIC, and BVF compared to group 1.|
|(Experimental)||(NA)||Group 2: ALE||HIST|
|Jakobsen et al.||10 Female dogs||Group 1: saline||Group 2:||12||Push-out test||Group 2 presented significantly higher biomechanical fixation, and BVF compared to group 1|
|(Experimental)||(NA)||Group 2: ALE||5 ml ALE solution (2 mg ALE x 1 ml saline)||HIST||No significant difference in BIC between groups 1 and 2|
|Intra cavity injection (60 seconds)|
|Jakobsen et al.||8 female dogs||Group 1: saline||Group 2: 15 ml ALE solution (1 mg ALE × 1 ml saline); intra-cavity injection (60 s)||4||Push-out test||Group 2 presented significantly higher BIC and BA compared to group 1|
|(Experimental)||(11.5 months old)||Group 2: ALE||HIST||No significant difference in strength of fixation between groups 1 and 2|