STAGES OF MATURITY IN CHILDHOOD AND ADOLESCENCE

Chronological age does not adequately represent the diversity between children in the timing and intensity of the physiological changes that occur during growth.¹⁸ Early and late maturing children of identical chronological age can differ by as much as six years developmentally.¹⁹ Further, children at the same initial developmental stage may advance at vastly different rates.⁷ Therefore, it is crucial that paediatric studies define the participants by both age and maturity.

There are a number of commonly used methods to assess a child's maturity. Skeletal age by standard radiography, although safe, is used rarely because it involves the use of ionising radiation. Tanner staging by self assessment, on the other hand, is non-invasive and has approximately the same degree of precision as assessing developmental age with hand-wrist radiographs.^20,21 Children classify themselves as Tanner stage 1–5 based on developmental diagrams of breasts (girls), pubic hair (for both girls and boys), and genitalia (boys).¹⁸ Children in Tanner stage 1 are considered prepubertal, Tanner stages 2 and 3 represent the early pubertal phases, Tanner stage 4 adolescents are considered to be in the late stages of puberty, whereas Tanner stage 5 represents full maturity, or the postpubertal adolescent.

There is a wide range of chronological ages within each Tanner stage. For example, in our study of early pubertal girls, Tanner stage 2 girls were 8.8–11.8 years old.²² Tanner staging indicates the sequence of the events of puberty more aptly than does chronological age. In most girls, menarche is achieved after Tanner breast stage 3, and immediately after (about 7 months) peak height velocity. These events can occur any time between 10.5 and 15.5 years of age,¹⁸ but are most commonly observed in girls at age 12.7 years (fig 1⇓).^14,23 For the purposes of this review, “immature” and “mature” refer to the state of the reproductive system, with menarche in girls generally signalling maturational advancement (a fully “mature” girl or boy is Tanner stage 5).¹⁹ Childhood is the period between infancy and the onset of puberty, and adolescence refers to the time after pubertal onset during which a mature reproductive system is attained.¹⁹

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Figure 1

Peaks for height velocity, bone mineral content (BMC) velocity, growth hormone (GH) amplitude, and insulin-like growth factor-I (IGF-I) amplitude, and trends for oestrogen and testosterone levels in girls relative to average age and Tanner stage. Peaks (connected to age by dotted lines) for height velocity, BMC velocity, GH, and IGF-I show the average age/Tanner stage at which maximum gains in height or BMC are made, and when maximum levels of GH and IGF-I occur. In boys, peak height velocity and peak BMC velocity occur about 1.5 years later than in girls (at 13.4 years (Tanner stage 3) and 14.0 years (Tanner stage 4) respectively). Relations between peaks for height and bone velocities and peaks for GH and IGF-I are similar for boys and girls. Adapted from several references.^{14,18,19,25,43}

Finally, physical maturity in children may be assessed relative to peak height velocity, provided that a minimum of three years of longitudinal data have been collected. By this direct measurement method, a child can be identified along an individual growth continuum, whereas by Tanner staging, a child must be represented by one of five categories. On average, peak height velocity occurs at 11.7 years (Tanner stage 3) in girls and 13.4 (Tanner stage 4) years in boys.^14,18

ENDOCRINE EVENTS IN MATURATION: THE BIOLOGICAL MECHANISMS OF CHANGE IN BONE

As we assume the reader is familiar with the various endocrine events in maturation, we briefly highlight the emerging influence of growth hormone (GH), insulin-like growth factor-I (IGF-I), and sex hormones on bone during this transition. Figure 1⇑ illustrates the average changes in amplitude of these factors relative to maturational stage.

The peak amplitude of GH pulsatile secretion coincides with peak height velocity (fig 1⇑),^24,25 and its influence on bone is probably mediated through insulin-like growth factors.²⁶ In prepubertal children, GH is the primary contributor to linear bone growth, whereas sex steroids act in concert with GH to exert a significant influence on bone during and beyond puberty.

The simultaneous, and possibly synergistically anabolic, rise in GH and IGF-I levels is unique to the pubertal growth period.²⁷ IGF-I levels increase abruptly around the Tanner stage 1–2 transition, with a peak occurring around Tanner stage 4–5, and declining quickly thereafter.²⁸ In one large cross sectional study of boys and girls, IGF-binding protein-1 decreased from prepuberty to peripuberty, with a slight rise noted after the of age 17 years, indicating a higher level of free, biologically active IGF during puberty.²⁸

“ . . .a particularly opportune time to intervene with loading exercise is probably when free, biologically active IGF-I levels are climbing.”

Serum IGF levels are associated with bone mineral in early pubertal girls,²⁹ and cross sectional and cortical bone areas in 7–18 year old girls and boys.³⁰ An 18 month longitudinal study of Tanner stage 1 and 2 male gymnasts showed a strong correlation (r = 0.67, p<0.05) between change in calcaneal ultrasound bone variables and baseline serum IGF-I.³¹ Thus, the bone change resulting from extreme high impact activity may be mediated, or promoted, by high levels of IGF-I. Although exercise is recommended to maximise bone health at all stages of life, one can speculate that a particularly opportune time to intervene with loading exercise is when free, biologically active IGF-I levels are climbing (Tanner stages 2 – 4; fig 1⇑).

With respect to sex hormones, in both girls and boys, oestrogens probably have greater influence on bone accrual,³² bone turnover, linear growth,³³ apposition of bone on the endosteal surface,³⁴ and epiphyseal closure.³⁵ Androgens probably have stronger ties to cortical bone size.^32,33 In girls, oestrogen levels increase significantly between Tanner stages 2 and 4,^36,37 corresponding to the timing of peak bone velocity,¹⁴ as well as menarche (fig 1⇑).²³ The steepest slope of increase for testosterone in girls was noted between Tanner stages 2 and 3.³⁶ In maturing boys, the greatest absolute change in oestrogen occurred between Tanner stages 4 and 5,²⁵ corresponding to the timing of peak bone velocity.¹⁴ A surge in testosterone follows Tanner stage 2.^25,38

BONE MINERAL ACCRUAL AND STAGES OF MATURITY

Through the concerted influences of growth and systemic hormones, bone mineral accrual is substantially altered between childhood and puberty. A six year longitudinal study in 53 girls and 60 boys (initially 8–14 years of age) showed an approximately one year lag between peak height velocity and peak bone velocity (12.5 years in girls and 14.1 years in boys) (fig 1⇑).¹⁴ Importantly, about 26% of final adult bone is accumulated during the two years surrounding peak bone velocity, which approximates the amount of bone lost during the postmenopausal years.⁷ These two critical years correspond to ages 11.5–13.5 for girls (Tanner stages 2–4) and 13.05–15.05 in boys (Tanner stages 3–5).

The maturity related changes occurring at the endosteal and periosteal bone surfaces that may be influenced by exercise are reviewed elsewhere.^26,34,40 It is notable that aspects associated with growth culminate to offer greater potential for an osteogenic response when the mechanical loading environment is changed. Immature bone is capable of modelling, which is responsible for adaptations in bone size, shape, and content.⁴¹ Also, there is substantial gain of cortical bone on both the periosteal and endocortical surfaces, which is unique to the pubertal growth spurt.⁴²

EXERCISE AND BONE MINERAL ACCRUAL IN CHILDREN AND ADOLESCENTS

Activity and bone change related to maturity

Few intervention studies offer insight into the time during growth when bone responds optimally to physical loading.⁴³ There is, however, a substantial body of research that supports the strong influence of high impact activities (gymnastics, triple jump, racquet sports, power lifting) on bone modelling changes in children.^9–11,44–,⁴⁶

General levels of physical activity are positively related to both the magnitude and rate of bone mineral accrual during peak growth.¹⁴ In the six year University of Saskatchewan bone mineral accrual study, active girls and boys accrued 10–40% more bone (depending on skeletal region) during the two years surrounding peak bone velocity than inactive children. However, this study provides no data on the relative rates of accrual between active and inactive children at different pubertal stages.

One cross sectional study investigated the relation between maturity and bone mineral in 91 female racquet sport players aged 7–17 and healthy, maturity matched counterparts.¹¹ Proximal humerus, humeral shaft, and distal radius side to side areal BMD differences were significantly greater in players than controls at Tanner stages 3, 4, and 5. There were no differences between Tanner stage 1 players and controls; Tanner stage 2 girls differed only at the humeral shaft, the most heavily loaded site. A limitation of this observational study was that training volumes also increased with Tanner stage and critics have suggested that this may have influenced greater bone gains in Tanner 3–5 girls, independently of maturity.⁴⁷ Haapasalo et al¹¹ showed that training time did not correlate with side to side areal BMD differences in the Tanner stage 1 or 2 players, whereas these variables correlated moderately in Tanner stage 3–5 players. Thus, frequent training was not significantly associated with bone gain in Tanner stages 1 and 2. The side to side areal BMD differences between peripubertal players and controls (about 10% at Tanner stage 3 and beyond) raise the possibility of a synergism between advancing pubertal status and loading induced bone gain. However, only prospective studies that intervene with similar amounts and intensities of activity across maturity levels can truly investigate the presence of a window of opportunity for peripubertal bone gain. The remainder of this systematic review is structured according to maturity status and focuses on intervention studies in children that met the inclusion criteria outlined above. Table 1⇑ summarises the data.

Exercise intervention studies in prepubertal children

There have been two exercise intervention studies in children who were classified as prepubertal at both baseline and after the intervention (table 1⇑).^2,4 The difference in eight month bone mineral gain between intervention and control groups was 1.2–5.6% by BMC and/or areal BMD, depending on measurement site (table 1⇑). With respect to bone structure,² cortical thickness increased more in intervention boys than controls. This change was due to greater endosteal apposition, not an increase in periosteal diameter.² Further work is needed to make the link between increases in BMC or areal BMD and increases in bone strength.

Although the response over eight months was similar between studies, the intervention programmes were distinct (table 1⇑). One study prescribed a 30 minute, 3 times/week extracurricular weight-bearing exercise programme involving a range of games and activities.² The other implemented a highly intensive, repetitive, box jumping programme⁴ (table 1⇑). This elicited ground reaction forces of 9 times body weight, compared with typical paediatric ground reaction forces of 3 times body weight during running,⁴⁸ and 10 times body weight in elite gymnastics training.⁴⁹

From these studies it appears that, for prepubertal children, the format or specificity of intervention may be less important than the magnitude of increase in weight-bearing activity. The activities in both interventions supplemented the regular two hours/week² and 30 minutes/week⁴ physical education curricula. There were no differences in extracurricular physical activity or sports participation between intervention and control groups in either study. Thus, the interventions represented substantial 75%² and 150%⁴ increases respectively in weight-bearing activity compared with that undertaken by controls in their regular physical education classes and extracurricular activities.

These data show that the prepubertal skeleton is responsive to intense, aggressive exercise programmes that introduce a significant amount of mechanical loading, beyond that which is typically provided in physical education classes.^2,4 Bone mineral change and growth in prepuberty are largely influenced by GH, and occur independently of the input of sex steroids (unlike during early puberty and peripuberty). Acute bouts of intense exercise may activate the GH-IGF-I axis in both prepuberty⁵⁰ and peripuberty.³⁷ Long term activation and elevation of these hormones may mediate an effect on bone over time. Skeletal loading intervention studies have not thus far investigated the hormonal mechanisms underlying modelling changes in immature bones. It is unclear whether increases in GH are necessary to promote bone gain, and whether less vigorous programmes—ones that take less time, and incorporate a variety of moderate impact activities—could be effective in promoting bone mineral accrual in prepubertal children.

McKay et al³ implemented a less vigorous, school based, bone loading programme, facilitated by the participants' regular classroom within the physical education curriculum. The group was largely (89%) prepubertal at baseline. During each physical education class, children performed games and circuits involving jumping or skipping, and did 10 tuck jumps³ (table 1⇑). The intervention did not require children to participate in any extra physical activity outside of school compared with that of children at control schools, and therefore the programme represented a change in activity type rather than an increase in duration. Changes in areal BMD at the trochanter were significantly greater (1.4%, p<0.01) in the intervention children. Other studies of prepubertal children did not measure² or did not report⁴ change at the trochanter. The less vigorous nature of the school based intervention may explain the non-signficant difference in change at other measured sites. As many of the activities involved running with jumping, muscle pull at the trochanter may have been substantial, resulting in greater change in this highly trabecular area.^51,52

Exercise intervention studies in early pubertal children

Using a similar intervention as Bradney et al² (table 1⇑), Morris and colleagues investigated the bone response at several skeletal sites in a mixed group of prepubertal and early pubertal (all premenarcheal) girls.¹ After controlling for differences in change in height and weight, girls in the intervention group gained significantly more total body, lumbar spine, and proximal femur bone mineral (2.3–5.5%, depending on bone site and parameter; table 1⇑) than controls. This study was the first to address exercise induced bone gain in immature girls, and the greater differences in bone mineral gain between intervention and control groups in this study compared with previous exercise studies in adults^53–,⁵⁶ highlighted the growing years as a potentially important time for intervention. Before menarche, oestrogen, GH, IGF-I, and testosterone levels reach higher levels (fig 1⇑), all factors that enhance bone formation. In combination with accelerating growth velocity, bone modelling and remodelling may occur more readily under the influence of mechanical loading.

Exercise intervention studies in adolescents

Two exercise intervention studies in postmenarcheal girls failed to significantly increase bone mineral compared with the control groups.^57,58 In both studies, the intervention and control girls were well matched for maturational status, and the exercise programmes involved substantial amounts of training. The first implemented a progressive, 6.5 month weight training programme, involving exercises on hydraulic machines targeting both the trunk and limbs.⁵⁷ Changes in lumbar spine bone variables did not differ significantly between intervention and control girls during the intervention. The use of hydraulic machines may not have created an optimal strain environment (in terms of impact and novel distributions)⁵⁹ to elicit changes in bone. However, the role of maturity becomes apparent when intervention girls failed to show greater changes in BMC than their maturity matched controls after completing a complex, high impact, intense, nine month, plyometric training programme⁵⁸ (table 1⇑). As shown in fig 1⇑, postmenarche (Tanner stages 4–5) corresponds to the descent of peaks for height and bone velocities, GH, and IGF-I. As these pivotal bone enhancing factors decrease, it probably becomes more difficult to promote modelling changes in bone. Furthermore, as has been shown in animal studies, the bone response to a given level of strain decreases with maturity.^60,61

Exercise intervention studies in two distinct maturational groups

A recently published prospective intervention addressed the issue of maturity related skeletal responsiveness to mechanical loading by simultaneously intervening with an intense jumping programme (table 1⇑) in premenarcheal (n = 25, Tanner stage 1 –3) and postmenarcheal girls (n = 38 Tanner stage 3–5, n = 1 Tanner stage 2).⁵ BMC changes at the lumbar spine and femoral neck were 3–4% greater in premenarcheal intervention girls than premenarcheal controls; changes did not differ by intervention and control groups in the postmenarcheal girls.

Premenarcheal exercisers tended to have greater, although not significant, gains in cortical cross sectional area (relating to a change in bone structure) and cortical density, at the tibial midshaft, as measured by peripheral quantitative computed tomography.⁵ Changes in section modulus (an estimation of bone strength) at the tibial shaft did not differ significantly between groups. Peripheral quantitative computed tomography can be used in future studies to compare changes in both bone mass and structure between more highly trabecular areas—for example, distal tibia—and the highly cortical tibial midshaft.⁵

Heinonen et al⁵ provided some evidence that the osteotrophic potential may be greater in the premenarcheal years compared with postmenarche. It is important to note that premenarche includes both prepubertal and early pubertal children, who, biologically have different mechanisms of bone change.

We recently intervened in prepubertal (Tanner stage 1) and early pubertal (Tanner stage 2 and 3) girls who took part in the same seven month, circuit training programme of jumping exercises within their physical education classes (table 1⇑).⁶ Early pubertal girls on this programme had greater bone change at the femoral neck and lumbar spine than maturity matched controls. Analysing these data using the hip structural analysis programme⁶² elucidated the structural changes that underpin the bone mass gains in the early pubertal intervention girls.⁴⁰ These girls had a greater change in femoral neck bone cross sectional area and reduced endosteal expansion, accompanied by a greater improvement in section modulus (bending strength) than controls. The bone mineral⁶ and structural⁴⁰ changes in the prepubertal intervention girls did not differ at any site from those of their prepubertal controls (table 1⇑). Taken together, results from these studies^5,6,40 may indicate that bone mass and structure are particularly responsive to certain exercise prescriptions during the earliest onset of puberty in girls, corresponding, on average, to ages 10–12 years. In boys, the corresponding maturational stage would be 12–14 years, but studies in prepubertal, peripubertal, and postpubertal boys are needed to substantiate this.

EXERCISE DURING CHILDHOOD AND BONE IN LATER LIFE

To qualify as a legitimate long term prescription for bone health in adulthood and later life, the effects on bone of exercise during childhood must persist so that fracture is prevented. Whether gains in bone mineral and bone strength from exercise in childhood reduce fracture risk in later life is a controversial issue—the “Achilles heel of exercise”.^63–,⁶⁵ Currently, there is very little research to support either side of the argument, as follow up studies are rare. In a five year follow up study, previously elite, retired racquet sport athletes maintained higher bone mineral, even with greatly reduced training, compared with controls of similar age.¹² Two retrospective studies in previously elite, retired ballet dancers¹³ and gymnasts¹⁰ provide evidence of a persistence of a bone mineral advantage over controls. Follow up studies of exercise interventions in children have yet to be conducted and published. However, in women, six months of detraining diminished the positive effects on bone apparent after a 12 month resistance training programme,⁶⁶ and a cross sectional study of retired male soccer players indicated that, after 35 years of retirement, areal BMD was similar between the former athletes and controls.⁶⁷

Further work linking childhood exercise to bone health in later life is critical. Future studies need to incorporate diverse measures, such as magnetic resonance imaging and peripheral computed quantitative tomography at several bone regions, to adequately approximate the full impact of an intervention in an immature population. There is a need for a controlled exercise intervention that tests the magnitude of skeletal effects separately across all stages of maturation to fully assess the existence of a window of opportunity when the skeletal response to loading exercise is at a maximum. At this point, the best recommendation is to encourage loading exercise during growth, which will ideally foster the maintenance of an active lifestyle and promote bone health over one's lifetime.

The clinician can play an active role to help ensure the attainment of a healthy peak bone mass by discussing with young patients and their parents the importance of an active lifestyle for bone mineral gain during growth. In a Journal of Pediatrics editorial, Stanford paediatrician, Laura Bachrach emphasised, “the time has come . . . to recognise the importance of (childhood) exercise as an essential component of osteoporosis prevention.”⁶⁸