Spaceflight results in reduced mechanical loading of the skeleton, leading to dramatic bone loss. Low bone mass is also associated with increased fracture risk, and this combination may compromise future long-term spaceflight missions. In two companion spaceflight studies we sought to examine the impact of spaceflight on bone healing and osteoblast function. The first spaceflight launched February 19, 2017 on SpaceX CRS-10. A total of 160, 9-week-old, male C57BL/6 mice were recruited into this study. There were 4 primary groups: spaceflight, ground controls (housed in spaceflight hardware under identical conditions), vivarium ground controls (housed in standard caging under standard laboratory conditions), and baseline controls (euthanized at launch). Each group was further subdivided into 4 groups: sham (no surgery), segmental bone defect (SBD) surgery treated with saline, SBD treated with bone morphogenetic protein 2 (BMP-2), and SBD treated with the main megakaryocyte growth factor, thrombopoietin (TPO). Sample size for each group was n=10. Mice were euthanized approximately 4 weeks after launch and numerous tissues were collected for phenotypic and multi-omic analyses. The second spaceflight launched July 25, 2019 on SpaceX CRS-18. This in vitro companion study contained a total of 20 bioreactors seeded with mouse calvarial osteoblasts: 10 spaceflight and 10 identical ground control bioreactors. Here there were 4 control bioreactors, 3 BMP-2 treated bioreactors, and 3 TPO treated bioreactors in spaceflight and on Earth. Cells were cultured for 2 weeks and were then fixed and processed for multi-omic analyses. Here we will discuss the complicated, yet rewarding aspects of conducting spaceflight investigations and will present preliminary findings as analyses are ongoing. Our hope is that these efforts will provide a better understanding of bone healing processes, and will provide insights into current and future bone healing agents that could help space travelers and terrestrial patients alike.