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Bone response to multiple exposures of microgravity remains a concern for astronauts. More astronauts are making repeat flights, and some have taken the bisphosphonate alendronate (ALN) to prevent bone loss during flight. Given the long-lasting effects of these drugs, it is possible that protection may persist for subsequent flights. In addition, newer bisphosphonates such as zoledronic acid (ZOL) have generally higher potency than alendronate, so there is interest in how the two drugs would compare in this kind of scenario. Findings generated should have clinical relevance more broadly and also help understand and mitigate risks associated with human exploration of space. The primary risks addressed by this research are: (a) Risk of Bone Fracture, and (b) Risk of Early Onset Osteoporosis Due To Spaceflight.
The adult hindlimb unloaded (HU) rat model was used to simulate two successive missions using a modification of the Morey-Holton method of tail traction. In this model, the animal is suspended by the tail through the use of a custom-made harness attached to the tail to remove weight-bearing loads from the hindlimbs of the animal. The height of the animal’s hindquarters was adjusted to prevent any contact of the hindlimbs with the cage floor, resulting in approximately a 30° head-down tilt. The forelimbs of the animal maintain contact with the cage floor allowing the rat full access to the entire cage.
Adult Sprague-Dawley male rats 6 months of age were block assigned to aging control (AC) and HU groups by body weight. HU animals were exposed to 28 days of HU, followed by 56 days of recovery, and then a second 28-day HU exposure. Subsets of HU animals were administered ALN (ALN+HU), ZOL (ZOL+HU), or nothing (HUC) for the initial 28d of HU only. ALN (2.4 µg/kg) was injected 3x/week for 5 weeks, starting the week before the first HU. ZOL (60 µg/kg) was injected in a single dose prior to the first HU. In vivo peripheral quantitative computed tomography (pQCT) scans were taken of the proximal tibia metaphysis (PTM) at baseline (BL) and every 28 days. This research was supported through the Omnibus mechanism, with the entire duration of the project therefore limited to only 1 year. Accordingly, more comprehensive and destructive ex vivo tests and analyses were conducted only at the final time point at the end of the study, following the 2nd HU period (day 112).
For in vivo pQCT results, ALN prevented losses for the first HU, as both total bone mineral content (BMC) and volumetric bone mineral density (vBMD) for HU+A were not different from baseline (BL) or AC at day 28. In contrast, ZOL induced absolute gains in both total BMC and vBMD, with HU+Z significantly higher after the first HU compared to BL, AC, and HUC. The efficacy of ZOL continued throughout the 56d recovery period, with both total BMC and vBMD significantly higher for HU+Z compared to BL, AC, HUC, and HU+A. For the second HU, total vBMD was unchanged for HU+Z and remained significantly higher than BL (+14.2%), AC (+13.7%), HUC (+16.2%), and HU+A (+10.7%). For HU+A, total vBMD was not different from AC at the start and end of the second HU.
Additional tests and analyses were conducted on specimens harvested from animals at the end of the study (day 112). For these ex vivo results, bone volume fraction (BV/TV) from microCT was significantly higher for HU+Z compared to BL, AC, HUC, and HU+A; however, BV/TV values were not different for HU+A compared to BL, AC, or HUC. Trabecular thickness (Tb.Th) was higher for HU+Z than HUC and HU+A, but not different from BL or AC. For HU+A, Tb.Th was not different from BL, AC, or HUC. These microarchitectural parameters of the trabecular compartment demonstrate the superior potency of ZOL, whereas ALN was not beneficial for these measures. For ex vivo mechanical testing, the femoral neck (FN) maximum fracture load was significantly higher for HU+Z compared to every other group, with no other statistical differences. Maximum fracture loads from 3-point bending of both the tibia and femur were significantly higher for HUC, HU+Z, and HU+A compared to BC.
Results from this unique study design support the hypothesis that beneficial effects of both ALN and ZOL do extend to the second HU exposure when treatments were given for the first HU only. ALN was generally protective for both HU bouts as reflected by in vivo pQCT measures. ZOL was broadly more robust in enhancing a wide range of parameters for both in vivo and ex vivo measures, including cortico-cancellous region densitometric properties, trabecular microarchitecture, and mechanical properties. ZOL benefits appear to be mainly due to bone accrual during the first HU that continued for the 56-day recovery period. These findings suggest that crew members taking a bisphosphonate for one ISS mission may experience benefits for subsequent missions without repeating treatments. More detailed comparisons of alendronate (ALN) and zolendronic acid (ZOL) are continuing, as additional mechanical testing and histological analyses are underway and will not be completed for several more months.
Newest results will be further disseminated through conferences (ASBMR and ASGSR), as well as submitted for journal publication.
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Abstracts for Journals and Proceedings
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Lenfest SE, Brezicha JE, Boudreaux RD, Schaefer CM, Bloomfield SA, Allen MR, Hogan, HA. "Bisphosphonate Treatment During an Initial Unloading Period Also Protects Against Bone Loss for a Second Unloading." 36th Annual Meeting of the American Society for Bone and Mineral Research, Houston, Texas, September 12-15, 2014. 36th Annual Meeting of the American Society for Bone and Mineral Research, Houston, Texas, September 12-15, 2014. Poster Presentation SU0036. , Sep-2014
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Abstracts for Journals and Proceedings
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Lenfest SE, Brezicha JE, Boudreaux RD, Schaefer CM, Bloomfield SA, Allen MR, Hogan HA. "Benefits of Bisphosphonate Treatment During an Initial Unloading Period Extends to a Second Unloading Period." Poster Presentation (IP.37). 30th Annual Meeting of the American Society for Gravitational and Space Research, Pasadena, CA, October 22-26, 2014. 30th Annual Meeting of the American Society for Gravitational and Space Research, Pasadena, CA, October 22-26, 2014. , Oct-2014
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Abstracts for Journals and Proceedings
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Lenfest SE, Brezicha JE, Narayanan A, Reyna W, Bloomfield SA, Allen MR, Hogan HA. "Comparison of Protective Effects of Alendronate and Zoledronic Acid for Two Successive Unloading Exposures." Poster Presentation. 2015 NASA Human Research Program Investigators’ Workshop, Galveston, TX, January 13-15, 2015. 2015 NASA Human Research Program Investigators’ Workshop, Galveston, TX, January 13-15, 2015. Abstract #0044. , Jan-2015
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