Overview
Pharmaceutical Countermeasure Effects on Tissue-Level Quality of Immobilized Bone (Postdoctoral Fellowship)
Principal Investigator:
Devendra Bajaj, Ph.D.
Organization:
University of Medicine and Dentistry of New Jersey
Technical Summary
Astronauts suffer from rapid bone loss due to disuse in microgravity. Recovery of such bone loss requires substantial rehabilitation on return to Earth’s gravity. Bisphosphonate drugs are being considered as potential countermeasures to suppress bone loss in microgravity and therefore, expedite recovery on earth. However, there are concerns over long-term safety of the drug and its effects on bone fragility. In this project, the researchers are investigating whether risedronate (RIS), a bone anti-resorptive (bisphosphonate) treatment, given during a long-term (six months) limb immobilization (see methods in appendix) in beagles would: 1) slow bone loss; 2) enhance the recovery by restoration of mechanical usage with remobilization (for 12 months); and 3) maintain the tissue-level mechanical properties.
Specific Aims
1) Characterize tissue-level material properties (microdamage, mineralization, fatigue life and fatigue crack growth resistance) in the distal forelimb (radius) to determine how immobilization without pharmaceutical intervention (vehicle control) and with risedronate modify cortical bone tissue’s resistance to fatigue and fragility fracture.
2) Characterize tissue-level material properties to determine how remobilization, with or without previous risedronate treatment, modifies cortical bone tissue’s resistance to fatigue and fragility fracture.
Key Findings
Results obtained thus far suggest that RIS-treatment slows bone loss during long-term immobilization (IM), and also allows for better recovery during remobilization (RM). However, 12-month RM may be insufficient for complete recovery of trabecular bone lost during IM. On the contrary, 12-month RM was sufficient to restore cortical width by new bone formation in the marrow cavity. Immobilization also resulted in an increase in cortical bone porosity (Fig. 5), which regardless of RIS-treatment and RM remained significantly elevated compared to control. The deleterious effects of this cortical bone loss during IM were most evident by decreased strength, stiffness and toughness. However, RIS-treatment during IM preserved tissue-level mechanical properties and RM completely restored cortical bone stiffness. RM also resulted in partial recovery of strength at least in the strongest structural orientation (i.e. stress applied perpendicular to bone length). However, RM of previously RIS-treated bone resulted in a significant reduction in toughness versus control (-30% to -40%). Overall, RIS-treatment during immobilization preserved bone and tissue-level mechanical properties. However, restoration of mechanical usage by remobilization reduced the cortical bone toughness.
Current work is quantifying the extent of microdamage accumulation and the mechanical properties of cortical bone beams under fatigue loading. This investigation has allowed for measurement of changes in tissue-level mechanical properties of immobilized bone treated with risedronate and subsequent remobilization. The outcomes thus far have shown the benefit of RIS in slowing bone loss during long-term IM and thus highlight potential benefits over long duration space flights. However, reduction in tissue-level toughness may point to an increase in susceptibility towards crack propagation with RIS and RM, is a concern, and requires further investigation. This work will be carried out in the subsequent aim (year 2) of this study.
Specific Aims
1) Characterize tissue-level material properties (microdamage, mineralization, fatigue life and fatigue crack growth resistance) in the distal forelimb (radius) to determine how immobilization without pharmaceutical intervention (vehicle control) and with risedronate modify cortical bone tissue’s resistance to fatigue and fragility fracture.
2) Characterize tissue-level material properties to determine how remobilization, with or without previous risedronate treatment, modifies cortical bone tissue’s resistance to fatigue and fragility fracture.
Key Findings
Results obtained thus far suggest that RIS-treatment slows bone loss during long-term immobilization (IM), and also allows for better recovery during remobilization (RM). However, 12-month RM may be insufficient for complete recovery of trabecular bone lost during IM. On the contrary, 12-month RM was sufficient to restore cortical width by new bone formation in the marrow cavity. Immobilization also resulted in an increase in cortical bone porosity (Fig. 5), which regardless of RIS-treatment and RM remained significantly elevated compared to control. The deleterious effects of this cortical bone loss during IM were most evident by decreased strength, stiffness and toughness. However, RIS-treatment during IM preserved tissue-level mechanical properties and RM completely restored cortical bone stiffness. RM also resulted in partial recovery of strength at least in the strongest structural orientation (i.e. stress applied perpendicular to bone length). However, RM of previously RIS-treated bone resulted in a significant reduction in toughness versus control (-30% to -40%). Overall, RIS-treatment during immobilization preserved bone and tissue-level mechanical properties. However, restoration of mechanical usage by remobilization reduced the cortical bone toughness.
Current work is quantifying the extent of microdamage accumulation and the mechanical properties of cortical bone beams under fatigue loading. This investigation has allowed for measurement of changes in tissue-level mechanical properties of immobilized bone treated with risedronate and subsequent remobilization. The outcomes thus far have shown the benefit of RIS in slowing bone loss during long-term IM and thus highlight potential benefits over long duration space flights. However, reduction in tissue-level toughness may point to an increase in susceptibility towards crack propagation with RIS and RM, is a concern, and requires further investigation. This work will be carried out in the subsequent aim (year 2) of this study.