The effects of spaceflight and rhGH treatment on cancellous bone microarchitecture in the femoral head are shown in figure 1. The 4–day flight resulted in lower cancellous bone volume fraction (A), connectivity density (B), trabecular thickness (C) and trabecular number (D), and higher trabecular separation (E). Treatment with rhGH had no significant effect on the endpoints measured. Significant spaceflight by rhGH interactions were likewise not detected for any of the endpoints evaluated. Alterations in the bone microarchitecture in flight animals can be readily appreciated in three-dimensional images of the cancellous bone compartment evaluated in the femoral head (F).
Histomorphometric analysis of muscle and bone in male Sprague Dawley rats flown on STS-41 detected soleus atrophy but no change in femur length, cortical bone cross-sectional area in femur diaphysis or cancellous bone volume fraction in the distal femur metaphysis. rhGH had no effect on soleus muscle but stimulated periosteal bone formation in the femur diaphysis in control and flight animals. The inability to detect changes in bone microarchitecture following this 4–day flight by conventional histomorphometry may have been due to limitations of two-dimensional analysis. Alternatively, the femoral head evaluated in the present study may be more sensitive to skeletal unloading. A 14–day spaceflight on STS-58 resulted in region-specific changes in gene expression levels for bone matrix proteins. Notably, the proximal femur from flight animals on STS-58 exhibited lower mRNA levels for osteocalcin, osteonectin and type 1 collagen. The distal femur metaphysis from flight animals exhibited reduced mRNA levels for osteonectin and type 1 collagen but not osteocalcin and no change in mRNA levels occurred in midshaft diaphysis or distal femur epiphysis. These findings provide support for the possibility that the proximal femur is highly sensitive to microgravity.
To our knowledge, the effect of spaceflight on the femoral head has not been previously evaluated. STS-62 (14–day spaceflight using ovariectomized Fisher 322 rats) is the only spaceflight study reporting three-dimensional microarchitecture of rat bone. Cancellous bone loss occurred in flight animals in lumbar vertebra and distal femur metaphysis but not in distal humerus. Bone in the proximal femur was not evaluated.
Because of the very young age of the rats in the present study, it is likely that the lower bone volume in the femoral head of flight animals reflects reduced bone accrual during growth rather than net bone loss; lower trabecular thickness and lower trabecular number contributed to the lower cancellous bone volume fraction. The change in microarchitecture is consistent with increased resorption of primary spongiosa (reduced trabecular number) in combination with reduced addition of bone onto primary spongiosa (reduced trabecular thickness). This proposed cellular mechanism is consistent with results of studies evaluating the response of cancellous bone to spaceflight in tibia and femur by dynamic histomorphometry.
Cancellous bone loss occurred in the distal femur metaphysis and epiphysis of ovariectomized Fisher 322 rats flown on STS-62 (14–day spaceflight). It is noteworthy that the most severe bone loss during long duration spaceflight in astronauts is in the proximal femur. Thus, future studies performed in more skeletally mature animals should evaluate this site thoroughly.
GH plays an important role in bone growth and maturation and reduced GH signaling has been proposed to contribute to bone loss during spaceflight, in part, due to a microgravity-induced secretory dysfunction. GH has potent anabolic actions on the musculoskeletal system and there has been long-term interest in whether GH, alone or in combination with other anabolic agents, has therapeutic value in prevention of disuse osteopenia and sarcopenia. In the present study, treatment with rhGH did not prevent the skeletal changes incurred during spaceflight. This finding does not support the hypothesis that decreased GH secretion, which when severe is known to reduce bone formation in growing rats, is responsible for reduced bone accrual during spaceflight. However, the study does not rule out the possibility that increasing GH levels above normal may partially counteract the detrimental skeletal effects of microgravity. Here we focused on cancellous bone in a region where there was no response to increased levels of the hormone but some research suggests that GH has a more potent effect on cortical bone.
Microgravity experiments in mice are being performed using a variety of platforms, including the International Space Station, but to date studies detailing bone microarchitecture have been few in number. In the future, it should be possible to establish whether there is concordance in microgravity-associated changes in bone microarchitecture between rats and mice. Similar responses in both species would add credence to the generalizability of the current results. Additional analysis of archived tissue from space shuttle studies using rats would contribute to achieving this goal.