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) / Bisphosphonates, drugs which inhibit bone resorption and remodeling, are currently prescribed for the treatment of osteoporosis. Previous research suggests that decreased bone turnover may lead to accumulation of microdamage, possibly increasing the risk for fracture in some sites. The effects of bisphosphonate therapy on the mandibular condyle have not been quantitatively studied. The purpose of the proposed study was to histomorphometrically quantify the effects of etidronate (a bisphosphonate) on trabecular bone sites of the dog mandibular condyle and to compare this to another trabecular bone site (vertebrae) to determine whether the two sites were affected differently. Eleven mature female dogs were treated with high- (5 mg/kg/d) and low- (0.5 mg/kg/d) dose etidronate therapy for seven months. Fluorochrome labels were used to mark sites of bone mineralization for the calculation of static and dynamic histomorphometric parameters. High-dose therapy resulted in a complete inhibition of remodeling, as shown by the reduction of mineral apposition rate (MAR), bone formation rate (BFR), and mineralizing surface (MS/BS) to zero. Low-dose therapy also decreased BFR and MS/BS. Osteoid accumulation was only significant in the high-dose therapy group, but there was no evidence of osteomalacia (osteoid volume < 5%). Etidronate treatment had no significant effect on bone volume, trabecular number, trabecular thickness, or trabecular separation. Vertebral trabeculae ranged from 5.5 to 9.5 times greater in number than mandibular trabeculae, but were 45 to 60 percent thinner and closer together. The interaction between dosage and site was insignificant for all parameters studied. Further investigation is needed to determine whether these effects will prove to be harmful to the mandibular condyle, especially over a long period of time.

Osteoporosis is a significant public health problem in the U.S. It not only affects the physical well-being of the older women but also creates a substantial financial burden for the health care system. The mainstay of osteoporosis medications is bisphosphonate treatment of which alendronate and risedronate are the most commonly prescribed in clinical practice. However, there have been no head-to-head randomized controlled trials (RCTs) evaluating the effects of these two bisphosphonates on fracture outcomes. In the absence of RCTs, observational studies are necessary to provide alternative evidence on the comparative effectiveness between alendronate and risedronate on fracture outcomes. However, existing observational studies have provided inconclusive results partially due to residual confounding from unobserved variables such as patients’ health status or behavior. IV analysis may be one method to address unmeasured confounding bias in observational studies. While it has not been applied in bisphosphonate research, it has been used in research on a variety of other prescription medications. In this dissertation, we applied the IV approach with an IV, date of generic alendronate availability, to evaluate the comparative effectiveness between alendronate and risedronate using observational data. This dissertation improved current research in several ways. First, we extended the IV approach to research on bisphosphonates. Second, compared with the current observational studies on bisphosphonates, this dissertation may more accurately estimate the relative effects between alendronate and risedronate because IV analysis is not subject to unmeasured confounding bias. Third, the study results extended the current evidence of the comparative effectiveness between the two most commonly prescribed bisphosphonates. Finally, we proposed and provided empirical evidence of a new IV that might be used for future prescription drug research. The finding of this dissertation can be summarized from three aspects. First, we found that the evidence supported the validity of the date of generic availability as an IV in the study of bisphosphonates. Second, applying IV approach to study the comparative effectiveness of alendronate and risedronate, we found that alendronate and risedronate were comparable to reduce the risk of 12-month non-vertebral fractures in older women. Since generic alendronate is availability on the market while generic risedronate is not, promoting the use of alendronate may help reduce the healthcare cost and not sacrifice the clinical effectiveness. Finally, by comparing the proposed IV with a popular IV-physician preference, we found that both the calendar time IV based on the date of generic availability and the physician preference appeared to be valid. It might be practically easier to use the calendar time IV than the physician preference IV.