Like pyrophosphates, various studies revealed that bisphosphonates are also capable of preventing dental calculus and caries [100]. This also applies to TRK-530, a new bisphosphonate, which Sikder and Shinoda et al. administered topically for anticalculus purposes in rats [83, 86].

Considering clinical usage, Koch et al. were able to reveal a significant anticaries profile by the use of bisphosphonates in a 3-year controlled clinical trial with more than 1,000 patients [45]. Thereby, toothpastes with 250 or 1,000 ppm fluoride were either applied with 1-hydroxyethylidene-1.1-bisphosphonate (HEBP), azacycloheptylidene-2.2-bisphosphonate (AHBP) or as control group in more than 1,100 children at 11 and 12 years of age. After 3 years of unsupervised brushing, AHBP exhibited significant better results compared to single fluoride treatments.

Based on pharmacological perceptions, bisphosphonates can increase bone mineralization.

In a study with beagle dogs, Yoshinari et al. showed that the coating of titanium implants with calcium phosphate followed by pamidronate immobilization for 24 h at 37 ° C results in higher osseointegration and bone formation rates than in the uncoated control groups [111]. Moon et al. interpreted this fact to generally enhanced alkaline phosphatase (ALP) and osteoclast inhibition rates [60]. In several more studies, Stadelmann et al. could reveal higher bone densities, bone thickness, and bone mineralization by the application of zoledronate in orthopedic applications [89–91, 94]. In dentistry, subsequent patient studies showed generally higher stability quotient rates for bisphosphonate-coated dental titanium implants [2, 3].

Teeth loosening, loss of teeth, and teeth extraction often result in elevated bone resorption processes, which makes bone augmentation prior to implant treatment mandatory.

In animal experiments, intravenous or subcutaneous application of zoledronate or alendronate results in diminished bone resorption after teeth extraction [6, 31, 42]. Jee et al. detected significant differences in vertical and horizontal alveolar crests after subcutaneous application of alendronate (1 mg/kg/day), whereas Abtahi and Kuroshima et al. only accomplished satisfactory results by using soft tissue coverage therapies characterized by a mucoperiosteal flap or parathyroid hormone usage [1, 40, 46]. Vertical and horizontal higher alveolar crests were also detected by Graziani et al. in a randomized clinical trial [35].

Other animal studies showed that prolonged systemic applications of zoledronate can induce BRONJ, inhibit angiogenesis, and lead to bacterial colonization, whereas these effects could not be proven for alendronate and etidronate [5, 44, 109]. However, pharmacological actions and side effects of bisphosphonates have to be interpreted with special regard to the dose and frequency of application (cumulative dose) [8, 64].

When reimplanting teeth after accidents or surgical procedures demanding teeth extraction, topical application of alendronate, zoledronate, and etidronate can be used to prevent inflammatory resorptive processes [17, 61, 81].

Periodontitis must be seen as one of the major risk factors for the development of teeth loosening, loss of teeth, and periimplantitis after implant treatment. Besides systematically planned mechanical interventions and control appointments, medications for plaque prevention and removal are necessary and highly questioned.

Various animal studies showed positive effects of alendronate, clodronate, etidronate, risedronate, tiludronate, TRK-530, and zoledronate on the inhibition of bone resorption, bone mineralization, and bone formation after experimentally induced periodontitis [4, 12, 20, 30, 33, 58, 65, 71, 72, 75, 83, 84, 102, 107]. In an ovariectomized rat model that simulated postmenopausal estrogen deficiency, Said, Xiong, and Duarte et al. were not able to completely restore bone balance by the application of bisphosphonates [20, 75, 107]. For the overall suppression of osteoclasts, Goes and Price et al. were able, among others, to show additive suppressive effects for alendronate and statins [30, 34, 70, 102]. In two studies, Buduneli et al. revealed additive antiresorptive effects by using alendronate and doxycycline [13, 14]. Furthermore, Buduneli, as well as Menezes et al., demonstrated anti-inflammatory and antibacterial effects of alendronate [13, 33, 56]. Alendronate was also capable to lower bone specific alkaline phosphatase and alveolar bone loss significantly [33]. Topical application of 1 % alendronate gel improved the overall gingival index as well as probing depth and clinical attachment level [71].

Shoji and Aguirre et al. detected dose-dependent actions of risedronate and zoledronate on osteoclastogenesis and therefore bone resorption [4, 84]. Thereby, higher doses of subcutaneous risedronate enhance bone-protecting effects, whereas 80 μg/kg zoledronate results in further periodontal bone defects. Within all mentioned animal studies, the route of drug administration (oral, intravenous, subcutaneous, subperiosteal) does not seem to determine positive or negative effects as well as side effects of bisphosphonate application. However, some bisphosphonates, as shown by Cetinkaya and Kim et al., seem to have negative effects on bone microcirculation [15, 42]. Thus, disturbances in bone circulation were connected to the occurrence of BRONJ [22, 23, 64].

In several clinical controlled study trials with at least 52 periodontal defects and a follow-up between 6 and 12 months, Pradeep and Sharma et al. revealed positive effects of 1 % alendronate gel on probing depth, bleeding index, clinical attachment level, and overall bone deposition [68, 69, 79, 80]. These results were also detected by Lane et al. in a study with 27 patients [47]. In two other studies, radiologic evidence of the positive effects of alendronate was shown by El-Shinnawi and Veena et al. [21, 99]. Besides alendronate, also etidronate has positive effects on bone resorption over 5 years as shown by Takaishi et al. in a study with four women [92]. While Rocha et al. revealed positive effects of alendronate on periodontal bone resorption and cementoenamel junction, Jeffcoat et al. only detected an overall positive impact of alendronate in the prevention and development of manifesting periodontitis [41, 74].

With regard to drug administration developments, Samdancioglu et al. developed microspheres with alendronate on chitosan and poly(lactide-co-glycolide) acid (PLGA) basis that showed slower and faster drug release kinetics [76].

Overall, positive effects of bisphosphonates on bone resorption, bone formation, and periodontal processes were shown in the enumerated studies above.

Meraw and Shibutani et al. detected macroscopic and radiologic bone formation and less bone resorption by topical and intramuscular application of alendronate and pamidronate in a dog model [57, 82]. Thereby, Shibutani et al. did not detect significant differences of the serum markers osteocalcin and deoxypyridinoline [82].

As a prognostic marker in peri-implant inflammatory processes, detection of matrix metalloproteinases (MMPs) in the peri-implant sulcus fluid and periodontal ligament cells plays a crucial role [43]. In vitro and in vivo studies of Ozdemir, Nakaya, and Teronen et al. showed the inhibition of MMP-1, MMP-3, MMP-8 and MMP-9 by clodronate and tiludronate [62, 66, 93]. Despite these significant results, RNA levels were not affected [62].