Physical activity and bone quality




Laurence VICO, PhD
Université de Lyon
Saint-Etienne and
INSERM U890/IFR143
Saint-Etienne, FRANCE

Physical activity and bone quality

by L . Vico,France

Physical exercise acts directly on bone through mechanical stress, and indirectly by changes in cardiovascular, ventilatory, metabolic, and hormonal parameters. Studies in athletes show that activities such as running, performing gymnastics, and weight lifting induce bone gain, whereas cycling and swimming are poorly osteogenic. Bone gain is mostly observed in the parts of the body involved in the exercise. Failing to continue exercising during adulthood could be detrimental to bone gain. In the early stages of puberty, exercising increases bone mass, whereas in postmenopausal women and in the elderly, exercise does not always provide bone gain. Nevertheless, it may prevent osteopenia and improve muscle tone, cardiovascular function, and balance, thus limiting the risk of falling. As is the case for some young people, too much training can be harmful, as evidenced by cortical thinning in older cyclists who train more than 6 hours per week. This is evidence of a nonlinear effect of exercise on the skeleton. High-impact exercises are hardly applicable to fragile subjects. Whole-body vibrations (WBV) may have osteogenic potential. In animal models of bone loss, WBV improves bone mass and quality. In humans, certain studies show a potential benefit of WBV with regard to muscle, bone, and posture. The therapeutic use of WBV is not standardized, and the impact and scope of application still needs to be defined in terms of frequency, amplitude, duration, etc. This will require tailoring WBV to the characteristics of the users and assessing its effect on the whole body as well as on individual compartments (cartilage, peripheral circulation, tendons).

Medicographia. 2010;32:377-383 (see French abstract on page 383)

As early as 1892, Wolff1 suggested that the distribution of mechanical stress at the tissue level determines bone architecture. In 1971, Thompson2 and Frost3 introduced the concept of adaptation of skeletal tissue to stress, through regulation of bone cell populations. Exposure to stress causes the tissue to deform, resulting in local alterations designated as microstrains (10 000 microstrain (με)=1% change in length, or 1 strain (ε)=100%).

Moreover, it appears that the capacity of bone to adapt to mechanical stress occurs during dynamic stress (cyclic), whereas static stress entails no tissue response.4 These mechanical signals act on the bone cells themselves, which, through a cascade of reactions starting from the extracellular matrix, transform the mechanical signal into a biological response. This phenomenon is known as mechanotransduction.

Mechanoadaptation of the bone—tissue support

_ Mechanotransduction: in vitro studies
Bone cells, particularly those of osteoblastic lineage, are the most studied cells. This lineage comprises mesenchymal precursor cells to osteocytes, which is the final stage of differentiation, and represents 90% of bone cells. Understanding the mechanotransduction of all these stages is crucial: in precursors, it can guide their commitment to osteoblastogenesis at the expense of adipogenesis5; in osteoblasts, it affects the physicochemical properties of the newly synthesized matrix6; and finally in osteocytes, it coordinates bone remodeling.7 One of the major cellular components of mechanotransduction is the cytoskeleton. Indeed, it is an intracellular cable network comprising microtubules that are resistant to contractile strains of actin filaments and intermediate filaments that stabilize microtubules and microfilaments of actin.

This compression-tension network physically links with the extracellular matrix through transmembrane receptors (particularly integrins, mechanical transfer areas). Intracellular tension forces are therefore able, through the connected system, to balance out the forces of the extracellular matrix (and vice versa). This regulatory mechanism influences and integrates the effects of biochemical factors, by using or crossing these same regulatory pathways.

The model that takes into account all these forces, which, separately or jointly, affect the fate and/or activity of the bone cells, is referred to as the tensegrity (= tensional integrity)model (Figure 1).

_ At tissue level
The tensegrity model also applies to a musculoskeletal system in which the bones are compressed under the effect of gravity (weight, load) and under tension caused by the action of muscles, tendons, and ligaments. Such hierarchical structures can explain the mechanical transmission of information and coordinated response of an organ to a stimulus by mechanical coupling.

In bone, osteocytes undergo deformation variations resulting from movements that give rise to compression, tension, and torsion forces. Without functional osteocytes (targeted deletions) bone cannot adapt to changes in mechanical stress. In addition, pressure gradients caused by the tissue as it deforms create a flow of extracellular fluid around the osteocytes. However, mechanical and shear forces are not the only phenomena that occur: the deformation creates piezoelectric effects and the fluid causes the formation of electric fields called “streaming potentials.”8 Each of these three phenomena plays a role in mechanotransduction.

Figure 1
Figure 1. Cellular mechanotransduction.

The adherent cell stabilizes to its support thanks to equilibrium between forces of tension and compression. Microtubules are at the center of a network of compressive stress exerted by actin filaments. The focal contacts physically link the
inner cytoskeleton to extracellular matrix. If the matrix changes its physicochemical properties or if it is subjected to deformation, the forces are re-balancing (in-out and out-in arrow). The focal contacts are also necessary to activate many intracellular signaling pathways where mechanical effects are coupled with other biochemical effects (responses to growth factors, for example).

The resistance of bone to stress, to which it is constantly subjected (posture, physical activity), is determined both by its macroscopic characteristics (shape, size, structure) and a series of microscopic material and structural properties of the tissue. The stiffness (elastic zone of the bone) and the toughness (plastic zone of the bone) are examples of the biomechanical torque, which is the most studied in mineralized tissues. As a result of the nature of the materials, it is difficult to associate a very high stiffness with an extensive range of mechanical resistances. There are different ways of combining the two, but it might make the material extremely anisotropic, in the sense that it becomes rigid and hard in one direction, but weak and fragile in other directions. The balance between the function and structure of mineralized biological materials has led to a compromise between stiffness and toughness. Bone stiffness is mainly related to its mineral fraction, rendering it resistant to compressive forces. In contrast, the organic fraction, consisting mainly of collagen, gives bone its toughness and renders it resistant to tensile forces.

Another aspect of the mechanoadaptation of bone is the formation of microcracks resulting from bone fatigue caused by cyclic loading of critical areas that concentrate the stress and which are known to increase with age. The theory of bone’s adaptation to stress by microcracks is reinforced by findings from in vivo9 and ex vivo studies, which have analyzed the initiation and propagation of microcracks in bone samples.10 Microcracks were experimentally generated in vivo by physiological deformations, and the relatively significant remodeling activities were found to correlate with the experimentally induced damage. These activities that induce elevated remodeling are responsible for maintaining the structural integrity of bone and repairing fatigue damage produced by normal mechanical use. The osteocytes are responsible for this regulatory process by stimulating bone resorption at the site of a microcrack, either because their apoptosis initiates a cycle of resorption and the remodeling of a unit, or because the rupture of osteocyte dendrites affects signaling networks such as RANKL/OPG (receptor activator of nuclear factor kappaB ligand / osteoprotegerin). During the remodeling process, sclerostin, synthesized by osteocytes, has been shown to be a new player that inhibits bone formation. Its synthesis is stimulated by immobilization, which induces inhibition of the betacatenin Wnt pathway11 and is inhibited by stress.12

It thus appears that accumulation of fatigue is a stimulus of bonemodeling/remodeling, which could explain the osteogenesis triggered by certain types of sports. Moreover, it seems possible that a mechanically overstretched bone or bone in an osteoporotic subject may not be able to “repair” the microdamage, thus creating a situation conducive to fracture. This aspect of bone fatigue is poorly understood, due to a lack of noninvasive tools for the visualization of microcracks.

Effects of physical exercise on the human skeleton

Thirty per cent of BMD is independent of genetic factors and may be controlled by other factors includingmechanical stress. But the bone’s response to physical activity is itself influenced by a genetic component. In a study in female twins,13 it was shown that those who had been active over a period of 30 years had increased bone mass at the tibial diaphysis (cortical thickness, bending strength) and epiphysis (trabecular BMD)—as measured by a tomography device—as compared with their respective sedentary twin. Moreover, this benefit wasmore pronounced inmonozygotes than in heterozygotes. The study demonstrated that physical activity is a major determinant, independent of genotype, capable of acting on the mechanical properties of bone tissue.

Figure 2
Figure 2. Sports inducing an increase in BMD, in decreasing order: weight lifting, gymnastics, running, cycling, and swimming.

The pure effects of mechanical stress on bone, as a result of physical exercise, are difficult to evaluate because of the numerous concomitant physiological changes (cardiovascular, ventilatory, metabolic, and hormonal), which are all likely to modify the bone response. The literature dealing with the effects of exercise on bone reports very heterogeneous results that can be classified into two types of sporting activities: osteogenic and nonosteogenic.

_ Effects of different types of sports
Differences exist with respect to the type of sport performed. Running, gymnastics, and weight lifting induce bone gain of increasing amplitude.14 In contrast, with low-impact sports with limited loads, such as swimming, the effects on the bonemass in the lower limbs, or even the whole body, are negligible (Figure 2).15 Other findings suggest that a physical activity involving a significant impact, physical contact, and/or rotational forces, not only has beneficial effects on the areas under load, but also on the peripheral and axial bones not subjected to load. The magnitude of the difference between a state under load or not seems to be the decisive parameter. Indeed, weight lifters who are subjected to very high stresses appear to increase their bone mass more compared with any other sport.16 A distinction should bemade between sports that generatemechanical stress based on themode of loading (weight lifting) and those that generate mechanical stress through repeated impacts (running).

The musculoskeletal system of humans has evolved to adapt to endurance running. We can thus imagine that in loadbearing bones, large forces are needed to generate unusual strains. With regard to swimming, the loads developed by movements against the resistance of water, as well as the muscle contractions generating them are insufficient for inducing stimuli to the inferior limb bones. However, when it comes to non–load-bearing bones, such as the humerus, the deformations caused by muscle contractions are osteogenic.17 Consequently, the effect of pulling the muscles by their attachments on the bone has an impact on bone that depends on the function of load-bearing bones in the considered area. This has been confirmed in astronauts, another extreme model in which bone mass is lost in load-bearing bones, but not in non–load-bearing bones18 despite the substantial exercise programs they follow, but with which they cannot—or rarely—exceed accelerations above 1 g.

_ Thresholds effects
Under certain circumstances, carrying out a sport that is known to be osteogenic may have a deleterious effect on bone tissue. Intensive running by adults not accustomed to training can cause stress fractures. In marathon runners, both male and female, bone deficiency is frequently observed at the lumbar spine.19 In highly trained female athletes, a problem known as the “female athlete triad” (eating disorders + amenorrhea/oligomenorrhea + decreased bone mineral density) is more accentuated because of the harmful effects of overtraining on the hormonal cycle and of inadequate nutrition. This stresses the interdependence of the determinants of bone mass. These data suggest that exercise of too great intensity is damaging to the bone tissue. Indeed, a study in women and men over 50 shows that exercising (with loads) more than 5 hours per day (running, dancing or brisk walking), results in a decrease in spinal mineral density.20 This mineral deficiency can be explained by age, body mass, or estrogen status. We have also shown that increased bone resorption occurs in men over 60 practicing more than 6 hours of sport per week.21 These studies point to a nonlinear effect of exercise on bone mass. Another study showed that in soccer players training for up to 6 hours per week, femoral mineral density increased in proportion to the duration of training, but plateaued beyond this limit, without additional benefit to the bone.22

These studies indicate that not only intensity, but also duration of exercise is an important factor for the bone’s response to exercise. The tibia is one of site where fractures occur frequently in adolescents and young adults, especially in the diaphyseal region. Very few reports exist with regard to metaphyseal or epiphyseal fractures.23 Similarly, these fractures are rare in the distal femur24; most studies refer to fractures of the axis or neck of the femur.

_ Prevention of osteoporosis
Studies consistently confirm the role of certain types of physical exercise as a means for preventing osteoporosis. Prevention programs focus primarily on two populations: adolescents, in order to optimize their bone mass at the end of growth, and female adults and postmenopausal women, in order to reduce the slope of bone loss. The most important period for bone gain certainly is the peripubertal period, as shown in young tennis players in whom the increase in bone mass—and even more importantly in bone size—in the playing arm, can exceed 10%.25

Even if the effects of exercise on the BMD in postmenopausal women are modest, epidemiological studies suggest that physical activity and levels of dietary calcium are capable of reducing the risk of fracture.26 Walking alone is not enough to prevent bone loss. Consequently, exercise—even if it is dynamic and based on feedback of the limbs on the ground— must also achieve a certain level of frequency and intensity to be effective on bone tissue.27 More recent studies using peripheral tomography have shown, in this population, a positive association between physical activity scored over several years and cortical bone geometric parameters related to the radius, tibia, or femur.28,29 These data are invaluable since a minimal diaphyseal expansion induces a substantial improvement in flexural strength. It is possible that dual-energy x-ray absorptiometry (DXA) is not sufficiently powerful for the visualization of these changes.30

In elderly subjects

As we saw in the previous section, the knowledge we have of the effects of exercise on bone tissue is essentially what high-level athletes have taught us. These effects are much more difficult to identify in a vast population. In the elderly, it remains unclear whether exercise programs or the fact of having been active offers protection from osteoporotic fractures. At a certain age, exercising (gymnastics, walking) does not always provide significant bone gain. It could, however, possibly prevent rapid bone loss and thus reduce the risk of fracture, while also improving muscle tone, cardiovascular function, balance, and posture, thereby limiting the risk of fractures from falls. Recent reviews31,32 conclude that there is a need for better-targeted randomized controlled trials to evaluate the true effectiveness of exercise. In other words, this subject is not closed (Figure 3).

Instead of talking about physical activity, particularly when it comes to the elderly, one could speak of mechanical systems that are aimed at generating an effective stimulus to the skeleton. Hope is permitted, because it has been shown that use of vibration programs could be osteogenic. However, given all that has been said previously, this seems somewhat unlikely. Indeed, we know that very-high-amplitude (>2000 με) and low-frequency (<2 Hz) signals, which exist during strongimpact physical activities, are osteogenic4,33 until a threshold beyond which deleterious effects occur,34 based on Frost’s mechanostat theory.35

Since a pioneering study from 199036 and the early 2000s, it has been shown that low-amplitude signals, well below the amplitudes that can cause fractures, can also, when applied at high frequencies, induce an osteogenic response. Several studies using strain gauges attached to the limbs of different animals report that mechanical stimuli generated during motion (walking, running), or in static position (subject standing, sitting), induced signals of amplitudes around 500 to 2000 μεoccurring at low frequencies (<2 Hz), but also signals of low amplitude (<300 με) occurring at higher frequencies (10 to 50 Hz).37,38 It should be noted that the lower the amplitude of the signals, the higher their frequency and the more they are represented during daily activities (thousands of times) in contrast to high-amplitude signals, which are weakly represented, and this, regardless of the species or the bone site studied. Moreover, studies have shown that a force applied at high frequency (10 to 20 Hz) was more osteogenic than the same force applied at a lower frequency, as the motion frequency (1 Hz).39 This property of high frequencies as well as the balance of low-amplitude signals during everyday activities, has provided further insights into the understanding of their roles on bone tissue.

The origin of these signals is unclear. The observed high frequencies could be harmonics of large-amplitude signals (which occur at low frequency). The signals could also originate from muscle activity. A sarcopenia of type II fibers is observed in the elderly, which causes a decrease in muscle strength, as well as a decrease in muscle activity, with frequencies ranging from 30 at 50 Hz. This sarcopenia also causes an alteration of mechanical signals that regulate bone. Thus, muscle wasting is an etiologic factor in osteoporosis.40

Various studies have therefore investigated the effect of lowamplitude/ high-frequency signals on bone. Those of Rubin et al are the most illustrative.41,42 These researchers showed that sessions of 20 minutes of low-amplitude (0.3 g, 5 με), high-frequency (30 Hz) signals, applied for 1 year to the hindlimbs of adult ewes were able to increase the density and volume of the trabecular bone in the proximal femur.41

Furthermore, a signal simulating a physical activity (sinusoidal signal; 3 N; 2 Hz) coupled to low-amplitude (0.3 N) and highfrequency (0 to 50 Hz) signals applied during two consecutive days, 30 s/day, on mouse ulna in vivo has been shown to raise the rate of bone formation by approximately a factor of 4, as compared to a signal simulation exercise on its own.43 In humans, one can easily understand the relevance of employing this type of noninvasive, nonpharmacological mechanical system in frail or disabled individuals, who are incapable of carrying out regular physical exercise.

Figure 3
Figure 3. Exercise and prevention of bone fragility.

Exercise plays a pivotal role in prevention of bone fragility, and falls in the elderly population. Exercise regimens chosen for bone or balance are diverse and not all exercise regimens are effective. The optimal type, intensity, frequency and duration of exercise to maximize prevention of fractures remain incompletely characterized.

In 70 postmenopausal women, a prospective, randomized, double-blind study during a period of 1 year showed that episodes of less than 20 minutes with subjects standing on vibrating tables (<0.3 g; 20 to 90 Hz) were able to reduce bone loss in the lumbar and femoral regions. Compliance was increasingly high for increasingly frail subjects.44 Another interesting study was carried out in postmenopausal women undergoing three sessions per week on vibrating tables during 6 months (35 to 40 Hz; 2.28 to 5.09 g), who were asked to carry out knee bending exercises.

Results showed a gain of proximal femur bone and an increase in isometric and dynamic muscle strength.45 Gusi et al reported improved balance and reduced body fat following a gain in the neck of the femur in postmenopausal women after 8 months of training (3 times/week, 12.6 Hz, 3 cm displacement amplitude of the pad).46

In contrast, another group of postmenopausal women who carried out vibration exercises of 30 to 40 Hz 3 times/week in addition to resistance training during 8months did not achieve any additional gain in bone mass or muscle strength, as opposed to those carrying out solely resistance training.47

Studies on a larger scale are now required to not only confirm the benefits with regard to bone and muscle in different populations, but also to assess micro- and macro-scale changes in bone architecture at the and the impact on the risk of fracture. Other potential circulatory, postural, and neurovestibular effects should also be studied in parallel. A dosage effect needs to be established, not only with regard to time of use, but also with regard to the acceleration transmitted to different segments based on various postures when standing on the aforementioned vibrating tables.

Conclusion

Optimal response to loading appears to occur during the prepubertal stage, at least in girls (the window might be larger in boys). According to estimates, an increase in peak bone mass of 10% (depending on the type of sport) would delay the onset of osteoporosis by 13 years,48 suggesting that this period of life is the most important one for ensuring prevention of osteoporosis later in life.

Data from short-term prospective studies indicate a positive association between areal BMD and physical activity, but bone benefits may be lost if the practice of sports is stopped. In the elderly, physical activity may also reduce fracture risk through othermechanisms than those affecting BMD. Decreased bone mass, muscle strength, tissue perfusion, systemic hormones, and articular cartilage are common in elderly individuals.Wholebody vibration therapy may be efficient in alleviating these deteriorations, but its use for therapeutic purposes is far from being standardized. Although areal BMD measured by DXA is a common surrogate for bone strength, it is now possible to measure other aspects of bone strength such as bone geometry and volumetric BMD, using three-dimensional imaging techniques. Evaluation of bone macro- and micro-architectural parameters is gaining widespread acceptance and will improve our understanding of human skeletal adaptation to mechanical loading. _

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Keywords: sports; leisure; bone; whole body vibration therapy; puberty; menopause; cortical bone; mechanotransduction