Dr. Mitchell Schaffler is evaluating whether drugs with the potential to maintain bone mass in space may paradoxically compromise bone’s mechanical quality and lead to increased fracture risk. The study will provide an increased understanding of the cellular mechanisms involved in maintaining bone mass and bone quality and may point to the need for two separate countermeasures addressing different cellular mechanisms.
Overview
Resorption Suppression and Bone Health in Disuse
Principal Investigator:
Mitchell B. Schaffler, Ph.D.
Organization:
Mount Sinai School of Medicine
Technical Summary
Osteoporosis in higher mammals due to loss of normal mechanical loading results from elevated osteoclastic resorption. Thus, targeting osteoclasts to prevent bone loss seems an obvious countermeasure strategy. To that end, during the last two years of our NSBRI research, we examined whether a clinical bisphosphonate prevented bone loss in dogs subjected to long-duration single-limb immobilization.
We are testing the hypotheses that 1) long-term suppression of bone remodeling in disuse will successfully maintain bone mass, microarchitecture, stiffness and strength, but will result in compromised fracture resistance properties; and 2) decreased mechanical usage in the presence of an antiresorptive agent results in loss of osteocyte integrity and accumulation of bone with impaired viability. Bone health is assessed from conservation of bone mass, microarchitecture, tissue mechanical properties and from in situ assessments of osteocyte viability.
We are testing the hypotheses that 1) long-term suppression of bone remodeling in disuse will successfully maintain bone mass, microarchitecture, stiffness and strength, but will result in compromised fracture resistance properties; and 2) decreased mechanical usage in the presence of an antiresorptive agent results in loss of osteocyte integrity and accumulation of bone with impaired viability. Bone health is assessed from conservation of bone mass, microarchitecture, tissue mechanical properties and from in situ assessments of osteocyte viability.
To date, we have completed the in vivo studies, as well as bone density and histomorphometric analyses. Our studies reveal some important and surprising results. In particular, we found that bisphosphonates were only partially effective in attenuating long-term bone loss resulting from long-term disuse. Risedronate treatment of dogs subjected to long-duration single-limb immobilization resulted in a 30 to 50 percent reduction in bone loss compared with non-treated disuse animals. While we must consider any conservation of bone in disuse osteoporosis to be beneficial, we do not yet know whether this treatment reduces bone resorption enough such that bone that remains after long-term disuse can make a complete recovery when loading is restored. Moreover, these observations stand in contrast findings for other osteoporoses where bisphosphonates more effectively inhibited bone loss. Thus, these results suggest that disuse is different from other osteoporoses in its sensitivity to anti-resorptive treatment.
In the coming year, we will complete our histomorphometric analyses of tissues. We will also undertake confocal microscopic studies of osteocyte integrity and perform the biomechanical testing needed to determine whether treated bones maintain their mechanical properties in proportion to the amount of bone conserved, and determine whether long-term bisphosphonate treatment adversely affect bone tissue mechanical properties during disuse.
This project's funding ended in 2004