The Effects of Etidronate on Healing of Implant-Supporting Bone

Abstract

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.