We performed this study to elucidate bone blood flow and metabolism in humans because both circulatory aspects and metabolic demands of the bone blood flow in physiologically demanding conditions, such as during physical exercise, remains poorly characterized in humans. Our major novel findings are that bone blood flow increases with physical exercise, but that the increase appears to level off with increasing intermittent isometric exercise intensities. In addition, although moderate systemic hypoxia does not change bone blood flow at rest or during exercise, intra-arterially administered pharmacological vasodilator adenosine is capable of enhancing bone blood flow in humans, to levels similar to those found during dynamic exercise. Furthermore, glucose uptake of the bone was noticed to be enhanced by almost fivefold in response to moderate intensity dynamic exercise, suggesting that metabolic requirements of bone in the moving leg are substantially enhanced.
We document in the present study that resting bone blood flow is similar in women and men. Bone blood flow increases in response to both intermittent isometric and dynamic exercise, but appears to level off when intermittent isometric exercise intensity increases. In this respect, bone behaves differently from muscle, in which blood flow is well known to increase with increasing intensities until maximal workload is attained, although in terms of isometric exercise some limitations may be present, especially during the highest intensities and/or workloads. However, we have previously shown that in this isometric exercise model, with intermittent work and resting periods performed at fairly low exercise intensities, muscle blood flow increases proportionally with increasing exercise intensities.18 Indirectly, these findings suggest that the metabolism of the bone increases from rest to exercise, as confirmed by glucose uptake determinations. These blood flow results are in good agreement with earlier animal studies, which suggest that when exercise intensity is low, bone blood flow may increase, but when intensity increases, vascular resistance in bone also increases and blood flow decreases.5, 13, 15–17, 23 It is likely that the blood flow levels off with increasing exercise intensity because muscle contractions and relaxations create pressure fluctuations in the bone marrow, and during muscle contractions the exciting veins can be occluded, especially when contraction intensity increases, resulting in increased pressure and thus reduced flow in bone marrow.4, 8 It is also highly likely that adrenergic nervous constraints play a role in this constrictor response,13 but higher exercise intensities and modalities that involve larger muscle mass are likely needed to elicit this constrictor response.13, 15–17 Other putative mechanisms may also be involved, but they remain to be studied in humans. Interestingly, however, the increase in vascular resistance, and thus decrease in conductance, during whole-body treadmill exercise in awake animals is more prevalent in bones other than the femur.13 Also, in the femur, the increase in vascular resistance occurs largely in bone regions other than the marrow cavity, where blood flow remains unchanged in response to exercise with increasing intensities.13 Although resolution limitations do not allow us to differentiate cortical blood flow from blood flow in marrow, in our analysis bone marrow likely accounts for a major part of blood flow in the femur (Fig. 1). Therefore, in this regard, increased vascular conductance from rest to exercise in both intermittent isometric and dynamic exercise in the present study is the finding that can be expected, and suggests that active vasodilation occurs in bone marrow in response to exercise, but the mediators of this phenomenon remains to be identified in humans.
In contrast to an animal study that showed reduced bone blood flow in response to systemic arterial hypoxia,13 we did not observe in the present study either elevated or reduced blood flow in bone while subjects were breathing moderately hypoxic gas. As it appears that bone blood flow is under the control of sympathetic nervous system,13 it is likely that in our study hypoxia did not create sufficiently high stimulus to sympathetic nervous system blood flow to be reduced, at rest or during exercise. Moreover, the finding also suggests that constrictive stimulation of arterial chemoreceptors predominates over a local hypoxic vasodilation, in bone in humans. However, the powerful vasodilator, adenosine, which was locally infused into the femoral artery, increased bone blood flow substantially. In fact, the blood flow in bone during adenosine was much higher than it has been previously observed by direct intra-arterial infusion of sodium nitroprusside,21 and comparable to that of during dynamic exercise. Interestingly, vascular conductance during the infusion was even higher than during exercise, indicating that human bone blood flow and vascular conductance can also be increased to physiologically relevant levels with vasodilator drugs. Also in this respect our results are well in line with the previous results in anesthetized dogs, in which adenosine significantly reduced bone vascular resistance from resting baseline.13 Therefore, in general, it appears that many of the previous findings from animal studies directly applies to humans as well, but had remained uncharacterized until the present study.
Even if the present study is basic in nature, there are a number of points that might also be clinically meaningful. First, our results provide mechanistic insight that likely largely account for many of the beneficial effects of physical activity in strengthening bone.1–4 Thus, the beneficial changes in mineral content and structure are likely made possible by increased blood flow that we document here, which supplies bone with nutrients and oxygen in accordance with its metabolic needs,4–8 which are also increased in response to exercise according to the present results. In comparison to other connective and structural tissues of the body, it appears that the metabolism of bone is substantially larger than the metabolism of tendons in a similar exercise model that was also applied here.24 Second, the fact that bone blood flow can be substantially increased by pharmacological means may provide some underlying mechanistic explanations of the findings, which showed positive effects of nitrates, potential vasodilators, on bone mineral density.25, 26
As a result of the imaging limitations, the exercise models applied in the present study were fairly localized small muscle mass exercises that also induce little vibration stimulus for bone, which is known to affect bone metabolism substantially, and it may be that the results would have been slightly different if certain whole-body exercise such as running could have been used as the exercise model. Additionally, because of the resolution limitations, differentiating cortical bone from marrow cavity in femur in the present study was not reliable; but as can also be seen from the illustration in Fig. 1, showing the imaged thigh region, bone marrow likely accounts for a major part of blood flow and glucose uptake in the femoral bone in the present study, which is also generally known based on animals studies using microspheres.13, 27 Finally, although the femoral bone represents one of the most important load-bearing and muscle-moving bones in a human body, the characteristics of blood flow and metabolism of bones other than the femoral bone warrant further investigation in humans.
In conclusion, resting femoral bone blood flow is similar in healthy young women and men and increases by physical exercise, but levels off with increasing intermittent isometric exercise intensities. Moreover, although moderate systemic hypoxia does not change bone blood flow at rest or during exercise, an intra-arterially administered pharmacological powerful vasodilator, adenosine, is capable of markedly enhancing bone blood flow and vascular conductance in humans. Finally, enhanced metabolic requirements of bone in the moving leg were documented in the present study; glucose uptake of the bone was found to be elevated by almost fivefold in response to moderate-intensity dynamic exercise. Altogether, these physiological results in healthy young subjects in vivo are likely to help in better understanding the beneficial effects of physical activity in strengthening bone.1–4