Dr H. Montgomery

INTRODUCTION

Clinical and basic-science research preparation is increasingly required if astronauts are to function safely and effectively over long-duration space flights. Given the inability to perform long-term studies in the microgravity environment itself, such research must per force be land-based, and must utilise innovative approaches. Such research- in whichever gravitational environment it is conducted- offers similar reciprocal development of novel biomedical data, which may find its place in a greater understanding of earthbound physiology and disease.

BONE DEMINERALISATION AS AN EXAMPLE
Demineralisation as a generic problem

Microgravity: Microgravity-induced osteoporosis presents one of the most formidable obstacles to long duration astronaut deployment. Current studies predict progressive bone mineral density loss of 1-2% per month. Countermeasures, including resistive exercise regimes, have been employed to overcome this, although none appear routinely effective. In addition there are marked, unexplained, inter-individual variations in the degree of osteoporosis observed.
Earth: Osteoporosis is similarly a major health problem to both men and women: half of all women will develop osteoporotic fractures: < 20% die within 6 months of hip fracture, 50% remain unable to walk unaided, and a further 25% require long-term care. Males lose up to 43% of peak bone mass by the age of 80. At any time, 1.5% of European hospital beds are occupied by osteoporotic patients.
The mechanism regulating bone turnover in man will be the same in space and on earth, and the pattern of activation of such processes may be very similar in both environments.

Genetic strategies of investigation
Functional genetic polymorphisms seemingly play a pivotal role in the regulation of bone mineral density (BMD) and mass. These differ greatly (< 40%) between races even in the foetus, and increasingly during adolescent growth. Indeed, genetic differences account for between 60% and 75% of the variance in interindividual peak bone mass/density and a substantial proportion of the variance in rate of loss. The association of a minor genetic variation (polymorphism) in a single gene with a specific skeletal phenotype would thus demonstrate a role for that gene product in its regulation. Such candidate gene association studies thus provide a novel means by which to investigate normal bone physiology. Appropriate prospective physiological investigative strategies and models are, however, required.

Potential genemic-phyisological models
Prospective gene-environment interaction models are appropriate for the investigation of bone mineralisation/demineralisation in relation to both terrestrial and microgravity environments. Such models may be:
Exercise training, We have developed a model in which the alterations in bone density (DXA), microstructure (ultrasound) and morphology (MRI) with exercise training are studied. British military recruits are examined both before and after 10 weeks of exercise training. Three candidate genes have already been studied and shown to influence such responses.
ESA Bedrest study Over the last 8 months our group has worked towards a working collaboration with ESA. Male subjects aged 25 to 45) from the ongoing ESA Bed Rest Studies will be used in a series of candidate gene-association studies. The ESA long term (120 day) bed rest study at MEDES in Toulouse, is in its second phase. It is to date the largest, most comprehensive study of human physiology in a simulated microgravity environment. The study is essentially an effort, on the part of the European Space Agency, to study the physiological effects of long duration space deployment on human crews in preparation for expedition class missions (i.e. Mars). It also complements the International Space Station research programme.
The bed rest itself caused musculoskeletal unloading. The total duration of each study is 120 days: 90 days in strict -6° head down tilt, with a preparatory period of 15 days beforehand and a 15 day recovery phase after. The first study period ran from August to December 2001 with 14 volunteers participating; they are all being tested through to the end of the experiment. The second period started on 22 March and will end on 27 July 2002. Eleven volunteers have been selected this time. Like the first period, the study comprises a 15-day preparation phase, a three-month bed rest phase and a 15-day recovery phase. As one end-point, bone demineralisation is being studied. In addition to bone densitometry, magnetic resonance imaging and muscular biopsy are being performed.
Given our retrospective involvement, candidate gene association studies may lack power. However, in future, it is envisaged that individuals may be selected by candidate gene for any given study, and such studies appropriately powered.

Summary
Prospective collaborative studies of this sort offer intellectual and financial added value in our assessment of physiology and pathophysiology pertinent to both microgravity and terrestrial environments.

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