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INVITED REVIEW

HIGHLIGHTED TOPIC
Biology of Physical Activity in Youth

Physical activity and bone development during childhood: insights from animal models

School of Biomedical Sciences, The University of Queensland, Brisbane, Queensland, Australia

	ABSTRACT

TOP ABSTRACT INSIGHTS FROM ANIMAL MODELS INSIGHTS FROM HUMAN STUDIES CONCLUSION REFERENCES

 
Animal studies illustrate greater structural and material adaptations of growing bone to exercise than in adult bones but do not define effective training regimes to optimize bone strength in children. Controlled loading studies in turkey, rat, or mouse bones have revealed mechanisms of mechanotransduction and loading characteristics that optimize the modeling response to applied strains. Insights from these models reveal that static loads do not play a role in mechanotransduction and that bone formation is threshold driven and dependent on strain rate, amplitude, and partitioning of the load. That is, only a few cycles of loading are required at any time to elicit an adaptive response, and distributed bouts of loading, incorporating rest periods, are more osteogenic than single sessions of long duration. These parameters of loading have been translated into feasible public health interventions that exploit the insights gained from animal experiments to achieve adaptive responses in children and adolescents. Studies manipulating estrogen receptors (ER) in mice also demonstrate that skeletal sensitivity to loading during the peripubertal period is due to a direct regulation of mechanotransduction pathways by ER, and not just a simple enhancement of cell activity already marshaled by the hypothalamic-pituitary axis. Unfortunately, because the rate and timing of growth in small animals are completely different from those in humans, these models can be poor tools to elucidate periods during growth in youths, during which the skeleton is more sensitive to loading. However, there are insights from studies of human growth that can improve the interpretation of data from such studies of growth and development in animals.

growth; exercise; maturation; mechanotransduction

From the oyster to the eagle, from the swine to the tiger, all animals are to be found in men and each of them exists in some man, sometimes several at the time. Animals are nothing but the portrayal of our virtues and vices made manifest to our eyes, the visible reflections of our souls. God displays them to us to give us food for thought. —Victor Hugo, Les Misérables, 1862

IN A LETTER to Robert Hooke, Newton remarked "... If I have seen a little further it is by standing on the shoulders of Giants." Likewise, the observation that the skeleton is an efficient design to achieve mechanical objectives is not a recent one. In his 70s, ill and going blind (and while living under house arrest for defending Copernican astronomy), Galileo Galilei published his last book in 1638, Dialogue Concerning Two New Sciences (27). Using the classical device of a discussion among three individuals, he demonstrated, for example, allometric scaling of bones in relation to animal size. He also showed how structural adaptations, such as a hollow diaphysis, adapt bones for strength and lightness in the same way that "... men have discovered, therefore, that in order to make lances strong as well as light they must make them hollow" (27). Galileo did not occupy Salviati or Sagredo, and certainly not Simplicio, with questions of biological mechanisms for their mechanical analyses, but such questions have continued to exercise scientific debate. When subjected to loading, the ability of bones to resist fracture depends on their mass, material properties, geometry, and tissue quality (21). An increasing topic of debate has been whether these characteristics can be optimized during growth so that the risk of fracture during normal activities of adulthood and old age is minimized (11, 19, 64). For example, many natural experiments demonstrate that skeletal growth in limbs that were paralyzed (42), or proximal to limb segments that were amputated (5), led to bones that were architecturally and mechanically inferior to those subjected to normal mechanical loading during growth. It is no surprise, then, that animal and human studies provide compelling evidence that growing bone also has a greater capacity to respond to increased loading than the skeleton of adults (25, 36, 39, 64, 75, 93). This observation is exemplified in unilateral sports like tennis in which the differences between bones of dominant and nondominant arms are greatest in players who started training before puberty compared with those who started playing during adulthood (Fig. 1) (38, 41).

View larger version (10K): [in this window] [in a new window]   Fig. 1. Differences in bone mineral content (BMC) between bones of the dominant and nondominant arms of female tennis and squash players were greatest in players who started training before puberty (years before menarche) compared with those who started playing during adulthood (years after menarche). [Adapted from Kannus et al. (38).]

The aim of this review is to evaluate the contribution of animal studies to our understanding of physical activity effects on the growth and development of the skeleton. Furthermore, it considers where animal studies fail to provide valid models of physical activity and skeletal maturation, and suggests how studies of animal physiology might even be informed by human investigations.

	INSIGHTS FROM ANIMAL MODELS

TOP ABSTRACT INSIGHTS FROM ANIMAL MODELS INSIGHTS FROM HUMAN STUDIES CONCLUSION REFERENCES

 
In laboratory animals, growing bone responds to exercise of low or moderate intensity through significant structural adaptations. This occurs in cortical and trabecular bone and results in adaptation through both periosteal expansion, endocortical contraction, and reduced trabecular remodeling (25). Activation of remodeling in cortical bone declines in growing bone in response to exercise, reducing porosity and the temporary deficit of bone that occurs between resorption and formation (known as the remodeling space) (13, 46, 55, 101). The heterogeneity of exercise designs for animals varies widely, however, making it difficult to draw unequivocal conclusions about optimizing skeletal adaptation during growth. Consequently, investigators have turned to controlled loading studies in which the load magnitude, frequency, and partitioning can be accurately applied. Such models have included loading of the turkey, rat, and mouse ulnae (45, 77, 86), tibial four-point (24, 88, 89) and axial loading (17), and compressive loading of rat caudal vertebrae (12, 14). This set of models, in particular, has advanced our knowledge of dynamic skeletal adaptation considerably during the past 20 years.

Human studies notwithstanding (4, 7, 68, 99, 100), animal models clearly illustrate the problematic nature of areal bone mineral density (aBMD), as assessed by dual-energy X-ray absorptiometry (DEXA) during growth or adaptive alterations in bone geometry. This is partly because DEXA does not distinguish between changes in geometry and density (21, 68), nor cortical or cancellous bone, but also because its resolution is too low to detect small changes in bone dimensions that elicit substantial increases in bone strength (the holy grail of skeletal adaptation) (23). An excellent example of this characteristic is the modest 5% increase in the aBMD of the rat ulnae after 16 wk of axial loading three times per day (74). This is starkly contrasted by an incredible 64% increase in the ulna's ultimate breaking strength, as assessed by axial compression of the ulna to failure after the 16-wk loading program (73). Such a marked discrepancy occurs because the new bone formation occurs at the periosteal surface where a relatively small increase in bone apposition provides a disproportionate mechanical advantage at the locations of greatest strain. That is, the small amount of bone is strategically placed away from the axis of bending where it has an exponential effect to resist bending loads. The use of micro-computed tomography (micro-CT) in animal studies (3, 37, 87, 97), and peripheral quantitative CT (pQCT) in children (15, 30, 48, 50, 96), allows these adaptations in density and geometry to be distinguished, but there remains a balance to be achieved between the radiation dose and a desirable resolution for studies in vivo.

Insights from controlled loading.   To investigators working with children and adolescents, it may appear arcane to understand exercise by bending the tibia, or squeezing the vertebrae, of a rat. This may be partly true because the objectives of physical activity are not simply focused on the skeleton, but on health and well being in general. But if fracture prevention can equally be a consequence of an activity program, then we need to know what it is that effectively stimulates bones. For a start, controlled application of loads to the bones of rabbits, turkeys, and rats demonstrates that static, or isometric, loading provides very little stimulus to mechanotransduction (31–33, 77, 91) and may even inhibit normal appositional growth (72). Activation of new bone formation also requires that a threshold level of loading is exceeded (88), but that there is an interaction between strain rate and amplitude of loading (62, 63, 88, 90, 91) that modulates this threshold. The moderating effect of strain rate occurs because bone tissue is viscoelastic and interstitial fluid mechanics underlie transduction of applied dynamic loads into bone cell responses (40, 90). These responses are optimal in a range of loading frequencies up to 2.0 Hz (90), a frequency encompassing typical physical activities, after which the response to increasing strain rate diminishes due to viscoelastic stiffening of the cells (35). In terms of exercise, this means that activities that create relatively high strain rates will be more osteogenic than loads applied gently, or in which a strain magnitude is held constant for a period of time. That is, jumping and plyometrics will create a bigger osteogenic effect than simply walking or doing isometric strength exercises. What was not immediately apparent in earlier studies was that the relationship between strain magnitude and bone formation rate itself was altered by loading at higher strain rates (34), such that a given strain magnitude has greater osteogenic potential when delivered at higher strain rates.

A key characteristic of loading, revealed in Rubin and Lanyon's pioneering experiments, is that very few loading cycles are actually required to elicit new bone formation (76–78). This effect saturated very quickly in turkey ulnae such that increasing the duration of loading beyond 40 cycles per day had little additional effect on new bone formation (Fig. 2) (77), and a similar effect was seen in rat tibiae for just five loading cycles per day (94). That is, prolonging an exercise session will have diminishing returns if we are interested in strengthening bones. This is good news for physical activity because we don't have to ask children to participate in laborious periods of exercise or disrupt their normal schedule of activities, or inactivity, to any great extent to tweak their skeleton. Just as learning a motor skill is facilitated by distributed bouts of learning, a given number of loading cycles will also be more osteogenic if they are broken up into shorter bouts with rest periods in between (70, 71, 73, 74). This is because the sensitivity of the bone cells to the loading stimulus returns after a period of rest. This was tested by Robling et al. (70), who divided 360 cycles of tibial loading into one bout of 360, two bouts of 180, four bouts of 90, or six bouts of 60 cycles per day for 2 wk. In groups receiving four and six bouts per day, the bone formation rate in the loaded tibia was 80% greater than that in the group receiving one bout of 360 cycles per day (Fig. 3). When this design was applied to rat ulnae and extended to 16 wk, groups that received four bouts of 90 cycles per day had significantly greater bending strength than those receiving the single bout of 360 cycles (73).

View larger version (10K): [in this window] [in a new window]   Fig. 2. In Rubin and Lanyon's classic experiment (76, 77), the ulna of turkeys was isolated and maintained unloaded, or subjected to cyclical loading at 4, 36, 360, or 1,800 cycles per day (cpd) for 6 wk (360 cpd not shown here). Four cpd was sufficient to maintain the level of BMC as measured by single-photon absorptiometry. Thirty-six cpd increased BMC, but no advantage was gained when the duration of loading was extended to 360 or 1,800 cpd.

View larger version (7K): [in this window] [in a new window]   Fig. 3. Osteogenic potential of activities is increased when a large number of cycles is divided into shorter bouts of loading with rest periods between them. Bone formation rate (BFR) induced by mechanical loading at the endocortical surface of rat tibiae was significantly enhanced when 360 cycles per day was divided into 4 bouts of 90 (90 x 4) or 6 bouts of 60 cycles per day (60 x 6) for 2 wk. [Adapted from Robling et al. (70).]

Do these observations have implications for public health, or do they just make stronger rats? Physical educators are starting to pay attention to the principles learned from animal studies because such approaches have been adopted increasingly in recent physical activity interventions (26, 50–54, 56, 66). Although numerous controlled trials have applied some of these principles to maximize modeling in growing bone (8, 26, 30, 47, 60, 82), the Healthy Bones II (51–54) and "Action Schools! BC" program (49, 50, 56) in Vancouver were specifically designed around principles to optimize the osteogenic index of a practical and sustainable activity intervention. In Action Schools! BC, the bone-loading component of the program included an extra 15 min of simple activities for 5 days/wk, and "bounce at the bell (56)" in which just 3 min of variegated jumping activities were implemented three times per day (at each school bell) for 4 days/wk. During initial trials, the program induced an increase in bone mass [bone mineral content (BMC)] at the lumbar spine and femoral neck of 2% in boys and girls (56).

More recently, controlled trials with the program effected increased bone strength, estimated using pQCT, in the distal tibia (50) and 2–4% increases in spine and total body BMC (49) of prepubertal boys, and BMC and section modulus of the femoral neck (an index of bending strength) in peripubertal girls (49). By optimizing the osteogenic index, this program is able to achieve modest but significant increases in parameters of bone strength that are similar to other studies that involve more intensive bone-loading programs (8, 26, 30, 47, 53). The next important question to address will be whether these changes are maintained into adulthood and old age, but that is outside of the scope of these insights and considered elsewhere (18).

It is also well accepted that estrogen is a key regulator of skeletal growth and maturation, modulating linear growth through the systemic growth hormone (GH)-IGF-I axis, as well as by direct effects at the growth plate (65). It would seem logical that beneficial effects of exercise during the pre- and peripubertal periods of growth may be due to an interaction with the hormonal regulation of linear growth and maturation. Certainly the evidence, while not universal (50, 83), is mounting that the prepubertal and early pubertal periods are more advantageous than postpuberty to elicit an adaptive response in growing bones (8, 38, 49, 50, 52, 54, 60, 66, 83, 84, 95, 106). But does the stimulus of mechanical loading simply augment modeling processes already activated by growth, or is there another role for sex steroids during this period? An unequivocal role for estrogen in mechanotransduction has been difficult to ascertain because estrogen levels, in vivo, have not been directly linked to mechanical sensitivity of bone cells.

Lanyon's group argues that this is in fact consistent with observations in vitro and in vivo that estrogen receptors (ER), rather than estrogen itself, mediate the adaptive response. For example, when ER is absent or blocked by antagonists in vitro (16, 43), proliferation of bone cells following applied strains or fluid shear is absent. Conversely, this response is augmented when receptor numbers are increased by transfection (104). When ER is knocked out (KO) in mice in vivo, mechanically induced bone formation is substantially less than when it is present (Fig. 4) (44). This is not simply a permissive effect of estrogen, either, because absence of ER in cultured osteoblasts extracted from ER KO mice reduce the activity of the Wnt/β-catenin pathway stimulated by strain (2). That is, ER has been directly linked with regulation of key molecules associated with skeletal mechanotransduction (1, 69). The level of expression of ER is normally regulated by circulating estrogen, but not by local strain (103). Therefore, the increase in estrogen levels in boys and girls during adolescence may augment the amount of functional ER available to facilitate strain-related responses in bone, explaining the enhanced effects of physical activity noted above.

View larger version (8K): [in this window] [in a new window]   Fig. 4. Knocking out the estrogen receptor (ERKO) in mice reduced the mechanical sensitivity of their ulnae to axial bending (44). Ulnae were loaded 3 times/wk for 2 wk. Change in cortical area of loaded ulnae in ERKO mice was 30% of that in their wild-type (ER+) littermates. [Adapted from Lee et al. (44).]

	INSIGHTS FROM HUMAN STUDIES

TOP ABSTRACT INSIGHTS FROM ANIMAL MODELS INSIGHTS FROM HUMAN STUDIES CONCLUSION REFERENCES

 
With some exceptions (61, 105), animal models of exercise or loading generally do not consider sex differences in effects within the same experiment, nor do they face wide variations in the maturational status of individual animals. Where sexual dimorphism has been considered, the potential for differences in rate or timing of growth between male and female animals may not be considered, or it may simply have less relevance to understanding the biology of physical activity in children and adolescents. It is possible that this is a serious flaw in the design of some animal studies. The vast majority of animal studies use males or females. Furthermore, age and body weight are generally controlled by specifying these characteristics at the time of procuring animals. It is frequently necessary, therefore, to infer sex differences in exercise response from a range of studies, requiring complex interpretation of different designs. Because some animals, like rodents, continue to grow well after puberty, animal models fail to provide guidelines to help investigators account for the wide variation in maturational status that exists among children and adolescents. For such problems, we must rely on methods developed for studying human growth and development, or longitudinal studies in these populations and the analytical power that they provide.

At any given age during adolescence, a wide variation exists among children in size, physique, body composition, rate of growth, and biological timing of maturation. In boys, for example, peak velocities in lean mass, bone mineral, and strength always follow peak linear growth (peak height velocity), in that order. In girls, menarche is coincident with peak bone mass following after peak height velocity and peak weight velocity, in that order (4). The normal range in the onset of these events is high, being anywhere from 9 to 17 yr of age for menarche alone. Although growth curves could be referred to more frequently, such maturational complexity is difficult (although not impossible) to replicate in animal models, and we must rely on methods developed for studying human growth. These can include radiographic assessment, but the exposure to radiation needs to be considered; evaluation of secondary sex characteristics, but the range and variation among given stages is wide and cannot be used to compare males and females; use of serum or urinary markers of sex hormones (59), useful to determine the onset of puberty, but less effective to discriminate subsequent pubertal stages; and anthropometric measures, such as timing of peak height velocity (PHV). The latter is a useful landmark for normalizing maturation in adolescents but generally relies on longitudinal design for its determination (Fig. 5). However, data from the Saskatchewan Pediatric Bone Mineral Accrual Study have been used to develop a regression equation to predict the age of PHV, from a one-time measurement of growth (58). Investigators can then apply this predicted age of PHV as an indicator of maturity where other methods cannot be used or the duration of an intervention is short (49). The prediction applies to populations of similar ethnic background and tends to be most accurate for children approaching PHV and less accurate the further a child is from PHV, but it is an approach that could be considered to reduce the wide variability inherent in cross-sectional or short-term longitudinal studies.

View larger version (15K): [in this window] [in a new window]   Fig. 5. Velocity of growth for stature in boys and girls can be plotted as a function of chronological age, or aligned with respect to the age of peak height velocity (PHV) (A). In A, the velocity of growth in girls precedes that in boys by 2 yr. Valid comparison of the magnitude of growth at a given chronological age, therefore, cannot be made because boys and girls are at different maturational stages. Alignment of data with respect to age at PHV (at right) effectively controls for the wide range of maturational differences at the same chronological age. B: using data from Gupta and Elbracht (29), a hypothetical case is illustrated where peak weight velocity (PWV) during the pubertal growth spurt is compared in control rats (PWV Control) and a hypothetical group of rats exhibiting delayed growth (PWV Delayed). Similar to the case in humans, the most valid comparison of skeletal variables would be for groups selected at the same maturational time point, at or relative to PWV.

	CONCLUSION

TOP ABSTRACT INSIGHTS FROM ANIMAL MODELS INSIGHTS FROM HUMAN STUDIES CONCLUSION REFERENCES

 
Animal studies of exercise provide evidence that growing bone has a greater capacity for adaptation than the skeleton of adult animals, but not necessarily the most efficient way of stimulating a response. Controlled loading studies, such as those applying known strains to turkey, rat, or mouse bones, have contributed to our knowledge of mechanotransduction and loading characteristics that optimize an appropriate modeling response to increase bone strength. Insights from these models reveal that static loads do not play a role in mechanotransduction and that bone formation is threshold driven and dependent on strain rate, amplitude, and partitioning of the load. That is, only a few cycles of loading are required at any time to elicit an adaptive response, and distributed bouts of loading, incorporating rest periods, are more osteogenic than single sessions of long duration. These parameters of loading are being translated into feasible public health interventions that exploit the insights gained from animal experiments to achieve adaptive responses in the bones of children and adolescents. Studies manipulating ERs in mice also demonstrate that the sensitivity of the skeleton to loading during the peripubertal period is due to a direct regulation of mechanotransduction pathways by ER, and not just a simple enhancement of cell activity already marshaled by the hypothalamic-pituitary axis. Unfortunately, animal models are poor tools for extending our understanding of interactions between loading and maturation that exist in our studies of children and adolescents. However, there are insights from studies of human growth that can improve the interpretation of data from animal studies of growth and development.

	FOOTNOTES

 

Address for reprint requests and other correspondence: M. R. Forwood, School of Biomedical Sciences, Dept. of Anatomy and Developmental Biology, The Univ. of Queensland, Brisbane, Queensland 4072, Australia (e-mail: m.forwood{at}uq.edu.au)

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TOP ABSTRACT INSIGHTS FROM ANIMAL MODELS INSIGHTS FROM HUMAN STUDIES CONCLUSION REFERENCES

 

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