Effects of different interventions on microgravity-induced bone loss

Microgravity-induced bone loss

In the microgravity environment, the absence of mechanical stress stimulation leads to a series of adverse changes in the skeletal system, including bone metabolism disorders [22], bone loss [23], and decreased bone density [24] (Table 1). Specifically, the lack of mechanical stress in microgravity accelerates bone loss. Significant cortical bone loss and trabecular bone loss were observed in the tibia during both 1 and 6 months of spaceflight, accompanied by a marked decrease in ultrasound broadband ultrasonic attenuation (BUA) of the heel bone. This declining trend became increasingly pronounced with time [25]. Similar findings were also observed in another study, where 15 astronauts spent 1, 2, and 6 months staying on the Russian space station. The results indicated that the tibia exhibited cortical and cancellous bone loss starting from the first month, which progressively worsened over time. However, the loss of cortical bone was less pronounced compared to cancellous bone. Notably, no significant loss of cancellous or cortical bone was detected at the radius, suggesting that the skeletal regions subjected to greater mechanical loads in a microgravity environment are more affected [26]. Besides the tibia, the lumbar spine and hip are also major load-bearing sites in the skeletal system [27]. After reviewing data from 35 astronauts with spaceflight durations of 120–180 days at a convened skeletal summit, the U.S. National Aeronautics and Space Administration (NASA) found that the lumbar spine experienced approximately 10 % areal bone mineral density (aBMD) loss, severely compromising skeletal integrity [28]. Additionally, 14 crewmembers who spent 4–6 months flying on the International Space Station (ISS) underwent dual-energy X-ray absorptiometry (DXA) testing combined with QCT evaluation. The results revealed that vertebral aBMD decreased at a rate of 0.9 %/month, trabecular volumetric BMD decreased at a rate of 0.7 %/month, and there was significant cortical bone loss in the hips, primarily due to cortical thinning [29]. After a 6-month space flight, astronauts exhibited a trend of decreasing vertebral trabecular density in both the upper and lower regions of the vertebrae compared to the pre-flight levels [30]. In summary, astronauts experience varying degrees of bone loss in different parts of the skeleton during space missions due to prolonged exposure to microgravity. Among these, the lumbar vertebrae and the heel bone, as the primary load-bearing bones of the human body, exhibit a much higher rate of bone loss compared to other skeletal regions. Conversely, non-weight-bearing bones such as the radius in the upper limbs show a slower rate of bone loss.

Nowadays, to more comprehensively investigate the effects of microgravity on human body functions and given the high cost of conducting experiments in space, ground-based simulations such as hindlimb unloading models or bed rest experiments are frequently employed. Although hindlimb unloading cannot fully replicate the effects of microgravity, experiment results often exhibit comparable outcomes [31], 32]. Therefore, by observing skeletal changes in different parts of the hindlimb under the hindlimb unloading model, a deeper understanding and prediction of microgravity’s impact on the skeletal system can be achieved [33], 34]. Following a 4-week tail suspension in healthy SD male rats, significant trabecular bone loss in the distal femur, decreased cortical BMD, and reduced levels of bone remodeling-related cytokines, such as Interferon-γ (IFN-γ) and Interleukin-10 (IL-10), were observed compared to the control group [35]. Additionally, the three-point bending test revealed a significant reduction in maximum load and stiffness in the femoral diaphysis. Similarly, the simulated microgravity environment significantly affected the tibia. In 6-month-old SD male rats subjected to 4 weeks of tail suspension, there was an approximate 8 % decrease in total proximal tibial bone area, a 9 % decrease in volumetric bone mineral density (vBMD), a 17 % decrease in total bone mineral content, and a marked reduction in tibial diaphysis flexion force [36]. These studies demonstrated that the microgravity environment accelerates bone loss in the femur and tibia, primarily characterized by trabecular bone loss and weakened bone biomechanical properties. Beyond the femur and tibia, the hip bone is another major weight-bearing bone in the human body [39]. After 4 or 8 weeks of tail suspension in female rats, the acetabulum’s width and length decreased, and the iliac wing angle diminished over time. The cartilage thickness between the ilium and ischium gradually thinned [37]. The effects of microgravity on bones extend beyond weight-bearing bones like the femur; similar manifestations were observed in non-weight-bearing bones, such as the humerus. After 4 weeks of tail suspension in male SD rats, the vBMD of the humeral proximal end significantly decreased, and total bone mineral content markedly declined. However, the total bone density of the humerus and the vBMD of the metaphysis cortical bone increased significantly [38]. This phenomenon suggests that in a microgravity environment, cancellous bone and cortical bone exhibit differential sensitivity to mechanical changes, leading to complex alterations in the bone structure.

At present, microgravity-induced bone loss has become one of the important research projects in the field of aerospace medicine. In microgravity, the lack of mechanical stress stimulation on bones affects bone homeostasis, resulting in bone loss. This not only seriously reduces the efficiency of astronauts’ mission execution, but also poses a serious challenge to their health, and this effect has a time effect. Analyzing the effects of bone loss is conducive to the scientific prevention and treatment of microgravity-induced bone loss.

In order to further investigate the impact of the space environment on human bone health, NASA has initiated a new phase of its human research program. This project aims to determine whether space-induced bone changes alter the risk of fractures and osteoporosis. Research has demonstrated that microgravity-induced bone loss is typically characterized by the reduction of bone trabeculae [40], decreased bone mineral content [41], and deterioration of bone quality [42]. Among these factors, the loss of bone trabeculae and damage to the bone microstructure serve as significant predictors of osteoporosis [43]. In microgravity conditions, the reduction in the number of bone trabeculae and the thinning of their thickness lead to alterations in bone microstructure. Both strength and rigidity are dependent on bone mineral content. Thus, the decrease in bone mineral content under microgravity reduces bone strength and rigidity, significantly increasing the risk of osteoporosis [44] and fracture [17], 45]. These effects pose substantial challenges to astronauts’ mission performance in space and their daily activities upon returning to Earth. Although the skeletal system struggles to rapidly adapt to gravitational forces after returning to Earth, astronauts often experience difficulties in walking and instability. Over time, the bone mass may gradually recover, and improvements in the trabecular structure can occur [46], 47]. However, the recovery process is lengthy, and permanent deterioration may ensue in some cases [26], 48]. Additionally, the recovery rate varies depending on the specific bone location, and in certain instances, further deterioration may occur [7].

The microgravity environment presents a significant challenge to the maintenance of bone health, not only complicating astronaut missions, but also posing a threat to their bone health. Various interventions have been proposed and validated, offering new scientific insights into mitigating bone loss in astronauts. Such as pharmacotherapy, nutritional supplementation, and exercise interventions. The therapeutic approaches and efficacy of different intervention modalities vary considerably (Figure 2). By comprehensively evaluating the strengths and limitations of these modalities, targeted strategies can be developed to address bone loss effectively, thereby enhancing the physical health and quality of life for astronauts.

Figure 2:

Different intervention methods attenuate microgravity-induced bone loss.

Pharmacotherapy

The absence of mechanical stress in microgravity diminishes the mechanosensitivity of osteoblasts, thereby disrupting bone homeostasis [49]. Specifically, the accelerated formation of osteoclasts and enhanced osteoclast-dominated contribute to bone loss [50], 51]. Although medications exist that can effectively suppress osteoclast-dominated bone resorption and restore bone homeostasis, there are no drugs approved for microgravity-induced bone loss so far. The most widely used drugs for bone loss include bisphosphonates, denosumab, and teriparatide [52]. Bisphosphonates have demonstrated therapeutic potential in experimental settings both in space and on Earth.

Bisphosphonates have demonstrated promising potential in inhibiting bone resorption [53]. They suppress osteoclastogenesis by targeting key regulatory enzymes within osteoclasts [54], thereby reducing the activity of these enzymes. Furthermore, bisphosphonates effectively prevent the degradation of hydroxyapatite, which plays a critical role in mitigating excessive bone resorption [18]. However, in the context of microgravity-induced bone loss, the application of bisphosphonates remains largely experimental within aerospace medicine. This is primarily due to the limited number of astronaut samples, the inability to conclusively assess the efficacy of bisphosphonates under prolonged microgravity conditions, and the associated side effects. Despite these challenges, bisphosphonates exhibit therapeutic potential. Supplementing astronauts with bisphosphonates during routine exercise regimens has been shown to significantly delay bone resorption, reduce NTX levels, and enhance hip trabecular density [19]. This regimen has demonstrated superior therapeutic potential compared to single resistance exercise [19], 55]. Furthermore, in a study involving 15 healthy participants [56], treatment with bisphosphonates following 150 days of bed rest resulted in a marked reduction in the number of osteoclasts and effectively inhibited bone resorption, further underscoring the role of bisphosphonate in mitigating significant bone resorption. While bisphosphonates have exhibited substantial efficacy in inhibiting osteoclast activity, their regulation of the bone microenvironment remains limited, such as insufficient deep regulation of the bone microenvironment by bisphosphonate drugs [57] and certain toxic side effects associated with long-term use [18]. In contrast, denosumab has shown promise in enhancing bone metabolism [58]. Denosumab is a monoclonal antibody to the nuclear factor kappa-B (NF-κB) ligand-receptor activator, which is effective in inhibiting the process of osteoclast-mediated bone resorption [59]. Although its efficacy in preventing bone loss has not been extensively reported in flight studies, bed rest experiments, or suspension models, it has demonstrated notable application value in treating postmenopausal osteoporosis [60] and other bone loss-related diseases, making it a potential drug candidate for addressing microgravity-induced bone loss. A trial involving 7,868 postmenopausal osteoporotic patients revealed that denosumab treatment significantly reduced the risk of vertebral and hip fractures compared to the placebo group, while also markedly improving BMD in the hip and lumbar spine [61]. Moreover, compared to bisphosphonate treatment, denosumab not only enhanced lumbar spine BMD but also femoral neck BMD, with even pronounced improvements observed [58], 62].

Considering the potential toxic side effects and adverse impacts of bisphosphonates and other drug treatments, it is important to investigate alternative Pharmacological strategies for the prevention and treatment of bone loss (Table 2). Recent studies have demonstrated that both synthetic drugs and traditional Chinese medicine extracts hold significant value in addressing bone loss, providing a scientific rationale for targeting and mitigating microgravity-induced bone loss. Mika Ikegame et al. utilized goldfish scales as a skeletal model coexisting with osteoclasts and osteoblasts. Their findings revealed that melatonin treatment during space flight significantly decreased osteoclast activity, reduced the number of osteoclasts, down-regulated the expression of osteoclast-related factors such as Mmp9, Ctsk, and RankL, and effectively inhibited bone resorption. Simultaneously, the expression of bone-forming factors, including Runx2, Osx, and Ocn, was up-regulated, thereby promoting bone formation and alleviating bone loss [63]. Low molecular weight chondroitin sulfate (LMWCS), an aminoglycan widely distributed in bones and cardiovascular tissues, exhibits notable antioxidant and anti-inflammatory properties [64]. In tail-suspended mice treated with LMWCS, CT imaging confirmed its efficacy in preventing tibia cortical bone loss and attenuating bone turnover. Furthermore, LMWCS treatment significantly up-regulated the expression of antioxidant enzymes such as Nrf2 mRNA while down-regulating MDA expression in the femur and serum [65], suggesting that LMWCS mitigates bone loss by reducing oxidative stress levels. Compared to synthetic drugs, herbal extracts demonstrate unique advantages in improving bone loss due to their fewer side effects. Angelica sinensis, a traditional Chinese herb rich in alkaloids and phenolic acids, possesses anti-inflammatory activity [66] and effectively inhibits osteoclast differentiation, thus suppressing bone resorption [67]. 4 weeks of tail suspension in mice fed A. sinensis extract alleviated femoral and vertebral bone loss [68] and enhanced osteoblast differentiation, promoting bone formation. Icariin, a flavonoid glucoside derived from Epimedium, exhibits potent anti-inflammatory and antioxidant effects. It has been shown to inhibit bone resorption while promoting bone formation [69], 70]. Oral administration of Epimedium glycosides to SD rats during hindlimb suspension revealed that cancellous bone loss in the distal femur was alleviated, and mRNA levels of Osteoclast-related factors such as RANKL were down-regulated, and the serum calcium ion level was restored to the normal level [71]. Compared to antiresorptive drugs such as bisphosphonates, these natural herbal compounds not only effectively inhibit the microgravity-induced increases in bone resorption but also promote osteoblast-mediated bone formation through multi-targeted regulation of bone metabolism, achieving bidirectional regulation of bone metabolism. Notably, these natural compounds exhibit significant multi-organ protective effects. For instance, Icariin improves cardiac functions [72], lung [73], skin [74], and other organ functions. The value of one-drug-multiple-action applications in aerospace medicine warrants further in-depth exploration.

The mechanism of action of antiresorptive drugs (e.g., bisphosphonates) in mitigating bone loss has been validated in space missions. However, due to the limited sample size of astronauts and the prolonged observation period, further in-depth exploration is required to clarify the profound effects of this drug class on the skeletal system. Additionally, long-term pharmacotherapy may increase the risk of certain skeletal disorders, while the microgravity environment can affect drug pharmacokinetics [75], leading to reduced stability of therapeutic efficacy. Meanwhile, real-time monitoring of bone metabolism markers and bone density changes in the space environment remains challenging, thereby hindering the accurate assessment the drug efficacy. The microgravity environment may alter the composition and functional profile of the intestinal microbiota, thereby impacting gastrointestinal digestive and absorptive functions [76]. Interindividual variations in digestion and absorption not only exacerbate difficulties in evaluating drug efficacy but also lead to discrepancies between the dosage of nutritional supplements and their actual biological effects. Notably, the improvement of microgravity-induced bone loss by Chinese herbs such as A. sinensis has been demonstrated in animal models, suggesting the development potential of natural medicines in the prevention and treatment of osteopenia. Targeted drug delivery strategies for skeletal protection therefore warrant further investigation.

Nutritional supplementation

Microgravity-induced bone loss is not only attributable to the lack of mechanical loading but is also closely associated with nutritional metabolic disorders [77]. Studies have demonstrated that astronauts’ long-term missions in space may accelerate metabolic imbalances of calcium, vitamin D, and other nutrients, potentially exacerbating the onset and progression of bone loss [78], 79]. Consequently, nutritional supplementation represents one of the strategies for preventing microgravity-induced bone loss by targeting and regulating bone metabolism signaling pathways and related mechanisms. During space flight, the absence of mechanical stress disrupts bone homeostasis, leading to increased bone resorption while bone formation remains relatively unchanged. Additionally, intestinal calcium absorption capacity decreases, resulting in reduced calcium content, which triggers substantial bone mineral loss and induces bone loss [78], 80]. Therefore, increasing calcium levels through supplementation with various nutrients can effectively mitigate bone loss. Vitamin D plays a critical role in skeletal calcium and phosphorus absorption as well as maintaining bone homeostasis [81]. However, vitamin D supplementation alone appears insufficient to alleviate microgravity-induced bone loss. The decrease in bone formation markers such as ALP and the increase in bone resorption markers observed in eight astronauts after high calcium intake combined with vitamin D supplementation during a mission suggest that this approach may be ineffective due to the limited inhibitory effect of vitamin D on bone resorption and the lack of adequate light exposure [82]. Interestingly, astronauts supplemented with vitamin K for 6 weeks during a 6-month spaceflight exhibited a significant increase in bone formation markers such as ALP and Ocn, effectively mitigating bone loss [86]. Furthermore, oral administration of vitamin K to SD rats during 4 weeks of tail suspension improved bone mineral density and maintained trabecular bone structures [87], indicating that vitamin K contributes to alleviating microgravity-induced bone loss. In addition to vitamin D and vitamin K, nutrients such as omega-3 fatty acids play a protective role in bone health. Microgravity-induced bone mineral loss was effectively mitigated, and bone microarchitecture was improved following fish oil supplementation with omega-3 fatty acids among crew members of short-duration space flights [88]. Beyond nutrient supplementation, the overall acid-base balance of the dietary regimen plays a non-negligible role in protecting bone health. Seventeen astronauts underwent 4 days of dietary control (i.e., high or low animal protein-to-potassium ratio) during their missions. The study revealed that excessive sulfur and sodium intake following high animal protein consumption may promote bone resorption by increasing the acid load. Conversely, increasing the intake of alkaline foods such as vegetables and fruits, while ensuring adequate calcium content, effectively reduces the acid load and maintains acid-base balance, thereby improving bone density [89]. This suggests that a reasonable dietary acid-base balance provides crucial support for maintaining astronauts’ bone health.

Numerous studies have now confirmed that various nutritional supplementation regimens (Table 3) exhibit potential ameliorative effects on microgravity-induced bone loss in animal models. During the 4-week period of tail suspension in SD rats, when a combined supplementation regimen of collagen peptide and calcium citrate was adopted, although it partially improved the deterioration of bone microstructure and upregulated the expression level of osteocalcin, compared with the suspension group, its effect on improving BMD was not significant [90]. This suggests that while nutrient supplementation is effective in mitigating microgravity-induced bone loss to some extent, more potent nutritional supplementation strategies may be required to further enhance bone health. Natural compounds have emerged as one of the key research focuses in aerospace medicine due to their rich nutritional value and therapeutic potential. For instance, after mice received naringenin (NAR) supplementation during a 4-week tail suspension, NAR was effective in improving the bone microstructure compared to the suspension group by promoting osteoblast differentiation through activation of the Nrf2/HO-1 signaling pathway [91]. This led to an increase in trabecular number, thickness, and overall bone biomechanical properties. Spirulina platensis, a nutrient-rich spherical microalgae, contains abundant proteins and polysaccharides that effectively alleviate bone density reduction in hindlimb-suspended mice. It inhibits FoxO3 expression and enhances Wnt signaling via activation of the FoxO3/Wnt/β-catenin pathway, thereby promoting bone formation [92]. Given its positive impact on bone health, NASA has listed it as one of the key nutritional supplements for astronauts [93].

Nutritional supplementation represents one of the critical strategies for combating bone loss in astronauts, improving bone health by compensating for nutrient deficiencies, and targeting bone metabolic signaling pathways. Compared to single-nutrient supplementation, which mitigates bone loss to some extent but lacks significant inhibitory effects on bone resorption, natural compounds offer a superior alternative. In the future, efforts should focus on the development and application of novel nutrients, integrating them into personalized nutritional programs to provide a more comprehensive strategy for managing astronauts’ bone health.

Exercise interventions

Although pharmacological treatments and nutritional supplements effectively inhibit the increase in bone resorption through biochemical modulation, their promotion of bone formation remains limited. Given the potential toxic side effects associated with pharmacological treatments, it is imperative to actively explore sustainable interventions for improving bone health. Exercise, as a non-pharmacological treatment free of toxic side effects, has been shown to enhance bone health in terrestrial environments [94], 95]. Despite the challenges posed by microgravity in space, exercise interventions still demonstrate certain potential and advantages [96]. 

Studies have indicated that different exercise modes alleviate microgravity-induced bone loss by modulating distinct mechanisms. In aerospace medicine, there is a consensus that aerobic and resistance exercises are the primary interventions for maintaining an astronaut’s health [97], 98]. Astronauts from various countries performing aerobic exercises on second-generation treadmills and bicycle ergometers during missions to the ISS effectively mitigated bone loss. However, BMD at the hip and femur still tended to decrease, which was highly correlated with exercise intensity and loading conditions [102]. Additionally, Lower Body Negative Pressure Running (LBNP), a novel form of aerobic exercise, shows promise in improving bone loss by providing a low-gravity environment for the lower body via pneumatic pressure technology, thereby reducing physiological burden [103], 104]. Seven women undergoing LBNP during 30 days of bed rest found that LBNP effectively mitigated the decrease in BMD induced by prolonged bed rest [105]. Furthermore, LBNP decreased the synthesis of bone resorption markers such as NTX [106], likely due to alterations in systemic blood distribution caused by LBNP. While aerobic exercise can partially mitigate bone loss, resistance exercise often represents a superior exercise intervention in microgravity due to its greater mechanical stimulation of the skeleton [107] and the current maturity of resistance equipment technology for space applications [108]. Resistance exercise has been shown to be the primary intervention for improving bone loss in both men and women, providing stronger mechanical stimulation that not only facilitates bone mass recovery but also significantly reduces the risk of falls and fractures [109]. After six months aboard the ISS, during which 10 astronauts underwent resistance training using the Advanced Resistive Exercise Device (ARED), post-flight testing via DXA and QCT revealed some suppression of femoral neck volumetric BMD (vBMD) decline and alleviation of bone loss. However, a trend toward decreased hip trabecular vBMD persisted, and the expression of bone resorption biomarkers was up-regulated [96]. Although Resistance exercise demonstrated positive effects in improving bone loss, its inhibitory effect on bone resorption was not significant, suggesting the need for combined interventions. To better investigate the effects of microgravity on bone loss, prolonged bed rest has been used as a simulated microgravity environment [110], 111]. Nine participants performed resistance exercise on a horizontal exercise machine 6 days per week during 17 weeks of bed rest, including upper vs. lower body exercises. After 17 weeks of bed rest, the relevant data from these nine subjects were compared with those of 18 control subjects. It was found that the BMD of the lumbar spine and other parts significantly decreased, while the BMD of the exercise group significantly increased, and the levels of bone formation markers such as BSAP and ALP were elevated [111]. However, bone resorption markers such as N-terminal peptide maintained an up-regulation trend, consistent with previous findings, indicating that resistance training promoted bone formation more significantly than it inhibited bone resorption. Historically, astronauts on the ISS have typically employed a high-intensity resistance exercise combined with aerobic exercise strategy, demonstrating more significant improvements in bone health compared to single-modality exercise [112], 113]. Interestingly, the combination of resistance exercise and aerobic exercise was not effective in inhibiting bone resorption. After an exercise regimen combining LBNP with flywheel resistance exercise during 60 days of bed rest in eight women, bone resorption markers such as N-terminal cross-linked telopeptides were higher than pre-bed rest levels, and bone resorption was not inhibited. However, the regimen did promote the production of markers of bone formation such as ALP, facilitating bone formation [114].

Although aerobic exercise and resistance exercise have demonstrated some effectiveness in mitigating microgravity-induced bone loss, they are insufficient to fully address the problem. In recent years, numerous studies have indicated that vibration training may represent one of the novel interventions for combating microgravity-induced bone loss [115]. In SD female rats subjected to localized vibration training twice daily during a 21-day tail suspension, significant improvements were observed in trabecular BMD of the femur and tibia, as well as biomechanical properties such as maximum load and bending stiffness compared to the suspension group [116]. Interestingly, another study found that femoral BMD did not improve significantly when rats underwent tail suspension for 28 days followed by vibration training during their recovery period [117]. This may be related to the decreased mechanosensitivity of osteoblasts after the onset of bone loss. It is important to note that while vibration training alone has shown some efficacy in ameliorating bone wasting, its efficacy may be limited by insufficient stimulus intensity. In recent years, with advancements in research on complex mechanical stimulation interventions, resistive vibration training has emerged as a promising novel intervention for stimulating bone remodeling. In a study involving 14 men who underwent resistance vibration exercises during 60 days of bed rest, reduced bone loss was observed in the hip, lumbar spine, and Achilles tendon compared to the control group. Additionally, no significant changes were noted in urinary calcium and creatinine levels, while Ocn levels were significantly elevated [118]. This suggests that resistance vibration exercises exhibit potential for mitigating microgravity-induced bone loss. In another study, 24 male participants who performed high-load resistance exercise combined with whole-body vibration training during 60 days of bed rest demonstrated greater preservation of bone mass in the proximal femur and tibial diaphysis compared to those receiving resistance exercise alone [119]. Furthermore, exercise as a preventive modality is effective in preventing the occurrence of bone loss [120], laying a theoretical foundation for combating microgravity-induced bone loss through exercise preadaptation. However, excessive participation in high-intensity aerobic exercise prior to spaceflight may accelerate tibial trabecular bone loss during flight [121], potentially due to the relationship between exercise intensity and exercise pattern.

In conclusion, in a microgravity environment, exercise intervention can effectively slow down bone loss. It promotes bone formation through mechanical stimulation and regulates bone metabolism, as shown in Table 4. Maintaining resistance exercise during flight is more effective in improving bone health. However, engaging in intense exercise before a flight may accelerate the bone loss of astronauts in the space environment. For instance, a study by Leigh et al. found that when astronauts increased their running volume before an aircraft flight, the loss of trabecular bone in their tibia became more severe [121]. Exercise intervention is currently a common strategy for astronauts to maintain bone mass during space missions, but its application still faces challenges, such as the lack of fully defined exercise doses and parameters, as well as differing responses across skeletal regions following exercise. In the future, it will be necessary to focus on exploring personalized exercise prescriptions based on bone metabolic markers and analyzing the mechanisms of mechanical signals and bone responses using multi-omics technology to further refine the scientific strategies for combating bone loss through exercise.

Combined intervention

Although interventions such as pharmacological treatment, nutritional supplementation, and exercise interventions have demonstrated certain application value in the prevention and treatment of microgravity-induced bone loss, their improvement effects may be limited by factors such as the singularity of the regulatory target and the unilateral regulation of bone metabolism. Considering the complex mechanisms of skeletal diseases in microgravity environments, multidimensional and synergistic interventions may present a more preferable option for achieving systematic protection of bone health.

As discussed in the preceding section, combined bisphosphonate supplementation under daily exercise in space is more effective than single bisphosphonate supplementation in ameliorating bone loss. This is primarily manifested in the fact that resistance exercise combined with bisphosphonates not only attenuates cortical bone loss but also further mitigates trabecular bone loss, thereby realizing bidirectional regulation of bone homeostasis – simultaneously promoting bone formation and inhibiting bone resorption [19]. Another ambulatory trial also demonstrated that resistance exercise combined with bisphosphonate therapy attenuated the increase in serum calcium ions and the decrease in plasma calcitonin in subjects. Additionally, this combined intervention rescued femoral neck mineral loss [122]. These findings suggest that resistance exercise combined with bisphosphonate therapy holds significant potential for improving microgravity-induced bone loss. Although antiresorptive drugs combined with exercise interventions achieve bidirectional regulation of bone metabolism and mitigate the progression of bone loss, their long-term effects may be limited by drug-induced gastrointestinal complications, which can reduce drug absorption rates [123]. Notably, nutritional supplementation combined with exercise intervention has demonstrated the applied value in maintaining bone health [124]. During 4–6 month space missions, astronauts maintained an adequate amount of resistance exercise (including ARED and iRED) and supplemented sufficient amounts of nutrients such as vitamin D, sodium, iron, and potassium through dietary intake. Upon returning to Earth, it was found that the decreasing trend of pelvic mineral content was slowed [125]. This indicates that nutritional supplementation combined with exercise intervention can effectively inhibit bone loss in microgravity environments, maintain bone density levels, and reduce the risk of osteoporosis.

Although joint interventions have shown some potential for improving microgravity-induced bone loss, there is currently insufficient clinical data to determine the effectiveness and safety of different combined intervention modes for bone protection. Further optimization of relevant protocols is therefore required. In the future, longer-term studies should be conducted, and better combinations should be selected using relevant databases and microarray technology to construct novel protection models.

A comprehensive comparison of intervention strategies

In summary, after systematically exploring the ameliorative effects of pharmacological treatments, nutritional supplementation, and exercise interventions on microgravity-induced bone loss, we further analyzed and compared these intervention modalities (Table 5). While these modalities demonstrated certain improvements, differences remained in terms of intervention timing, efficacy, and potential side effects.

In terms of efficacy, pharmacological treatments for microgravity-induced bone loss have primarily focused on inhibiting bone resorption. Anti-resorptive drugs such as bisphosphonates and denosumab target and regulate osteoclast activity and the expression of osteoclast-associated factors, thereby mitigating increased bone resorption caused by stressful mechanical deficits due to microgravity. Additionally, pharmacological treatment rapidly increased BMD in the short term. For instance, bisphosphonate supplementation exhibited anti-resorptive efficacy and significantly down-regulated NTX expression over 15–30 days compared to exercise alone when daily exercise was maintained [19]. Therefore, pharmacological treatments are more suitable for addressing rapid bone loss associated with short-term space missions. However, medications may include toxic side effects. Studies have shown that long-term use of bisphosphonate medications may increase the risk of skeletal disorders such as jaw osteonecrosis [126] and atypical femur fracture [127]. Furthermore, anti-resorptive drug therapy may synergistically inhibit osteoblast differentiation, reducing the rate of bone recovery [128]. Long-term use of denosumab may induce chronic inflammation, cause pharmacologic injury [129], and rapidly lead to renewed bone loss upon discontinuation of the drug [130]. Nutritional supplementation regulates bone homeostasis by providing nutrients related to bone metabolism, such as vitamin D and vitamin K. Nutritional supplementation typically requires a longer duration and is influenced by individual metabolic and absorption capacities. Excessive intake of calcium or vitamin D may induce hypercalcemia and hypercalciuria [131], necessitating strict monitoring of nutritional intake. Compared with pharmacological treatments, exercise interventions primarily promote bone formation by applying mechanical loads to maintain bone homeostasis [96]. Exercise can also effectively improve the function of various tissues in astronauts, including the muscular system [132] and the cardiovascular system [133]. However, given the weak inhibitory effect of exercise on bone resorption and the high dependence on equipment in the space environment, joint interventions such as exercise-pharmacologic intervention or exercise-supplementation combinations may represent better options (Figure 3).

Figure 3:

Comparison of the effects of single intervention and combined intervention on bone loss.