REVIEWInterventions to prevent bone loss in astronauts
during space ﬂight
Jun Iwamoto,1 Tsuyoshi Takeda1 and Yoshihiro Sato2
1Department of Sports Medicine, Keio University School of Medicine, Japan
2Department of Neurology, Mitate Hospital, Fukuoka, Japan(Received for publication on June 30, 2004)(Revised for publication on January 5, 2005)(Accepted for publication on January 20, 2005)

Abstract. This paper reviews the interventions to stabilize calcium balance and bone metabolism andprevent bone loss in astronauts during space ﬂight. Weightlessness during space ﬂight results in calcium, vitamin D, and vitamin K deﬁciency, increases urinary calcium excretion, decreases intestinal
calcium absorption, and increases serum calcium level, with decreased levels of serum parathyroid
hormone and calcitriol. Bone resorption is increased, whereas bone formation is decreased. The loss ofbone mineral density (BMD) in the spine, femoral neck and trochanter, and pelvis is 1.0–1.6% permonth. High calcium intake and vitamin D supplementation during space ﬂight does not affect bonemetabolism, but prevents an elevation of serum calcium level through increased calcitriol level, whilevitamin K counteracts the reduction in bone formation. However, there are no data to show the efﬁcacy
of pharmaceutical agents for prevention of development of osteoporosis in astronauts during ﬂight,
although the preventative effect of bisphosphonates, testosterone, and vitamin K2 on cancellous
bone loss in the tibia or BMD loss in the hindlimb was reported in tail-suspended mature rats. It still
remains uncertain whether these agents can prevent cortical bone loss caused by weightlessness in tailsuspended rats. Therefore, in addition to calcium, vitamin D, and vitamin K supplementation, agentsthat have both potent anti-resorptive and anabolic effects on cancellous and cortical bone may beneeded to stabilize calcium balance and bone metabolism and prevent bone loss in astronauts during
space ﬂight. (Keio J Med 54 (2): 55–59, June 2005)
Key words: Bone formation, bone resorption, calcium, microgravity, osteoporosis

volumetric (v) BMD was lost during 4- to 6-monthspace ﬂight at a rate of 0.9% per month and cancellous
vBMD was lost at 0.7% per month, while in the hip integral, cortical, and cancellous vBMD was lost at rates
of 1.2–1.5%, 0.4–0.5%, and 2.2–2.7% per month, respectively. Thus, bone mass changes may be site speciﬁc
and bone loss seems to be greater in cancellous bonethan in cortical bone especially in the leg.
Thus, the physiologic changes in bone in astronauts
during space ﬂight have been studied. Osteoporosis
after space ﬂight may lead to an increased risk of fractures in later life. To our knowledge, the effects of calcium, vitamin D, and vitamin K on calcium balance andbone metabolism during space ﬂight in astronauts havebeen reported, and the efﬁcacy of bisphosphonates,

Introduction
It is known that weightlessness during space ﬂight
causes osteoporosis. The loss of bone mineral density(BMD) in the spine, femoral neck and trochanter, andpelvis is 1.0–1.6% per month.1 The loss of bone mass inthe whole body and legs, which are rich in corticalbone, is 0.3–0.4% per month.1 According to Collet
et al.,2 6 months of space ﬂight resulted in 13.2% loss of
calcaneus broadband ultrasound attenuation (BUA),
4.5% and 2.9% decreases in tibia cancellous andcortical bone mass, respectively, but 0.2% and 0.5%
increases in radius cancellous and cortical bone mass,
respectively. Skull BMD increases after space ﬂight.3
Recently, Lang et al.4 demonstrated that spinal integral

Reprint requests to: Dr. Jun Iwamoto, Department of Sports Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku,
Tokyo 160-8582, Japan, e-mail: jiwamoto@sc.itc.keio.ac.jp55

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Iwamoto J, et al: Prevention of bone loss during space ﬂight

parathyroid hormone (PTH), testosterone, and vitamin
K2 for bone metabolism and bone mass has also beenstudied in the tail-suspended rat as a model of astronauts. The effect of exercise on bone metabolism andbone mass has rarely been reported, although its efﬁcacy is expected. This paper discusses interventions,
except for exercise, to stabilize calcium balance andbone metabolism and prevent bone loss in astronauts
during space ﬂight based on a review of the literature.

that the former may be observed in the early phase ofweightlessness, while the latter may follow the former
in the late phase with decreased bone formation.
Intervention for Bone Loss During Space Flight
Astronaut study
Calcium and vitamin D

Changes in Bone Metabolism and Calciotropic
Hormones During Space Flight
Astronaut study
Smith et al.5 analyzed numerous reports on changes
in bone metabolism during space ﬂight without any
interventions such as medication and exercise. Weightlessness during space ﬂight increases urinary calcium
excretion, decreases intestinal calcium absorption,and increases serum calcium level, with decreased
levels of serum PTH and calcitriol. Bone resorption isincreased as indicated by increased urinary pyridinoline, deoxypyridinoline, and cross-linked N-terminal
telopeptide of type I collagen, and urinary and serumcross-linked C-terminal telopeptide of type I collagenlevels, whereas bone formation is decreased as indicated by decreased serum bone-speciﬁc alkaline phosphatase and C-terminal peptide of type I procollagenlevels, followed by increased serum undercarboxylated
osteocalcin level.
Animal model study
Bone histomorphometric studies of bones from rats
after space ﬂight for various periods provided the timecourse of the cancellous bone cellular events; a transient increase in resorption and sustained decrease inbone formation.6 A tail-suspended rat model has beenused to study the changes in bone metabolism as well ascancellous and cortical bone loss induced by weightlessness. Tail-suspension transiently increases bone resorption as indicated by a transient increase in urinary
deoxypyridinoline level.7 Tail-suspension increases
bone resorption and decreases bone formation in cancellous bone and/or decreases bone formation in cortical bone in young growing and/or mature rats.7–9 With
regard to weightlessness-induced bone loss in rats, suppression of bone formation seems to play a predominant role rather than acceleration of bone resorption.10
Parﬁtt11 proposed two mechanisms of bone loss; reversible bone loss due to increased bone turnover interms of increased birth rate of osteoclasts and osteoblasts and irreversible bone loss due to overactive
osteoclasts and/or underactive osteoblasts. We surmise

Because bone loss during space ﬂight may be partly
associated with low calcium intake and vitamin D deﬁciency due to inadequate sunlight (ultraviolet light) exposure, calcium and vitamin D supplementation may be
a reasonable intervention for it. However, high calcium
intake and vitamin D supplementation during space
ﬂight do not prevent the development of osteoporosis,
because they do not counteract the increase in bone
resorption and the decrease in bone formation despite
prevention of the elevation of serum calcium level
through increased calcitriol level and subsequent
increased intestinal calcium absorption.12–14
Vitamin K
Vitamin K is known to be involved in the formationof g-carboxyglutamic acid (Gla) in proteins, such as
the calcium-binding bone Gla-proteins osteocalcin andmatrix Gla-protein. Space ﬂight induces vitamin K
deﬁciency as indicated by increased calcium-binding
capacity of osteocalcin and urinary excretion of freeGla. Therefore, vitamin K supplementation may be areasonable intervention to stabilize calcium balanceand bone metabolism. It was reported that vitamin K2
decreased the serum undercarboxylated osteocalcin
level and increased the serum osteocalcin level, sustaining lumbar BMD and preventing fractures inpatients with osteoporosis.15 However, the effects ofvitamin K2 on bone metabolism and bone mass havenever been reported. On the other hand, vitamin K1 inastronauts during space ﬂight has no effect on bone
resorption as indicated by no alteration in urinary
cross-linked C-terminal telopeptide of type I collagenlevel, but counteracts the reduction in bone formation as indicated by decreased serum bone-speciﬁc
alkaline phosphatase level, and decreases the serum
undercarboxylated osteocalcin level.16,17 Because anincreased percentage of serum undercarboxylated
osteocalcin level correlates with the hip fracture rate inelderly women,17 the effect of vitamin K1 on serum
undercarboxylated osteocalcin level may be importantto prevent future osteoporotic fractures in astronauts.
Vitamin K may play a signiﬁcant role in bone turnover
during space ﬂight.

Keio J Med 2005; 54 (2): 55–59

Animal model study
Tail-suspended young growing rats
Tail-suspended young growing rats have been well
utilized to test the efﬁcacy of interventions for bonemetabolism and bone mass during weightlessness. The
anti-resorptive agent pamidronate prevented an increase in bone resorption and prevented bone loss
despite a further reduction in bone formation in cancellous bone (secondary spongiosa) of the tibia of tailsuspended young growing rats, but could not restore
normal growth-induced periosteal bone apposition andbone strength in cortical bone because it did not affectthe weightlessness-induced decrease in periosteal boneformation.7 The preventative effect of pamidronate onloss of cancellous bone mass might be associated withthe formation of a substantial amount of primary spongiosa as a result of suppressed bone remodeling in theconversion of primary spongiosa to secondary spongiosa carried out by micromodeling and remodeling.7 It
was conﬁrmed that pamidronate was unable to restore
normal periosteal apposition, but could restore cancellous bone mass. Thus, potent anabolic agents were
expected to restore growth-induced periosteal bone
apposition in tail-suspended young rats.
The potent anabolic agent PTH (intermittent administration) prevented a reduction in bone formationand prevented bone loss in cancellous bone (secondary
spongiosa) of the tibia of tail-suspended young growing
rats.8,18 Surprisingly, however, it could not prevent a
reduction in periosteal bone formation and therefore
failed to prevent cortical bone loss.8,18
Both potent anti-resorptive and anabolic agents may
not be able to prevent the marked decrease in growthrelated periosteal bone formation in the tibia of tailsuspended young rats. Thus, exercise during space ﬂight
may be needed to counteract the decrease in periostealbone apposition or enhance the effect of PTH on periosteal bone formation, because exercise could increase
periosteal bone formation in young growing rats.19–21
Tail-suspended mature rats
Tiludronate prevented bone loss despite a further
decrease in bone formation in cancellous bone (secondary spongiosa) of the tibia of tail-suspended maturerats.22 This preventative effect of tiludronate might
be related to the alteration in bone remodeling withan increase in trabecular bone number in cancellous
bone.22 However, the effect of tiludronate on corticalbone in this model remains uncertain.
Testosterone is anabolic to osteoblasts and muscle
and also decreases bone turnover. Serum testosterone
level was markedly suppressed in tail-suspended57

adult male rats, and this might partially contribute toweightlessness-induced bone loss.23 Testosterone prevented loss of muscle mass and BMD in the hindlimb oftail-suspended mature male rats.24
Recently, anti-resorptive and anabolic effects ofvitamin K2 on bone in vivo were reported in ovariectomized, orchidectomized, sciatic neurectomized, or
glucocorticoid-treated rats.25–28 Vitamin K2 prevented
the elevation of bone resorption and the reduction inbone formation, counteracting loss of BMD or cancellous bone mass in the hindlimb of tail-suspended mature rats.9
The tail-suspended mature or adult rat model rather
than the tail-suspended young growing rat model may
be more suitable to study the interventions to preventbone loss by weightlessness because of the less inﬂuence of bone growth on bone mass and metabolism.
Although a preventative effect of tiludronate, testosterone, and vitamin K2 on BMD and/or cancellous bonemass in tail-suspended mature rats was reported, thedirect effect on cortical bone mass remains uncertain.
Thus, further studies are needed to clarify whether
these or other agents are able to prevent both cancellous and cortical bone mass in tail-suspended maturerats.
Conclusions
Table 1 summarizes the alterations in bone mass andbone metabolism during space ﬂight in astronauts.
Data on interventions to stabilize bone metabolism
and prevent bone loss in astronauts during space ﬂight
are limited. A high calcium intake and vitamin D supplementation during space ﬂight prevents an elevationof serum calcium level through increased calcitriol
level, while vitamin K counteracts the reduction in boneformation. However, there are not data to show the efﬁcacy of pharmaceutical agents for prevention of development of osteoporosis in astronauts during space
ﬂight. In an animal model of weightlessness, the tailsuspended mature rats, cancellous bone loss of the tibia
was prevented by the bisphosphonate tiludronate, and
BMD loss of the hindlimb was counteracted by testosterone and vitamin K2 by preventing an increase inbone resorption and a reduction in bone formation.
However, it still remains uncertain whether theseagents can prevent cortical bone loss caused by weightlessness in tail-suspended rats. We surmise that inaddition to calcium, vitamin D, and vitamin K supplementation, agents that have both potent anti-resorptive
and anabolic effects on cortical and cancellous bone
may be needed to stabilize calcium balance and bonemetabolism and prevent bone loss in astronauts during
space ﬂight.
It remains uncertain whether or if possible, when

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Table 1

Iwamoto J, et al: Prevention of bone loss during space ﬂight
Alterations in Bone Mass and Bone Metabolism during Space Flight in Astronauts

Bone mass2–4

Bone metabolism5,12,16

Parameters

Alterations

Spine, femoral neck and trochanter, and pelvis BMD
Spine integral and cancellous vBMD
Hip integral, cortical, and cancellous vBMD
Tibia cancellous and cortical bone mass
Radius cancellous and cortical bone mass
Calcaneus BUA
Skull BMD

1.0–1.6% decreases per months
0.9% and 0.7% decreases per month, respectively
1.2–1.5%, 0.4–0.5%, and 2.2–2.7% decreases permonth, respectively
4.5% and 2.9% decreases for 6 months, respectively
0.2% and 0.5% increases for 6 months, respectively
13.2% decrease for 6 months
Increase

Urinary calcium excretion
Intestinal calcium absorption
Serum calcium level
Serum PTH and calcitriol levels
Bone resorption (urinary PYR, DPD, NTX, and CTX)
Bone formation (serum BAP and P1CP)

Increase
Decrease
Increase
Decrease
Increase
Decrease

BMD: bone mineral density, vBMD: volumetric BMD, BUA: broadband ultrasound attenuation, PTH: parathyroid hormone, PYR: pyridinoline, DPD: deoxypyridinoline, NTX: cross-linked N-terminal telopeptide of type I collagen, CTX: cross-linked C-terminal telopeptide of type I
collagen, BAP: bone-speciﬁc alkaline phosphatase, P1CP: C-terminal peptide of type I procollagen.

bone loss caused by weightlessness during space ﬂight
in astronauts will be restored after reconditioning. Further studies are also needed to conﬁrm this issue.

10.
11.

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