Chemical structure of pyrophosphate and bisphosphonates
Daily commodities containing bisphosphonates and pyrophosphates
Crystal, metal, and other surfaces
Prevention of stone formation, corrosion, and pollution
Softener of water
Plasticizer in wool
Plastics and polymer industry
Cosmetics, photograph, toothpaste, hair shampoos, soap, disinfectant, dispersant
With regard to their pharmacokinetic and pharmacodynamic profile, pyrophosphates can only be administered intravenously and exhibit a poor pharmacological impact, which antagonizes their broad use. On the other hand, bisphosphonates feature superior modes of action and can also be applied locally or orally [22, 24, 25].
Besides the already known indications for bisphosphonates like osteoporosis and bone tumors, especially maxillofacial and dental application purposes have become a developing field with new indications for broader implementations of bisphosphonates [55, 87].
Perspectives of Bisphosphonates in Dentistry
Anticalculus and Anticaries Effects
Like pyrophosphates, various studies revealed that bisphosphonates are also capable of preventing dental calculus and caries . 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 . 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.
Dental Implant Coating
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 . Moon et al. interpreted this fact to generally enhanced alkaline phosphatase (ALP) and osteoclast inhibition rates . 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 .
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].
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 . Topical application of 1 % alendronate gel improved the overall gingival index as well as probing depth and clinical attachment level .
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 . 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 . 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 .
Bisphosphonates and Periimplantitis
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 .
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 . 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 .
Potential Applications in Other Diseases of the Maxillofacial Region
Bisphosphonates can also be applied for other diseases and indications of the maxillofacial area. Numerous studies revealed beneficial effects of bisphosphonates in the treatment of Paget’s disease, osteogenesis imperfecta, osteoradionecrosis, giant cell granuloma, and fibrous dysplasia [10, 16, 18, 19, 38, 48, 51, 73, 78, 112]. In diffuse sclerosing osteomyelitis and SAPHO syndrome, bisphosphonates successfully reduced pain, bone resorption, and bone turnover [7, 36, 49, 52, 88, 106, 110].
Against all presumptions, the vast majority of studies did not reveal any hard or soft tissue necrosis after systemic or topical application of various bisphosphonates. Besides even more application possibilities in the future, the great advantages of bisphosphonates influencing bone resorption should not be forgotten in oral and maxillofacial surgery and other medical specialties.
Additional Applications for Bisphosphonates
Intoxications with uranyl nitrate are another major field of experimental bisphosphonate application. Uranyl nitrate is, among other applications, important for the nuclear processing of enriched uranium. In a study with rats, Ubios and Bozal et al. systematically applied ethane-1-hydroxy-1,1-bisphosphonate after uranyl intoxication [11, 97]. Thereby, bone growth, bone and cartilage thickness, and metaphyseal activity were not different to control groups. In this case, bisphosphonates act as uranyl chelating agents [27–29, 37, 53, 54, 96, 108].
Overall, bisphosphonates as well as pyrophosphates can be used in a broad and still expanding range of indications in maxillofacial surgery, dentistry, and other medical specialties.
Besides the prevalent application in osteoporosis and bone metastasis, the substances are already regularly used in daily products like toothpastes and chemical reagents for anticalculus, anti-calcification, and cleaning purposes. In various studies, bisphosphonates were applied for periodontitis, periimplantitis, socket preservations, and uranyl intoxications and in coated implants. In these studies, bisphosphonates successfully antagonize bone resorption and even stimulated bone growth. In radiology, bisphosphonates and pyrophosphates can be used with radioactive nuclides as bone markers.
However, additional research has to be done regarding advantages and disadvantages, side effects, pharmacokinetics, and application profiles of bisphosphonates, before evidence-based recommendations for new indications can be given.
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