Resistive exercise in astronauts on prolonged spaceflights provides partial protection against spaceflight-induced bone loss

Highlights

• Bone loss in space is rapid and may induce irreversible changes.

• Bone turnover markers suggest a net bone resorption in space.

• Advanced resistive exercise can attenuate postflight deficits in bone density.

• Advanced resistive exercise cannot suppress elevated resorption biomarkers.

• Addition of a bisphosphonate can mitigate increased bone resorption in space.

Abstract

Bone loss in astronauts during spaceflight may be a risk factor for osteoporosis, fractures and renal stone formation. We previously reported that the bisphosphonate alendronate, combined with exercise that included an Advanced Resistive Exercise Device (ARED), can prevent or attenuate group mean declines in areal bone mineral density (aBMD) measured soon after ~ 6-month spaceflights aboard the International Space Station (ISS). It is unclear however if the beneficial effects on postflight aBMD were due to individual or combined effects of alendronate and ARED. Hence, 10 additional ISS astronauts were recruited who used the ARED (ARED group) without drug administration using similar measurements in the previous study, i.e., densitometry, biochemical assays and analysis of finite element (FE) models. In addition densitometry data (DXA and QCT only) were compared to published data from crewmembers (n = 14–18) flown prior to in-flight access to the ARED (Pre-ARED). Group mean changes from preflight (± SD %) were used to evaluate effects of countermeasures as sequentially modified on the ISS (i.e., Pre-ARED vs. ARED; ARED vs. Bis+ARED). Spaceflight durations were not significantly different between groups. Postflight bone density measurements were significantly reduced from preflight in the Pre-ARED group. As previously reported, combined Bis+ARED prevented declines in all DXA and QCT hip densitometry and in estimates of FE hip strengths; increased the aBMD of lumbar spine; and prevented elevations in urinary markers for bone resorption during spaceflight. ARED without alendronate partially attenuated declines in bone mass but did not suppress biomarkers for bone resorption or prevent trabecular bone loss. Resistive exercise in the ARED group did not prevent declines in hip trabecular vBMD, but prevented reductions in cortical vBMD of the femoral neck, in FE estimate of hip strength for non-linear stance (NLS) and in aBMD of the femoral neck. We conclude that a bisphosphonate, when combined with resistive exercise, enhances the preservation of bone mass because of the added suppression of bone resorption in trabecular bone compartment not evident with ARED alone.

Introduction

Astronauts have served on the International Space Station (ISS) for durations of spaceflight mostly between 4 and 6 months where they have returned from long-duration space missions with lower areal bone mineral densities (aBMDs) compared to preflight, i.e., beyond the Least Significant Change (LSC) for DXA measurements at Johnson Space Center (JSC) [1]. Space, a weightless environment, appears to induce a musculoskeletal adaptation in astronauts that resembles the effects of immobilization or paralysis. The losses in bone mass during spaceflight are not stochastic, but appear to target skeletal sites that are weight-bearing on Earth, suggesting a primary role of biomechanics for skeletal adaptation in space. Overall, it is unclear as to what these spaceflight-induced changes mean to the affected astronaut in terms of fracture risk or impacts to long-term skeletal health.

In another report that focused on resistive exercise and nutrition as countermeasures to mitigate losses in aBMD during spaceflight, resistive exercise on the ARED (Advanced Resistive Exercise Device) was capable of maintaining, after typical 6-month spaceflights, the aBMD (group mean value ± SD) of astronauts at their preflight hip and the lumbar spine [2]; these observations with DXA densitometry suggested possible skeletal benefits with ARED and nutrition alone. The positive aBMD outcome using the ARED has been attributed to the ability to perform resistive exercise that more closely resembles weight-lifting in Earth's 1 g environment. This advanced capability included an increased loading capability (600 pound-force (lbf), or 2669 Newton (N)), and a higher ratio of eccentric to concentric loading than was possible with the previous exercise device (i.e., the interim resistive exercise device, or IRED) [3]. The IRED, in contrast, provided a maximum resistance of only 300 lbf or 1334 N which appears to be insufficient mechanical loading in astronauts to preserve skeletal mass during spaceflight or to facilitate recovery after spaceflight [4,5].

Despite findings with DXA measures that show that the development of osteoporosis (T score <−2.5) did not occur in astronauts after ~6-month spaceflights [6], there are spaceflight-induced changes to bone that have raised concern that the degree of bone loss may be deleterious and that its prevention would be desirable [7]. Collective evidence substantiate i) perturbed bone remodeling during spaceflight with bone resorption increased and uncoupled from bone formation [6,8,9], ii) bone loss still evident in some astronauts who are using ARED (this paper and confidential medical communication) and iii) an associated bone loss that is accelerated relative to bone loss due to aging [1,5,7]. Specifically, the calculated average of hip trabecular vBMD loss over 6 months from reported population data is ~0.4% which is ~20-fold less than the average hip trabecular vBMD loss over 6 months reported for crewmembers using exercise alone (ARED only, no bisphosphonates) in this report. Moreover, it has not been possible to predict which astronauts might lose bone from the data acquired to-date from ~70 long-duration astronauts.

Previously, we have described that 70 mg/week of alendronate, an oral bisphosphonate (Bis), appeared to attenuate BMD loss in astronauts, to prevent an elevation of biomarkers for bone resorption, and to reduce the typically increased urinary excretion of calcium during spaceflight [10]. However, the effects of alendronate were obscured because ISS astronauts who were taking alendronate concurrently performed resistive exercise on the ARED. From the perspective of mission operations and for the planning of missions beyond low-Earth orbit, it is important to delineate whether the postflight benefits observed in the Bis+ARED group can be achieved with ARED alone since each countermeasure is associated with its own in-flight risks and/or requirements for implementation.

To this end, we conducted two flight investigations. One study reported the anti-resorptive effect of a bisphosphonate in space in combination with ARED [10]. The other flight study, described here in, investigated the efficacy of ARED in the absence of a bisphosphonate as a strategy to prevent bone loss during spaceflight. We hypothesized that ARED alone would not completely protect astronauts against bone loss because of an inability to mitigate bone resorption and this inability would be detected by QCT measurement of trabecular bone, a bone sub-region that is sensitive to osteoclast activity.