Review of NASA's Evidence Reports on Human Health Risks: 2017 Letter Report (2018)

2008 Letter Report, the risk was not critiqued specifically. However, 2008 report recommendations relevant to the elevation of fracture risk due to bone loss are discussed in the early onset osteoporosis report review that follows.

RISK OF EARLY ONSET OSTEOPOROSIS DUE TO SPACE FLIGHT

As is documented in the 2017 Evidence Report Risk of Early Onset Osteoporosis Due to Space Flight (Sibonga et al., 2017b), and summarized in a recent publication (Orwoll et al., 2013), a major limitation to long-duration spaceflight is the rapid and sustained loss of bone, a loss that at least by QCT assessments may not be readily reversible on return to Earth. For unknown reasons the rate of bone loss and subsequent recovery are quite variable among subjects. Although ARED and/or bisphosphonate therapy may ameliorate the bone loss, the data provided suggest that the protection is not complete, and such preventive measures carry their own risks. Although at this point existing data from astronauts do not show bone loss to the level that meets the definition of osteoporosis, the loss of bone during spaceflight and the variable recovery on return to Earth could, with time, subject astronauts to an increased fracture risk even in a 1 g environment.

Does the Evidence Report Provide Sufficient Evidence, as Well as Sufficient Risk Context, That the Risk Is of Concern for Long-Term Space Missions?

The report provides compelling evidence that during spaceflight, bone loss is rapid and, to the extent that data are available, continuous with no evidence of a plateau. These data are well illustrated in figures 9 and 10 of the report. Table 2 of the evidence report lists the percent bone loss per month in a number of different skeletal locations, with the most rapid losses in the hip and lumbar spine, as assessed by DXA. Bone loss in these regions averages from 1.06 to 1.56 percent per month (LeBlanc et al., 2000), far exceeding the rate of bone loss even in females in the early postmenopausal period. DXA is an areal measurement that includes cortical and trabecular bone. Changes in trabecular bone are generally more rapid than those in cortical bone. QCT, on the other hand, is a volumetric determination suitable for the assessment of trabecular bone and

so is more sensitive to changes in bone than DXA. When QCT was used to assess bone loss, the rate of bone loss was found to be greater than that shown by DXA, with a mean bone loss of −2.7 percent per month of the trabecular bone at the femoral neck (Lang et al., 2004). Although bone loss can be partially mitigated by ARED alone and in combination with alendronate as shown in the study by LeBlanc and colleagues (2013), knowledge about the degree to which such preventive measures are effective is generally incomplete, and there is variability among individuals (see figure 18 of the evidence report). Furthermore, it will be important to consider the options for countermeasures in spaceflight situations in which extensive exercise may not be feasible due to the size of the spacecraft or other factors. The report provides compelling evidence that the rate and degree to which bone is lost are highly variable from person to person as seen in the large standard deviations in rates of bone loss summarized in tables 2 (p. 17) and 4 (p. 21). Similarly, the rate of recovery of bone after landing was quite variable among the astronauts, although when DXA measurements were used, the recovery seemed to approach baseline after about 3 to 4 years (figure 12, p. 23, of the evidence report provides data from a 2007 study by Sibonga and colleagues). However, more recent QCT data suggest that after an initial recovery there was resumption of loss of bone in the spine and hip, with no evidence for recovery by 4 years, although these results varied substantially among the different subjects (Orwoll et al., 2013). This implies that some if not all astronauts face an increased risk of developing osteoporosis and fractures as they age.

Does the Evidence Report Provide Evidence That the Named Gaps Are the Most Critical Presented?

The seven listed gaps capture many of the critical issues that, if better understood, could help in monitoring and/or mitigation of bone loss, in enhancing recovery, and in decreasing the risk of subsequent fractures. These gaps are apparent from the data presented in the evidence report, although they are not necessarily flagged as such in the report. Thus, they could be highlighted more effectively in the report itself.

Are There Any Additional Gaps or Aspects to Existing Gaps That Are Not Addressed for This Specific Risk?

Several additional gaps that flow from the data are reported but are not currently listed as gaps:

• The reasons for the heterogeneity of bone loss, response to preventive measures, and recovery need to be better understood. As noted above, both the loss of bone and the rate of recovery after landing varied considerably among subjects. At this point no obvious effort has been made to understand this variability. However, being able to determine which subjects will experience greater bone loss during spaceflight or have a decreased ability to recover the lost bone on landing could help tailor screening or preventive measures to reduce the risk of osteoporosis.
• Better methods need to be developed to predict prior to spaceflight which subjects are likely to be high-rate bone losers or have problems recovering bone post flight. This relates to the above gap, as understanding the mechanisms underlying the variability will be essential for developing such predictive methods.
• The report should discuss the influence of changes in muscle composition on bone and on the risk of falling. The evidence report does not include a discussion of the role of muscle function and composition as altered by spaceflight, although this was the subject of earlier evidence reports. Strong muscles help protect against falls in the terrestrial environment, and they may provide a compressive load that helps maintain some bone strength. An analysis of the interaction between bone and muscle is achieving much greater attention in the musculoskeletal literature (e.g., Cardozo and Graham, 2017).
• The report does not take advantage of plausible models of immobilization in younger adults. For example, one could consider models such as those involving spinal cord injuries with chronic paraplegia or quadriplegia or prolonged immobilization models with recovery in both young adults and in preclinical animal models. Paraplegia from spinal cord injuries, like spaceflight, results in rapid bone loss. Research into the prevention of such bone loss and into rehabilitation methods for restoring bone that has been lost could inform the space program (Coupaud et al., 2015). Moreover, work with animal models for investigating the

Does the Evidence Report Address Relevant Interactions Among Risks?

The report briefly alludes to changes in hormonal regulators of bone and mineral metabolism, and it also discusses the increase in urine calcium that occurs during microgravity. The accompanying report on renal stones (Sibonga and Pietrzyk, 2017) shows how the increase in urinary calcium could contribute to an increased risk of kidney stones or of nephrocalcinosis or both. Similarly, this report briefly discussed changes in hip strength (of the femur), as predicted by finite element analysis, that could lead to changes in stance or fall loads predisposing an individual to fracture. As previously noted, missing from the report were data on muscle strength and composition prior to flight, immediately after the flight, and at any later time points as well as discussion of the potential influence of muscle strength and composition on bone strength and fall risk. Cross-references to the evidence report on reduced muscle mass (Ploutz-Snyder et al., 2015) would be helpful. Changes in vestibular function, which are associated with exposure to altered gravity, affect balance and the likelihood of falling but are hardly mentioned in the report. A discussion of physiological stress responses to spaceflight and their potential impact on bone loss was missing and should be added. Spaceflight involves unique activities, such as EVA, that could increase the risk of fractures not generally considered in the evaluation of osteoporosis risk factors on Earth, so task analysis and the unique risks posed to the skeleton by these spaceflight activities could have been further discussed. Furthermore, there was no mention of nutritional influences on bone health in light of the limits on diet imposed by long-term spaceflight.

What Is the Overall Readability and Quality?

The authors are to be commended for the excellent quality of the writing and organization of this evidence report.