The Efficacy of Bisphosphonate Pre-treatment in Preventing Losses in Densitometric and Mechanical Properties during Hindlimb Unloading and throughout Reambulation in the Distal Femur Metaphysis of Adult Male Rats
MetadataShow full item record
Microgravity-related bone loss in astronauts is a well-known consequence of space travel. These losses are a result of the catabolic reaction of the skeleton to unloading. Anti-catabolics like bisphosphonates (BPs) have been used to combat bone loss in osteoporosis patients. Their mechanism of action also makes them a possible treatment for preventing the microgravity induced bone loss experienced by astronauts. There are a variety of BPs on the market, and many choices in treatment administration schedule. In this study, the efficacy of pre-treatment with BPs was evaluated by observing changes in bone densitometry measures, geometry, and mechanical properties over different periods. The periods of interest were the hindlimb unloading (HU) period during which microgravity is simulated and the recovery period following HU. Simulating microgravity is achieved by hindlimb unloading adult rats using the model described by Morey-Holton. Six-month old Sprague-Dawley rats were split into four groups which were ambulatory controls (AC), hindlimb unloading controls (HUC), risedronate pre-treatment (RIS), alendronate pre-treatment (ALN). During the 28 day pre-treatment period, the ALN and RIS groups were administered their respective BP pre-treatments. Following that, all groups except the ambulatory controls underwent a 28 day unloading period. Rats were reambulated and recovered for 56 days after the unloading period. Bones were harvested at baseline (day 0), end of pre-treatment (day 28), end of unloading (day 56), end of recovery (day 112) and analyzed. Ex vivo scans of the distal femur metaphysis (DFM) were taken using both peripheral quantitative computed tomography (pQCT) and micro computed tomography (μCT). Cross-section specimens of the DFM were isolated and compressed between two platens to estimate mechanical properties. The results of scans and tests were analyzed to determine if the pre-treatment approach prevented bone loss during HU and throughout recovery. A BP was considered protective if there were significant differences between the HUC group and AC group, but no difference between the AC group and the respective BP group. The resulting data demonstrated that both pre-treatments prevented (HU) related losses that the HUC group experienced in several densitometric and geometric parameters. HUC did not see statistically significant losses in mechanical properties; however, RIS did enhance them as compared to HUC after HU. The AC group experienced losses in cancellous bone at the end of recovery which were likely attributable to age-related decline. When AC was lowest, either both treatment groups or just RIS were significantly better. Both BP groups had enhanced intrinsic mechanical properties at the end of recovery as compared to AC. It was a reoccurring trend that RIS was significantly better than HUC while ALN would differ from neither HUC nor AC. This was true for all mechanical properties, trabecular number, and trabecular spacing after HU. After recovery, the control group (HUC or AC) with the lowest average value varied so this trend in indirect BP group differences becomes less clear. The RIS group had the lowest average densitometric and geometric results in the cortical region. Risedronate seemed to have the stronger effect on cancellous bone and total bone over the unloading period. However, the RIS group’s protection of the cortical region seemed to dissipate by the end of recovery. ALN was only slightly inferior to RIS and still protected bone during HU. Alendronate’s beneficial effects also seemed to persist better than RIS’ effects did through the recovery period in both the cortical and cancellous regions. Risedronate was the more effective BP while it persisted, but this was at the cost of inferior retention in the cortical region during recovery. These results suggest that pre-treatment with either BP would be effective at combatting bone loss due to mechanical unloading. Comparisons with the results of other studies, though limited by differences in design, indicate that a pre-treatment approach is as effective in protecting bone as concurrent treatment. In some cases, it appears that the pre-treatment approach may be more effective. Their enhancement of mechanical performance makes BP pre-treatment a promising course of treatment for astronauts. Practical limitations would likely necessitate this BP pre-treatment approach to be tested in combination with aRED in a human spaceflight study. However, this pretreatment approach could first be assessed with a controlled human bedrest study.
Kosniewski, Jennifer Lauren (2017). The Efficacy of Bisphosphonate Pre-treatment in Preventing Losses in Densitometric and Mechanical Properties during Hindlimb Unloading and throughout Reambulation in the Distal Femur Metaphysis of Adult Male Rats. Master's thesis, Texas A & M University. Available electronically from