Why does space cause bone loss

In the FREEDOM clinical trial, denosumab subcutaneous administration at the dose of 60 mg every six months was effective in reducing fracture risk in women with postmenopausal osteoporosis. Furthermore, denosumab also significantly improved bone mineral density at various skeletal sites, including the total hip, lumbar spine, femoral neck and trochanter bone [ 43 , 44 ].

For its proven efficacy and safety, denosumab is being considered by NASA as a potential countermeasure for bone loss due to microgravity and results from experiments regarding its employment in space are still pending.

Antiresorptive drugs are potent agents in preventing bone loss and reducing fracture risk. However, long-term use of those medications, such as what might be done in space travel, can produce rare but potentially serious adverse effects, such as osteonecrosis of the jaw and atypical femoral fractures [ 44 , 45 ].

When thinking about drug therapy, especially in conditions that could alter per se pharmacokinetic parameters, such as space environment [ 46 ], several variables must be considered.

These include the safety profile, route of administration and frequency: in fact, a drug with an easy route of administration, such as oral or intranasal, could ensure better adherence to the drug regimen, while a reduced frequency in assumption could decrease the onset of undesirable effects due to a continuous and repeated exposure to the medication [ 47 ].

To meet this last requirement, a medication must demonstrate a prolonged pharmacological action and, to date, some drugs that fall into the bisphosphonate class possess this property; indeed, some of them, in addition to an oral route of administration, also has a weekly alendronate or risedronate or even monthly pamidronate dosage. The frequency in its administration changes according to the type of pathology considered.

For the prevention and treatment of osteoporosis, it corresponds to an infusion of 4—5 mg of zoledronic acid, respectively, every one or two years [ 49 ]. Although the route of administration is complicated and requires the intervention of specialized healthcare personnel, its unusual frequency in dosage may suggest its use as a single infusion pre-launch.

The same reasoning could be applied to the monoclonal antibody denosumab, whose dosage schedule is a subcutaneous administration of 60 mg every 6 months [ 43 , 44 ]. Considering adverse effects produced by antiresorptive agents, the focus and medical interest are shifting to developing pharmacological countermeasures acting through different mechanisms of action. Among these, anabolic drugs exert their function by increasing bone formation rather than inhibiting resorption.

Currently available anabolic agents improve bone mass and reduce fractures through stimulation of the parathyroid hormone receptor-1 on osteoblasts and their precursors. In a healthy organism, PTH functions as an essential endocrine regulator of calcium and phosphate concentrations in the extracellular space, which is crucial for maintaining serum and urinary calcium levels within the physiological range [ 50 ]. Usually, teriparatide is also administered in combination with vitamin D — IU and calcium mg supplementation [ 51 ].

Many other studies confirm the efficacy of teriparatide in preventing bone fractures and increasing BMD in osteoporosis patients and safety, considering no severe adverse reactions have been reported after long-term administration [ 52 ].

Nowadays, the administration of teriparatide through daily subcutaneous injections seems to be the most employed method. However, in environments such as the one aboard the ISS, it perhaps may not be indicated due to the difficulty in administration, which could hamper the compliance of the therapeutic regime. For this reason, it would be appropriate to evaluate different routes of administration.

Several studies in the literature have demonstrated that oral formulations at higher doses 2. To enhance absorption and bioavailability of therapeutic peptides, a new delivery system has been developed by Altaani and colleagues [ 55 ] in a preliminary in vivo study, which relies on teriparatide encapsulation in oleic acid-based nanoemulsions to be administered orally.

Therefore, studies with teriparatide, as an additional countermeasure for circulating PTH fall in microgravity and hypercalciuria, would be interesting in future space missions. The effect of teriparatide, as an anabolic agent aimed at increasing BMD, is confined to a well-defined therapeutic window. Among the factors that mitigate the bone-forming activity, it must be considered that PTH, in addition to the bone-forming effect exerted on osteoblasts and osteocytes, also displays an indirect resorptive action by stimulating osteoclasts through a well-known molecular mechanism, already described elsewhere [ 50 , 58 ].

Indeed, several studies have shown that long-term administration of teriparatide beyond 24 months leads to increased resorptive markers and to a reduction in pro-forming bone markers, shifting the balance in the opposite direction. For this reason, using hrPTH is limited to a maximum period of 2 years, beyond which the anabolic effect on bones declines in favor of a catabolic action [ 60 , 61 ]. Teriparatide therapeutic regime, described in the previous paragraph, may be compatible with the duration of the current missions since astronauts rarely stay on the ISS for more than a year.

To date, only the cosmonaut Valery Polyakov currently holds the overall record for the longest space mission, having completed a stay of days aboard the ISS [ 62 ]. The problem arises when evaluating the possibility of long-term space flights, such as future expeditions to Mars, where extensive use of teriparatide alone will not only be able to counteract microgravity resorptive effects but instead could cause a synergic catabolic activity alongside the one induced by microgravity, leading to a dangerous risk for human health.

For long-term treatment of osteoporosis, researchers have focused their attention on developing combined and sequential drug therapies with both anabolic and antiresorptive mechanisms of action.

Soon after, an extension study followed, aimed at evaluating the effect of sequential therapies on osteoporosis: women originally assigned to months of teriparatide received months of denosumab; subjects originally randomized to months of denosumab shifted to months of teriparatide; and subjects, who originally received both drugs, received an additional months of denosumab alone [ 64 ].

BMD continued to increase transitioning from teriparatide to denosumab, whereas switching from denosumab to teriparatide resulted in progressive or transient bone loss. According to the authors, 2 years of combined therapy followed by 2 years of denosumab alone is associated with the largest cumulative BMD increases at the hip and radius, an important clinical outcome since increases obtained were greater than any currently available therapy taken for a similar duration.

The additive effect of these two drugs appears to be linked to the ability of denosumab to fully inhibit teriparatide-induced bone resorption but only partially inhibit anabolic bone formation [ 64 ]. This combined and sequential approach could be evaluated for its effectiveness in long-term space travels.

Ground-based simulated studies are needed and should be carried out to validate the potential of this 4-year therapeutic regimen. However, observations in real space conditions could be difficult due to the excessively long time astronauts should spend on the ISS. To date, no information is available regarding the effects of space exposome on human physiology over such prolonged times. Furthermore, it is unclear what effect stopping this therapy may have once the astronaut returns to normal gravity conditions.

All pharmacological countermeasures described above are effective in reducing bone loss associated with unloading conditions. However, they show some undesirable effects, even serious ones, which may arise after long-term use. For this reason, efforts have been made to find more riskless drugs for the prevention of bone loss during space flight.

In this regard, researchers have focused their attention on melatonin, a hormone produced by the pineal gland, synthesized almost exclusively in the dark. Melatonin is known for its wide variety of physiologic functions, including hypothalamic control of circadian rhythms, body temperature, bone homeostasis and displays effects on both cardiovascular and immune systems [ 65 , 66 , 67 ].

The implication of melatonin in the maintenance of skeletal apparatus physiology has been raised by several studies associating a decrease in the nocturnal production of melatonin, due to aging or to light exposure at night, with increased risk of osteoporosis [ 68 , 69 ].

Today, molecular mechanisms responsible for melatonin anabolic effects on bone density have been extensively investigated and can be summarized in Figure 1. Briefly, melatonin can act on osteoblasts, favoring proliferation and differentiation, and simultaneously manifest inhibitory effects on osteoclast differentiation and bone-resorbing activity [ 65 , 69 ].

These factors, such as bone morphogenetic proteins 2 and 4 BMPs , runt-related transcription factor 2 Runx2 and osteocalcin OCN , display anabolic action as they are positively involved in controlling the bone formation and osteoblasts and osteocyte differentiation from precursor cell lines [ 65 , 66 , 69 ].

The factors involved in controlling the bone formation and osteoblasts and osteocyte differentiation from precursor cell lines are bone morphogenetic proteins 2 and 4 BMPs , runt-related transcription factor 2 Runx2 and osteocalcin OCN. In bone tissue, differentiation and activation of osteoclasts are generally influenced by interactions with osteoblastic lineage cells. RANKL signaling is usually inhibited by osteoprotegerin OPG , a decoy receptor produced by stromal cells, as negative feedback to control osteoclastogenesis.

Melatonin intracellular signaling leads to the modulation of genes that influence osteoclast differentiation and activity; specifically, a downregulation of RANKL and upregulation of OPG have been observed in cell culture studies after stimulation with melatonin, hence shifting the RANKL:OPG ratio towards an anti-osteoclastogenic activity [ 69 ].

This finding is also supported by clinical trials showing that in women treated with melatonin supplements, ratios of type-I collagen crosslinked N-telopeptide NTX a bone resorption marker to OCN trended downward compared to placebo. This is an important finding because as women transition through menopause, the NTX:OCN ratio increases such that osteoclast activity outpaces osteoblast activity leading to bone loss [ 73 ].

Recent studies on fishbone scales and chick calvariae models demonstrated that melatonin is also able to upregulate, in osteoblasts and their precursors, the transcription and production of another hormone, calcitonin, involved in bone remodeling [ 74 , 75 ].

However, more in-depth studies must be performed to verify this pattern also in human bone cells. Melatonin has also been proposed to produce an upregulation of calcitonin, whose binding to its receptor calcitonin binding receptor or CTR on osteoclasts induces a rapid cell contraction, causes inhibition of osteoclast motility.

Calcitonin also inhibits red arrows other pathways associated with osteoclast activity, such as the release of acid phosphatase and the expression of carbonic anhydrase II CA II , a cytosolic enzyme involved in the maintenance of an acidic environment, necessary for osteoclast resorption. Calcitonin is a amino acid linear polypeptide usually produced in humans primarily by the parafollicular cells of the thyroid gland. Focusing on calcitonin antiresorptive activity, the binding of this hormone to its receptor calcitonin binding receptor or CTR induces a rapid cell contraction and, therefore, causes inhibition of osteoclast motility which negatively affects cell capacity to resorb bone surfaces.

However, this effect is temporary, and osteoclasts have been shown to gradually escape this inhibition after several hours [ 78 , 79 , 80 ]. Besides its action on cell motility, calcitonin also inhibits other pathways associated with osteoclast activity, such as the release of acid phosphatase and the expression of carbonic anhydrase II, a cytosolic enzyme involved in the maintenance of an acidic environment, necessary for osteoclast resorption [ 79 , 80 , 81 ].

Calcitonin also has been demonstrated to interfere with osteoclast differentiation from precursor cells and the fusion of mononucleated precursors to form multinucleated osteoclasts in bone marrow cultures [ 79 , 80 ]. Considering evidence indicating melatonin as a new therapeutic approach for the treatment of osteoporosis on Earth, through its dual anabolic and antiresorptive action, its use in space medicine could be advantageous for the treatment not only of osteopenia related to microgravity but also for the reestablishment of all those alterations linked to circadian rhythms.

It is known. Indeed, changes in lighting and work schedules during spaceflight missions can impact circadian clocks and disrupt sleep, especially in the early stages of adaptation to living conditions on the ISS, hence compromising the mood, cognition and performance of orbiting astronauts [ 82 , 83 ].

To date, using melatonin in space has been mainly considered as a non-pharmacological remedy for the treatment of circadian misalignment and sleep deficiency. However, its clinical use for the treatment of microgravity-induced osteoporosis was first hypothesized by Ikegame and colleagues in , thanks to their studies on interactions between osteoclasts and stromal cells in real microgravity conditions, using a new experimental bone model based on goldfish scales flown on the ISS [ 74 ].

Their interesting studies provide evidence that melatonin suppresses osteoclast bone-resorbing activity in bone tissues under microgravity conditions via the upregulation of calcitonin and the downregulation of RANKLin osteoblasts.

Taking together all the aspects described in the previous paragraph, a more in-depth study of the dual, anabolic and antiresorptive effect of melatonin on bone metabolism is, therefore, highly encouraged in both simulated and real microgravity conditions.

In the previous paragraphs, the effect that the loss of bone mass can cause on the resistance and strength of the entire skeletal system has been brought to light several times. Indeed, one of the main consequences of severe bone mass loss and demineralization due to unloading conditions is the raised risk of both vertebral and nonvertebral fractures. Beyond fractures due to progressive osteopenia induced by microgravity, it must also be considered that traumatic injuries, such as bone fractures and wounds, can naturally occur during routine operational procedures or extravehicular activities EVA [ 84 , 85 ].

Despite the evident medical need, however, the systemic response to fracture injury and the mechanism of human bone repair in unloading conditions is poorly investigated.

In normal conditions, tissue regeneration involves a coordinated interaction of cells, proteins, proteases, growth factors, small molecules and extracellular matrix ECM components to restore tissue morphology and functioning. Just like skin repair, also the bone healing process can be divided into multiple steps, and a communication network between stromal, endothelial, bone and immune cells is very important in determining the course of healing and recovery of tissue function [ 86 , 87 , 88 ].

Briefly, the first response to a bone fracture is constriction of the injured blood vessels and activation of platelets that form a fibrin clot or hematoma to cease blood flow and provide a scaffold for incoming cells by releasing signaling and growth factors, which, in turn, activate the migration of inflammatory cells and repair cells, such as fibroblasts, osteoblasts, stem cells and vascular endothelial cells [ 88 ].

The recruited fibroblasts begin to lay down the stroma that helps support vascular ingrowths while the responding macrophages remove tissue debris. Inflammatory cells also release growth factors and cytokines signals to recruit mesenchymal stem cells MSCs , which proliferate and differentiate into osteoprogenitor cells and then into osteoblasts and osteoclasts to form and remodel newly formed bone tissue [ 86 , 87 ].

Much evidence in the literature highlights the pivotal role of blood vessels in the process of bone repair and osteogenesis, which indicates intimate molecular crosstalk between endothelial cells and osteoblasts [ 88 , 89 ]. Angiogenesis is required at different steps and, among the key roles played in the process, it furnishes oxygen and nutrient supply for the regenerating tissue, while endothelial cells ECs secrete osteogenic growth factors [ 90 ] to promote osteogenesis and osteoblast differentiation from their precursors.

Newly formed blood vessels ensure steady transport of circulating osteoclast and osteoblast precursors to remodeling sites, regulating, therefore, osteoprogenitor cell invasion [ 90 , 91 ].

Many studies in the literature have reported that cell lines responsible for bone repair MSC, fibroblasts, macrophages, osteoblasts, osteoclasts, and ECs , taken individually, are highly sensitive to microgravity and undergo morphological, functional, and biochemical changes under these conditions [ 16 , 27 , 92 , 93 ]. Besides osteoblast, osteoclast, and MSC alterations discussed previously, simulated microgravity studies have shown that ECs undergo important cytoskeletal remodeling and show impairment in proliferation and survival.

However, there are still controversial data about ECs capacity to migrate and organize in 3D structures, and therefore, to sustain full angiogenic responses in unloading conditions [ 94 ], especially in the processes of wound or fracture healing. Given the above, it could be deduced that if individual cell types manifest alterations in their morphology and function, the entire regeneration process may somehow be compromised by the lack of canonical gravitational forces.

To date, very limited data in this regard is available. However, all studies performed on murine or rat models, both in real and simulated microgravity conditions, provide strong evidence and convey the same conclusion that the fracture healing is compromised in microgravity conditions and manifests in both histological and morphometric alterations and differences between animals healed in space or on Earth [ 95 , 96 , 97 ].

While these data demonstrate that microgravity has a deleterious effect on bone healing, the direct translation of these results to human bone healing is difficult due to the numerous differences between rodent and human bone microstructure and healing process. Furthermore, the molecular crosstalk among these cell lines in bone regeneration following fracture injuries is not fully known in conditions of real or simulated microgravity, and it is not yet clear how these physiological and key interactions can change.

Besides studying the phenomenon from a molecular point of view, it would also be interesting to evaluate whether nonsurgical options currently in use on Earth to promote and facilitate bone regeneration in patients with healing deficiencies could be applied to space medicine for the treatment of mild fractures, which, in long-term spaceflights, could compromise astronaut performance.

The advantage of using nonsurgical countermeasures would lie in their non-invasive nature and easy application, which could allow the astronaut, in the event of minor fractures, rapid self-medication. Advances in regenerative medicine are focused on the employment of mesenchymal stem cells MSCs to improve bone regeneration with interesting results due to their self-renewal and differentiation capacity and their ability to secrete bioactive molecules and regulate the behavior of other cells in different host tissues [ ].

Instead, other research lines are evaluating pharmacological approaches based on the regulation of molecular mechanisms, such as antagonists of the WNT pathway [ , ], or using bone tissue morphogenic factors [ , ]. However, these lines of research have yet to find a consolidated use for the treatment of bone healing deficiencies on Earth, and their employment in space medicine will be subsequently validated.

Bone plays an important role as a structure that supports the body and represents a mineral reservoir for calcium and phosphate. The skeletal apparatus is in continuous reshaping, and its homeostasis is finely tuned by a balance in bone resorption and formation operated by osteoblasts, osteoclasts and osteocytes [ 3 , 4 ]. In a microgravity environment, because of reduced loading stimuli, this equilibrium is lost, and bone resorption prevails on bone formation, leading to bone mass loss at a rate of about ten times that of Earth osteoporosis [ 1 , 24 ].

Microgravity-induced osteopenia is, therefore, a significant and unresolved health risk for space travelers, which leads to a raised likelihood for irreversible changes that weaken skeletal integrity and to an increment in the onset of fracture injuries and renal stones formation [ 84 , 85 ]. Today several pharmacological and non-pharmacological countermeasures to this problem have been proposed, including physical exercise, diet supplements and administration of antiresorptive Bisphosphonates or denosumab or anabolic drugs teriparatide.

However, each class of pharmacological agents presents several limitations as prolonged and repeated employment of both antiresorptive and anabolic agents singularly is not exempt from the onset of serious side effects, which limit their use within a well-defined therapeutic window.

Antiresorptive and anabolic drug therapeutic schedules, described in previous paragraphs, may be compatible with permanence in space comparable to that of the current missions since astronauts rarely stay on the ISS for more than a year.

For long-term treatment of osteoporosis on Earth, researchers have focused their attention on developing sequential drug therapies with both anabolic and antiresorptive mechanisms of action, which could prove to be very effective and useful in future exploration missions.

However, the potential use of this pharmacological approach in space flights has yet to be validated through studies in real or simulated microgravity conditions. Furthermore, the 4-year therapeutic regimen applied in clinical studies on Earth to treat menopause osteoporosis is hardly applicable to observations in real space conditions due to the excessively long time astronauts should spend on the ISS. For this reason, the search for both safe and effective drugs for the long-term treatment of microgravity-related osteopenia, given longer space expeditions, remains an open challenge that requires major efforts to be resolved.

In the last decade, several studies have brought to light the role of melatonin in regulating and maintaining skeletal apparatus physiology. We assumed that any method used to measure bone density provides different degrees of precision and accuracy in assessment of the same quantity. We excluded two studies that used ultrasound to evaluate bone density in three astronauts 24 , 59 because two ultrasound measurement techniques reported inconsistent data for the same individuals.

Bone density measures were grouped into four skeletal regions: skull and neck region 1 , upper limbs and thorax region 2 , lumbar vertebrae and pelvis region 3 , and lower limbs region 4. Mission-level standard deviations SD i were computed in one of three ways:. For biochemical marker data, first the variation among different markers reported per individual or group of astronauts at particular time point, SD m , was computed as in step 1.

Then, the variation among astronauts SD a was computed as in step 2. Single- and cumulative-study exclusion analysis assessed the impact of individual datasets on the overall outcome and heterogeneity, as well as homogeneity threshold T H Publication bias was assessed by assuming that in the absence of bias study-level outcomes have a funnel shape distribution due to random sampling error.

The division for the subgroup analysis was performed to achieve approximately equal size group in each category. For fitting a non-linear model, or considering additional variance for a linear relationship, a Monte-Carlo error propagation method 61 was used with MetaLab 57 , or a custom MATLAB script for piecewise functions Supplementary Methods 3.

Custom MATLAB code used to fit piece-wise functions to biochemical bone resorption and formation data post-flight can be found in Supplementary Methods 3. Vico, L. Cortical and trabecular bone microstructure did not recover at weight-bearing skeletal sites and progressively deteriorated at non-weight-bearing sites during the year following international space station missions.

Bone Miner. Orwoll, E. Skeletal health in long-duration astronauts: nature, assessment, and management recommendations from the NASA bone summit. PubMed Google Scholar. Pivonka, P. Functional adaptation of bone: the mechanostat and beyond. Copp, D. The homeostatic function of bone as a mineral reservoir. Oral Surg. Oral Med. Oral Pathol. Taichman, R. Blood and bone: two tissues whose fates are intertwined to create the hematopoietic stem-cell niche.

Blood , — Lemann, J. Bone buffering of acid and base in humans. CAS Google Scholar. Robling, A. Mechanical signaling for bone modeling and remodeling. Gene Expr. Zerath, E. Effects of microgravity on bone and calcium homeostasis. Space Res. Effects of spaceflight on cells of bone marrow origin. Smith, S.

Fifty years of human space travel: implications for bone and calcium research. Webber, C. Photon absorptiometry, bone densitometry and the challenge of osteoporosis. Greenblatt, M. Bone turnover markers in the diagnosis and monitoring of metabolic bone disease.

Kuo, T. Bone biomarker for the clinical assessment of osteoporosis: recent developments and future perspectives. Male astronauts have greater bone loss and risk of hip fracture following long duration spaceflights than females.

Google Scholar. Biryukov, E. Leblanc, A. Bisphosphonates as a supplement to exercise to protect bone during long-duration spaceflight. Mack, P. Roentgenographic bone density changes in astronauts during representative Apollo space flight.

Miyamoto, A. Medical baseline data collection on bone and muscle change with space flight. Bone 22 , S79—S82 Oganov, V. Reactions of the human bone system in space flight: phenomenology. Sibonga, J. Resistive exercise in astronauts on prolonged spaceflights provides partial protection against spaceflight-induced bone loss. Bone , Stupakov, G. Evaluation of changes in axial skeleton bones during prolonged space flight.

Vogel, J. Bone-mineral measurement—Skylab experiment M Acta Astronaut. Vose, G. Review of roentgenographic bone demineralization studies of Gemini space-flights. Collet, P. Effects of 1- and 6-month spaceflight on bone mass and biochemistry in two humans.

Bone 20 , — Gluten and You. Arctic Tundra Biome. The Science of Breadmaking. How does water move in plants? What is the molecular clock?

Plants Can Make Memories. What happened to the Tasmanian tiger? How does your stomach work? Whale Poo and You. Bringing Back the Woolly Mammoth. Learn to Love Lichens. Where did the Zika Virus come from? Snow Leopard: Ghost of the Mountains. How long can people live? Make a Handheld Gimbal out of your Phantom 3 Drone. How the Body Adjusts to Altitude. Collecting Bugs in Sweden. Collecting Bugs in the Amazon.

How to Make Science and Nature Films. Will Cortisone Make Things Worse? The Endangered Giant Panda. How to Create a Hyperlapse. What's Wrong with Science on TV?

Mysteries of the Driftless Wins Emmy. The Science of Cider. In a microgravity environment, because of reduced loading stimuli, there is increased bone resorption and no change in or possibly decreased bone formation, leading to bone mass loss at a rate of about ten times that of osteoporosis. The proximal femoral bone loses 1. Bisphosphonate is a therapeutic agent that has been used to treat osteoporosis patients for more than a decade, with a proven efficacy to increase bone mass and decrease the occurrence of bone fracture.

Through day bed rest research on Earth, we confirmed that this agent has a preventive effect on the loss of bone mass. Based on these results as well as studies conducted by others, JAXA and NASA decided to collaborate on a space biomedical experiment to prevent bone loss during space flight. Matsumoto, Tokushima University, are the two principal investigators of this study.