Previous research has shown that bone loss due to disuse, including that induced during space flight, is a consequence of a disruption in the signal molecules that function as intermediaries between the mechanical and metabolic processes involved in bone loss. The endocrine hormones, like estrogen, have been shown to inhibit bone loss during unloading, whereas the parathyroid hormone (PTH), in contrast, has been shown to increase bone formation during unloading. The overlap in these two pathways of control will be utilized to explore a possible novel pharmacological method of intervention to mitigate bone loss during periods of disuse.
Estrogen deficiency and hypogravity have additive effects on bone loss in rats. Also, skeletal unloading resulted in bone loss in males and females by gender-independent mechanisms, increased bone resorption and decreased bone formation in both. However, the results also demonstrated that most of the bone loss in rats subjected to microgravity is due to decreased bone formation in animals with normal estrogen levels whereas it is due to increased bone resorption in estrogen deficient rats. As a consequence, the ideal drug (or exercise) intervention may have to take into consideration the gonadal hormone status individual astronauts.
There is compelling evidence that estrogen sensitizes the skeleton to mechanical loading. The investigators have studied the possible contributions of metabolites of 17ß-estradiol, to the estrogen effect, especially those which are important following the menopause. These studies have revealed that 16 alpha-hydroxyestrone is a complete estrogen agonist on bone but a partial agonist on other estrogen target tissues. Tibolone, a synthetic steroid which undergoes tissue selective metabolism into several metabolites having estrogenic, progestogenic or androgenic activities, has direct beneficial effects on bone cells.
Gender differences in bone mass and bone turnover in adult rats were studied. These differences (e.g., females have a higher rate of bone turnover than males) are similar to what was observed in human iliac crest bone biopsies. Future studies will be needed to establish whether there are gender specific differences in the rates of bone loss. Additionally, studies should be performed to establish whether there are gender differences in the rates of recovery during hypogravity.
Intermittent PTH can completely prevent the pronounced inhibitory effects of hindlimb microgravity on bone formation as well as prevent bone loss. However, PTH was only effective in preventing the detrimental skeletal effects of hindlimb unloading at dose rates that greatly exceed those used in humans. In contrast, therapeutic dose rates of PTH were highly bone anabolic in weight bearing limbs. Also, the requirement of PTH for weight bearing is much greater for cortical than cancellous bone.
The investigators studied the mechanisms mediating the detrimental side effects of PTH. This is important because side effects are likely to occur in some individuals receiving PTH therapy to prevent bone loss and the incidence of side effects might occur during hypogravity. They obtained evidence that the catabolic bone effects of PTH require PDGF-A signaling. Antagonizing this signaling with an inhibitor of PDGF-A expression and receptor binding blunted PTH-induced bone marrow fibrosis, hypercalcemia and bone resorption.
The hypogravity environment changes the response to “life style factors” and nutritional factors. The investigators have studied how selected “life style factors” such as alcohol consumption alter the skeletal response to mechanical unloading. These studies demonstrated that alcohol and hindlimb unloading have independent detrimental effects on bone formation. It is unlikely that astronauts will be consuming alcohol during space flight. However, the data suggests that detrimental skeletal effects of consuming alcohol persist when drinking ceases and could potentially exaggerate the effects of hypogravity.
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