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Peak bone mineral accrual and age at menarche in adolescent girls: A 6-year longitudinal study
P
Peak bone mineral accrual and age at menarche in adolescent girls: A 6-year longitudinal study
Heather A. McKay, PhD, Donald A. Bailey, PhD, Robert L. Mirwald, PhD, K. Shawn Davison, MSc, and Robert A. Faulkner, PhD
Background and objectives: The greatest increase in bone mineral content occurs during adolescence. The amount of bone accrued may significantly affect bone mineral status in later life. We carried out a longitudinal investigation of the magnitude and timing of peak bone mineral content velocity (PBMCV) in relation to peak height velocity (PHV) and the age at menarche in a group of adolescent girls over a 6-year period.
Methods: The 53 girls in this study are a subset of the 115 girls (initially 8 to 16 years) in a 6-year longitudinal study of bone mineral accretion. The ages at PBMCV and PHV were determined by using a cubic spline curve fitting procedure. Determinations were based on height (n = 12) and bone (n = 6) measurements over 6 years.
Results: The timing of PBMCV and menarche were coincident, preceded approximately 1 year earlier by PHV. Correlation showed a negative relationship between age at menarche and both peak bone mineral accrual (r = –0.42, P < .002) and PHV (r = –0.45, P < .001). Conclusions: This longitudinal study demonstrated the close association between age at PBMCV and age at menarche and confirmed the relationship between greater PBMCV and PHV in earlier, as compared with later, maturing girls. (J Pediatr 1998;133:682-7)
Osteoporosis, although predominantly an adult disease, may begin early in life when optimal bone mineral accretion is critical to the attainment of a healthy From the College of Physical Education, University of Saskatchewan, Saskatoon, Canada; School of Human Kinetics, University of British Columbia, Vancouver, British Columbia, Canada; and Human Movement Studies, Brisbane, Australia. Supported by grant no. 6608-1261 from the National Health Research and Development Program (NHRDP) of Canada. Submitted for publication Dec 16, 1997; revisions received May 14, 1998, and Aug 11, 1998; accepted Sept 4, 1998. Reprint requests: Heather A. McKay, PhD, School of Human Kinetics, University of British Columbia, Vancouver, BC V6J 1K7 Canada. Copyright © 1998 by Mosby, Inc. 0022-3476/98/$5.00 + 0 9/21/94317
682
skeleton.1-3 Most adult bone mass is achieved by the end of adolescence, and subsequent gains are small.4-7 For this reason, there is increasing interest in normal growth and mineralization of the skeleton, especially across puberty when maximum accrual velocities occur.8 Because longitudinal studies that span the entire pubertal period are time-consuming and costly, most of what we know of skeletal growth and development has been determined from cross-sectional4,9-13 and short-term longitudinal5 studies. In a cross-sectional cohort,8 our group has previously demonstrated the rapid acceleration in growth and bone mineralization at puberty, culminating in peak velocities. After 6 years of data collection, a subset of this cohort is repre-
sented longitudinally; and the nuances of the growth process, masked within crosssectional analyses, can be observed. Accompanying this period of rapid somatic growth at puberty, secondary sex characteristics develop and the reproductive system matures. The neuroendocrine system signals the onset of puberty with elevated nocturnal levels of luteinizing hormone and increased overall production of gonadotropins and follicle-stimulating hormone from the hypothalamic-pituitary system. Menarche, or the first menstrual bleed, is a relatively late event in pubertal development14 and represents a time during which all of these hormones are simultaneously elevated. On average, menarche occurs about a year after peak height velocity. This study investigates, over a 6-year period, the magnitude and timing of peak bone mineral content velocity in relation to peak height velocity and age at menarche.
BMC PBMCV PHV
Bone mineral content Peak bone mineral content velocity Peak height velocity
METHODS Subjects One hundred fifteen girls (initially 8 to 16 years) were originally recruited from 2 elementary schools in Saskatoon, Saskatchewan, Canada.15 The 53 girls in this study are a subset of those for whom complete data were available and for whom PBMCV was clearly evident. The subjects ranged in age from 7. 97 to 13. 26 years (mean age, 10.06 years) at first measurement. All were healthy Caucasians from middle-income neighborhoods.
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Measurement Protocol Height (in centimeters) and weight (in kilograms) were measured every 6 months over the 6-year period in the Department of Nuclear Medicine at the Royal University Hospital, Saskatoon, Saskatchewan. On each occasion, height as stretch stature, determined by using a wall stadiometer, and weight on a calibrated electronic scale were measured twice and recorded to the nearest 0.1. Total body BMC was measured annually by dual energy x-ray absorptiometry with a QDR 2000 bone densitometer (Hologic Inc, Waltham, Mass) in array mode. To minimize operator-related variability, all scans were analyzed by the same technologist using total body software version 5.67A (Hologic, Inc.). In our laboratory the short-term precision in vivo, with repositioning for the total body scan, was 0.5%. All subjects signed a written consent form. The study received approval from the University and Hospital Advisory Committee on Ethics in Human Experimentation.
Fig 1. Relative timing of PHV and PBMCV for 53 girls. TB, Total body.
Data Analysis CURVE FITTING. Differences in BMC between successive measurements (12 for height and 6 for BMC) were used to calculate whole-year BMC velocities. The number of data points around peak varied between subjects, depending on the child’s maturity level at entry. In every case each subject had at least 1 data point preceding and 1 data point following PBMCV. A cubic spline curve fitting procedure, which considers adjacent points to obtain a degree of global smoothness, was applied to each subject’s velocity data. The cubic spline curve provided the best fit of the data when compared with higher order polynomial fits. The advantages of the cubic spline procedure are that the ages at peak and the peak velocities themselves are individually determined and that the integrity of the data is maintained without transforming the growth characteristics (age at peak and peak velocity). This allows the unique pattern of growth to be optimally represented.
Fig 2. Comparison of magnitude of PBMCVs between an early and a late maturing girl. TB, Total body; PV, peak velocity.
MATURITY CATEGORIES. To examine the relationship between bone mineral accrued and timing of maturation, the girls were divided into early (menarche ≤12 years, n = 10), average (menarche 12.1 to 13.9 years,
n = 37), and late (menarche ≥14 years, n = 6) maturing groups. Bone mineral accrued was calculated, and the groups were compared at 3 periods: immediately before the 2-year interval of accelerated bone accrual 683
MCKAY ET AL
THE JOURNAL OF PEDIATRICS NOVEMBER 1998 was used to test the difference in bone mineral accrued during the 2 years around PBMCV (∆BMC, in grams) among the early, average, and late maturing girls. In addition, BMC was compared between groups at Pre-PBMCV and Post-PBMCV by using analysis of variance. Results are reported to the P < .05, unless otherwise indicated. SPSS-X software version 8.0 (SPSS Inc) was used for these analyses.
RESULTS Relative Timing of PHV, PBMCV, and Age at Menarche
Fig 3. Comparison of magnitude of PHVs between an early and a late maturing girl. PV, Peak velocity.
Mean age at PBMCV (12.50 ± 0.86 years) did not differ significantly from mean age at menarche (12.74 ± 0.98 years) in these subjects. PBMCV and menarche followed PHV (11.76 ± 0.93) by about 1 year. In 63% (n = 34) the interval between the age at PBMCV and menarche was less than 0.5 years. In 8, this interval was >1 year (Fig 1).
Relative Magnitude of PHV, PBMCV, and Age at Menarche PBMCV was 318 ± 60 g/y, and PHV was 8.6 ± 0.93 cm/y. There was a significant negative relationship between age at menarche and PBMCV (r = –0.42, P < .002) and between age at menarche and PHV (r = –0.45, P < .001). The difference in PBMCV between an early maturing girl (11.7 years) and a late (13.4 years) maturing girl, whose values are representative of the PBMCV-menarche relationship within their maturity groups, is shown (Fig 2). Fig 3 provides a comparison of the magnitude of PHV for these 2 subjects. The regression equation describing the relationship between PBMCV and age at menarche is also shown (Fig 4). Fig 4. Best (least-squares) fit line representing relationship between PBMCV and age at menarche. Dependence relationship is described by PBMCV = 644.47 – 25.61·AgeMen; R2 = .177, standard error of estimate = 54.86, P < .002.
around PBMCV (PBMCV – 1 year [PrePBMCV]), for the 2 years around PBMCV (∆BMC), and immediately after the 2 years of rapid accrual around PBMCV (PBMCV + 1 year [PostPBMCV]). 684
STATISTICAL ANALYSES. Descriptive statistics (means ± SD) for age and velocity at peak for both BMC and height are reported. Simple correlation was used to compare age at menarche with values for PBMCV and PHV. Analysis of variance
Comparison of BMC Accrual Among Early, Average, and Late Maturers BMC accrual for the 2-year interval around PBMCV was 619 ± 150 g, 578 ± 76 g, and 427 ± 63 g for the early, average, and late maturing girls, respectively. Although the late maturing girls were shorter and weighed less than the other 2 groups, this difference was not signifi-
THE JOURNAL OF PEDIATRICS VOLUME 133, NUMBER 5 cant. BMC accrued was significantly greater for the early (P < .001) and average (P < .004) groups, as compared with the late group. There was no difference in bone mineral accrued between the groups either before or after this 2-year PBMCV interval (Table).
DISCUSSION Timing of PHV, PBMCV, and Age at Menarche In this 6-year longitudinal study of 53 girls, we found that PBMCV was closely aligned with the timing of puberty as measured by age at menarche. PBMCV and menarche followed PHV by about 1 year and approximated the lag time of 1.2 years between PBMCV and PHV, determined by cross-sectional analysis of the larger Saskatoon cohort.16 Because PBMCV and PHV are not contemporaneous, the lag time between this period of rapid bone mineral accrual and the phase of accelerated longitudinal growth inevitably represents a time of relative bone fragility, which may explain an increased incidence of fractures observed during adolescence.3,17 This “temporary skeletal debt” may reflect a calcium requirement beyond that which is available from dietary sources and the consequent removal of calcium from cortical bone to meet the needs of the rapidly expanding metaphyses of the growing long bones.3 The timing of and interval between PHV and menarche reported here are consistent with values reported elsewhere.18-20 Adolescence has been identified as a crucial time for bone mineral accretion, with approximately 35% of adult total body and lumbar spine bone mineral and 27% of femoral neck bone mineral being deposited in the 4 years around PHV.15 Cross-sectional reports from our laboratory have previously demonstrated the pattern of steady-state bone mineral accrual to age 12 or 13, followed by an accelerated accrual phase at adolescence.8,15 We have also previously reported that at PHV girls had achieved about 57% of estimated adult total body BMC.21 Total bone mineral accrual during these times is consistent with literature that suggests that 90% of adult bone mineral is deposited by the end of adolescence.4,7,22-24
MCKAY ET AL
Table. Comparison of BMC among early, average, and late maturing girls at 1 year before PBMCV, 1 year after PBMCV, and for bone mineral accrued during the 2 years around PBMCV
Age at menarche (y) Height (cm) Weight (kg) BMC (g) One year before PBMCV BMC (g) One year after PBMCV BMC (g) Two years around PBMCV
Early (n = 10)
Average (n = 37)
Late (n = 6)
11.4 (0.41) 160.4 (5.4) 49.6 (8.1)
12.7 (0.50) 158.9 (6.9) 48.6 (8.7)
14.4 (0.27) 154.8 (5.6) 42.6 (3.3)
1229 (240)
1253 (279)
1112 (131)
1848 (330)
1831 (321)
1538 (154)
619 (150)
578 (75)
*427 (63)
Values are expressed as means with standard deviations in parentheses. *Significant difference between late maturing girls and the other 2 groups (P < .005).
Magnitude of PBMCV and Age at Menarche Age at menarche was negatively associated with both PBMCV and PHV. This suggests that the earlier maturing girls experience a greater velocity at peak bone mineral accretion and peak height than later maturing girls. Although the PBMCV-menarche relationship has not previously been reported with longitudinal data, the relationship between timing of maturity and magnitude of PHV is generally accepted.25 The longitudinal nature of this study clearly demonstrated the greater magnitude of peak velocities compared with data analyzed cross-sectionally. Both PBMCV and PHV values were approximately 25% greater than the cross-sectional velocities (240 g/y, 6.3 cm/y) determined by using the Preece-Baines curve fitting model.16 This “dampening” phenomenon is evident in cross-sectional studies that estimate rates of change of variables during growth. This effect is due to the large inter-subject variability in age at peak in a cross-sectional cohort. The large variability within the sample in turn reflects the differences in the timing of maturation for these girls.
Comparison of BMC Accrual Among Early, Average, and Late Maturers Accepting that the late maturing girls benefit from, on average, an additional period of normal growth (+1 year as compared with the average maturers and +2 years as compared with the early ma-
turers) before the accelerated period of accrual around peak, it seems reasonable to anticipate greater BMC values for the late group at the start of the acceleration period. Although the early and average maturing girls were accruing significantly more bone around peak than the late maturers, there was not a significant difference between the groups at either the Pre-PBMCV or Post-PBMCV interval periods. There was a trend to greater BMC in the average maturers as compared with the early maturers just before the PBMCV interval; however, this difference was not significant. The small number (n = 7) of late maturing girls and the large variability within the groups does not allow for the statistical power necessary to detect a significant difference, nor does it allow adequate generalizability of this group to a large population. Also, although weight was not significantly different between the late maturing girls and the other groups, this could reflect the small sample size. Body mass appears to be the greatest determinant of bone mineral density in mature adults, explaining roughly half of the population level variance26; therefore, the lower body weight of the late maturing girls could account, at least in part, for the differences observed in BMC in this cohort. Because the period of continued accrual to adult status is not accounted for in these analyses, these data do not necessarily imply that girls who reach menarche at an earlier age will have greater adult bone mineral. 685
MCKAY ET AL
Although the literature11,27,28 is inconclusive, it has been suggested that early menarche may confer some skeletal benefits. In retrospective, cross-sectional studies, early menarche and total estrogen exposure have been both positively associated27,28 and unassociated11 with high adult bone mineral density. In a recent cross-sectional study of Japanese girls, earlier menarche was associated with greater spine bone mineral density at the ages of 18 and 19 years.29 Because the girls in this study had not reached adult bone status, these relationships could not be directly examined.
Potential Mechanisms Although new information is available on the cooperative actions of androgen and estrogen on pubertal growth, the specific roles for these hormones in skeletal development remain unclear.30 Puberty represents the only time during the life span when growth hormone and the gonadal sex steroids are simultaneously elevated.31 These hormones in concert are responsible for the accelerated phase of linear growth, which continues for about 2 years from the onset of this accelerated growth period32 and culminates in PHV at age 11.8 years in this study, and at about age 12 in girls in general. An increased role for estrogen in the final phases of skeletal maturation has recently been discussed.30 In general, the effects of these hormones appear to be specific to the type of bone and the skeletal site.2 Estrogen appears to render its primary action at the axial skeleton and in trabecular bone, whereas the androgens exert a more profound effect at the appendicular skeleton and in compact bone.35,36 Dual energy xray absorptiometry studies of bone mineral are limited to the assessment of BMC and areal rather than volumetric density and do not identify the specific contributions of trabecular versus cortical bone, bone architecture, or bone geometry to the changes that accompany growth. Longitudinal studies into adulthood and more studies that examine both precocious and delayed puberty in relation to bone mineral accretion are needed to clarify many of the issues raised in this study. 686
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REFERENCES 1. Bailey DA, McCulloch RA. Are there childhood antecedents for an adult health problem? Can J Pediatr 1992;5:130-4. 2. Fassler ALC, Bonjour JP. Osteoporosis as a pediatric problem. Pediatr Nutr 1996;42:811-23. 3. Parfitt AM. The two faces of growth: benefits and risks to bone integrity. Osteoporos Int 1994;4:382-98. 4. Glastre C, Braillon P, David L, Cochat P, Meunier PJ, Delmas PD. Measurement of bone mineral content of the lumbar spine by dual energy x-ray absorptiometry in normal children: correlations with growth parameters. J Clin Endocrinol Metab 1990;70:1330-3. 5. Theintz G, Buchs B, Rizzoli R, et al. Longitudinal monitoring of bone mass accumulation in healthy adolescents: evidence for a marked reduction after 16 years of age at the levels of lumbar spine and femoral neck in female subjects. J Clin Endocrinol Metab 1992;75:1060-5. 6. Bonjour JP, Theintz G, Buchs B, Slosman D, Rizzoli R. Critical years and stages of puberty for spinal and femoral bone mass accumulation during adolescence. J Clin Endocrinol Metab 1991;73:555-63. 7. Slemenda CW, Reister TK, Hui SL, Miller JZ, Christian JC, Johnston CC. Influences on skeletal mineralization in children and adolescents: evidence for varying effects of sexual maturation and physical activity. J Pediatr 1994;125:201-7. 8. Bailey DA, Faulkner RA, McKay HA. Growth, physical activity, and bone mineral acquisition. In: Holloszy JO, editor. Exercise and sport sciences reviews. Vol 24. Baltimore: Williams & Wilkins; 1996. p. 233-66. 9. Specker BL, Brazerol W, Tsang RC, Levin R, Searcy J, Steichen J. Bone mineral content in children 1 to 6 years of age. Detectable sex differences after 4 years of age. Am J Dis Child 1987;141: 343-4. 10. Gilsanz V, Gibbens DT, Carlson M, Boechat MI, Cann CE, Schulz EE. Peak trabecular vertebral density in children: a comparison of adolescent and adult females. Calcif Tissue Int 1988;43:260-2. 11. Lu PW, Briody JN, Morely K, et al. Bone mineral density of total body, spine and femoral neck in children and young adults: a cross sectional and longitudinal study. J Bone Miner Res 1994;9:1451-8. 12. Lloyd T, Rollings N, Andon MB, et al. Determinants of bone density in young women. I. Relationships among pubertal development, total body bone mass, and total body bone density in premenarchal females. J Clin Endocrinol Metab 1992;75:383-7.
13. Trouerbach WT, de Man SA, Gommers D, Zwamborn AW, Grobbee DE. Determinants of bone mineral content in childhood. Bone Min 1991;13:55-67. 14. Malina RM, Bouchard C. Growth, maturation, and physical activity. Champaign (IL): Human Kinetics; 1991. 15. Bailey DA. The Saskatchewan Pediatric Bone Mineral Accrual Study: Bone mineral acquisition during the growing years. Int J Sports Med 1997;18(supp1 3):S191-4. 16. Martin AD, Bailey DA, McKay HA, Whiting SJ. Bone mineral and calcium accretion during puberty. Am J Clin Nutr 1997;66:611-5. 17. Bailey DA, Wedge JH, McCulloch RG, Martin AD, Bernhardson SC. Epidemiology of fractures of the distal end of the radius in children as associated with growth. J Bone Joint Surg Am 1989;71: 1225-31. 18. Malina RM, Bielicki T. Retrospective longitudinal growth study of boys and girls active in sport. Acta Paediatr 1996; 85:570-6. 19. Lindgren G. Growth of school children with early, average and late ages of peak height velocity. Ann Hum Biol 1978;5: 253-67. 20. Malina RM, Woynarowska B, Bielicki T, et al. Prospective and retrospective longitudinal studies of the growth, maturation, and fitness of Polish youth active in sport. Int J Sports Med 1997;18(suppl 3):S179-85. 21. Faulkner RA, Bailey DA, Drinkwater DT, Wilkinson AA, Houston CS, McKay HA. Regional and total body bone mineral content, bone mineral density and total body tissue composition in children 8-16 years of age. Calcif Tissue Int 1993;53:7-12. 22. Tylavsky FA, Bortz AD, Hancock RL, Anderson JJ. Familial resemblance of radial bone mass between premenopausal mothers and their college-age daughters. Calcif Tissue Int 1989;45:265-72. 23. Matkovic V, Jelic T, Wardlaw G, et al. Timing of peak bone mass in Caucasian females and its implication for the prevention of osteoporosis. J Clin Invest 1994;93:799-808. 24. Bonjour J, Theintz G, Buchs B, Slosman D, Rizzoli R. Peak bone mass. Osteoporos Int 1994;4(suppl 1):S7-13. 25. Tanner J, Whitehouse R, Takahashi M. Standards from birth to maturity for height, weight, height velocity, weight velocity: British children, 1965. Arch Dis Child 1966;41:454-71, 613-35. 26. Heaney RP. Pathogenesis of postmenopausal osteoporosis. In: Favus MJ, editor. Primer on the metabolic bone diseases and disorders of mineral metabolism. 3rd ed. Philadelphia: LippincottRaven; 1996. p. 252-4. 27. Dhuper S, Warren MP, Brooks-Gunn J,
THE JOURNAL OF PEDIATRICS VOLUME 133, NUMBER 5 Fox R. Effects of hormonal status on bone density in adolescent girls. J Clin Endocrinol Metab 1990;71:1083-8. 28. Ito M, Yamada M, Hayashi K, Ohki M, Uetani M, Nakamura T. Relation of early menarche to high bone mineral density. Calcif Tissue Int 1995;57:11-4. 29. Takahashi Y, Minamitana K, Kobayashi Y, Minagawa M, Yasuda T, Niimi H. Spinal and femoral bone mass accumulation during normal adolescence: comparison with female patients with sexual precocity and with hypogonadism. J Clin Endocrinol Metab 1996;81:1248-53. 30. Smith E, Korach K. Oestrogen receptor
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deficiency: consequences for growth. Acta Paediatr Suppl 1996;417:39-43. 31. Mauras N, Rogol AD, Haymond MW, Veldhuis JD. Sex steroids, growth hormone, insulin-like growth factor-l: neuroendocrine and metabolic regulation in puberty. Horm Res 1996;45:74-80. 32. Turner RT, Riggs BL, Spelsberg TC. Skeletal effects of estrogen. Endocr Rev 1994;15:275-300. 33. Malina RM. Physical growth and biological maturation of young athletes. In: Holloszy JO, editor. Exercise and sports science reviews. Vol 22. Baltimore: Williams & Wilkins; 1994. p. 389-433.
34. Tanner JM, Davies PW. Clinical longitudinal standards for height velocity for North American children. J Pediatr 1985;107:317-29. 35. Geusens PJ, Dequeker J, Verstraeten A, Nijs J. Age, sex, and menopause-related changes of vertebral and peripheral bone: population study using dual and single photon absorptiometry and radiogrammetry. J Nucl Med 1986;27:1540-9. 36. Geusens P, Cantatore F, Nijs J, Proesmans W, Emma F, Dequeker J. Heterogeneity of growth of bone in children at the spine, radius and total skeleton. Growth Dev Aging 1991;55:249-56.
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687
Peak bone mineral accrual and age at menarche in adolescent girls: A 6-year longitudinal study
Heather A. McKay, PhD, Donald A. Bailey, PhD, Robert L. Mirwald, PhD, K. Shawn Davison, MSc, and Robert A. Faulkner, PhD
Background and objectives: The greatest increase in bone mineral content occurs during adolescence. The amount of bone accrued may significantly affect bone mineral status in later life. We carried out a longitudinal investigation of the magnitude and timing of peak bone mineral content velocity (PBMCV) in relation to peak height velocity (PHV) and the age at menarche in a group of adolescent girls over a 6-year period.
Methods: The 53 girls in this study are a subset of the 115 girls (initially 8 to 16 years) in a 6-year longitudinal study of bone mineral accretion. The ages at PBMCV and PHV were determined by using a cubic spline curve fitting procedure. Determinations were based on height (n = 12) and bone (n = 6) measurements over 6 years.
Results: The timing of PBMCV and menarche were coincident, preceded approximately 1 year earlier by PHV. Correlation showed a negative relationship between age at menarche and both peak bone mineral accrual (r = –0.42, P < .002) and PHV (r = –0.45, P < .001). Conclusions: This longitudinal study demonstrated the close association between age at PBMCV and age at menarche and confirmed the relationship between greater PBMCV and PHV in earlier, as compared with later, maturing girls. (J Pediatr 1998;133:682-7)
Osteoporosis, although predominantly an adult disease, may begin early in life when optimal bone mineral accretion is critical to the attainment of a healthy From the College of Physical Education, University of Saskatchewan, Saskatoon, Canada; School of Human Kinetics, University of British Columbia, Vancouver, British Columbia, Canada; and Human Movement Studies, Brisbane, Australia. Supported by grant no. 6608-1261 from the National Health Research and Development Program (NHRDP) of Canada. Submitted for publication Dec 16, 1997; revisions received May 14, 1998, and Aug 11, 1998; accepted Sept 4, 1998. Reprint requests: Heather A. McKay, PhD, School of Human Kinetics, University of British Columbia, Vancouver, BC V6J 1K7 Canada. Copyright © 1998 by Mosby, Inc. 0022-3476/98/$5.00 + 0 9/21/94317
682
skeleton.1-3 Most adult bone mass is achieved by the end of adolescence, and subsequent gains are small.4-7 For this reason, there is increasing interest in normal growth and mineralization of the skeleton, especially across puberty when maximum accrual velocities occur.8 Because longitudinal studies that span the entire pubertal period are time-consuming and costly, most of what we know of skeletal growth and development has been determined from cross-sectional4,9-13 and short-term longitudinal5 studies. In a cross-sectional cohort,8 our group has previously demonstrated the rapid acceleration in growth and bone mineralization at puberty, culminating in peak velocities. After 6 years of data collection, a subset of this cohort is repre-
sented longitudinally; and the nuances of the growth process, masked within crosssectional analyses, can be observed. Accompanying this period of rapid somatic growth at puberty, secondary sex characteristics develop and the reproductive system matures. The neuroendocrine system signals the onset of puberty with elevated nocturnal levels of luteinizing hormone and increased overall production of gonadotropins and follicle-stimulating hormone from the hypothalamic-pituitary system. Menarche, or the first menstrual bleed, is a relatively late event in pubertal development14 and represents a time during which all of these hormones are simultaneously elevated. On average, menarche occurs about a year after peak height velocity. This study investigates, over a 6-year period, the magnitude and timing of peak bone mineral content velocity in relation to peak height velocity and age at menarche.
BMC PBMCV PHV
Bone mineral content Peak bone mineral content velocity Peak height velocity
METHODS Subjects One hundred fifteen girls (initially 8 to 16 years) were originally recruited from 2 elementary schools in Saskatoon, Saskatchewan, Canada.15 The 53 girls in this study are a subset of those for whom complete data were available and for whom PBMCV was clearly evident. The subjects ranged in age from 7. 97 to 13. 26 years (mean age, 10.06 years) at first measurement. All were healthy Caucasians from middle-income neighborhoods.
THE JOURNAL OF PEDIATRICS VOLUME 133, NUMBER 5
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Measurement Protocol Height (in centimeters) and weight (in kilograms) were measured every 6 months over the 6-year period in the Department of Nuclear Medicine at the Royal University Hospital, Saskatoon, Saskatchewan. On each occasion, height as stretch stature, determined by using a wall stadiometer, and weight on a calibrated electronic scale were measured twice and recorded to the nearest 0.1. Total body BMC was measured annually by dual energy x-ray absorptiometry with a QDR 2000 bone densitometer (Hologic Inc, Waltham, Mass) in array mode. To minimize operator-related variability, all scans were analyzed by the same technologist using total body software version 5.67A (Hologic, Inc.). In our laboratory the short-term precision in vivo, with repositioning for the total body scan, was 0.5%. All subjects signed a written consent form. The study received approval from the University and Hospital Advisory Committee on Ethics in Human Experimentation.
Fig 1. Relative timing of PHV and PBMCV for 53 girls. TB, Total body.
Data Analysis CURVE FITTING. Differences in BMC between successive measurements (12 for height and 6 for BMC) were used to calculate whole-year BMC velocities. The number of data points around peak varied between subjects, depending on the child’s maturity level at entry. In every case each subject had at least 1 data point preceding and 1 data point following PBMCV. A cubic spline curve fitting procedure, which considers adjacent points to obtain a degree of global smoothness, was applied to each subject’s velocity data. The cubic spline curve provided the best fit of the data when compared with higher order polynomial fits. The advantages of the cubic spline procedure are that the ages at peak and the peak velocities themselves are individually determined and that the integrity of the data is maintained without transforming the growth characteristics (age at peak and peak velocity). This allows the unique pattern of growth to be optimally represented.
Fig 2. Comparison of magnitude of PBMCVs between an early and a late maturing girl. TB, Total body; PV, peak velocity.
MATURITY CATEGORIES. To examine the relationship between bone mineral accrued and timing of maturation, the girls were divided into early (menarche ≤12 years, n = 10), average (menarche 12.1 to 13.9 years,
n = 37), and late (menarche ≥14 years, n = 6) maturing groups. Bone mineral accrued was calculated, and the groups were compared at 3 periods: immediately before the 2-year interval of accelerated bone accrual 683
MCKAY ET AL
THE JOURNAL OF PEDIATRICS NOVEMBER 1998 was used to test the difference in bone mineral accrued during the 2 years around PBMCV (∆BMC, in grams) among the early, average, and late maturing girls. In addition, BMC was compared between groups at Pre-PBMCV and Post-PBMCV by using analysis of variance. Results are reported to the P < .05, unless otherwise indicated. SPSS-X software version 8.0 (SPSS Inc) was used for these analyses.
RESULTS Relative Timing of PHV, PBMCV, and Age at Menarche
Fig 3. Comparison of magnitude of PHVs between an early and a late maturing girl. PV, Peak velocity.
Mean age at PBMCV (12.50 ± 0.86 years) did not differ significantly from mean age at menarche (12.74 ± 0.98 years) in these subjects. PBMCV and menarche followed PHV (11.76 ± 0.93) by about 1 year. In 63% (n = 34) the interval between the age at PBMCV and menarche was less than 0.5 years. In 8, this interval was >1 year (Fig 1).
Relative Magnitude of PHV, PBMCV, and Age at Menarche PBMCV was 318 ± 60 g/y, and PHV was 8.6 ± 0.93 cm/y. There was a significant negative relationship between age at menarche and PBMCV (r = –0.42, P < .002) and between age at menarche and PHV (r = –0.45, P < .001). The difference in PBMCV between an early maturing girl (11.7 years) and a late (13.4 years) maturing girl, whose values are representative of the PBMCV-menarche relationship within their maturity groups, is shown (Fig 2). Fig 3 provides a comparison of the magnitude of PHV for these 2 subjects. The regression equation describing the relationship between PBMCV and age at menarche is also shown (Fig 4). Fig 4. Best (least-squares) fit line representing relationship between PBMCV and age at menarche. Dependence relationship is described by PBMCV = 644.47 – 25.61·AgeMen; R2 = .177, standard error of estimate = 54.86, P < .002.
around PBMCV (PBMCV – 1 year [PrePBMCV]), for the 2 years around PBMCV (∆BMC), and immediately after the 2 years of rapid accrual around PBMCV (PBMCV + 1 year [PostPBMCV]). 684
STATISTICAL ANALYSES. Descriptive statistics (means ± SD) for age and velocity at peak for both BMC and height are reported. Simple correlation was used to compare age at menarche with values for PBMCV and PHV. Analysis of variance
Comparison of BMC Accrual Among Early, Average, and Late Maturers BMC accrual for the 2-year interval around PBMCV was 619 ± 150 g, 578 ± 76 g, and 427 ± 63 g for the early, average, and late maturing girls, respectively. Although the late maturing girls were shorter and weighed less than the other 2 groups, this difference was not signifi-
THE JOURNAL OF PEDIATRICS VOLUME 133, NUMBER 5 cant. BMC accrued was significantly greater for the early (P < .001) and average (P < .004) groups, as compared with the late group. There was no difference in bone mineral accrued between the groups either before or after this 2-year PBMCV interval (Table).
DISCUSSION Timing of PHV, PBMCV, and Age at Menarche In this 6-year longitudinal study of 53 girls, we found that PBMCV was closely aligned with the timing of puberty as measured by age at menarche. PBMCV and menarche followed PHV by about 1 year and approximated the lag time of 1.2 years between PBMCV and PHV, determined by cross-sectional analysis of the larger Saskatoon cohort.16 Because PBMCV and PHV are not contemporaneous, the lag time between this period of rapid bone mineral accrual and the phase of accelerated longitudinal growth inevitably represents a time of relative bone fragility, which may explain an increased incidence of fractures observed during adolescence.3,17 This “temporary skeletal debt” may reflect a calcium requirement beyond that which is available from dietary sources and the consequent removal of calcium from cortical bone to meet the needs of the rapidly expanding metaphyses of the growing long bones.3 The timing of and interval between PHV and menarche reported here are consistent with values reported elsewhere.18-20 Adolescence has been identified as a crucial time for bone mineral accretion, with approximately 35% of adult total body and lumbar spine bone mineral and 27% of femoral neck bone mineral being deposited in the 4 years around PHV.15 Cross-sectional reports from our laboratory have previously demonstrated the pattern of steady-state bone mineral accrual to age 12 or 13, followed by an accelerated accrual phase at adolescence.8,15 We have also previously reported that at PHV girls had achieved about 57% of estimated adult total body BMC.21 Total bone mineral accrual during these times is consistent with literature that suggests that 90% of adult bone mineral is deposited by the end of adolescence.4,7,22-24
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Table. Comparison of BMC among early, average, and late maturing girls at 1 year before PBMCV, 1 year after PBMCV, and for bone mineral accrued during the 2 years around PBMCV
Age at menarche (y) Height (cm) Weight (kg) BMC (g) One year before PBMCV BMC (g) One year after PBMCV BMC (g) Two years around PBMCV
Early (n = 10)
Average (n = 37)
Late (n = 6)
11.4 (0.41) 160.4 (5.4) 49.6 (8.1)
12.7 (0.50) 158.9 (6.9) 48.6 (8.7)
14.4 (0.27) 154.8 (5.6) 42.6 (3.3)
1229 (240)
1253 (279)
1112 (131)
1848 (330)
1831 (321)
1538 (154)
619 (150)
578 (75)
*427 (63)
Values are expressed as means with standard deviations in parentheses. *Significant difference between late maturing girls and the other 2 groups (P < .005).
Magnitude of PBMCV and Age at Menarche Age at menarche was negatively associated with both PBMCV and PHV. This suggests that the earlier maturing girls experience a greater velocity at peak bone mineral accretion and peak height than later maturing girls. Although the PBMCV-menarche relationship has not previously been reported with longitudinal data, the relationship between timing of maturity and magnitude of PHV is generally accepted.25 The longitudinal nature of this study clearly demonstrated the greater magnitude of peak velocities compared with data analyzed cross-sectionally. Both PBMCV and PHV values were approximately 25% greater than the cross-sectional velocities (240 g/y, 6.3 cm/y) determined by using the Preece-Baines curve fitting model.16 This “dampening” phenomenon is evident in cross-sectional studies that estimate rates of change of variables during growth. This effect is due to the large inter-subject variability in age at peak in a cross-sectional cohort. The large variability within the sample in turn reflects the differences in the timing of maturation for these girls.
Comparison of BMC Accrual Among Early, Average, and Late Maturers Accepting that the late maturing girls benefit from, on average, an additional period of normal growth (+1 year as compared with the average maturers and +2 years as compared with the early ma-
turers) before the accelerated period of accrual around peak, it seems reasonable to anticipate greater BMC values for the late group at the start of the acceleration period. Although the early and average maturing girls were accruing significantly more bone around peak than the late maturers, there was not a significant difference between the groups at either the Pre-PBMCV or Post-PBMCV interval periods. There was a trend to greater BMC in the average maturers as compared with the early maturers just before the PBMCV interval; however, this difference was not significant. The small number (n = 7) of late maturing girls and the large variability within the groups does not allow for the statistical power necessary to detect a significant difference, nor does it allow adequate generalizability of this group to a large population. Also, although weight was not significantly different between the late maturing girls and the other groups, this could reflect the small sample size. Body mass appears to be the greatest determinant of bone mineral density in mature adults, explaining roughly half of the population level variance26; therefore, the lower body weight of the late maturing girls could account, at least in part, for the differences observed in BMC in this cohort. Because the period of continued accrual to adult status is not accounted for in these analyses, these data do not necessarily imply that girls who reach menarche at an earlier age will have greater adult bone mineral. 685
MCKAY ET AL
Although the literature11,27,28 is inconclusive, it has been suggested that early menarche may confer some skeletal benefits. In retrospective, cross-sectional studies, early menarche and total estrogen exposure have been both positively associated27,28 and unassociated11 with high adult bone mineral density. In a recent cross-sectional study of Japanese girls, earlier menarche was associated with greater spine bone mineral density at the ages of 18 and 19 years.29 Because the girls in this study had not reached adult bone status, these relationships could not be directly examined.
Potential Mechanisms Although new information is available on the cooperative actions of androgen and estrogen on pubertal growth, the specific roles for these hormones in skeletal development remain unclear.30 Puberty represents the only time during the life span when growth hormone and the gonadal sex steroids are simultaneously elevated.31 These hormones in concert are responsible for the accelerated phase of linear growth, which continues for about 2 years from the onset of this accelerated growth period32 and culminates in PHV at age 11.8 years in this study, and at about age 12 in girls in general. An increased role for estrogen in the final phases of skeletal maturation has recently been discussed.30 In general, the effects of these hormones appear to be specific to the type of bone and the skeletal site.2 Estrogen appears to render its primary action at the axial skeleton and in trabecular bone, whereas the androgens exert a more profound effect at the appendicular skeleton and in compact bone.35,36 Dual energy xray absorptiometry studies of bone mineral are limited to the assessment of BMC and areal rather than volumetric density and do not identify the specific contributions of trabecular versus cortical bone, bone architecture, or bone geometry to the changes that accompany growth. Longitudinal studies into adulthood and more studies that examine both precocious and delayed puberty in relation to bone mineral accretion are needed to clarify many of the issues raised in this study. 686
THE JOURNAL OF PEDIATRICS NOVEMBER 1998
REFERENCES 1. Bailey DA, McCulloch RA. Are there childhood antecedents for an adult health problem? Can J Pediatr 1992;5:130-4. 2. Fassler ALC, Bonjour JP. Osteoporosis as a pediatric problem. Pediatr Nutr 1996;42:811-23. 3. Parfitt AM. The two faces of growth: benefits and risks to bone integrity. Osteoporos Int 1994;4:382-98. 4. Glastre C, Braillon P, David L, Cochat P, Meunier PJ, Delmas PD. Measurement of bone mineral content of the lumbar spine by dual energy x-ray absorptiometry in normal children: correlations with growth parameters. J Clin Endocrinol Metab 1990;70:1330-3. 5. Theintz G, Buchs B, Rizzoli R, et al. Longitudinal monitoring of bone mass accumulation in healthy adolescents: evidence for a marked reduction after 16 years of age at the levels of lumbar spine and femoral neck in female subjects. J Clin Endocrinol Metab 1992;75:1060-5. 6. Bonjour JP, Theintz G, Buchs B, Slosman D, Rizzoli R. Critical years and stages of puberty for spinal and femoral bone mass accumulation during adolescence. J Clin Endocrinol Metab 1991;73:555-63. 7. Slemenda CW, Reister TK, Hui SL, Miller JZ, Christian JC, Johnston CC. Influences on skeletal mineralization in children and adolescents: evidence for varying effects of sexual maturation and physical activity. J Pediatr 1994;125:201-7. 8. Bailey DA, Faulkner RA, McKay HA. Growth, physical activity, and bone mineral acquisition. In: Holloszy JO, editor. Exercise and sport sciences reviews. Vol 24. Baltimore: Williams & Wilkins; 1996. p. 233-66. 9. Specker BL, Brazerol W, Tsang RC, Levin R, Searcy J, Steichen J. Bone mineral content in children 1 to 6 years of age. Detectable sex differences after 4 years of age. Am J Dis Child 1987;141: 343-4. 10. Gilsanz V, Gibbens DT, Carlson M, Boechat MI, Cann CE, Schulz EE. Peak trabecular vertebral density in children: a comparison of adolescent and adult females. Calcif Tissue Int 1988;43:260-2. 11. Lu PW, Briody JN, Morely K, et al. Bone mineral density of total body, spine and femoral neck in children and young adults: a cross sectional and longitudinal study. J Bone Miner Res 1994;9:1451-8. 12. Lloyd T, Rollings N, Andon MB, et al. Determinants of bone density in young women. I. Relationships among pubertal development, total body bone mass, and total body bone density in premenarchal females. J Clin Endocrinol Metab 1992;75:383-7.
13. Trouerbach WT, de Man SA, Gommers D, Zwamborn AW, Grobbee DE. Determinants of bone mineral content in childhood. Bone Min 1991;13:55-67. 14. Malina RM, Bouchard C. Growth, maturation, and physical activity. Champaign (IL): Human Kinetics; 1991. 15. Bailey DA. The Saskatchewan Pediatric Bone Mineral Accrual Study: Bone mineral acquisition during the growing years. Int J Sports Med 1997;18(supp1 3):S191-4. 16. Martin AD, Bailey DA, McKay HA, Whiting SJ. Bone mineral and calcium accretion during puberty. Am J Clin Nutr 1997;66:611-5. 17. Bailey DA, Wedge JH, McCulloch RG, Martin AD, Bernhardson SC. Epidemiology of fractures of the distal end of the radius in children as associated with growth. J Bone Joint Surg Am 1989;71: 1225-31. 18. Malina RM, Bielicki T. Retrospective longitudinal growth study of boys and girls active in sport. Acta Paediatr 1996; 85:570-6. 19. Lindgren G. Growth of school children with early, average and late ages of peak height velocity. Ann Hum Biol 1978;5: 253-67. 20. Malina RM, Woynarowska B, Bielicki T, et al. Prospective and retrospective longitudinal studies of the growth, maturation, and fitness of Polish youth active in sport. Int J Sports Med 1997;18(suppl 3):S179-85. 21. Faulkner RA, Bailey DA, Drinkwater DT, Wilkinson AA, Houston CS, McKay HA. Regional and total body bone mineral content, bone mineral density and total body tissue composition in children 8-16 years of age. Calcif Tissue Int 1993;53:7-12. 22. Tylavsky FA, Bortz AD, Hancock RL, Anderson JJ. Familial resemblance of radial bone mass between premenopausal mothers and their college-age daughters. Calcif Tissue Int 1989;45:265-72. 23. Matkovic V, Jelic T, Wardlaw G, et al. Timing of peak bone mass in Caucasian females and its implication for the prevention of osteoporosis. J Clin Invest 1994;93:799-808. 24. Bonjour J, Theintz G, Buchs B, Slosman D, Rizzoli R. Peak bone mass. Osteoporos Int 1994;4(suppl 1):S7-13. 25. Tanner J, Whitehouse R, Takahashi M. Standards from birth to maturity for height, weight, height velocity, weight velocity: British children, 1965. Arch Dis Child 1966;41:454-71, 613-35. 26. Heaney RP. Pathogenesis of postmenopausal osteoporosis. In: Favus MJ, editor. Primer on the metabolic bone diseases and disorders of mineral metabolism. 3rd ed. Philadelphia: LippincottRaven; 1996. p. 252-4. 27. Dhuper S, Warren MP, Brooks-Gunn J,
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34. Tanner JM, Davies PW. Clinical longitudinal standards for height velocity for North American children. J Pediatr 1985;107:317-29. 35. Geusens PJ, Dequeker J, Verstraeten A, Nijs J. Age, sex, and menopause-related changes of vertebral and peripheral bone: population study using dual and single photon absorptiometry and radiogrammetry. J Nucl Med 1986;27:1540-9. 36. Geusens P, Cantatore F, Nijs J, Proesmans W, Emma F, Dequeker J. Heterogeneity of growth of bone in children at the spine, radius and total skeleton. Growth Dev Aging 1991;55:249-56.
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