completely at some skeletal sites.47 In contrast to what occurs in humans, bone resorption in rats was not substantially changed in one flight experiment.48 whereas it was increased in another.49 Most rodents flown in space have been immature and undergoing rapid bone growth.50 In these studies, bone formation dominates during growth, and so it is not surprising that greater changes were observed in bone formation than in bone mineral resorption. It is difficult to extrapolate from these data to the expected changes in the mature skeleton during long-term spaceflight. A few studies have used adult animals, and in these studies bone formation was suppressed at the periosteal surface.51,52,53 In contrast, longitudinal growth was minimally affected by either spaceflight or hindlimb unloading (HU).54 One study has shown bone loss in spaceflight to be greater than that in ground-based models, such as HU,55 although it is important to distinguish between bone loss, the removal of existing bone, and failure to gain bone in growing animals. In this model, traction applied to the tail of rodents elevates the lower extremities and eliminates generation of ground reaction forces.

In Vitro Studies

Bone cell culture experiments have been performed on space shuttle missions,56,57 on Skylab,58 and on the free-flyer Foton-M.59 These studies demonstrated differences in gene expression and growth factor production by osteoblasts.60 Osteoclasts were also affected by spaceflight.61 Interpretation of these experiments is a challenge, because cells in culture behave much differently than cells embedded in bone. Furthermore, the vibration during launch can confound cell culture experiments, particularly for short-term (1 to 2 weeks) experiments.62 The experimental complications during spaceflight and the difficulty with interpretation make bone cell experiments of lower priority compared with animal or human spaceflight studies. There is, however, a potential use of cultured bone cells in biotechnology applications.

Status of Countermeasures

Exercise Countermeasures

To date, NASA and the Russian space program have relied primarily on exercise countermeasures to attenuate bone loss,63,64,65 but no exercise has yet proven to be uniformly effective for maintaining bone mass66,67 during flight or bed rest. Similarly, low-magnitude, low-frequency mechanical signals were not effective in prolonged best rest.68 There is evidence that the external loading on previous exercise devices used in space has been insufficient to provide the required stimulus to bone.69,70 Recent (fall 2009) additions to the exercise devices on the ISS now offer the possibility for greater loading and for definitive research to examine the efficacy of exercise countermeasures. The capacity to measure loads was also added to these new devices, but interaction with NASA personnel indicates that further refinements are required to produce accurate load estimates. The ISS provides an excellent research platform for studies that are relevant to missions outside low Earth orbit because the microgravity environment on the ISS presents a greater challenge to the musculoskeletal system than does a partial-gravity environment.71

Ground-based research using bed rest (head-down for microgravity or head-up for lunar simulation) provides another important research platform for exercise countermeasures.72-81 For example, bed rest studies suggest that bone may be somewhat protected with sufficient loads and exercise time. Results from Vernikos et al.82 showed that intermittent upright posture and exercise reduce the increased blood calcium levels observed in bed rest, and data from Smith et al.,83,84 and Zwart et al.85 showed positive benefits of supine treadmill running within lower-body negative pressure during 30 and 60 days of bed rest. There are no studies indicating positive effects on bone in passive intermittent rotational artificial gravity.86 It is possible that lower-body negative pressure or centrifugation coupled with exercise may be more effective than exercise alone, perhaps through modulation of some other necessary physiological factor (e.g., improved blood flow, fluid shifts, or circulating hormones).

Pharmaceutical and Nutritional Countermeasures

Vitamin D supplementation has been used by NASA during spaceflight,87,88,89 but one report90 showed that serum 25-hydroxycholecalciferol was decreased after flight despite supplementation with vitamin D.

Short-term calcium supplementation has not been effective in reducing bone loss during spaceflight or head-down bed rest.91,92

Over the past 15 years, several drugs have been developed to prevent bone loss associated with osteoporosis

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