COMPUTATIONAL MODEL OF ALENDRONATE EFFECTS ON CANINE RIB REMODELING AND MICRODAMAGE
Bisphosphonates are a class of drugs used to prevent and treat bone diseases by inhibiting the resorption of bone by osteoclasts and suppressing bone remodeling. Osteoporosis is a bone disease that develops when bone resorption exceeds bone formation which results in an increase in bone porosity and fracture risk. The risk for fractures can be reduced by increasing bone mass. Alendronate is type of bisphosphonate that is approved by the Food and Drug Administration (FDA) to treat postmenopausal
... osteoporosis by suppressing basic multicellular unit (BMU) remodeling and increasing bone mass. The long term effects of bisphosphonates are still unclear due to the difficulty in obtaining long term data; therefore, developing a mathematical model based on data and relationships from short term studies can be a useful method in predicting the effects of the drug. The purpose of this study was to develop a computer model that could simulate the long term effects of alendronate treatment on canine rib remodeling, bone volume, and microdamage by matching 1 and 3 year experimental data results. The experimental effects of alendronate (ALN) were studied at the Indiana University School of Medicine. In two separate experiments, skeletally mature female beagles were subjected to 1 and 3 year treatments of saline vehicle (CON), or one of two doses of ALN (ALN0.2 or ALN1.0 mg/kg/day). The lower dose (ALN0.2) corresponds to the clinical dosage used v to treat postmenopausal osteoporosis and the higher dose (ALN1.0) is the dose used to treat Paget's disease. Bone volume fraction (BV/TV), damage, and remodeling activation frequency (Ac.f) of the rib were quantified using standard histomorphometric techniques. The mathematical model was developed by modifying a previous mathematical algorithm for trabecular bone remodeling, to create an equilibrium for cortical bone remodeling that matched the experimental control data from 1 year studies. Using the equilibrium conditions as a baseline model, ALN was modeled by suppressing activation frequency and reducing the resorption area. The changes in BV/TV, damage accumulation, and Ac.f were followed for 3 years and compared to the experimental results. The results for BV/TV, Ac.f, and damage for the 1 year model and the results for BV/TV and damage for the 3 year model were consistent with experimental studies. BV/TV results for both doses showed increases from 1 to 3 years with alendronate treatment. Ac.f results for both treatment doses at 1 year and ALN1.0 at 3 years were also within range of the experimental data; however, ALN0.2 for 3 years was not consistent with the experimental results. While the predicted Ac.f for ALN0.2 does show an initial decrease, it is not nearly as extreme as the results from the experimental data and the data remains fairly constant between 1 and 3 years, which is in contrast to the experimental results. The model also predicts damage accumulation is greatest early during bisphosphonate treatment, due to the initial suppression of bone resorption. This increase in microdamage accumulation was previously thought to impair the mechanical properties of bone; however, recent experimental studies show that while the initial increase in microdamage may contribute to alterations in bone properties at 1 year of vi treatment, other factors appear to contribute to their reduction long term. The simulation results are consistent with the experimental data, which suggest that damage increases for up to 1 year of treatment and then levels off thereafter. The results of the simulation suggest that since bisphosphonates do not cause further increases in microdamage accumulation after 1 year of treatment, ALN may not lead to increased bone fragility associated with microdamage long term and rather, may decrease fracture risk. vii ACKNOWLEDGMENTS I would like to thank all the people who have assisted me during my master study. I would especially like to show my appreciation to my advisor, Dr. Scott Hazelwood, for his guidance and patience during my research. Thank you for giving me the opportunity to work on this project.