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Principal Investigator:
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Christopher B. Ruff, Ph.D.
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Organization:
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Johns Hopkins University School of Medicine
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Project Ended:
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2000
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Bone loss under conditions of microgravity has been widely recognized as a potentially critical obstacle to carrying out long-term space missions. Loss of bone mass and density during spaceflight has been documented in both experimental animals and human astronauts and cosmonauts for several decades. However, the structural consequences of such bone loss, in terms of changes in bone strength and increased fracture risk, are much less well understood. Bone strength is a function of both the amount of material present (i.e., mass) and its geometric distribution (i.e., structure). The primary goal of this study was to document changes in mechanically-relevant parameters of bone structure in humans and animal models under conditions of microgravity, and to assess the effects of applied mechanical and pharmacological countermeasures on these changes. Using data derived from a detailed structural analysis of the proximal femur and a dynamic loading model, changes in hip fracture risk after prolonged spaceflight were estimated. The effectiveness of three potential countermeasures - partial weight-bearing, administration of a bisphosphonate, and vibrational mechanical stimuli - on bone strength were evaluated using a tail-suspended rat model. We have thus made major strides towards addressing the goals put forth in the NSBRI Critical Research Path and Bone Team objectives: to assess the probability of a fracture occurence without countermeasures, and to assess the efficacy of different countermeasures in preventing fractures.
The project had three complementary aims: 1) to measure bone structural changes in the hip, extracted from 2-D DXA (dual-energy x-ray absorptiometric) data, in humans subjected to microgravitational conditions, including bedrest on Earth and living aboard the Mir Space Station; 2) to construct 3-D finite element models of the hip from cadaveric femoral specimens which could then be altered using results from (1) to simulate microgravitational effects, and used together with dynamic link analysis to calculate changes in fracture risk; and 3) to assess the effectiveness of several countermeasures - partial (.5 G) mechanical loading, the administration of a bisphosphonate (ibandronate), and mechanical vibrational stimulation - on bone structural changes using a tail-suspended rat model. All of these objectives were accomplished during the three years of support.
Both the bedrest and Mir subjects showed significant declines in measures of bone strength during exposure to microgravity. Declines in the section modulus, an index of bending strength, were comparable in the proximal femoral shaft in bedrest and Mir subjects, averaging almost 1 percent/month, but rates of decline in the same index in the femoral neck averaged about twice as large in the Mir subjects (1.3 percent/month) than in the bedrest subjects (.7 percent/month), despite similar rates of decline in BMD (bone mineral density) (1.3 and 1.15 percent, respectively). The difference in section modulus changes in the femoral neck was due largely to a small but significant increase in the outer (periosteal) diameter of the bone in the bedrest subjects, an effect not seen in the Mir group. Follow-up studies of the Mir cosmonauts after return to Earth showed an increase in periosteal diameter of the femoral neck which helped to restore its strength, similar to some age changes that we have observed in the normal elderly population. We interpret these findings to indicate that a) geometry, not just bone mineral mass or density, is important in assessing bone strength, b) patterns of change in bone structure in spaceflight subjects are in some ways unique, and thus c) extrapolations from Earth-based studies may be misleading, and furthermore d) detailed geometric measurements should be included in any bone monitoring protocol during spaceflight and/or Mars exploration.
Two 3-D finite element (FE) models of the proximal femur were constructed from cadaveric specimens from a 36 year-old male and 32 year-old female. 3-D FE analysis allows a much more detailed and realistic modeling of both the geometry and loading conditions of the hip region than is possible using 2-D DXA-derived measurements. The failure loads and risk of fracture following a fall to the side (assuming an average body height and weight) were calculated for each femur, using a dynamic link model that accurately reflects in-vivo loadings. Using the structural information available from the DXA cosmonaut data and some assumptions derived from other experimental studies, these 3-D models were then altered to reflect the average change in structure that would occur after a year of spaceflight, and failure loads and fracture risks were recalculated. Load to failure was reduced by more than 20 percent on average in the two femora, resulting in an increase in risk for fracture averaging almost 30 percent. Because we found significant individual variation in how much bone is lost, and how much strength is reduced following exposure to microgravity in both the Mir and bedrest subjects, it is very likely that changes in failure load and fracture risk in some individuals would be even more extreme than these mean estimates. We also compared these results to those obtained through a simpler 2-D curved beam analysis, and found that predicted failure loads were comparable using the two models. The 2-D curved beam analysis has the advantage that it could be applied directly to DXA data gathered during spaceflight, thus enabling longitudinal monitoring of bone changes in astronauts/cosmonauts if a DXA-like apparatus were included on board.
In the tail-suspended rat study, rats were subjected to 35-day periods of partial weight-bearing using a custom-designed platform and mechanical feedback device. Long bone structural parameters were measured before and after treatment using pQCT (peripheral quantitative CT). Results of these studies indicated the following: 1) .5 G loading (similar to the Martian environment) is not sufficient to maintain bone strength. 2) Administration of ibandronate is an effective countermeasure for loss of bone strength under microgravitational conditions. 3) Mechanical stimulation via vibrations applied to the supporting substrate is also an effective countermeasure for maintenance of cortical bone strength, although not trabecular bone density. Thus, a combination of both pharmacologic and mechanical treatments may be necessary to maintain bone strength under microgravitational conditions.
These results show that bone distribution, or structure is a major factor in determining strength and fracture risk. This has implications not only for planning as part of the Critical Research Path for Mars exploration, but also for Earth-based health applications, in particular age-related osteoporosis. Fracture risk is a major medical problem among the elderly. Consideration of all structural components of a skeletal element should improve fracture risk evaluation; in fact, we are currently engaged in parallel studies of bone structural changes in several large demographic samples of the normal population, including the NHANES national survey and the SOF (Study of Osteoporotic Fractures). Studies of these kinds, carried out from a mechanical perspective, should aid in our understanding of both the etiology and consequences of bone loss under a variety of environmental conditions, and provide more accurate evaluation of the efficacy of countermeasures.
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