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EXERCISE AND PHARMACOLOGICAL COUNTERMEASURES FOR BONE LOSS DURING LONG-
DURATION SPACE FLIGHT
Peter R. Cavanagh1,2,3,5, Angelo A. Licata1,3,4, and Andrea J. Rice1,2
1Department of Biomedical Engineering, Lerner Research Institute,
2Center for Space Medicine,
3Department of Orthopaedic Surgery,
4Department of Endocrinology, Diabetes & Metabolism
5Orthopaedic Research Center, The Cleveland Clinic Foundation, Cleveland, OH

ABSTRACT
2003). This adaptation to microgravity renders the skeleton "at risk" for fracture, increases the risk of renal Bone loss in the lower extremities and lumbar spine is an stones (Whitson et al., 1999), and poses potential long- established consequence of long-duration human space flight. term health risks for astronauts on their return to Earth Astronauts typically lose as much bone mass in the proximal with reduced bone mass. femur in 1 month as postmenopausal women on Earth lose in 1 year. Pharmacological interventions have not been routinely In this article, we will examine the evidence for loss of used in space, and countermeasure programs have depended solely upon exercise. However, it is clear that the osteogenic bone mass during long-duration space flight, discuss the stimulus from exercise has been inadequate to maintain bone mechanisms for such loss, review countermeasures that mass, due to insufficient load or duration. Attention has have been attempted to date, and examine the potential of therefore been focused on several pharmacological interventions pharmaceutical countermeasures in the future. The that have been successful in preventing or attenuating implications of recent findings regarding the genetic osteoporosis on Earth. Anti-resorptives are the class of drugs determinants of bone mass will also be discussed. most commonly used to treat osteoporosis in postmenopausal women, notably alendronate sodium, risedronate sodium, BONE LOSS IN SPACE: THE EVIDENCE
zoledronic acid, and selective estrogen receptor modulators, such as raloxifene. There has also been considerable recent interest in anabolic agents such as parathyroid hormone (PTH) Bone loss during space flight has been a concern since the and teriparatide (rhPTH [1-34]). Vitamin D and calcium Gemini flights (1-14 day missions, 1962-1966). Mack supplementation have also been used. Recent studies of and colleagues (Mack et al., 1967; Mack and LaChance, kindreds with abnormally high bone mineral density have 1967), reported what they called "small but significant" provided insight into the genetic regulation of bone mass. This bone loss. If one extrapolated their results to long- has led to potential therapeutic interventions based on the LRP5, duration flights, these changes would have been Wnt and BMP2 pathways. Another target is the RANK- alarming—ranging from 5.3% per month in the calcaneus L/osteoprotegerin signaling pathway, which influences bone during Gemini 7 to 89% per month in the finger turnover by regulating osteoclast formation and maturation. phalanges during Gemini 4. The observations were based Trials using such therapies in space are being planned. Among the factors to be considered are dose-response relationships, on the use of densitometry of plain X-rays, which is now bone quality, post-use recovery, and combination therapies—all regarded as an inaccurate methodology (Rambaut et al., of which may have unique characteristics when the drugs are 1975). It is, however, interesting to note that these authors also measured urinary and fecal loss of calcium in a group of bed rest subjects and reported a correlation of -0.7 between loss of bone mass and mean calcium intake. Soviet researchers (Biriukov and Krasnykh, 1970; The human skeleton has evolved in an environment where Krasnykh, 1969—reported by Rambaut et al., 1975) the force of Earth's gravity has been a continual presence. found average losses of 4.7% per month in the os calcis in It is, therefore, not surprising that removal of gravity subjects in a bed rest study, and they reported that net during long-duration space flight results in a loss of losses during 8-10 weeks of bed rest were equivalent to homeostasis in the skeleton, which adapts to the new those seen in the 18-day Soyuz 9 flight. environment by shedding calcium (Lang et al., 2004) at a rate that is almost 10 times greater than that in a In the Apollo flights (6-14 day missions, 1968-1972), postmenopausal woman (Iki et al., 1996; Sirola et al., neutron activation analysis of fecal specimens (Brodzinski et al., 1971) (Apollo VII-XI; 6-11 days), densitometry from plain radiographs (Mack and Vogt, 1971) (Apollo * Correspondence to: Peter R. Cavanagh, Ph.D., D.Sc. VII and VIII; 11 and 6 days, respectively), and single- The Cleveland Clinic Foundation photon absorptiometry of calcaneus and forearm 9500 Euclid Avenue / ND-20 Cleveland, OH 44195 (Rambaut et al., 1975) (Apollo XIV-XVI; 9, 12, and 11 Email: [email protected] days, respectively) were used to assess changes in bone Phone: 216-445-6980; Fax: 216-445-6083 status. Brodzinski et al. (1971) called the Gemini findings of Mack and LaChance (1967) "dubious," and their own Gravitational and Space Biology 18(2) June 2005 39 P.R. Cavanagh - Preventing Bone Loss in Space measurements of calcium loss in Apollo VII-XI changes was not correlated with flight time, presumably crewmembers suggested less substantial changes. They due to individual differences in rates of bone loss. estimated that loss of total body calcium could be as little as 7.5% per year of space flight, but they suggested that a McCarthy et al. (2000) used three techniques (dual energy calcium balance experiment should be conducted on X-ray absorptiometry [DXA], ultrasonic measurements of Skylab, and this was in fact accomplished (see below). velocity [SOS], and broadband attenuation [BUA] of the calcaneus) to evaluate changes in bone during two Using similar methodology to their earlier studies, Mack missions, of 180 and 20 days, to the Mir space station, and Vogt (1971) reported average losses of 11.6% per involving three subjects. DXA measurements resulted in month in the lower extremity and 22.6% losses in the significant variation between different sites in the body upper extremity of six Apollo VII and VIII crew for changes in BMD, with the greatest losses occurring in members. As discussed above, in retrospect, these the lumbar spine and proximal femur. changes in "bone density" measured from plain radiographs were clearly erroneous; control subjects on Earth did not show such large changes. The single gamma photon absorptiometry of Rambaut et al. (1975) found a loss of 5.1% per month in the lower extremity, a gain of 0.6% per month in the radius, and a loss of 4.6% per month in the ulnae of nine Apollo XIV- XVI crew members. D/Month (%)
One of the most complete series of calcium balance studies in space was conducted during the Skylab missions (Skylab 2, 28 days, 1973; Skylab 3, 59 days, 1973; Skylab 4, 84 days, 1973-1974—Rambaut and Johnston, 1979; Smith et al., 1977; Smith et al., 1998; Smith et al., 1999; Tilton et al., 1980; Whedon et al., 1977). Commencing 21 days prior to flight, during flight, and for 18 days post flight, the intake of 30 nutrients were Figure 1a: Change in bone mineral density in different
monitored, 24-hour pooled urine collections were made, anatomical regions (in percent change per month; negative and fecal samples were vacuum dried for analysis. values represent loss) during Mir missions and bed rest. Data Weekly plasma samples were also taken. A 56-day adapted from LeBlanc et al. (2000). ground-based control experiment was also conducted. During the Skylab 4 mission, average negative calcium The application of modern imaging techniques to bone balances of -100 (+25), -180 (+36), -229 (+60), -223 changes during space flight was first accomplished by (+42), -88 (+52) were reported for the pre-flight, flight LeBlanc and colleagues (LeBlanc et al., 1996; LeBlanc et days 1-24, 25-56, 57-84, and post-flight measurements, al., 1998; LeBlanc et al., 2000). In 1989, they installed a respectively. In addition, using single-photon absorp- Hologic 1000W dual X-ray absorptiometry (DXA) tiometry, Smith et al. (1977) indicated that a mean loss of scanner at the cosmonaut training center in Star City, 0.4% per month occurred in the calcanei of all nine Moscow, in the former USSR. Between 1990 and 1995, Skylab 2-4 crew members, while the investigators they studied 18 cosmonauts who had flown for between detected negligible losses in the radii (0.06% per month) 126 and 438 days (LeBlanc et al., 1996; LeBlanc et al., and a gain in the ulnae (0.4% per month). 2000). These measurements showed regional losses during flight of between 1.06% and 1.56% per month in Rambaut et al. (1979) pointed out that "the chain of the spine, pelvis and proximal femur, but no significant events leading ultimately to bone loss inflight remains changes in the upper extremities (Figure 1a). Losses were elusive." In an article almost 20 years later, in which the parallel, but smaller, during bed rest, except in the arms, urine of Skylab crew members was re-analyzed, Smith et where losses were greater than during flight. These data al. (1998) shed light on this mechanism by demonstrating showed, for the first time, a pattern of lower-extremity that urinary excretion of collagen breakdown products loss and upper-extremity preservation during flight. The during the Skylab 4 mission was 40-45% higher than pre- authors concluded that the in-flight exercise programs flight values, indicating that space flight is associated were not sufficient to completely ameliorate bone loss with increased bone resorption. during flight (no countermeasures were used during bed Using computer tomography (CT), Oganov et al. (1990) measured mineral density of lumbar vertebrae in four Lang et al. (2004) provided data from DXA, volumetric Salyut-7 crew members before and after extended flights quantitative computer tomography (vQCT), and (5-7 months' duration). These authors reported that bone quantitative ultrasound (QUS) on crew members from the mineral density (BMD) diminished only in some of the Expeditions 2-6 to the International Space Station (ISS; test subjects and emphasized that the magnitude of 2001-2003, 130-197 days). The authors' data confirmed 40 Gravitational and Space Biology 18(2) June 2005 P.R. Cavanagh - Preventing Bone Loss in Space that little progress had been made in preventing loss of PRIOR COUNTERMEASURES
bone mineral in the 30 years since Skylab. Notably, vQCT allowed an examination of the loss in both The only countermeasure that has so far been used in trabecular and cortical fractions of bone and also space for bone loss, albeit unsuccessfully, is exercise. estimates of the volumetric BMD (vBMD) as well as the Astronaut-physician William E. Thornton was a tireless conventional areal BMD (aBMD). These data confirmed proponent of exercise countermeasures, and his accounts the large losses in the spine and proximal femur (Figure of exercise countermeasures and devices (Thornton, 1b), and indicated that the rate of loss of bone mineral 1989a; Thornton, 1989b; Thornton, 1989c) are required content (BMC) in trabecular bone in the proximal femur reading in order to understand the history of use of this was approximately twice that of the cortical loss. Since modality. There is also a good description of exercise and trabecular bone cannot be replaced after loss of trabecular other countermeasures in Nicogossian et al. (1994). The continuity (Langton et al., 2000), this later finding is of countermeasure tradition began in the confined space of particular concern. The authors also found that calcaneal the Gemini capsule, where a bungee cord held by a loop estimates are not good surrogates for central or upper to the feet was pulled to exercise the arms and legs extremity skeletal measures and concluded that there was (Dietlein, 1965). There is no record of its efficacy, a continuing need to improve countermeasures to bone although measurements of heart rate, blood pressure, and loss, as it has become clear that current efforts are respiration rate were taken during exercise to record cardiac response to exercise in space (Dietlein and Rapp, The Soyuz 9 flight (18 days, 1970), on which bungee and expanders were also used for exercise (Nicogossian et al., 1994), highlighted the need for more effective countermeasures to combat the general loss of conditioning (Yegorov et al., 1972). Subsequently, some of the Salyut Space orbital stations (Salut 1, 1971 to Salyut 6, 1985) were equipped with a passive treadmill, a bicycle ergometer, and a gravity simulation suit for long wear (Gazenko et al., 1976). The efficacy of this "Penguin Suit" (Nicogossian et al., 1994) has not been Figure 1b: Data showing change in regional bone (in percent
change per month; negative values represent loss) from 13 crew The Skylab astronauts used several on-board exercise members on the International Space Station. Data adapted from devices, including a bicycle ergometer and a Teflon® Lang et al. (2004). plate, not available until Skylab 4, on which they performed an unusual form of tethered locomotion It is interesting to note that long-duration space flight (Figure 2a; Thornton and Rummel, 1977; Thornton, continues to be a male bastion, and thus we do not have 1989a). They also had a Mini Gym exercise device, adequate data on gender differences in bone loss in space. which allowed concentric muscular exercise to be For the 32 subjects for whom DXA data are available, performed, primarily benefiting the arms and trunk. there are only two women: one in the LeBlanc et al. Although this device probably transmitted higher forces (2000) series, who was reported to have similar responses to the legs than those from the bicycle ergometer, the to the mean of the group, and one in the Lang et al. (2004) force levels were still considered inadequate (Thornton series, whose data were not uniquely identifiable. and Rummel, 1977). No systematic record of the use of Presumably, privacy issues prevented this disclosure, but these devices by Skylab crew members is available in the one would hope that all crew members would make such literature, although it is likely that such records were kept. data available in the future in the interest of science. Gravitational and Space Biology 18(2) June 2005 41

P.R. Cavanagh - Preventing Bone Loss in Space Cosmonauts on Mir have been said to perform exercise "up to 3 hours per day" (Nicogossian et al., 1994), while others believe that the exercise was 2-3 hours on 3 of 4 days (LeBlanc et al., 2000). The passive treadmill was considered the "stadium" from which exercise was performed. While the subject was tethered in place using bungees, he not only walked and ran, but also performed calisthenics and upper-body exercises using additional bungee cords for resistance (Figure 3). The data from LeBlanc et al. (2000) showed clearly that this protocol, even if faithfully performed, is not an effective countermeasure for bone loss. The exercise facilities available on the ISS through Expedition 12 consist of a Treadmill Vibration Isolation and Stabilization System (TVIS; Figure 2c; McCrory et Figure 2a: A Teflon® plate on which Skylab astronauts
al., 1999), a cycle ergometer with vibration isolation exercised in an unusual form of locomotion (Thornton and (CEVIS; Figure 2d), and the Interim Resistive Exercise Rummel, 1977; Thornton, 1989a). Artwork courtesy of NASA. Device (iRED; Figure 2e; Schneider et al., 2003). There is also a bicycle ergometer available in the Russian Thornton is thought to be the first man to run around the segment. None of these devices has a force measurement world in low Earth orbit. This feat was performed during capability, and there is very little published information one complete orbit of STS-8 (1983) on a treadmill that about their performance characteristics. When running on Thornton helped to design. Because the mid-deck of the the treadmill, a subject must be tethered using a subject Space Shuttle was not particularly spacious, the passive load device (SLD) to restrain him on the treadmill treadmill had to be stowable in a locker, a fact that surface, and, optionally, a subject position device (SPD) severely limited its belt length (Figure 2b). The subject is used to keep the subject in an area of the treadmill was tethered by bungee cords, which applied an unknown where a pitch oscillation of the treadmill will not be tension to return the crew member to the treadmill initiated. Each crew member is assigned a period of 2.25- surface. Kinematic analysis of on-orbit film taken during 2.5 hours every day for exercise—including set-up and running on the treadmill (Thornton et al., 1998) indicated break-down time, which can consume more than 50% of that there was restricted range of motion at the lower- the assigned period. The work of Lang et al. (2004) extremity joints and a plantar-flexed "tip-toe" gait. No showed that these devices as they are presently used are measurements of the foot forces were made. not effective as a countermeasure for bone loss during long-duration flights. As we shall discuss below, prolonged bed rest is considered to be a viable analog of space flight. Shackelford et al. (2004) conducted a program of vigorous resistance training (averaging 74% of one repetition maximum) in nine individuals during a 17-week confinement. The exercise was found to have a beneficial effect on BMD during bed rest compared to controls, specifically in the lumbar spine (+3% vs. -1%), total hip (+1% vs. -3%), heel (+1% vs. -3%), total body (0% vs. -1%), and pelvis (-0.5% vs. -3%). However, the high levels of load imposed on the muscle groups studied have never been achieved in space, and it is unlikely that in-flight exercise devices currently in use will permit such loads to be achieved. Figure 2b: The passive Shuttle treadmill designed by
Astronaut-Physician William Thornton (Thornton, 1989c).
Artwork courtesy of NASA. 42 Gravitational and Space Biology 18(2) June 2005

P.R. Cavanagh - Preventing Bone Loss in Space Figure 2c: The International Space Station Treadmill with a
Figure 2d: The Cycle Ergometer with Vibration Isolation and
Vibration Isolation and Stabilization System (TVIS). (NASA Stabilization System (CEVIS) in use on the International Space photography) Station. (NASA photography)
Figure 2e: The Interim Resistive Exercise Device (iRED) in use on the International Space Station (ISS). (NASA photography)
Gravitational and Space Biology 18(2) June 2005 43 P.R. Cavanagh - Preventing Bone Loss in Space Figure 3: A page from the Mir cosmonaut exercise instruction manual showing a 24-stage exercise session performed on the treadmill.
44 Gravitational and Space Biology 18(2) June 2005 P.R. Cavanagh - Preventing Bone Loss in Space WHY HAVE EXERCISE COUNTERMEASURES IN
BONE REMODELING
SPACE NOT BEEN EFFECTIVE?
Bone is an active tissue that is constantly being Since exercise has been the only countermeasure to bone remodeled, principally by the action of two cell types: loss so far attempted in space, and since considerable osteoclasts, which resorb bone, and osteoblasts, which bone loss has occurred on all flights to date, it would be build new bone (Figure 4). It is estimated that all of the tempting to conclude that exercise is not an appropriate bone in the adult skeleton is replaced every 10 years countermeasure. There are, however, several reasons why (Marx, 2004). Homeostasis of bone is only maintained if such a conclusion may be premature: (1) There has never the opposing—or perhaps complementary—actions of been a controlled study of exercise, either in space or osteoblasts and osteoclasts are balanced. A defect in during bed rest. The lack of such a study in the more than either process can result in accumulation of bone (as in 40 years that this problem has been recognized is highly osteopetrosis) or in a net loss of bone (as in osteoporosis) perplexing to the current authors and perhaps reflects the (Helfrich, 2003; Phan et al., 2004). The mineral phase of fact that NASA has traditionally been an engineering bone is of primary importance to density, and therefore rather than a science agency; (2) The loads applied to the BMD has been used in the past as a main indicator of body by any piece of exercise equipment were not bone status (Kanis, 2002). However, there is now measured prior to 2003, so it is not known whether or not increasing interest in measures of bone "quality" that equipment exerted 1-g-like loads; (3) Exercise adherence include structural as well as compositional information may have been less than optimal and, contrary to common (Ammann and Rizzoli, 2003; Turner, 2002), and it is belief, the ISS program was the first time a mandatory likely that a composite measure will eventually replace exercise program was instituted as part of a flight plan; BMD as the parameter of choice. (4) It is not known if a single daily concentrated "dose" of exercise in 0-g can effectively replace a "dose" that in 1-g The majority of current therapeutic interventions could be is distributed throughout the day; (5) The duration of classed as resorption-prevention drugs. A number of exercise programmed to date may not have been adequate advances in understanding how osteoclasts differentiate, to achieve the desired result; (6) There is considerable mature, and are activated have recently been made (Boyle debate in the scientific community about the optimal et al., 2003; Marx, 2004). Prevention of osteoclast loading strategy that will provide an osteogenic stimulus formation (osteoclastogenesis) and development has been to bone (Turner, 1998; Turner and Pavalko, 1998). a prime target through a number of different pathways Evidence in the literature ranges from a few intermittent (see below). On the formation side of the equation, large loads per day (Lanyon, 1996) to 18,000 small- preventing osteoblast cell death (apoptosis) is also of amplitude vibrations in a 10-minute period (Rubin et al., interest, and a number of other "anabolic" or bone- 2002a; Rubin et al., 2002b). There is also debate building drugs with uncertain mechanisms are also being regarding the relative role of force and rate of change of explored (Bisello et al., 2004; Deal and Gideon, 2003). force (Cullen et al., 2001; Linde et al., 1991; Mosley and Our own experiments using force-measuring insoles Traditionally, supplementation of daily intake of vitamin during exercise on the ISS (Rice et al., 2004) have D and calcium (current recommended daily allowances suggested that neither the load nor the duration of [RDAs] 400 IUs and 1500 mg, respectively) have been treadmill exercise in the current ISS exercise program is considered mainstays of osteoporosis prevention. adequate to replace 1-g exercise. Adequate calcium is needed for mineralization, and vitamin D plays a role in the regulation of calcium Only when all six issues noted above have been carefully deposition for bone mineralization. Both of these agents examined can the role of exercise as a countermeasure to have weak antiresorptive properties (compared, for in-flight bone loss be determined. Until such time, it is example, to bisphosphonates [Reginster, 2004]—see reasonable that the flight medicine community is looking below), but combined therapy for 18 months (1200 mg to explore the use in space of pharmacological options calcium plus 800 IU vitamin D3 [cholecalciferol]) has that are being used on Earth to prevent postmenopausal been shown to be effective in reducing hip fracture in elderly women who were Vitamin D deficient (Chapuy et al., 1992). The bioavailability of the various forms of The remainder of this review will examine the cellular calcium used in supplementation (calcium carbonate, and molecular targets for such therapy, present the citrate, phosphate, lactate, and formate) have been shown currently available options, and discuss the limitations of to be different (Hanzlik et al., 2005). knowledge required for the implementation of these therapies in space. Since it is not always clear whether or not dietary intake of these agents is adequate, most drug trials routinely include calcium and vitamin D supplementation in control, placebo, and treatment arms. Astronaut diets can Gravitational and Space Biology 18(2) June 2005 45 P.R. Cavanagh - Preventing Bone Loss in Space Figure 4: Schematic of a bone multi-cellular unit (BMU). Osteoclasts resorb a cavity that is later occupied by osteoblasts that lay down new bone in the form of osteoid that subsequently undergoes mineralization (Deal and Gideon, 2003). Reprinted with the permission of The Cleveland Clinic Foundation. be closely controlled, so inclusion of RDA and considered the regulator of the female skeleton and supplementation in diet can be easily accomplished. testosterone the male regulator. The discovery of mutations in the aromatase gene in men and concurrent HORMONE REPLACEMENT THERAPY
abnormalities in skeletal metabolism (osteopenia and unfused epiphyses) have focused attention on the Estrogen, in the form of 17β-estradiol, has a complex importance of estrogen physiology. Aberrations in agonistic action on estrogen receptors (ERs) in the osteoclast acivity due to deficiency of inhibitors may nucleus of osteoblastsic cells (Riggs and Hartmann, attend the loss of estrogen with aging in both men and 2003), which in turn affect estrogen receptor elements women and cause increased bone turnover (Carani et al., (EREs) in target genes. In estrogen deficiency, resorption 1997; Khosla et al., 2002; Khosla et al., 2004). outpaces formation, resulting in net bone loss. Estrogen also stimulates breast epithelial cell production and has SELECTIVE ESTROGEN RECEPTOR
been implicated in breast cancer risk (Riggs and MODULATORS (SERMS)
Hartmann, 2003). Because of the side effects of HT, there has been
Hormone replacement therapy (HT) using estrogen increased interest in this class of nonhormonal drugs that (unopposed HT) or estrogen-progestin (opposed HT) was target the ER. SERMs can have both agonist and widely recommended for postmenopausal women until antagonist effects in different tissues (e.g., tamoxifen the landmark Women's Health Initiative (WHI) study [Tamofen], used in the treatment of ER-positive breast (Rossouw et al., 2002) demonstrated a number of adverse cancer, is an antagonist that slows the proliferation of responses (increased risk of coronary artery disease, tumor cells, whereas raloxifene [Evista] is a bone agonist stroke, thromboembolism, and breast cancer) in subjects that has an antiresorptive effect) (Riggs and Hartmann, using opposed HT. Riggs and Hartmann (2003) stated 2003). Different SERMs that have similar effects on bone that estrogen was the most widely prescribed drug in the (e.g., raloxifene and idoxifene [investigational]) appear to world and that it was taken by 38% of postmenopausal have their modes of action through different molecular women in the United States. In addition to reducing the pathways (Nuttall et al., 2000). Because raloxifene, risk for nonvertebral fractures (Torgerson and Bell-Syer, which is administered orally once per day, has a 2001), HT also had the added advantage of relieving a preferential effect on vertebral fracture risk reduction number of perimenopausal symptoms. Because of the (Ettinger et al., 1999), it is possible that there are increased risk of adverse side effects, HT is no longer differences between the action of SERMs on trabecular recommended for prevention or treatment of osteoporosis vs. cortical bone. There are some indications that raloxifene therapy Estrogen also has significant effects on skeletal decreases cardiovascular events in women with risk metabolism in men. Traditionally, estrogen was factors at baseline (Barrett-Connor et al., 2002) but carries 46 Gravitational and Space Biology 18(2) June 2005 P.R. Cavanagh - Preventing Bone Loss in Space with it a small increase in the risk for thromboembolism ANTIRESORPTIVE DRUGS
(Daly et al., 1996). SERMs do not appear to alleviate postmenopausal symptoms (National Osteoporosis The largest class of antiresorptive drugs is the Foundation, 2002; Cranney et al., 2002). bisphosphonates (such as alendronate [Fosamax], etidronate [Didronel], ibandronate [Boniva], pamidronate The common risk for both therapies is that of deep vein [Aredia], risedronate [Actonel], zoledronate [Zometa], thrombosis, especially in conditions of clotting and tiludronate (Skelid)]. The drugs are distinguished by abnormalities. This risk is small but nonetheless present their potency, which is usually positively affected by the statistically. In other situations the drugs have divergent presence of a nitrogen atom (e.g., etidronate [low] to risks. Breast hyperplasia and breast cancer are not found zoledronate [high]), by their mode of delivery (e.g., with the SERM agents as they are with estrogen. intravenously for pamidronate and zoledronate, orally for Moreover, the SERM drugs do not cause cervical alendronate, orally, intravenously, or by injection for endometrial hyperplasia, menstrual bleeding, or cervical ibandronate), and by the frequency and size of dosing (e.g., 5 or 10 mg daily or weekly for alendronate, 2.5 mg daily for ibandronate, 10-90 mg annually for zoledronate). The SERM drugs may offer an option for treatment of An excellent review of these drugs is provided by prostate cancer. In the presence of decreasing androgens Reginster (2004). with aging, estrogen induces prostatic hyperplasia and neoplasia. Antiestrogens and SERMs suppress prostate Bisphosphonates are powerful and specific inhibitors of carcinogenesis. Some preliminary studies suggest that osteoclasts (Figure 5). They were originally thought to SERMs may not be useful as a general treatment for male exert their action via incorporation in the skeleton by osteoporosis, but there are some male patients, small in mimicking pyrophosphate and binding to the hydroxy- number, with the requisite balance of estrogen and apatite crystals in the bone matrix (Licata, 2005), testosterone for whom SERMs may be beneficial (Steiner especially at sites of remodeling, the bone multicellular and Raghow, 2003; Doran et al., 2001). units (BMUs) (Russell et al., 1999).
Figure 5: Schematic of bisphosphonate action (Rodan and Fleisch, 1996). Where bisphosphonate (BP in the diagram) has been
incorporated into the bone matrix, osteoclastic resorption of bone cannot occur. Reprinted with permission.
Their actions have since been shown to be complex, function by "energy starving" the cell. Once incorporated, however. The amino bisphosphonates inhibit osteoclastic bisphosphonates remain bound at the bone surface and cholesterol synthesis and membrane function and increase exhibit extremely low serum concentrations, thus limiting cellular apoptosis. The non-amino bisphosphonates side effects. In general, the third generation (N2 produce ineffective ATP analogs and inhibit osteoclast containing) bisphosphonates have shown approximately Gravitational and Space Biology 18(2) June 2005 47 P.R. Cavanagh - Preventing Bone Loss in Space 40-50% reduction in the risk of vertebral and nonvertebral the upper gastrointestinal (GI) tract, constipation, fractures compared with placebo in postmenopausal flatulence, hypocalcemia, and diarrhea), but severe women (Black et al., 1996; Chesnut et al., 2004; Harris et esophageal reactions have been reported with alendronate al., 1999) and have also resulted in increased BMD in the (Schnitzer et al., 2000). Consequently, its use is not lumbar spine, total hip, and trochanter in women with and recommended for patients with a history of upper GI without osteoporosis (Cooper et al., 2003; Mortensen et al., 1998; Ravn et al., 1999). There is some concern that bone formed during the There are two bed rest studies involving bisphosphonates administration of bisphosphonates may not have the same that are relevant to the space program (LeBlanc et al., "quality" as normal bone, thus negatively affecting on the 2002; Watanabe et al., 2004). LeBlanc et al. (2002) mechanical integrity of the skeleton. Animal studies with administered 10 mg of alendronate daily to eight male bisphosphonates have shown a delay in fracture healing in subjects undergoing 17 weeks of horizontal bed rest. rats and rabbits and an increase in the presence and Compared with concurrent and historical controls, BMD persistence of microcracks and reduced remodeling, loss was significantly attenuated (or eliminated) in the suggesting a potential change in biomechanical factors (Li alendronate treatment group in the lumbar spine, femoral et al., 1999; Li et al., 2001; Mashiba et al., 2001; Lehman neck, trochanter, and pelvis (but not calcaneus). Most et al., 2004). In addition, it is notable that Ruggiero et al. markers of bone collagen breakdown and resorption (2004) have identified a cluster of patients on chronic (cross-linked N-teleopeptide of type I collagen [NTX], bisphosphonate therapy that had an associated risk of pyridinium [Pyd], and deoxypyridinium [D-Pyd]) in- osteonecrosis of the jaw. This condition is also seen in creased in both groups, but significantly less so in the the myeloma patients treated with i.v. zoledronic acid treated group than in controls. Markers of bone formation monthly (Lugassy et al., 2004), which is not the way it is (alkaline phosphatase, bone-specific alkaline phosphatase, used for treating osteoporosis. It is possible that such and osteocalcin) were unchanged in controls, but were patients may have immune compromise supporting local decreased in the treated group because of the reduced dental infection and subsequent bone destruction. bone turnover. These results demonstrate that the drug does not ablate the bone loss totally, thus the observed If sequential combination therapy of different drugs is clinical effects may require simultaneous mechanical planned, Gasser et al. (2000) showed in studies of rat bone that the response to an anabolic drug (see below) was delayed in animals pretreated with bisphosphonates. Watanabe et al. (2004) administered 60 mg of pamid- However, in clinical studies, long-term use of alendronate ronate to seven male subjects 14 days before 90 days of 6- and risedronate for 7-10 years shows no similar findings. degree head-down bed rest. These authors also showed Both drugs still suppress fractures, which argues against that alendronates, in addition to their osteoprotective the adverse effects seen in animal models. Furthermore, properties, decrease the risk of renal stones. Compared histomorphometry shows no abnormal characteristics in with sedentary and resistance training controls, the patients after 3 or more years of use. pamidronate-treated subjects not only maintained significantly more bone in the proximal femur and lumbar ANABOLIC DRUGS
spine, but also showed no evidence of urolithiasis (stones in the urinary tract). In the other groups, six subjects Drugs in this class exert their mode of action by were found to have radiographic evidence of stone increasing bone formation rather than by inhibiting formation during bed rest. All but one of these stone- resorption. The important role of parathyroid hormone forming subjects had baseline hypercalciuria (>250 mg (PTH) in regulating bone and mineral metabolism has per day). Such patterns of stone formation may be a been known for more than 70 years (Bisello et al., 2004), feature of all bed rest studies, and perhaps of long- but classical teaching identifies PTH as a powerful duration space flight, that has been previously mobilizer of skeletal calcium into the serum in the overlooked. However, it is extremely unusual for healthy presence of hypocalcemia (i.e., a state of secondary patients with no prior stone risk to become "at-risk" in hyperparathyroidism). Evidence from animal exper- such a short time, and these results, although cautionary, iments has shown that daily injection of PTH had need to be replicated. anabolic effects on bone, and recent work has resolved these apparently paradoxical effects by showing a Shapiro et al. (personal communication), in an as yet dependency on the pattern of exposure. Chronic elevation unpublished study, showed a reduction of bone loss in the of PTH (as in primary hyperparathyroidism) leads to lower extremities of patients with spinal cord injuries who increased bone resorption, whereas intermittent elevation had been administered intravenous zoledronate. The (as in once-daily injections with a short half-life) leads to paradigm of spinal cord injury has been suggested to be increased formation. The mechanism of action of PTH another analog of space flight, although the absence of appears to be the stimulation of existing osteoblasts via muscular action may tend to make it even more severe surface PTH receptors and interaction with RANK-L from a disuse point of view. (NF-κB; see below) (Deal and Gideon, 2003). It is The side effects of bisphosphonate therapy from the major known that the amino-terminal region of PTH (the first 34 study series have generally been mild (adverse effects in amino acids) is necessary and sufficient for full activity, 48 Gravitational and Space Biology 18(2) June 2005 P.R. Cavanagh - Preventing Bone Loss in Space and the only anabolic agent that is currently Food and activator of nuclear factor-κB ligand (RANK-L) ratio (see Drug Administration (FDA) approved for use in the below) (Locklin et al., 2001). treatment of osteoporosis is recombinant teriparatide (rhPTH [1-34] [Forteo]). RANK-L/OPG
Administration of teriparatide (daily subcutaneous In 1997, a new pathway regulating bone resorption was injection 20 µg or 40 µg for 19 months) to women with identified (serendipitously) by a group looking for novel low bone mass and a history of prior fracture resulted in genes in the rat intestine (Simonet et al., 1997). The an almost 10% increase in vertebral BMD; treatment transgenic mouse overexpressing one particular gene was reduced the risk of a second vertebral fracture by found to have ostopetrosis and a deficiency of osteoclasts approximately 65% and that of a nonvertebral fracture by (Khosla, 2001) and the responsible protein was called approximately 50% compared with placebo. There is osteoprotegerin for its protective role in maintaining bone some concern that high doses of teriparatide (up to 60 mass. Simultaneously, Yasuda et al. (1998) found the times greater than approved human doses) have caused same protein in a targeted search for the signaling link osteosarcoma in rats, but not monkeys. No similar that had been previously hypothesized to exist between complications have been observed in human studies, but osteoclasts and ostoblasts (Rodan and Martin, 1982). The an initially promising trial conducted in men (Orwoll et pathway that has been identified as a result of these and al., 2003) was terminated because of concern regarding subsequent studies is shown in Figure 6. OPG is secreted the animal results. as a soluble protein from bone marrow stromal cells and appears to be a decoy receptor, which binds to RANK-L. It is also known that PTH-related peptide (PTHrP), a Since RANK-L is a major factor in osteoclast differ- protein with some homology to PTH that is produced by entiation, activation, and apoptosis inhibition, it follows tumors and leads to hypercalcemia, shares many of the that the binding of RANK-L to OPG, rather than to its actions of PTH but has receptors that are much more target RANK on the osteoclast precursor cell, will prevent widely distributed (Bisello et al., 2004). The authors have bone resorption. Because RANK-knockout mice also initial evidence from human studies that PTHrP has the exhibited osteopetrosis and absence of osteclasts (Li et al., potential to be a powerful anabolic agent, and clinical 2000), the existence of a new OPG/RANK/RANK-L trials to explore this possibility are ongoing. pathway in the control of bone resorption was confirmed. Several genetic mutations of this pathway are associated It is possible that the mechanism for the differential with bone diseases such as the family of hyperphos- effects of intermittent vs. continuous levels of PTH is in phatasias, Paget's disease, and possible bone loss in the modulation of the osteoprotegerin (OPG)/receptor inflammatory arthritis (Boyle et al., 2003; Khosla, 2001). Figure 6: Schematic of the OPG/RANK-L pathway (Khosla, 2001). Note that OPG acts as a decoy receptor preventing RANK from
attaching to its ligand RANK-L and therefore inhibiting osteoclast differentiation. Copyright 2001, The Endocrine Society. Reprinted with
permission.
Gravitational and Space Biology 18(2) June 2005 49

P.R. Cavanagh - Preventing Bone Loss in Space OPG was an obvious choice as a clinical therapeutic agent feature of calcitonin is that it can be administered by to prevent osteoporosis, and indeed two forms of the many routes, including nasally in the form of a daily (or protein were examined by Amgen in clinical trials of intermittently administered [Tekeoglu et al., 2005]) spray. osteoporosis (Bekker et al., 2001) and multiple myeloma and breast carcinoma (Body et al., 2003). A presumed BONE GENETICS
combination of concerns regarding efficacy, safety, treatment duration and manufacturing factors has resulted In the last 5 years, early insights into some of the genetic in OPG's no longer being examined for clinical use. OPG determinants of bone mass have been obtained. Ralston does, however, continue to be explored for the treatment (2003) and Recker (2004) have recently reviewed the of bone tumors (Wittrant et al., 2004). A fully human status of present knowledge in this area. Johnson et al. monoclonal antibody for RANK-L, AMG 162, is being (2004) have commented regarding "how little we really developed as an osteoporosis treatment instead (Bekker et know about the genes that control bone mass." The al., 2004; McClung et al., 2004). Phase III clinical trials genetic basis for diseases caused by a defect in osteoclasts were initiated in late 2004 for AMG 162. is discussed by Helfrich (2003). CALCITONIN
Gong et al. (2001) found that that the LRP5 gene, which encodes the low-density lipoprotein receptor-related The peptide calcitonin exerts a complex inhibitory action protein 5, is important in bone mass accrual. They on osteoclast function (Kajiya et al., 2003). It has been reported that loss-of-function mutations in LRP5 caused used in trials of both men and women with low bone mass the autosomal recessive disorder osteoporosis- and has been shown to stabilize (or prevent) bone loss pseudoglioma syndrome and that Wnt-mediated signaling (Toth et al., 2005) and, in women, to decrease vertebral via LRP5 affects bone accrual during growth and peak fracture rate (Munoz-Torres et al., 2004). One attractive bone mass (Figure 7). Figure 7: The Wnt signaling pathway that has been discovered through genetic studies of patients with high bone mass (Johnson et al.,
2004). Adapted and reproduced from J Bone Miner Res 2004;19:1749-1757 with permission of the American Society for Bone and
Mineral Research.
Subsequently, mutations in the same gene were also
Johnson et al. (2004). Genes regulating lipoxygenase are found to be associated with diseases in which there was also believed to influence bone mass (Klein et al., 2004). high bone mass (Boyden et al., 2002; Little et al., 2002). The lack of inhibitory action of the protein Dkk-1 on the There are indications that the Wnt signaling pathway is Wnt signaling pathway suggested this protein as a activated in response to mechanical loading (Johnson, potential therapeutic target for modulating bone mass. A 2004), and this may be a key element in the elusive review of LRP5 and Wnt signaling is presented by mechanotransduction that has long been hypothesized to exist. 50 Gravitational and Space Biology 18(2) June 2005 P.R. Cavanagh - Preventing Bone Loss in Space An alternative approach to the human linkage and Finally, the early discovery of the vitamin D receptor association studies described above is the use of mouse gene helped introduce the notion that bone mass had a models in quantitative trait locus (QTL) analysis (Liu et genetic basis (Eisman, 1995). al., 2003; Rosen et al., 2001). QTL is basically a statistical analysis, sometimes of the entire genome, to The complexity of BMD as a trait and the importance of identify which regions of the genome contain loci that gene-environment interactions have been emphasized in a influence the phenotype of interest. study of risk factors for low spine and hip BMD involving 12 candidate gene loci and lifestyle factors by Lau et al. The genes encoding type I collagen (COLIA1 and COLIA2) are mutated in osteogenesis imperfecta and may be useful markers of other osteoporotic phenotypes While these various studies of genetic influence on bone (Mottes et al., 1998). mass are in their early stages, there is a high likelihood that they will eventually identify new therapeutic targets. The estrogen receptor gene may regulate some aspects of bone density since the discovery of a male patient with a gene mutation and osteoporosis (Gennari et al., 2005). Table 1. The major classes of osteoprotective therapeutic drugs Drug Manufacturer
Class Action
Alendronate sodium Merck Bisphosphonate Novartis Bisphosphonate Procter & Gamble / Bisphosphonate Inhibit Inhibit osteoclast Inhibit osteoclast Inhibit osteoclasts PTHrP Osteotrophin Inhibit osteoclast
SPECIAL CONSIDERATIONS FOR
astronaut corps comprises primarily younger men (see THERAPEUTIC DRUG USE IN SPACE
remarks above regarding the number of women astro- nauts/cosmonauts who have undergone long-duration The use of therapeutic drugs in space requires both the space flight), and such individuals are likely to be in good provider and the patient to accept a different set of bone health at the time of treatment. Such clinical trials standards, assumptions, and approvals compared with the typically take many years to accomplish (for example, the use of the same drugs on Earth. For example, the primary WHI study, mentioned above, was scheduled for 8.5 criterion that the FDA uses for approval of drugs designed years), and the time frame could slow the identification to treat osteoporosis is a demonstrated reduction of and application of effective therapies. fracture risk, usually hip or vertebral fracture. Such Given current NASA priorities, it is almost certain that evidence usually comes from a clinical trial of there will not be a sufficient number of astronauts to postmenopausal women with evidence of osteoporosis allow a placebo-controlled dose-ranging on-orbit trial that is blinded, placebo controlled, and randomized. This with sufficient statistical power to be mounted in the next approach may not be appropriate for decisions regarding decade. It is, therefore, likely that the decision to use a drugs for use in long-duration space flight, since the therapeutic drug for astronauts will be based on evidence Gravitational and Space Biology 18(2) June 2005 51 P.R. Cavanagh - Preventing Bone Loss in Space from a bed rest study supported by experience in a few Evaluation) randomized trial. Journal of the American individual volunteers who will take the drugs prior to Medical Association 287(7):847-57 and/or during space flight. Bekker, P.J., Holloway, D., Nakanishi, A., Arrighi, M., Among the questions that will need to be answered in Leese, P.T., and Dunstan, C.R. 2001. The effect of a these human trials are: (1) What is the bioavailability of single dose of osteoprotegerin in postmenopausal women. the various drug therapies in 0-g? (2) Are the dose- Journal of Bone and Mineral Research 16(2):348-60 response curves similar in 0-g to those established in 1-g? (3) What are the post-flight consequences for bone health Bekker, P.J., Holloway, D.L., Rasmussen, A.S., Murphy, of taking osteoprotective drugs? (4) If drugs need to be R., Martin, S.W., Leese, P.T., Holmes, G.B., Dunstan, taken on-orbit, how should they be stored for maximum C.R., and DePaoli, A.M. 2004. A single-dose placebo- effectiveness? (5) How will a drug's effectiveness be controlled study of AMG 162, a fully human monoclonal determined on-orbit so that doses can be modulated? (6) antibody to RANKL, in postmenopausal women. Journal What is the best combination of drug and exercise of Bone and Mineral Research 19(7):1059-66 countermeasures? Biriukov, E.N., and Krasnykh, I.G. 1970. Changes in the SUMMARY AND CONCLUSIONS
Optical Density of Bone Tissue an din teh Calcium Metabolism of the Astronauts. In: Kosmicheskaia This review has defined the current status of exercise and Biologiia i Meditsina. (Nikivaev, A.G., and Sevastianov, therapeutic drug countermeasures for bone loss during V.I. Eds) Moscow: pp. 42-45. long-duration space flight. The available data indicate that exercise countermeasures to date have not been Bisello, A., Horwitz, M.J., and Stewart, A.F. 2004. effective and crew members continue to lose significant Parathyroid hormone-related protein: an essential bone mass in the lower extremities and lumbar spine. physiological regulator of adult bone mass. Better-designed studies are needed to determine if the Endocrinology 145(8):3551-3 entire distributed daily dose of exercise that occurs in 1-g can be successfully replaced by short periods of high- Black, D.M., Cummings, S.R., Karpf, D.B., Cauley, J.A., intensity exercise on-orbit. Exercise dose on-orbit must Thompson, D.E., Nevitt, M.C., Bauer, D.C., Genant, also be quantified. H.K., Haskell, W.L., Marcus, R., Ott, S.M., Torner, J.C., Quandt, S.A., Reiss, T.F., and Ensrud, K.E. 1996. Drug therapeutics for bone have not yet been used in Randomised trial of effect of alendronate on risk of space, and, given the considerable experience using fracture in women with existing vertebral fractures. several classes of osteoprotective drugs on Earth (mostly Fracture Intervention Trial Research Group. Lancet in postmenopausal women with low bone mass), it seems 348(9041):1535-41 wise to explore such interventions for use during space flight. However, the many differences between the 1-g Body, J.J., Greipp, P., Coleman, R.E., Facon, T., Geurs, clinical studies and the 0-g individual prescription must F., Fermand, J.P., Harousseau, J.L., Lipton, A., Mariette, be carefully considered. Many new therapies can be X., Williams, C.D., Nakanishi, A., Holloway, D., Martin, expected in the future as investigators achieve a better S.W., Dunstan, C.R., and Bekker, P.J. 2003. A phase I understanding of the genetic regulation of bone mass, and study of AMGN-0007, a recombinant osteoprotegerin genetic screening may offer a means of selecting crew construct, in patients with multiple myeloma or breast members with a low susceptibility to bone loss. carcinoma related bone metastases. Cancer 97(3 Boyden, L.M., Mao, J., Belsky, J., Mitzner, L., Farhi, A., Supported by National Space Biomedical Research Mitnick, M.A., Wu, D., Insogna, K., and Lifton, R.P. Institute grants BL00401 and BL00402 through NASA 2002. High bone density due to a mutation in LDL- NCC 9-58. The assistance of Ted Bateman, Ph.D., was receptor-related protein 5. New England Journal of Medicine 346(20):1513-21 REFERENCES
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