Indiana University-Purdue University Indianapolis (IUPUI) / The bisphosphonate etidronate, a drug commonly used to treat osteolytic bone disorders, produces a long lasting inhibition of bone resorption. Since continual bone remodeling appears crucial for the long-term success of endosseous implants, the effects of this drug on the bone surrounding implants were investigated. The specific objective was to quantify the static and dynamic histomorphometric properties of bone surrounding implants placed in 12 beagle dogs treated with this drug. The dogs were divided into three groups (4 dogs/group) based on the bisphosphonate treatment dose: 0, 0.5 and 5.0 mg/kg/day. Since remodeling is different at distinct sites around implants, we analyzed bone at different distances (<1, 1-2 and 2-3 mm from the implant) and in different regions (periosteal and endosteal calluses and intracortical bone). Factorial ANOVA with repeated measures was used to compare site and regional differences in the dose groups. Results show that etidronate treatment produced a decrease in remodeling activity in the treated groups. The high dose group had impaired bone formation and a complete inhibition of remodeling. Low dose produced the same trend, but was not statistically different from controls. The significant differences (p < 0.05) were shown by the high dose group compared to controls for Mineralizing Surface (MS/BS), Activation Frequency (AcF), Mineral Apposition Rate (MAR), Bone Formation Rate (BFR), Formation Period (FP), Mineralization Lag Time (MLT), Adjusted Apposition Rate (AjAr) and Bone Volume (BV/TV), while Osteoid Volume (OV/TV) and Osteoid Thickness (OTh) were higher (p < 0.05) in the high dose group. Since it has been suggested that a remodeling rate of 500 percent per year is achieved in the first millimeter around an implant in successful osseointegration, the area within the first millimeter, as expected, was more affected by all the parameters than further away. These results agree with earlier studies in which areas of high remodeling were shown to be more affected by bisphosphonate therapy than areas of low remodeling. The area closest to the implant showed significantly greater BV/TV, Void Volume (VV/TV), Osetoid Volume over Bone volume (OV/BV), Osteoid Surface (OS/BS), MS/BS, BFR, FP, AcF and MLT while OV/TV was significantly increased in the area most distant from the implant. It was found that etidronate interfered with normal bone mineralization, since there was a decrease in MLT and an accumulation of osteoid. If remodeling is high around implants so as to repair or prevent microdamage, then etidronate could impair this from happening, thereby resulting in eventual implant failure. Though these high doses are not ordinarily used for the clinical treatment of osteoporosis, a low dose might still be harmful if given long-term. These data confirm our hypothesis that etidronate affects bone resorption and mineralization around an implant, when given at the high dose. Two hypotheses were rejected, since in this study, the effect of etidronate was not dose-dependent. This study was supported by NIH 2PO1AG05793, Merck and CO., and Procter and Gamble Pharmaceuticals.

Indiana University-Purdue University Indianapolis (IUPUI) / It has been proposed that the accumulation of microdamage in bone of aging individuals may play a causative and synergistic role in increased fracture incidence. If microdamage production were somehow increased, or reparative remodeling was somehow decreased, the scales may tip towards pathologic fracture. It is known that bisphosphonates increase microdamage accumulation in ribs, lumbar vertebrae, and ilium. The specific aim of this study was to histomorphometrically quantify the microdamage effect of the bisphosphonates alendronate and risedronate therapy on alveolar bone surrounding the first mandibular molar in the dog to determine if this response differs from that in non-bisphosphonate treated dogs. Thirty-four dogs were randomly assigned in two test, and one control groups. Test groups received pharmacologically equivalent doses of either alendronate (11 dogs) or risedronate (11 dogs). The control group (12 dogs) received subcutaneous injections of saline solution. The mandibular right first molar was analyzed for this study. Histomorphometric measurements were made using a x150 Nikon Optiphot-2 fluorescence microscope equipped with brightfield sources (Nikon, Inc.) using the semi-automatic Bioqant digitizing system (R & M Biometrics). There was no significant differences in cortical bone area across treatment groups for any of the regions, nor were any expected. Overall, there was almost twice as much crotical bone found in the Middle (Combined) regions compared with the Coronal (Combined) regions. The precent cortical area was universally high across all treatment groups averaging in the mid-90% range. The Apical region averaged 96.05%, followed by the Coronal region with 95.04% and the Middle region with 93.80%. The number of labeled osteons per cortical area in the alendronate and risedronate groups both tended to be lower relative to the control group (0.92/mm2 and 0.93/mm2 vs. 1.26mm2, respectively), but were not significantly different. On average, the coronal regions had nearly three times the LOn/CtAr as the Middle and Apical regions (1.90/mm2 vs. 0.63/mm2 and 0.57/mm2 respectively). Only in one region was MAR statistically higher in the Coronal (1mm) region, relative to all other regions compared. The Middle region demonstrated a low MAR. The WTh was significantly higher in the risedronate and alendronate groups than that of the control group for the Coronal region. This illustrates that with respect to the bisphosphonates, there is more formation and less resorption. In one region of a significantly lower WTh for the alendronate group relative to the risedronate group was noted. This implies a more potent inhibition in the risedronate treated groups. The WTh for the entire Coronal was statistically lower than every Middle measurement, but was not different than observed in the Apical region. This would tend to signify that in the Coronal, the turnover rate is more of a rapid nature, and therefore the osteons are not as large, while in the Apical, there were so many missing values due to the low rate of turnover, the numbers are skewed to the low end. In the Coronal (Combined) region, the risedronate (108.79 days) group exhibiting a significantly higher FP than the alendronate (62.88 days) and the control (56.13 days) groups. This would imply an increased potency of risedronate over alendronate. Regionally, the FP was significantly lower in the Coronal, relative to Middle or Apical. This is consistent with a more rapid turnover in the Coronal regions observed earlier. The Acf for alendronate (6.41/mm2 per day) and risedronate (5.69/mm2 per day) both tended to be lower by approximately 40% when compared with the control group (10.11/mm2 per day). Overall, the Acf for the Coronal region was 14.15/mm2 per day vs. 2.98/mm2 per day for the Middle and 9.13/mm2 per day for the Apical regions. This shows a significantly increased amount of turnover events taking place not just in the Coronal region, but in the region immediately adjacent to the tooth in the Coronal region. In no region did bone formation differ significantly when treated with bisphosphonates. The Coronal (1mm) region was statistically greater than every region it was measured against, individual and combined. Based on this observation, the second hypothesis that within the first molar alveolar site, bisphosphonate therapy with alendronate, and risedronate would inhibit remodeling more in the coronal region than in the middle and apical region, is rejected. When measuring microdamage accumulation (CrDn), only in the Middle (1mm) region was a significant difference across treatment groups notes. There were no other statistical differences across groups for any other regions. This observation demonstrates that bisphosphonate treatment does not increase the accumulation of microcracks in the dentate alveolar bone. Therefore, the first hypothesis that within the dentate mandible, bisphosphonate therapy with alendronate and risedronate would increase microdamage accumulation around the first molar compound to control, is rejected. When CrDn was compared by region, significant differences were noted. As expected, the Coronal (1mm) region demonstrated a significantly increased CrDN compared with the Apical and Middle regions. Coupled with the information that the BFR is increased in the Coronal and Middle (1-3mm) regions would argue for a reparative function of remodeling in the Coronal and outer Middle regions, which is in response to microdamage accumulation. Significant differences were observed in the Middle (1mm) and Middle (Combined) regions, with the alendronate group demonstrating an increased CrSDn relative to control. There was no statistical difference across treatment groups for any of the regions studied. When compared by regions, the Coronal (1mm) was statistically higher than all regions it was measured against. The Middle regions demonstrated elevated CrSDn relative to the apical region, which displayed the lowest CrSDn values of all regions. One final measure of microdamage is mean crack length. There were no statistically significant differences across any groups for any regions. The only significant differences, when observed across regions, was in reference to the Middle (1mm) region, which was significantly larger than the Coronal (1mm), Coronal (Combined), and the Middle (1-3mm) region. Otherwise, there is no observable trend, and no significant difference between regions. In conclusion, this study found that there was no an increase in microdamage in the dentate mandible of the dogs with bisphosphonate therapy, thereby rejecting the first hypothesis. While there were isolated regions of remodeling inhibition, the hypothesis that bisphosphonate therapy would inhibit remodeling more in the coronal region than in the middle and apical region is rejected. Therefore, based on the findings of this study, we conclude that bisphosphonates do inhibit remodeling in the dentate alveolus generally, but inhibition is not localized to any particular region. Finally, the administration of bisphosphonates do not result in an increase in microdamage accumulation in the dentate alveolus of dogs.