Because anti-resorptive effects of bisphosphonates (BP) are known to persist following treatment cessation, we hypothesised that beneficial effects of BP treatment given for an initial unloading exposure only, and then withdrawn, would extend to a second unloading exposure. The adult hindlimb unloaded (HU) rat model was used to simulate two successive spaceflight missions, and two BPs were compared, alendronate (AL) and zoledronic acid (ZA). Adult Sprague-Dawley male rats (6 mo.) were block assigned to ageing control (AC) and HU groups by body weight. HU animals were exposed to 28d of HU, followed by 56d of recovery, and then a 2nd 28d HU exposure. Subsets of HU animals were administered AL (HU+A), ZA (HU+Z), or nothing (HUC) for the initial 28d of HU only. AL (2.4 μg/kg) was injected 3x/week for 5 weeks, starting the week before the first HU. ZA (60 μg/kg) was injected in a single dose prior to the first HU. In vivo pQCT scans were taken of the proximal tibia metaphysis (PTM) at baseline (BL) and every 28 days. Ex vivo analyses, conducted after the end of the study following the 2nd HU period, included micro-CT of the PTM and both pQCT and mechanical testing of the femoral neck (FN). For in vivo pQCT results, AL prevented losses for the 1st HU, as both total bone mineral content (BMC) and density (vBMD) for HU+A were not different from baseline (BL) or AC at day 28. In contrast, ZA induced absolute gains in both total BMC and vBMD, with HU+Z significantly higher after the 1st HU compared with BL, AC, and HUC. The efficacy of ZA continued throughout recovery and into the 2nd HU, with total vBMD unchanged for HU+Z and 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 2nd HU. For ex vivo results, bone volume fraction (BV/TV) was significantly higher for HU+Z compared to BL, AC, HUC, and HU+A; whereas, BV/TV values were not different for HU+A. Trabecular thickness (Tb.Th) results were similar, with ZA more beneficial than AL. 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. The primary effects on pQCT results at the FN were significantly higher trabecular BMD for all groups compared with HU, with ZA the highest (23%; v. 16% for AL).
Disclosure: The authors declared no competing interests. Support provided by NASA Grant NNX13AQ87G (Human Research Program Omnibus) is appreciated.