Long Term Effects of Bisphosphonate Therapy on Bone

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DESCRIPTION (provided by applicant): The proposed research concerns bisphosphonate treatment of postmenopausal and other osteoporoses. In osteoporotic individuals, bones become fragile because Basic Multicellular Unit (BMU) remodeling is increased and the amount of bone replaced within each BMU falls short of that removed. Bisphosphonates help correct this problem by reducing BMU activation and the amount of bone removed by each BMU, without altering the amount of bone replaced. However, studies by Prof. David Burr at Indiana University have shown that treatment with bisphosphonates for 1 year interferes with damage removal to the point that microdamage accumulates and fracture resistance begins to decline. This work is currently being pursued by a set of 3 year experiments in Prof. Burr's laboratory. Our own laboratory has a history of research focused on the relationships between bone structure, fatigue resistance, and remodeling. Included in this work have been computer simulations of these relationships and, recently, bisphosphonate effects. These models predict the damage accumulation seen in the 1 year canine studies, but they also predict that damage accumulation will subsequently be reversed if, as current data suggest, the drug results in a positive BMU-level bone balance. Thus, we hypothesize that while initial responses to bisphosphonate treatment are primarily due to reduced remodeling and include increased microdamage, subsequent skeletal responses arising from a positive BMU-level bone balance will erase the excess microdamage burden. We propose to test this hypothesis by pursuing 2 specific aims: 1. Adapt our computational models for remodeling in response to bisphosphonate treatment to trabecular and cortical regions of the canine skeleton and use data from a 1-3 year alendronate study to determine whether microdamage accumulation slows as treatment progresses. 2. Analyze microdamage removal by BMU remodeling in bone from control and alendronate treated dogs to determine if damage removal is enhanced by osteonal "steering" toward damage.